INTRODUCTION

The HIV in the United States: A Time for Action Wafaa M. El-Sadr, MD, MPH, MPA,* Kenneth H. Mayer, MD,† and Adaora A. Adimora, MD, MPH‡

t is not uncommon to encounter in a hospital emergency room in San Francisco, Atlanta, INew York City, or Washington, DC, a young man or woman with the diagnosis of life- threatening cryptococcal or pneumonia caused by Pneumocystis jirovecii as the first manifestation of HIV . How could this be possible in 2010, fully 3 decades into the epidemic in the United States? How could this be possible in a country that prides itself on the widespread availability of HIV testing and treatment options? How could this be possible in a country with broad access to health messages and a plethora of communication tools? How could this be possible in one of the richest countries on earth? The answers to these questions are sobering. HIV in the United States is currently an invisible epidemic, largely confined to vulnerable and disenfranchised populations. It has disappeared from the public discourse. The prevailing perception is that HIV is a problem of the past, with few new and with miracle drugs available for all those living with HIV. Yet, beside the tragic anecdotes cited above, data indicate that there are an estimated 56,000 new infections per year in the United States, with an alarming impact on men who have sex with men and African American men and women. Great disparities remain in access to care and treatment for racial/ethnic minorities with HIV. How to address these disparities is the immediate challenge. The articles included in this supplement focus on some of the populations who have been most heavily impacted by the domestic HIV epidemic, including disenfranchised women of color, men who have sex with men, transgender persons, and substance users. Some of the articles describe specific venues, both physical and virtual, that are common in the lives of people living with, and at increased risk for, HIV, such as prisons, bathhouses, and the Internet; others discuss some of the factors that potentiate susceptibility to infection, such as substance use and depression. This supplement also features a wide array of approaches designed to slow the tide of the epidemic, ranging from culturally nuanced social, behavioral, and structural approaches to biomedical interventions, such as HIV testing, vaccines, and the use of antiretroviral drugs for prevention. Another paper describes lessons from Africa that could inform the response to the US HIVepidemic. The underlying theme is that HIV is spread in diverse communities, influenced by multiple biological, behavioral, cultural, societal, economic, and structural factors, and that curbing the epidemic will require an extensive variety of tactics carefully titrated to the needs of communities and individuals. The newly released National HIV/AIDS Strategic Plan, the first in the history of the epidemic in the United States, offers a fitting framework for action. This supplement to the Journal of Acquired Immunodeficiency Syndrome is an attempt at articulating a path ahead. Yet,substantial progress will not be achieved unless there is a concerted effort by the breadth of stakeholders to work together tirelessly and selflessly to reach defined priority goals. From policy makers to funders, researchers, providers, community organizations, and individuals living with HIV, all must be fully engaged in a united front to confront this epidemic in our midst. The time for action is now.

From the *International Center for AIDS Care and Treatment Programs, Mailman School of Public Health, the College of Physicians and Surgeons, Columbia University, and the Harlem Hospital Center, New York, NY; †Division of Infectious , Department of Medicine and the Department of Community Health, Alpert Medical School, Brown University, Miriam Hospital, Providence, RI; and ‡School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC. Correspondence to: Wafaa El-Sadr, MD, MPH, MPA, International Center for AIDS Care and Treatment Programs, Mailman School of Public Health, 722 W 168th Street, Room 715, New York, NY 10032 (e-mail: [email protected]). Copyright Ó 2010 by Lippincott Williams & Wilkins

J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 www.jaids.com | S63 SUPPLEMENT ARTICLE

Epidemiology of HIV in the United States Amy Lansky, PhD, John T. Brooks, MD, Elizabeth DiNenno, PhD, James Heffelfinger, MD, MPH, H. Irene Hall, PhD, and Jonathan Mermin, MD, MPH

studies of behavioral and clinical indicators, and estimates of Background: The United States has a comprehensive system of and . Additional studies, such as HIV surveillance, including case reporting and staging, longitudinal cohorts of HIV-infected persons, contribute to estimates of incidence, behavioral, and clinical indicators and understanding of disease over time in individuals. The data monitoring of HIV-related mortality. These data are used to monitor highlight substantial changes in HIV and late disease stage the epidemic and to better design, implement, and evaluate public (AIDS) incidence, prevalence, and mortality, and profound health programs. disparities across populations related to sexual behavior, drug use, race, ethnicity, geography, and socioeconomic Methods: We describe HIV-related surveillance systems and review status. recent data. Results: There are more than 1.1 million people living with HIV in the United States, and approximately 56,000 new HIV infections INCIDENCE AND PREVALENCE OF HIV annually. Risk behavior data show that 47% of men who have sex AND AIDS with men engaged in unprotected anal intercourse in the past year, State and local governments hold legal authority for and 33% of injection drug users had shared syringes. One third (32%) public health surveillance, including the designation of of people diagnosed with HIV in 2008 were diagnosed with AIDS reportable conditions and reporting methods. Reporting of within 12 months, indicating missed opportunities for care and HIV surveillance data to the federal government is voluntary. prevention. An estimated 72% of HIV-diagnosed persons received AIDS reporting started in 1981; by 1986, all 50 states, the HIV medical care within 4 months of initial diagnosis. District of Columbia, and several US territories had instituted 1 Conclusions: Conducting accurate and comprehensive HIV AIDS case reporting. Beginning in 1985, many states surveillance is critical for measuring progress toward the goals of implemented HIV case reporting as part of an integrated the 2010 National HIV/AIDS Strategy: reduced HIV incidence, HIV and AIDS surveillance system; although recommended increased access to care, and improvements in health equity. by the Centers for Disease Control and Prevention (CDC) since 1999, the implementation of HIV reporting across the Key Words: antiretroviral therapy, behavior, epidemiology, HIV, United States occurred at different points in time.2,3 As of sexual , surveillance 2008, all states had implemented confidential, name-based (J Acquir Immune Defic Syndr 2010;55:S64–S68) HIV reporting. CDC’s HIV surveillance system tracks new diagnoses of HIV infection and stage 3 disease (AIDS). Most cases are initially reported to state or local health departments through INTRODUCTION routine laboratory reporting of confirmatory HIV antibody, The United States has a comprehensive system of HIV viral detection, or CD4 cell count test results. Completion of surveillance that includes HIV case reporting and staging of case reports occurs through provider-based reporting or disease, monitoring of HIV-related mortality, supplemental follow-up by health department staff. For 2006, it was estimated that 1.1 million people were living with HIV in the United States (95% confidence limit: From the Division of HIV/AIDS Prevention, National Center for HIV/AIDS, 1.06 to 1.16 million), with considerable geographic variation.4 Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA. For example, AIDS diagnosis rates vary across states, ranging The findings and conclusions in this article are those of the authors and do not from 1.8 per 100,000 in Vermont to 27.7 per 100,000 in necessarily represent the views of the Centers for Disease Control and Maryland (Fig. 1A). In addition, because of higher total Prevention. population and rates of AIDS in certain states, the epidemic is None of the authors has any financial affiliations related to any component of concentrated in certain geographic regions; 50% of reported this article. Some data from this article have been presented at the XVIII International AIDS cases in 2008 were from 5 states: New York, California, 5 AIDS Conference, July 18–23, 2010, Vienna, Austria; and at the 2010 Florida, Texas, and Georgia. Furthermore, within states, Annual Meeting of the Infectious Diseases Society of America, October higher numbers of cases are generally reported from urban 21–24, 2010, Vancouver, British Columbia, Canada. areas (Fig. 1B). Correspondence to: Amy Lansky, PhD, Division of HIV/AIDS Prevention, NCHHSTP, Centers for Disease Control and Prevention, Mailstop D-21, HIV disproportionately affects different populations. 1600 Clifton Rd, Atlanta, GA 30333 (e-mail: [email protected]). HIV incidence estimates indicated that there were 56,300 new Copyright Ó 2010 by Lippincott Williams & Wilkins HIV infections in 2006.6 Of these new HIV infections, 45%

S64 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Epidemiology of HIV in the US

FIGURE 1. A, Estimated rates of AIDS diagnoses, 2008—United States and dependent areas. B, Estimated AIDS cases in the United States and Puerto Rico—cumulative through 2008 (n = 1,105,592). Data have been adjusted for reporting delays. Data are presented for AIDS cases re- ported to CDC through June 2009. Each dot represents 50 AIDS cases. were among blacks and 17% among Latinos (Fig. 2A); the HIV surveillance data are used to estimate HIV incidence among blacks was 7 times, and among Latinos prevalence in the United States, including the estimated 3 times, the rate among whites. More than half (53%) of new number of persons infected but undiagnosed. Of the HIV infections were among men who have sex with men estimated 1.1 million persons living with HIV in the United (MSM); 12% were among injection drug users, 4% among States, 21% were undiagnosed and presumed to be unaware MSM who inject drugs, and 31% attributable to heterosexual of their infection.4 The National Health and Nutrition contact (Fig. 2B). MSM are estimated to have a diagnosis of Examination Survey is a national household-based survey HIV infection at a rate more than 40 times the rate among other that conducts interviews and testing, including for HIV men and among women.7 infection. Data from National Health and Nutrition q 2010 Lippincott Williams & Wilkins www.jaids.com | S65 Lansky et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

HIV TESTING Persons who do not know they are HIV infected account for a disproportionate percentage of new transmissions because they are more likely to engage in high-risk sexual behavior than persons who have learned they have HIV.13 To increase the number of persons who know their HIV status and who are, if positive, linked to clinical and preventive services early, CDC recommends offering universal routine opt-out voluntary HIV screening for all persons ages 13–64 years in health care settings and repeat annual testing for persons at high risk for HIV.14 Data from the National Health Interview Survey indicate that between 1987 and 2006, the number of persons reporting having ever been tested for HIV infection rose from 6% to 38%.15 Among MSM participating in NHBS during 2008 in 21 cities, HIV prevalence was 19% among all tested men, of whom 44% were unaware of their infection, and 28% among black MSM,ofwhom59%wereunawareoftheirinfection.16 In a study of black and Latino MSM conducted in Los Angeles, New York, and Philadelphia, 17% of black and 5% of Latino MSM who did not know they had HIV tested positive.17 Among young black MSM college students and black women in North Carolina, most reported that at the time of their positive HIV test they believed they were unlikely to be infected.18,19 Late HIV diagnoses are an indicator that testing needs to reach more persons earlier. It is estimated that 32% of people FIGURE 2. A, Estimated percentage of new HIV infections by diagnosed with HIV received a diagnosis of AIDS within race/ethnicity—United States, 2006. B, Estimated percentage 12 months of diagnosis.5 The median first CD4 cell count is of new HIV infections by transmission category—United States, 3 2006. low, between 167 and 175 cells/mm , within 12 months of HIV diagnosis.20 However, recent reports suggest improvements may be occurring.21,22 Examination Survey during the period 1999–2006 indicated that 0.5% of the adult population had HIV infection, with ACCESS TO CARE AND QUALITY OF CARE considerable disparities. The prevalence was 2.0% among 8 To maximize the benefit of early HIV diagnosis and blacks and 9.4% among MSM. treatment, patients need to have access to high-quality medical services. Receipt of care depends on prompt linkage to services and retention in care after diagnosis. A meta-analysis of studies from the mid-1990s to 2006 found that 72% of HIV- MEASURES OF BEHAVIORAL AND SOCIAL RISK diagnosed persons in the United States entered HIV medical FOR HIV INFECTION care within 4 months of diagnosis.23 Among persons entering The National HIV Behavioral Surveillance System (NHBS) is a community-based survey that conducts inter- views and HIV testing among 3 populations: MSM, injection drug users, and heterosexuals at increased risk for HIV infection. NHBS is conducted in large metropolitan statistical areas in the United States, where approximately 60% of the nation’s AIDS cases had been reported.9 Risk behavior data from NHBS have shown that 47% of MSM had engaged in unprotected anal intercourse during the past year,10 and 33% of injection drug users reported sharing needles.11 Data from NHBS highlight that HIV infection is influenced by social, structural, and economic systems. In impoverished urban areas (ie, where $20% of residents have household incomes below the poverty level), 2.1% of heterosexual NHBS participants were infected with HIV.12 Infection was independently associated with lower household FIGURE 3. Incidence of first AIDS-defining opportunistic income, unemployment, lack of housing, and low education, infections in the HIV Outpatient Study, by year—1994–2007. but did not differ significantly by race or ethnicity. Reprinted with permission.24

S66 | www.jaids.com q 2010 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Epidemiology of HIV in the US care, 69% completed $2 visits during a 6-month interval and adjusting data for reporting delays that require 4 years of 59% completed $3 visits during a 12-month period. experience with reporting data.5 These data will provide the Much of the morbidity and mortality benefit associated clearest picture of the epidemic to date; funding opportunity with widespread use of highly active antiretroviral therapy has announcements targeting dollars by group or geography will been derived from the associated profound reductions in follow suit. AIDS-defining opportunistic illnesses (Fig. 3).24 Since its With the release of the National HIV/AIDS Strategy for advent in 1996, the timing of highly active antiretroviral the United States in July 2010,51,52 epidemiologic data will therapy initiation has been an area of considerable interest and take on new importance for addressing the HIV epidemic. The controversy. Recently revised US guidelines recommend constellation of surveillance systems and cohort studies initiating antiretroviral therapy at CD4 cell counts ,500 cells provides data to monitor the epidemic and better design, per cubic millimeter with the option of initiating at higher CD4 implement and evaluate public health programs. The success- cell counts.25 Evidence from a clinical trial26 and multiple ful impact of the National HIV/AIDS Strategy will be assessed cohort studies suggests that patients initiating antiretroviral using epidemiologic data collected from these systems to therapy at higher CD4 cell counts experience improved measure reduced incidence, increased access to care, and survival27–29 and have reduced risk for non-AIDS–defining improvements in health equity. illnesses and complications and toxicities of treatment with antiretroviral drugs.26,30–33 Initiation of antiretroviral therapy at higher CD4 cell counts does not seem to increase the risk of developing antiretroviral drug resistance34 or of exhausting ACKNOWLEDGMENT available treatment options and failing therapy.35 The authors acknowledge Kim Elmore for creating To evaluate the impact of these recommendations, the maps. researchers examined data from the Medical Monitoring Project, a national, population-based surveillance system of HIV-infected persons who receive clinical care. The project REFERENCES uses a 3-stage sampling design to obtain annual cross-sectional 1. Centers for Disease Control and Prevention. Current trends update: acquired immunodeficiency syndrome—United States. MMWR Morb probability samples of adults receiving outpatient care for HIV Mortal Wkly Rep. 1986;35:17–21. infection in 23 jurisdictions. Data are collected by interview 2. Centers for Disease Control and Prevention. Guidelines for national and medical record review.36 Survey data from 2007 indicated human immunodeficiency case surveillance, including monitoring that patients with CD4 ,500 cells per microliter who were not for human immunodeficiency virus infection and acquired immunode- ficiency syndrome. MMWR Recomm Rep. 1999;48(RR13):1–27. already taking antiretroviral drugs accounted for 8% of the 3. Glynn MK, Lee LM, McKenna MT. The status of national HIV case analysis population (4% with CD4 ,350 cells/uL—the surveillance, United States 2006. Public Health Rep. 2007;122:63–71. previously recommended threshold—and 4% with CD4 4. Centers for Disease Control and Prevention. HIV prevalence estimates— between 350 and 499 cells/uL). Based on these data, under United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;57:1073–1076. the current guidelines, state and local jurisdictions may need to 5. Centers for Disease Control and Prevention. HIV Surveillance Report, 2008. Vol 20. Atlanta, GA: Centers for Disease Control and Prevention; provide treatment resources to an additional 10% of HIV- 2010. Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/ 37 infected patients in care. reports. Accessed August 16, 2010. Studies continue to demonstrate that widespread use of 6. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the antiretroviral therapy since 1996 has led to sustained and United States. JAMA. 2008;300:520–529. continually improving reductions in morbidity and mortality 7. Purcell D, Johnson C, Lansky A, et al. Calculating HIV and rates 38,39 for risk groups: estimating the national population size of men who have among HIV-infected adults and children. In the United sex with men. Abstract #22896. Presented at: 2010 National STD States, life expectancy after HIV infection increased from 10.5 Prevention Conference; March 8–11, 2010; Atlanta, GA. to 22.5 years between 1996 and 2005, respectively.40 With 8. McQuillan GM, Kruszon-Moran D, Granade T, et al. Seroprevalence of improved survival on antiretroviral therapy, HIV-infected HIV in the US household population aged 18–49 years: the National Health and Nutrition Examination Surveys, 1999–2006. J Acquir Immune persons are increasingly affected by chronic and often pre- Defic Syndr. 2010;53:117–123. 41–44 45–49 ventable illnesses and non-AIDS–defining cancers ; 9. Gallagher KM, Sullivan PS, Lansky A, et al. Behavioral surveillance further reductions in mortality and morbidity will require among people at risk for HIV infection in the US: the National HIV effective prevention and treatment of these conditions.50 Behavioral Surveillance System. Public Health Rep. 2007;122:32–38. 10. Sanchez T, Finlayson T, Drake A, et al. Human immunodeficiency virus (HIV) risk, prevention, and testing behaviors—United States, National HIV Behavioral Surveillance System: men who have sex with men, November FUTURE DIRECTIONS 2003–April 2005 [erratum in: MMWR Morb Mortal Wkly Rep. 2006;55: Throughout the 30 years of the HIV epidemic, US 752]. MMWR Surv Summ. 2006;55(SS–6):1–16. surveillance systems and cohort studies have tracked many 11. Centers for Disease Control and Prevention. HIV-associated behaviors among injecting-drug users—23 cities, United States, May 2005– changes. HIV incidence peaked in the mid-1980s with February 2006. MMWR Morb Mortal Wkly Rep. 2009;58:329–332. approximately 130,000 infections per year and has decreased 12. Denning P, DiNenno E. Communities in crisis: is there a generalized HIV to approximately 56,000 infections per year more recently.6 epidemic in impoverished urban areas of the United States? Abstract Confidential name-based HIV reporting in all 50 states will WEPDD101. Presented at: XVIII International AIDS Conference, July 18–23, Vienna, Austria. greatly improve our ability to monitor the epidemic nationally. 13. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV The first national reports on trends of diagnoses of HIV from persons aware and unaware that they are infected with the virus in the infection will be available for 2012 data, due to methods for USA. AIDS. 2006;20:1447–1450. q 2010 Lippincott Williams & Wilkins www.jaids.com | S67 Lansky et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

14. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommenda- 33. Reekie J, Kosa C, Engsig F, et al. Relationship between current level of tions for HIV testing of adults, adolescents, and pregnant women in immunodeficiency and non-acquired immunodeficiency syndrome-de- health-care settings. MMWR Recomm Rep. 2006;55(RR14):1–17. fining malignancies. Cancer. 2010. doi:10.1002/cncr.25311. Published 15. Centers for Disease Control and Prevention. Persons tested for HIV— online ahead of print July 26, 2010. United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;57:845–849. 34. Uy J, Armon C, Buchacz K, et al, and the HOPS Investigators. Initiation 16. Centers for Disease Control and Prevention. Prevalence and awareness of of HAART at higher CD4 cell counts is associated with a lower frequency HIV infection among men who have sex with men-21 cities, United of antiretroviral drug resistance mutations at virologic failure. J Acquir States; 2008. MMWR Morb Mortal Wkly Rep. 2010;59:1201–1207. Immune Defic Syndr. 2009;51:450–453. 17. Marks G, Millett GA, Bingham T, et al. Understanding differences in HIV 35. Phillips AN, Leen C, Wilson A, et al. Risk of extensive virological failure sexual transmission among Latino and black men who have sex with men: to the three original antiretroviral drug classes over long-term follow-up the Brothers y Hermanos Study. AIDS Behav. 2009;13:682–690. from the start of therapy in patients with HIV infection: an observational 18. Centers for Disease Control and Prevention. HIV transmission among cohort study. Lancet. 2007;370:1923–1928. black college student and non-student men who have sex with 36. McNaghten AD, Wolfe MI, Onorato I, et al. Improving the representa- men—North Carolina, 2003. MMWR Morb Mortal Wkly Rep. 2004;53: tiveness of behavioral and clinical surveillance for persons with HIV in the 731–734. United States: the rationale for developing a population-based approach. 19. Centers for Disease Control and Prevention. HIV transmission among PLoS One. 2007;2(6):e550. doi:10.1371/journal.pone.0000550. black women—North Carolina, 2004. MMWR Morb Mortal Wkly Rep. 37. Do A, Heffelfinger J, Frazier E, et al. Increased need for antiretroviral 2005;54:89–94. therapy following changes in treatment guidelines. Abstract. Presented at: 20. Centers for Disease Control and Prevention. Reported CD4+ T- 48th Annual Meeting of the Infectious Diseases Society of America lymphocyte results for adults and adolescents with HIV/AIDS—33 (IDSA); October 21–24, 2010; Vancouver, British Columbia, Canada. states, 2005. HIV/AIDS Surveill Suppl Rep. 2005;11:1–31. Available at: 38. Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2005supp_ antiretroviral therapy era: changing causes of death and disease in the HIV vol11no2/default.htm. Accessed August 17, 2010. outpatient study. J Acquir Immune Defic Syndr. 2006;43:27–34. 21. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human 39. Patel K, Hernan MA, Williams PL, et al. Long-term effectiveness of immunodeficiency virus care in the United States and Canada. Clin Infect highly active antiretroviral therapy on the survival of children and Dis. 2010;50:1512–1520. adolescents with HIV infection: a 10-year follow-up study. Clin Infect Dis. 22. Castel A, Samala R, Griffin A, et al. Monitoring the impact of expanded 2008;46:507–515. HIV testing in the District of Columbia using population-based HIV/ 40. Harrison KM, Song RG, Zhang XJ. Life expectancy after HIV diagnosis AIDS surveillance data. Abstract 34. Presented at: 17th Conference on based on national HIV surveillance data from 25 states, United States. Retroviruses and Opportunistic Infections; February 16–19, 2010; San J Acquir Immune Defic Syndr. 2010;53:124–130. Francisco, CA. 41. Crum-Cianflone N, Roediger MP, Eberly L, et al. Increasing rates of 23. Marks G, Gardner LI, Craw J, et al. Entry and retention in medical care obesity among HIV-infected persons during the HIVepidemic. PLoS One. among HIV-diagnosed persons in the United States: a meta analysis. AIDS. 2010;5:e10106. doi:10.1371/journal.pone.0010106. 2010; DOI: 10.1097/QAD.0b013e32833f4b1b. [Epub ahead of print]. 42. Sobieszczyk ME, Hoover DR, Anastos K, et al. Prevalence and predictors 24. Brooks JT, Kaplan JE, Holmes KK, et al. HIV-associated opportunistic of metabolic syndrome among HIV-infected and HIV-uninfected women infections—going, going, but not gone: the continued need for prevention in the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr. and treatment guidelines. Clin Infect Dis. 2009;48:609–611. 2008;48:272–280. 25. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines 43. Tesoriero JM, Gieryic SM, Carrascal A, et al. 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Ann Intern Med. 2008;148:728–736. deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009; 46. Bedimo R. Non-AIDS-defining malignancies among HIV-infected 360:1815–1826. patients in the highly active antiretroviral therapy era. Curr HIV/AIDS 28. Sterne JAC, May M, Costagliola D, et al. Timing of initiation of Rep. 2008;5:140–149. antiretroviral therapy in AIDS-free HIV-1-infectedpatients: a collaborative 47. Simard EP, Pfeiffer RM, Engels EA. Spectrum of cancer risk late after analysis of 18 HIV cohort studies. Lancet. 2009;373:1352–1363. AIDS onset in the United States. Arch Intern Med. 2010;170:1337–1345. 29. Funk MJ, Fusco JS, Cole SR, et al. HAART initiation and clinical 48. Franceschi S, Lise M, Clifford GM, et al. Changing patterns of cancer outcomes: insights from the CASCADE cohort of HIV-1 seroconverters incidence in the early- and late-HAART periods: the Swiss HIV Cohort on ’When to Start’. Abstract THLBB201. Presented at: XVIII Study. Br J Cancer. 2010;103:416–422. International AIDS Conference; July 18–23; Vienna, Austria. 49. Polesel J, Franceschi S, Suligoi B, et al. Cancer incidence in people with 30. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS AIDS in Italy. Int J Cancer. 2010;127:1437–1445. diseases following initial treatment for HIV infection. AIDS. 2008;22: 50. Justice AC. Prioritizing primary care in HIV: comorbidity, toxicity, and 841–848. demography. Top HIV Med. 2006;14:159–163. 31. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in 51. White House Office of National AIDS Policy. National HIV/AIDS antiretroviral therapy (ART)-naive participants and in those not Strategy for the United States. Washington, DC: The White House; 2010. receiving ART at baseline in the SMART study. JInfectDis. 2008; Available at: http://www.whitehouse.gov/ONAP. Accessed August 197:1133–1144. 19, 2010. 32. Lichtenstein KA, Armon C, Buchacz K, et al. Initiation of antiretroviral 52. 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Challenges of a Hidden Epidemic: HIV Prevention Among Women in the United States Sally L. Hodder, MD,* Jessica Justman, MD,† Danielle F.Haley, MPH,‡ Adaora A. Adimora, MD, MPH,§ Catherine I. Fogel, PhD, WHCNP,k Carol E. Golin, MD,¶ Ann O’Leary, PhD# Lydia Soto-Torres, MD, MPH,** Gina Wingood, PhD,†† and Wafaa M. El-Sadr, MD, MPH†‡‡ on behalf of the HIV Prevention Trials Network Domestic Prevention in Women Working Group

INTRODUCTION Abstract: HIV/AIDS trends in the United States depict a concen- HIV incidence in the United States has remained an trated epidemic with hot spots that vary by location, poverty, estimated 56,000 cases annually since 1991.1 The lack of race/ethnicity, and transmission mode. HIV/AIDS is a leading cause substantive progress in reducing new HIV infections for of death among US women of color; two-thirds of new infections almost 20 years is noteworthy despite remarkable advances,2 among women occur in black women, despite the fact that black including the advent of rapid HIV testing, opt-out testing, and women account for just 14% of the US female population. The a variety of potent once-daily antiretroviral therapies and the gravity of the HIV epidemic among US women is often not availability of evidence-based behavioral interventions.3 appreciated by those at risk and by the broader scientific community. Unlike the generalized epidemic in regions of sub- We summarize the current epidemiology of HIV/AIDS among US Saharan Africa, the US HIV epidemic is concentrated among women and discuss clinical, research, and public health intervention certain subpopulations, particularly men who have sex with components that must be brought together in a cohesive plan to men (MSM) and persons of color.4 Although the high HIV reduce new HIV infections in US women. Only by accelerating prevalence among MSM in the United States is well research and programmatic efforts will the hidden epidemic of HIV recognized, the impact of HIV on women is less widely among US women emerge into the light and come under control. appreciated. Moreover, women at risk for HIV acquisition Key Words: HIV in women, HIV prevention science, racial disparity frequently do not appreciate this risk. The HIV epidemic among US women is, in many ways, hidden from effective (J Acquir Immune Defic Syndr 2010;55:S69–S73) dialogue, both among the populations at risk and within the broader scientific community. We summarize current epide- miology of HIV/AIDS among US women and discuss critical components that must be brought together in a cohesive plan to From the *University of Medicine and Dentistry of New Jersey, Newark, NJ; reduce new HIV infections in US women. †The International Center for AIDS Care and Treatment Programs, Mailman School of Public Health, and College of Physicians and Surgeons, Columbia University, New York,NY; ‡FHI, Durham, NC; §The School of Medicine; kThe School of Nursing; and the {School of Public DISCUSSION Health, University of North Carolina at Chapel Hill, Chapel Hill, NC; #Centers for Disease Control and Prevention, Atlanta, GA; **Division of Epidemiology of HIV in US Women AIDS, National Institutes of Health, Bethesda, MD; ††Rollins School of Prevalence and incidence trends depict a concentrated Public Health, Emory University, Atlanta, GA; and ‡‡Harlem Hospital, epidemic with hot spots that vary by location, poverty rate, New York, NY. This project was supported by the HIV Prevention Trials Network and sponsored race/ethnicity, and transmission mode. By 2003, an estimated by the National Institute of Allergy and Infectious Disease and the National 1.1 million US adults and adolescents were HIV infected; Institute of Mental Health, both in Bethesda, MD, under award number U01 approximately 21% of HIV-infected individuals are unaware AIO68619. The authors’ work on this article was supported in part by grants of their infection.5,6 Although US HIV incidence estimates from National Institute of Allergy and Infectious Disease and the National Institute of Mental Health, under award numbers U01 AI069466-0351 peaked at 150,000 cases per year during the mid-1980s, (Dr S.L.H.), U01 AI069466 (Dr W.M.E. and Dr J.J.), AI06819 (Dr J.J.), U01 followed by a plateau at about 56,000 cases per year since AIO68619 (Ms D.F.H.), and U01 AIO69423 (Dr A.A.A., Dr C.I.F., and 1991,1 the annual rate of new HIV cases has been increasing in Dr C.E.G.); and the Emory Center for AIDS Research, Atlanta, GA, under certain subgroups, particularly MSM and black and Latina award number P30 AI050409 (Dr G.W.). women. Eighty percent of HIV cases in women occur in black The views expressed herein are solely the responsibility of the authors and do not necessarily represent the official views of National Institute of Allergy and Hispanic women, who together constitute just 25% of the 7 and Infectious Disease, the National Institute of Mental Health, National US female population. Using back-calculation modeling, Institutes of Health, the HIV Prevention Trials Network, the Centers for Rosenberg and Biggar8 reported that although HIV incidence Disease Control and Prevention, or the funders of these organizations. was declining in white men aged 20–25 years, it was Correspondence to: Sally L. Hodder, MD, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, 185 South Orange increasing in women in the same age group. Avenue, MSB I-510, Newark, NJ 07101 (e-mail: [email protected]). The HIV epidemic among US women is concentrated in Copyright Ó 2010 by Lippincott Williams & Wilkins the Northeast and South, with a significantly higher proportion

J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 www.jaids.com | S69 Hodder et al J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 of HIV infections occurring in areas with high poverty rates.9 prevalence of concurrent partnerships observed in US black and Heterosexual activity has been the major mode of HIV Hispanic men may contribute to racial disparities in HIV rates acquisition for US women since 1995, when it surpassed among US women.30 Sexual mixing patterns connecting women injection drug use (IDU).10 Of women newly identified as HIV at low risk for HIV with men at higher risk may increase HIV infected, 83% are estimated to have acquired HIV heterosex- acquisition in women; such mixing patterns have been observed ually, with most of the remaining acquiring HIV through IDU.7 among black men and women in the southeastern US.20 Trends in AIDS rates among US women are of particular Recent studies demonstrate strong associations between concern. Although women accounted for only 15% of AIDS prior incarceration9 or incarceration of a partner31 with HIV cases from 1981 to 1995, they accounted for 27% of AIDS infection in US women. Though correctional inmates may cases from 2001 to 2004.11 The Centers for Disease Control view themselves at low or no risk for HIV acquisition,32 HIV and Prevention reported a 15% increase in AIDS cases among prevalence among prisoners is more than 2.5 times higher than women from 1999 to 2003, compared with a 1% increase in the general US population with a relatively high proportion of men.11 In addition, estimated AIDS diagnoses are 23 times HIV-infected persons passing through the correctional greater in black women than in white women.12 system.33–35 The racial disparity of incarceration is striking: Mortality trends among women with HIV are striking. 1 in 9 black men between the ages of 20 and 34 is incarcerated, Although the death rate due to HIV has decreased, HIV compared with 1 in 30 US men in the same age group.36 remains the third most common cause of death among black Incarceration influences sexual networks by disrupting stable women aged 35–44 and the fourth most common cause of sexual partnerships and has been associated with concurrent death among younger black women aged 25–34.12 The age- partnerships and dissortative mixing that promote HIV adjusted annual death rate due to HIV among black women transmission.20,31,37 To date, incarceration has not been during 2001–2005 was higher than that observed in every consistently used as an HIV prevention opportunity; condoms racial/ethnic group except non-Hispanic black males.13 and clean injection equipment are unavailable to inmates in Similarly, when compared with white women, black women some correctional systems. Similarly, HIV testing policies with HIV have a 13-fold mortality risk ratio.14 vary widely among correctional systems. Why Are Women at Risk for HIV? HIV Prevention for US Women: Current Status Many factors contribute to HIV acquisition among Early domestic HIV prevention successes included women. Gender inequalities, both social and economic, implementation of mandatory blood product screening hamper some women’s abilities to negotiate condom use and effective programs for prevention of mother-to-child and other safer sex behaviors.15,16 Interpersonal violence is transmission.2 Harm reduction programs throughout the a risk factor for HIV among women, regardless of race or United States have contributed to sharp declines in new ethnicity.17 Factors associated with transmission of HIV and HIV diagnoses among IDUs.38,39 other sexually transmitted infections (STIs) include poverty, Unfortunately, although consistent male condom use is lack of access to medical care, poor knowledge about known to be efficacious in reducing HIV transmission40 and HIV/AIDS, lower social status,18,19 financial dependence on female condoms have been assumed to be similar to male male partners, assortative mixing within HIV prevalence condoms in preventing HIV,41 condom implementation has not communities,20 feelings of invincibility, low self-esteem, and been effectively realized to decrease numbers of new HIV alcohol and drug use.21 infections. Over the past decade, multiple microbicide trials However, individual risk behaviors do not explain the have been disappointing.42–46 However, a number of ongoing dramatic racial disparities in STI and HIV rates.22,23 In one trials are assessing new vaginal microbicides and antiretroviral study, black men and women with ‘‘low-risk’’ behaviors had drugs for pre-exposure prophylaxis,47,48 and results from the 25-fold higher incidence of HIV and STIs compared with their CAPRISA 004 microbicide study (a double-blind randomized white counterparts,23 a disparity that remains unexplained. placebo-control study among 989 women) recently demon- Black women may underestimate the HIV risk status of their strated tenofovir 1% vaginal gel to have 40% efficacy in male partners; 6% of HIV-infected black women versus 14% of preventing HIV acquisition.49 To date, multiple vaccine trials HIV-infected white women reported having a bisexual male have failed to prevent HIV transmission,50,51 with the possible partner, despite the fact that more than twice as many black exception of a recombinant canarypox vaccine (ALVAC- HIV-infected men as white HIV-infected men (34% vs 13%) HV) plus 2 booster injections of recombinant gp120, which reported sex with both men and women.24 More black men and demonstrated vaccine efficacy of 31.2% (95% CI: 1.1 to 52.1; women than white are unaware of their HIV infection.25,26 These P = 0.04) in modified intent-to-treat analysis.52 Although data may reflect a number of factors, including differences in statistically significant and perhaps useful to inform develop- HIV testing uptake, HIV prevalence, and structural features of ment of future vaccines, this 6-injection vaccine series did not the social environment. Sexual networks shaped not only by demonstrate statistically significant efficacy in the per protocol individual preferences and behaviors but also by macroeco- analysis and had no effect on the level of HIV-1 viremia. nomic, political, societal, and other structural features of the Antiretroviral treatment as a strategy to decrease environment play a critical role in HIV acquisition among HIV transmission has been the subject of recent interest.53–56 women.20,27,28 Concurrent sexual partnerships can amplify HIV However, individuals with known HIV infection in the transmission, particularly when one partner has early HIV United States confront an array of barriers to health care infection, a period with high transmissibility.27,29 The higher access, medication adherence, and achievement of optimal

S70 | www.jaids.com q 2010 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 The Challenges of HIV Prevention Among US Women virologic outcomes needed for this approach to effectively incorporating community, correctional institutions, and prevent HIV transmission.57 treatment programs (including support services such as Multiple behavioral interventions to prevent HIV substance abuse programs). Only by accelerating both acquisition by women have been developed. However, a recent research and programmatic efforts will the hidden epidemic review of this area identified only 7 behavioral interventions of HIV among US women emerge into the light and be demonstrating subsequent reductions in unprotected sexual effectively addressed. intercourse3 and STIs,58,59 and none of the studies used HIV incidence as an end point. An additional limitation of most of these studies was a requirement that participating women ACKNOWLEDGMENTS attend multiple sessions, limiting the feasibility of broad The authors wish to acknowledge the contributions implementation of these interventions in at-risk communities. of Drs. Sten Vermund, Quarraisha Abdool-Karim, David Furthermore, few of the interventions attempted to directly Metzger, Nirupama Sista and Ms. Harmony Waller. This influence social networks or sexual behaviors of women’s project was supported by the HIV Prevention Trials Network partners—a critical component to HIV prevention in US (HPTN) and sponsored by the National Institute of Allergy women.60–62 Of 11 interventions listed as effective for women and Infectious Diseases (NIAID) in Bethesda, MD, under of color by the Centers for Disease Control and Prevention,63 award number U01 AI068619. The authors’ work on this none have assessed effect on HIV acquisition. manuscript was supported in part by grants from NIAID and NIMH, under award numbers U01 AI069466 (Dr Hodder), The Way Forward U01 AI069466 (Dr El-Sadr and Dr Justman), AI06819 Four areas must be urgently addressed to effectively (Dr Justman), U01 AI068619 (Ms Haley), and U01 decrease new HIV infections in US women. First, an absence AI069423 (Dr Adimora, Dr Fogel, and Dr Golin); and the of rigorous HIV incidence data among at-risk women impedes Emory Center for AIDS Research, Atlanta, GA, under award design of prevention trials with HIV incidence as primary end number P30 AI050409 (Dr Wingood). The views expressed point; sample size calculations are not feasible without reliable herein are solely the responsibility of the authors and do not estimates of incidence in the target population. necessarily represent the official views of NIAID, NIH, the Second, behavioral strategies addressing male partners HPTN, the Centers for Disease Control and Prevention, or of women are needed. To date, only limited research has its funders. attempted to alter the sexual attitudes and behaviors of heterosexual and bisexual men.58,61,62 Research evaluating strategies that favorably influence gender norms and behaviors REFERENCES of men are critically needed. Although data suggest that sexual 1. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the networks may be effectively used to identify cases of United States. JAMA. 2008;300:520–529. doi:10.1001/jama.300.5.520. undiagnosed HIV,64 few sexual or social network interventions 2. Centers for Disease Control and Prevention. 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Mental Health and HIV Risk in Men Who Have Sex With Men Steven A. Safren, PhD,*† Sari L. Reisner, MA,†‡ Amy Herrick, MA,§ Matthew J. Mimiaga, ScD, MPH,*†‡ and Ronald D. Stall, PhD, MPH§

the largest group of individuals infected with HIV in the Abstract: Evidence-based HIV prevention interventions with men United States; they comprise more than half of all new HIV who have sex with men (MSM) in the United States have moderate infections annually.8,9 Given that MSM are more than 44 times effect sizes in reducing HIV sexual risk behavior. Mental health and more likely to be newly diagnosed with HIV than other men,10 psychosocial problems, which both disproportionately affect MSM a focus on ameliorating disparities in HIV infection is essential populations and are implicated in HIV transmission risk behaviors, for enhancing the health of MSM at the population level. also likely interfere with the uptake of HIV behavioral interventions. A question that warrants immediate attention for both the Moreover, given that mental health and psychosocial problems such science of HIV prevention and public health practice: How can as depression, substance use, and violence frequently co-occur for we enhance current HIV behavioral interventions to improve many MSM (eg, as conditions), what is probably needed current effect sizes and promote long-term and sustainable are combination prevention efforts, or prevention ‘‘cocktails,’’similar behavior change to reduce HIV sexual risk among MSM? to treatment ‘‘cocktails,’’ that address the psychological and behavioral mechanisms that interact to produce elevated risk for HIV. Such interventions should incorporate a holistic framework to DISCUSSION address the sexual health and overall well being of MSM. Addressing HIV Risk in MSM Occurs in the Context of co-occurring psychosocial risk factors is apt to improve effect sizes of Other Mental Health and current HIV prevention interventions and allow for more effective uptake by MSM. Psychosocial Problems Most research on sexual minority men’s health in the Key Words: mental health, HIV, MSM HIVera has focused on risk for sexual transmission of sexually (J Acquir Immune Defic Syndr 2010;55:S74–S77) transmitted infections, including HIV. However, increasing evidence has shown that US MSM populations also suffer from very high rates of depression, violence victimization, and substance abuse across the life course,11–21 among other health problems. Moreover, research has demonstrated that the psychosocial factors that disproportionately affect MSM— INTRODUCTION depression, for example—are related to HIV sexual risk taking.22–25 Evidence-based HIV prevention interventions with men Although many studies involving MSM have shown who have sex with men (MSM) (because not all men identify interconnections between psychosocial factors and HIV risk, 21,26 as ‘‘gay,’’ we use the term ‘‘MSM’’ throughout this com- such as substance use and high-risk sex, recent studies mentary) in the United States have successfully reduced HIV have focused on documentation of how these diverse psy- sexual risk behaviors.1–7 A meta-analysis of 44 HIV behavioral chosocial issues interact to produce elevated HIV risk behav- 27,28 interventions found that randomized controlled trials of pre- ior among MSM, a phenomena known as a syndemic. vention interventions and model intervention programs with According to the Centers for Disease Control and Prevention, MSM reduced sexual risk by about one third.6 Despite these a syndemic is ‘‘two or more afflictions, interacting synergis- empirically grounded prevention efforts, MSM continue to be tically, contributing to excess burden of disease in a popula- tion.’’29 Psychosocial health problems such as substance use, depression, and violence have a tendency to interact so that From the *Massachusetts General Hospital/Harvard Medical School, Boston, their impact on the overall health of the individual is greater MA; †The Fenway Institute, Fenway Health, Boston, MA; ‡Harvard than one would expect the additive effect to be.28 School of Public Health, Boston, MA; and §Department of Behavioral and The ‘‘syndemic condition’’ has been documented in Community Health Sciences, Graduate School of Public Health, 28 27 University of Pittsburgh, Pittsburgh, PA. samples of adult and young MSM. Using a probability 28 Some of the funding for investigator time to prepare this article comes from sample of MSM in four major US cities, Stall et al found that grants MH084757 (Dr S.A.S) from the National Institute of Mental Health the more psychosocial health problems an individual endorsed, and DA022936 (Dr R.S.) from the National Institute of Drug Abuse. the greater their risk for both participation in sexual risk Correspondence to: Steven Safren, PhD, Massachusetts General Hospital, 1 27 Bowdoin Sq., 7th Floor, Boston, MA 02114 (e-mail: ssafren@partners. behaviors and HIV infection. Mustanski et al found similar org). results among a sample of young MSM ages 16 to 24, where Copyright Ó 2010 by Lippincott Williams & Wilkins endorsement of each additional psychosocial health problem

S74 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Mental Health and HIV Risk in MSM significantly increased the odds of unprotected anal inter- group-level, and community-level intervention effects in the course [odds ratio (OR) = 1.42, confidence interval (CI) = 1.19 moderate range.2–6 to 1.68], multiple sex partners (OR = 1.24, CI = 1.05 to 1.47), Interventions for HIV risk reduction among MSM have and HIV seroprevalence (OR = 1.42, CI = 1.12 to 1.80). This been delivered at the individual level and generally target pair of studies demonstrated that as the number of psy- social psychology variables theorized to be associated with chosocial conditions endorsed by individuals increased, their health behavior change. These variables include self-efficacy, odds of engaging in HIV sexual risk behaviors also increased, attitudes and beliefs, motivations, perceived social norms, as did their odds of HIV infection. It has been suggested that perceived risks and benefits of a health behavior, information, this set of co-occurring health problems (ie, the presence of a and skills building.31 Given the high frequency of co-occurring syndemic condition) may actually be driving the HIVepidemic psychosocial problems and their association to HIV sexual risk among MSM. behavior, it is necessary to know how such problems would If sexual minority men suffer from a syndemic that is interact with the aforementioned social psychology variables working to drive HIV risk, we must question why MSM are at that are at the basis of existing HIV risk reduction inter- greater risk than other populations of men and examine what ventions for MSM. might be driving the syndemic condition among sexual Clinical depression and anxiety are examples of mental minority men. Young men’s development is influenced by health conditions that have the potential to interfere with the many contextual factors, including socioeconomics, race/ effect of existing behavioral interventions for HIV risk ethnicity, and familial variables. However, sociocultural reduction in MSM: The symptoms of these conditions can pressures, including the pressure to meet socially valued be directly related to the psychological variables at their base. masculinity norms (not the least of which includes hetero- Symptoms of depression, for example, include persistent sexuality) also affect the development and behavioral patterns sadness, anhedonia, concentration problems, feelings of guilt of MSM. Masculine socialization stress results from the and worthlessness, and loss of energy. In more than 30 years of ‘‘shaming and other punishment of gay males for failing to research using Aaron Beck’s empirically tested cognitive achieve masculine ideals.’’30 This gender role-related stress theory of depression, studies have demonstrated that de- occurs through overt homophobia, such as hate crimes and the pression is related to excessively negative and distorted use of derogatory language, and in more institutionalized and cognitions and beliefs, including thoughts and cognitions subtle forms, such as the recent proliferation of so-called about one’s self, others, and the world; and the past, present, promarriage legislation. and future.32 Consider such symptoms and associated negative Further, if homophobia is a culture-wide phenomenon, beliefs with respect to a social cognitive model of sexual risk then it affects everyone, including children. Homophobic taking that includes variables such as self-efficacy and attacks directly made against or witnessed by boys who will in perceived social norms.33–35 Self-efficacy, the variable at the time grow up to be sexual minority men are thus occurring at core of this model, is the belief that a person feels he or she has an age when they are unlikely to be able to understand why the ability to do a certain task—in this case, use a condom in these attacks are occurring or to find social support to fend off different situations. According to this theory, a sexual minority the attacks. To the extent that men internalize these attacks to man with clinical depression who has negative thoughts about mean that they are less worthy than other males, that their himself and the world would, therefore, likely hold distorted sexuality is something that is shameful and should be hidden, negative cognitions and beliefs related to his own self-efficacy, or that their sexuality is forbidden by religious script or social norms about condom use, or the other cognitive contrary to ‘‘nature,’’ these boys will grow up to be men at variables related to sexual risk. higher risk for depression, substance abuse, or revictimization, We recently tested the hypothesis that depression may which can snowball into raising levels of risk for HIV and moderate the degree to which a social cognitive theory could other sexually transmitted infections. Finding ways to address predict HIV transmission risk behavior in a sample of HIV- multiple psychosocial health conditions so that they support infected MSM.36 We found that for those who did not screen in HIV risk reductions may well increase the effect sizes of HIV for major depression, the model fit the data well, with negative prevention interventions. expectancies about condom use and social norms about condom use being associated with self-efficacy, and self- efficacy in turn being associated with less HIV transmission These Mental Health and Psychosocial risk behavior. For those who screened in for major depression, Problems Likely Interfere With Existing HIV however, the model did not fit the data. In this case, self- Prevention Interventions efficacy, the central hypothesized mediator, was not associated The high rates of significant and distressing psychoso- with the central outcome: HIV transmission risk behavior. cial problems facing MSM are not only associated with HIV Although this was the first study to empirically examine the risk behavior and HIV infection rates in this population, but degree to which a clinically significant mental health problem also likely interfere with the ability of high-risk individuals to (in this case, depression) would interfere with a conceptual benefit from traditional HIV prevention interventions that do model of unsafe sex, our belief is that such a phenomenon not address the context of HIV risk behavior. Evidence of this would extend to other syndemic conditions, such as post- can be seen in four meta-analyses of behavioral interventions traumatic stress disorder, other anxiety disorders, substance for sexual risk taking among HIV-uninfected MSM conducted abuse, or current intense life stressors, such as domestic since 2003, which generally have shown individual-level, violence. Mental health problems moderating the effect of q 2010 Lippincott Williams & Wilkins www.jaids.com | S75 Safren et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 models behind behavioral interventions to reduce HIV risk and disentangling these from those variables that did not behaviors would be consistent with a secondary analysis from account for much change at all. After this type of analysis was project EXPLORE that suggested that childhood sexual abuse completed, one could examine the intervention content, may have moderated the potential efficacy of the EXPLORE augment those activities that seemed to be associated with intervention for HIV-negative MSM.19 greater change processes, cut down those intervention Currently, few interventions address mental health in the components that did not seem to contribute to change, and context of HIV sexual risk.3 However, a variety of cogni- end up with a more empirically guided and tailored form of the tive behavioral interventions are well studied and validated for intervention. Retesting the efficacy of the revised intervention the treatment of mood and anxiety disorders.37 Typically, these might well yield more impressive effect sizes. treatments are approximately 12–20 sessions long and involve As stated above, psychosocial and mental health therapy sessions and home practice with a trained therapist. problems, which are disproportionally prevalent for MSM, Behavioral interventions for HIV risk reduction could be may moderate the ability of existing prevention efforts to integrated into such treatments. For example, an intervention reduce HIV risk. In this article, we argue for conceptualizing presented by Mimiaga et al integrates behavioral activation HIV prevention efforts in MSM as prevention ‘‘cocktails’’ that therapy and HIV risk reduction counseling in MSM who abuse address psychological and behavioral mechanisms that interact crystal meth ampetamine.38 The conceptual model focuses on to produce elevated risk for HIV and that incorporate a more anhedonia (a loss of interest in previously enjoyed activities) holistic framework to address MSM’s sexual health and overall as a consequence of continued meth use. For individuals who well being. Although potentially more costly than interven- abuse meth, drug use becomes the central means for (or the tions that are easier to administer, addressing co-occurring only means for) obtaining enjoyment.39 The hypothesized psychosocial risk factors may not only improve the mental mechanism of intervention action is that behavioral activation health of those at risk for HIV but also should improve effect will gradually allow individuals to relearn how to engage in sizes of current HIV prevention interventions and allow for pleasurable, goal-directed, nondrug use activities (eg, interests more effective uptake of risk reduction. or hobbies that were enjoyable before meth use). These life activities then serve as a natural reinforcement for functional behavior by increasing pleasure and mastery, and improving REFERENCES mood when not on meth, thereby resulting in reductions in 1. Crepaz N, Lyles CM, Wolitski RJ, et al. Do prevention interventions unprotected sex and meth use. Additionally, we have an reduce HIV risk behaviors among people living with HIV? A meta- intervention in progress that addresses another highly analytic review of controlled trials. AIDS. 2006;20:143–157. 2. Herbst JH, Sherba RT, Crepaz N, et al. A meta-analytic review of HIV prevalent psychosocial problem among MSM discussed behavioral interventions for reducing sexual risk behavior of men who above—childhood sexual abuse. This intervention involves have sex with men. J Acquir Immune Defic Syndr. 2005;39:228–241. integrating cognitive processing therapy40 with HIV risk 3. Herbst JH, Beeker C, Mathew A, et al. The effectiveness of individual-, reduction counseling for HIV-uninfected MSM with a history group-, and community-level HIV behavioral risk reduction interventions of childhood sexual abuse. By addressing the relevant mental for adult men who have sex with men. Am J Prev Med. 2007;32:S38–S67. 4. Johnson WD, Hedges LV, Diaz RM. Interventions to modify sexual risk health problem, individuals may be better equipped to respond behaviors for preventing HIV infection in men who have sex with men. to integrated HIV prevention counseling. Cochrane Database Syst Rev. 2003;1:CD001230. 5. Johnson WD, Holtgrave DR, McClellan WM, et al. HIV intervention research for men who have sex with men: A 7-year update. AIDS Educ Prev. 2005;17:566–589. CONCLUSIONS 6. Johnson WD, Diaz RM, Flanders WD, et al. Behavioral interventions to Current HIV prevention intervention approaches aimed reduce risk for sexual transmission of HIV among men who have sex with at reducing HIV risk behavior among MSM in the United men. Cochrane Database Syst Rev. 2008;16:CD001230. States are the metaphorical equivalent of early AZT 7. Lyles CM, Kay LS, Crepaz N, et al. Best-evidence interventions: findings monotherapy to treat HIV infection. Current behavioral from a systematic review of HIV behavioral interventions for U.S. populations at high risk, 2000–2004. Am J Public Health. 2007;97: change technologies produce modest and statistically signif- 133–143. icant effect sizes but typically only for short periods of time. 8. Centers for Disease Control and Prevention. HIV Surveillance Report, Increasing the effect sizes of current intervention trials 2008. Vol 20. Atlanta, GA: Centers for Disease Control and Prevention. represents an important task moving forward. Integrating the Available at: www.cdc.gov/hiv/topics/surveillance/resources/reports/. Accessed June 21, 2010. treatment of mental health problems that frequently co-occur 9. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the as may be one important way to do this. United States. JAMA. 2008;300:520–529. Other steps may improve the effect sizes of existing 10. Purcell DW, Johnson C, Lansky A, et al. Calculating HIV and syphilis interventions. One possibility would be to conduct in-depth rates for risk groups: estimating the national population size of men who qualitative interviews with men who did not change during have sex with men. Abstract #22896. Presented at: 2010 National STD Prevention Conference; March 10, 2010; Atlanta, GA. Available at: http:// an HIV prevention intervention and men who did change. www.cdc.gov/hiv/topics/msm/resources/research/msm.htm. Accessed Interviews may allow for greater understanding of positive June 1, 2010. change and strengths-based processes, and of barriers and 11. Berlan ED, Corliss HL, Field AE, et al. Sexual orientation and bullying obstructers that impede changes in men whose levels of HIV among adolescents in the Growing Up Today Study. J Adolesc Health. 2010;46:366–371. risk stays the same. Another possibility would be to conduct 12. King M, Semlyen J, Tai SS, et al. A systematic review of mental disorder, mediational analyses of proven interventions, with a view suicide, and deliberate self harm in lesbian, gay, and bisexual people. toward identifying the variables that predicted the most change BMC Psychiatry. 2008;18:70. doi:10.1186/1471-244X-8-70.

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13. Meyer IH. Prejudice, social stress, and mental health in lesbian, gay, and preliminary evidence of a syndemic in need of attention. Ann Behav Med. bisexual populations: conceptual issues and research evidence. Psychol 2007;34:37–45. Bull. 2003;129:674–697. 28. Stall R, Mills TC, Williamson J, et al. Association of co-occurring 14. Cochran SD, Sullivan JG, Mays VM. Prevalence of mental disorders, psychosocial health problems and increased vulnerability to HIV/AIDS psychological distress, and mental services use among lesbian, gay, and among urban men who have sex with men. Am J Public Health. 2003;93: bisexual adults in the United States. J Consult Clin Psychol. 2003;71: 939–942. 53–61. 29. Centers for Disease Control and Prevention. Syndemic Prevention 15. Cochran SD, Ackerman D, Mays VM, et al. Prevalence of non-medical Network: Spotlight on Syndemics. Web page. Atlanta, GA: Centers for drug use and dependence among homosexually active men and women in Disease Control; January 30, 2008. Available at: http://www.cdc.gov/ the US population. Addiction. 2004;99:989–998. syndemics/. Accessed June 21, 2010. 16. Cochran SD, Mays VM. Lifetime prevalence of suicide symptoms and 30. Stall R, Friedman M, Catania J. Interacting and ’s affective disorders among men reporting same-sex sexual partners: health: a theory of syndemic production among urban gay men. In: Results from NHANES III. Am J Public Health. 2000;90:573–578. Wolitski RJ, Stall R, Valdiserri RO, eds. Unequal Opportunity: Health 17. Gilman SE, Cochran SD, Mays VM, et al. Risk of psychiatric disorders Disparities Affecting Gay and Bisexual Men in the United States.New among individuals reporting same-sex sexual partners in the National York, NY: Oxford University Press; 2008:251. Comorbidity Survey. Am J Public Health. 2001;91:933–939. 31. Mimiaga MJ, Reisner S, Reilly LC, et al. Individual interventions. In: 18. Marshal MP, Friedman MS, Stall R, et al. Sexual orientation and Mayer KH, Pizer H, eds. HIV Prevention: A Comprehensive Approach. adolescent substance use: a meta-analysis and methodological review. Amsterdam, Netherlands: Academic Press; 2009:203–239. Addiction. 2008;103:546–556. 32. Beck AT. The evolution of the cognitive model of depression and its 19. Mimiaga MJ, Noonan E, Donnell D, et al. Childhood sexual abuse is neurobiological correlates. Am J Psychiatry. 2008;165:969–977. highly associated with HIV risk taking behavior and infection among 33. Bandura A. Social Foundations of Thought and Action: A Social MSM in the EXPLORE Study. J Acquir Immune Defic Syndr. 2009;51: Cognitive Theory. Englewood Cliffs, NJ: Prentice Hall; 1986. 340–348. 34. Wulfert E, Wan CK. Condom use: a self-efficacy model. Health Psychol. 20. Safren SA, Heimberg RG. Depression, hopelessness, suicidality, and 1993;12:346–353. related factors in sexual minority and heterosexual adolescents. J Consult 35. Wulfert E, Wan CK, Backus CA. Gay men’s safer sex behavior: an Clin Psychol. 1999;67:859–866. integration of three models. J Behav Med. 1996;19:345–366. 21. Stall R, Paul J, Greenwood G, et al. Alcohol use, drug use, and alcohol- 36. Safren SA, Traeger L, Skeer MR, et al. Testing a social-cognitive model of related problems among men who have sex with men: The Urban Men’s HIV transmission risk behaviors in HIV-infected MSM with and without Health Study. Addiction. 2001;96:1589–1601. depression. Health Psychol. 2010;29:215–221. 22. Chesney MA, Koblin BA, Barresi PJ, et al. An individually tailored 37. Barlow DH, ed. Clinical Handbook Of Psychological Disorders: A intervention for HIV prevention: baseline data from the EXPLORE study. Step-by-Step Treatment Manual. 4th ed. New York, NY: Guilford Press; Am J Public Health. 2003;93:933–938. 2008. 23. Reisner SL, Mimiaga MJ, Skeer M, et al. Clinically significant depressive 38. Mimiaga MJ, Reisner SL, Pantalone DW, et al. An open phase pilot of symptoms as a risk factor for HIV infection among black MSM in behavioral activation therapy and risk reduction counseling for MSM with Massachusetts. AIDS Behav. 2009;13:798–810. crystal methamphetamine abuse at risk for HIV infection. Paper Session 2. 24. Rogers G, Curry M, Oddy J, et al. Depressive disorders and unprotected Presented at: Society of Behavioral Medicine 2010 Annual Meeting; April casual anal sex among Australian homosexually active men in primary 7–10, 2010; Seattle, Washington. PowerPoint available at: http:// care. HIV Medicine. 2003;4:271–275. www.sbm.org/meeting/2010/presentations/Thursday/Paper%20Sessions/ 25. The EXPLORE Study Team. Effects of a behavioural intervention to Paper%20Session%2002/An%20open%20phase%20pilot%20of%20 reduce acquisition of HIV infection among men who have sex with men: behavioral%20activation%20therapy.pdf. Accessed August 10, 2010. the EXPLORE randomised controlled study. Lancet. 2004;364:41–50. 39. Mimiaga MJ, Fair AD, Mayer KH, et al. Experiences and sexual behaviors 26. Hirshfield S, Remien RH, Humberstone M, et al. Substance use and high- of HIV-infected MSM who acquired HIV in the context of crystal risk sex among men who have sex with men: a national online study in the methamphetamine use. AIDS Educ Prev. 2008;20:30–41. USA. AIDS Care. 2004;16:1036–1047. 40. Resick PA, Monson CM, Chard, KM. Cognitive Processing Therapy: 27. Mustanski B, Garofalo R, Herrick A, et al. Psychosocial health problems Veteran/Military Version. Washington, DC: Department of Veterans’ increase risk for HIV among urban young men who have sex with men: Affairs; 2007.

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Testing for HIV, Sexually Transmitted Infections, and Viral Hepatitis in Jails: Still a Missed Opportunity for Public Health and HIV Prevention Timothy P. Flanigan, MD,*†‡ Nickolas Zaller, PhD,*†‡ Curt G. Beckwith, MD,*†‡ Lauri B. Bazerman, MS,† Aadia Rana, MD,*† Adrian Gardner, MD,*† David A. Wohl, MD,§ and Frederick L. Altice, MD, MAk

passed through a jail.1 These individuals are primarily poor Abstract: Jails provide an underutilized public health opportunity and male, have comorbid substance use disorders, and have for screening for HIV,sexually transmitted infections (STIs), and viral had poor access to the health care system2–4; collectively, these hepatitis, and for such other infectious diseases as . same characteristics correlate with higher risks for HIV and Incarcerated individuals are more likely to be men, poor, persons of other infectious diseases. Individuals passing through jails are color, and at high risk for HIV.The vast majority of jails in the United also likely to be estranged from traditional medical care States do not screen routinely for HIV or STIs, thereby missing an systems and therefore may not have accessed HIV prevention opportunity for HIV and STI diagnosis, treatment, and prevention. services. Jails, therefore, provide a key opportunity to imple- Nesting HIV testing within STI testing and treatment in conjunction ment brief interventions that are widely accepted by the public with testing and treatment for other infectious diseases, as appropriate health and medical communities and that are recommended by based on community prevalence, provides a public health opportunity the Centers for Disease Control and Prevention (CDC). Yet and will enhance HIV prevention. HIV testing and linkage to care, many US jails do not adhere to these recommendations for both within corrections and in the community, comprise an important routine screening for HIV and sexually transmitted infections component of the ‘‘seek and treat’’ strategy to further prevent HIV linked to medical evaluation. We therefore provide an infection. Jail-based screening of infectious diseases, especially for overview of potential impediments to routine testing and HIV and STIs, in conjunction with treatment and linkage to suggest mechanisms to mobilize and to implement infectious community care has thus far been a neglected component of HIV diseases screening as part of a comprehensive HIV prevention prevention among high-risk communities. strategy within this correctional setting. Key words: HIV, STI, viral hepatitis, testing, prevention, jails Epidemiology of Incarceration, Substance Use, (J Acquir Immune Defic Syndr 2010;55:S78–S83) and Infectious Diseases In 2009, approximately 12.8 million men and women passed through jails within the United States. Jails are typically INTRODUCTION under city, county, or other local jurisdiction and house inmates for short periods. As a result, jails are often chaotic, The United States has extraordinarily high rates of with high turnover. For example, the average daily inmate incarceration. In 2008, more than 4% of the adult population population for the Department of Corrections ranges between 13,000 and 18,000.5 Although the average From the *Alpert Medical School of Brown University, Providence, RI; length of stay in New York City Department of Corrections †Department of Medicine, Division of Infectious Diseases; and ‡Center facilities is 45 days, 50% of the population is released within for Prisoner Health and Human Rights, The Miriam Hospital, Providence, 10 days.5,6 Most jail stays are days to weeks, making it RI; §Department of Medicine, Division of Infectious Diseases, University challenging to deliver health care services during incarcera- of North Carolina at Chapel Hill, Chapel Hill, NC; and kYale University School of Medicine and Center for Interdisciplinary Research on AIDS, tion. Furthermore, substance-use disorders, including alcohol, Yale University School of Public Health, New Haven, CT. cocaine, methamphetamine, or opioid use, and mental illness The authors’ work on this article was supported in part by grant numbers are common comorbidities among those incarcerated.7–9 For P30AI42853 from the National Institutes of Health, Center for AIDS example, the Office of National Drug Control Policy reported Research (NIH/CFAR); P30DA013868 from the National Institutes of that 33% of prisoners were under the influence of an illegal Health, the Center for Drug Abuse and AIDS Research; H97HA08535 from the Special Projects of National Significance, Health Resources and drug at their time of arrest, and 57% reported use of any illicit 10 Services Administration; K23DA021095 (Dr. C.G.B.) and K24DA017072 substance in the month before arrest. Mental illness remains (Dr. F.L.A.) from the National Institute on Drug Abuse; and a critical comorbidity among those who interface with jails R01MH079720-01A1 (Dr. D.A.W.) from the National Institute on Mental such that 38.7% of those entering jails have an Axis I Health, National Institutes of Health. 4,11 Correspondence to: Timothy P. Flanigan, MD, 1125 N. Main Street, disorder. Substance use and mental health disorders are Providence, RI 02906 (e-mail: tfl[email protected]). both highly prevalent and play a key role in the overlap of Copyright Ó 2010 by Lippincott Williams & Wilkins infectious diseases and incarceration.4,11–14

S78 | www.jaids.com J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 Testing for HIV, STIs, and Viral Hepatitis in Jails

Minority populations, particularly African American Why Jails? and Hispanic men, are overrepresented within US correctional Jail incarceration is a key opportunity to provide health facilities. Black males are 7 times and Hispanic males are interventions for 2 reasons. First, many more individuals pass twice as likely as white males to be incarcerated.1,14 The through jails than prisons. As demonstrated by figures from the epidemics of HIV, sexually transmitted infections (STIs), and Bureau of Justice Statistics for 2008, approximately 735,000 hepatitis C virus (HCV) also disproportionately affect were released from prison, while more than 12 million passed communities of color,15 particularly African Americans, through jails.14 Jail-based interventions are necessary if the who account for approximately 45% of new HIV infections public health goal is to reach the majority of the incarcerated annually and have an HIV prevalence 7 times that of white population. Second, reducing the morbidity of prevalent Americans.16 Similarly, gonorrhea and rates are 8 infections and reducing incident infections of HIV, TB, STIs, and 19 times higher among African Americans, respectively, and HCV among jail detainees will likely lower the rates of than among whites.17 these infections in the community. This is particularly true if Because individuals with substance use and mental health the incarcerated individuals are rendered noninfectious (cured, disorders are much more likely to be both incarcerated and in the case of STIs) or markedly less infectious (by reduction of infected with HIV,STIs, or HCV,it is not surprising that a heavy HIV-1 RNA levels due to antiretroviral therapy), even with little burden of these diseases is concentrated behind bars. Using or no changes in risky behavior. Reduction of infectiousness is modeling data, it has been estimated that 14% of all those with particularly important in the case of communicable diseases such as pulmonary TB, which are spread via airborne routes of HIV and nearly 20% of HIV-infected African Americans and 24 Hispanics passed through a correctional facility during 2006.18 transmission. The challenge, however, is to complete the In a 2006 blinded seroprevalence survey of entrants to New York screening and implement treatment within this setting given the City jails, 5% of entrants were HIV infected; of these, 28% were limited time frame of jail incarceration. not diagnosed by the jail, although it is unknown how many Data from several studies have suggested that screening were previously unaware of their status.19 Most undiagnosed and treatment of inmates for STIs such as syphilis and chlamydia may reduce their prevalence in the community at inmates denied traditional HIV risk factors, affirming the need 25,26 to avoid risk-based testing. large. For example, routine testing and treatment of Viral hepatitis is also prevalent among those who enter gonorrhea and chlamydia among men in a San Francisco jail was associated with declining rates of these infections among jails.20 Up to 40% of all Americans with chronic viral hepatitis women attending an STI clinic in a part of the city that had and approximately 30% of persons with acute hepatitis B virus 26 21 high rates of poverty and incarceration. Additionally, a strong (HBV) infection have been incarcerated. Among patients correlation has been established between rates of incarceration with acute HBV reported to the CDC, 5.6% have a history of 22 among black males and HIV risk experienced by their sexual incarceration during the disease . HBV partners.27,28 Similar correlations across races exist between infection is known to be transmitted within correctional the incarceration of an individual’s partner and his or her risk settings, and incidence has ranged from 0.82% to 3.8% per of HIV infection.29,30 year.20 Among HBV outbreaks in correctional settings, the source patients were found to have subclinical infection that could have been identified by routine screening; this provides Is It Possible to Implement Medical support for the CDC recommendation for HBV vaccination in Interventions Within Jails? correctional settings. There is ample evidence that medical interventions can Data from 1997 suggested that between 29% and 43% of be successfully implemented in environments such as jails, all persons with HCV infection and 40% of all persons with which are often overcrowded and have high rates of turnover tuberculosis (TB) passed through a correctional facility in that and limited health care budgets.25,31–34 In providing services, year.23 In the CDC’s STI surveillance report from 2007, jails operate by creating protocols, testing them, and then between 2% and 19% of individuals #24 years of age in implementing them with little deviation. Effective protocols in a correctional facility tested positive for gonorrhea or jail settings have included screening for suicide risk, mental chlamydia, with the highest prevalence among women aged illness, and substance use disorders (urine testing) and for HIV #20 years.17 Although we do not fully understand the and STIs. Although its timing may vary among facilities, complex interaction among the myriad social, cultural, and a medical evaluation is part of the intake process in most jails economic factors underlying these facts, their confluence has and provides an opportunity to integrate interventions. a significant impact on the risks for both incarceration and In 2 controlled studies of routine HIV testing in acquisition of HIV infection. In the United States, many Connecticut, male and female jail detainees were significantly communities of color confront similar social and structural more likely to be HIV tested if routine testing was offered disparities that contribute to both of these risks. Further, many within 24 hours of admission and linked to medical screening. inmates, particularly those with HIV infection, face a multitude This finding reinforces the need to link screening procedures of challenges during community reentry, including relapse to with care. Although HIV prevalence was high (;4%) in substance use or dependence, mental illness, unstable housing, these studies, only a single new HIV-infected person was unemployment, lack of health insurance. Many of these identified.35,36 The process was important, however, in challenges, if not addressed, perpetuate the revolving door identifying a large number of previously identified individuals of reincarceration. and allowing for them to be reengaged in HIV care. q 2010 Lippincott Williams & Wilkins www.jaids.com | S79 Flanigan et al J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010

The Washington, DC, jail system provides an example of successful routine HIV rapid testing among jail inmates.37,38 The program was implemented in conjunction with city-wide efforts to improve HIV detection and treatment rates. The DC correctional testing algorithm utilizes ‘‘automatic’’ HIV testing upon jail entrance, with a provision for opting out of HIV testing available. Among 33,162 intakes between June 2006 and May 2008, 68% (22,515) of jail inmates were tested, with a confirmed HIV seropositivity rate of 3%. Although data are not currently available to determine the effectiveness of this strategy, it does provide proof-of-concept that routine large-scale HIV testing can be implemented in a busy city jail. It is hoped that the testing and linkage to care program will lead to better treatment coverage for HIV-infected individuals in Washington, DC, resulting in better virologic control and, hence, less transmission. FIGURE 1. Proportion of inmates entering the North Carolina In 1997, the Institute of Medicine report, ‘‘The Hidden Department of Correction tested for HIV infection before and Epidemic,’’ recommended providing STI services in prisons, after change from opt-in to opt-out testing in November 2008. jails, and juvenile facilities as part of a comprehensive STI prevention program.39 New York City successfully imple- mented routine STI testing within city jails. When gonorrhea and requiring outside counselors and thus additional time and 48,49 and chlamydia screening was added to the medical evaluation, often additional funding. chlamydia and gonorrhea cases increased in the jails by 1636% and 1023%, respectively, resulting in a 59% increase in Screening Can Be Tailored Based on total STI cases identified citywide. In the midst of a TB Community and Correctional Prevalence epidemic in Chicago, Cook County Jail instituted radiographic Prevalence of HIV,STIs, and HCV varies widely by state screening of inmates for pulmonary TB at intake. This resulted and community. The benefits of identifying HIV infections are in increased case finding rates and facilitated earlier airborne enormous, both in preventing progression to AIDS (via isolation of infectious cases.40 These examples demonstrate antiretroviral therapy) and in preventing HIV transmission to that it is possible to implement effective routine screening and others.50,51 Jail detainees who are newly diagnosed with HIV treatment procedures for a number of infectious diseases can be counseled and linked with care, although the pro- within jails. In each of the examples above, there was clear cess can be challenging. Continuity of care for released alignment in goals from the leadership within the jail and HIV-infected jail detainees has been dismal, at best. Among community health settings that were conjoined with political HIV-infected detainees in the San Francisco jail, as few as 15% will and commitment of resources. received continuous antiretroviral therapy after their release.52 A number of important lessons have been learned from For many HIV-infected individuals who already know their these experiences. Voluntary testing, in which inmates opt in, diagnosis, another positive HIV test is an opportunity for has repeatedly confirmed lower rates of testing than routine directed counseling and reinitiation of HIV care. Even opt-out strategies.41 In North Carolina, although prisoners relatively low rates of HIV justify routine screening.53,54 rather than jail detainees were targeted, a November 2008 Although HIV testing itself has not been demonstrated to change in HIV screening policy for incoming prison inmates reduce HIV risk behaviors among those testing negative, it from opt-in to opt-out resulted in an increase in testing from does provide an opportunity to introduce brief HIV risk 61%–91% (Fig. 1).42 These numbers are similar to those of reduction interventions that have been proven to reduce HIV successful HIV testing programs among sentenced prisoners in risk behaviors.55 Rhode Island. Inmates who opt-in and volunteer for HIV Screening for STIs in jails in higher prevalence testing have lower HIV prevalence than those who do not get communities is recommended but very rarely implemented.56 tested in the general inmate population.43 Indeed, among STI prevalence is highly age specific, and current guidelines women entering jail in Connecticut, risk-based testing resulted recommend targeting STI testing to younger men and in only 62% of HIV-infected women being identified using women.57 Data from the CDC and other studies, however, blinded serosurveillance,44 and routine HIV testing among confirm that expanding STI testing to those younger than pregnant women in jails proved cost-effective.45 Testing that 30 years confers high yield in jails.17,58 Testing practices may relies on self-identified risk behaviors within corrections often focus on regional differences as follows: in 2007, the South misses the majority of infections.46 Stigma within criminal had the highest gonorrhea and chlamydia rates in the justice settings is often a significant barrier to self- country.17 Successful implementation of STI testing with high identification of risk behaviors.47 In jails, routine HIV testing treatment rates in correctional facilities in high prevalence programs must be implemented in a timely fashion to communities will necessitate coordination between the maximize case identification before detainees’ release.35,36 correctional facility and the local health department,58 not Testing for HIV and other infectious diseases is better only for provision of treatment but also for contact tracing in integrated into a medical evaluation than ‘‘exceptionalized’’ the community.

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Screening for HBV in correctional settings is not only recommended by the CDC but also has been demonstrated to be cost-effective.59 Unlike HIV,STIs, and HCV,HBV infection can be prevented by an effective vaccine. Yet routine HBV testing and vaccination in jails is rare.60 Completing the standard series of HBV requires 6 months, but protective antibodies are present with even a single dose of vaccine (30% to 50%) or 2 doses (89%).61 Accelerated vaccination schedules that complete the 3-part series in 3 weeks62 or 2 months63 may hold promise for jail settings. Much less is known regarding the feasibility, costs, and impact of HCV screening in jails. HCV screening is currently recommended by the CDC but only for inmates with iden- tifiable HCV risk factors (ie, injection drug use, men who have FIGURE 2. New HIV diagnoses at the Rhode Island Department sex with men, etc); this is another missed opportunity. of Corrections, 2000–2009. Although jails do house a population with increased HCV,the diagnoses may not be made because many HCV-infected inmates do not admit to risk behaviors.64 Screening is The Way Forward indicated because, as shown for injection drug users with Although incarceration itself poses challenges to public 69 HCV65 and HIV,individuals who learn that they have a chronic health and to HIV prevention and treatment, it provides infection tend to reduce their risk behaviors by more than 50%. a structured setting in which a number of interventions may be Previously, HCV testing required phlebotomy; it took several effectively implemented. The concentration of infectious dis- days to obtain results, and it was costly. However, the eases within the criminal justice system, affecting a population availability of new HCV rapid testing technology approved by that is often estranged from traditional community services, the US Food and Drug Administration, less expensive and warrants reconsideration of jails as sentinel sites for screening, more feasible, may tip the balance toward an expansion of prevention, and treatment activities. routine HCV testing within correctional settings. The expected availability of new direct-acting HCV antiviral medications that are more effective and reduce the duration of treatment CONCLUSIONS may stimulate additional screening and treatment. These Diagnosing and treating infectious diseases such as HIV medications hold the potential for improved outcomes, and STIs have a high cost–benefit ratio; screening and treating providing barriers to treatment—in the form of costs, these infectious diseases will prevent spread in the community. toxicities, and the numerous challenges to implementing Economic and logistical obstacles to testing in jails, stigma routine HCV testing and providing HCV treatment to this surrounding incarceration, and lack of political will need to be population—can be overcome. addressed for progress to be made in implementing HIV, STI, and HCV testing and care programs within jails. Promoting Decreasing HIV Burden in Some Correctional screening for infectious diseases within jails, particularly HIV, Systems Associated With HIV Testing, STIs, and HCV, is the first step. The next is improved Comprehensive HIV Treatment and Linkage treatment, both within jails and prisons, and in the community after release. Diagnosis within jails, linked with treatment, will to Care result in improved prevention of HIV and other serious Comprehensive HIV testing, treatment, and linkage to care programs in Rhode Island and Connecticut have been in place for the past 2 decades.66 Connecticut has greatly enhanced HIV testing using increased targeted testing in prisons and routine testing efforts in jails; New Haven was the first community in the United States to implement and study syringe exchange programs67 and to enhance community linkages to care and substance abuse treatment for drug users.68 Similarly, Rhode Island has had routine HIV testing in prisons and has implemented coordinated community activ- ities. During this period, the number of newly diagnosed HIV- infected individuals within the state’s correctional system has decreased substantially (Fig. 2). The annual census of HIV within the Connecticut correctional system has substantially decreased (Fig. 3) as well. Simultaneous with these correction– community partnerships, the number of new HIV cases among injection drug users in both states also has significantly FIGURE 3. Inmates in Connecticut state custody known to be decreased over the same period. HIV infected at year end, 1995–2008. q 2010 Lippincott Williams & Wilkins www.jaids.com | S81 Flanigan et al J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 infections within both correctional facilities and the commu- 21. Khan A, Goldstein S, Williams I, et al. Opportunities for hepatitis B nity as a whole. prevention in correctional facilities and sexually transmitted disease treatment settings. Antiviral Ther. 2000;5(Suppl 1):22. 22. Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982–1998: implications for vaccination programs. J Infect Dis. 2002;185:713–719. REFERENCES 23. Hammett TM, Harmon PM, Rhodes W. The burden of infectious disease 1. West HC. Statistical Tables: Jail Inmates at Midyear 2009 [NCJ among inmates of and releasees from US correctional facilities, 1997. 230122].Washington, DC: Bureau of Justice Statistics, Office of Justice Amer J Pub Health. 2002;92:1789–1794. Programs, US Department of Justice; June 2010. Available at: http:// 24. Jones TF, Woodley CL, Fountain FF, et al. Increased incidence of the bjs.ojp.usdoj.gov/index.cfm?ty=pbdetail&iid=2200. Accessed August 1, outbreak strain of Mycobacterium tuberculosis in the surrounding 2010. community after an outbreak in a jail. South Med J. 2003;96:155–157. 2. Kulkarni S, Baldwin S, Lightstone AS, et al. Is incarceration a contributor 25. Blank S, McDonnell DD, Rubin SR, et al. New approaches to syphilis to health disparities? Access to care of formerly incarcerated adults. control: finding opportunities for syphilis treatment and congenital J Community Health. 2010;35:268–274. syphilis prevention in a women’s correctional setting. Sex Transm Dis. 3. Greenberg GA, Rosenheck RA. Homelessness in the state and federal 1997;24:218–226. prison population. Crim Behav Ment Health. 2008;18:88–103. 26. Barry P, Kent CK, Scott KC, et al. Is jail screening associated with 4. Greenberg GA, Rosenheck RA. Jail incarceration, homelessness, and a decrease in chlamydia positivity among females seeking health services mental health: a national study. Psychiatr Serv. 2008;59:170–177. at community clinics? San Francisco, 1997–2004. Sex Transm Dis. 2009; 5. New York City Department of Correction. The Borough Jail Plan: 36:S22–S28. Increasing Community Access to a Right-Sized City Jail System.New 27. Johnson R, Raphael S. The effects of male incarceration dynamics on York: New York City Department of Corrections; 2009:12. acquired immune deficiency syndrome infection rates among African 6. New York City Department of Correction. About DOC. Web page. American women and men. J Law Econ. 2009;52:251–293. Available at: http://www.nyc.gov/html/doc/html/about/facilities_ 28. Adimora AA, Schoenbach VJ, Doherty IA. HIVand African Americans in overview.shtml. Accessed July 15, 2010. the southern United States: sexual networks and social context. Sex 7. Sevigny EL, Coontz PD. Patterns of substance involvement and criminal Transm Dis. 2006;33(Suppl 7):S39–S45. behavior: a gender-based cluster analysis of Pennsylvania arrestees. Int J 29. Epperson MW, Khan MR, El-Bassel N, et al. A longitudinal study of Offender Ther Comp Criminol. 2008;52:435–453. incarceration and HIV risk among methadone maintained men and their 8. Goode R. Drug Arrests at the millennium. Society. 2002;39:41–45. primary female partners. Published online ahead of print January 9, 2010. 9. Beckett K, Nyrop K, Pfingst L, et al. Drug use, drug possession arrests, AIDS Behav. doi: 10.1007/s10461-009-9660-9. and the question of race: lessons from Seattle. Soc Prob. 2005;52: 30. Khan MR, Doherty IA, Schoenbach VJ, et al. Incarceration and risky 419–441. sexual partnerships in a southern US city. JUrbanHealth. 2008;85:100–113. 10. Office of National Drug Control Policy Information Clearinghouse. Drug Use 31. Lincoln T, Kennedy S, Tuthill R, et al. Facilitators and barriers to Trends. Washington, DC: Executive Office of the President, Office of National continuing healthcare after jail: a community-integrated program. J Ambul Drug Control Policy; October 2002. Available at: http://www.whitehousedrug- Care Manage. 2006;29:2–16. policy.gov/publications/factsht/druguse/drugusetrends.pdf. Accessed August 1, 32. Lobato MN, Roberts CA, Bazerman LB, et al. Public health and correctional 2010. collaboration in tuberculosis control. AmJPrevMed. 2004;27:112–117. 11. Wilper AP, Woolhandler S, Boyd JW, et al. The health and health care of 33. White MC, Mehrotra A, Menendez E, et al. Jail inmates and HIV care: US prisoners: results of a nationwide survey. Am J Public Health. 2009; provision of antiretroviral therapy and Pneumocystis carinii pneumonia 99:666–672. prophylaxis. Int J STD AIDS. 2001;12:380–385. 12. Colfax G, Coates TJ, Husnik MJ, et al. Longitudinal patterns of 34. Beckwith CG, Atunah-Jay S, Cohen J, et al. Feasibility and acceptability methamphetamine, popper (amyl nitrite), and cocaine use and high-risk of rapid HIV testing in jail. AIDS Patient Care STDS. 2007;21:41–47. sexual behavior among a cohort of San Francisco men who have sex with 35. Kavasery R, Maru DS, Cornman-Homonoff J, et al. Routine opt-out HIV men. J Urban Health. 2005;82(Suppl 1):i62–i70. doi: 10.1093/jurban/ testing strategies in a female jail setting:a prospective controlled trial. jti025. PLoS One. 2009;4:e7648. doi: 10.1371/journal.pone.0007648. 13. Strathdee S, Stockman J. Epidemiology of HIV among injecting and non- 36. Kavasery R, Maru DS, Sylla LN, et al. A prospective controlled trial of injecting drug users: current trends and implications for interventions. routine opt-out HIV testing in a men’s jail. PLoS One. 2009;4:e8056. doi: Curr HIV/AIDS Rep. 2010;7:99–106. 10.1371/journal.pone.0008056. 14. Sabol WJ, West HC, Cooper M. Prisoners in 2008 [NCJ 228417].Wash- 37. Castel AD, Jolaosha T, West T, et al. Rapid testing of central detention ington, DC: Bureau of Justice Statistics, Office of Justice Programs, US facility inmates during a city-wide HIV screening campaign, Washington Department of Justice; December 2009. Revised June 30, 2010. Available DC, 2007. Abstract B08-2. Presented at: 2007 National HIV Prevention at: http://bjs.ojp.usdoj.gov/content/pub/pdf/p08.pdf. Accessed August 1, Conference; December 2–5, 2007; Atlanta, GA. 2010. 38. Brown D. D.C. breaks ground with automatic HIV testing program. 15. Lelutiu-Weinberger C, Pouget ER, Des Jarlais DC, et al. A meta-analysis Corrections Today. June 2008;70(3)18–20. Available at: Academic Search of the hepatitis C virus distribution in diverse racial/ethnic drug injector Complete, Ipswich, MA. Accessed August 11, 2010. groups. Soc Sci Med. 2009;68:579–590. 39. Institute of Medicine. Committee on Prevention and Control of Sexually 16. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the Transmitted Diseases. Eng TR, Butler WT, eds. The Hidden Epidemic: United States. JAMA. 2008;300:520–529. Confronting Sexually Transmitted Diseases. Washington, DC: National 17. Centers for Disease Control and Prevention. Sexually Transmitted Disease Academy Press; 1997. Surveillance, 2007. Atlanta, GA: US Department of Health and Human 40. Puisis M, Feinglass J, Lidow E, et al. Radiographic screening for tuberculosis Services; December 2008. Updated January 20, 2009. Available at: http:// in a large urban county jail. Public Health Rep. 1996;111:330–334. www.cdc.gov/std/stats07/toc.htm. Accessed August 1, 2010. 41. Rosen DL, Schoenbach VJ, Wohl DA, et al. An evaluation of HIV testing 18. Spaulding AC, Seals RM, Page MJ, et al. HIV/AIDS among inmates of among inmates in the North Carolina prison system. Am J Public Health. and releasees from US correctional facilities, 2006: declining share of 2009;99(Suppl 2):S452–S459. epidemic but persistent public health opportunity. PLoS One. 2009;4: 42. Wohl D, Smith P, Green K, et al. Opt-out HIV testing on prison entry e7558. doi:10.1371/journal.pone.0007558. increases the proportion of individuals screened for HIV and the number 19. Begier EM, Bennani Y, Forgione L, et al. Undiagnosed HIV infection testing seropositive. Abstract W-197. Presented at: 17th Conference on among New York City jail entrants, 2006: results of a blinded serosurvey. Retroviruses and Opportunistic Infections (CROI); February 16–19, 2010; J Acquir Immune Defic Syndr. 2010;54:93–101. San Francisco, CA. 20. Gupta S, Altice FL. Hepatitis B virus infection in US correctional 43. Kassira EN, Bauserman RL, Tomoyasu N, et al. HIV and AIDS facilities: a review of diagnosis, management, and public health surveillance among inmates in Maryland prisons. J Urban Health. 2001; implications. J Urban Health. 2009;86:263–279. 78:256–263.

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44. Altice FL, Marinovich A, Khoshnood K, et al. Correlates of HIV infection 57. US Preventive Services Task Force.Screening for chlamydial infection: an among incarcerated women: implications for improving detection of HIV evidence update for the US Preventive Services Task Force. Clinical infection. J Urban Health. 2005;82:312–326. Guidelines. Ann Intern Med. 2007;147:135–142. Available at: http:// 45. Resch S, Altice FL, Paltiel AD. Cost-effectiveness of HIV screening for www.annals.org/content/147/2/128.long. Accessed August 1, 2010. incarcerated pregnant women. J Acquir Immune Defic Syndr. 2005;38: 58. Mertz KJ, Schwebke JR, Gaydos CA, et al. Screening women in jails for 163–173. chlamydial and gonococcal infection using urine tests: feasibility, 46. Mason DL, Birmingham L, Grubin D, et al.Substance use in remand acceptability, prevalence, and treatment rates. Sex Transm Dis. 2002;29: prisoners: a consecutive case study. BMJ. 1997;315:18–21. Available at: 271–276. http://www.bmj.com/cgi/content/full/315/7099/18?view=long&p- 59. Pisu M, Meltzer MI, Lyerla R. Cost-effectiveness of hepatitis B mid=9233320. Accessed August 1, 2010. vaccination of prison inmates. Vaccine. 2002;21:312–321. 47. Derlega V, Winstead B, Brockington J. AIDS stigma among inmates and 60. Tedeschi SK, Bonney LE, Manalo R, et al. Vaccination in juvenile staff in a USA state prison. Int J STD AIDS. 2008;19:259–263. correctional facilities: state practices, hepatitis B, and the impact on 48. Centers for Disease Control and Prevention. HIV Testing Implementation: anticipated sexually transmitted infection vaccines. Public Health Rep. Guidance for Correctional Settings. January 2009. Available at: http:// 2007;122:44–48. www.cdc.gov/hiv/topics/testing/resources/guidelines/correctional-settings/ 61. Altice FL, Bruce RD, Walton MR, et al. Adherence to hepatitis B virus pdf/Correctional_Settings_Guidelines.pdf. Accessed August 10, 2010. vaccination at syringe exchange sites. J Urban Health. 2005;82:151–161. 49. MacGowan R, Margolis A, Richardson-Moore A, et al. Voluntary rapid 62. Grau LE, Green TC, Singer M, et al. Getting the message straight: effects human immunodeficiency virus (HIV) testing in jails. Sex Transm Dis. of a brief hepatitis prevention intervention among injection drug users. 2009;36(Suppl 2):S9–S13. Harm Reduct J. 2009;6:36. 50. Bamford LP, Ehrenkranz PD, Eberhart MG, et al. Factors associated with 63. Wright NM, Campbell TL, Tompkins CN. Comparison of conventional delayed entry into primary HIV medical care after HIV diagnosis. AIDS. and accelerated hepatitis B immunisation schedules for homeless drug 2010;24:928–930. users. Commun Dis Public Health. 2002;5:324–326. 51. Ulett KB, Willig JH, Lin HY, et al. The therapeutic implications of timely 64. Macalino G, Dhawan D, Rich JD. A missed opportunity: hepatitis C linkage and early retention in HIV care. AIDS Patient Care STDS. 2009; screening of prisoners. Am J Public Health. 2005,95:1739–1740. 23:41–49. 65. Kwiatkowski CF, Fortuin Corsi K, et al. The association between 52. Pai NP, Estes M, Moodie EE, et al. The impact of antiretroviral therapy in knowledge of hepatitis C virus status and risk behaviors in injection drug a cohort of HIV infected patients going in and out of the San Francisco users. Addiction. 2002;97:1289–1294. county jail. PLoS One. 2009;4:e7115. doi:10.1371/journal.pone.0007115. 66. Flanigan TP, Beckwith CG, Bazerman LB, et al. A 44% and 69% 53. Olges JR, Murphy BS, Caldwell GG, et al. Testing practices and reduction in HIV in Connecticut (CT) and Rhode Island (RI) correctional knowledge of HIV among prenatal care providers in a low seroprevalence facilities concurrent with routine HIV testing, treatment and linkage to state. AIDS Patient Care STDS. 2007;21:187–194. community care [abstract TUPE0429]. Presented at: XVIII International 54. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommenda- AIDS Conference; July 18–23, 2010; Vienna, Austria. tions for HIV testing of adults, adolescents, and pregnant women in 67. Heimer R, Kaplan EH, O’Keefe E, et al. Three years of needle exchange in health-care settings. MMWR Recomm Rep. 2006;55(RR14):1–17. New Haven: what have we learned? AIDS Public Policy J. 1994;9:59–74. 55. Rhodes F, Stein JA, Fishbein M, et al. Using theory to understand how 68. Liebman J, Pat Lamberti M, Altice F. Effectiveness of a mobile medical interventions work: project RESPECT, condom use, and the integrative van in providing screening services for STDs and HIV. Public Health model. AIDS Behav. 2007;11:393–407. Nurs. 2002;19:345–353. 56. Parece MS, Herrera GA, Voigt RF, et al. STD testing policies and practices 69. Maru DS, Basu S, Altice FL. HIV control efforts should directly address in US city and county jails. Sex Transm Dis. 1999;26:431–437. incarceration. Lancet Infect Dis. 2007;7:568–569.

q 2010 Lippincott Williams & Wilkins www.jaids.com | S83 SUPPLEMENT ARTICLE

Progress in HIV Reduction and Prevention Among Injection and Noninjection Drug Users Natalie D. Crawford, MPH*† and David Vlahov, PhD, RN*

would not quit drug use, a second tier advised using sterile Abstract: Substantial progress has been made in reducing HIV syringes and disposing of them safely. The third tier, among injection drug users (IDUs) in the United States, despite a recommendation applicable when sterile injection equipment political and social resistance that reduced resources and restricted was unavailable, was disinfection with bleach.5,8 These access to services. The record for HIV prevention among non- messages have been successfully implemented by combining injecting drug users is less developed, although they are more interventions at individual, community, and policy levels9 that numerous than IDUs. Newer treatments for opiate and alcohol abuse promoted education through community outreach and HIV can now be integrated into primary HIV care; treatment for stimulant testing; behavioral interventions10; drug abuse treatment,11 abuse is less developed. All drug users present challenges for newer including opioid agonist therapies12; and syringe exchange HIV prevention strategies (eg, ‘‘test and treat,’’ nonoccupational programs,13 which were later supplemented by providing postexposure prophylaxis and preexposure prophylaxis, contingency syringe access through pharmacies14,15 (Fig. 1). Concerns management, and conditional cash transfer). A comprehensive HIV about the potential for syringe access to encourage initiation of prevention program that includes multicomponent multilevel ap- drug use among youth and to increase drug use, needle proaches (ie, individual, network, structural) has been effective in sharing, and crime, proved unfounded.13 Even before the HIV prevention among IDUs. Expanding these approaches to availability of antiretroviral therapy, HIV prevalence and noninjecting drug users, especially those at highest risk (eg, minority incidence among injection drug users declined.16–18 The men who have sex with men) and incorporating these newer purpose of this brief review is to discuss newer approaches to approaches is a public health priority. HIV prevention strategies and potential implementation Key Words: contingency management, epidemiology, HIV,injection challenges for prevention both among noninjecting drug users drug use, noninjection drug use, prevention, treatment (NIDUs), sometimes mistakenly referred to as ‘‘recreational users,’’ who have received insufficient attention for HIV (J Acquir Immune Defic Syndr 2010;55:S84–S87) prevention and among IDUs—framed within consideration of hurdles encountered in the prevention hierarchy of IDUs.

ational data have consistently estimated that 20.1 million NAmericans use illicit drugs.1 Of those, roughly NONINJECTING DRUG USERS 1.2 million inject drugs, a practice that has been recognized HIV risk, prevalence and transmission rates vary widely for its role in HIV transmission, accounting for 11% of HIV among NIDUs using crack, cocaine methamphetamine, infections.1,2 Among injection drug users (IDUs) in the United alcohol, pills and noninjected heroin, but may be relatively States, the HIV rate has been estimated to be 28%.3 high because of the co-occurrence of drug use with sexual risk Addressing the challenge of the HIV epidemic in injectors behaviors (eg, unprotected sex, multiple partners, and survival 19–22 was made difficult by powerful political and social resistance sex) and the overlapping of social network risk groups. (eg, zero tolerance campaigns) that dampened access to These associations have been dramatic, especially among men 23–26 important resources for drug users.4 However, during this who have sex with men (MSM). period, the US Public Health Services developed and disseminated a hierarchy of prevention.2,5–7 Briefly, its first Approaches to Screening and Prevention tier called for abstinence, which could be facilitated through Targeted interventions with outreach specialized to treatment for drug abuse. For those IDUs who could not or reach types of NIDUs according to drug of choice may be necessary given different behavioral patterns of drug use. However, in general, NIDU interventions should be compre- hensive in their ability to serve multiple risk groups (eg, drug From the *Center for Urban Epidemiologic Studies, New York Academy of Medicine, and †Department of Epidemiology, Mailman School of Public users, MSM) with multiple risk factors (eg, drug use, sex, 27 Health, Columbia University, New York, NY. mental health). For example, multicomponent interventions Supported by National Institute on Drug Abuse DA022144, DA022123, such as MP3 (Methods for Prevention Package Programs) and DA04334, DA019964 (N.D.C and D.V.), and RC1DA028284. Screening, Brief Intervention, Referral, and Treatment28 need Correspondence to: David Vlahov, PhD, RN, New York Academy of Medicine, Center for Urban Epidemiologic Studies, 1216 Fifth Avenue, to include approaches along with wraparound services to be New York, NY 10029 (e-mail: [email protected]). comprehensive in addressing drug users’ multiple complex Copyright Ó 2010 by Lippincott Williams & Wilkins needs (eg, relating to sex, mental health, homelessness, and

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nPEP and PrEP for IDUs Elsewhere in this issue, nPEP and PrEP in general have been discussed. Data are sparse on nPEP for drug users and for IDUs in particular,35,36 and results of PrEP trials in IDUs are not yet available.37 Should the data show effectiveness, the next challenge will be to appropriately disseminate informa- tion via street outreach strategies. Although some view nPEP and PrEP for IDUs and NIDUs with trepidation because of valid concerns over drug toxicities, drug users’ ability to adhere to treatment, and the potential for development of drug resistance that would subsequently limit potential treatment options,38 it is feasible to integrate provision of these drugs FIGURE 1. Multilevel HIV prevention hierarchy, past and into drug treatment programs and pharmacies, where there is the present. *SEP denotes syringe exchange programs. ability to frequently perform HIV testing and creates linkages to providers to monitor patients. However, additional infrastruc- ture is needed to attract and engage both IDUs and NIDUs. infectious and chronic disease).29 Current efforts in the United States are focused on reaching and engaging minority MSM, Substance Abuse Treatment who have particularly high rates of HIV infection.30,31 In this Substance abuse treatment has been a mainstay for HIV population, as in others, interventions need to go beyond ‘‘test prevention among drug users. For opiate abuse and de- and treat’’ (TNT) to assess and address drug use issues, pendence, methadone and now buprenorphine/naloxone are including polydrug use.32 In a broader sense, incarceration and established treatments,12 which have the advantage of neighborhood factors that have been shown to influence unchallenged integration into primary HIV care.39 The greater availability and opportunity for drug use also need to be challenge has been the ability to produce effective substance considered in addressing drug-related concerns.15,33 abuse treatment for stimulant abuse. Several pharmacothera- pies have been tested, and others are in the pipeline. For treatment of methamphetamine abuse, little or no benefit has WHERE ARE WE NOW? been seen in trials for bupropion40 and modafinil,41 but efforts Especially with the advent of antiretroviral therapies, the continue with newer agents such as varenicline are under spectrum of HIV prevention in drug users has broadened to investigation.42 The experience to date with pharmacologic include TNT; nonoccupational postexposure prophylaxis treatment for cocaine and crack is similarly disappointing; the (nPEP); and pre-exposure prophylaxis (PrEP). These inter- promise of antidepressants43 and carbamazepine44 has not ventions need to be tailored to ensure that they are accessible been realized, but examination of newer drugs is ongoing.45 and feasible for drug users and incorporated on multiple levels With the slower progress on pharmacologic treatments for (eg, individual, community, and structural). methamphetamines and other stimulants, the most promising approach to date has been cognitive behavioral therapy with Test and Treat contingency management.46,47 As has been shown for IDUs, TNT aims to reach virtually everyone in the US treatment combinations on multiple levels (eg, individual population and treat HIV infection with antiretroviral pharmacotherapy and behavioral change) are needed not only medications, an intervention that would presumably reduce to reduce drug use but also to successfully target and maintain population viral loads and HIV incidence.34 For NIDUs and integration of NIDUs into social services.21,48 IDUs alike, the success of TNT requires the ability to reach Alcohol, the most widely used drug, is also associated this more elusive population at higher risk of HIV exposure with sexual risk for HIV infection. Rapid screening tools for and to retain them in a program of frequent testing and alcohol abuse and dependence have been developed, yet only treatment. TNT could be expanded outside conventional half of HIV-infected problem drinkers discuss their pre- hospital, clinic, and emergency room settings to include those dicament with their HIV care providers.49 Given the who attend drug treatment and IDUs who have developed association of problem drinking with increased risk of HIV rapport with syringe exchange programs and pharmacies. transmission and acquisition, screening for alcohol use needs However, among hard-to-reach groups where HIV is making to be more widely incorporated into HIV care and research. inroads, the purported benefits of TNT may be suboptimal A number of pharmacologic treatment options for alcohol without explicit strategies to incorporate HIV testing into misuse are being studied, including naltrexone50 and di- a broad range of facilities on a widespread basis; to reach drug sulfiram.51 Yet no standard pharmacologic therapies for users who do not access services and are likely at highest risk alcohol abuse and dependence exist. Techniques of motiva- of HIV exposure; to train health care workers to communicate tional interviewing (MI) could possibly be effectively provided effectively with and engage this population; to optimize in primary HIV care settings.52,53 But MI’s effectiveness has approaches to maintain adherence to antiretroviral treatment, been demonstrated only as a multisession intervention, especially for those outside drug-abuse treatment; and to limiting its feasibility in many primary HIV care settings, ensure that all those at risk for HIV exposure have access to all where staff face many competing demands. This suggests that needed services. modifications are needed in the structure of MI content and its q 2010 Lippincott Williams & Wilkins www.jaids.com | S85 Crawford and Vlahov J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 requirement for health care provider involvement. Telephone 2. HIV diagnoses among injection-drug users in states with HIV counseling alone (or possibly as an adjunct to MI) has shown surveillance—25 states, 1994–2000. MMWR Morb Mortal Wkly Rep. 54 2003;52:634–636. some promise for problem drinkers. 3. Friedman SR, Lieb S, Tempalski B, et al. HIV among injection drug users Contingency management and conditional cash transfer in large US metropolitan areas, 1998. J Urban Health. 2005;82:434–445. are two iterations of another approach to substance abuse doi:10.1093/jurban/jti088. treatment and HIV prevention that has been used for some 4. Metzger DS, Navaline H. HIV prevention among injection drug users: the time.55 There is resistance to the idea of ‘‘rewarding’’ drug need for integrated models. J Urban Health. 2003;80(Suppl 3):iii59–iii66. doi:10.1093/jurban/jtg083. users, but available data from prospective studies suggest that 5. US Public Health Service. HIV prevention bulletin: medical advice this approach improves otherwise costly follow-up without to persons who inject illicit drugs. May 9, 1997. Available at: http:// increasing drug use.56 Addressing the challenge of missed www.cdc.gov/idu/pubs/hiv_prev.htm. Accessed August 20, 2010. doses for treatment, a recent trial of longer-acting implantable 6. Des Jarlais DC, Marmor M, Friedmann P, et al. HIV incidence among buprenorphine implantsshowed less opiate use than standard injection drug users in New York City, 1992–1997: evidence for a 57 declining epidemic. Am J Public Health. 2000;90:352–359. buprenorphine use. Likewise, naltrexone implants have 7. Nelson KE, Vlahov D, Solomon L, et al. Temporal trends of incident shown benefit over oral dosing for improved clinical out- human immunodeficiency virus infection in a cohort of injecting drug comes,58 and recently, Vivitrol (long-acting Naltrexone) has users in Baltimore, Md. Arch Intern Med. 1995;155:1305–1311. been approved by the U.S. FDA for treating opiate dependence 8. Vlahov D, Fuller CM, Ompad DC, et al. Updating the infection risk 59 reduction hierarchy: preventing transition into injection. J Urban Health. among those successfully detoxified from use. 2004;81:14–19. doi:10.1093/jurban/jth083. 9. Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet. 2008;372:669–684. doi:10.1016/S0140-6736(08)60886-7. CONCLUSIONS: FROM STIGMATA TO 10. Copenhaver MM, Johnson BT, Lee IC, et al. Behavioral HIV risk REDEMPTION—MAKING EFFECTIVE reduction among people who inject drugs: meta-analytic evi- INTERVENTIONS POSSIBLE dence of efficacy. J Subst Abuse Treat. 2006;31:163–171. PMCID: Multilevel, multicomponent interventions among IDUs PMC2452992. 11. Sorensen JL, Masson CL, Perlman DC. HIV/hepatitis prevention in drug have been successful at reducing HIV incidence and provide abuse treatment programs: guidance from research. Sci Pract Perspect. a model for more broadly addressing HIV prevention. Yet 2002;1:4–11. Available at: http://www.drugabuse.gov/PDF/perspectives/ challenges remain—not only for IDUs but for the much larger vol1no1/02Perspectives-HIVHep.pdf. Accessed August 19, 2010. population of noninjectors. Drug use needs to be approached 12. Sullivan LE, Metzger DS, Fudala PJ, et al. Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for comprehensively to reach and provide options for those who injection drug users. Addiction. 2005;100:150–158. doi:10.1111/j.1360- do not or cannot quit drugs. Further, going beyond specific 0443.2004.00963.x. programs into the policy choices that create resources to 13. Heimer R. Syringe exchange programs: lowering the transmission of ensure access to services and support for adherence to the syringe-borne diseases and beyond. Public Health Rep. 1998;113(Suppl 1): evidence-informed health supporting protocols that are 67–74. PMCID: PMC1307728. 14. Des Jarlais DC, Perlis T, Arasteh K, et al. HIV incidence among injection currently available is warranted. Practical strategies to over- drug users in New York City, 1990 to 2002: use of serologic test algorithm come problems of access and adherence include utilizing our to assess expansion of HIV prevention services. Am J Public Health. standard tools of (1) ‘‘education,’’ to increase knowledge about 2005;95:1439–1444. PMCID: PMC1449378. behaviors that can prevent HIV infection at the individual and 15. Fuller CM, Galea S, Caceres W, et al. Multilevel community-based intervention to increase access to sterile syringes among injection drug community levels; (2) ‘‘HIV testing’’ in nontraditional settings users through pharmacy sales in New York City. Am J Public Health. (eg, pharmacies) to reach drug users whose activities put them 2007;97:117–124. PMCID: PMC1716247. at high risk of HIV exposure; (3) ‘‘behavioral interventions’’ 16. Santibanez SS, Garfein RS, Swartzendruber A, et al. Update and overview that not only address drug use–associated behaviors and health of practical epidemiologic aspects of HIV/AIDS among injection drug problems but also HIV risk behaviors to lure and integrate users in the United States. J Urban Health. 2006;83:86–100. PMCID: PMC2258331. drug users who are members of other overlapping risk groups; 17. Moss AR, Vranizan K, Gorter R, et al. HIV seroconversion in intravenous (4) ‘‘drug treatment,’’ which should be expanded, especially in drug users in San Francisco, 1985–1990. AIDS. 1994;8:223–231. communities where access is now poor and in primary HIV 18. Mehta SH, Galai N, Astemborski J, et al. HIV incidence among injection care settings; and, for IDUs, (5) ‘‘syringe access,’’ to increase drug users in Baltimore, Maryland (1988–2004). J Acquir Immune Defic Syndr. 2006;43:368–372. access to sterile equipment. It is a combination of these 19. Celentano DD, Latimore AD, Mehta SH. Variations in sexual risks in drug strategies applied simultaneously on individual, community, users: emerging themes in a behavioral context. Curr HIV/AIDS Rep. and policy levels that have been successful in reducing HIV 2008;5:212–218. PMCID: PMC2801160. incidence and prevalence among drug users to date, and it is 20. Mitchell MM, Latimer WW. Unprotected casual sex and perceived risk of these strategies that researchers, community members, and contracting HIVamong drug users in Baltimore, Maryland: evaluating the influence of non-injection versus injection drug user status. AIDS Care. policy makers should work to expand for use and application 2009;21:221–230. doi:10.1080/09540120801982897. of upcoming HIV interventions. 21. Strathdee SA, Sherman SG. The role of sexual transmission of HIV infection among injection and non-injection drug users. J Urban Health. 2003;80(Suppl 3):iii7–iii14. doi:10.1093/jurban/jtg078. REFERENCES 22. Centers for Disease Control and Prevention. Methamphetamine use 1. Substance Abuse and Mental Health Services Administration. Results and HIV risk behaviors among heterosexual men—preliminary results From the 2007 National Survey on Drug Use and Health: National from five northern California counties, December 2001–November Findings. Rockville, MD: US Department of Health and Human Services; 2003. MMWR Morb Mortal Wkly Rep. 2006;55:273–277. Available at: 2008. Available at: http://www.oas.samhsa.gov/nsduh/2k7nsduh/ http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5510a2.htm. Accessed 2k7results.cfm. Accessed August 18, 2010. 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23. Colfax G, Coates TJ, Husnik MJ, et al. Longitudinal patterns of 41. Heinzerling KG, Swanson AN, Kim S, et al. Randomized, double-blind, methamphetamine, popper (amyl nitrite), and cocaine use and high-risk placebo-controlled trial of modafinil for the treatment of methamphet- sexual behavior among a cohort of San Francisco men who have sex with amine dependence. Drug Alcohol Depend. 2010;109:20–29. doi:10.1016/ men. J Urban Health. 2005;82(Suppl 1):i62–i70. doi:10.1093/jurban/jti025. j.drugalcdep.2009.11.023. 24. Mimiaga MJ, Reisner SL, Fontaine YM, et al. Walking the line: stimulant 42. Zorick T, Sevak RJ, Miotto K, et al. Pilot safety evaluation of varenicline use during sex and HIV risk behavior among Black urban MSM. Drug for the treatment of methamphetamine dependence. J Exp Pharmacol. Alcohol Depend. 2010;110:30–37. doi:10.1016/j.drugalcdep.2010.01.017. 2010;2:13–18. Available at: http://www.dovepress.com/pilot-safety- 25. Ostrow DG, Plankey MW, Cox C, et al. Specific sex drug combinations evaluation-of-varenicline-for-the-treatment-of-methamphet-peer-reviewed- contribute to the majority of recent HIV seroconversions among MSM in article-JEP. Accessed August 20, 2010. the MACS. J Acquir Immune Defic Syndr. 2009;51:349–355. doi: 43. Lima MS, Reisser AA, Soares BG, et al. Antidepressants for cocaine 10.1097/QAI.0b013e3181a24b20. dependence. Cochrane Database Syst Rev. 2003(2):CD002950. doi: 26. Reisner SL, Mimiaga MJ, Bland S, et al. Problematic alcohol use and HIV 10.1002/14651858.CD002950. risk among Black men who have sex with men in Massachusetts. AIDS 44. Lima AR, Lima MS, Soares BG, et al. Carbamazepine for cocaine Care. 2010:22:1–11. doi:10.1080/09540120903311482. dependence. Cochrane Database Syst Rev. 2002(2):CD002023. doi: 27. Meade CS, Sikkema KJ. HIV risk behavior among adults with severe 10.1002/14651858.CD00 2023. mental illness: a systematic review. Clin Psychol Rev. 2005;25:433–457. 45. Preti A. New developments in the pharmacotherapy of cocaine abuse. doi:10.1016/j.cpr.2005.02.001. Addict Biol. 2007;12:133–151. doi:10.1111/j.1369-1600.2007.00061.x. 28. Babor TF, McRee BG, Kassebaum PA, et al. Screening, brief intervention, 46. Lee NK, Rawson RA. A systematic review of cognitive and behavioural and referral to treatment (SBIRT): toward a public health approach to the therapies for methamphetamine dependence. Drug Alcohol Rev. 2008;27: management of substance abuse. Subst Abus. 2007;28:7–30. 309–317. doi:10.1080/09595230801919494. 29. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, 47. Shoptaw S, Reback CJ, Larkins S, et al. Outcomes using two tailored referral to treatment (SBIRT) for illicit drug and alcohol use at multiple behavioral treatments for substance abuse in urban gay and bisexual men. healthcare sites: comparison at intake and 6 months later. Drug Alcohol J Subst Abuse Treat. 2008;35:285–293. doi:10.1016/j.jsat.2007.11.004. Depend. 2009;99:280–295. doi:10.1016/j.drugalcdep.2008.08.003. 48. Degenhardt L, Mathers B, Vickerman P, et al. Prevention of HIV infection 30. Gorbach PM, Murphy R, Weiss RE, et al. Bridging sexual boundaries: men for people who inject drugs: why individual, structural, and combination who have sex with men and women in a street-based sample in Los Angeles. approaches are needed. Lancet. 2010;376:285–301. doi:10.1016/S0140- J Urban Health. 2009;86(Suppl 1):63–76. PMCID: PMC2705489. 6736(10)60742-8. 31. Tobin KE, Latkin CA. An examination of social network characteristics of 49. Metsch LR, Pereyra M, Colfax G, et al. HIV-positive patients’ discussion men who have sex with men who use drugs. Sex Transm Infect. 2008;84: of alcohol use with their HIV primary care providers. Drug Alcohol 420–424. doi:10.1136/sti.2008.031591. Depend. 2008;95:37–44. doi:10.1016/j.drugalcdep.2007.12.006. 32. Mimiaga MJ, Reisner SL, Cranston K, et al. Sexual mixing patterns and 50. Ray LA, Chin PF, Miotto K. Naltrexone for the treatment of alcoholism: partner characteristics of black MSM in Massachusetts at increased risk clinical findings, mechanisms of action, and pharmacogenetics. CNS for HIV infection and transmission. J Urban Health. 2009;86:602–623. Neurol Disord Drug Targets. 2010;9(1):13–22. doi:10.1007/s11524-009-9363-6. 51. Barth KS, Malcolm RJ. Disulfiram: an old therapeutic with new 33. Friedman SR, Cooper HL, Osborne AH. Structural and social contexts of applications. CNS Neurol Disord Drug Targets. 2010;9:5–12. HIV risk among African Americans. Am J Public Health. 2009;99:1002– 52. Burke BL, Arkowitz H, Menchola M. The efficacy of motivational 1008. doi:10.2105/AJPH.2008.140327. interviewing: a meta-analysis of controlled clinical trials. J Consult Clin 34. Dieffenbach CW, Fauci AS. Universal voluntary testing and treatment Psychol. 2003;71:843–861. doi:10.1037/0022-006X.71.5.843. for prevention of HIV transmission. JAMA. 2009;301:2380–2382. doi: 53. Lundahl B, Burke BL. The effectiveness and applicability of motivational 10.1001/jama.2009.828. interviewing: a practice-friendly review of four meta-analyses. J Clin 35. Almeda J, Allepuz A, Simon BG, et al. Non-occupational post-exposure Psychol. 2009;65:1232–1245. doi:10.1002/jclp.20638. HIV prophylaxis. Knowledge and practices among physicians and groups 54. Brown RL, Saunders LA, Bobula JA, et al. Randomized-controlled trial of with risk behavior [in Spanish]. Med Clin (Barc). 2003;121:321–326. a telephone and mail intervention for alcohol use disorders: three-month 36. Vlahov D, Robertson AM, Strathdee SA. Prevention of HIV infection drinking outcomes. Alcohol Clin Exp Res. 2007;31:1372–1379. doi: among injection drug users in resource-limited settings. Clin Infect Dis. 10.1111/j.1530-0277.2007.00430.x. 2010;50(Suppl 3):S114–S121. doi:10.1086/651482. 55. Haug NA, Sorensen JL. Contingency management interventions for 37. Centers for Disease Control and Prevention. Pre-exposure prophylaxis HIV-related behaviors. Curr HIV/AIDS Rep. 2006;3:154–159. Available (PrEP) for HIV prevention; planning for potential implementation in the at: http://www.springerlink.com/content/q677577l2q007157/fulltext.pdf. U.S. Centers for Disease Control and Prevention Web site. Updated Accessed August 20, 2010. August 21, 2009. Available at: http://www.cdc.gov/hiv/prep/resources/ 56. Festinger DS, Marlowe DB, Croft JR, et al. Do research payments factsheets/implementation.htm#Planning. Accessed August 20, 2010. precipitate drug use or coerce participation? Drug Alcohol Depend. 2005; 38. Grant RM. Antiretroviral agents used by HIV-uninfected persons for 78:275–281. doi:10.1016/j.drugalcdep.2004.11.011. prevention: pre- and postexposure prophylaxis. Clin Infect Dis. 2010; 57. Ling W, Casadonte P, Bigelow G, et al. Buprenorphine Implants for 50(Suppl 3):S96–S101. doi:10.1086/651479. Treatment of Opioid Dependence:A Randomized Controlled Trial. JAMA. 39. 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q 2010 Lippincott Williams & Wilkins www.jaids.com | S87 SUPPLEMENT ARTICLE

HIV Prevention in Gay Bathhouses and Sex Clubs Across the United States William J. Woods, PhD, Jason Euren, MA, Lance M. Pollack, PhD, and Diane Binson, PhD

Clubs are an ideal environment in which to target this Abstract: Gay bathhouses (including sex clubs) contributed to HIV otherwise hard-to-reach population with appropriate pre- prevention from the early days of the AIDS epidemic, but the extent to vention interventions. Recent research has focused on the which prevention interventions are implemented in bathhouses is challenges of implementing HIV testing programs in clubs,12–15 unknown. Using telephone survey methodology, bathhouse managers whereas other studies have shown that men at clubs will avail provided data about HIV prevention in their bathhouses. All the themselves for testing when it is available on site7,16–18 and that bathhouses provided free condoms, and nearly all displayed such in-club testing has been associated with a reduced risk educational posters in public areas and had informational pamphlets behavior for more than a 3-month period.19,20 The scientific available for patrons. A few of the bathhouses offered outreach services literature indicates a wide range of HIV prevention programs, and counseling services. Almost all promoted testing for HIV/sexually and services have been initiated in clubs to try to reach men at transmitted infection (which included providing information about risk with important HIV prevention services and informa- where to get tested), and 75.5% had HIV testing programs in their tion.4,7,14,16–21 To determine the extent to which HIV prevention venues. Most of the HIV testing programs were started during the past is implemented in clubs across the United States, we 5 years, initiated by the bathhouse management or a community interviewed club managers. This article presents the findings agency, and operated by community-based agencies. About one third from that study. of the programs offered rapid HIV testing. The results of the telephone survey revealed that all the bathhouses engaged in prevention and many METHOD offered a wide range of prevention services, suggesting that managers The study population included all clubs operating in the have embraced the issue of HIV and collaborated in bringing United States and listed in the Damron Men’s Travel Guide prevention to high-risk men. The absence of studies evaluating these 2004 (a gay resource directory for the United States) or prevention efforts remains a concern and an obstacle for efficient use of www.cruisingforsex.com (at the time, the most comprehensive the prevention resources. Web listing of places for men to meet men for sex). Lists of Key Words: HIV prevention, gay bathhouse, sex clubs, sex establishments in these resources were inclusive of a variety of environments, gay men, men who have sex with men places where men meet for sex. We operationally defined a club as any listed business that provided a space where (J Acquir Immune Defic Syndr 2010;55:S88–S90) anonymous sex was permitted between male patrons, that had a permanent location, and that operated at least 3 days a week. Managers of these clubs served as key informants, INTRODUCTION providing data about the clubs they manage. To recruit these managers, we followed procedures used in a similar survey of Gay bathhouses and sex clubs (hereafter, simply clubs conducted from October 1996 to February 1997.4 Aletter ‘‘clubs’’) have contributed to and served as sites for HIV introducing the study was addressed to the general manager of prevention from the early days of the AIDS epidemic,1–3 and each club and mailed at least a week before the initial telephone they continue to do so without deleterious effects on their contact; attempts to complete direct contact with a club owner or businesses.4,5 Although data from probability samples of men manager followed and continued until a representative of the club leaving clubs show that risk behavior inside the clubs verbally declined study participation. During the subsequent themselves is atypical,6–9 clubs do attract men who engage initialdirectcontact,theinterviewerdescribedthestudy,answered in such behavior. High-risk men who have sex with men any questions, and determined whether the general manager or (MSM) are more likely than their peers to go to clubs,10 and whether someone else (eg, a manager who oversees the HIV more than half of all nontesting high-risk MSM go to clubs.11 prevention activities at the club) should be the respondent. Participation was voluntary, and the participants gave verbal From the Department of Medicine, University of California, San Francisco, CA. consent. The telephone interview lasted from 1.5 to 2.5 hours. Supported in part by the CAPS Innovative Grant Program (MH62246) and Interviewers used a computer-assisted telephone interview Community Prevention Policy & Programs in Risk Settings (MH070311), system. The questionnaire was developed from the formative both from the National Institute of Mental Health. work on HIV prevention services in clubs in New York, Los The authors have no funding or conflicts of interest to disclose. Correspondence to: William J. Woods, PhD, UCSF-CAPS, 50 Beale Street, Angeles, and San Francisco and was reviewed in advance by Suite 1300, San Francisco, CA 94105 (e-mail: [email protected]). 3 club managers. The interview included items requesting Copyright Ó 2010 by Lippincott Williams & Wilkins detailed data about the specific club’s size and amenities, its

S88 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 HIV Prevention in Gay Bathhouses rules and regulations, its prevention programs (including education and information, condom and lube distribution, TABLE 1. Prevention in the US Clubs (n = 53) and on-site testing programs for HIV/sexually transmitted Prevention Effort % infection), and the barriers to and facilitators for providing HIV Condoms testing services. All procedures and protocols were approved by Available for free 100 the Institutional Review Board at the University of California, Distributed at front desk 88.7 San Francisco. Distributed in public areas 81.1 Distributed in private rooms* 58.3 RESULTS Lubricant We identified 94 gay sex establishments in the United Available for free 41.5 States, of which 77 met the eligibility criteria (ie, provided Available for sale 100 space where sex was permitted, had a permanent location, and Educational materials/activities operated at least 3 days a week). We completed interviews with Posters 98.1 representatives of 53 clubs, a response rate of 70.1%. Informational pamphlets 98.1 These businesses used various terms to describe Outreach programs 45.3 themselves, including bathhouse (43.4%), health club Counseling services 15.1 (34.2%), sex club (13.2%), and sauna (5.7%); the remaining Special events 13.2 respondents did not know or preferred not to say (2.8%). Clubs Testing program varied widely in their size, as indicated by the range in the Promote HIV/STI testing 96.2 number of rentable rooms (22–129; mean = 55.0, median = Provide HIV testing inside club 75.5 55.0) and lockers (34–400; mean = 127.6, median = 100.0), Provide STI testing inside club 56.6 although 1 club offered neither rooms nor lockers to rent. In Special room built out for testing 34.0 general, clubs that offered rooms to rent were larger, and the *Among clubs with private rooms (n = 48). more rooms and lockers available to rent, the larger the club. About half the venues (50.9%) permitted sexual behavior among patrons in the public areas; 22 (81.5%) of these 27 clubs testing on average for 5.6 years (median = 4.5 years; range purposely kept the lighting levels lower in the public areas #1–25 years). At the time of the study, they operated on intended for sex. About 4 (41.5%) in 10 clubs had rules about average 3.7 days a month (median = 4.0 days, range = 1–12 safer sex (eg, it was the only type of sex permitted inside the days), constituting 13.6 hours of testing (median = 12.0 hours, club), and most of those (77.3%) asked patrons to agree in range = 2–48 hours), serving 26.4 clients per month (median = writing to follow the rules, usually at each visit (68.4%). All 16.0, range = 2–100). Of the 62 programs that offered HIV clubs had rules prohibiting the use of drugs (including alcohol), testing, 37 (59.7%) delivered test results inside the club, and of and a majority (60.4%) did a bag check at entry. A few clubs those, 10 (27.0%) delivered results solely inside the club. Of the (6.3%) prohibited on-premise use of ‘‘poppers’’ (ie, alkyl 41 programs (63.1%) that offered testing for sexually trans- nitrites, inhaled for recreational purposes), but more than half mitted infection, 20 (48.8%) delivered results inside the club. (56.6%) sold them. Methamphetamines and alcohol were most frequently reported as the substances causing the largest DISCUSSION problem at a club (29.9% and 16.1%, respectively). Clubs across the United States continue to provide a wide More than half of the clubs (58.5%) had a designated range of HIV prevention efforts. Rather than resist HIV employee responsible for oversight of club prevention activities, with about a quarter of these employees (25.9%) TABLE 2. Characteristics of 65 Testing Programs at Clubs dedicating 50% or more of their work time to managing That Offered Testing on Site prevention activities. Table 1 summarizes the range of Characteristic % prevention activities and the proportion of clubs engaging in each prevention activity. All the venues made free condoms Health department 26.2 available to all patrons, and nearly all displayed educational Community agency 70.8 posters in public areas and had informational pamphlets Do not know 3.1 available for patrons; a few clubs also offered other outreach Initiated by (%) services, but special events that focused on risk reduction and Club management 35.4 counseling services were not as prevalent. Almost all the clubs Health department 7.7 promoted HIV testing (at a minimum, providing information Community agency 29.2 about where to get tested), and 40 of 53 offered HIV testing on Do not know 27.7 site (ie, inside the ‘‘paid’’ area of the club). Test/screening offered (%) Of the clubs offering on-site HIV testing, 14 had HIV (standard) 98.4 more than 1 group providing testing at the club; 7 clubs HIV (rapid) 35.4 had 2 different groups offering testing, 3 clubs had 3 groups, Syphilis 53.8 and 4 clubs had 4 groups. Table 2 summarizes key features of Gonorrhea 38.5 the 65 testing programs implemented inside the 40 clubs that Chlamydia 26.2 offered testing on site. Those programs had been offering Hepatitis (A, B, or C) 27.7 q 2010 Lippincott Williams & Wilkins www.jaids.com | S89 Woods et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 prevention,22 club managers seemed to promote and engage conducted. They also wish to recognize the efforts of the survey actively in it. Our telephone survey found that most clubs have team, specifically Justin Bailey, Paul Cotten, Robert Siedle- assigned a specific employee to manage prevention activities Khan, Alberto Curotto, Gabriel Ortiz, and Joseph Morris. and that on-site testing programs were more likely to have been initiated by the clubs themselves than by any other single group of stakeholders. Although condom and information distribution REFERENCES remain the primary prevention activities, many clubs reported 1. Woods WJ, Binson D. Public health policy and gay bathhouses. J Homosex. 2003;44:1–21. additional prevention efforts, including outreach programs, 2. Helquist M, Osmon R. Sex and the baths: a not so secret report. Coming counseling services, and special events that focused on HIV Up. July 1984:17–22. Reprinted in: J Homosex. 2003;44:153–175. doi: prevention and testing. In fact, when compared with a similar 10.1300/J082v44n03_07. study conducted in 1996–1997,4 the percentage of clubs 3. Richwald GA, Morisky DE, Kyle GR, et al. Sexual activities in bathhouses in Los Angeles County: implications for AIDS prevention offering HIV testing programs has almost doubled. education. J Sex Res. 1988;25:169–180. The data presented described the extent to which 4. Woods WJ, Binson D, Mayne TJ, et al. Facilities and HIV prevention in prevention programs were offered in clubs across the country. bathhouse and sex club environments. J Sex Research. 2001;38:68–74. Further research is needed to determine the efficacy of Available at: http://www.jstor.org/stable/3813263. Accessed August 12, prevention activities (such as where condoms are distributed 2010. 5. Huebner DM, Binson D, Pollack LM, et al. Implementing bathhouse- in the club), to develop best-practices standards for service based voluntary counseling and testing has no adverse effect on bathhouse programs (such as on-site HIV testing), and to identify the patronage among men who have sex with men. Int J STD AIDS. In press. facilitators that lead clubs to engage in prevention and the 6. Woods WJ, Binson D, Blair J, et al. Probability sample estimates of bathhouse barriers that stifle such engagement. Providing answers to these sexual risk behavior. J Acquir Immune Defic Syndr. 2007;45:231–238. 7. Bingham TA, Secura GM, Behel SK, et al. HIV risk factors reported by questions can help direct future prevention efforts by focusing two samples of male bathhouse attendees in Los Angeles, California, resources on effective programs and assisting public health 2001–2002. Sex Transm Dis.2008;35:631–636. officials and service providers in exploiting facilitators and 8. Reidy WJ, Spielberg F, Wood R, et al. HIV risk associated with gay minimizing barriers for clubs to engage in prevention. Although bathhouses and sex clubs: findings from two Seattle surveys of factors local jurisdictions have instituted many different policies to related to HIV and sexually transmitted infections. Am J Public Health. 2009;99:S165–S172. doi:10.2105/AJPH.2007.130773. establish particular approaches to prevention in clubs, little or 9. Binson D, Pollack LM, Blair J, et al. HIV risk at a gay bathhouse. J Sex no research has been conducted to determine whether any of Research. 2009;46:1–9. PMCID: PMC2891333. them are effective or more appropriate than other approaches.23 10. Binson D, Woods WJ, Pollack LM, et al. Differential HIV risk in bathhouses Studies of how these policies alter club environments in ways and public cruising areas. Am J Public Health. 2001;91:1482–1486. PMCID: PMC1446808. that might decrease risk behavior (eg, always using a condom 11. Binson D, Woods WJ, Pollack LM, et al. Bringing HIV/STI testing for anal sex) or increase protective behavior (eg, testing by high- programmes to high risk men. Int J STD AIDS. 2005;16:600–604. risk MSM) are required to better understand how these 12. Prost A, Chopin M, McOwan A, et al. ‘‘There is such a thing as asking for environments can facilitate prevention efforts that will reach trouble’’: taking rapid HIV testing to gay venues is fraught with the highest-risk segment of the MSM population. challenges. Sex Transm Infect. 2007;83:185–188. 13. Binson D, Blea L, Cotten PD, et al. Building an HIV/STI prevention program The following limitations should be kept in mind when in a gay bathhouse: a case study. AIDS Educ Prev. 2005;17:386–399. interpreting the results of this study. All data were provided by 14. Woods WJ, Erwin K, Lazarus M, et al. Building stakeholder partnerships 1 key informant at each site, without any observational or for an on-site HIV testing programme. Cult Health Sex. 2008;10:249–262. secondary source verification. It is possible that different 15. Spielberg F, Branson BM, Goldbaum GM, et al. Designing an HIV counseling and testing program for bathhouses: the Seattle experience information may have been provided had a different key with strategies to improve acceptability. J Homosex. 2003;44:203–220. informant been interviewed. It also is possible that we received 16. Spielberg F, Branson BM, Goldbaum GM, et al. Overcoming barriers to refusals from clubs that were not providing prevention efforts. HIV testing: preferences for new strategies among clients of a needle Finally, the information on HIV testing programs is limited, as exchange, a sexually transmitted disease clinic, and sex venues for men the program providers were not interviewed. who have sex with men. J Acquir Immune Defic Syndr. 2003;32:318–328. 17. Spielberg F, Branson BM, Goldbaum GM, et al. Choosing HIV In summary, nearly all the businesses engaged in HIV counseling and testing strategies for outreach settings: a randomized education and prevention. We found that free condom trial. J Acquir Immune Defic Syndr. 2005;38:348–355. distribution was a universal characteristic of prevention in clubs, 18. Daskalakis D, Silvera R, Bernstein K, et al. Implementation of HIV testing at 2 followed closely by such educational efforts as posters and New Yorkcity bathhouses: from pilot to clinical service. Clin Infect Dis. 2009; 48:1609–1616. pamphlets. Most clubs provided on-site HIV testing. The absence 19. Huebner DM, Binson D, Woods WJ, et al. Bathhouse-based voluntary of studies evaluating these prevention efforts remains a concern counseling and testing is feasible and shows preliminary evidence and an obstacle for efficient use of the resources. Nevertheless, of effectiveness. J Acquir Immune Defic Syndr. 2006;43:239–246. these data suggest that HIV prevention in clubs is perceived by 20. Huebner DM, Binson D, Dillworth SE, et al. Rapid vs standard HIV most managers as a necessary part of doing business. The testing in a bathhouse setting: what is gained and lost? AIDS Behav. 2010; 14:688–696. doi:10.1007/s10461-008-9442-9. willingness of these clubs to promote HIV prevention suggests 21. Woods WJ, Binson D, Pollack LM, et al. Characteristics of research- that the business aspect of venues that serve at-risk populations is related HIV testing programs contribute to detection of more HIV not necessarily an impediment to intervening in these venues. infections. Int J STD AIDS. 2010;21:19–22. 22. Shilts R. And the Band Played On: Politics, People, and the AIDS ACKNOWLEDGMENTS Epidemic. New York, NY: St. Martin’s Press; 1987. 23. Woods WJ, Binson D, Pollack LM, et al. Public policy regulating private The authors acknowledge the club owners and manag- and public space in gay bathhouses. J Acquir Immune Defic Syndr. 2003; ers, without whose cooperation the survey could not be 32:417–423.

S90 | www.jaids.com q 2010 Lippincott Williams & Wilkins SUPPLEMENT ARTICLE

HIV in Transgender Communities: Syndemic Dynamics and a Need for Multicomponent Interventions Don Operario, PhD* and Tooru Nemoto, PhD†

EPIDEMIOLOGICAL STUDIES Abstract: Transgender communities are among the groups at A systematic review by Herbst et al4 identified 29 studies highest risk for HIV infection in the United States. Using syndemic reporting biological or behavioral HIV data in transgender theory, we examine how HIV risk in transgender communities is communities, of which 22 reported HIV prevalence data on embedded in multiple co-occurring public health problems, including transgender women (or male-to-female transgenders) and poor mental health, substance use, violence and victimization, 5 reported data on transgender men (or female-to-male discrimination, and economic hardship. Although safer sex counsel- transgenders). Meta-analysis of biological data estimated ing and testing programs are essential platforms for HIV intervention, 28% HIV seroprevalence in transgender women, with these modalities alone may be insufficient in reducing new infections. extremely high seroprevalence (56%) in African Americans. Multicomponent interventions are necessary to respond to the Meta-analysis of self-report data estimated 12% HIV and 21% complex interacting syndemic factors that cumulatively determine prevalence of any other sexually transmitted infection (STI) in HIV vulnerability in transgender individuals. transgender women; STIs commonly assessed include Key Words: transgender, HIV, syndemics gonorrhea, chlamydia, herpes, syphilis, trichomoniasis, and hepatitis B and C. Compared with biological findings, lower (J Acquir Immune Defic Syndr 2010;55:S91–S93) self-reported HIV prevalence might reflect unknown infection or unwillingness to disclose. Two studies reported HIV incidence in transgender women: 7.8 infections per 100 person-years in a San Francisco study and 3.4 infections per 100 person-years in a Los Angeles study.5,6 Meta-analysis of data from transgender men was not conducted; only 1 study in transgender men reported HIV seroprevalence (2%),7 and INTRODUCTION 4 studies in transgender men found low self-reported HIV Transgender is an umbrella term referring to the infection (0%–3%).4 Another study of transgender women in population of individuals whose gender identity differs from New York city, released after the meta-analysis by Herbst et al, the gender assigned at birth. Researchers have described a state found a high HIV seroprevalence in African American and of emergency related to HIV in the transgender community.1–3 Hispanic (22% and 36%) transgender women (48% and 50%, To date, there exist no efficacious HIV prevention inter- respectively) compared with white transgender women (4%).8 ventions for transgender individuals. The lack of research High prevalence of syphilis and hepatitis B were also detected reflects, in part, the challenges in studying this population. For in African American (15% and 36%) and Hispanic (36% and example, no reliable estimates exist of the size of the 22%) (22% and 36%) transgender women. transgender population, many transgender individuals wish to Multiple HIV behavioral risk factors have been identified, be hidden, and assessing transgender identity and gender based mostly on studies of transgender women. Risk behaviors history remains difficult.3 We argue that the lack of progress in for transgender women include multiple partners, unprotected HIV prevention for transgender people is also due to the receptive anal intercourse, commercial sex, sex under the complexity of the epidemic in this community, attributable to influence of alcohol and drugs, and needle use for injecting multiple co-occurring public health problems that determine drugs and gender-related hormones or silicone.7,9,10 In several their HIV risk. studies, African American and Hispanic transgender women report greater risk behaviors compared with white and Asian and Pacific Islander transgender women.4 Few studies have From the *Department of Community Health, Brown University, Providence, examined behavioral risk factors in transgender men, but there RI; and †Public Health Institute, Oakland, CA. is emerging evidence of unprotected penetrative sex between Presented at the Domestic Prevention Working Group, 2010 HIV Prevention 11 Trials Network meeting, March 4–5, 2010, New York, NY. transgender men and biological men. Supported by National Institutes of Health/National Institute on Drug Abuse grant R01DA018621 (D.O.). The authors have no funding or conflicts of interest to disclose. HIV-Related Syndemics in Correspondence to: Don Operario, PhD, Department of Community Health, Brown University, 121 S Main Street, 5th Floor, Providence RI 02906 Transgender Communities (e-mail: [email protected]). Syndemic theory has been a useful framework for under- Copyright Ó 2010 by Lippincott Williams & Wilkins standing the determinants of HIV disparities in high-risk

J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 www.jaids.com | S91 Operario and Nemoto J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 populations.12,13 Syndemic refers to the concentration within Some individuals have a difficult time passing due to physical a specific population of multiple co-occurring epidemics characteristics that call attention to their transgender status, interacting and reinforcing one another and ultimately giving and these individuals may be more prone to stigma and rise to other health problems.14 Singer et al have described how discrimination and to ensuing syndemics of mental health, epidemics of substance abuse and violence facilitated a sub- substance use, and violence that facilitate HIV risk. sequent HIV epidemic in inner city Hartford,15 and Stall et al16 have examined the epidemics of substance use, mental health, Social and Structural Conditions for Syndemics and childhood abuse in men who have sex with men as in Transgender Communities interacting drivers of the domestic HIV epidemic in men who As noted, the syndemic dynamics described here reflect have sex with men. Similarly, data from studies of transgender social and structural conditions that govern the treatment of populations in the United States reveal syndemic dynamics transgender individuals. Because sex and gender are basic that facilitate sexual risk behaviors and HIV transmission. organizational principals in most societies, including contem- Mental health problems are frequently reported in porary US society, deviation from prescribed sex and gender transgender communities. Studies have shown high rates of dichotomies is reprimanded at nearly every level of social life. depression, emotional distress, loneliness, and social isolation Consequently, transgender individuals experience a develop- in transgender populations.3,10 Results from meta-analysis mental life course characterized by cumulative stigma, revealed that 54% of transgender individuals surveyed had alienation, and internalized stress.23,24 Studies of transgender suicidal thoughts and 31% had attempted suicide.4 Mental youth have documented unsupportive and frequently hostile health problems can undermine motivations to practice safer family members and peers.21,22 This adversity extends and sex behavior and can increase motivations for engaging in augments into adulthood, manifesting in explicit discrimina- unprotected sex as a means for cognitive escape, emotional tion, denial of opportunities, exposure to violence, and release, and feelings of love and intimacy.17–19 frequently unresponsive legal systems. Structural inequalities High rates of alcohol and drug use in transgender for transgender individuals are particularly salient in the health communities, including injection drug use (IDU), are also care system. Multiple studies report, among transgender reported. In a San Francisco study, 34% of transgender women communities, limited access to health services, inappropriate reported lifetime IDU and 18% reported past 6-month IDU, or nonexistent care protocols and facilities for transgender and 18% of transgender men reported lifetime IDU and 4% clients, and untrained and often discriminatory health reported past 6-month IDU.7 Other drugs commonly used providers and staff.25,26 include marijuana, cocaine, crack, and methamphetamine, although within-group differences are observed. For example, Not Just Testing and Condoms: Need for in San Francisco, cocaine and crack use were higher among Multicomponent Interventions African American transgender women than among trans- Recognition of multiple co-occurring epidemics and gender women in other ethnic groups, and methamphetamine challenging social and structural conditions call into question use was higher in Asian and Pacific Islander transgender the feasibility of standard HIV prevention approaches for women.9 Substance use before or during sex compromises addressing the needs of transgender women and men. cognitive or behavioral abilities to use condoms and is an Dominant paradigms in HIV prevention include testing and independent predictor of unprotected receptive anal sex in counseling, informational and motivational training to transgender women.9 improve condom use and encourage partner reduction, and Transgender women and men may be at an increased other approaches that focus on safer sex as the primary or sole risk for violence and victimization, including physical and outcome. Syndemic analysis of the determinants of HIV risk in sexual abuse. A national review of data from survey research, transgender communities—particularly in transgender women, police reports, and social service records highlights multiple who have been the focus of most previous studies reviewed forms of violence that transgender people experience here—reveals that more complex prevention approaches are throughout their lifetimes.20 Abuse may begin in adolescence warranted. Indeed, previous research has suggested that or childhood when transgender individuals begin to express transgender women are highly aware of their HIV-related atypical gender characteristics.21,22 Violence and victimization sexual risk behaviors but that HIV prevention is simply a low directly and indirectly lead to HIV risk. Forced sex confers priority compared with other immediate concerns.19 likelihood of exposure for HIV/STI transmission, and other Multicomponent interventions are necessary to mitigate forms of physical violence can contribute to mental health the HIV syndemic dynamics in transgender communities. problems and substance use, which increase the likelihood for Several recent articles have called for the development of sexual risk behaviors. multicomponent HIV interventions that recognize and address Studies have reported high levels of poverty, un- interactions among, for example, substance use, mental health, employment, and homelessness in transgender women and poverty, and HIV risk.27 Ickovics28 has described the benefit of men.3,4,10 These outcomes likely stem from general stigma and ‘‘bundling’’ HIV prevention services with other health/social job and housing discrimination against individuals whose services to achieve meaningful improvements in public health. transgender identity is exposed. Indeed, a goal for many In order for multiple services to form a meaningful bundle, transgender women and men is the ability to ‘‘pass’’ and re- they must be complementary, synergistic in their health ceive affirmation as their desired gender,10,19 which manifests benefit, cost-effective, and accepted by target audiences. HIV in the capacity to blend into mainstream society unnoticed. testing and behavioral–motivational risk reduction counseling

S92 | www.jaids.com q 2010 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Transgender HIV Syndemics offer platforms for bundling other intervention foci and sex with nontransgender men. J Assoc Nurses AIDS Care. 2009;20:398– modalities, which might include transgender support groups, 410. doi:10.1016/j.jana.2009.06.001. 12. Mustanski B, Garofalo R, Herrick A, et al. Psychosocial health problems brief substance use counseling and treatment referrals, brief increase risk for HIV among urban men who have sex with men: mental health counseling and referrals, life skills coaching and preliminary evidence of a syndemic in need of attention. Ann Behav Med. training, and other programs that correspond to recognized 2007;34:37–45. PMCID: PMC2219199. transgender syndemic dynamics. Intervention components 13. Freudenberg N, Fahs M, Galea S, et al. The impact of New York City’s must also consider developmental trajectories in transgender 1975 fiscal crisis on the tuberculosis, HIV, and homicide syndemic. Am J Public Health. 2006;96:424–434. doi:10.2105/AJPH.2005.063511. identity, including the needs of adolescents and young adults, 14. Singer M, Clair S. Syndemics and public health: reconceptualizing and prevention needs that might differ according to gender disease in bio-social context. Med Anthropol Q. 2003;17:423–441. doi: transformation procedures. Enhancing sensitive and appropri- 10.1525/maq.2003.17.4.423. ate channels of care and establishing linkages between care 15. Singer MC, Erickson PI, Badiane L, et al. Syndemics, sex and the city: understanding sexually transmitted diseases in social and cultural context. services are essential to this multicomponent approach. Soc Sci Med. 2006;63:2010–2021. doi:10.1016/j.socscimed.2006.05.012. The science of multicomponent HIV prevention in- 16. Stall R, Friedman MS, Catania JA. Interacting epidemics and gay men’s tervention for transgender and other high-risk populations is health: a theory of syndemic production among urban gay men. In: still in its infancy. Condoms and testing alone cannot reduce Wolitski RJ, Stall R, Valdiserri RO, eds. Unequal Opportunity: Health the burden of HIV infection and AIDS in transgender Disparities Affecting Gay and Bisexual Men in the United States.New York, NY: Oxford University Press; 2007:251–274. individuals and other high-risk populations. Major efforts 17. Bockting WO, Robinson BE, Rosser BR. Transgender HIV prevention: must be invested in developing and testing complex a qualitative needs assessment. AIDS Care. 1998;10:505–525. doi: population-focused interventions.27 For transgender commu- 10.1080/09540129850124028. nities, the capacity to respond to HIV syndemic dynamics can 18. Melendez RM, Pinto R. ‘‘It’s a really hard life’’: love, gender and HIV risk 2 among male-to-female transgender persons. Cult Health Sex. 2007;9:233– be a matter of life and death. 245. doi:10.1080/13691050601065909. 19. Nemoto T, Operario D, Keatley J, et al. Social context of HIV risk behaviours among male-to-female transgenders of color. AIDS Care. REFERENCES 2004;16:724–735. doi:10.1080/09540120413331269567. 1. Lombardi E. Enhancing transgender health care. Am J Public Health. 20. Stotzer RL. Violence against transgender people: a review of United 2001;91:869–872. PMCID: PMC1446458. States data. Aggress Violent Behav. 2009;14:170–179. doi:10.1016/ 2. Feinberg L. Trans health crisis: for us it’s life or death. Am J Public Health. j.avb.2009.01.006. 2001;91:897–900. PMCID: PMC1446107. 21. Garofalo R, Deleon J, Osmer E, et al. Overlooked, misunderstood and at- 3. De Santis JP. HIV infection risk factors among male-to-female risk: exploring the lives and HIV risk of ethnic minority male-to-female transgender persons: a review of the literature. J Assoc Nurses AIDS transgender youth. J Adolesc Health. 2006;38:230–236. doi:10.1016/ Care. 2009;20:362–372. doi:10.1016/j.jana.2009.06.005. j.jadohealth.2005.03.023. 4. Herbst JH, Jacobs ED, Finlayson TJ, et al; the HIV/AIDS Prevention 22. Stieglitz KA. Development, risk, and resilience of transgender youth. Research Synthesis Team. Estimating HIV prevalence and risk behaviors J Assoc Nurses AIDS Care. 2010;21:192–206. doi:10.1016/j.jana. of transgender persons in the United States: a systematic review. AIDS 2009.08.004. Behav. 2008;12:1–17. doi:10.1007/s10461-007-9299-3. 23. Morgan SW, Stevens PE. Transgender identity development as 5. Kellogg TA, Clements-Nolle K, Dilley J, et al. Incidence of human represented by a group of female-to-male transgendered adults. Issues immunodeficiency virus among male-to-female transgendered persons in Ment Health Nurs. 2008;29:585–599. doi:10.1080/01612840802048782. San Francisco. J Acquir Immune Defic Syndr. 2001;28:380–384. 24. Bith-Melander P, Sheoran B, Sheth L, et al. Understanding sociocultural 6. Simon PA, Reback CJ, Bemis CC. HIV prevalence and incidence among and psychological factors affecting transgender people of color in San male-to-female transsexuals receiving HIV prevention services in Los Francisco. J Assoc Nurses AIDS Care. 2010;21:207–220. doi:10.1016/ Angeles County [research letters]. AIDS. 2000;14:2953–2955. j.jana.2010.01.008. 7. Clements-Nolle K, Marx R, Guzman R, et al. HIV prevalence, risk 25. Bauer GR, Hammond R, Travers R, et al. ‘‘I don’t think this is theoretical; behaviors, health care use, and mental health status of transgender this is our lives’’: how erasure impacts health care for transgender people. persons: implications for public health intervention. Am J Public Health. J Assoc Nurses AIDS Care. 2009;20:348–361. doi:10.1016/j.jana. 2001;91:915–921. PMCID: PMC1446468. 2009.07.004. 8. Nuttbrock L, Hwahng S, Bockting W, et al. Lifetime risk factors for HIV/ 26. Sanchez NF, Sanchez JP,Danoff A.Health care utilization, barriers to care, sexually transmitted infections among male-to-female transgender and hormone usage among male-to-female transgender persons in New persons. J Acquir Immune Defic Syndr. 2009;52:417–421. doi:10.1097/ York city. Am J Public Health. 2009;99:713–719. doi:10.2105/ QAI.0b013e3181ab6ed8. AJPH.2007.13 2035. 9. Nemoto T, Operario D, Keatley J, et al. HIV risk behaviors among male- 27. Rotheram-Borus MJ, Swendeman D, Chovnick G. The past, present, and to-female transgender persons of color in San Francisco. Am J Public future of HIV prevention: integrating behavioral, biomedical, and Health. 2004;94:1193–1199. PMCID: PMC1448420. structural intervention strategies for the next generation of HIV 10. Kosenko KA. Contextual influences on sexual risk-taking in the prevention. Annu Rev Clin Psychol. 2009;5:143–167. PMCID: transgender community. J Sex Res. 2010;24:1–12. PMC2864227. 11. Sevelius J. ‘‘There’s no pamphlet for the kind of sex I have’’: HIV-related 28. Ickovics JR. ‘‘Bundling’’ HIV prevention: integrating services to promote risk factors and protective behaviors among transgender men who have synergistic gain. Prev Med. 2008;46;222–225. PMCID: PMC2276879.

q 2010 Lippincott Williams & Wilkins www.jaids.com | S93 SUPPLEMENT ARTICLE

HIV Prevention and Care in the Digital Age Mary Ann Chiasson, DrPH,*† Sabina Hirshfield, PhD,* and Cornelis Rietmeijer, MD, PhD‡

professionally. The transformation of the Internet from Web 1.0 Objectives: To describe the technologic advances in the digital as a unidirectional information source to the interactive and media, including computers, mobile phones, and the Internet, that participatory Web 2.0 has important implications for HIV have greatly expanded opportunities to deliver evidence-based HIV transmission, HIV education and prevention, and medical education, prevention, and treatment programs. management of HIV. The Internet’s borderless geographic and demographic social networks and equally limitless possibilities Methods: This article examines the use of digital media in the for interventions have the potential to change both community United States and its potential role in HIV prevention and care. norms and individual behavior cost-effectively. Results: Although the ‘‘digital divide’’ is shrinking, access varies by age, race/ethnicity, and education. The Internet is an important medium for delivering universal and targeted HIV education and DISCUSSION prevention, especially for men who have sex with men, who report Who’s Online going online to seek health information online and for social and In 2010, most adults (77%) and nearly all teenagers sexual networking. Online and off-line behavioral interventions using (93%) in the United States are online.1,2 Overall, 41% of digital media range from computerized multimedia interventions that Americans use social networking sites with the greatest use take into account individual behaviors to brief untailored video (75%) reported by those between 18 and 29 years of age.1 This interventions. Numerous Web sites facilitate access to care by group also leads in the use of mobile phones (94%) and providing a variety of services, including location of and linkage texting: 88% text, and of these, 80% texted a median of 20 to HIV testing and treatment sites. HIV treatment and adherence times during the past 24 hours.1 Yet even within this group, programs that use online medical records text messaging, paging, and there are variations by race/ethnicity and education, despite the tablet computer–based counseling tools are also being developed. high usage levels. Whites are more likely to use the Internet Conclusions: HIV prevention and care programs using digital (95%) than blacks (91%) or Hispanics (73%), and those with some college (96%) are more likely to be online than those media have great potential to cost-effectively meet the complex needs 1 of diverse and often underserved populations living with or at high without (83%), suggesting that the digital divide is closing. risk of HIV. However, disparities are still seen among 18–29 year olds who create profiles on a social networking site: whites (83%), Key Words: HIV,Internet, prevention, sexually transmitted infection, blacks (71%), Hispanics (52%), and those with some college computer technology, MSM (86%), compared with only 59% of those with no college.1 The (J Acquir Immune Defic Syndr 2010;55:S94–S97) limited data available on Internet access among those living with HIV show similar disparities by race/ethnicity and education but far lower overall rates. Only about the half report INTRODUCTION ever using the Internet (P. Messeri, MD, personal communi- cation, June 21, 2010).3 Not surprisingly, active drug use, Technologic advances in digital media, including com- poverty, and homelessness are associated with very low rates puters, mobile phones, and the Internet, have revolutionized of Internet access4; text messaging may be an effective way to the way we communicate with each other, both personally and contact such difficult-to-reach populations.5 From the *Research and Evaluation, Public Health Solutions, New York, NY; Seeking Sex Online and HIV Risk †Division of Infectious Diseases, Columbia University Medical Center, New York, NY; and ‡Internet and STD Center of Excellence, Denver Most studies of the relationship between Internet use Public Health Department, Denver, CO. and sexual behavior have focused on gay, bisexual, and other Supported in part by the Centers for Disease Control and Prevention and the men who have sex with men (MSM) because they account for Association for Prevention Teaching and Research Cooperative Agree- the majority of newly reported HIV-infected population in the ment No. 5U50CD300860-21, Project TS-1400. United States6 and frequently seek sexual partners online.7 Presented in part at the CDC National STD Prevention Conference (C.R.), March 8–11, 2010, Atlanta, GA; CDC National HIV Prevention Most population-based studies do not compare the prevalence 8 Conference (S.H.), August 23–26, 2009, Atlanta, GA; CDC National of seeking sex online by gender and sexual orientation. HIV Prevention Conference (M.A.C.), December 2–5, 2007, Atlanta, GA. Community-based studies have found that MSM are more The authors report no conflicts of interest to disclose. likely to seek sex partners online than gay women and hetero- Correspondence to: Mary Ann Chiasson, DrPH, Research and Evaluation, 9–12 Public Health Solutions, 220 Church Street, 5th floor, New York, NY sexual men and women. High-risk sexual behavior observed 10013 (e-mail: [email protected]). in online studies largely reflects the risk-taking profile of Copyright Ó 2010 by Lippincott Williams & Wilkins individuals who choose to seek sex partners both online and

S94 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 HIV Prevention and Care in the Digital Age off-line and is not associated with the Internet per se.10,12–17 partner notification programs have been developed,38 although (www.manhunt.net) and Adam4Adam (www. the effectiveness of the latter has not been demonstrated.39,40 adam4adam.com) are 2 of the largest Web sites for MSM Self-collection kits for mail-in testing for HIV41 and seeking sex partners in the United States and abroad. Manhunt a number of other STIs and home test kits can be purchased members can send e-mails, text messages, and instant video online, although the cost of kits from commercial sites can be messages to potential partners. Adam4Adam members can high.42 Self-collection kits for mail-in STI testing are also locate potential partners through ‘‘Plan-a-Trip’’ before they available from public health Web sites in some geographic reach their destination. MSM who meet sex partners online areas.43 HIVand STI self-collection kits for mail-in testing and report more sex partners,18–21 sex with casual partners,18–21 and home testing are appealing to many for reasons of both privacy more unprotected anal intercourse,22 although their behavior is and convenience.41,44,45 However, a recent study found that similarly risky with partners met off-line.14–16,23 Thus, those consumer services available from commercial Web sites may meeting partners online can expand their sexual networks, be poor and testing accuracy may be variable: Although mail- thereby increasing the potential for transmission of HIV and in specimen test results were highly accurate, home tests were other sexually transmitted infections (STIs).7,24,25 often inaccurate.42 Improving HIV Treatment and Adherence Health Education Online The Internet and development of Web-based applica- Many Americans search for health information online, tions have had a major impact on medical record keeping and with 75% of all adults and 28% of all teens online reporting access to medical records by patients. Web-based electronic this activity.2 At best, the Internet may provide access to the records can be shared easily by all who need access, including most current and most scientifically accurate information medical care providers and the patient. Using industry- available on all aspects of HIV/AIDS, from risk factors for standard software to protect the confidentiality of information, transmission and acquisition to early to Web-based electronic medical records offer the timely and HIV testing and treatment. There are numerous sites targeting active sharing of test results. The sharing of STI test results both professional and lay audiences. Two recently published online is a promising development that not only enhances studies provide comprehensive assessments of national and patients’ access to their test results but also may improve international HIV/AIDS resources online for clinicians and treatment outcomes.31,36 Likewise, the provision of HIV viral researchers that include sources for treatment guidelines, 26,27 load and CD4 test results online, including trends over time, disease management, and continuing medical education. could provide the patients with important tools in managing Web sites such as The Body (www.thebody.com) and their illness. Because adherence to antiretroviral treatment is POZ (www.poz.com) are dedicated to education and clinical critically important in adequately suppressing HIV in infected information on HIV/AIDS testing, diagnosis, treatment, and individuals and preventing the emergence of resistant HIV prevention for consumers and include access to experts, forums, strains, there has been considerable interest in developing blogs, and other digital media. In addition to traditional adherence interventions. One such intervention used an informational Web sites, a number of interactive safer sex Internet-based paging system to improve adherence among educational Web sites, many targeted to teens,28 and non- patients who had failed more traditional off-line adherence traditional sites, such as ‘‘Kicesie’s Sex Ed—What They Don’t systems46; another piloted the use of a tablet computer–based Teach You In School’’ on YouTube,29 have been developed. For counseling tool to improve adherence and to reduce secondary young gay men, the Internet fills an important unmet need for transmission of HIV in an HIV-infected population with mixed sexual health education and support during the coming out computer use experience.47 process, although it can also expose them to homophobic 30 messages. Despite this ready access to information, separating Behavioral Interventions Off-line and Online disinformation from scientific fact can be difficult even for Using Digital Media the most experienced searcher. Unsurprisingly, therefore, the HIV/STI behavioral interventions using digital media Internet is also a fertile field for AIDS denialists (those who have been developed in many forms, ranging from complex deny that HIV causes AIDS) and proponents of unproven computer-tailored multimedia interventions that take into treatments for HIV. account individual behaviors and stages of change to brief untailored video interventions.28,48–50 Interventions using digital Expanding Access to Care media are appealing because they can be delivered consistently The Internet can facilitate the diagnosis and treatment of either alone or in combination with more traditional counseling HIV and other STIs through Web sites that provide education modalities and in a variety of settings, either in person via and information about the location of community-based computer or video in clinics, social service agencies, and testing and clinic-based HIV and STI services (eg, www. schools51–57 or electronically via text messaging,58 handheld hivtest.org). Web-based,31–33 text,34 and instant messaging35 computers,2 or online.59–68 Effective HIV prevention interven- programs have also been developed to educate and encourage tions that use digital media are likely to be highly cost-effective testing through clinic referrals, preprinted laboratory requisi- because they are easily replicated after development, require tion slips, and provision of online access to STI test results.36 minimal staffing, and have unlimited geographic reach.69 In addition, Internet sex partner notification for STI exposure The development of online HIV prevention interven- is proving to be acceptable to MSM,37 and Internet-based tions of proven efficacy is an area of intensive research, q 2010 Lippincott Williams & Wilkins www.jaids.com | S95 Chiasson et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 although it lags far behind online interventions for smoking,70 10. Bolding G, Davis M, Hart G, et al. Heterosexual men and women who obesity,71 and mental72 and physical health problems.73 Of the seek sex through the Internet. Int J STD AIDS. 2006;17:530–534. 11. Rietmeijer C, Bull S, McFarlane M, et al. Risks and benefits of the Internet 7 published randomized trials of intensive individual-level for populations at risk for sexually transmitted infections (STIs): results of online HIV behavioral interventions primarily targeted to an STI clinic survey. Sex Transm Dis. 2003;30:15–19. MSM, 5 have demonstrated some reduction in 1 or more HIV 12. McFarlane M, Kachur R, Bull S, et al. Women, the Internet, and sexually risk behaviors,60–62 an increase in HIV testing,63 or short-term transmitted infections. J Womens Health (Larchmt). 2004;13:689–694. increases in knowledge, self-efficacy, and outcome expectan- 13. Al-Tayyib AA, McFarlane M, Kachur R, et al. Finding sex partners on the 64 65,66 Internet: what is the risk for sexually transmitted infections? Sex Transm cies. Two trials reported no changes in behavior, Infect. 2009;85:216–220. doi:10.1136/sti.2008.032631. attributable to a variety of factors, including loss to follow- 14. Chiasson MA, Hirshfield S, Remien RH, et al. A comparison of on-line up, participant fatigue, technical problems, Internet connection and off-line sexual risk in men who have sex with men: an event-based speed, single-session intervention, and content not tailored to on-line survey. J Acquir Immune Defic Syndr. 2007;44:235–243. all outcomes or study populations. Preliminary efficacy studies 15. Mustanski BS. Are sexual partners met online associated with HIV/STI 2 risk behaviours? Retrospective and daily diary data in conflict. AIDS Care. using soap opera video delivery to handheld computers, 2007;19:822–827. online dramatic video,59,67 chat room,68 and mobile phone 16. Bolding G, Davis M, Hart G, et al. Gay men who look for sex on the texting58 interventions have also been published in addition to Internet: is there more HIV/STI risk with online partners? AIDS. 2005;19: findings from a brief physician e-mail intervention to reduce 961–968. 17. Hirshfield S, Remien RH, Humberstone M, et al. Substance use and high- at-risk adolescents’ display of risk behavior on a social risk sex among men who have sex with men: a national online study in the 74 networking Web site. USA. AIDS Care. 2004;16:1036–1047. 18. Taylor M, Aynalem G, Smith L, et al. Correlates of Internet use to meet sex partners among men who have sex with men diagnosed with early FUTURE DIRECTIONS syphilis in Los Angeles County. Sex Transm Dis. 2004;31:552–556. 19. Rosser BR, Miner MH, Bockting WO, et al. HIV risk and the Internet: A new generation of HIV prevention interventions is results of the Men’s INTernet Sex (MINTS) Study. AIDS Behav. 2009;13: needed to stem the tide of infections in the United States. 746–756. doi:10.1007/s10461-008-9399-8. Digital media are increasingly being used in all aspects of HIV 20. Horvath KJ, Rosser BR, Remafedi G. Sexual risk taking among young prevention and care to meet the complex needs of diverse Internet-using men who have sex with men. Am J Public Health. 2008;98: 75 1059–1067. and often underserved, vulnerable populations worldwide. 21. Rosser B, Oakes J, Horvath K, et al. HIV sexual risk behavior by men who Effective evidence-based approaches using digital media have use the Internet to seek sex with men: results of the Men’s INTernet the potential to play an important role in achieving the goals of Sex Study-II (MINTS-II) AIDS Behav. 2009;13:488–498. doi:10.1007/ the National HIV/AIDS Strategy for the United States76 in the s10461-009-9524-3. 22. Hooper S, Rosser BR, Horvath KJ, et al. An online needs assessment of future; translation of existing evidence-based interventions a virtual community: what men who use the Internet to seek sex with men into digital media formats and development of new effective want in Internet-based HIV prevention. AIDS Behav. 2008;12:867–875. interventions that capitalize on the technologic advances in doi:10.1007/s10461-008-9373-5. digital media are both a priority. 23. Rhodes S, DiClement R, Cecil H, et al. Risk among men who have sex with men in the United States: a comparison of an Internet sample and a conventional outreach sample. AIDS Educ Prev. 2002;14:41–50. REFERENCES 24. McFarlane M, Bull SS, Rietmeijer CA. The Internet as a newly emerging risk 1. Taylor P, Keeter S, eds. Millennials: A Portrait of Generation Next: environment for sexually transmitted diseases. JAMA. 2000;284:443–446. Confident. Connected. Open to Change. Washington, DC: Pew Research 25. Klausner J, Wolf W, Fischer-Ponce L, et al. Tracing a syphilis outbreak Center; 2010:25–38. Available at: http://pewsocialtrends.org/assets/pdf/ through cyberspace. JAMA. 2000;284:447–449. millennials-confident-connected-open-to-change.pdf. Accessed August 26. Armstrong WS, del Rio C. HIV-associated resources on the internet. Top 10, 2010. HIV Med. 2009;17:151–162. 2. Jones S, Fox S. Generations Online in 2009. Pew Internet Project Data 27. Krakower D, Kwan CK, Yassa DS, et al. iAIDS: HIV-related Internet Memo. Washington, DC: Pew Research Center; 2009. Available at: http:// resources for the practicing clinician. Clin Infect Dis. 2010;51:813–822. www.pewinternet.org/Reports/2009/Generations-Online-in-2009.aspx. 28. Noar SM, Clark A, Cole C, et al. Review of interactive safer sex Web sites: Accessed July 8, 2009. practice and potential. Health Commun. 2006;20:233–241. 3. Shacham E, Stamm K, Overton ET. Can you hear me now? Limited use of 29. Rietmeijer CA, McFarlane M. Web 2.0 and beyond: risks for sexually technology among an urban HIV-infected cohort. AIDS Care. 2009;21: transmitted infections and opportunities for prevention. Curr Opin Infect 1000–1006. doi:10.1007/s10461-009-9652-9. Dis. 2009;22:67–71. doi:10.1097/QCO.0b013e328320a871. 4. Redpath DP, Reynolds GL, Jaffe A, et al. Internet access and use among 30. Mustanski B, Lyons T, Garcia SC. Internet use and sexual health of young homeless and indigent drug users in Long Beach, California. Cyberp- men who have sex with men: a mixed-methods study. Arch Sex Behav. sychol Behav. 2006;9:548–551. Epub ahead of print. doi:10.1007/s10508-009-9596-1. 5. Maher JE, Pranian K, Drach L, et al. Using text messaging to contact 31. Koekenbier RH, Davidovich U, van Leent EJ, et al. Online-mediated difficult-to-reach study participants. Am J Public Health. 2010;100: syphilis testing: feasibility, efficacy, and usage. Sex Transm Dis. 2008;35: 969–970. doi:10.2105/AJPH.2009.188391. 764–769. doi:10.1097/OLQ.0b013e31816fcb0a. 6. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the 32. Klausner JD, Levine DK, Kent CK. Internet-based site-specific United States. JAMA. 2008;300:520–529. interventions for syphilis prevention among gay and bisexual men. AIDS 7. Liau A, Millet G, Marks G. Meta-analytic examination of online sex- Care. 2004;16:964–970. seeking and sexual risk behavior among men who have sex with men. 33. Levine DK, Scott KC, Klausner JD. Online syphilis testing—confidential Sex Transm Dis. 2006;33:576–584. and convenient. Sex Transm Dis. 2005;32:139–141. 8. Princeton survey research associates international for the Pew Internet & 34. Levine D, McCright J, Dobkin L, et al. SEXINFO: a sexual health text American Life Project 2010. Available at: http://pewinternet.org/Reports/ messaging service for San Francisco youth. Am J Public Health. 2008;98: 2010/Mobile-Access-2010.aspx. Accessed August 10, 2010. 393–395. doi:10.2105/AJPH.2007.110767. 9. Lever J, Grov C, Royce T, et al. Searching for love in all the ‘‘Write’’ 35. Moskowitz DA, Melton D, Owczarzak J. PowerON: the use of instant message places: exploring Internet personals use by sexual orientation, gender, and counseling and the Internet to facilitate HIV/STD education and prevention. age. Int J Sex Health. 2008;20:233–246. Patient Educ Couns. 2009;77:20–26. doi:10.1016/j.pec.2009.01.002.

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36. Ling SB, Richardson DB, Mettenbrink CJ, et al. Evaluating a Web-based 57. Roye C, Silverman PP, Krauss B. A brief, low-cost, theory-based test results system at an urban STI clinic. Sex Transm Dis. 2010;37;259– intervention to promote dual method use by black and Latina female 263. doi:10.1097/OLQ.0b013e3181d3d037. adolescents: a randomized clinical trial. Health Educ Behav. 2007;34: 37. Mimiaga MJ, Tetu AM, Gortmaker S, et al. HIV and STD status among 608–621. MSM and attitudes about Internet partner notification for STD exposure. 58. Juzang I, Fortune T, Black S, et al. A pilot programme using mobile Sex Transm Dis. 2008;35:111–116. phones for HIV prevention. J Telemed Telecare. In press. 38. Levine D, Woodruff AJ, Mocello AR, et al. InSPOT: the first online STD 59. Hirshfield S, Chiasson MA, Scheinmann R, et al. Reduction in HIV partner notification system using electronic postcards. PLoS Med. 2008;5: transmission risk among HIV+ MSM in an online HIV prevention trial e213. doi:10.1371/journal.pmed.0050213. [abstract LB1-3]. Presented at: CDC National HIV Prevention Confer- 39. Kerani R, Fleming M, DeYoung B, et al. A randomized controlled trial ence; August 23-26, 2009; Atlanta, GA. comparing inSPOT and patient-delivered partner therapy to standard 60. Bull S, Pratte K, Whitesell N, et al. Effects of an Internet-based partner notification among MSM: the good, the bad, and the ugly [abstract intervention for HIV prevention: The Youthnet Trials. AIDS Behav. 2008; #91]. Presented at: 2010 National STD Prevention Conference; March 13:474–487. doi:10.1007/s10461-008-9487-9. 8–11, 2010; Atlanta, GA. 61. Carpenter KM, Stoner SA, Mikko AN, et al. Efficacy of a Web-based 40. Rietmeijer C, Westergaard B, Richardson D. Evaluation of an on-line intervention to reduce sexual risk in men who have sex with men. AIDS partner notification program [abstract #A7f]. Presented at: 2010 National Behav. 2010;14;549–557. doi:10.1007/s10461-009-9578-2. STD Prevention Conference; March 8–11, 2010; Atlanta, GA. 62. Rosser BR, Oakes JM, Konstan J, et al. Reducing HIV risk behavior of 41. Frank AP, Wandell MG, Headings MD, et al. Anonymous HIV testing MSM through persuasive computing: results of the Men’s INTernet Study using home collection and telemedicine counseling. A multicenter (MINTS–II). AIDS. 2010;24:2099–2107. evaluation. Arch Intern Med. 1997;157:309–314. 63. Blas MM, Alva IE, Carcamo CP, et al. Effect of an online video–based 42. Owens SL, Arora N, Quinn N, et al. Utilising the internet to test for intervention to increase HIV testing in men who have sex with men in sexually transmitted infections: results of a survey and accuracy testing. Peru. PLoS One. 2010;5:e10448. doi:10.1371/journal.pone.0010448. Sex Transm Infect. 2010;86:112–116. doi:10.1136/sti.2009.037226. 64. Bowen AM, Horvath K, Williams ML. A randomized control trial of 43. Gaydos CA, Dwyer K, Barnes M, et al. Internet-based screening for Internet-delivered HIV prevention targeting rural MSM. Health Educ Res. to reach non-clinic populations with mailed self- 2007;22:120–127. doi:10.1093/her/cyl057. administered vaginal swabs. Sex Transm Dis. 2006;33:451–457. 65. Bull SS, Lloyd L, Rietmeijer C, et al. Recruitment and retention of an 44. Tebb KP, Paukku MH, Pai-Dhungat MR, et al. Home STI testing: the online sample for an HIV prevention intervention targeting men who have adolescent female’s opinion. J Adolesc Health. 2004;35:462–467. sex with men: the Smart Sex Quest Project. AIDS Care. 2004;16:931–943. 45. Graseck AS, Secura GM, Allsworth JE, et al. Home screening compared 66. Lau JT, Lau M, Cheung A, et al. A randomized controlled study to with clinic-based screening for sexually transmitted infections. Obstet evaluate the efficacy of an Internet-based intervention in reducing HIV Gynecol. 2010;115:745–752. doi:10.1097/AOG.0b013e3181d4450d. risk behaviors among men who have sex with men in Hong Kong. AIDS 46. Safren SA, Hendriksen ES, Desousa N, et al. Use of an on-line pager Care. 2008;20:820–828. doi:10.1080/09540120701694048. system to increase adherence to antiretroviral medications. AIDS Care. 67. Chiasson M, Shaw FS, Humberstone M, et al. Increased HIV disclosure 2003;15:787–793. three months after an online video intervention for men who have 47. Skeels MM, Kurth A, Clausen M, et al. CARE+ user study: usability and sex with men (MSM). AIDS Care. 2009;21:1081–1089. doi:10.1080/ attitudes towards a tablet PC computer counseling tool for HIV+ men and 09540120902730013. women. AMIA Annu Symp Proc. 2006:729–733. 68. Rhodes SD, Hergenrather KC, Duncan J, et al. A pilot intervention 48. Noar SM, Black HG, Pierce LB. Efficacy of computer technology–based utilizing Internet chat rooms to prevent HIV risk behaviors among men HIV prevention interventions: a meta-analysis. AIDS. 2009;23:107–115. who have sex with men. Public Health Rep. 2010;125(Suppl 1):29–37. doi:10.1097/QAD.0b013e32831c5500. 69. Cohen DA, Wu SY, Farley TA. Comparing the cost-effectiveness of HIV 49. Lustria ML, Cortese J, Noar SM, et al. Computer-tailored health interventions prevention interventions. J Acquir Immune Defic Syndr. 2004;37: delivered over the Web: review and analysis of key components. Patient Educ 1404–1414. Couns. 2009;74:156–173. doi:10.1016/j.pec.2008.08.023. 70. Shahab L, McEwen A. Online support for smoking cessation: a systematic 50. Marsch LA, Bickel WK, Grabinski MJ. Application of interactive, review of the literature. Addiction. 2009;104:1792–1804. doi:10.1111/ computer technology to adolescent substance abuse prevention and j.1360-0443.2009.02710.x. treatment. Adolesc Med State Art Rev. 2007;18:342–356. 71. Enwald HP, Huotari ML. Preventing the obesity epidemic by second 51. O’Donnell C, O’Donnell L, Doval A, et al. Reductions in STD infections generation tailored health communication: an interdisciplinary review. subsequent to an STD clinic visit: using video-based patient education to J Med Internet Res. 2010;12:e24. doi:10.2196/jmir.1409. supplement provider interactions. Sex Transm Dis. 1998;25:161–168. 72. Spek V, Cuijpers P, Nyklicek I, et al. Internet-based cognitive behaviour 52. Rosser BR, Hatfield LA, Miner MH, et al. Effects of a behavioral therapy for symptoms of depression and anxiety: a meta–analysis. Psychol intervention to reduce serodiscordant unsafe sex among HIV positive men Med. 2007;37:319–328. doi:10.1017/S0033291706008944. who have sex with men: the Positive Connections randomized controlled trial 73. Cuijpers P, van Straten A, Andersson G. Internet-administered cognitive study. JBehavMed. 2010;33:147–158. doi:10.1007/s10865-009-9244-1. behavior therapy for health problems: a systematic review. J Behav Med. 53. Warner L, Klausner JD, Rietmeijer CA, et al. Effect of a brief video 2008;31:169–177. doi:10.1007/s10865-007-9144-1. intervention on incident infection among patients attending sexually 74. Moreno MA, Vanderstoep A, Parks MR, et al. Reducing at-risk transmitted disease clinics. PLoS Med. 2008;5:e135. doi:10.1371/ adolescents’ display of risk behavior on a social networking web site: journal.pmed.0050135. a randomized controlled pilot intervention trial. Arch Pediatr Adolesc 54. Marsch LA, Bickel WK. Efficacy of computer-based HIV/AIDS Med. 2009;163:35–41. doi:10.1001/archpediatrics.2008.502. education for injection drug users. Am J Health Behav. 2004;28:316–327. 75. Swendeman D, Rotheram-Borus MJ. Innovation in sexually transmitted 55. Chen HT, Grimley DM, Waithaka Y, et al. A process evaluation of the disease and HIV prevention: Internet and mobile phone delivery vehicles implementation of a computer-based, health provider–delivered HIV- for global diffusion. Curr Opin Psychiatry. 2010;23:139–144. doi: prevention intervention for HIV-positive men who have sex with men in 10.1097/YCO.0b013e328336656a. the primary care setting. AIDS Care. 2008;20:51–60. 76. The White House Office of National AIDS Policy. National HIV/AIDS 56. Lightfoot M, Comulada WS, Stover G. Computerized HIV preventive Strategy for the United States. Washington, DC: The White House; 2010. intervention for adolescents: indications of efficacy. Am J Public Health. Available at: http://www.whitehouse.gov/sites/default/files/uploads/ 2007;97:1027–1030. NHAS.pdf. Accessed August 10, 2010.

q 2010 Lippincott Williams & Wilkins www.jaids.com | S97 SUPPLEMENT ARTICLE

Couple-Based HIV Prevention in the United States: Advantages, Gaps, and Future Directions Nabila El-Bassel, DSW,* Louisa Gilbert, PhD,* Susan Witte, PhD,* Elwin Wu, PhD,* Tim Hunt, MSW,* and Robert H. Remien, PhD†

individual or group interventions, neglecting the critical role Abstract: This article presents an overview of couple-based HIV partners may play in transmission.2–4 Among both hetero- prevention research to date, advantages of using and core components sexuals and MSM, sexual transmission of HIV occurs most of couple-based interventions, gaps in the current understanding of frequently in the context of intimate relationships,5,6 a fact that couple-based HIV prevention, status of dissemination research and underscores the need for couple-based HIV prevention (ie, the transportability of effective couple-based HIV prevention and involving both intimate sex partners in the HIV intervention). treatment to real-world settings, and recommendations for future A systematic review of couple-based HIV studies found directions in couple-based prevention and treatment. Couple-based that couple-based approaches are generally efficacious in studies conducted among several populations—heterosexuals, men promoting safer sex behaviors.7 Compared with individual- who have sex with men, and drug users—reported in the research level approaches, couple-based interventions are more literature were reviewed. Commonalities and limitations were noted efficacious in promoting HIV counseling and testing,7,8 in customary focus areas of the couple-based approaches: sexual and supporting medication adherence among HIV-infected indi- drug risk reduction, HIV testing behaviors, adherence to HIV viduals in serodiscordant relationships,9 and improving treatment, and prevention of mother-to-child transmission. Couple- adherence to treatment regimens for preventing mother- based intervention strategies have been rigorously tested and are to-child transmission.10,11 a valuable addition to the arsenal of HIV prevention strategies. The few couple-based HIV interventions conducted in Immediate needs and opportunities include couple-based intervention the United States have mostly focused on reducing unsafe sex strategies for prevention of HIV and other sexually transmitted or improving adherence to HIV medication. Most studies infections among serodiscordant couples, couples who do not know conducted internationally have focused on voluntary counsel- their HIV status, and couples in whom both partners are HIV negative ing and testing or prevention of mother-to-child transmission but at risk of HIV infection. There is a particular need to develop of HIV.7 All but 2 couple-based studies in the United States couple-based intervention strategies for men who have sex with men have been conducted with heterosexual men and women.7 This and for drug-involved couples. article presents the advantages and challenges of couple-based Key Words: HIV/AIDS, couples, prevention approaches, describes core components included in the couple-based studies, highlights the state of science of (J Acquir Immune Defic Syndr 2010;55:S98–S101) couple-based HIV research in the United States and the state of dissemination of these approaches to real-world settings, and discusses future directions that may improve couple-based HIV research in the United States. INTRODUCTION Although a 2008 surveillance report by the Centers for Disease Control and Prevention indicates that 86% of new DISCUSSION HIV cases in the United States were attributed to sexual Advantages and Challenges of Couple-Based transmission, either through men who have sex with men HIV Prevention (MSM; 54%) or heterosexual contact (32%), and although the The literature identifies several advantages of couple- proportion of new HIV cases attributed to sexual transmission 1 based approaches. They provide an opportunity for the 2 has steadily increased since 2005, most HIV prevention members of the couple to recognize their mutual responsibility efforts in the United States have continued to focus on for protecting each other from HIV transmission and to work together to stay healthy.12–14 Couple-based approaches accentuate the relationship’s context (ie, commitment, love, From the *Social Intervention Group, School of Social Work, Columbia University, New York, NY; and †HIV Center for Clinical and Behavioral trust) and its connection to HIV acquisition, and then, they Studies, New York State Psychiatric Institute and Columbia University, redirect attention to the value of the couple’s relationship and New York, NY. the power of the dyad in behavior change.12–14 A safe The authors have no funding or conflicts of interest to disclose. environment is created that fosters discussion of sensitive or Correspondence to: Nabila El-Bassel, DSW, Columbia University School of Social Work, 1255 Amsterdam Avenue, New York, NY 10027 (e-mail: taboo topics (eg, sexual concurrency, power imbalances in the [email protected]). relationship, couple’s sexual preferences, and sexual coercion). Copyright Ó 2010 by Lippincott Williams & Wilkins A couple-based modality allows the pair to learn together,

S98 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Couple-Based HIV Prevention in vivo with a third party (a facilitator), skills in couple infected partner and thus the risk of HIV transmission.9,20 Core communication, negotiation, problem solving, and couple goal components of interventions to promote adherence include setting as well as technical skills in condom use. Joint enhancing a couple’s commitment to maintain a steady supply processing with the facilitator promotes accountability and of medications, helping to identify and resolve ongoing increases commitment to change.12–15 barriers to adherence, improving communication and mutual caretaking, promoting sexual risk reduction skills, and Core Components of Couple-Based HIV encouraging regular HIV testing for uninfected partners. In Prevention in the United States prevention of mother-to-child transmission interventions, There is a notable heterogeneity in HIV intervention couple sessions also focus on HIV testing for the male partner.10 content in couple-based studies.7 Most studies explore the knowledge of HIV and sexually transmitted infections (STIs), Gaps in the Science of Couple-Based Research technical skills in condom use, couple skills in communication Since the HIV epidemic began, only 6 couple-based and negotiation as well as problem solving and goal setting; studies have been conducted in the United States.9,15,17,18,21,22 couple power imbalances associated with sexual decision Six of these focused on sexual risk reduction; 1 included both making7, and ways to promote and maintain a healthy relation- sexual risk reduction and adherence to antiretroviral therapy, ship. Other content of HIV interventions addresses couple HIV where HIV prevention was incorporated into treatment and counseling and testing, family planning, a review of cultural care.9 Two included MSM,9,18 and of these, 1 was conducted values to reinforce commitment to protect one’s partner and with MSM who use drugs.18 None was conducted solely with community, and changing couples’ peer norms regarding safer drug-using non-MSM populations. None has focused on sex practices.7,12–15 This combination of couple-based skills primary prevention among HIV-uninfected couples who engage and intervention content are illustrated in 3 studies conducted in HIV risks or among HIV-infected seroconcordant couples.7 in the United States by the authors of this article. Existing models vary in their definition of a ‘‘couple.’’ In The project Connect, with 217 heterosexual couples, studies conducted by the authors, couples include ongoing was the first study funded by the National Institute of Mental dyadic heterosexual or same-sex relationships, which may Health of the National Institutes of Health to test a relationship- include but are not limited to relationships between spouses, based HIV/STI risk reduction intervention. The intervention, common-law spouses, intimate partners, lovers, and casual a series of 6 once-weekly sessions (delivered to couples in sexual partners. Most couple intervention models allow the 1 study arm and to women alone in another), was found to be index participant to identify his or her partner. Several efficacious in increasing condom use, compared with the third have more stringent criteria, such as length of the relation- study arm, the control—a single HIV/STI information ship, level of commitment, and sexual orientation.15,17 Thus, session.12,13,15 The weekly sessions targeted the relationship key questions remain unanswered: To what extent are the context, and all exercises and homework assignments were findings generalizable? For whom are the interventions parti- geared toward the couple; all participants attending these cularly efficacious? sessions were asked to practice the communication, negoti- Most couple-based studies are limited by 1 or more ation, and condom skills that they learned in the weekly methodological drawbacks, including relatively small sample sessions with their partners. Connect is currently being dis- sizes, lack of a randomized control design, and/or the lack of seminated by the Centers for Disease Control and Prevention biologically confirmed STIs as an outcome variable.7 None as a DEBI (diffusion of effective behavioral interventions) and of the couple-based studies to date have been sufficiently tested for adoption by 80 New York State agencies.16 powered to examine new STI and HIV infections as outcomes. The project Eban, with 535 African American serodis- To date, few studies have examined whether couple- cordant couples in 4 US cities, was recently completed.14,17 level interventions are effective in reducing extradyadic sexual Couples assigned to the Eban couples risk reduction relationships among partners. This is an important outcome to intervention compared with a health promotion comparison consider, as partner concurrency has been found to increase condition were more likely to increase condom use over the HIV risk within a partner’s sexual network and within the 12-month period.17 dyad.23 It is unclear whether existing couple-based HIV pre- The project Connect with Pride, an adaptation of vention approaches reduce HIV risk with extradyadic partners. Connect that was targeted to African American MSM couples Couple-based HIV prevention approaches have used composed of at least 1 methamphetamine user, was recently different modalities to deliver their intervention. The science piloted with 34 MSM dyads with promising results.18 of couple-based HIV prevention has yet to tell us which Couple-based prevention research on drug-related HIV modality works better. Are interventions more effective when risks is emerging. Specific core components of drug-related sessions are delivered to each couple individually, when interventions include syringe disinfection skills, triggers for the sessions bring a group of couples together, or when some drug use, gender imbalances in HIV risks associated with sessions are delivered in small, single-gender groups? Future a couple’s drug-using contexts, and improved access to harm research should address the question of which is the most reduction programs.19 efficacious and/or cost-effective modality. Addressing treatment adherence within a couple has the The particular mechanisms that lead to behavior change potential advantage of not only improving the health of remain unspecified. To advance the science of HIV prevention persons living with HIV but also reducing the risk of trans- intervention with couples, there is a need to identify mediators mission within the pair by reducing the viral load of the responsible for behavioral change. Moreover, greater attention q 2010 Lippincott Williams & Wilkins www.jaids.com | S99 El-Bassel et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 must be given to the use of relationship-based theories that move STIs and HIV. More attention and resources must be given to beyond social cognitive theory, which has guided most couple- the dissemination of evidence-based, couple-based prevention based studies.7 Statistical techniques using data collected from and treatment research into real-world settings. Advancing the couples also need to be developed more thoroughly. Examples science of couple-based research (eg, efficacy, effectiveness, of areas to be targeted for development include the following: Is and dissemination) has the potential to reduce HIV acquisition the unit of analysis the individual or the couple? What is and transmission among vulnerable populations. a conservative way to handle discrepant reports from partners on conjoint behaviors? A number of challenges need to be highlighted in the REFERENCES couple-based interventions. Although some evidence suggests 1. Centers for Disease Control and Prevention. Diagnoses of HIV Infection that couple-based HIV prevention interventions may not work and AIDS in the United States and Dependent Areas, 2008. HIV as well for couples experiencing severe conflict or intimate Surveillance Report. Vol 20. Atlanta, GA: Division of HIV/AIDS 24,25 Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB partner violence, research has yet to identify whether the Prevention, Centers for Disease Control and Prevention; 2010. Available effects of couple-based interventions are moderated by certain at: http://www.cdc.gov/hiv/surveillance/resources/reports/2008report/. relationship characteristics (eg, length and type of relationship, Accessed August 12, 2010. relationship satisfaction level, history of intimate partner 2. Herbst JH, Beeker C, Mathew A, et al. The effectiveness of individual-, group-, and community-level HIV behavioral risk-reduction interventions violence). Another challenge is that couple-based interven- for adult men who have sex with men: a systematic review. Am J Prev tions require more clinical training and skills than individual- Med. 2007;32:38–67. doi:10.1016/j.amepre.2006.12.006. based interventions. Agency clinical staffs also tend to be 3. Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV more comfortable conducting individual interventions and transmission: how to make them work better. Lancet. 2008;372:669–684. PMCID: PMC2702246. may take more time to feel comfortable delivering couple- 4. Johnson BT, Carey MP, Chaudoir SR, et al. Sexual risk reduction for based sessions. persons living with HIV: research synthesis of randomized controlled trials, 1993 to 2004. J Acquir Immune Defic Syndr. 2006;41:642–650. Dissemination of Couple-Based PMCID: PMC2424183. 5. Sullivan PS, Salazar L, Buchbinder S, et al. Estimating the proportion of Prevention Interventions HIV transmissions from main sex partners among men who have sex with Despite their demonstrated value in reducing risk men in five US cities. AIDS. 2009;23:1153–1162. behaviors and improving adherence to HIV medication, 6. Higgins JA, Hoffman S, Dworkin SL. Rethinking gender, heterosexual couple-based approaches are rarely employed in HIV service men, and women’s vulnerability to HIV/AIDS. Am J Public Health. 2010; settings. Even partners who present and want to be treated 100:435–445. doi:10.2105/AJPH.2009.159723. 7. Burton J, Darbes LA, Operario D. Couples-focused behavioral inter- together will likely not find such services. Most DEBI ventions for prevention of HIV: systematic review of the state of evidence. approaches that have been disseminated are delivered using AIDS Behav. 2010;14:1–10. doi:10.1007/s10461-008-9471-4. individual or group modalities.16 Reasons for the limited 8. Desgre´es-du-Louˆ A, Orne-Gliemann J. Couple-centred testing and dissemination and scaling up of couple-based HIV interven- counselling for HIV serodiscordant heterosexual couples in sub-Saharan Africa. Reprod Health Matters. 2008;16:151–161. doi:10.1016/S0968- tions to date may include common ideological preferences of 8080(08)32407-0. staff and administrators for individual or group services, lack 9. Remien RH, Stirratt MJ, Dolezal C, et al. Couple-focused support to of structure to provide couple services within agencies, lack of improve HIV medication adherence: a randomized controlled trial. AIDS. access to evidence-based HIV interventions for couples, and 2005;19:807–814. lack of funding and staff training in couple-based modalities. 10. Semrau K, Kuhn L, Vwalika C, et al. Women in couples antenatal HIV counseling and testing are not more likely to report adverse social events. Expanding the scope of dissemination and scaling up couple- AIDS. 2005;19:603. based HIV interventions will require commitment on the part 11. Kiarie JN, Kreiss JK, Richardson BA, et al. Compliance with antiretroviral of government and donors to fund research on dissemination regimens to prevent prenatal HIV-1 transmission in Kenya. AIDS. 2003; and implementation as well as training for providers in couple- 17:65–71. 12. El-Bassel N, Witte SS, Gilbert L, et al. HIV prevention for intimate based approaches. couples: a relationship-based model. Fam Syst Health. 2001;19(4):379– 395. doi:10.1037/h0089467. 13. El-Bassel N, Witte SS, Gilbert L, et al. Long-term effects of an HIV/STI CONCLUSIONS sexual risk reduction intervention for heterosexual couples. AIDS Behav. Couple-based HIV interventions are in the early stages 2005;9:1–13. doi:10.1007/s10461-005-1677-0. 14. NIMH Multisite HIV Prevention Trial for African American Couples of development in the United States, compared with individual Group. Eban HIV/STD risk reduction intervention: conceptual basis and and group-level HIV interventions. Yet the advantages of procedures. J Acquir Immune Defici Syndr. 2008;49:S15–S27. couple-based approaches are evident. They can reduce drug 15. El-Bassel N, Witte SS, Gilbert L, et al. The efficacy of a relationship- and sexual behaviors that drive transmission of HIV and based HIV/STD prevention program for heterosexual couples. Am J improve adherence to antiretroviral therapy and can, in turn, Public Health. 2003;93:963–969. PMCID: PMC1447878. 16. Witte SS.Use of multimedia technologies to disseminate HIV prevention. decrease risk of transmission. However, there remains a need Presented at: 2nd Annual NIH Conference on the Science of for more research on couple-based approaches, especially for Dissemination and Implementation; January 28–29, 2009; Bethesda, drug users and MSM and for seroconcordant couples. MD. Abstract 43. Available at: http://conferences.thehillgroup.com/obssr/ The science of couple-based research can be advanced di2008/01_Program%20Book/01_DI09%20FINAL%20ProgramBook.pdf. Accessed August 17, 2010. by addressing the gaps and challenges discussed in this article, 17. El-Bassel N, Jemmott JB, Landis JR, et al. NIMH Multisite Eban HIV/ particular assessing the impact of couple-based interventions STD Prevention Intervention for African American HIV serodiscordant on concurrent sexual relationships and biological outcomes of couples: a cluster randomized trial. Arch Int Med. 2010;170:1594–1601.

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18. Wu E, El-Bassel N, McVinney L, et al. Adaptation of a couple-based HIV 22. Koniak-Griffin D, Lesser J, Henneman T. HIV prevention for Latino intervention for methamphetamine-involved African American men who adolescent mothers and their partners. West J Nurs Res. 2008;30:724–742. have sex with men. Open AIDS J. 2010;4:123–131. PMCID: PMC2908928. doi:10.1177/0193945907310490. 19. Gilbert L, El-Bassel N, Terlikbayeva A, et al. Couple-based HIV prevention 23. Halperin DT, Epstein H. Concurrent sexual partnerships help to explain for injecting drug users in Kazakhstan: a pilot intervention. JPrevInterv Africa’s high HIV prevalence: implications for prevention. Lancet. 2004; Community. 2010;38:162–176. doi:10.1080/10852351003640914. 364:4–6. doi:10.1016/S0140-6736(04)16606-3. 20. Attia S, Egger M, Muller M, et al. Sexual transmission of HIV according to 24. Greene K, Bogo M. The different faces of intimate violence: viral load and antiretroviral therapy: systematic review and meta-analysis. implications for assessment and treatment. J Mar Fam Ther. 2002;28: AIDS. 2009;23:1397–1404. doi:10.1097/QAD.0b013e32832b7dca. 455–466. 21. Harvey SM, Bird ST, Galavoti C, et al. Relationship power, sexual 25. Jacobson NS, Gottman JM. When Men Batter Women: New Insights decision making and condom use among women at risk for HIV/STDs. into Ending Abusive Relationships. New York, NY: Simon & Women Health. 2002;36:69–84. doi:10.1300/J013v36n04_06. Schuster; 1988.

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The Future of HIV Testing Bernard M. Branson, MD

EVOLUTION IN HIV TEST TECHNOLOGY Abstract: HIV testing is the essential entry point for both treatment Figure 1 depicts the appearance of laboratory markers at and prevention. The need to identify acute HIV infection (the period different stages of HIV infection. As recently as 2006, nearly immediately after HIVacquisition, when persons are most infectious) 70% of public health laboratories employed first-generation or and HIV-2 infection, which does not respond to many first-line second-generation assays that detect only immunoglobulin G antiretroviral agents, poses challenges for the traditional algorithm of antibodies to HIV-1, and only on average 45–60 days after Western blot confirmation after a repeatedly reactive antibody infection.4,5 Thus, infection went undetected in many persons screening test. Immunoassays that detect antibodies earlier, tests for who were tested during the infectious seroconversion HIV RNA, and combination assays that screen simultaneously for ‘‘window period.’’ During the 1990s, third-generation assays both p24 antigen and HIV antibody are now approved for HIV were developed that also detected immunoglobulin M (the first diagnosis by the Food and Drug Administration. A revised testing antibodies generated in the immune response) and did so an algorithm can address the challenges posed by acute infection, HIV-2 average 20–25 days after infection (Fig. 2).6 These tests also infection, and the shortcomings of the Western blot. These new incorporated specific antigens to detect both HIV-1 and HIV-2. diagnostic strategies will allow earlier more accurate identification of Because they were more expensive, third-generation assays infected persons so that they can benefit from effective treatment and were not widely adopted until the remaining first-generation also enhance abilities to focus prevention efforts where HIV HIV-1 assay was withdrawn from the market in 2007.7 The transmission is most active. third-generation assays also complicate confirmatory testing Key Words: HIVantibody tests, acute HIV Infection, HIV diagnosis, because they become reactive before any bands appear on the 8 HIV confirmatory tests Western blot. Although some clinicians order RNA viral load assays to diagnose early HIV infection, the first qualitative (J Acquir Immune Defic Syndr 2010;55:S102–S105) RNA assay was not approved by the Food and Drug Administration (FDA) for HIV diagnosis until 2006.9 EIAs are best suited for batch processing of large ntibody tests have been essential to the diagnosis of HIV volumes of specimens in centralized laboratories. Because Ainfection since the first HIV enzyme immunoassay (EIA) typical turnaround times for results range from a few days to was introduced 25 years ago. Early concerns about false- more than a week, many infected persons failed to receive positive test results in a setting of low prevalence1 led to testing conventional test results.10 Since 2002, the FDA approved algorithms that emphasized specificity and the concept of 6 rapid HIV antibody tests with sensitivities and specificities ‘‘confirmatory’’ testing: positive HIV antibody test results similar to those of first or second generation conventional require a repeatedly reactive screening test validated by EIAs.11 Because these rapid assays can be performed in a supplemental more specific test (such as the Western blot).2 30 minutes or less, their use allows many more patients to This testing algorithm served to establish the diagnosis of HIV receive their test results.12 Several factors, however, have for nearly 80% of the estimated 1.1 million infected persons in begun to temper the initial enthusiasm for rapid tests. First, the United States.3 Identifying the estimated 21% of persons many persons who receive preliminary positive rapid test still unaware that they are infected and guiding effective future results do not return for their confirmatory test results and thus prevention efforts will require tests that detect HIV infection might not access necessary medical care.13 Second, reduced earlier, faster, and at less cost. sensitivity during the early stages of infection contributes to false-negative results in some high-risk frequently tested populations in which rapid tests are often used. In one clinic, From the Division of HIV/AIDS Prevention, National Center for HIV, Viral rapid tests detected infection in only 91% of antibody-positive Hepatitis, STD, and TB Prevention, Centers for Disease Control and men who have sex with men and in only 80% of those whose Prevention, Atlanta, GA. infection was documented by a combination of conventional No outside sources of support. antibody and RNA assays.14 Finally, rapid tests are impractical Presented, in part, at the CDC/APHL 2010 HIV Diagnostics Conference, March 24–26, 2010, Orlando, FL. for large-scale screening programs in health care settings. Single- Disclaimer: The findings and conclusions in this report are those of the author use rapid tests are time consuming to perform, and their cost and do not necessarily represent the views of the Centers for Disease remains persistently higher than that of conventional tests or the Control and Prevention or the US Department of Health and Human $1–$3 charged for identical tests outside the United States. Services. Since 2006, 2 random-access third-generation chemilu- Correspondence to: Bernard M. Branson, MD, 1600 Clifton Road, Mailstop 15,16 D-21, Atlanta, GA 30329 (e-mail: [email protected]). minescent immunoassays have received FDA approval. Copyright Ó 2010 by Lippincott Williams & Wilkins These run on automated platforms for a variety of tests in

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FIGURE 1. Sequence of appearance of laboratory markers in HIV infection. addition to HIV, can test specimens individually or in batches, levels of infectious virus are detectable in serum and genital and generate test results in 1 hour or less. Random-access secretions and persist for 10–12 weeks.19 Cohort studies platforms are already widely available in many hospital and suggest that the rate of transmission during AHI is 26 times as clinical laboratories and are well suited for screening programs high as that during established HIV infection.20 Mathematical that include HIVas one of the battery of tests ordered routinely models indicate that AHI, despite its short duration, can for patients being seen in the emergency department or account for 10%–50% of all new HIV infections, especially in admitted to the hospital. Combination p24 antigen-HIV the context of high sexual partner concurrency or high rates of antibody (Ag/Ab) fourth-generation assays that identify partner change.21–23 AHI screening programs that applied $80% of HIV infections otherwise detectable only by RNA RNA assays to pooled antibody-negative specimens (to reduce have been used extensively worldwide for several years. The per-patient costs) found that AHI generally represents only first fourth-generation Ag/Ab combination assay recently a small proportion (0.02% to 0.3%) of persons with negative received FDA approval, and others are expected soon to HIV antibody tests but constitutes a substantial proportion become commercially available.17 (10%–25%) of new HIV diagnoses, especially among men who have sex with men.14,24–26 Until now, the high cost of CHALLENGES FOR HIV TESTING RNA assays made routine screening for AHI impractical. Once Acute HIV infection (AHI) is defined as the interval they are commercially available, Ag/Ab assays that detect AHI 4–5 days later than RNA assays (Fig. 2) will allow widespread between the appearance of HIV RNA and that of detectable 27 antibodies (Fig. 1).18 Beginning with AHI, extremely high screening for AHI with an initial screening test. Because most do not distinguish antigen from antibody reactivity, new testing algorithms will be required to distinguish AHI from established HIV infection. Differentiating HIV-1 from HIV-2 poses another chal- lenge. The number of HIV-2 diagnoses in the United States is believed to be low, but definitive diagnosis is difficult and surveillance is incomplete. Persons and partners of persons who acquired HIV-2 in West Africa have been diagnosed in Western Europe and the United States.28 Because of cross-reactivity between HIV-1and HIV-2antigens, the HIV-1Western blot may be interpreted as positive in patients with HIV-2.29 ‘‘Cryptic’’ HIV-2 infection is thus often identified only after patients with an HIV-1 diagnosis manifest clinical deterioration despite a repeatedly undetectable HIV-1viral load. HIV-2has important implications for prognosis and treatment because HIV-2 does FIGURE 2. Reactivity of FDA-approved assays for HIV-1 not respond to nonnucleoside reverse transcriptase inhibitors or compared with Western blot. to several protease inhibitors.30 q 2010 Lippincott Williams & Wilkins www.jaids.com | S103 Branson J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

NEW STRATEGIES FOR HIV TESTING the number of infected persons whose infection is undetectable. Contemporary HIV testing strategies need to emphasize This suggests that persons seeking an HIV test after 1 or more sensitivity, especially for the highly contagious phase recent risky exposures, especially in populations with an immediately after infection. Despite longstanding concerns increased frequency of AHI, should be encouraged to retest in about false-positive test results, false-positive tests will be 3–4 weeks, even if their Ag/Ab test was negative. Evaluating discovered and resolved promptly as part of subsequent testing factors associated with AHI can also be used to develop for clinical evaluation. False-negative results, however, might prediction models for persons at higher risk for HIV acquisition not be detected for years, until HIV disease has advanced, after who need more frequent retesting and more intensive prevention 34 early effective treatment has been delayed, and after partners interventions. If it is not possible to screen with Ag/Ab tests (for might have been unknowingly infected. example, in outreach settings when rapid HIV tests are used), A revised testing algorithm has been proposed to retesting recommendations deserve particular attention. Individ- address not only the challenges posed by AHI and HIV-2 but uals whose activities put them at higher risk of HIV acquisition also the shortcomings of the Western blot.31 Testing begins and those from high-prevalence populations should be asked with the most sensitive test possible, optimally a fourth- about recent potential exposures, multiple or concurrent sex generation combination Ag/Ab test (Fig. 3). Repeatedly partners, and other behaviors associated with increased HIV reactive specimens are then tested with an assay that dif- incidence (eg, methamphetamine use), and those with a higher ferentiates HIV-1 from HIV-2 antibodies. Specimens that are likelihood of recent exposure should be encouraged to retest in repeatedly reactive on the Ag/Ab screening test but negative 4–6 weeks. for antibodies are then tested for HIV-1 RNA. Detectable HIV testing is the entry point for both care and RNA establishes the diagnosis of AHI, which requires, in prevention, and progress continues at a rapid pace. Rapid addition to linkage to medical care, urgent intervention to Ag/Ab combination tests and point-of-care tests for HIV RNA prevent further transmission and elicitation and evaluation are in clinical trials. Promising techniques to determine of recent sex partners. In one study, persons with AHI named whether antibody-positive persons were infected recently will 2.5 times as many partners and nearly twice as many part- soon help guide case finding and prevention and inform efforts ners with undiagnosed HIV infection as did persons with to measure incidence. Because effective HIV treatment is longstanding HIV infection.32 However, the majority of available, doing everything possible to find infected persons HIV-infected persons will be antibody positive and can be and link them to care is more important than ever. immediately linked to medical care, where the recommended baseline clinical evaluation includes plasma HIV RNA (viral REFERENCES 33 load). If RNA is undetectable, further antibody testing 1. Meyer KB, Pauker SG. Screening for HIV: can we afford the false positive (eg, Western blot) is indicated to determine whether HIV rate? N Engl J Med. 1987;317:238–241. infection is present. 2. Centers for Disease Control. Interpretation and use of the Western blot The frequency of AHI should be monitored to guide assay for serodiagnosis of human immunodeficiency virus type 1 infections. MMWR Morb Mortal Wkly Rep. 1989;38(Suppl 7):S1–S7. retesting recommendations. Both RNA and Ag/Ab tests reduce 3. Campsmith ML, Rhodes PH, Hall HI, et al. Undiagnosed HIV prevalence the window period after infection—they don’t eliminate it. The among adults and adolescents in the United States at the end of 2006. 10-day duration of the eclipse period during which infection is J Acquir Immune Defic Syndr. 2010;53:619–624. doi: 10.1097/QAI. undetectable (Fig. 1) is approximately the same as the interval 0b013e3181bf1c45. 4. Busch MP, Lee LL, Satten GA, et al. Time course of detection of viral and during which AHI can be identified in antibody-negative persons. serologic markers preceding human immunodeficiency virus type 1 Therefore, the number of AHI cases might roughly approximate seroconversion: implications for screening of blood and tissue donors. Transfusion. 1995;35:91–97. 5. Association of Public Health Laboratories. Public Health Laboratory Issues in Brief: 2006 HIV Diagnostics Survey. Silver Spring, MD: Association of Public Health Laboratories; November 2007. Available at: http://www.aphl.org/aphlprograms/infectious/documents/hiv_issue_ brief_2007.pdf. Accessed August 8, 2010. 6. Fiebig EW, Wright DJ, Rawal BD, et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003;17:1871–1879. doi: 10.1097/01.aids.0000076308.76477.b8. 7. Association of Public Health Laboratories. HIV: 2009 Diagnostic Survey. Silver Spring, MD: Association of Public Health Laboratories; March 2010. Available at: http://www.aphl.org/aphlprograms/infectious/hiv/ Documents/HIV_2009_Survey.pdf. Accessed August 8, 2010. Issues in Brief: Member Survey of HIV Assay Use. 8. Owen SM, Yang C, Spira T, et al. Alternative algorithms for human immunodeficiency virus infection diagnosis using tests that are licensed in the United States. J Clin Microbiol. 2008;46:1588–1595. PMCID: PMC2395119. 9. Food and Drug Administration. Approval Letter—APTIMAÒ HIV-1 RNA Qualitative Assay. October 4, 2006. Available at: http://www.fda. gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/ FIGURE 3. Proposed diagnostic algorithm for HIV diagnosis. LicensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ *Denotes if Ag/Ab combo test is used. ucm149928.htm. Accessed August 8, 2010.

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10. Centers for Disease Control and Prevention. Update: HIV counseling and 23. Prabhu VS, Hutchinson AB, Farnham PG, et al. Sexually acquired HIV testing using rapid tests—United States, 1995. MMWR Morb Mortal Wkly infections in the United States due to acute-phase HIV transmission: an Rep. 1998;47:211–215. update. AIDS. 2009;23:1792–1794. doi:10.1097/QAD.0b013e32832e7d04. 11. Greenwald JL, Burstein GR, Pincus J, et al. A rapid review of rapid HIV 24. Pilcher CD, Fiscus SA, Nguyen TQ, et al. Detection of acute infections during antibody tests. Curr Infect Dis Rep. 2006;8:125–131. HIV testing in North Carolina. NEnglJMed. 2005;352:1873–1883. 12. Hutchinson AB, Branson BM, Kim A, et al. A meta-analysis of the 25. Patel P, MacKellar D, Simmons P, et al. Detecting acute human effectiveness of alternative HIV counseling and testing methods to immunodeficiency virus infection using 3 different screening immuno- increase knowledge of HIV status. AIDS. 2006;20:1597–1604. assays and nucleic acid amplification testing for human immunodefi- 13. Martin EG, Salaru G, Paul SM, et al. Statewide implementation of ‘‘rapid- ciency virus RNA, 2006–2008. Arch Intern Med. 2010;170:66–74. rapid’’ testing in New Jersey: our first 25,000. Presented at: 2010 HIV 26. Centers for Disease Control and Prevention. Acute HIV infection—New Diagnostics Conference; March 24–26, 2010; Orlando, FL. Available at: York City, 2008. MMWR Morb Mortal Wkly Rep. 2009;58:1296–1299. http://www.hivtestingconference.org/PDF/Presentations/Martin.pdf [page Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5846a3. 18]. Accessed August 18, 2010. htm. Accessed August 8, 2010. 14. Stekler JD, Swenson PD, Coombs RW, et al. HIV testing in a high- 27. Pandori MW,Hackett J Jr, Louie B, et al. Assessment of the ability of a fourth- incidence population: is antibody testing alone good enough? Clin Infect generation immunoassay for human immunodeficiency virus (HIV) antibody Dis. 2009;49:444–453. doi: 10.1086/600043. and p24 antigen to detect both acute and recent HIV infections in a high-risk 15. Food and Drug Administration. Letter—ADVIA Centaur HIV 1/O/2 setting. JClinMicrobiol. 2009; 47:2639–2642. PMCID: PMC2725691. Enhanced ReadyPack Reagents. May 18, 2996. Available at: http:// 28. Dougan S, Patel B, Tosswill JH, et al. Diagnoses of HIV-1 and HIV-2 in www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/Approved England, Wales, and Northern Ireland associated with west Africa. Sex Products/PremarketApprovalsPMAs/ucm091283.htm. Accessed August 8, Transm Infect. 2005;81:338–341. PMCID: PMC1745000. 2010. 29. Dragavon J, Gallardo C, Espinosa E, et al. Use of Multispot HIV-1/HIV-2 16. Food and Drug Administration. Approval of VITROS Anti-HIV 1+2 Rapid Test to confirm HIV-1/HIV-2 Plus O Enzyme immunoassay results, diagnostic immunoassay [announcement]. March 27, 2008. Available at: shorten reporting time for HIV testing and identify cryptic HIV-2 http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ infection. Presented at: 2010 HIV Diagnostics Conference; March 24–26, HIVandAIDSActivities/ucm121720.htm. Accessed August 18, 2010. 2010; Orlando, FL. Available at: http://www.hivtestingconference.org/ 17. Food and Drug Administration. Approval Letter—ARCHITECT HIV Ag/ PDF/Presentations/Coombs.pdf. Accessed August 18, 2010. Ab Combo. June 18, 2010. Available at: http://www.fda.gov/Biologics 30. Ren J, Bird LE, Chamberlain PP, et al. Structure of HIV-2 reverse BloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProducts transcriptase at 2.35-A resolution and the mechanism of resistance to non- BLAs/BloodDonorScreening/InfectiousDisease/ucm216300.htm. Accessed nucleoside inhibitors. Proc Natl Acad Sci U S A. 2002;99:14410–14415. August 8, 2010. PMCID: PMC137897. 18. Pilcher CD, Eron JJ Jr, Galvin S, et al. Acute HIV revisited: new 31. Branson B. Conference wrap-up: unified laboratory algorithm. Presented opportunities for treatment and prevention. J Clin Invest [erratum: J Clin at: 2010 HIV Diagnostics Conference; March 24–26, 2010; Orlando, FL. Invest. 2006;116:3292]. 2004;113:937–945. PMCID: PMC379335. 32. Moore ZS, McCoy S, Kuruc J, et al. Number of named partners and 19. Morrison CS, Demers K, Kwok C, et al. Plasma and cervical viral loads number of partners newly diagnosed with HIV infection identified by among Ugandan and Zimbabwean women during acute and early HIV-1 persons with acute versus established HIV infection. J Acquir Immune infection. AIDS. 2010;24:573–582. doi: 10.1097/QAD.0b013e32833433df. Defic Syndr. 2009;52:509–513. 20. Hollingsworth TD, Anderson RM, Fraser C. HIV-1 transmission, by stage 33. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. of infection. J Infect Dis. 2008;198:687–693. doi: 10.1086/590501. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults 21. Jacquez JA, Koopman JS, Simon CP,et al. Role of the primary infection in and Adolescents. US Department of Health and Human Services; epidemics of HIV infection in gay cohorts. J Acquir Immune Defic Syndr. December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/ 1994;7:1169–1184. AdultandAdolescentGL.pdf. Accessed August 8, 2010. 22. Brenner BG, Roger M, ARouty JP, et al. High rates of forward 34. Menza TW, Hughes JP, Celum CL, et al. Prediction of HIV acquisition transmission events after acute/early HIV-1 infection. J Infect Dis. 2007; among men who have sex with men. Sex Transm Dis. 2009;36:547–555. 195:951–959. doi: 10.1086/512088. doi: 10.1097/OLQ.0b013e3181a9cc41.

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Secondary Prevention of HIV in the United States: Past, Current, and Future Perspectives Jeffrey D. Fisher, PhD, Laramie R. Smith, BA, and Erin M. Lenz, BA

to others and, at the same time, can protect the health of Abstract: To provide a synopsis of past, current, and potential next- PLWHA by lowering their likelihood of acquiring other generation approaches to prevention for positives (PfP) interventions .1–4 The rationale for PfP interventions as a critical in the United States. For a variety of reasons, PfP interventions, with element of HIV prevention involves the fact that all ‘‘new’’ the goals of limiting HIV transmission from people living with HIV infections must begin with an HIV-positive individual, HIV/AIDS (PLWHA) to others and protecting the health of PLWHA, and the finding that some PLWHA who are aware of their did not appear with any frequency in the United States until about antibody status continue to practice risky behavior.5–9 2000. Even today, the number and breadth of evidence-based PfP For these reasons, from an HIV prevention perspective, it interventions is very limited. Nevertheless, meta-analytic evidence can be highly efficient to intervene with PLWHA3,10 and demonstrates that such interventions can be effective, perhaps even highly effective.1,11,12 Strengthening this argument is that more so than interventions targeting HIV-uninfected individuals. We because large numbers of PLWHA are on antiretroviral therapy review early and more recent PfP interventions and suggest that next- (ART), HIV prevalence in the United States will continue to generation PfP interventions must involve behavioral and biologic rise,3,13 along with the number of individuals capable of components and target any element that affects HIV risk behavior transmitting HIV, and even drug resistant HIV, through risky and/or infectivity. Next-generation PfP interventions should include behavior.1,3 increased HIV testing to identify additional PLWHA, components to About 1.1 million Americans are living with HIV,13,14 initiate and maintain HIV care, to initiate antiretroviral therapy and 75% to 80% of whom are aware of their antibody status.13,15,16 promote adherence, and to reduce sexual and injection drug use risk About one third of these PLWHA continue to engage in risk behavior, as well as ancillary treatments and referrals to services. behaviors that can transmit HIV to others.5–9 Reasons vary Comprehensive next-generation PfP interventions, including all of widely and include dynamics such as lack of critical these elements and effective linkages among them, are discussed. information, motivation, and behavioral skills needed to Key Words: positive prevention, secondary prevention of HIV, practice safer behaviors, alcohol and drug use, mental health issues, extreme poverty, and intimate partner violence, among prevention for positives interventions, HIV prevention, people living 1,17–20 with HIV, behavioral-biologic interventions others. These have been reviewed elsewhere. Despite a critical need, PfP interventions were rare until (J Acquir Immune Defic Syndr 2010;55:S106–S115) 2 decades into the US epidemic.21 The delay in funding and addressing the prevention needs of PLWHA likely occurred because US policy was late in prioritizing this issue. For reasons synthesized in a recent article,21 policies and programmatic approaches highlighting the importance of INTRODUCTION 22–24 Prevention for positive (PfP) interventions are support- PfP emerged only circa 2000. A review article in 2000 described PfP as a ‘‘new ive prevention efforts administered to people living with 25,26 HIV/AIDS (PLWHA) and tailored to their needs. They involve issue.’’ In fact, to date, the vast majority of HIV prevention behavioral and biologic strategies (Fig. 1., components B-G) interventions in the United States have not focused on the HIV that can benefit the public health by limiting HIV transmission prevention needs of PLWHA. Literally, hundreds of HIV prevention intervention studies and many meta-analytic reviews of this work have been published, and almost all From the Center for Health, Intervention, and Prevention, University of the populations targeted in this work were selected for Connecticut, Storrs, CT. characteristics other than serostatus.11,21,27 As reported in Supported by the National Institute of Mental Health Grant R01MH077524- study by W. Fisher et al,21 of 898 HIV prevention interventions 04, integrating HIV prevention into care for people living with HIV/AIDS between 1988 and 2006 identified in a research synthesis in South Africa. Presented in part at the HIV Prevention Trials Network Annual Meeting, May project database of the US Centers for Disease Control, only 4–8, 2009, National Harbor, MD, and the XVIII International AIDS 6.6% were directed at PLWHA, most occurring after 2000. Conference, July 18–23, 2010, Vienna, Austria. The overall dearth of evidence-based PfP interventions is also The authors have no funding or conflicts of interest to disclose. manifest in the very small number of such interventions Correspondence to: Jeffrey D. Fisher, PhD, Center for Health, Intervention, and Prevention, University of Connecticut, 2006 Hillside Road, Unit 1248, identified by the US Centers for Disease Control as ‘‘best’’ or Storrs, CT 06269-1248 (email: jeffrey.fi[email protected]). ‘‘promising evidence’’ and targeted for widespread dissemi- Copyright Ó 2010 by Lippincott Williams & Wilkins nation.21 This is the case despite strong arguments that PfP

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FIGURE 1. A comprehensive approach to next-generation PfPs. Degree of evidence supporting be- havioral and/or biologic transmis- sion risk: Bold face denotes that there is substantial evidence, **emerging evidence, or ‡limited to no support. interventions, which focus, in part, on serostatus and its effect Our own program of PfP research, the Options Project, on HIV risk and preventive behavior, are a critical component was funded by the National Institute of Mental Health in 1999 of an effective comprehensive approach to HIV to develop, implement, and rigorously evaluate a PfP in- prevention.1,3,10,21,23,28,29 tervention delivered by HIV-care providers with PLWHA in a clinical care setting. It was based on the information– motivation–behavioral (IMB) skills model of HIV risk and prevention.30–32 In terms of the model, HIV risk behavior in EARLY PfP INTERVENTIONS PLWHA, and others, is often associated with weaknesses in The first 2 meta-analytic reviews of PfP interventions individuals’ levels of HIV prevention IMB. Individual-level were conducted on trials published before early 2005 and PfP interventions, which address these elements, should lead involved outcomes on sexual risk behavior,11,12 sexually to sustained increases in HIV prevention. Options involved transmitted infections (STI),11 and drug use risk behavior.11 having providers assess the IMB dynamics of patients’ HIV Eighteen distinct interventions, meeting strict criteria, were risk behavior and intervene to remediate any weaknesses. included in these meta-analyses. All but 2 interventions were Some US studies revealed that these brief interventions, conducted exclusively within the United States and 14 embedded in regular patient care, led to significant and exclusively targeted PLWHA. Across both meta-analyses, sustained changes in patient risk behavior.10,28 PfP interventions effectively reduced the sexual risk, particularly instances of unprotected vaginal or anal in- tercourse, and did so more effectively than earlier interven- MORE RECENT PfP INTERVENTIONS tions with seronegative populations. Crepaz et al11 also found Since the two 2006 meta-analyses, additional PfP that PfP interventions targeting biologic end points were intervention trials have been published. Two descriptive effective in reducing STI incidence. However, significant reviews published in 2009 identified 7 new intervention reductions were not observed in the number of sex partners12 outcome studies and 14 characterizations of interventions and in needle-sharing outcomes.11 Nevertheless, Crepaz et al11 under development or investigation. Across both reviews, PfP concluded that the overall magnitude of sexual risk reduction interventions continued to be effective across a variety of observed across all interventions and end points reviewed intervention design and delivery processes.1,33 implied that PfP would likely be cost-effective in terms of Table 1 summarizes all US PfP interventions with larger-scale health benefits. Meta-analyses also identified behavioral or biologic outcomes conducted, evaluated, and specific PfP intervention elements with respect to intervention published between January 1, 2005 (the approximate cutoff for design (eg, theoretically based; individual vs group level), the two 2006 meta-analyses), and July 13, 2010. We utilized content, delivery (eg, by a health care provider or professional all search terms [Search terms were combined as follows, counselor), and population characteristics, related to more Group 1 (OR between each term): HIV positive, prevention effective outcomes.11,12 with positives, prevention for positives, positive prevention, q 2010 Lippincott Williams & Wilkins www.jaids.com | S107 Fisher et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

TABLE 1. US PfP Interventions Published in English, Reporting Behavioral or Biologic Transmission Risk Outcomes Between January 1, 2005, and June 13, 2010 Outcomes: Direction and Intervention Design: Level of Intervention Description: Significance of outcomes in IG vs Study: Setting(s); Target Intervention; Intervention Intervention Goal; Theory; IG; and CG; (Behavioral, Biomedical, and Population; Project Name (Date) Delivery; Intensity–Duration CG Brief Descriptions Psychosocial Variables) Coleman et al34: RCT (2 arm), feasibility pilot test: Goal: increase proportion of Sex outcomes: Setting: classroom-like setting; Level: group; consistent condom use for each [consistent condom use total sample: Population*: PLWHA (age $ 50); Delivery: by group facilitators, Cog– anal sex act; observed in both arms, slight trend African American MSM; CLN, Behavioral techniques; Theory: SCT, TRA, TPB; in IG arm; COMM; Intensity–Duration: 4 sessions IG (n = 30): taught condom [consistent condom use if Project: no name (2006–2007) (120 min ea); 1-mo duration; last negotiation skills with role-play inconsistent at BL: trend; FU 3 mo and contextual risk negotiation, YProportion of MSM with multiple provided health-focused information; partners: trend CG (n = 30): time-and attention- matched health-focused control arm Fisher et al10: Quasi-experimental (2 arms): Goal: reduce UVA/O through brief, Sex outcomes: Setting: 2 HIV clinics; Level: individual; ongoing risk reduction counseling; YUVA/O all partners: SIG; Population: PLWHA, CLN; Delivery: by HIV providers during Theory: IMB; YUVA/O HIV-/? partners: trend; Project: Options/Opciones (2000– routine care visits; MI approach; IG (n = 252)†: patient-centered YNo. HIV-/? partners: trend; 2003) Intensity–Duration: ; 6 sessions conversations around sex or drug Drug outcomes; (5–10 min ea); 18 mo duration; use behaviors; assess readiness to low response rate, not analyzed last FU 18 mo address risk behaviors, provide risk reduction strategy options, develop tailored risk reduction goal; CG (n = 245)†: standard of care, risk counseling at providers’ discretion Gardner et al35: Prepost (1 arm); demonstration Goal: evaluate reduced risk of Sex outcomes: Setting: 7 HIV clinics; project: transmission in multiclinic study; YUVA all partners: SIG; Population*: PLWHA, CLN; Level: individual; Theory: N/A; YUVA HIV-/? partners: SIG; Project: Positive Steps (2005–2006) Delivery: by HIV providers during IG (n = 767)†: screen for risk, deliver YUVA HIV+ partners: SIG; routine care visits; risk reduction messages, and create Drug outcomes: Intensity–Duration: ; 3 sessions risk reduction plan with providers; low response rate, not analyzed; (; 3 min ea); 12-mo duration; last provide supplemental brochures STI outcomes: FU 12 mo and posters; low BL prevalence, not analyzed CG: N/A; longitudinal cohort, with only participants who had data at all time points included in analysis Gilbert et al36: RCT (2 arms): Goal: reduce illicit drug use, risky Sex outcomes: Setting: 5 HIV clinics; Level: individual; alcohol consumption, and UVA; YUVA: SIG; Population*: PLWHA, CLN; Delivery: by computers during routine Theory: N/A; [condom use all partners: trend Project: Positive Choice (2003–2006) care visits; MI approach; IG (n = 243): computer-based risk observed in both arms, no Intensity–Duration: 2 sessions assessment preceding a tailored difference between arms; (; 24 min ea); 3-mo duration; last ‘‘Video Doctor’’ risk reduction YNo. casual partners: SIG ‡; FU 6 mo counseling session; printout of Drug outcomes: behavioral assignment and referrals Ydrug use: SIG; for substance use and harm- Ymean days of ongoing drug use: reduction services; trend; CG (n = 233): computer-based risk Yalcohol risk: observed in both arms, assessment, followed by standard no difference between arms of care, risk counseling at providers’ discretion The Healthy Living Project37: RCT (2 arms): Goal: reduce number of sex-related Sex outcomes: Setting: 4 sites (HIV clinic, research, Level: individual; risk acts with HIV-/? partners, Ymean no. sex risk acts with HIV-/? and community service sites); Delivery: by facilitators; execute effective coping responses, partners: SIG ‡; Population*: PLWHA, CLN, Cog–Behavioral techniques; enhance adherence with PLWHA Yno. sex risk acts with HIV-/? COMM; Intensity–Duration: 15 sessions # 85% adherent at BL; partners from BL; observed in both Project: the Healthy Living Project (90 min ea); 5-mo duration; last FU Theory: social action theory; arms, no difference between arms; (2000–2004) 25 mo IG (n = 467)†: 3 modules focused on Adherence outcomes: stress, coping, and adjustment; [adherence in nonadherers at BL: reducing transmission risk SIG ‡; behaviors; enhancing health Psychosocial outcomes: promotion via adherence to changes in psychosocial adjustment: medical care and ART; NS; Changes in psychosocial CG (n = 469)†: wait-list control adjustment among PLWHA with comparison group depressive symptoms at BL: NS

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TABLE 1. (continued) US PfP Interventions Published in English, Reporting Behavioral or Biologic Transmission Risk Outcomes Between January 1, 2005, and June 13, 2010 Outcomes: Direction and Intervention Design: Level of Intervention Description: Significance of outcomes in IG vs Study: Setting(s); Target Intervention; Intervention Intervention Goal; Theory; IG; and CG; (Behavioral, Biomedical, and Population; Project Name (Date) Delivery; Intensity–Duration CG Brief Descriptions Psychosocial Variables) Illa et al38: RCT: (2 arms); Goal: target sexual risk reduction in Sex outcomes: Setting:1 HIV clinic; Level: group; older PLWHA; YUVA all partners: SIG; Population*: PLWHA (age $ 45); Delivery: based on project Theory: IMB, self-efficacy theory; YUVA HIV-/? partners: SIG; CLN; INSPIRE45; IG (n = 149)†: tailored YUVA HIV+ partners: NS; Project: Project ROADMAP (2004– Intensity–Duration: 4 sessions (1–2.5 psychoeducational group sessions to Psychosocial outcomes: 2006) hr ea); intervention duration NR; address HIV, its effects on sexual [HIV knowledge: observed in both last FU 6 mo behaviors, and harm reduction arms, no difference between arms; approaches; safer-sex negotiation [sexual self-efficacy: NS skills and strategies for older PLWHA; CG (n = 92): received educational brochure, followed by standard of care Lightfoot et al39: Quasi-experimental (3 arms): Goal: provide brief risk reduction Sex outcomes: Setting: 6 HIV clinics; Level: Individual; intervention to enhance motivation Yno. HIV-/? partners: SIG (IG-1 Population: PLWHA, CLN; Delivery: By computer or HIV and encourage PLWHA to act in compared with IG-2 and CG arms); Project: no name (2001–2004) provider/staff during routine care accordance with their values; YUVA HIV-/? partners: SIG (IG-1 visits; FRAMES; Theory: N/A; compared with CG arm) Intensity–Duration: # 11 sessions IGs 2 intervention conditions: (10 min ea computer, 5–15 min ea computer-delivered arm (IG-1, n = providers); 30-mo duration; last FU 325)†; provider-delivered arm (IG-2, 30 mo n =209)†; assess/provide feedback on behavior and personal values; enhance self-efficacy and behavior change; CG (n =229)†: standard of care provided in control comparison clinics Margolin et al40: Quasi-experimental, prepost (2 arm): Goal: increase motivation for HIV risk outcomes (low response Setting: 1 methadone clinic; Level: individual; abstinence, HIV prevention, and rate): Population: PLWHA, methadone- Delivery: therapist-led; Cog– medication adherence; decrease YHIV transmission risk behaviors: maintained drug users, COMM; Behavioral and Buddhist impulsivity in HIV-positive drug- NS; Project: 3-S+ therapy (dates NR) psychologies; using population; Drug outcomes; Intensity–Duration: 12 sessions Theory: cognitive self-schema theory, Yintoxicant use: trend; (session time NR); 3-mo duration; Buddhist principles; [motivation for drug abstinence: last FU 3 mo IG (n = 21)†: weekly therapy focused SIG; on replacing addict self-schema Psychosocial outcomes: with a spiritual self-schema; and on Yimpulsivity: SIG; increasing awareness of addiction [mean influence of spirituality on and its impact on adherence, risk, motivation for health-promoting and HIV care behaviors; behaviors: SIG CG (n = 17)†: standard-of-care methadone-maintenance therapy; nonrandomized; participants elected to complete preassessments and postassessments only Mausbach et al41: RCT (2 arms): Goal: increase safer sexual behaviors in Sex outcomes: Setting: NR; Level: individual; presence of methamphetamine use; Ytotal UVA over time: NS; Population*: PLWHA, MSM who use Delivery: therapist-led; MI approach; Theory: SCT, TRA; [proportion protected sex acts: SIG; methamphetamines, CLN, COMM; Intensity–Duration: 8 sessions IG (n =170)†: targeted skills training [no. protected sex acts over time: Project: EDGE (1999–2004) (90 min ea); 3-mo duration; last FU andproblemsolvingtoenhance SIG; 12 mo knowledge and self-efficacy with Psychosocial outcomes; condom use/negotiation; serostatus [self-efficacy condom use: SIG; disclosure to partners in context of [self-efficacy condom negotiation: ongoing substance use; observed in both arms, no CG (n = 171)†: time–attention control difference between arms diet and exercise sessions

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TABLE 1. (continued) US PfP Interventions Published in English, Reporting Behavioral or Biologic Transmission Risk Outcomes Between January 1, 2005, and June 13, 2010 Outcomes: Direction and Intervention Design: Level of Intervention Description: Significance of outcomes in IG vs Study: Setting(s); Target Intervention; Intervention Intervention Goal; Theory; IG; and CG; (Behavioral, Biomedical, and Population; Project Name (Date) Delivery; Intensity–Duration CG Brief Descriptions Psychosocial Variables) Mitchell et al42: Prepost (1 arm), feasibility pilot: Goal: support adoption and Sex and drug outcomes (low response Setting: 1 HIV clinic; Level: individual; maintenance of medication rate): Population: PLWHA, marginally Delivery: by case managers; adherence and HIV risk reduction Ysexual and substance-using risk housed, substance-using, CLN; strengths-based approach; behaviors; behaviors: NS; Project: DAART+ (2003–2006) Intensity–Duration: daily mDOT Theory: TTM stages of change, IMB; Viral load outcomes: sessions tapered to biweekly, then IG (n = 30)†: integrated discussions viral load data for participants with monthly; 12-mo duration; last FU on adherence barriers and current final assessment (n = 18), 83% 3–6 mo sex and substance-use behaviors in achieved viral suppression the context of mDOT; CG: N/A; longitudinal cohort, with no comparison group available Naar-King et al43: RCT (2 arm): Goal: enhance viral response in Viral load outcomes: Setting: 5 HIV clinics; Level: Individual; young PLWHA with multiple Yviral load: SIG‡ Population*: PLWHA (aged 16–24 Delivery: therapist-led; MI approach; transmission-related risk behaviors; years), multiple risk factors, CLN; Intensity–Duration: 4 sessions (60 Theory: N/A; Project: Healthy Choices (2005– min ea); 2.5-mo duration; last FU IG (n = 94): MI sessions to address 2 2007) 9mo risk factors (eg, nonadherence; sex or drug risk) and access to enhanced support services for sexual risk, drug use, mental health, and medication adherence; CG (n = 92)†: standard of care, access to enhanced support services Petry et al44: RCT (2 arm): Goal: assess efficacy of contingency- Sex outcomes: Setting: HIV drop-in center; Level: group; based rewards on supporting and YSexual risk scores: SIG ‡; Population: PLWHA, cocaine- or Delivery: therapist delivered; sustaining both health and Drug outcomes: opioid-dependent diagnosis, Intensity–Duration: 24 sessions (60 substance use reduction behaviors: Ydrug risk scores: NS; COMM; min ea); 6-mo duration; last FU 12 Theory: N/A; [no. consecutive drug-free urine Project: no name (2003–2007) mo IG (n = 89): support group with tests: SIG; contingency-based rewards [proportion drug-free urine tests: NS; provided for substance use Viral load outcomes: abstinence and completion of Yviral load: SIG‡ health enhancement components; integrated support and substance use reduction messages; CG (n = 81): 12 step–based group support, abstinence messages Purcell et al45: RCT (2 arm): Goal: reduce sexual and injection risk Sex and injection-drug outcomes: Setting: 4 community health centers; Level: individual, group; behaviors, increase utilization of Ysex and injection risk observed in Population*: PLWHA, IDU, COMM; Delivery: by paraprofessionals; HIV care and adherence to ART; both arms, no difference between Project: INSPIRE (2001–2005) Intensity–Duration: 10 sessions Theory: SLT, social identity theory, IMB; arms; (session time NR); 1.25-mo IG (n = 486): focus on motivation/ Health care utilization outcomes: duration; last FU 12 mo skills for increasing use of HIV [care utilization: NS; care, for adherence, and for Adherence outcomes: reducing sex and drug risk [adherence: NS behaviors through developing new social role as a peer–mentor; CG (n = 480): discuss videos focusing on information for HIV-infected IDU Rosser et al46: RCT (3 arms): Goal: reduce frequency of Sex outcomes: Setting: 6 community sites; Level: group; serodiscordant UAI: Yfrequency of serodiscordant UAI: Population*: PLWHA, MSM, CLN, Delivery: by HIV+ MSM-identified Theory: sexual health model; observed in all 3 arms, no COMM; or MSM-identified health IGs across 2 arms: health seminars difference between arms; Project: Positive Connections professional facilitators (matched identified and address sexual health Psychosocial outcomes: (2005–2008) to intervention arm); and HIV risk concerns from an [intentions to avoid high-risk Intensity–Duration: 1 session (14–16 HIV+ MSM (IG-1, n = 248)† or behaviors: SIG‡ (IG-1 and IG-2 hr); 1 weekend long; last FU 18 mo general, serostatus-neutral, MSM arms) (IG-2, n = 237)† perspective; CG (n =190)†: viewed and evaluated MSM HIV prevention–focused DVDs

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TABLE 1. (continued) US PfP Interventions Published in English, Reporting Behavioral or Biologic Transmission Risk Outcomes Between January 1, 2005, and June 13, 2010 Outcomes: Direction and Intervention Design: Level of Intervention Description: Significance of outcomes in IG vs Study: Setting(s); Target Intervention; Intervention Intervention Goal; Theory; IG; and CG; (Behavioral, Biomedical, and Population; Project Name (Date) Delivery; Intensity–Duration CG Brief Descriptions Psychosocial Variables) Serovich et al47: Randomized control, crossover Goal: reduce UAI and enhance Sex outcomes (small sample size, low Setting: NR: design (3 arms); pilot study; disclosure to casual partners in MSM: response rate CG): Population: PLWHA, MSM, COMM; Level: individual; Theory: consequences theory of Ymean frequency of UAI all partners: Project: no name (dates NR) Delivery: by facilitator, or computer disclosure; NS; increased odds of UAI observed and facilitator; IGs 2 intervention conditions: one with in both IG-1 and IG-2 compared Intensity–Duration: 4 sessions facilitator risk assessment and with CG arm, despite a reduction in (session time NR); 1-mo duration; facilitator delivery (IG-1, n =40)§,the UAI over time in IG-1 arm; last FU 3 mo other with computer risk assessment Disclosure outcomes: and facilitator delivery (IG-2, n = [favorable disclosure attitudes: SIG 37)§; both assessed cost and benefits (IG-1 arm); of disclosure and disclosure triggers [favorable disclosure behaviors: trend and strategies; (IG-1 arm); CG (n = 21)§: wait-list control condition [favorable intentions to disclose: NS Sikkema et al48: RCT (2 arms): Goal: improve coping and reduce Sex outcomes: Setting: 1 community health center; Level: Group; sexual risk behavior in PLWHAwith YUAV all partners: SIG; Population: PLWHA, childhood Delivery: By cotherapists; Cog– childhood sexual abuse history; YUAV HIV-/? partners: SIG sexual abuse–related trauma, CLN, Behavioral and coping strategies; Theory: cognitivetheoryofstressand COMM; Intensity–Duration: 15 sessions (90 coping; Project: LIFT (2002–2004) min ea); 3.75-mo duration; last FU IG (n = 124)†: taught adaptive coping 12 mo and problem-solving strategies to identify individual triggers and select goals; skills building for dealing with sexual abuse–related trauma and risk reduction; CG (n = 123)†: time-matched HIV support group comparison condition Teti et al49: RCT (2 arms): Goal: support HIV+ women in Sex outcomes: Setting: 1 HIV clinic; Level: individual, group; decreasing UVA and other sexual [condom use during vaginal/anal Population: PLWHA, women, CLN; Delivery: 3 components (by HIV risks; increase serostatus disclosure intercourse: trend; Project: Protect and Respect (2004– providers during routine care visits, to partners; Disclosure outcomes: NR) health educators, HIV+ peers); Theory: TTM stages of change, [proportion of partners disclosed Intensity–Duration: provider sessions modified AIDS risk reduction serostatus to: SIG‡; (3–5 min ea), health education model, theory of gender and power; [total no. partners disclosed group 5 sessions (1.5 hr/wk), IG (n = 92)†: brief risk reduction serostatus to: NS optional peer support group conversation with HIV providers; (1 hr/wk); 1.25-mo duration; last health educator–led group sessions for FU 18 mo sexual risk reduction education and skills building; weekly HIV+ peer-led support group to discuss skills; CG (n =92)†: standard of care; brief provider risk-reduction messages Velasquez et al50: RCT (2 arms): Goal: reduce both alcohol use and Sex and drinking outcomes: Setting: NR; Level: individual, group; unprotected sexual behaviors: Yno. days with both UAI and heavy Population*: PLWHA, MSM with Delivery: by therapist and HIV+ Theory: TTM stages of change and drinking: SIG‡; diagnosed alcohol use disorder, MSM group facilitators; MI processes of change; Drinking outcomes: COMM; approach; IG (n = 118)†: individual therapy Yno. drinks in past 30 days: SIG‡; Project: Positive Choices (1999– Intensity–Duration: 8 sessions sessions enhanced motivation and Yno. heavy drinking days in past 30 2003) (session time NR); 2-mo duration; skills to change alcohol, sexual days: SIG‡ last FU 12 mo behavior; peer support group sessions focused on HIV risk reduction and safer sexual behaviors; CG (n = 135)†: resource referral control condition

*Participants were screened for recent history of risk behaviors and/or sexual activity. †Attrition rates .20% as reported or calculated based on sample size reported at BL and last FU. ‡Significant difference between IG and CG shows some decay over time. §Sufficient information to calculate attrition was not provided. BL, baseline assessment; CG, comparison group; CLN, HIV medical clinic–based sample; Cog–Behavioral, cognitive–behavioral intervention delivery techniques; COMM, community-based sample; ea, each; FRAMES, Feedback–Responsibility–Advise–Menu of Options–Empathy–Self-Efficacy; FU, follow-up; IDU, injection drug users; IG, intervention group; IMB, information– motivation–behavioral skills model; mDOT, modified directly observed therapy; MI, motivational interviewing intervention delivery techniques; NR, information not reported in manuscript; NS, changes in outcome between IG and CG were nonsignificant (P # 0.05); PLWHA, adults living with HIV aged 18 or older, unless otherwise noted; SCT, social cognitive theory; SIG, changes in outcomes between the IG and CG were significant (P # 0.05); SLT, social learning theory; TPB, theory of planned behavior; TRA, theory of reasoned action; trend, a nonsignificant trend was observed in the IG; TTM, transtheoretical model; UAI/UVA/UVAO, unprotected anal, vaginal–anal, vaginal–anal–oral intercourse; HIV-/?, HIV negative or status unknown; RCT, randomized controlled trial; DVD, digital video disc; INSPIRE, Investigating New Standards for Prophylaxis in Reduction of Exacerbation; LIFT, Living In the Face of Trauma. q 2010 Lippincott Williams & Wilkins www.jaids.com | S111 Fisher et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

HIV prevention with positives, HIV/AIDS prevention with CRITICAL COMPONENTS OF NEXT- positives, secondary HIV prevention. Group 2 (OR between GENERATION PfPS each term): prevention, HIV prevention, HIV counseling, Increased HIV testing (component B) is a critical transmission, risk behavior, risk reduction, harm reduction. element in next-generation PfP. This will identify PLWHA Combine Group 1 AND Group 2 AND intervention.] provided who were previously unaware of their serostatus. When in all previous reviews.1,11,12,33 Eighteen PfP interventions 10,34–50 individuals learn that they are HIV infected, substantial, self- reporting behavioral or biologic outcomes are depicted initiated, postdiagnosis reductions in risk behavior often in Table 1. Twenty-seven additional studies were identified follow.82,83 Testing may also help reduce the number of reporting intermediate prebehavioral outcomes (eg, informa- PLWHA unaware of their status during periods of increased tion, self-efficacy)51–53 or characterizing intervention devel- infectiousness (ie, acute, symptomatic, and late stages), which opment and implementation processes.29,54–76 All were can affect transmission.4,78 Achieving postdiagnosis linkages identified through searches in PubMed, Psych Info, Cumula- to HIV care (component C, path i) to reduce biologic risk of tive Index to Nursing and Allied Health (CINAHL), and the transmission (eg, through identification and treatment of STIs previous reviews. and access to ART medications), as well as ensuring linkages Across the 18 studies with behavioral or biologic to ancillary services (component G, path x) to address outcomes, PfP interventions continue to be effective, with all behavioral risk–related contextual factors, are essential. but 3 reducing targeted sexual and/or drug-related risk behaviors; Initiating and maintaining HIV care (component C) aims Table 1 provides specifics of relevant studies. Most of the to facilitate routine primary care visits and continued interventions contained elements consistent with those identified 84 11,12 monitoring of patients’ overall health. Routine appointments earlier as contributing to effective outcomes. For example, 79,85,86 most were developed using one10,37,46–48,50 or more34,38,40–42,45,49 have been related to lower levels of behavioral and biologic risk (eg, treatment of existing STIs, increased viral health-behavior theories and were delivered in either an HIV 87–89 10,35,36,38,39,42,43,45,48,49 40,44 suppression, decreased resistance), whereas prolonged clinic or another HIV service venue and 90,91 by professional counselors/therapists40,41,43,44,48,50 or HIV care absences from care relate to poorer health outcomes. providers/other medical staff.1,35,39,49 A relatively small number Routine care provides ongoing opportunities to reduce biologic of interventions targeted multiple HIV risk–related behaviors transmission through ART initiation (component D, path ii), (eg, increasing disclosure, reducing heavy drinking or drug use, sustained ART monitoring, and adherence support (component or enhancing coping skills36,37,40–45,48,50) and targeted biologic E, path iii). Behavioral risk reduction ideally integrates PfP transmission risk factors (eg, increased adherence to ART, support (component F, path iv) and referral to ancillary services 37,40,42–45 (component G, path v), addressing contextual risk factors such reduced viral load ). Compared with previous re- 4,86,92,93 views,1,11,33 we note an increase in the number of PfP as social isolation or depression. interventions tailored to risk dynamics unique to specific Initiation of ART (component D) rapidly curbs viral subpopulations of PLWHA (eg, decreasing sexual risk in replication and reduces the amount of viral load present in substance-using seropositive MSM).34,40,41,45–47,50,76 Future plasma or genital tracts, reducing biologic risk of transmission 94–97 meta-analysis should evaluate the effectiveness of emerging and facilitating overall health. The relationship between efforts to use multicomponent and more tailored intervention risk behaviors and being on ART or achieving viral approaches to reduce overall transmission risk. suppression is complex. Any increases in risk behavior are likely a result of treatment-related beliefs98 and underlying NEXT-GENERATION PfPS contextual risk factors,2,18,92 not individuals’ receipt of ART or 98 We believe that a synergistic package of PfP inter- a suppressed viral load, per se. As biologic risk reduction ventions at the intersection of behavior and biology will have requires sustaining health and high levels of adherence, optimal impact on limiting HIV transmission and maintaining support in both continuing routine HIV care (component C, 99 PLWHA health.1–4,77 In Figure 1, we identify vital components path ii) and initial and ongoing access to ART adherence 94,96,100 and linkages of a comprehensive behavioral–biomedical support (component E, path vi) are needed. conceptualization of next-generation PfP interventions (with ART adherence behavioral interventions (component E) an alphanumeric system denoting the various components and sustain viral suppression through enhancing adherence behav- paths as well as ‘‘movement’’ within the model, eg, to iors. Optimal adherence decreases biologic risk by controlling component C from component B via path i). both viral replication and the potential to develop treatment All components and linkages need to be copresent and resistance.94,96,101 Meta-analyses report that adherence interven- integrated in such an approach. To date, these elements remain tions significantly improve adherence behavior96,101 and support separate unintegrated components of HIV prevention and of viral suppression.101 Co-occurrence of both nonadherence and treatment science for PLWHA. Finally, we emphasize that the HIV risk behaviors are often identified, likely resulting from model must be evaluated and supported over the disease common underlying barriers (eg, substance use, social isolation, course of PLWHA (component A), understanding that what is psychological distress/depression).2,18,92 Integration with ongo- needed to optimize the effect of each component and path may ing PfP behavioral support (component F, path vii) and referral vary by disease stages78 and subpopulations (eg, PLWHAwho to ancillary services (component G, path viii) to address root are MSM vs injection drug user; young vs older PLWHA; contextual risks4,18,92 can strengthen adherence. incarcerated vs unincarcerated PLWHA; PLWHA with PfPs behavioral interventions (component F) support different comorbid conditions38,39,43,48,57,77,79–81). safer sex and drug use behaviors, and overall health of

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PLWHA. Meta-analyses of PfP interventions discussed earlier 8. Kalichman SC. Positive Prevention. Reducing HIV Transmission Among demonstrate their efficacy in reducing behavioral11,12 and People Living with HIV/AIDS. New York, NY: Kluwer; 1999. 11 9. Kelly JA, Kalichman SC. Behavioral research in HIV/AIDS primary and potentially biologic risk (ie, STIs ). In the context of existing secondary prevention: recent advances and future directions. J Consult ART, future PfP interventions need to address ART-related Clin Psychol. 2002;70:626–639. beliefs98 and integrate ART adherence support (component E, 10. Fisher JD, Fisher WA, Amico KR, et al. An information–motivation– path vii). Referrals to or incorporation of ancillary services to behavioral skills model of adherence to antiretroviral therapy. Health address root contextual risks (component G, path ix) are also Psychol. 2006;25:462–473. 1,3,48,80,102 11. Crepaz N, Lyles CM, Wolitski RJ, et al. Do prevention interventions critical. reduce HIV risk behaviours among people living with HIV? A meta- Ancillary treatments and referrals to services (compo- analytic review of controlled trials. AIDS. 2006;20:143–157. nent G) address contextual factors and vulnerabilities that may 12. Johnson BT, Carey MP, Chaudoir SR, et al. Sexual risk reduction for undermine necessary health behaviors (eg, ability to maintain persons living with HIV: research synthesis of randomized controlled trials, 1993 to 2004. J Acquir Immune Defic Syndr. 2006;41:642–650. care, medication adherence, or risk reduction) through 13. Centers for Disease Control and Prevention (CDC). HIV prevalence referrals to treatment and support services (see a sample list estimates—United States, 2006. MMWR Morb Mortal Wkly Rep. 2008; of services in box for component G in Fig. 1). These referrals 57:1073–1076. may emanate from HIV testing (component B, path x), HIV 14. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the care (component C, path v), adherence interventions (com- United States. JAMA. 2008;300:520–529. 15. Campsmith ML, Rhodes PH, Hall HI, et al. Undiagnosed HIV ponent E, path viii), and PfP behavioral interventions prevalence among adults and adolescents in the United States at the (component F, path ix), among other sources. Simultaneously, end of 2006. J Acquir Immune Defic Syndr. 2010;53:619–624. PLWHA receiving ancillary treatments or services and who are 16. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV in need of testing, medical care, and behavioral support for from persons aware and unaware that they are infected with the virus in the USA. AIDS. 2006;20:1447–1450. existing adherence and risk reduction issues should be 17. Shuper PA, Joharchi N, Irving H, et al. Alcohol as a correlate of identified and connected to other components, as appropriate. unprotected sexual behavior among people living with HIV/AIDS: For example, HIV testing for high-risk individuals (component review and meta-analysis. AIDS Behav. 2009;13:1021–1036. B, path x), reengaging PLWHA not in HIV care or who never 18. Kalichman SC, Simbayi LC, Vermaak R, et al. Randomized trial of initiated care postdiagnosis (component C, path v), and a community-based alcohol-related HIV risk-reduction intervention for men and women in Cape Town, South Africa. Ann Behav Med. 2008;36: providing access to existing adherence (component E, path 270–279. viii) and risk reduction (component F, path ix) behavioral 19. Weiser SD, Leiter K, Bangsberg DR, et al. Food insufficiency is interventions are critical. associated with high-risk sexual behavior among women in Botswana Due to space limitations, our discussion of a compre- and Swaziland. PLoS Med. 2007;4:1589–1598. 20. Dunkle KL, Jewkes RK, Brown HC, et al. Gender-based violence, hensive behavioral–biomedical approach to PfP addresses relationship power, and risk of HIV infection in women attending model components and their links in a somewhat arbitrary antenatal clinics in South Africa. Lancet. 2004;363:1415–1421. linear fashion. We recognize that the need for any component 21. Fisher WA, Kohut T, Fisher JD. AIDS exceptionalism: on the social and relevant linkages could occur along paths not discussed. psychology of HIV prevention research. Soc Issues Policy Rev. 2009;3:45–77. The next generation of PfP interventions must attend to 22. Centers for Disease Control and Prevention. Incorporating HIV prevention into the medical care of persons living with HIV: reducing both behavioral and biologic risk factors across the recommendation of the CDC, the Health Resources and Service components in Figure 1 and ensure the linkages among them. Administration, the National Institutes of Health, and the HIV Medicine Fortunately, some emerging PfP interventions are beginning to Association of the Infectious Diseases Society of America. MMWR incorporate elements of behavioral and biologic risk reduction, Morb Mortal Wkly Rep. 2003;52(RR12):1–24. but they are not comprehensive and the links are not always 23. Janssen RS, Holtgrave DR, Valdiserri RO, et al. The serostatus approach 37,43,45 to fighting the HIV epidemic: prevention strategies for infected fleshed out. Future PfP intervention development needs individuals. Am J Public Health. 2001;91:1019–1024. to ensure that the linkages among these components are 24. National Institutes of Health. National Institutes of Health Consensus maintained, enhanced, and evaluated. Development Statement on Interventions to Prevention HIV Risk Behaviors. Bethesda, MD: NIH Office of Medical Applications Research; 1997. REFERENCES 25. Moatti JP, Souteyrand Y. 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Psychol Bull. 2005;131:856–897. programs into healthcare settings. Psychosom Med. 2008;70:612–619. 28. Fisher JD, Cornman DH, Osborn CY, et al. Clinician-initiated HIV risk 5. Marks G, Burris S, Peterman TA. Reducing sexual transmission of HIV reduction intervention for HIV+ persons; formative research, accept- from those who know they are infected: the need for personal and ability, and fidelity of the Options Project. J Acquir Immune Defic Syndr. collective responsibility. AIDS. 1999;13:297–306. 2004;32:S78–S87. 6. Metsch LR, McCoy CB, Lai S, et al. Continuing risk behaviors among 29. Kalichman SC, Cherry J, Cain D. Nurse-delivered antiretroviral HIV-seropositive chronic drug users in Miami, Florida. AIDS Behav. treatment adherence intervention for people with low literacy skills 1998;2:161–169. and living with HIV/AIDS. J Assoc Nurses AIDS Care. 2005;16:3–15. 7. Crepaz N, Marks G. Towards an understanding of sexual risk behavior in 30. Fisher WA, Fisher JD. 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Markham CM, Shegog R, Leonard AD, et al. +CLICK: harnessing Web- 22–63. based training to reduce secondary transmission among HIV-positive 33. Gilliam PP, Straub DM. Prevention with positives: a review of published youth. AIDS Care. 2009;21:622–631. research, 1998–2008. J Assoc Nurses AIDS Care. 2009;20:92–109. 54. Callahan EJ, Flynn NM, Kuenneth CA, et al. Strategies to reduce HIV 34. Coleman CL, Jemmott L, Jemmott JB. Development of an HIV risk risk behavior in HIV primary care clinics: brief provider messages and reduction intervention for older seropositive African American men. specialist intervention. AIDS Behav. 2007;11(Suppl 1):S48–S57. AIDS Patient Care STDS. 2009;23:647–655. 55. Chen HT, Grimley DM, Waithaka Y, et al. A process evaluation of the 35. Gardner LI, Marks G, O’Daniels CM, et al. Implementation and implementation of a computer-based, health provider-delivered HIV- evaluation of a clinic-based behavioral intervention: positive steps for prevention intervention for HIV-positive men who have sex with men in patients with HIV. AIDS Patient Care STDS. 2008;22:627–635. the primary care setting. AIDS Care. 2008;20:51–60. 36. Gilbert P, Ciccarone D, Gansky SA, et al.Interactive ‘‘Video Doctor’’ 56. Collins CB Jr, Hearn KD, Whittier DN, et al. Implementing packaged counseling reduces drug and sexual risk behaviors among HIV-positive HIV-prevention interventions for HIV-positive individuals: consider- patients in diverse outpatient settings. PLoS One. 2008;3: e1988. doi: ations for clinic-based and community-based interventions. Public 10.1371/journal.pone.0001988. Health Rep. 2010;125(Suppl 1):55–63. 37. The Healthy Living Project Team. Effects of a behavioral intervention to 57. Copenhaver M, Chowdhury S, Altice FL. Adaptation of an evidence- reduce risk of transmission among people living with HIV: the Healthy based intervention targeting HIV-infected prisoners transitioning to the Living Project randomized controlled study. J Acquir Immune Defic community: the process and outcome of formative research for the Syndr. 2007;44:213–221. Positive Living Using Safety (PLUS) intervention. AIDS Patient Care 38. Illa L, Echenique M, Jean GS, et al. Project ROADMAP: reeducating STDS. 2009;23:277–287. older adults in maintaining AIDS prevention: a secondary intervention 58. Czuchry M, Timpson S, Williams ML, et al. Improving condom self- for older HIV-positive adults. AIDS Educ Prev. 2010;22:138–147. efficacy and use among individuals living with HIV: the Positive Choices 39. Lightfoot M, Rotheram-Borus MJ, Comulada WS, et al. Efficacy of brief Mapping Intervention. J Subst Use. 2009;14:230–239. interventions in clinical care settings for persons living with HIV. 59. Estrada BD, Trujillo S, Estrada AL. Supporting healthy alternatives J Acquir Immune Defic Syndr. 2010;53:348–356. through patient education: a theoretically driven HIV prevention 40. Margolin A, Schuman-Olivier Z, Beitel M, et al. A preliminary study of intervention for persons living with HIV/AIDS. AIDS Behav. 2007; spiritual self-schema (3-S(+)) therapy for reducing impulsivity in HIV- 11(Suppl 1):S95–S105. positive drug users. J Clin Psychol. 2007;63:979–999. 60. Golin CE, Davis RA, Przybyla SM, et al. SafeTalk, a multicomponent, 41. Mausbach BT, Semple SJ, Strathdee SA, et al. Efficacy of a behavioral motivational interviewing-based, safer sex counseling program for intervention for increasing safer sex behaviors in HIV-positive MSM people living with HIV/AIDS: a qualitative assessment of patient’s methamphetamine users: results from the EDGE study. Drug Alcohol views. AIDS Patient Care STDS. 2010;24:237–245. Depend. 2007;87:249–257. 61. Golin CE, Patel S, Tiller K, et al. Start talking about risks: development 42. Mitchell CG, Freels S, Creticos CM, et al. Preliminary findings of an of a motivational interviewing-based safer sex program for people living intervention integrating modified directly observed therapy and risk with HIV. AIDS Behav. 2007;11(Suppl 1):S72–S83. reduction counseling. AIDS Care. 2007;19:561–564. 62. Grimley DM, Bachmann LH, Jenckes MW, et al. Provider-delivered, 43. Naar-King S, Parsons JT, Murphy DA, et al. Improving health outcomes theory-based, individualized prevention interventions for HIV-positive for youth living with the human immunodeficiency virus: a multisite adults receiving HIV comprehensive care. AIDS Behav. 2007;11 randomized trial of a motivational intervention targeting multiple risk (Suppl 1):S39–S47. behaviors. Arch Pediatr Adolesc Med. 2009;163:1092–1098. 63. Holstad MM, DiIorio C, Magowe MK. Motivating HIV-positive women 44. Petry NM, Weinstock J, Alessi SM, et al. Group-based randomized trial to adhere to antiretroviral therapy and risk reduction behavior: the of contingencies for health and abstinence in HIV patients. J Consult KHARMA Project. Online J Issues Nurs. 2006;11:5. Clin Psychol. 2010;78:89–97. 64. Kalichman SC, Cherry C, White D, et al. Altering key characteristics of 45. Purcell DW, Latka MH, Metsch LR, et al. Results from a randomized a disseminated effective behavioral intervention for HIV positive adults: controlled trial of a peer-mentoring intervention to reduce HIV the ‘‘healthy relationships’’ experience. J Prim Prev. 2007;28:145–153. transmission and increase access to care and adherence to HIV 65. Knauz RO, Safren SA, O’Cleirigh C, et al. Developing an HIV- medications among HIV-seropositive injection drug users. J Acquir prevention intervention for HIV-infected men who have sex with men in Immune Defic Syndr. 2007;46(Suppl 2):S35–S47. HIV care: Project Enhance. AIDS Behav. 2007;11(Suppl 1):S117–S126. 46. Rosser BR, Hatfield LA, Miner MH, et al. Effects of a behavioral 66. Lightfoot M, Rotheram-Borus MJ, Tevendale H. An HIV-preventive intervention to reduce serodiscordant unsafe sex among HIV-positive intervention for youth living with HIV. Behav Modif. 2007;31:345–363. men who have sex with men: the Positive Connections randomized 67. Mitchell CG, Perloff J, McVicker J, et al. Integrating prevention in controlled trial study. J Behav Med. 2010;33:147–158. residential and community care settings: a multidimensional program 47. Serovich JM, Reed S, Grafsky EL, et al. An intervention to assist men evaluation. AIDS Educ Prev. 2005;17(1 suppl A):89–101. who have sex with men disclose their serostatus to casual sex partners: 68. Naar-King S, Wright K, Parsons JT, et al. Healthy choices: motivational results from a pilot study. AIDS Educ Prev. 2009;21:207–219. enhancement therapy for health risk behaviors in HIV-positive youth. 48. Sikkema KJ, Wilson PA, Hansen NB, et al. Effects of a coping AIDS Educ Prev. 2006;18:1–11. intervention on transmission risk behavior among people living with 69. Naar-King S, Lam P, Wang B, et al. Brief report: maintenance of effects HIV/AIDS and a history of childhood sexual abuse. J Acquir Immune of motivational enhancement therapy to improve risk behaviors and HIV- Defic Syndr. 2008;47:506–513. related health in a randomized controlled trial of youth living with HIV. 49. Teti M, Bowleg L, Cole R, et al. A mixed methods evaluation of the J Pediatr Psychol. 2008;33:441–445. effect of the protect and respect intervention on the condom use and 70. Nollen C, Drainoni ML, Sharp V.Designing and delivering a prevention disclosure practices of women living with HIV/AIDS. AIDS Behav. project within an HIV treatment setting: lessons learned from a specialist 2010;14:567–579. model. AIDS Behav. 2007;11(Suppl 1):S84–S94. 50. Velasquez MM, von Sternberg K, Johnson DH, et al. Reducing sexual 71. Raja S, McKirnan D, Glick N. The Treatment Advocacy Program–Sinai: risk behaviors and alcohol use among HIV-positive men who have sex a peer-based HIV prevention intervention for working with African with men: a randomized clinical trial. J Consult Clin Psychol. 2009;77: American HIV-infected persons. AIDS Behav. 2007;11(Suppl 1): 657–667. S127–S137.

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72. Raja S, Teti M, Knauz RO, et al. Implementing peer-based intervention 87. Erbelding EJ, Stanton D, Quinn TC, et al. Behavioral and biologic in clinic-based settings: lessons from a multi-site HIV prevention with evidence of persistent high-risk behavior in an HIV primary care positives initiative. J HIV AIDS Soc Serv. 2008;7:7–26. population. AIDS. 2000;14:297–301. 73. Rutledge SE. Single-session motivational enhancement counseling to 88. Mellins CA, Elkington KS, Bauermeister JA, et al. Sexual and drug use support change toward reduction of HIV transmission by HIV positive behavior in perinatally HIV-infected youth: mental health and family persons. Arch Sex Behav. 2007;36:313–319. influences. J Am Acad Child Adolesc Psychiatry. 2009;48:810–819. 74. Teti M, Rubinstein S, Lloyd L, et al. The Protect and Respect Program: 89. Takizawa C, Cheng D, Samet J, et al. Primary medical care and a sexual risk reduction intervention for women living with HIV/AIDS. reductions in HIV risk behaviors in adults with addictions. J Addict Dis. AIDS Behav. 2007;11(Suppl 1):S106–S116. 2007;26:17–25. 75. Williams JK, Ramamurthi HC, Manago C, et al. Learning from 90. Giordano TP,Gifford AL, White AC Jr, et al. Retention in care: a challenge successful interventions: a culturally congruent HIV risk-reduction to survival with HIV infection. Clin Infect Dis. 2007;44:1493–1499. intervention for African American men who have sex with men and 91. Parks DA, Jennings HC, Taylor CW, et al. Pharmacokinetics of once- women. Am J Public Health. 2009;99:1008–1012. daily tenofovir, emtricitabine, ritonavir and fosamprenavir in HIV- 76. Sikkema KJ, Hansen NB, Kochman A, et al. Outcomes from a group infected subjects. AIDS. 2007;21:1373–1375. intervention for coping with HIV/AIDS and childhood sexual abuse: 92. Berg CJ, Michelson SE, Safren SA. Behavioral aspects of HIV care: reductions in traumatic stress. AIDS Behav. 2007;11:49–60. adherence, depression, substance use, and HIV-transmission behaviors. 77. Hart GJ, Elford J. Sexual risk behaviour of men who have sex with men: Infect Dis Clin North Am. 2007;21:181–200. emerging patterns and new challenges. Curr Opin Infect Dis. 2010;23: 93. Myers JJ, Shade SB, Rose CD, et al. Interventions delivered in clinical 39–44. settings are effective in reducing risk of HIV transmission among people 78. Eaton LA, Kalichman SC. Changes in transmission risk behaviors across living with HIV: results from the Health Resources and Services stages of HIV disease among people living with HIV. J Assoc Nurses Administration (HRSA)’s special projects of national significance AIDS Care. 2009;20:39–49. initiative. AIDS Behav. 2010;14:483–492. 79. Coleman SM, Rajabiun S, Cabral HJ. Sexual risk behavior and behavior 94. Bangsberg DR. Preventing HIV antiretroviral resistance through better change among persons newly diagnosed with HIV: the impact of targeted monitoring of treatment adherence. J Infect Dis. 2008;197(Suppl 3): outreach interventions among hard-to-reach populations. AIDS Patient S272–S278. Care STDS. 2009;23:639–645. 95. Bangsberg DR, Acosta EP, Gupta R, et al. Adherence-resistance 80. Grossman CI, Gordon CM. Mental health considerations in secondary relationships for protease and non-nucleoside reverse transcriptase HIV prevention. AIDS Behav. 2010;14:263–271. inhibitors explained by virological fitness. AIDS. 2006;20:223–231. 81. Peretti-Watel P, Spire B, Schiltz MA, et al. Vulnerability, unsafe sex and 96. Amico KR, Harman JJ, Johnson BT. Efficacy of antiretroviral therapy non-adherence to HAART: evidence from a large sample of French HIV/ adherence interventions: a research synthesis of trials, 1996 to 2004. AIDS outpatients. Soc Sci Med. 2006;62:2420–2433. J Acquir Immune Defic Syndr. 2006;41:285–297. 82. Marks G, Crepaz N, Senterfitt JW,et al. Meta-analysis of high-risk sexual 97. Lalani T, Hicks C. Does antiretroviral therapy prevent HIV transmission behavior in persons aware and unaware they are infected with HIV in the to sexual partners? Curr HIV/AIDS Rep. 2007;4:80–85. United States: implications for HIV prevention programs. J Acquir 98. Crepaz N, Hart TA, Marks G. Highly active antiretroviral therapy and Immune Defic Syndr. 2005;39:446–453. sexual risk behavior: a meta-analytic review. JAMA. 2004;292:224–236. 83. Weinhardt LS, Carey MP, Johnson BT, et al. Effects of HIV counseling 99. Mannheimer SB, Morse E, Matts JP, et al. Sustained benefit from a long- and testing on sexual risk behavior: a meta-analytic review of published term antiretroviral adherence intervention. Results of a large randomized research, 1985–1997. Am J Public Health. 1999;89:1397–1405. clinical trial. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S41–S47. 84. Horstmann E, Brown J, Islam F, et al. Retaining HIV-infected patients in 100. Simoni JM, Amico KR, Smith L, et al. Antiretroviral adherence care: where are we? Where do we go from here? Clin Infect Dis. 2010;50: interventions: translating research findings to the real world clinic. Curr 752–761. HIV/AIDS Rep. 2010;7:44–51. 85. Gardner LI, Marks G, Metsch LR, et al. Psychological and behavioral 101. Simoni JM, Pearson CR, Pantalone DW, et al. Efficacy of interventions correlates of entering care for HIV infection: the Antiretroviral in improving highly active antiretroviral therapy adherence and HIV-1 Treatment Access Study (ARTAS). AIDS Patient Care STDS. 2007;21: RNA viral load: a meta-analytic review of randomized controlled trials. 418–425. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S23–S35. 86. Latkin CA, Buchanan AS, Metsch LR, et al. Predictors of sharing 102. Remien RH, Mellins CA. Long-term psychosocial challenges for people injection equipment by HIV-seropositive injection drug users. J Acquir living with HIV: let’s not forget the individual in our global response to Immune Defic Syndr. 2008;49:447–450. the . AIDS. 2007;21(Suppl 5):S55–S63.

q 2010 Lippincott Williams & Wilkins www.jaids.com | S115 SUPPLEMENT ARTICLE

Antiretroviral Therapy: A Promising HIV Prevention Strategy? Wafaa M. El-Sadr, MD, MPH, MPA,*†‡ Megan Affrunti, MPH, MSW,* Theresa Gamble, PhD,§ and Allison Zerbe, MPH*

derided the model’s optimistic assumptions, which included Abstract: The use of antiretroviral therapy (ART) has been annual HIV testing for all adults older than 15 years, associated with significant improvement in morbidity and survival immediate ART initiation for the vast numbers of individuals of persons living with HIV. In addition, recently, there has also been found to be HIV infected, and achievement of high rates of intense interest in the potential impact of ART on HIV transmission adherence with treatment.3 Further, many questioned the and consequently on the trajectory of the HIV epidemic globally. feasibility of achieving such goals in low-income and middle- Evidence from mathematical modeling analyses and observational income countries, settings already struggling with efforts to and ecological studies supports the potential for ART as prevention. expand HIV testing to their populations and to provide access However, definitive data from clinical trials are awaited. In the United to antiretroviral drugs for those with advanced HIV disease States, the feasibility and potential of using ART as a prevention who are in urgent need of this life-saving treatment. strategy presents particular challenges: the large number of Nevertheless, the findings from the model generated great individuals with undiagnosed HIV; the predominance of disenfran- interest in exploring the feasibility of this ‘‘test and treat’’ chised individuals affected by the epidemic; evidence of delay in strategy, particularly in view of the limited effectiveness engagement in HIV care after diagnosis with attendant late initiation demonstrated by other prevention interventions to date and the of ART; and difficulties with consistent long-term adherence to ART lack of progress in controlling the global HIV epidemic.3–5 and concerns regarding long-term risk-behavior change. Thus, for At the core of the rationale for use of ART for prevention this novel effort to succeed, a multidimensional approach is necessary are findings that demonstrate that antiretroviral drugs can lead that must include policy changes, social mobilization, and improved to suppression of viral replication in the bloodstream and in access to clinical and supportive services for persons living with HIV, genital tract secretions, with the potential consequence of a with a particular focus on the unique needs of at-risk populations, decrease in infectiousness.6–8 However, the concurrence of combined with engagement of all cadres of health care providers and suppressed virus in plasma and genital secretions has not been community constituencies. consistently demonstrated, and HIV detection in the genital Key Words: antiretroviral therapy, HIV treatment, prevention, secretions may be influenced by the presence of concurrent transmission sexually transmitted infections, the genital sampling method, and the timing of specimen collection, particularly in relation (J Acquir Immune Defic Syndr 2010;55:S116–S121) to the menstrual cycle.9–12 The use of ART in HIV-infected patients as a strategy for HIV prevention is not a novel idea. Several publications from indings from a mathematical modeling study of the effect as early as 2000 have suggested this possibility.8,13 In addition, Fof antiretroviral therapy (ART) on HIV incidence and other mathematical models have examined the issue, some prevalence, reported by Granich et al in early 2009, were met using less optimistic assumptions than those used by Granich 1 with a mix of excitement and disbelief. Using data from the et al, resulting in a less dramatic effect on HIV incidence.14–16 HIV epidemic in South Africa, this model suggested that with Accumulating evidence from observational and ecological expanded HIV testing and prompt initiation of ART by all studies provides additional support for possible effectiveness those found to be HIV infected, a substantial decrease in of treatment for prevention. A study in Uganda found that the 2 incidence of HIV could be achieved in that country. Skeptics risk of HIV transmission was 0.9 per 1000 person-years with the use of ART compared with 45.7 per 1000 person-years without.17 An analysis of linked HIV transmission in HIV discordant heterosexual couples from sub-Saharan Africa demonstrated that use of ART by the HIV-infected partners From the *International Center for AIDS Care and Treatment Programs, 18 Mailman School of Public Health; †College of Physicians and Surgeons, was associated with a 92% decrease in HIV transmission. Columbia University; and ‡Harlem Hospital Center, New York, NY; and However, conflicting findings were reported from a study of §FHI, Durham, NC. discordant couples in China, where use of ART was not Correspondence to: Wafaa El-Sadr, MD, MPH, MPA, International Center for associated with a statistically significant decrease in HIV AIDS Care and Treatment Programs, Mailman School of Public Health, 722 W 168th Street, Room 715, New York, NY 10032 (e-mail: wme1@ transmission to the HIV-uninfected partner, raising concerns columbia.edu) that suboptimal long-term adherence could compromise Copyright Ó 2010 by Lippincott Williams & Wilkins ART’s benefit in decreasing infectiousness.19

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In terms of ecological evidence in support of the potential effect of ART on HIV transmission, in one study, a decrease in median community viral load in San Francisco was reported to be associated with a decrease in new HIV in- fections.20 Similarly, data from British Columbia, Canada, indicated that an increase in the proportion of HIV-infected individuals with undetectable viral loads was associated with a decrease in number of new HIV infections.21 Similarly, in a study from Taiwan, a decrease in HIV transmission by 53% was noted after establishment of a national program for provision of free ART to all HIV-infected individuals in that country.22 Findings from such observational and ecological data, however, must be interpreted with caution due to possible selection biases. For example, individuals who initiate ART versus those who do not may differ in certain characteristics (eg, sexual risk taking). Moreover, ecological studies cannot account for viral load levels among individuals unaware of their HIV diagnosis in any given community; this will affect the imputations used to take into account missing viral load measurements. Thus, it is important to appreciate that definitive data supporting the long-term impact of ART on HIV incidence are not yet available and to await the results of randomized clinical trials, including HIV Prevention Trials Network (HPTN 052), an ongoing study evaluating the effect of immediate versus deferred ART on transmission of HIV to the uninfected member of the discordant couple.23 The HIV epidemic in the United States is an entrenched one, with about 56,000 new infections occurring per year over the past decade, and no evidence to date of a decrease in the annual number of new infections.24 Although screening the blood supply, promoting the use of condoms and the expansion of syringe access and exchange, limiting the number of partners, and serosorting, and interventions for prevention of mother-to-child transmission, have shown FIGURE 1. Common characteristics of the United States HIV epidemic and challenges for achieving potential for ART as positive effects in reducing transmission in the United States, prevention. *AIDS drug assistance programs, ART. particularly in the early years of the epidemic, the unchanged magnitude of new infections in the past decade clearly motivates the need for innovative prevention strategies, 1 million individuals living with HIV,21% are unaware of their including an exploration of the test and treat approach. HIV status.25 Evidence suggests that these individuals are However, certain characteristics of the HIV epidemic need to responsible for more than 50% of new sexually transmitted be taken into account when such a strategy is considered, and infections and are 2.5 times more likely to transmit HIV than several challenges must be confronted if the promise of ART individuals who are aware of their HIV infection.26 Of further for prevention can be realized in the United States. These concern is the fact that the proportion of individuals unaware characteristics include the large numbers of individuals who of their HIV infection is even higher among blacks, a group at (1) are unaware of their HIV infection; (2) are diagnosed late particular risk for HIV in the United States. In a study with HIV infection; (3) delay or face barriers to accessing care conducted among men who have sex with men (MSM), 77% and initiate ART at late-stage HIV disease; (4) have suboptimal of those found to be HIV infected were unaware of their HIV adherence to ART over time; and (5) continue to engage in status; of this group, 91% were black and 60% white.27 HIV transmission risk behaviors. Figure 1 illustrates these A further challenge to identification of individuals with challenges and highlights many of the behavioral, economic, HIV in the United States is the localized nature of the HIV societal, and policy issues that impede individuals from epidemic, disproportionately targeting vulnerable and disen- achieving milestones that are critical to the success of the ART- franchised populations, particularly MSM and blacks within for-prevention approach. specific geographic regions.28 For example, in Washington, DC, the city with the highest HIV seroprevalence in the United States, HIV prevalence is highest among black males (6.5%); LACK OF AWARENESS OF HIV STATUS among MSM in that city, blacks account for 58% of all Identifying all individuals with HIV infection in HIV/AIDS cases.29 In New York City, the US city with the a community is the foundation of effective use of ART for largest number of people living with HIV, 1 in 10 MSM are prevention. However, US data indicate that of the estimated estimated to be infected with HIV.30 Additionally, recently q 2010 Lippincott Williams & Wilkins www.jaids.com | S117 El-Sadr et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 published data found that black men comprise the city’s largest 1928 newly diagnosed individuals, only 63.7% were linked to demographic group of new HIV diagnoses (33%) and persons HIV care within 3 months, and 17.2% never initiated care.43 living with HIV/AIDS (29%) and have the city’s highest HIV Studies demonstrate that not only is HIV care initiated late or prevalence (3.7%).31 Special efforts are needed to effectively not at all in some cases but also there are racial, ethnic, gender, reach these populations in a culturally appropriate manner that and other disparities related to when and whether care is avoids further stigmatization. started. Multiple studies demonstrate that nonwhite race, Although the Centers for Disease Control and Pre- foreign birth, and female sex predict delayed initiation of vention recommended almost 4 years ago that all Americans care.43–45 Studies have also shown that injection drug users aged 13–64 be tested for HIV at least once, only 10% indicate delay care and are particularly likely to be homeless and that they were HIV tested during the past year.32,33 Many incarcerated and to have untreated psychiatric illness that may factors impede expansion of HIV screening, including health hinder or complicate ART delivery and adherence. Injection care providers’ continued reliance on risk-based testing rather drug users also experience more rapid HIV disease pro- than on routine screening. It is more common for health care gression.46,47 The personal and societal benefits of timely HIV providers to offer testing when HIV is suspected clinically or diagnosis can be realized only when it is combined with timely based on their perception of an individual’s risk.34 This initiation of clinical care. Earlier linkage to care results in greater approach is fraught with limitations since HIV risk in the opportunities for virological and immunologic monitoring and United States is often related more to an individual’s sexual initiation of ART, once eligibility is established, and greater network than to his or her risk behaviors—information that access to interventions for prevention for positives.48 many persons do not share with their health care providers.34,35 Despite the challenges, successful initiatives have ex- panded HIV testing in some geographic regions. A recent scale- INITIATION OF ART AT LOW CD4+ up effort led by the New York City Department of Health, called CELL COUNTS ‘‘The Bronx Knows,’’ has coincided with a statistically significant Studies have shown that many HIV-infected individuals increase in the percent of Bronx residents between the ages of in the United States initiate ART at low CD4+ cell counts, 18–64 reporting that they have ever been tested for HIV.36 substantially below the thresholds currently recommended by US guidelines for use of ART.49 In a study, among 35,009 DIAGNOSIS AT LATE STAGE OF DISEASE patients followed from 1996 to 2007, although the median CD4+ cell count at first presentation slightly increased from 234 Evidence indicates that many individuals in the United to 327 cells per cubic millimeter, 53% of patients still had States are being tested late in the course of their HIV infection: CD4+ cell counts at presentation below the prevailing guideline Approximately 40% of individuals receiving their first HIV- threshold for ART initiation.50 In another study, treatment- positive test result are diagnosed with AIDS within a year.37 In eligible injection drug users from Baltimore who were observed New York City in 2008, 25% of those tested had a concurrent from 1996 to 2007 initiated therapy, after lengthy delays, with HIV/AIDS diagnosis.38 In a study that examined surveillance advanced immunosuppression. Nearly one third of individuals data from New York City, concurrent diagnosis of AIDS who became eligible for treatment had not initiated ART when and HIV infection was substantially more common among guidelines would suggest optimal benefit.51 blacks and Latinos than among whites.39 The frequency of In addition to late diagnoses of HIV, a number of other late diagnosis is of concern both to the individual and the factors contribute to delays in ART initiation, including limited community. Those testing late in the course of HIV infection treatment literacy; patient refusal to begin ART for fear of side miss out on the clinical benefits of HIV care and treatment effects; and reluctance by some providers to prescribe ART and may also unknowingly contribute to the spread of HIV due to real or perceived barriers to adherence.52 Resource to others within their communities because their higher constraints among state AIDS drug assistance programs, plasma HIV RNA levels are also correlated with increased which provide support for ART to approximately one quarter infectiousness. Alone, expanded HIV testing could have a of all patients enrolled in HIV/AIDS care in the United substantial impact on HIV transmission in the United States, States,53 also account for some delays in ART initiation. Some as it has the potential to lead to earlier diagnosis of HIV and AIDS drug assistance programs already have waiting lists for earlier adoption of safer behaviors40 and allows for earlier patients in need of ART, a situation that may be exacerbated in access to care and treatment, with its demonstrated benefits view of the revised ART guidelines released in 2009, which in terms of immunological response and better outcomes recommend initiation of ART at higher CD4+ cell count and survival.41,42 thresholds, combined with limited public health resources in the setting of a severe economic recession.54 DELAY IN LINKAGE TO HIV CARE AFTER HIV DIAGNOSIS The promise of treatment as a prevention strategy also DIFFICULTY IN ACHIEVING AND depends on individuals promptly linking to care, initiating MAINTAINING HIGH RATES OF ADHERENCE treatment when recommended, and achieving sustained viral WITH ART suppression and decreasing risk-taking behavior. In terms of Achievement of viral suppression on ART is dependent linkage to care, findings from New York City indicate that of on correct and consistent use of effective antiretroviral

S118 | www.jaids.com q 2010 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 HIV Treatment as Prevention regimens. Results from a meta-analysis of 31 adherence such as stigma, mistrust of health systems, misperceptions of studies showed that only 55% of HIV-infected patients HIV risk, access to services, support for comorbid conditions, achieved adequate ART adherence in North America.55 and psychosocial impediments need to be addressed if the test However, research suggests that high levels of adherence, and treat approach is to succeed. In a parallel manner, between 80% and 95% depending on regimen type, may be interventions will be needed to address provider skills and necessary to maintain viral suppression.56 Various complex attitudes regarding HIV testing, perceptions of eligibility for factors have been shown to contribute to suboptimal ART initiation, skills in support of adherence, and attitudes adherence, including active substance use (including the use regarding the balance of patient versus societal benefits of of alcohol), young age, and depression—all issues that ART. Indeed, beyond a focus on test and treat as the 2 elements highlight the importance of providing HIV-infected patients of a successful ART-for-prevention strategy, the United States with access to supportive services.57,58 Indeed, retaining epidemic compels a much more comprehensive perspective patients in care is a prerequisite for achievement of the high that entails a seek, test, link, treat, and support approach, rates of ART utilization and adherence required for garnering necessitating an unprecedented partnership involving com- the potential benefits of the ART for prevention strategy. munities, providers, support organizations, and persons living A recently published modeling study in which the effective- with HIV themselves. ness of a comprehensive approach to test and treat that included enhanced linkage to care after diagnosis and high retention in care was compared with solely universal test and ACKNOWLEDGMENTS treat demonstrated that the former package of interventions The authors wish to acknowledge contributions by was associated with substantially increased benefits.59 It is also Blayne Cutler, Lucia Torian, Shannon Hader, Tiffany West, important to note that even with optimal adherence, and Nnemdi Kamanu Elias. We acknowledge support by the suppression of viral replication is not always achievable and HIV Prevention Trials Network. Financial support provided by the possibility of discordance between HIV viral load in the the National Institute of Allergy and Infectious Diseases and plasma and genital secretions remains, issues that underscore the National Institute of Mental Health under award number the need for other interventions for prevention for positives.60 U01 AI069466. Several positive prevention interventions have been shown to be associated with a decrease in high-risk behaviors (eg, REFERENCES unprotected anal sex), a decrease in substance use, and an 1. Garnett GP, Baggaley RF. Treating our way out of the HIV pandemic: increase in condom use.60 Ultimately, the use of such could we, would we, should we? Lancet. 2009;373:9–11. doi:10.1016/ S0140-6736(08)61698-0. interventions will be critical to complement the effects of 2. Granich RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with ART for prevention. immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373:48–57. doi: 10.1016/S0140-6736(08)61697-9. THE WAY FORWARD 3. Cohen MS, Mastro TD, Cates W Jr. Universal voluntary HIV testing and immediate antiretroviral therapy [correspondence; authors’ reply, 1080– Continued HIV transmission in the United States has 1081]. Lancet. 2009;373:1077–1081. doi:10.1016/S0140- generated interest in the potential use of ART for prevention. 6736(09)60640-1, doi:10.1016/S0140-6736(09)60648-6. A recent report of the results of a mathematical model utilizing 4. Dieffenbach CW, Fauci AS. Universal voluntary testing and treatment for data from Washington, DC, demonstrated only a modest effect prevention of HIV transmission. JAMA. 2009;301:2380–2382. doi: on HIV transmission with expanded HIV screening and 10.1001/jama.2009.828. 16 5. Assefa Y, Lera M. Universal voluntary HIV testing and immediate ART. Nonetheless, momentum has been generated to test this antiretroviral therapy. Lancet. 2009;373:1080–1081. doi:10.1016/S0140- concept by embarking on feasibility studies of such an 6736(09)60647-4. approach. From a conceptual perspective, taking into account 6. Cu-Uvin S, Snyder B, Harwell JI, et al. Association between paired the unique characteristics of the HIV epidemic in the United plasma and cervicovaginal lavage fluid HIV-1 RNA levels during 36 months. J Acquir Immune Defic Syndr. 2006;42:584–587. doi: 10.1097/ States is critical to the design of such studies and to the design 01.qai.0000229997.52246.95. of the types of interventions to include as part of the test and 7. Cohen MS, Hoffman IF, Royce RA, et al. Reduction of concentration of treat strategy. One study to address these issues is in HIV-1 in semen after treatment of urethritis: implications for prevention of development by the HIV Prevention Trials Network (HPTN sexual transmission of HIV-1. AIDSCAP Malawi Research Group. Lancet. 1997;349:1868–1873. doi:10.1016/S0140-6736(97)02190-9. 065), the Test, Link to Care, Plus Treat study, a collaboration 8. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual between the National Institutes of Health, the Centers for transmission of human immunodeficiency virus type 1. Rakai Project Disease Control and Prevention, local health departments, and Study Group. N Engl J Med. 2000;342:921–929. a broad array of stakeholders.61 The study will focus on 9. Fiore JR, Suligoi B, Saracino A, et al. Correlates of HIV-1 shedding in specific interventions to optimize testing, linkage to care, and cervicovaginal secretions and effects of antiretroviral therapies. AIDS. 2003;17:2169–2176. doi:10.1097/01.aids.0000088178.01779.b4. suppression of viral replication in the Bronx and Washington, 10. Nagot N, Ouedraogo A, Weiss HA, et al. Longitudinal effect following DC, and may inform other large-scale domestic initiatives in initiation of highly active antiretroviral therapy on plasma and cervico- the future. Based on the issues delineated above, embarking on vaginal HIV-1 RNA among women in Burkina Faso. Sex Transm Infect. such an effort will require addressing the factors that influence 2008;84:167–170. doi:10.1136/sti.2007.027987. 11. Xu C, Politch JA, Tucker L, et al. Factors associated with increased levels a cascade of events: individuals’ access to and acceptance of of human immunodeficiency virus type 1 DNA in semen. J Infect Dis. HIV testing and the impediments to engagement in HIV care, 1997;176:941–947. Available at: http://www.journals.uchicago.edu/doi/ adherence to ART and positive prevention behaviors. Barriers pdf/10.1086/516539. 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12. Al-Harthi L, Kovacs A, Coombs RW, et al. A menstrual cycle pattern for 32. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommenda- cytokine levels exists in HIV-positive women: implication for HIV vaginal tions for HIV testing of adults, adolescents, and pregnant women in and plasma shedding. AIDS. 2001;15:1535–1543. Available at: http:// health-care settings. MMWR Recomm Rep. 2006;55(RR14):1–17. Avail- journals.lww.com/aidsonline/Fulltext/2001/08170/A_menstrual_cycle_ able at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm. pattern_for_cytokine_levels.11.aspx. Accessed August 15, 2010. Accessed August 15, 2010. 13. Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could widespread 33. Centers for Disease Control and Prevention. Persons tested for HIV— use of combination antiretroviral therapy eradicate HIVepidemics? Lancet United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;57:845–849. Infect Dis. 2002;2:487–493. doi:10.1016/S1473-3099(02)00346-8. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ 14. Wagner BG, Kahn JS, Blower S. Should we try to eliminate HIV mm5731a1.htm. Accessed August 15, 2010. epidemics by using a ÔTest and Treat’ strategy? AIDS. 2010;24:775–776. 34. Beckwith CG, Flanigan TP, del Rio C, et al. It is time to implement doi:10.1097/QAD.0b013e3283366782. routine, not risk-based, HIV testing. Clin Infect Dis. 2005;40:1037–1040. 15. Dodd PJ, Garnett GP, Hallett TB. Examining the promise of HIV doi:10.1086/428620. elimination by Ôtest and treat’ in hyperendemic settings. AIDS. 2010;24: 35. Millett GA, Peterson JL. The known hidden epidemic HIV/AIDS among 729–735. doi:10.1097/QAD.0b013e32833433fe. black men who have sex with men in the United States. Am J Prev Med. 16. Walensky RP, Paltiel AD, Losina E, et al. Test and treat DC: forecasting 2007;32(Suppl 1):S31–S33. doi:10.1016/j.amepre.2006.12.028. the impact of a comprehensive HIV strategy in Washington DC. Clin 36. EpiQuery: NYC Interactive Health Data System, Community Health Infect Dis. 2010;51:392–400. doi:10.1086/655130. Survey 2009. Database online. New York,NY: New YorkCity Department 17. Bunnell R, Ekwaru JP, Solberg P, et al. Changes in sexual behavior and of Health and Mental Hygiene. Available at: http://nyc.gov/health/ risk of HIV transmission after antiretroviral therapy and prevention epiquery. Accessed August 15, 2010. interventions in rural Uganda. AIDS. 2006;20:85–92. Available at: http:// 37. Valdiserri RO, Holtgrave DR, West GR. Promoting early HIV diagnosis journals.lww.com/aidsonline/Fulltext/2006/01020/Changes_in_sexual_ and entry into care. AIDS. 1999;13:2317–2330. behavior_and_risk_of_HIV.12.aspx. Accessed August 15, 2010. 38. New York City Department of Hygiene and Mental Health. HIV 18. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission Epidemiology and Field Services Semiannual Report. Vol 4, No 1. April after initiation of antiretroviral therapy: a prospective cohort analysis. 2009. Available at: http://www.nyc.gov/html/doh/downloads/pdf/dires/ Lancet. 2010;375:2092–2098. doi:10.1016/S0140-6736(10)60705-2. dires-2009-report-semi1.pdf. Accessed August 15, 2010. 19. Wang L, Ge Z, Luo J, et al. HIV transmission risk among serodiscordant 39. Hanna DB, Pfeiffer MR, Torian LV,et al. Concurrent HIV/AIDS diagnosis couples: a retrospective study of former plasma donors in Henan, China. increases the risk of short-term HIV-related death among persons newly J Acquir Immune Defic Syndr. 2010;55:232–238. Published online ahead diagnosed with AIDS, 2002–2005. AIDS Patient Care STDS. 2008;22: of print, post author corrections, July 26, 2010. 17–28. doi:10.1089/apc.2007.0042. 20. Das M, Chu PL, Santos GM, et al. Decreases in community viral load are 40. Marks G, Crepaz N, Senterfitt JW, et al. Meta-analysis of high-risk sexual accompanied by reductions in new HIV infections in San Francisco. PLoS behavior in persons aware and unaware they are infected with HIV in the One. 2010;5(6):e11068. doi:10.1371/journal.pone.0011068. United States: implications for HIV prevention programs. J Acquir 21. Montaner JS, Lima VD, Barrios R, et al. Association of highly active Immune Defic Syndr. 2005;39:446–453. antiretroviral therapy coverage, population viral load, and yearly new HIV 41. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T diagnoses in British Columbia, Canada: a population-based study. Lancet. cell subsets on combination antiretroviral therapy in the AIDS Clinical 2010;376:532–539. Trials Group Protocol 384. Clin Infect Dis. 2009;48:350–361. doi: 22. Fang CT, Hsu HM, Twu SJ, et al. Decreased HIV transmission after 10.1086/595888. a policy of providing free access to highly active antiretroviral therapy in 42. Sterne JA, May M, Costagliola D, et al. Timing of initiation of Taiwan. J Infect Dis. 2004;190:879–885. doi:10.1086/422601. antiretroviral therapy in AIDS-free HIV-1-infectedpatients: a collaborative 23. Cohen MS, Gay CL. Treatment to prevent transmission of HIV-1. Clin analysis of 18 HIV cohort studies. Lancet. 2009;373:1352–1363. doi: Infect Dis. 2010;50(Suppl 3):S85–S95. doi:10.1086/651478. 10.1016/S0140-6736(09)60612-7. 24. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the 43. Torian LV,Wiewel EW, Liu KL, et al. Risk factors for delayed initiation of United States. JAMA. 2008;300:520–529. PMCID:PMC2919237. medical care after diagnosis of human immunodeficiency virus. Arch 25. Campsmith ML, Rhodes PH, Hall HI, et al. Undiagnosed HIV prevalence Intern Med. 2008;168:1181–1187. Available at: http://archinte.ama- among adults and adolescents in the United States at the end of 2006. assn.org/cgi/content/full/168/11/1181. Accessed August 15, 2010. J Acquir Immune Defic Syndr. 2010;53:619–624. Erratum in: J Acquir 44. Gebo KA, Fleishman JA, Conviser R, et al. Racial and gender disparities Immune Defic Syndr. 2010;54:112. doi:10.1097/QAI.0b013e3181bf1c45. in receipt of highly active antiretroviral therapy persist in a multistate 26. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV sample of HIV patients in 2001. J Acquir Immune Defic Syndr. 2005;38: from persons aware and unaware that they are infected with the virus in 96–103. Available at: http://journals.lww.com/jaids/Fulltext/2005/01010/ the USA. AIDS. 2006;20:1447–1450. doi:10.1097/01.aids.0000233579. Racial_and_Gender_Disparities_in_Receipt_of_Highly.17.aspx. Accessed 79714.8d. August 15, 2010. 27. MacKellar DA, Valleroy LA, Secura GM, et al. Unrecognized HIV 45. Reif S, Whetten K, Thielman N. Association of race and gender with infection, risk behaviors, and perceptions of risk among young men who use of antiretroviral therapy among HIV-infected individuals in the have sex with men: opportunities for advancing HIV prevention in the southeastern United States. South Med J. 2007;100:775–781. doi: third decade of HIV/AIDS. J Acquir Immune Defic Syndr. 2005;38: 10.1097/SMJ.0b013e3180f626b4. 603–614. 46. Lucas GM, Griswold M, Gebo KA, et al. Illicit drug use and HIV-1 28. El-Sadr WM, Mayer KH, Hodder SL. AIDS in America—forgotten but disease progression: a longitudinal study in the era of highly active not gone. N Engl J Med. 2010;362:967–970. doi:10.1056/ antiretroviral therapy. Am J Epidemiol. 2006;163:412–420. doi:10.1093/ NEJMp1000069. aje/kwj059. 29. Department of Health, HIV/AIDS Administration. District of Columbia 47. Strathdee SA, Stockman JK. Epidemiology of HIV among injecting and HIV/AIDS Epidemiology Update 2008. Washington, DC: Government of non-injecting drug users: current trends and implications for interven- the District of Columbia. February 2009. Available at: http://dchealth.dc. tions. Curr HIV/AIDS Rep. 2010;7:99–106. doi:10.1007/s11904-010- gov/doh/lib/doh/pdf/dc_hiv-aids_2008_updatereport.pdf. Accessed August 0043-7. 15, 2010. 48. Stall R. Efforts to prevent HIV infection that target people living with 30. Nguyen TQ, Gwynn RC, Kellerman SE, et al. Population prevalence of HIV/AIDS: what works? Clin Infect Dis. 2007;45(Suppl 4):S308–S312. reported and unreported HIV and related behaviors among the household doi:10.1086/522555. adult population in New York City, 2004. AIDS. 2008;22:281–287. doi: 49. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human 10.1097/QAD.0b013e3282f2ef58. immunodeficiency virus care in the United States and Canada. Clin Infect 31. Wiewel EW, Hanna DB, Begier EM, et al. High HIV prevalence and Dis. 2010;50:1512–1520. doi:10.1086/652650. diagnosis rates in New York City black men. J Community Health. 50. Althoff K, Gange S, Klein M, et al. Late presentation for HIV care in Published online ahead of print June 24, 2010. doi:10.1007/s10900-010- the US and Canada. Paper #982. Presented at: 17th Conference of 9291-0. Retroviruses and Opportunistic Infections (CROI); February 16–19, 2010;

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San Francisco, CA. Poster presentation available at: http://www.retro- 55. Mills EJ, Nachega JB, Buchan I, et al. Adherence to antiretroviral therapy conference.org/2010/PDFs/982.pdf. Accessed August 15, 2010. in sub-Saharan Africa and North America: a meta-analysis. JAMA. 2006; 51. Mehta SH, Kirk GD, Astemborski J, et al. Temporal trends in highly active 296:679–690. Available at: http://jama.ama-assn.org/cgi/content/full/296/ antiretroviral therapy initiation among injection drug users in Baltimore, 6/679. Accessed August 15, 2010. Maryland, 1996–2008. Clin Infect Dis. 2010;50:1664–1671. doi:10.1086/ 56. Bangsberg DR. Preventing HIV antiretroviral resistance through better 652867. monitoring of treatment adherence. J Infect Dis. 2008;197(Suppl 3): 52. Bogart LM, Kelly JA, Catz SL, et al. Impact of medical and nonmedical S272–S278. doi:10.1086/533415. factors on physician decision making for HIV/AIDS antiretroviral 57. Lazo M, Gange SJ, Wilson TE, et al. Patterns and predictors of changes in treatment. J Acquir Immune Defic Syndr. 2000;23:396–404. Available adherence to highly active antiretroviral therapy: longitudinal study of men at: http://journals.lww.com/jaids/Fulltext/2000/04150/Impact_of_Medical_ and women. Clin Infect Dis. 2007;45:1377–1385. doi:10.1086/533415. and_Nonmedical_Factors_on.6.aspx. Accessed August 15, 2010. 58. Levine AJ, Hinkin CH, Castellon SA, et al. Variations in patterns of highly 53. Crustinger-Perry B, Penner MC, Pund B, For the National Alliance of active antiretroviral therapy (HAART) adherence. AIDS Behav. 2005;9: State and Territorial AIDS Directors (NASTAD). National ADAP 355–362. doi:10.1007/s10461-005-9009-y. Monitoring Project Annual Report. May 2010. Washington, DC: 59. Bendavid E, Brandeau ML, Wood R, et al. Comparative effectiveness of NASTAD; 2010. Available at: http://www.nastad.org/Docs/highlight/ HIV testing and treatment in highly regions. Arch Intern Med. 201053_2010%20National%20ADAP%20Monitoring%20Report.pdf. 2010;170:1347–1354. doi:10.1001/archinternmed.2010.249. Accessed August 15, 2010. 60. Fisher JD, Smith LR, Smith EM. Secondary prevention of HIV in the 54. Sack K. Economy hurts government aid for H.I.V. drugs. The New York United States: past, current, and future perspectives. J Acquir Immune Times. June 30, 2010. Available at: http://www.nytimes.com/2010/07/01/ Defic Syndr. 2010;55(Suppl 2):S116–S121. us/01aidsdrugs.html?_r=1&scp=1&sq=Economy%20Hurts%20Govern- 61. Vermund SH, Hodder SL, Justman JE, et al. Addressing research priorities ment%20Aid%20for%20HIV%20Drugs&st=cse. Accessed August 15, for prevention of HIV infection in the United States. Clin Infect Dis. 2010; 2010. 50(Suppl 3):S149–S155. doi:10.1086/651485.

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Chemoprophylaxis for HIV Prevention: New Opportunities and New Questions Kenneth H. Mayer, MD* and Kartik K. Venkatesh, PhD†

individuals.8 Numerous animal model studies have demon- Abstract: Growing data suggest that antiretrovirals can be used as strated that ART administered parenterally, orally, or topically an effective means of HIV prevention. This article reviews the current before or just after retroviral challenge was protective against status and future clinical prospects of utilizing antiretroviral chemo- HIV acquisition.9,10 Historically, treatment as prevention, or prophylaxis before and after high-risk HIV exposure to prevent HIV chemoprophylaxis, has been routinely used for other in- transmission. The discussion about using antiretrovirals as a means fectious diseases, including , tuberculosis, and sexually of primary HIV prevention has moved to the forefront of public transmitted infections (STIs),11,12 but the duration of admin- health discourse because of a growing evidence base, the increased istration is generally days to months rather than many years as tolerability of the medications, the decreased cost, the ever-expanding may be the case with HIV medications. formulary, and the limitations of other approaches. Antiretroviral postexposure prophylaxis (PEP) to pre- vent HIV acquisition was first recommended for use in Key Words: AIDS, ART, HIV, primary prevention, preexposure 13 prophylaxis, postexposure prophylaxis, topical microbicides occupational settings more than a decade ago. Subsequent studies have led to recommendations for its use in non- (J Acquir Immune Defic Syndr 2010;55:S122–S127) occupational settings, and research is underway to examine whether ART preexposure prophylaxis (PrEP) could be an effective method of primary prevention for individuals who have ongoing risks for becoming HIV infected.9,14 This article reviews the current status and future clinical prospects of WHY ANTIRETROVIRALS FOR PRIMARY utilizing antiretroviral chemoprophylaxis before and after HIV PREVENTION? high-risk HIV exposure to prevent HIV transmission. With more than 2.5 million new HIV infections annually,1 HIV prevention is at a crucial juncture because most biomedical interventions have failed to effectively POSTEXPOSURE PROPHYLAXIS decrease HIVacquisition,2 an effective HIV preventive vaccine The best proof of concept for the relationship between remains years away,3 and many behavioral strategies have not ARVs and HIV transmission comes from studies of the led to durable reductions in the number of new HIV prevention of mother-to-child transmission15,16 and a case– infections.4 Growing observational and modeling data suggest control study of PEP after needle stick injury in health care that antiretrovirals (ARVs) can be used as an effective means settings.17 The Centers for Disease Control and Prevention of HIV prevention.5 Antiretroviral therapy (ART) for pre- registry documented that health care workers who took vention includes not only prompt initiation of HIV-infected zidovudine (AZT) monotherapy after occupational exposure individuals on treatment to decrease the risk of transmis- were one fifth as likely to become HIV infected as those who sion6,7,8 but also ART prophylaxis for at-risk uninfected did not take treatment.13,17 The rhesus macaque simian immunodeficiency virus challenge model has suggested that 28 days of ART is needed for optimally effective PEP18 and From the *Division of Infectious Diseases, Department of Medicine, and has been the basis for the recommendation of a 4-week course Department of Community Health, Alpert Medical School, Brown for humans exposed to HIV.In the past, a major impediment to University, Miriam Hospital, Providence, RI; and †The Fenway Institute, Fenway Community Health, Boston, MA. wider implementation of PEP utilization was the relative This research has been facilitated by the infrastructure and resources provided intolerability of first-line agents, such as azidothymidine and by the Lifespan/Tufts/Brown Center for AIDS Research (grant# P30 protease inhibitors.19 A study examining PEP uptake in several AI42853; PI, Charles Carpenter) and the Brown/Tufts/Miriam Fogarty European emergency departments found that almost half of the AIDS International Training and Research Program (grant# D43TW000237; individuals did not complete the full 28-day PEP course PI, K.H.M.). K.K.V. is supported by NIMH Ruth Kirschstein National Research Service Award (NRSA; grant # F30 MH079738-01A2). because of decreased tolerability of regimens, including K.H.M. conceived the study. K.H.M. and K.K.V. synthesized analyzed and AZT/lamivudine and either ritonavir-boosted lopinavir or wrote the article. atazanavir.20 A subsequent case–control study of nonoccupa- The authors have no conflicts of interest. tional PEP found that men who took tenofovir–emtricitabine Correspondence to: Kenneth H. Mayer, MD, Division of Infectious Diseases, were more likely to complete a 28-day course of PEP Department of Medicine, Miriam Hospital, 164 Summit Avenue, 21 Providence, RI 02906 (e-mail: [email protected]). than historical controls taking 2-drug AZT-based regimens. Copyright Ó 2010 by Lippincott Williams & Wilkins Other newer drugs may also offer opportunities for novel PEP

S122 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 ART and HIV Primary Prevention strategies due to improved tolerability and novel mechanisms resistant strains. Thus, other ARVs have been suggested as of action (eg, raltegravir)22 and/or high genital tract concen- promising candidates for a multidrug PrEP regimen. Lam- trations (eg, maraviroc).23 It remains to be fully elucidated ivudine and emtricitabine may be optimal for use as PrEP whether 2 would be preferable to 3 for PEP. A 2-drug regimen because of their great tolerability and long safety record, and would decrease regimen complexity (eg, 1–3 coformulated strains that become resistant to these drugs almost invariably pills a day), increasing tolerability and completion rates, but develop the M184V mutation, conferring decreased viral alternatively, if the individual has been exposed to a treatment- fitness,32 minimizing the risk of onward transmission to sex experienced HIV-infected source, more drugs could provide partners. Other well-studied antiretroviral agents may not be extra protection against the selection for drug-resistant virus.24 optimal for PrEP because they do not penetrate genital tissues Though PEP has not been widely utilized outside in adequate concentrations,33 which is a function of relative occupational health care settings, concerns have been raised by protein binding and other pharmacodynamic properties.34 some that wider utilization may be counterproductive among Protease inhibitors are highly protein bound, achieving lower individuals at increased risk for HIV by decreasing their concentrations in the genital tract, compared with nucleoside protective behaviors. A study of men who have sex with men analogues and nonnucleoside reverse transcriptase inhibi- (MSM) in Brazil did not demonstrate increases in risk-taking tors.35,36 The oral CCR5 coreceptor antagonist maraviroc behaviors after PEP,and HIV incidence was significantly lower achieves high genital tract and rectal concentrations37 and in PEP users.25 Because this was not a randomized controlled could be effective as PrEP.37 If the initial tenofovir-based PrEP trial, unintended biases could have been present (eg, PEP users trials demonstrate efficacy, future studies may focus on the being generally less risky, etc). Other studies have included evaluation of other drugs with novel mechanisms of action prevention counseling to increase the intervention’s long-term and/or different pathways of resistance. efficacy to optimize the educable moment when at-risk individuals are seeking to protect themselves from in- fection.25,26 Despite efforts to use the PEP clinical encounter CURRENT STATUS OF PrEP CLINICAL TRIALS as a means to help people decrease risk-taking behavior, the Multiple clinical PrEP trials are underway among San Francisco Health Department STD Clinic found that 1.3% different communities globally to examine the impact of oral of PEP users became HIV infected within 6 months after and/or vaginal tenofovir or emtricitabine/tenofovir on HIV completing their medication course, underscoring the need for acquisition (Table 1). These trials will enroll more than 20,000 sustained behavioral interventions for those at increased risk in HIV-uninfected men and women to address a variety of addition to the provision of drugs.27 questions, including proof of concept, and if effective, then whether intermittent PrEP can be used, whether topical or oral PrEP is more effective, and whether drug resistance emerges PREEXPOSURE PROPHYLAXIS as a clinical problem because of extensive use of these In situations where the likelihood of HIV exposure can medications for chemoprophylaxis. All of these studies are be anticipated ahead of time, ARVs delivered in either oral or examining the influence of PrEP on risk-taking behaviors.38 topical formulations could be a logical mode of primary These studies are occurring among MSM in the Americas, prevention. The groundwork for current clinical PrEP research Thailand, and South Africa; among at-risk women in sub- has been provided by animal studies over the past decade.10 Saharan Africa; among HIV-discordant couples in Africa; and The most widely studied antiretroviral for PrEP, tenofovir, has among Thai injection drug users. Most of these trials are many features that are desirable in a chemoprophylactic agent, evaluating daily dosing; a few will also include intermittent including long intracellular half-life, activity in monocyte/ dosing strategies.39 A community-based organization, the AIDS macrophages and other cells that may transmit HIV in genital Vaccine Advocacy Coalition (www.avac.org), has developed a secretions, and high concentrations in genital tissues.28 PrEPWatch feature that provides continuously updated infor- Preclinical nonhuman primate studies that evaluated the effi- mation about the status of clinical trials currently underway. cacy of tenofovir-based PreP found that the drug could protect The results of the first human PrEP study, a phase II against HIV acquisition when used topically or systemically.29 randomized double-blinded placebo controlled trial, was Subsequent macaque studies suggested possibility of inter- completed in 2007 and demonstrated the safety of daily oral mittent dosing, given the high rates of protection found as long tenofovir compared with a placebo for HIV prevention among as animals received at least one dose preexposure, and another high-risk West African women who received HIV testing, about 2 hours after the viral challenge.30,31 counseling, and condoms.40 Women in the intervention arm The ideal PrEP agent would have a long half-life, had fewer seroconversions than women in the control arm achieve high concentrations in target tissues, have a high (8 versus 2), but this difference was not statistically barrier to the development of drug resistance, and be safe and significant.40,41 Importantly, both groups of women reduced inexpensive (Fig. 1). Although all current clinical trials of their behavioral risk during the course of the study. Initial data PrEP involve tenofovir plus or minus emtricitabine, concerns suggests that efficient recruitment and implementation of have been raised about reliance on these drugs for large-scale phase III PrEP trials is possible with motivated chemoprophylaxis because they are mainstays of treatment. participants and community engagement.42 One earlier In the worst case scenario, individuals might use chemopro- planned PrEP study among Cambodian female sex workers phylaxis intermittently, and if they did not undergo frequent never began enrollment because of community concerns, HIV screening, they could select for and then transmit drug- which led to extensive discussions among researchers, public q 2010 Lippincott Williams & Wilkins www.jaids.com | S123 Mayer and Venkatesh J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

FIGURE 1. PrEP delivered as a pill versus gel. officials, and other key stakeholders to anticipate concerns that effective for each specific population because local anatomy might be raised in different communities—for example, (eg, vaginal versus rectal mucosa) and tissue pharmacology regarding access to medication after trial completion.43 Over may determine the relative advantages of one approach over the next few years, data will become available to address another. The VOICE trial being conducted by the National whether oral tenofovir by itself, oral tenofovir coformulated Institutes of Health–funded Microbicide Trials Network with emtricitabine, or topical tenofovir gel (ie, a microbicide) (www.mtnstophiv.org) will be the first to evaluate an will be more effective relative to placebo.44 antiretroviral gel compared with oral medication and may be An area of concern has been the development of drug a harbinger of future studies to determine the optimal resistance through the continued use of PrEP if participants chemoprophylactic strategies. unknowingly become HIV infected, either by exposure to The success of the CAPRISA 004 study is important to a drug-resistant virus, suboptimal adherence, or failure of the prevention science, as the first demonstration of the ability of regimen (eg, inadequate tissue penetration). Individuals who chemoprophylaxis to decrease HIV incidence and as the first had 2 weeks of tenofovir monotherapy (as a run-in to a study proof of the protective effects of a topical microbicide. Future of a 3-drug-regimen) did not develop tenofovir resistance.45 In microbicide trials will evaluate other topical antiretroviral monkeys who were challenged with tenofovir-resistant SHIV, drugs, including dapivirine, a nonnucleoside reverse tran- the use of tenofovir as PEP prevented HIV infection.46 scriptase agent, and other targets of the HIV life cycle, such as Mathematical models of HIV prophylaxis have suggested entry and integrase inhibitors. Future human studies will also that less than 1% of the predicted serconversions would assess whether other delivery mechanisms, ranging from develop a tenofovir-resistant strain.47 Due to the increasing use vaginal rings to injectable compounds, might enhance product of tenofovir as part of first-line treatment regimens, continued efficacy by decreasing the challenges of daily or coitally monitoring to assess the effects of PrEP is warranted. dependent adherence. More current information can be found Data from oral and topical PrEP studies were presented on the Microbicide Trials Network (www.mtnstop at the International AIDS Society meetings in Vienna in July shiv.org) and the AIDS Vaccine Advocacy Coalition website 2010. A study of 400 at-risk MSM, recruited in 3 US cities, (www.avac.org). compared the use of oral tenofovir with a placebo and found no evidence of increased clinical toxicities (particularly no increased renal insufficiency, bone demineralization, or other IMPLEMENTATION OF side effects) or increased sexual risk taking among the men ANTIRETROVIRAL CHEMOPROPHYLAXIS assigned to tenofovir compared with those who received the If PrEP is found to be an effective mode for HIV placebo.48 Although this safety study was not powered to prevention, concerns about wider utilization include risk demonstrate drug efficacy, no new HIV infections were compensation, cost (ie, who will pay?), acquisition of resistant detected among the men who received the tenofovir. Another virus, adherence, and drug-related toxicities. The Centers for very important study, CAPRISA 004, studied tenofovir gel in Disease Control and Prevention and the World Health high-risk women in KwaZulu-Natal, South Africa, and found Organization have begun to meet regularly to anticipate that the women assigned to the tenofovir gel were significantly community responses and to work with clinicians, national less likely to become HIV infected than those who used governments, and representatives of at-risk communities as placebo gel49). Although the route of administration is efficacy data become available.50 Providing ART to uninfected different than oral chemoprophylaxis, the finding of a signif- individuals will also need to be balanced with the imperative to icant level of protection by a topical antiretroviral medication provide prompt treatment access to HIV-infected individuals is a key observation, raising the hope that oral PrEP studies meeting guidelines for treatment initiation. However, it is will also demonstrate a protective effect. Ultimately, it will be possible that PrEP could be a cost-effective means of HIV important to determine which route of administration is most prevention for younger and high-risk populations in the United

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TABLE 1. Current Trials of Tenofovir-based PrEP Trial Means of Expected Name Population Location Drug Administration Sample Size Results US Gay United States TDF Daily oral 400 TDF is safe and Extended men; MSM well-tolerated as Safety Trial PrEP for MSM (CDC 4323) iPrEX Gay men; MSM Brazil, Ecuador, TDF/FTC Daily oral 2500 Fully enrolled 2009; Peru, South Africa, results probable Thailand, United States by late 2010 Bangkok Injecting Thailand TDF Daily oral 2400 Completed enrollment Tenofovir drug users 2010; possible results Study 2010/early 2011 (CDC 4370) CAPRISA Heterosexual South Africa TDF Coitally dependent 1000 First demonstration of 004 women topical vaginal gel the efficacy of tenofovir gel TDF2 Heterosexual men Botswana TDF/FTC Daily oral 1200 Enrollment stopped 2009; (CDC 4940) and women safety data likely 2010 Partners Serodiscordant Kenya, Uganda TDF and Daily oral 3900 Enrolling; data PrEP heterosexual couples TDF/FTC expected 2012 FEM-PrEP Heterosexual Kenya, Malawi, TDF/FTC Daily oral 3900 Enrolling; data women South Africa, expected 2013 Tanzania, Zambia VOICE Heterosexual South Africa, Uganda, TDF; Daily oral 5000 Enrolling; data (MTN 003) women Zambia, Zimbabwe; TDF/FTC (TDF, TDF/FTC); expected 2013 additional sites Daily topical to be determined vaginal gel (TDF) ATN 082 High-risk United States TDF/ Daily dosing with 100 Enrolling; results in young MSM FTC or without a 2011 or 2012 behavioral intervention Studies Involving Intermittent PrEP (i-PrEP) IAVI Serodiscordant Kenya, Uganda TDF/ Daily oral; 150 Full enrollment E001 couples and FTC intermittent oral expected 2010 and E002 at-risk men (twice weekly + and women coital dosing) HPTN Low-risk United States TDF/ Different dosing 48 Intense 066 men FTC strategies planned pharmacokinetic and women study HPTN High-risk Thailand, TDF/ Fixed interval 360 In planning stages 067 women South Africa FTC vs coitally dependent and MSM

CDC, Centers for Disease Control and Prevention; FTC, emtricitabine; TDF, tenofovir; IAVI, the International AIDS Vaccine Initiative; and HPTN, the HIV Prevention Trials Network.

States,51 given the high cost of treating new HIV infections . Addressing these questions will require expanded over the life course. safety and effectiveness trials and the development of public If PrEP is found to be effective, questions will arise as to surveillance systems to monitor HIV incidence, risk compen- who should prescribe these drugs and how best to train sation, and resistant virus evolution. Patients in clinical providers. ART as PrEP will require researchers and clinicians settings will require ongoing and regular HIV testing to avoid to optimally utilize these agents in a focused manner to reduce substandard therapy in the case of becoming HIV infected. the number of new HIV infections. Identifying individuals at Individuals with tenofovir-resistant virus could compromise high risk for HIV infection and then initiating them on PrEP their own treatment options and could spread resistant virus to could be a major challenge, given continued stigma associated their sex partners or offspring. with behaviors that putindividuals at increased risk of Potential risk compensation among individuals using acquiring HIV. Major areas that will require further clinical PrEP may also compromise its effectiveness.52 It is possible research include monitoring long-term safety, development of that individuals could obtain off-label access to drugs in adherence strategies, assessing methods of optimal drug advance of efficacy data becoming available. Reports of ART delivery and dosing, and minimizing selection of resistant being sold at clubs and of self administration prior to high-risk q 2010 Lippincott Williams & Wilkins www.jaids.com | S125 Mayer and Venkatesh J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 sexual activity have emerged,53,54 but studies from urban US 7. Granich R, Crowley S, Vitoria M, et al. Highly active antiretroviral centers have found minimal off-label PrEP use to date.55,56 treatment for the prevention of HIV transmission. J Int AIDS Soc. 2010; 13:1. PMCID: PMC2822750. However, the potential for widespread and unregulated use 8. El-Sadr W, Affrunti M, Gamble T, et al. Antiretroviral Therapy: A persists, and the demand could quickly change, based on when Promising HIV Prevention Strategy? J Acquir Immune Defic Syndr. 2010; data become available to suggest a beneficial effect of PrEP.53 55(Suppl 2):S116–S121. To ensure that PrEP does not lead to risk compensation and to 9. Mayer K. Antiretrovirals for HIV prevention: panacea or Pandora’s box? provide PrEP as part of a risk reduction strategy, optimal Paper #63. Presented at: 17th Conference on Retroviruses and 57 Opportunistic Infections; February 16–19, 2010; San Francisco, CA. prevention counseling packages will need to be developed. 10. Mayer K, Venkatesh, KK. Antiretroviral therapy for HIV prevention: current status and future prospects. Am J Public Health. 2010;100:1867–1876. 11. Cohen M, Kashuba AD. Antiretroviral therapy for prevention of HIV infection: new clues from an animal model. PLoS Med. 2006;5:e30. doi: CONCLUSIONS: FUTURE OF ART FOR 10.1371/journal.pmed.0050030. 12. American Thoracic Society, Centers for Disease Control, and Infectious PRIMARY PREVENTION Diseases Society of America. Treatment of tuberculosis. MMWR Recomm The promise of ART chemoprophylaxis for uninfected Rep. 2003;52(RR11):1–77. Erratum in: MMWR Recomm Rep. 2005;53:1203. individuals is great, but the field is still in an early stage, and 13. Division of STD Prevention, National Center for HIV/AIDS, Viral major questions remain. The discussion about using ART as Hepatitis, STD, and TB Prevention, Centers for Disease Control. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. a means of primary HIV prevention has moved to the forefront 2006;55(RR11):1–94. Erratum: MMWR Recomm Rep. 2006;55:997. of public health discourse because of the increased tolerability 14. Centers for Disease Control and Prevention. Updated U.S. Public Health of the medications, the decreased cost, the ever expanding Service guidelines for the management of occupational exposures to HBV, formulary, and the limitations of other behavioral and HCV, and HIV and recommendations for postexposure prophylaxis. biomedical approaches. Optimizing the use of antiretroviral MMWR Recomm Rep. 2001;50(RR11):1–52. 15. Cohen MS, Gay C, Kashuba AD, et al. Narrative review: antiretroviral agents for HIV prevention will require careful consideration of therapy to prevent the sexual transmission of HIV-1. Ann Intern Med. adherence, sustained access, behavioral risk reduction, and 2007;146:591–601. STI diagnosis and treatment. The ability to implement ART for 16. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal–infant primary prevention in the United States will depend on transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study effectively engaging at-risk individuals and educating their Group. N Engl J Med. 1994;331:1173–1180. providers and decreasing the economic impediments to 17. De Cock K, Fowler MG, Mercier E, et al. Prevention of mother-to-child optimal use. HIV transmission in resource-poor countries: translating research into It is conceivable that in the future certain drugs may be policy and practice. JAMA. 2000;283:1175–1182. reserved for specific preventive and therapeutic interventions. 18. Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Further research in pharmacology, virology, behavioral Centers for Disease Control and Prevention Needlestick Surveillance science, and health care service delivery will be needed to Group. N Engl J Med. 1997;337:1485–1490. better understand the intended and unintended consequences 19. Tsai C, Emau P, Follis KE, et al. Effectiveness of postinoculation (R)-9- of widely using ART for prevention. PEP and PrEP will likely (2-phosphonylmethoxypropyl) adenine treatment for prevention of persis- tent simian immunodeficiency virus SIVmne infection depends critically on be part of a larger HIV prevention toolbox that will be used to timing of initiation and duration of treatment. JVirol. 1998;72:4265–4273. reduce the number of new infections, a toolbox that would also 20. Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral postexposure include behavioral risk reduction strategies, expanded HIV prophylaxis after sexual, injection-drug use, or other nonoccupational testing, male circumcision, prevention of mother-to-child exposure to HIV in the United States: recommendations from the U.S. transmission, and possibly STI treatment.4,58 The search for an Department of Health and Human Services. MMWR Recomm Rep. 2005: 54(RR21):1–20. Available at: http://www.cdc.gov/mmwr/preview/ effective HIV vaccine must continue as well. But in the mean mmwrhtml/rr5402a1.htm. Accessed September 1, 2008. time, the use of multiple partially effective interventions could 21. Diaz-Brito V,Leo´n A, Knobel H, et al, And the DATEMPEP Study Group. significantly slow the epidemic. An open randomized multicenter clinical trial comparing zidovudine/ lamivudine (ZDV/3TC) plus lopinavir/ritonavir (LP/r) or plus atazanavir (ATV) used as postexposure prophylaxis (PEP) for HIV infection. Paper #956. Presented at: 17th Conference on Retroviruses and Opportunistic REFERENCES Infections; February 16–19, 2010; San Francisco, CA. 1. United Nations. Joint United Nations Programme on AIDS. 2008 Report 22. Mayer KH, Mimiaga MJ, Cohen D, et al. Tenofovir DF plus lamivudine or on the Global AIDS Epidemic. Geneva, Switzerland: Joint United Nations emtricitabine for nonoccupational postexposure prophylaxis (NPEP) in Programme on AIDS. Available at: http://www.unaids.org/en/Knowl- a Boston Community Health Center. J Acquir Immune Defic Syndr. 2008; edgeCentre/HIVData/GlobalReport/2008/2008_Global_report.asp. Ac- 47:494–499. cessed August 10, 2010. 23. Mayer K, Mimiaga M, Gelman M, et al. Tenofovir DF/emtricitabine/raltegravir 2. Padian NS, Buve´ A, Balkus J, et al. 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Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al, for the CAPRISA Montreal, Quebec, Canada. 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral 33. V an Rompay KK, Matthews TB, Higgins J, et al. Virulence and reduced microbicide, for the prevention of HIV infection in women. Published fitness of simian immunodeficiency virus with the M184V mutation in online ahead of print July 19, 2010. Science. doi: 10.1126/science. reverse transcriptase. J Virol. 2002;76:6083–6092. 1193748. 34. Eron J, Vernazza PL, Johnston DM, et al. Resistance of HIV-1 to 51. Part of the Solution: Setting Expectations for WHO and UNAIDS.New antiretroviral agents in blood and seminal plasma: implications for York, NY: AVAC. Available at: http://www.avac.org/ht/d/sp/a/GetDocu- transmission. AIDS. 1998;12:F181–F191. mentAction/i/2275. Accessed December 26, 2009. AVAC Report 2009. 35. Taylor S, Pereira AS. Antiretroviral drug concentrations in semen of 52. Paltiel A, Freedberg KA, Scott CA, et al. HIV preexposure prophylaxis in HIV-1 infected men. Sex Transm Infect. 2001;77:4–11. the United States: impact on lifetime infection risk, clinical outcomes, and 36. Ghosn J, Chaix ML, Peytavin G, et al. Penetration of enfuvirtide, cost-effectiveness. Clin Infect Dis. 2009;48:806–815. tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1- 53. Abbas U, Anderson RM, Mellors JW. Potential impact of antiretroviral infected men. AIDS. 2004;18:1958–1961. chemoprophylaxis on HIV-1 transmission in resource-limited settings. 37. Pereira A, Kashuba AD, Fiscus SA, et al. Nucleoside analogues achieve PLos ONE. 2007;2:e875. doi:10.1371/journal.pone.0000875. high concentrations in seminal plasma: relationship between drug 54. Mansergh G, Colfax, G, McKirnan D, et al, And the Project MIX Study concentration and virus burden. J Infect Dis. 1999;180:2039–2043. Group. Use and sharing of antiretroviral medications for pre- and post- 38. Veazey R, Ketas T, Dufour J, et al. Protection of rhesus macaques from exposure prophylaxis to prevent sexual transmission of HIV among high- vaginal infection by maraviroc, an inhibitor of HIV-1 entry via the CCR5 risk, substance-using men who have sex with men in 4 US cities. Paper co-receptor. Paper #84LB. Presented at: 17th Conference on Retroviruses #957. Presented at: 17th Conference on Retroviruses and Opportunistic and Opportunistic Infections; February 16–19, 2010; San Francisco, CA. Infections; February 16–19, 2010; San Francisco, CA. 39. Buchbinder S.HIV prevention. Paper #6. Presented at: 16th Conference on 55. Kellerman SE, Hutchinson AB, Begley EB, et al. Knowledge and use of Retroviruses and Opportunistic Infections; February 8–11, 2009; HIV pre-exposure prophylaxis among attendees of minority gay pride Montreal, Quebec, Canada. Available at: http://app2.capitalreach.com/ events, 2004. J Acquir Immune Defic Syndr. 2006;43:376–377. esp1204/servlet/tc?c=10164&cn=retro&e=10642&m=1&s=20415&& 56. Mimiaga MJ, Case P, Johnson CV, et al. Preexposure antiretroviral espmt=2&mp3file=10642&m4bfile=10642&br=80&audio=false [Web prophylaxis attitudes in high-risk Boston area men who report having cast]. Accessed August 16, 2010. sex with men: limited knowledge and experience but potential for 40. HIV Prevention Trials Network.Ongoing studies and studies in de- increased utilization after education. J Acquir Immune Defic Syndr. velopment [Web page]. Available at: www.htpn.org/research_studies.asp. 2009;50:77–83. Accessed June 3, 2010. 57. Liu AY, Kittredge PV, Vittinghoff E, et al. Limited knowledge and use of 41. Peterson L, Taylor D, Roddy R, et al. Tenofovir disoproxil fumarate for HIV post- and pre-exposure prophylaxis among gay and bisexual men. prevention of HIV infection in women: a phase 2, double-blind, randomized, J Acquir Immune Defic Syndr. 2008;47:241–247. placebo-controlled trial. PloS Clin Trials. 2007;2:e27. PMCID: PMC1876601. 58. Underhill K, Operario D, Skeer M, et al. Packaging PrEP to prevent 42. Peterson L, Taylor D, Clarke EE, et al. Findings from a double-blind, HIV: an integrated framework to plan for pre-exposure prophylaxis randomized, placebo-controlled trial of tenofovir disoproxil fumarate implementation in clinical practice. Published online ahead of print (TDF) for prevention of HIV infection in women. Abstract THLB0104. August 13, 2010. J Acquir Immune Defic Syndr. doi: 10.1097/QAI. Presented at: XVI International AIDS Conference; August 13–18, 2006; 0b013e3181e8efe4. Toronto, Ontario, Canada. 59. Burns D, Dieffenbach CW, Vermund SH. Rethinking HIV-1 prevention of 43. Baeten J, Ndase P, Mugo N, et al, And the Partners PrEP Study HIV type 1 infection. Published online ahead of print August 13, 2010]. Team. Demographic, behavioral, and clinical characteristics of HIV-1 Clin Infect Dis. 2010;51. doi: 10.1086/655889.

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Lessons Drawn From Recent HIV Vaccine Efficacy Trials Jonathan D. Fuchs, MD, MPH,*† Magda E. Sobieszczyk, MD, MPH,§ Scott M. Hammer, MD,§ and Susan P. Buchbinder, MD*†‡

has not delivered one. A recently completed vaccine efficacy Abstract: A safe and effective HIV vaccine is needed to curtail the trial has inspired new hope that an HIV vaccine is US and global epidemics. However, the search for one has been achievable. Here we describe how the results from these elusive despite more than 25 years of focused research. Results from large clinical studies, some unexpected, are driving vaccine the RV144 Thai efficacy trial have renewed hope that a vaccine may discovery. We also outline important lessons about data protect against HIV acquisition. We can draw several scientific and analysis, dissemination, and recruitment of communities operational lessons from RV144 and other recent tests-of-concept at risk. efficacy trials. Here we describe how trial results, some unexpected, highlight the fundamental role these clinical studies play in HIV vaccine discovery. These trials also teach us that transparency in data HIV VACCINE EFFICACY TRIALS TO DATE analysis and results dissemination can yield substantial rewards and Since the first gp160 vaccine entered clinical testing in that efforts to engage communities, particularly those most heavily 1987, more than 150 trials of different vaccine candidates have affected by the epidemic, are needed to augment research literacy and been conducted.2 These trials reflect 3 distinct waves of trial recruitment. Future efficacy trial designs may incorporate novel, vaccine development, including approaches designed to elicit partially effective prevention strategies. Although greater in size and broadly neutralizing antibodies and cell-mediated immune complexity, these trials may offer unique opportunities to explore (CMI) responses, and the latest wave, focused on generating synergies with vaccines under study. combined humoral and CMI responses.3 However, only 6 trials testing 4 distinct strategies have advanced to efficacy trials Key Words: clinical trials, combination prevention, efficacy trials, (Table 1). We have previously outlined several lessons gleaned HIV vaccines from the VAX 004 study, conducted largely among US men (J Acquir Immune Defic Syndr 2010;55:S128–S131) who have sex with men (MSM).9 Here we will focus attention on more recent efficacy trials.

LESSONS LEARNED INTRODUCTION Good Science Often Leads to Approximately 56,000 people in the United States Surprising Results become infected with HIVeach year—one new HIV infections The pair of test-of-concept efficacy trials evaluating every 9½ minutes—reinforcing the urgent need to expand 1 a replication incompetent adenovirus serotype 5 (MRKAd5) access to proven prevention strategies and identify new ones. trivalent HIV vaccine has advanced our understanding of Historically, vaccines have been the most effective method to vaccines designed to induce CMI responses. In September combat a wide range of infectious pathogens and in the 2007, the first interim analysis of the Step trial in men and United States are responsible for eradicating the threat from women from North and South America, the Caribbean, and smallpox and poliomyelitis. It is widely believed that Australia demonstrated that the MRKAd5 HIV vaccine failed a vaccine must be a component of the HIV prevention to prevent infection or reduce early viral load.6 Unexpectedly, armamentarium, yet more than 25 years of vaccine research post hoc analysis revealed that male participants who were uncircumcised and Ad5 seropositive at baseline were at higher From the *HIV Research Section, San Francisco Department of Public Health, risk for HIV acquisition if they received the vaccine than if San Francisco, CA; †Departments of Medicine; and ‡Epidemiology, they received placebo. Investigators have suggested mecha- University of California, San Francisco; and §Department of Medicine, nisms by which the vaccine could increase susceptibility to Division of Infectious Diseases, Columbia University College of infection among participants with preexisting Ad5 anti- Physicians and Surgeons, New York, NY. body,10,11 although none have been demonstrated in actual J.F. and S.B. are supported under Division of AIDS CTU and MP3 awards 12,13 (U01AI069496, 5R01AI083060); M.S. and S.H. are supported under trial volunteers. On the other hand, several analyses CTU and CTSA awards (U01AI069470, UL1RR024156). suggest that the vaccine may have caused transient modest Presented at the Microbicide 2010 Conference (M2010), May 22–25, 2010, reductions in early viral load,14,15 giving leads about Pittsburgh, PA. potentially effective vaccine-induced immune responses to Correspondence to: Jonathan D. Fuchs, MD, MPH, HIV Research Section, San Francisco Department of Public Health, 25 Van Ness Avenue, Suite build upon. In the Phambili trial, a companion trial to the Step 710, San Francisco, CA 94102 (e-mail: [email protected]). trial among heterosexuals in South Africa, vaccinations were Copyright Ó 2010 by Lippincott Williams & Wilkins halted after only 801 of 3000 participants were enrolled. No

S128 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Lessons From HIV Vaccine Efficacy Trials

TABLE 1. HIV Vaccine Efficacy Trials Vaccine Seroincidence Manufacturer(s) Trial (Dates Populations and (No. per 100 Vaccine Strategy and Regimen* Conducted) Locations Tested Person-Years)† Results Summary Completed trials Recombinant, VaxGen, Inc VAX 004 (1997–2002) VAX 004: 5417 Men: 2.7 Neither VAX 004 or monomeric gp120 IM injections MSM and Women 0.8 VAX 003 demonstrated subunit (B/B; B/E) at 0, 1, 6, heterosexual efficacy to prevent 12, 18, 24, women in the infection or alter viral and 30 months United States, load/CD4 count in infected Canada, vaccinees4,5 Netherlands VAX 003 (1999–2003) VAX 003: Overall: 3.4 2546 male and female Thai IDU Recombinant Ad 5 Merck Research Step (2004–2009) 3000 MSM, Men V: 3.8; No effect on HIV acquisition (clade B gag/pol/ nef) Laboratories heterosexual P: 2.8 or early VL set point in IM injections at 0, 1, men and Women Step or Phambili; possible and 6 months women in the V: 0.52; increased HIV infection United States, P: 0.51 rate among subgroup of Ad5 Canada, Seropositive, uncircumcised Caribbean, men in Step6 South America, Australia Phambili (2006–2009) 801 South African Men V:4.2; NS reduction in early heterosexual men P: 3.7; VL set point among women 7 and women Women V:6.8; in Phambili P: 5.9 Recombinant Sanofi Aventis RV144 (2003–2009) 16,402 Thai men and Men V: 0.20; Modest efficacy to prevent Canarypox virus (ALVAC) and women, largely at P: 0.27 infection in primary MITT (ALVAC vcp 1521) VaxGen, Inc heterosexual risk; 31% (confidence interval: prime + IM injections of mostly at low or Women V: 0.19; 1.1 to 51%, P = 0.04). monomeric ALVAC medium risk of P: 0.31 No effect on postinfection 8 gp120 (B/E) boost at 0, 1, 3, infection early VL set point or CD4 count and 6 months; gp120 boost at 3 and 6 months Ongoing trials Multiclade DNA NIH Vaccine HVTN 505 (2009–) 1350 US MSM Currently Currently enrolling prime + multiclade Research Center enrolling Ad5 boost IM injections of DNA via Biojector at 0, 1, and 2 months; Ad5 boost at 6 months

*All intramuscular injections delivered via needle and syringe unless otherwise stated. †For VAX004, overall seroincidence rates are provided for men and women as they were identical in vaccinees and placebo recipients; the pooled and not sex-specific seroincidence estimates for VAX003 were reported by Pitisuttithum, et al. Overall, 201 infections were detected in men (100 in vaccinees, 101 in placebo recipients); 10 infections were detected in women (6 in vaccinees, 4 in placebo recipients). Ad5, adenovirus serotype 5; HVTN, HIV Vaccine Trials Network; IM, intramuscular; MITT, modified intent to treat; VL, viral load; NS, non significant; V, vaccine; P, placebo.

overall efficacy was seen, although analyses among female but were not found to correlate with either protective or vaccinees vs. placebo recipients found a nonsignificant trend harmful effects in these trials.16 Although developers are using toward lower early viral load (12,000 vs. 35,000, P = 0.14) and a number of strategies such as DNA priming of vector-based a significant reduction in progression to CD4 ,350 cells per regimens17,18 and novel HIV inserts19 to produce immune cubic millimeter (hazard ratio: 0.33, 95% confidence interval: responses of greater magnitude, breadth, or quality, 0.12 to 0.91).7 laboratory correlates of protection must be determined in Taken together, findings from Step and Phambili offer clinical trials. a number of key lessons. First, the field is looking beyond the Second, the Step trial reinforced limitations of non- gamma interferon ELISpot assay as the central measure human primate (NHP) challenge models to predict efficacy in of CMI; responses were detected in a majority of vaccinees humans. We learned that a challenge model using a chimeric q 2010 Lippincott Williams & Wilkins www.jaids.com | S129 Fuchs et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 simian immunodeficiency virus (SHIV 89.6P) failed to predict have opened up data and specimens to the broad scientific the results of human trials.20 In addition, NHP studies were not community, which has established an important standard in designed to evaluate the potential for increased susceptibility advancing HIV vaccine science and increasing transparency to infection nor the impact of vector-based preexisting during the discovery process. immunity or the role of foreskin on vaccine effects. NHP models can be used to study events that cannot be adequately It Takes a Village (Several, Actually) monitored in human trials, such as events shortly after simian The success of large-scale efficacy trials depends heavily immunodeficiency virus exposure. Clinical trials must inform on the mobilization and participation of communities at risk how best to use NHP models and to ultimately validate the for infection. Sustained community engagement efforts are utility of these models to predict responses in humans. needed to address the lack of urgency about HIV/AIDS and Another lesson from these trials is the potential for limited knowledge of HIV vaccine research, particularly heterogeneity of vaccine effects in different populations. The among African Americans, Latinos, and MSM.29 Recruitment Phambili trial, although limited in size and power, suggested into large-scale efficacy trials, an activity distinct from but potential for gender-based differences in vaccine effects, as has inextricably linked to community education, has become been seen in studies of a vaccine.21 Although increasingly challenging yet pressing because the rate of new more than one third of enrolled participants in the Step trial HIV diagnoses in MSM is 44 times that of other men in the were women—many of whom reported high levels of unpro- United States.30 In HVTN 505, an ongoing trial of the Vaccine tected sex with numerous partners—HIV incidence was quite Research Center’s DNA prime Ad5 boost regimen, the early low in this group. Despite a substantial HIV epidemic in phase of enrollment has been slower than anticipated. This subpopulations of US women,1 identifying high seroincidence may be due, in part, to the need to identify men and trans- cohorts of US women has been challenging.22,23 Two feasi- gender women who are fully circumcised and Ad5 seroneg- bility studies testing novel approaches to recruit at-risk women ative (inclusion criteria based on data from Step that this group in the United States are currently underway in the NIAID- was not at elevated risk for HIV after Ad5 vaccination). But sponsored HIV Vaccine and Prevention Trials Networks. several other complex social forces may be at play including The RV144 study, conducted by the US Military HIV prevention fatigue,31 saturation of HIV messages in public Research Program in collaboration with several Thai media, and competition for MSM participants across different institutions, met with early skepticism among members of HIV prevention studies, among other reasons. the scientific community24 due to the vaccine regimen’s rela- Operationally, the Step trial highlighted the importance tively poor immunogenicity by standard cytotoxic T lympho- of centrally coordinated recruitment strategies and sharing of cyte assays.25 As a welcome surprise to many, the trial materials and techniques across participating trial sites. The demonstrated a 31% reduction in HIV incidence, a marginal most effective campaigns may be those that feature the but statistically significant result.8 More than 30 investigators altruistic motivations that encourage MSM to come forward to working in teams are actively attempting to identify potential join trials in the first place.32,33 In addition, both Step and correlate(s) of immune protection in this study,26 with HVTN 505 have made significant use of new Internet-based a particular focus on antibody-mediated mechanisms, includ- recruitment strategies, including online social media sites, to ing binding antibodies and antibody-dependent cell-mediated attract MSM who often use the Web to find sexual partners.34 cytotoxicity.27 Also surprising was the suggestion of increased The effectiveness of these online recruitment approaches efficacy among participants with lower reported baseline risk requires further evaluation and should be optimized to behavior, raising the possibility that vaccines with modest accelerate recruitment efficiency. efficacy may have a threshold effect, with limited efficacy for participants who are heavily exposed to HIV. There is No Silver Bullet for HIV Prevention A first-generation HIV vaccine will likely be partially Transparency Yields Many Rewards protective35—a fact evidenced by the RV144 findings. The standards of Good Participatory Practices outlined Ultimately, it is hoped that such a vaccine can be combined by AVAC and the Joint United Nations Program on with other partially protective biomedical and behavioral HIV/AIDS28 state that research teams must engage with strategies to achieve synergistic effects. For example, Hallett relevant stakeholders at all stages of the trial life cycle. In the et al have modeled HIV incidence in Southern Africa and have Step and Phambili trials, study sites released results to found that a circumcision intervention applied with behavioral participants and the public beginning within 72 hours of the risk reduction interventions will lead to a much greater impact Data and Safety Monitoring Board review of interim Step than would be expected on the basis of either alone.36 A efficacy results. In addition, when the suggestion of increased partially effective antiretroviral-based microbicide was iden- susceptibility in the Step study came to light, the protocol team tified in July 2010,37 and several clinical trials of preexposure worked closely with trial sites, community advisory boards, prophylaxis regimens will report results over the next 3 years. and advocates to develop a clear communication plan to To detect vaccine-induced effects, future trial designs that disseminate these complex results and make decisions about incorporate any of these new strategies with ongoing risk study unblinding. The RV144 study team developed a com- reduction counseling may be greater in size and complexity. munication plan that chose to share results with participating But they may also provide new opportunities to explore communities before presenting data to scientific audiences at potential synergies with vaccines under study. Ultimately, the AIDS Vaccine 2009 conference and in print. These studies there is no silver bullet for HIV prevention. Incremental

S130 | www.jaids.com q 2010 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Lessons From HIV Vaccine Efficacy Trials successes in vaccine and drug discovery are the norm and will 17. Koup RA, Roederer M, Lamoreaux L, et al. Priming immunization with continue to be driven by our large-scale efficacy trials DNA augments immunogenicity of recombinant adenoviral vectors for both HIV-1 specific antibody and T-cell responses. PLoS One. 2010;5: enrolling engaged and willing participants from communities e9015. at risk. 18. McCormack S, Sto¨hr W, Barber T, et al. EV02: A Phase I trial to compare the safety and immunogenicity of HIV DNA-C prime-NYVAC-C boost to ACKNOWLEDGMENTS NYVAC-C alone. Vaccine. 2008;26:3162–3174. 19. Barouch DH, O’Brien KL, Simmons NL, et al. Mosaic HIV-1 vaccines We thank Jennifer Sarche´ and Albert Liu for their helpful expand the breadth and depth of cellular immune responses in rhesus comments on an early draft of this article. We would also like monkeys. Nat Med. 2010;16:319–323. to acknowledge the study volunteers, trial site staff, and 20. Watkins DI, Burton DR, Kallas EG, et al. Nonhuman primate models and participating community advisory boards dedicated to the the failure of the Merck HIV-1 vaccine in humans. Nat Med. 2008;14: search for a safe and effective HIV vaccine. 617–621. 21. Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D- adjuvant vaccine to prevent . N Engl J Med. 2002;347: REFERENCES 1652–1661. 1. Hall HI, Song R, Rhodes P, et al. Estimation of HIV Incidence in the 22. Seage GR III, Holte SE, Metzger D, et al. Are US populations United States. JAMA. 2008;300:520–529. appropriate for trials of human immunodeficiency virus vaccine? The 2. 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Structural Interventions for HIV Prevention in the United States Adaora A. Adimora, MD, MPH* and Judith D. Auerbach, PhD†

HIV-associated health disparities, the strategy envisions a Background: Structural interventions change the environment in United States ‘‘where new HIV infections are rare and when which people act to influence their health behaviors. Most structural they do occur, every person, regardless of age, gender, race/ interventions research for HIV infection has focused on developing ethnicity, sexual orientation, gender identity or socioeconomic countries, with the United States receiving substantially less circumstances, will have unfettered access to high quality, life- attention. This article identifies some social determinants of HIV extending care, free from stigma and discrimination.’’1 vulnerability in the United States and structural interventions to This vision reflects an understanding increasingly shared address them. by public health researchers and practitioners that social determinants—the conditions in which people are born, live, Methods: Review of the medical, public health, and social science work, and age2—are critical influences on health and that these literature. determinants, which are shaped by the distribution of money, Results: Evidence supports widespread implementation of a number power, and resources, can be influenced in positive ways. of structural interventions in the United States clearly proximate to HIV, Structural interventions for HIV prevention attempt to affect including comprehensive sex education, universal condom availability, these determinants by changing the environment in which expanded syringe access for drug users, health care coverage, and individuals engage in health-related behaviors.3 Evidence stable housing. Sociological plausibility supports evaluation and suggests that interventions that address the contextual factors implementation of other interventions that target social determinants that influence people’s behavior are more successful than more distal but of relevance to HIV, such as initiatives to eliminate interventions that focus solely on individuals and ignore the racial and ethnic disparities in criminal sentencing, to promote early larger context.4 In addition, financial analyses show that childhood education and to decrease poverty. structural changes, although costly, may have the greatest effect over the long term in reducing the number of new HIV Conclusions: Structural interventions that address social determi- infections, and yielding other social benefits, such as nants of HIV infection may be among the most cost effective methods improvements in economic productivity and advances in of preventing HIV infection in the United States over the long term. human rights.5 Key Words: HIV, structural interventions, United States Structural interventions for HIV prevention typically involve at least one of the following: effecting policy or legal (J Acquir Immune Defic Syndr 2010;55:S132–S135) changes; enabling environmental changes; shifting harmful social norms; catalyzing social and political change; and empowering communities and groups.6,7 Interest in structural interventions has grown in recent years, but most research and programmatic efforts in this realm have focused on developing INTRODUCTION countries.8–10 We argue, however, (as have others11–13) that In July 2010, the Obama Administration released the much can be done in the United States to address key social first National HIV/AIDS Strategy for the United States. determinants of the nation’s epidemic and help achieve both The strategy targets and coordinates the nation’s response to the goals and the vision of the National HIV/AIDS Strategy by the domestic HIV epidemic. With its goals of reducing new implementing structural interventions of various types. After HIV infections, increasing access to care and improving health identifying some key social determinants, we outline examples outcomes for people living with HIV infection, and reducing of structural interventions to address them. Some of these have been well described elsewhere; others may seem more novel in their connection to HIV/AIDS. From the *Department of Medicine, School of Medicine and UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC; and †San Francisco AIDS Foundation, San Francisco, CA. SOCIAL DETERMINANTS UNDERPIN THE US This research was supported by National Institutes of Health HIV EPIDEMIC 1K24HD059358-01 (Dr. A.A.A.). Substantial evidence documents the role of social Correspondence to: Adaora A. Adimora, MD, MPH, School of Medicine, determinants in health outcomes at the individual level and University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 14 (e-mail: [email protected]). community level. Macroeconomic and social forces, such as Copyright Ó 2010 by Lippincott Williams & Wilkins poverty, racism, sexism, and homophobia, help fuel HIV

S132 | www.jaids.com J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Structural interventions for HIV in the US epidemics, although the pathways between these forces and housing and homelessness, which in turn increase likelihood HIV infection are complex and not always clear.15–19 The US of HIV risk behaviors.30 epidemic—with its disproportionate impact on gay and other men who have sex with men (MSM), people of color, drug users, and people living in the South—concentrates HIVamong STRUCTURAL INTERVENTIONS TO TARGET groups that often overlap demographically and geographically SOCIAL DETERMINANTS and share some core social determinants of infection. Anumberofstructuralapproaches effect policy–legal More than half of new HIV infections in the United changes, enable environmental changes, shift harmful social States (53%) occur among gay and other MSM.20 Homopho- norms, catalyze social and political change, or empower bia and homonegativity promote HIV transmission. Negative communities and groups to address social drivers that fuel HIV attitudes about homosexuality have been translated into legal in the United States. Some are well researched and documented by and policy restrictions on sexual behaviors (eg, sodomy) and strong empirical evidence, and others have sociological plausi- 19 relationships (eg, marriage) among gay people. These bility but have not yet been connected as directly to HIV/AIDS. restrictions tend to marginalize and exclude gay people and Structural Interventions With Evidence drive their relationships underground. Thus, many MSM do not publicly identify (or self identify) as ‘‘gay,’’ or seek HIV of Efficacy prevention and sexual health information services targeted Comprehensive Sex Education With Access to Male to gay communities. Internalized homonegativity has been and Female Condoms associated with unprotected anal intercourse, a major route of Sex education is an essential HIV prevention strategy, HIV transmission, particularly for gay and other MSM.21 and access to accurate sexual health information is a funda- About 12% of new HIV infections in the United States mental human right.31,32 Comprehensive sex education occur among injecting drug users.20 Lack of access to sterile programs include respectful acknowledgement of gender needles and syringes and addiction treatment programs and sexual diversity, and health promotion and disease contributes to the spread of HIV among injectors, their sex prevention information and access to the tools to engage in partners, and others within their social/sexual networks.6 safer sex (ie, condoms). Such programs have frequently met Although harm reduction services markedly decrease HIV with opposition at federal, state and local levels despite their incidence and prevalence,22 their availability is limited, in large effectiveness in decreasing risky sexual behaviors (promoting part because of the ban on the use of federal funds to support delayed initiation of intercourse, reduced frequency of syringe exchange programs that existed under US law until intercourse, decreased number of sex partners) among young January 2010 and the persistent shortage of addiction people.33,34 Nevertheless, broad implementation of compre- treatment and substitution therapy programs.6 Despite the hensive sex education and condom availability through, for fact that drug misuse and addiction are fundamentally example, contingent funding policies ought to and can be put biological, psychological, and social problems manifest at in place now as a structural intervention with potential for the individual level, society dictates the availability of significant impact in reducing both gender and racial programs and services to combat them. Resistance to harm disparities in HIV rates. reduction efforts is ideological and political; the United States has adopted a no-tolerance approach, aggressively criminal- Syringe Exchange Programs izing drug use but with relatively little public health response. Syringe exchange programs, a harm reduction in- Criminalization of drug users and the war on drugs have tervention, aim to reduce risk of disease transmission in the helped make US incarceration rates the highest in the world;23 context of continued drug use. These programs, usually about 1% of Americans were incarcerated in jail or prison in initiated by community-based organizations and advocates, 2007.24 Blacks and Hispanics are imprisoned at dramatically have demonstrated efficacy in reducing HIV transmission,35,36 disproportionate rates—not only because of the war on drugs, are cost-effective,37,38 and do not promote injection drug use.39 which has targeted blacks,25 but also because of pervasive However, wider implementation of syringe exchange pro- ongoing racial disparities in sentencing related to many other grams in the United States has been limited by the previous types of convictions.26 High incarceration rates disrupt sexual long-standing ban on the use of federal funds to support them, partnerships, impoverish individuals and communities, and by state and local legal and regulatory restrictions, and, at times, alter the ratio of men to women that, together, help drive sexual by local community opposition.39 The recent policy–legal network patterns, and ultimately increase the vulnerability of change allowing federal funding of syringe exchange programs communities and individuals to HIV infection.16 and the guidance documents developed by federal agencies for HIV prevalence is higher in the United States among the use of such funds themselves constitute a structural people who are poor than among those who are not poor.27 intervention that should have significant impact on drug-use– A number of pathways link poverty and HIV infection.16 For driven HIV and hepatitis epidemics in the United States and example, poverty decreases health care access, which can should mitigate some of the racial disparities in HIV infections. increase the duration of treatable sexually transmit- ted diseases, which facilitate HIV transmission.28 Targeted Health Care Availability marketing of crack cocaine to poor neighborhoods29 in- Health care availability and quality are important creases residents’ risk of exposure to crack use and exchange social determinants of health.14 Disparities in access to health of sex for drugs. Poverty increases the risk of unstable care are much greater in the United States than in other q 2010 Lippincott Williams & Wilkins www.jaids.com | S133 Adimora and Auerbach J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 industrialized countries and contribute to the dramatic racial Projects are currently being piloted in the United States as and ethnic disparities in rates of chronic diseases, including structural interventions to decrease the economic dependency HIV.40 In 2008, 46.3 million people in the United States that promotes high-risk behaviors and resultant HIV infection (15.4% of the population) lacked health insurance.41 Health (Kevin Fenton, personal communication, July 8, 2010). care reform, a structural intervention that was finally enacted in 2010, should substantially reduce the number of uninsured persons. Effective health care involves access to services and CONCLUSIONS: IMPLEMENTATION medications shown to be effective, such as HIV testing and AND RESEARCH antiretroviral therapy. Addressing the social determinants of the domestic HIV epidemic through widespread implementation of structural Stable Housing interventions, although essential, is not without scientific and A growing body of evidence indicates that provision of political challenges. Establishing the evidence base for the stable housing is an effective strategy for both reducing HIV- efficacy and effectiveness of such interventions requires associated risk behaviors and increasing access to care and seriously embracing this approach as a legitimate research adherence to antiretroviral medications.42,43 Guaranteed pursuit and expanding efforts beyond the traditional bio- housing, provided through laws and subsidies, would not medical and behavioral research paradigms. Research must only affect a substantial number of the estimated 3.5 million clearly trace the pathways between social determinants and people in the United States who experience homelessness HIV infection and develop new methodologies to develop and annually44 but would also decrease morbidity from HIV/AIDS test structural interventions to disrupt these pathways.6,9 Given and numerous other chronic diseases. the scope and scale of this research, it will require development and strengthening of collaborations among Sociologically Plausible Structural communities, academia, government, and the private sector.12 Interventions Findings from such research will help convince the public, Most of the structural interventions mentioned above policy makers, and funders that understanding and success- target immediate conditions of social life that increase fully addressing the social and structural determinants of HIV vulnerability to HIV and its negative health outcomes. Few infection in the United States will ultimately save money and evaluated interventions actually target the social determinants help us achieve the goals of the National HIV/AIDS Strategy. that underlie those conditions—that is, those that render people homeless or drug addicted in the first place.45 Nevertheless, there is substantial sociological plausibility that addressing these ACKNOWLEDGMENTS upstream factors would decrease the domestic HIV epidemic. We thank Drs. Victor J. Schoenbach, Paul A. Godley, For example, as noted earlier, the high incarceration Kevin A. Fenton, and Myron S. Cohen for their insightful rates in the United States that contribute to the domestic HIV comments. epidemic, especially among blacks and Hispanics, are maintained in part by pervasive and ongoing racial disparities REFERENCES 26 in sentencing. One of the stated goals of the Department of 1. White House Office of National AIDS Policy. 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Income, Poverty, and Health Accessed August 6, 2010. Insurance Coverage in the United States: 2008. Washington, DC: US 20. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Government Printing Office; 2009. US Census Bureau, Current Division of HIV/AIDS Prevention. HIV Incidence. Atlanta, GA: Centers Population Reports P60-236. Available at: http://www.census.gov/prod/ for Disease Control and Prevention; 2008. Available at: http:// 2009pubs/p60-236.pdf. Accessed August 10, 2010. www.cdc.gov/hiv/topics/surveillance/incidence.htm. Accessed June 29, 42. National AIDS Housing Coalition. Housing Is the Foundation of HIV 2010. Prevention and Treatment: Results of the National Housing and HIV/ 21. Ross MW, Rosser BR, Neumaier ER. The relationship of internalized AIDS Research Summit. NAHC Housing Summit Policy Paper. homonegativity to unsafe sexual behavior in HIV-seropositive men who Washington, DC: National AIDS Housing Coalition; 2005. Available have sex with men. AIDS Educ Prev. 2008;20:547–557. at: http://www.nationalaidshousing.org/PDF/Housing%20 &%20HIV- 22. Wodak A, Cooney A. Effectiveness of sterile needle and syringe AIDS%20Policy%20Paper%2005.pdf. Accessed June 22, 2010. programmes. Int J Drug Policy. 2005;16(Suppl 1):S31–S44. 43. Wolitski RJ, Kidder DP, Pals SL, et al. Randomized trial of the effects of 23. Walmsley R. World Prison Population List. 8th ed. London, United housing assistance on the health and risk behaviors of homeless and Kingdom: King’s College London International Centre for Prison Studies; unstably housed people living with HIV. AIDS Behav. 2010;14:493–503. 2009. Available at: http://www.kcl.ac.uk/depsta/law/research/icps/ 44. National Coalition for the Homeless. How Many People Experience downloads/wppl-8th_41.pdf. Accessed August 6, 2010. Homelessness? Washington, DC: National Coalition for the Homeless; 24. Pew Center on the States. One in One Hundred: Behind Bars in America 2009. 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Schweihart L, Montie J, Xiang Z, et al. Lifetime Effects: The High/Scope Perry Holmes K, Per-Anders M, Sparling PF, et al, eds. Sexually Transmitted Preschool Study through Age 40. Ypsilanti, MI: High/Scope Press; 2005. Diseases. New York, NY: McGraw-Hill; 1999. 49. McLaughlin AE, Campbell FA, Pungello EP, et al. Depressive symptoms 29. Krieger N. Embodying inequality: a review of concepts, measures, and in young adults: the influences of the early home environment and early methods for studying health consequences of discrimination. Int J Health educational child care. Child Dev. 2007;78:746–756. Serv. 1999;29:295–352. 50. Reynolds AJ, Temple JA, Ou SR, et al. Effects of a school-based, early 30. Aidala A, Cross JE, Stall R, et al. Housing status and HIV risk behaviors: childhood intervention on adult health and well-being: a 19-year follow-up implications for prevention and policy. AIDS Behav. 2005;9:251–265. of low-income families. Arch Pediatr Adolesc Med. 2007;161:730–739. 31. 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Emerging Answers 2007: Research Findings on Programs to project: an innovative economic enhancement and HIV prevention Reduce Teen Pregnancy and Sexually Transmitted Diseases. Washington, intervention study targeting drug using women involved in prostitution. DC: National Campaign to Prevent Teen Pregnancy; 2007. AIDS Care. 2006;18:1–11. q 2010 Lippincott Williams & Wilkins www.jaids.com | S135 SUPPLEMENT ARTICLE

Challenges in the Design of HIV Prevention Trials in the United States Deborah Donnell, PhD,* James P. Hughes, PhD,† and Thomas R. Fleming, PhD†

of antiretroviral regimens in the mother and the newborn infant Abstract: The design of studies evaluating the safety and efficacy of have efficacies ranging from 33% to 98%1–6; and high interventions for HIV prevention is challenging in the US context, coverage has been achieved using existing antenatal care where there is low generalized prevalence. HIV incidence is facilities in the United States. In resource-limited countries, sufficiently high in the at-risk US population of men who have sex however, achieving high coverage remains the greatest with men that prevention trials using HIV infection end points are impediment to reducing perinatal HIV transmission. In the feasible. In other US populations at higher risk of HIV exposure, United States, other HIV prevention interventions that target efficacy trials of HIV prevention are likely not feasible. However, for small or hard-to-reach populations face a fundamental public interventions where efficacy is already established, conducting trials health challenge, especially if efficacy is modest. As a that test different implementation strategies in these populations hypothetical example, suppose a behavioral intervention for could provide definitive evidence about how to achieve high levels of stimulant-using men who have sex with men (MSM) achieves coverage. a 30% reduction in HIV transmission. If a quarter of the 50% of new HIV infections attributed to MSM in the United States Key Words: prevention trial, trial design, HIV seroincidence, 7 implementation each year occur in stimulant-using MSM, and 50% coverage of this target population is achieved, we would expect to avert (J Acquir Immune Defic Syndr 2010;55:S136–S140) only 2% of the new infections currently occurring annually in the United States (50% new infections in MSM 3 25% occurring in stimulant using MSM 3 50% coverage 3 30% effectiveness). In this article, we briefly discuss the challenges of PUBLIC HEALTH IMPACT AND designing HIV prevention trials in the context of the US HIV PREVENTION epidemic, utilizing the 3 elements cited above that determine the public health impact of potential interventions. Three elements are essential if an HIV prevention program is to meaningfully reduce the annual rate of new HIV infections in the United States. ELEMENT 1: TARGETING POPULATIONS AT 1. A large identifiable target population that is at risk for exposure to HIV. RISK FOR HIV IN THE UNITED STATES 2. An intervention with established effectiveness in the target The first prevention design challenge is identifying population. a population at substantial HIV risk. The general population in 3. A mechanism for delivery and uptake of the intervention by the United States is at very low risk, with estimated 56,300 a substantial fraction of the target population. new infections in 2006 and annual incidence of 22 per 100,000.8 Low event rates necessitate very large studies: In the Programs to prevent mother-to-child transmission of 9 HIV illustrate a case that has achieved considerable impact: low incidence setting of the Thai vaccine trial, even though The population of pregnant women with HIV infection is 16,402 volunteers were followed for 3 years, only 132 HIV identifiable (although not large in the United States); a variety infections occurred. Thus, research evaluating HIV prevention in the United States needs to be conducted in targeted populations having approximately 100-fold the level of HIV From the *Vaccine and Infectious Disease Division, Fred Hutchinson Cancer risk in the overall population. As noted in the 2008 Centers for Research Center, Seattle, WA; and †Department of Biostatistics, Disease Control and Prevention Surveillance Report and University of Washington, Seattle, WA. Table 1,7 the US subpopulations accounting for the highest Supported by the HIV Prevention Trials Network sponsored by the National proportion of newly detected infections are MSM (55%), Institute of Allergy and Infectious Diseases, National Institutes of Child Health and Human Development, National Institute on Drug Abuse, especially black and Hispanic MSM (32%), black and National Institute of Mental Health, and Office of AIDS Research of the Hispanic women, primarily at heterosexual risk (20%), and National Institutes of Health, US Department of Health and Human injection drug users (IDUs) (13%). MSM, women, and IDUs Services (U01-AI-46745, U01-AI-48054, U01-AI068613). have each been enrolled in HIV trials in the United States. The authors have no funding or conflicts of interest to disclose. Correspondence to: Deborah Donnell, PhD, 1100 Fairview Avenue N M2- Table 2 summarizes seroincidence rates in targeted HIV risk 200, PO Box 19024, Seattle WA 98109 (e-mail: [email protected]). cohorts since 1995. In MSM cohorts at a high risk of HIV Copyright Ó 2010 by Lippincott Williams & Wilkins exposure, incidence has consistently been above 1.5 per 100

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for blacks and 13 per 100,000 for Hispanic women and TABLE 1. Estimated New HIV Diagnoses in 2008, Proportion Latinas—is low.7 Cohorts of women at heterosexual risk, of Total New Diagnoses by Gender, Transmission Category, and Race in the 37 States With Confidential Name-Based selected for elevated risk of HIV exposure through personal Reporting (n = 41,087)7 sexual behavior and risk behavior of their sexual partners, have found low HIV incidence (Table 2). A new strategy for Transmission Category All, % Black, % Hispanic, % White, % identifying women at risk for HIV according to sociodemo- Male graphic characteristics is being tested in an ongoing study in MSM 55 22 10 21 the HIV Prevention Trials Network (HPTN), the ISIS study IDU 6 3 1 1 (HPTN 064).20 However, until we can identify characteristics MSM+IDU 3 1 1 1 that distinguish women at a high risk for HIV (ie, 20–40 times Heterosexual 11 8 2 1 the background rate) and until we can demonstrate the ability Other 0 0 0 0 to recruit and retain such women in a trial, the feasibility of Total male (n = 30,754) 75 35 14 24 conducting studies of the efficacy of new interventions for Female reducing HIV risk in such US populations is limited. IDU 4 2 1 1 IDUs in cities with high HIV prevalence are readily Heterosexual 21 15 3 3 identifiable and have been successfully enrolled and retained in Other 0 0 0 0 HIV seroincidence studies (Table 2). However, the number of Total female (n = 10,333) 25 17 3 4 new HIV/AIDS cases attributed to injection drug use in the United States has fallen steadily since 1993,21 and recent US person-years. Identifying and enrolling such MSM has been cohorts of IDUs with high risk for HIVexposure through needle shown to be feasible in multiple HIV prevention trials,10–14 and use have had low HIV incidence, even in settings of high HIV conducting prevention research in this population continues to prevalence (Table 2). Ironically, the study of prevention be viable in the United States. interventions for IDUs cannot proceed unless it is possible to Although black and Hispanic/Latina women in the enroll a large IDU population that remains at risk for HIV. United States have heightened HIV risk, the absolute rate of Heterosexual HIV risk can be identified through cohorts newly detected infections in minority women—56 per 100,000 of HIV discordant couples. The National Institute of Mental

TABLE 2. Cohorts Followed for HIV Seroincidence in the United States Since 1995 No. HIV Seroincidence 95% Confidence n Seroconversion Person-Years Rate Interval MSM VPS10 (1995–1997) 3257 72 4645 1.55 1.23 to 1.95 EXPLORE11 (1999–2003) 4295 259 12,240 2.12 1.9 to 2.4 VAX00412 (1998–2002) 5095 362 13,407 2.70 2.43 to 2.99 STEP13 (2004–2007)* 1058 44 1225 3.59 2.61 to 4.82 Women at heterosexual risk Project ACHIEVE14 (1995–1997) 89 0 122 0 0.00 to 3.13 VPS10 (1995–1997) 511 8 705 1.13 0.57 to 2.27 VPS 215 (1998–1999) 1647 13 1411 0.92 0.51 to 1.52 VAX00412 (1998–2002) 308 6 750 0.8 0.29 to 1.74 STEP12 (2004–2007)* 445 1 433 0.23 0.00 to 1.26 Discordant couples EBAN16 (2003–2008) 535 5 535† 0.94 0.30 to 2.18 Intravenous drug users Baltimore IDU17 (1995–1998) Women 399 16 845 1.89 1.08 to 3.08 Men 1447 42 2308 1.82 1.31 to 2.46 VPS10 (1995–1997) Women 354 6 482 1.24 0.56 to 2.77 Men 770 4 1053 0.38 0.14 to 1.01 New IDU (1997–1999) Women 109 2 46 4.32 0.72 to 13.3 HPTN03718 (2003–2006) Men 385 4 608 0.66 0.18 to 1.68 Women 181 4 276 1.45 0.39 to 3.71

HPTN, HIV prevention trials network; VPS, vaccine preparedness study. *Seventy-three percent of the STEP cohort was enrolled in the United States; the balance comprises participants from the Caribbean, South America, and Australia. †Person-years of follow-up not explicitly stated. q 2010 Lippincott Williams & Wilkins www.jaids.com | S137 Donnell et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

Health’s EBAN study enrolled 535 US African American facilitates rapid accrual, rather than to the United States, where discordant couples in stable relationships. But HIV incidence the epidemic is concentrated in specific risk populations. was low (Table 2), and the study took 4 years to accrue, Structural interventions or community-wide delivery of making this population, too, challenging to be utilized for prevention services mandate a community randomized trial studying HIV prevention interventions in the United States. (CRT) design to evaluate effectiveness.31–33 However, CRTs are inevitably more costly than individually randomized trials. Several factors lead to increased study size for CRTs: partial coverage and/or adherence lead to effect dilution; correlation ELEMENT 2: EFFICACY TRIAL DESIGN IN A US of outcomes within a community increases the variance of the TARGET POPULATION estimated intervention effect; and the intervention mechanisms The design of randomized clinical trials to test of action are often indirect. For example, in Project ACCEPT prevention efficacy is intimately linked to the specifics of an (HPTN 043), a CRT of mobile voluntary counseling and intervention, its intended mechanism, and its target popula- testing,33 only a subset of the community (ie, those who tion. An intervention that targets HIV-uninfected individuals is receive voluntary counseling and testing) experience the inter- most efficiently studied with an individually randomized vention, diluting the anticipated effectiveness. Also, the design. These have been used in most HIV prevention trials, expected mechanism of action—decreasing risky behavior with targeted intervention efficacies ranging from modest in HIV-infected individuals through awareness of their decreases (25%–35%)12,11,22,23 to substantial reductions (50%– infection—results in indirect protection of HIV-uninfected 60%).24–28 The resources required to evaluate HIV prevention individuals. Finally, underlying variation in the HIVepidemics interventions increase exponentially with decreased effective- across communities leads to a need for a large number of ness and linearly with decreased incidence of HIV infection: In participating communities to detect an intervention effect. an individually randomized trial, to achieve 90% power with Conducting HIV prevention CRTs in the United States 1-sided 2.5% false-positive error rates for detecting anticipated presents unique difficulties. First, defining communities in the effectiveness of 50%, 40%, and 30%, it requires 88, 161, and United States is challenging. The ideal community is closed: to 330 events, respectively. For a trial with (control arm) incidence prevent contamination and/or dilution of the intervention of 2.0 per 100 person-years, achieving these targeted numbers effect, neither people nor the intervention would travel among of events requires planning for 5866, 10,062, and 19,412 communities during the trial. High mobility and efficient person-years of follow-up, respectively; a rate of 1.0 per 100 communication in the US adult population makes defining person-years requires double the person-years of follow-up. a community problematic and may result in rapid diffusion of Given these constraints, it would be feasible to conduct the intervention between control and intervention communi- individually randomized trials in the United States with HIV ties. Second, low incidence in the general US population incidence end points in MSM populations. But trials in other means that HIV incidence must be measured in a sentinel risk populations in the United States are not feasible until we population, raising concerns about bias, retention, and are able to identify substantial subpopulations with HIV risk generalizability. These factors are particularly relevant for a levels similar to the risk found in MSM cohorts. HIV prevention community randomized trial because the Interventions that target HIV-infected persons to prevent intervention effect may take several years to be fully realized,34 sexual transmission to their HIV-uninfected partners require an thereby requiring the communities to remain largely intact (ie, HIV discordant couple or community randomized design. The stable, with constant background prevention efforts) for an resources required to enroll and follow a discordant couple extended period. cohort are close to double that of an individually randomized Given the low incidence in most US populations, design, which largely offsets the potential design efficiency surrogate end points such as self-reported behaviors, viral achieved from relatively high incidence. It should also be load, or acquisition of other sexually transmitted infections are noted that a substantial fraction of the transmissions in the often proposed as more feasible outcomes. Ideally, a surrogate HIV-uninfected partner may occur outside the couple,29 end point lies in the causal pathway between the intervention resulting in a dilution of effectiveness and consequently and the end point (HIV incidence) and captures the entire necessitating an increase in the sample size. Finally, discordant intervention effect.35 Unfortunately, none of these surrogates couple studies require stable long-term partnerships—short- have proved reliable as a proxy for HIV incidence, and the use term partnerships compromise the study design because HIV- of imperfect surrogates can be misleading. A potentially useful uninfected partners who leave the partnership are no longer role for surrogate end points in HIV research in the United exposed to the intervention (dilution of the effect) and new States might be in the evaluation of strategies for the partners identified after randomization may be subjected to implementation of known effective interventions. referral bias. In sub-Saharan Africa, HIV discordant couples have been rapidly accrued, and HIV seroincidence has remained sufficiently high to allow successful completion of ELEMENT 3: DESIGNS TO STUDY prevention trials with HIV end points,29,30 a situation that has IMPLEMENTATION STRATEGIES FOR HIV not yet been replicated in stable discordant couples in the PREVENTION IN THE UNITED STATES United States.16 Discordant partner studies appear better For any intervention that is proven to be effective in suited to generalized epidemic settings such as sub-Saharan a trial outside the United States, important research questions Africa, where the high prevalence of stable discordant couples remain about implementation in the US setting. Assuming the

S138 | www.jaids.com q 2010 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 Design of US HIV Prevention Trials evidence for effectiveness from randomized clinical trials is rapidly completed. The national HIV/AIDS surveillance data strong and fundamental principles suggest the intervention provide a unique and promising resource for assessment of will be equally effective in US populations, we can conduct community-based implementation trials within the HIV- rigorous studies that compare methods to achieve high infected population. coverage. This addresses the critical third element of public health prevention, delivering the intervention to a substantial fraction of the target population. A comparative study of REFERENCES 1. Leroy V, Karon JM, Alioum A, et al. Twenty-four month efficacy of program implementation strategies is feasible in major a maternal short-course zidovudine regimen to prevent mother-to-child populations exposed to HIV risk in the United States, using transmission of HIV-1 in West Africa. AIDS. 2002;16:631–641. well-defined program target populations and outcomes that 2. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single- measure program uptake rates. dose nevirapine compared with zidovudine for prevention of mother-to- child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of To illustrate the opportunity for rigorous study of the HIVNET 012 randomised trial. Lancet. 2003;362:859–868. doi: implementation strategies for prevention in the United States, 10.1016/S0140-6736(03)14341-3. we describe the Test, Link-to-Care Plus Treatment study 3. Gaillard P,Fowler MG, Dabis F, et al. Use of antiretroviral drugs to prevent (HPTN 065: TLC-Plus20), which includes a component designed HIV-1 transmission through breast-feeding: from animal studies to ran- to assess the impact of financial incentives to achieve high domized clinical trials. J Acquir Immune Defic Syndr. 2004;35:178–187. 4. Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/ linkage to care and high adherence to antiretroviral therapy newborn nevirapine and standard antiretroviral therapy to reduce perinatal for HIV-infected individuals in the United States. Definitive HIV transmission: a randomized trial. JAMA. 2002;288:189–198. trials are underway to evaluate the efficacy of HIV testing 5. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral and linkage to care for HIV prevention33 and the efficacy of strategies for the treatment of pregnant HIV-1-infected women and 36 prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. antiretroviral treatment for prevention of HIV transmission. 2002;29:484–494. However, there is clear therapeutic benefit for the HIV-infected 6. Petra Study Team. Efficacy of three short-course regimens of zidovudine person in improved linkage to care and treatment. and lamivudine in preventing early and late transmission of HIV-1 from TLC-Plus will compare the use of financial incentives mother to child in Tanzania, South Africa, and Uganda (Petra study): to the standard of care for linking newly diagnosed and out- a randomised, double-blind, placebo-controlled trial. Lancet. 2002;359: 1178–1186. doi:10.1016/S0140-6736(02)08214-4. of-care HIV-infected patients to a medical provider, using 7. Centers for Disease Control and Prevention. Diagnoses of HIV Infection and a cluster randomized trial design, with 40 HIV test facilities AIDS in the United States and Dependent Areas, 2008. HIV Surveillance assigned at random to either strategy. For HIV-infected partici- Report. Vol 20. Atlanta, GA: Division of HIV/AIDS Prevention, National pants who have initiated antiretroviral therapy, 40 medical care Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention; 2010. Available at: http://www.cdc.gov/ facilities will be cluster-randomized to compare financial hiv/surveillance/resources/reports/2008report/. Accessed August 12, 2010. incentives with the standard of care for achieving viral sup- 8. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the pression, which for most is achieved through high adherence United States. JAMA. 2008;300:520–529. to antiretroviral therapy. In most prevention trials, specific 9. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with procedures and facilities must be developed for collecting ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209–2220. doi:10.1056/NEJMoa0908492. outcome data. TLC-Plus will use the US national HIV/AIDS 10. Seage GR III, Holte SE, Metzger D, et al. Are US populations appropriate surveillance systems maintained by local health departments for trials of human immunodeficiency virus vaccine? The HIVNET and funded and supported by the Centers for Disease Control Vaccine Preparedness Study. Am J Epidemiol. 2001;153:619–627. and Prevention to evaluate key trial end points—the proportion 11. Koblin B, Chesney M, Coates T; and the EXPLORE Study Team. Effects of a behavioural intervention to reduce acquisition of HIV infection of cases linked to care for each test facility and the proportion among men who have sex with men: the EXPLORE randomised controlled of a care facility’s patients with suppressed viral load—using study. Lancet. 2004;364:41–50. doi:10.1016/S0140-6736(04)16588-4. laboratory tests captured in the surveillance data. Using these 12. Flynn NM, Forthal DN, Harro CD, et al. Placebo-controlled phase 3 trial process outcomes, the trial is well powered to assess the of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. financial incentive strategies. J Infect Dis. 2005;191:654–665. doi:10.1086/428404. 13. Buchbinder SP,Mehrotra DV,Duerr A, et al. Efficacy assessment of a cell- mediated immunity HIV-1 vaccine (the STEP Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372: CONCLUSIONS 1881–1893. PMCID: PMC2721012. HIV prevention efficacy trials can be conducted 14. Brown-Peterside P, Chiasson MA, Ren L, et al. Involving women in HIV vaccine efficacy trials: lessons learned from a vaccine preparedness study efficiently only in large target populations having HIV in New York City. J Urban Health. 2000;77:425–437. incidence rates that are at least as high as approximately 2 15. Seage GR III, Holte S, Gross M, et al. Case-crossover study of partner and per 100 person-years; the only risk population in the United situational factors for unprotected sex. J Acquir Immune Defic Syndr. States that currently meets this requirement is MSM. Ongoing 2002;31:432–439. efforts are needed to understand how to target high-risk 16. El-Bassel N, Jemmott JB, Landis JR, et al. National Institute of Mental Health Multisite Eban HIV/STD prevention intervention for African subgroups within other major populations affected by HIV. American HIV serodiscordant couples: a cluster randomized trial. Arch Rigorous trials for evaluating how to implement Intern Med. 2010;170:1594–1601. doi:10.1001/archinternmed. 2010. 261. effective HIV prevention interventions are feasible within 17. Nelson KE, Galai N, Safaeian M, et al. Temporal trends in the incidence of the United States because coverage and uptake are the primary human immunodeficiency virus infection and risk behavior among injection drug users in Baltimore, Maryland, 1988-1998. Am J Epidemiol. outcomes of interest. These trials are likely to be community 2002;156:641–653. based and conducted in tandem with pilot program imple- 18. Latkin CA, Donnell D, Metzger D, et al. The efficacy of a network mentation. Compared with efficacy trials, such trials could be intervention to reduce HIV risk behaviors among drug users and risk q 2010 Lippincott Williams & Wilkins www.jaids.com | S139 Donnell et al J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010

partners in Chiang Mai, Thailand and Philadelphia, USA. Soc Sci Med. 27. Padian NS, van der Straten A, Ramjee G, et al. Diaphragm and lubricant 2009;68:740–748. PMCID: PMC2724962. gel for prevention of HIV acquisition in southern African women: 19. Buchbinder SP, Douglas JM Jr., McKirnan DJ, et al. Feasibility of human a randomised controlled trial. Lancet. 2007;370:251–261. doi:10.1016/ immunodeficiency virus vaccine trials in homosexual men in the United S0140-6736(07)60950-7. States: risk behavior, seroincidence, and willingness to participate. J Infect 28. Gray RH, Kiwanuka N, Quinn TC, et al; for the Rakai Project Team. Male Dis. 1996;174:954–961. circumcision and HIV acquisition and transmission: cohort studies in 20. HPTN 065. Evaluating methods to increase HIV testing, access to HIV care, Rakai, Uganda. AIDS. 2000;14:2371–2381. and HIV prevention strategies (TLC+) [ClinicalTrials.gov Web site]. Available 29. Celum C, Wald A, Lingappa JR, et al. Acyclovir and transmission of HIV- at: http://clinicaltrials.gov/ct2/show/study/NCT01152918?term=HPTN065& 1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362: rank=1. Accessed July 14, 2010. 427–439. doi:10.1056/NEJMoa0904849. 21. Centers for Disease Control and Prevention. Estimates of New HIV 30. Hira SK, Feldblum PJ, Kamanga J, et al. Condom and nonoxynol-9 use Infections in the United States. CDC HIV/AIDS Facts. Atlanta, GA: and the incidence of HIV infection in serodiscordant couples in Zambia. Centers for Disease Control and Prevention; 2008. Available at: http:// Int J STD AIDS. 1997;8:243–250. doi:10.1258/0956462971919994. www.cdc.gov/hiv/topics/surveillance/resources/factsheets/pdf/incidence.pdf. 31. Grosskurth H, Gray R, Hayes R, et al. Control of sexually transmitted Accessed August 17, 2010. diseases for HIV-1 prevention: understanding the implications of the 22. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al.Vaccination with Mwanza and Rakai trials. Lancet. 2000;355:1981–1987. doi:10.1016/ ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J S0140-6736(00)02336-9. Med. 2009;361:2209–2220. Available at [supplementary appendix]: http:// 32. Wawer MJ, Sewankambo NK, Serwadda D, et al; and the Rakai Project www.nejm.org/doi/suppl/10.1056/NEJMoa0908492/suppl_file/nejm_rerks- Study Group. Control of sexually transmitted diseases for AIDS ngarm_2209sa1.pdf. Accessed August 19, 2010. prevention in Uganda: a randomised community trial. Lancet. 1999; 23. Karim SA, Coletti A, Richardson B, et al. Safety and effectiveness of 353:525–535. doi:10.1016/S0140-6736(98)06439-3. vaginal microbicides BufferGel and PRO 2000 Gel for the prevention 33. Genberg BL, Kulich M, Kawichai S, et al. HIV risk behaviors in sub- of HIV infection in women: results of the HPTN 035 trial [abstract 48LB]. Saharan Africa and Northern Thailand: baseline behavioral data from Presented at: 16th Conference on Retroviruses and Opportunistic Infections Project Accept. J Acquir Immune Defic Syndr. 2008;49:309–319. (CROI); February 8–11, 2009; Montreal, Quebec, Canada. 34. Hallett TB, Garnett GP, Mupamberiyi Z, et al. Measuring effectiveness in 24. Auvert B, Taljaard D, Lagarde E, et al. Randomized, controlled intervention community randomized trials of HIV prevention. Int J Epidemiol. 2008; trial of male circumcision for reduction of HIV infection risk: the ANRS 37:77–87. doi:10.1093/ije/dym232. 1265 Trial. PLoS Med. 2005;2:e298. doi:10.1371/journal.pmed.0020298. 35. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we 25. Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition being misled? [Perspectives]. Ann Intern Med. 1996;125:605–613. in herpes simplex virus 2 seropositive women and men who have sex with 36. Cohen MS, Bollinger RC, Celentano D, et al. HPTN 052. A randomized men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008; trial to evaluate the effectiveness of antiretroviral therapy plus HIV 371:2109–2119. doi:10.1016/S0140-6736(08)60920-4. primary care versus HIV primary care alone to prevent the sexual 26. Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV transmission of HIV-1 in serodiscordant couples [HIV Prevention Trials prevention in young men in Kisumu, Kenya: a randomised controlled trial. Network Web site]. Available at: http://www.hptn.org/research_studies/ Lancet. 2007;369:643–656. doi:10.1016/S0140-6736(08)60920-4. HPTN052StudyDocuments.asp#Protocol. Accessed January 20, 2010.

S140 | www.jaids.com q 2010 Lippincott Williams & Wilkins SUPPLEMENT ARTICLE

Lessons From Africa Miriam Rabkin, MD, MPH,*†‡ Wafaa M. El-Sadr, MD, MPH,*†‡ Peter Mugyenyi, MB, ChB, FRCPI, FRCPEdin,§ Mphu K. Ramatlapeng, MD,k and Kevin M. De Cock, MD, FRCP(UK), DTM&H¶

the critical role of retention in care and adherence to treatment, Abstract: Delayed access to HIV care and treatment in sub-Saharan the need for multidisciplinary teams of providers, and the key Africa meant that the early years of HIV scale-up were characterized role for PLWH in shaping the response to the HIV epidemic. by a largely North-to-South transfer of knowledge and resources. These principles are now accepted as fundamental to effective Clinicians from wealthy countries were among the first to gain HIV programs. experience with antiretroviral treatment and care of people living with Times have changed, however, and the flow of in- HIV and shared key lessons with their colleagues in sub-Saharan formation and experience is no longer a one-way street. Africa. Ten years later, lessons from Africa learned from the Clinicians and public health practitioners in many lower- remarkable achievements of HIV programs now have the potential to income countries have rapidly acquired proficiency in the inform the response to the US domestic epidemic. prevention, care, and treatment of HIV and now lead the Key Words: HIV scale-up, program implementation, lessons, Africa development and implementation of their national guidelines and trainings. The response to the African HIV epidemic has (J Acquir Immune Defic Syndr 2010;55:S141–S143) provided successful models of rapid program scale-up and highlighted the fact that global health requires global financing. Fiscal sustainability is unlikely to be achieved in INTRODUCTION the near future, but technical sustainability is much more The global response to the HIV epidemic has often been promising. Although funds and technical assistance from the perceived as a North-to-South transfer of expertise, as well as global North are still welcome and necessary in many settings, resources. Because HIV care and treatment, including local solutions and expertise often provide the most effective antiretroviral therapy (ART), were first widely available in interventions. This new equilibrium highlights the fact that wealthy countries, practitioners from the United States, innovations and best practices are generated worldwide—and western Europe, and similarly well-resourced settings were that South–South and South–North transfers and technical among the first to gain experience treating people living with assistance have important roles to play. Indeed, despite marked HIV (PLWH), the first to develop clinical guidelines, and the differences in the magnitude and characteristics of the HIV first to design and implement HIV service delivery programs. epidemics in the United States and in sub-Saharan Africa, the The delayed initiation of HIV care and treatment programs in response to the US HIVepidemic may be enhanced by some of sub-Saharan Africa created a ‘‘lost decade,’’ in which millions the lessons learned from the enormous success of HIV of PLWH were deprived of life-saving interventions and only program scale-up in Africa. a few African clinicians gained experience with HIV care and treatment. When resources finally became available, key CONTRASTING REALITIES insights from years of experience in the North informed the Sub-Saharan Africa has a generalized HIV epidemic scale-up in the South. Examples include the importance of with high seroprevalence rates in many countries, although combination ART and the perils of sequential monotherapy, recent data indicate that specific subpopulations are more severely impacted. For example, young women in southern From the *International Center for AIDS Care and Treatment Programs, Africa are at particular risk for HIV infection when contrasted Columbia University Mailman School of Public Health, New York, NY; with young men of the same age, and there are high rates of †Department of Medicine, Columbia University College of Physicians and HIV infection among drug users and men who have sex with Surgeons, New York, NY; ‡Department of Epidemiology, Columbia 1 University Mailman School of Public Health, New York, NY; §Joint Clinical men in some countries. In contrast, the overall HIV Research Center, Kampala, Uganda; kLesotho Ministry of Health and Social prevalence in the United States is much lower, and the US Welfare, Maseru, Lesotho; and {U.S. Centers for Disease Control and epidemic is a localized one, with foci of high prevalence Prevention, Atlanta, GA. rivaling that in some parts of sub-Saharan Africa, particularly The findings and conclusions in this report are those of the authors and do not 2 necessarily represent the official position of either the US Centers for among men who have sex with men and African Americans. Disease Control or the Lesotho Ministry of Health and Social Welfare, Another contrast is the state of health systems in the Maserv, Lesotho. United States compared with those in sub-Saharan Africa. In The authors have no funding or conflicts of interest to disclose. 2007, per capita total expenditure on health was $7285 in the Correspondence to: Wafaa M. El-Sadr, MD, MPH, International Center for United States, compared with $819 in South Africa, $79 in AIDS Care and Treatment Programs, 722 West 168th Street, Room 715, 3 New York, NY 10032 (e-mail: [email protected]). Zambia, and $39 in Mozambique. Out-of-pocket expendi- Copyright Ó 2010 by Lippincott Williams & Wilkins tures represent 12% of the total health expenditures in the

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United States, compared with 33% in the African region as a settings, these guidelines have also averted the ‘‘pharma- whole.4 There is a glaring difference in the availability of cologic chaos’’seen in some resource-rich settings, in which health workers, with approximately 27 physicians and 560 personalized prescribing and disregard of guidelines can health workers per 10,000 inhabitants in the United States devolve into unnecessarily complex care, over-use of lab- compared with 2 and 23 per 10,000 inhabitants in the African oratory investigations, and even reported misuse of ART.8 region.3,4 The United States has 31 hospital beds per 10,000 Know your epidemic: With the exception of data from the people, compared with 1.8 in Ethiopia, 4 in Coˆte d’Ivoire, and National Health and Nutrition Examination Survey, the 13 in Lesotho.5 In 2007, healthy life expectancy at birth was 70 United States lacks the detailed information found in years in the United States and 45 years in the African region.3 Demographic Health Surveys, Multiple Indicator Cluster Although precise data are lacking, PLWH in the United States Surveys, antenatal sentinel surveillance, and initiatives such have far greater access to HIV care and treatment than those in as the 2007 Kenya AIDS Indicator Survey, which provides Africa. However, the US response to the HIVepidemic has not a detailed and profoundly useful snapshot of the epidemic in been without its challenges, including continued HIV trans- that country.9 On the other hand, national disease mission and disparities in access to HIV services.6 surveillance systems (especially those based on case reporting) are typically much more robust in resource-rich settings like the United States. LESSONS FROM AFRICA Task shifting: Driven by a critical shortage of physicians and The response to HIV in Africa is as diverse and nurses,10,11 the HIV response in sub-Saharan Africa has heterogeneous as the epidemic itself, with important within- been characterized by health workforce innovations, task country and between-country differences. Although general- shifting, and task sharing.12,13 For example, in some izations about the 47 different countries in sub-Saharan Africa countries, nurses and clinical officers can now prescribe are not always helpful, several recurrent lessons have emerged. and/or refill antiretroviral medications,14,15 whereas in the We note that these innovations are not limited to the African United States, these activities are limited to physicians and region and that additional important lessons are available from nurse practitioners. Similar vision and creativity about around the world. professional roles and responsibilities may help the United National plans: Since 2004, the UNAIDS has emphasized States face one of its key challenges—substantially the importance of the ‘‘Three Ones’’: a single national AIDS expanding and improving HIV screening and testing coordinating authority, a single national HIV/AIDS action programs, identifying the estimated 250,000 undiagnosed framework, and a single national monitoring and evaluation HIV-infected individuals, and linking them to care and system for HIV programs.7 Countries such as Kenya and treatment services and providing services to an increased Ethiopia have had national plans for years, with targets and number of newly identified PLWHs. In addition, addressing budgets supporting concrete objectives and activities. the disparities in access to services for PLWHs as priorities Although clinical guidelines have been available for many in the national HIV strategy will require availability of ever years, the United States released its first-ever National HIV/ increasing numbers of providers.6 AIDS Strategic Plan in 2010.6 Diagnostics and case finding: Although countries in sub- Targets and accountability: The United States can learn Saharan Africa have a long way to go in achieving broad from many African countries that have developed specific access to HIV testing for their populations, these same numeric targets for HIV testing, care, and treatment based countries were quick to adopt rapid HIV testing assays, on the best available information about the local prevalence utilizing algorithms that do not include Western blot assays. and need. Enrollment and coverage targets have been They also pioneered the provision of such testing by lay developed for the site, district, province, and national levels, workers trained to perform rapid HIV tests in mobile, and the progress against targets is reported and shared. In community, and even home-based settings. At health Ethiopia, for example, the Federal Ministry of Health and facilities, provider initiated point-of-service screening for the Federal HIV/AIDS Prevention and Control Office HIV enables rapid testing at multiple venues, from antenatal publish monthly data on the enrollment in HIV care and care, to tuberculosis (TB) clinics, to outpatient departments. ART for each region, and for every health care facility Integration of services: Although access to integrated service providing HIV services in the country. ART coverage is an delivery varies from site to site and country to country, some indicator in WHO’s World Health Statistics report, which types of integrated services are often more developed and publishes annual estimates of national ART coverage among more accessible in African programs than in the United people with advanced HIV infection and prevention of States. The integration of HIVand TB services, including TB mother-to-child transmission coverage among HIV-infected screening for patients with HIV and HIV testing for patients pregnant women in more than 100 countries; these data are with TB, is one example; the use of antenatal care programs difficult to ascertain for the United States. for the provision of prevention of mother-to-child trans- Algorithmic guidelines: The development of simple algo- mission and the identification and enrollment of women and rithmic HIV treatment guidelines in response to physician families with HIV into HIV services is another. shortages has enabled not only rapid scale-up of HIV Research: Studies conducted in sub-Saharan Africa have services but also the standardization of first- and second-line contributed substantially to the world’s knowledge base on treatment, streamlined drug procurement, and task shifting HIV/AIDS, directly influencing practice elsewhere. After from physicians to nurses and other health workers. In many years of productive research in descriptive and analytic

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epidemiology focusing on natural history, risk factors and Available at: http://www.who.int/whr/2006/en/index.html. Accessed disease associations,16 Africa is now a vibrant setting for October 15, 2010. 5. WHO Global Health Observatory [database online]. Geneva, Switzerland; clinical trials of relevance worldwide, in areas such as 2010. Available at: http://apps.who.int/ghodata/. Accessed October 15, prevention and treatment of HIV-associated tuberculosis, 2010. HIV prevention, microbicides, and other interventions.17–19 6. The White House Office of National AIDS Policy. National HIV/AIDS Strategy for the United States. Washington, DC: The White House; 2010. Available at: http://www.whitehouse.gov/sites/default/files/uploads/NHAS. pdf. Accessed October 15, 2010. CONCLUSIONS 7. The Joint United Nations Programme on HIV/AIDS (UNAIDS). The Despite the horrific impact of the HIV epidemic, it has ‘‘Three Ones’’: principles for the coordination of national AIDS also triggered an outpouring of solidarity within and between responses. Available at: http://www.unaids.org/en/CountryResponses/ MakingTheMoneyWork/ThreeOnes/default.asp. Accessed October 15, nations. Again and again, we see the impact of generous 2010. support from individuals, communities, and countries. 8. Cocohoba J, Wang QJ, Cox C, et al. Consistency of initial antiretroviral Although common wisdom suggests that financial and therapy with HIV treatment guidelines in a US cohort of HIV-infected technical inputs from resource-rich settings can and should women. JAIDS. 2008;47:377–383. continue to inform the design and implementation of HIV 9. National AIDS and STI Control Programme (NASCOP). Kenya AIDS Indicator Survey 2007: Final Report. Nairobi, Kenya: Ministry of Health; programs in the global South when appropriate, the potential 2009. Available at: http://www.aidskenya.org/public_site/webroot/cache/ benefits of South–South and South–North contributions article/file/Official_KAIS_Report_20091.pdf. Accessed October 15, 2010. should also be acknowledged. Remarkable innovations have 10. Chen L, Evan T, Anand S, et al. Human resources for health: overcoming germinated in Africa in the process of scaling up HIV the crisis. Lancet. 2004;364:1984–1990. 11. Joint Learning Initiative. Human Resources for Health: Overcoming the prevention, care, and treatment programs; many of these can Crisis. Cambridge, MA: Harvard University Press; 2004. inform the response to the HIV epidemic. As the United States 12. Sherr K, Pfeiffer J, Mussa A, et al. The role of nonphysician clinicians in continues its quest to control the epidemic in its midst, we the rapid expansion of HIV care in Mozambique. JAIDS. 2009;52: should pause and consider what we can learn from Africa. S20–S23. 13. Samb B, Celletti F, Holloway J, et al. Rapid expansion of the health workforce in response to the HIV epidemic [sounding board]. N Engl J Med. 2007:357;2510–2514. ACKNOWLEDGMENTS 14. World Health Organization (WHO). Task Shifting: Rational Redistribu- The authors acknowledge their valued colleagues in the tion of Tasks Among Health Workforce Teams. Global Recommendations United States and in Africa who have contributed so much to the and Guidelines. Geneva, Switzerland: WHO; 2008. Available at: http:// www.who.int/healthsystems/TTR-TaskShifting.pdf. Accessed October response to the HIVepidemic, as well as the patients and families 15, 2010. who have trusted us with their care. They also acknowledge 15. Dohrn J, Nzuama B, Murrman M. The impact of HIV scale-up on the contributions by Shannon Hader and Chris Collins. role of nurses in South Africa: Time for a new approach. JAIDS. 2009;52: S27–S29. 16. De Cock KM, Ekpini E, Gnaore E, et al. The public health implications of REFERENCES AIDS research in Africa. JAMA. 1994;272:481–486. 1. The Joint United Nations Programme on HIV/AIDS (UNAIDS) and 17. Abdool Karim, SS, Naidoo K, Grobler A, et al. Timing of initiation of World Health Organization (WHO). AIDS Epidemic Update: November antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362: 2009. Geneva, Switzerland: UNAIDS; 2009. 697–706. 2. El-Sadr WM, Mayer KH, Hodder SL. AIDS in America—forgotten but 18. Lingappa JR, Baeten JM, Wald A, et al. Daily acyclovir for HIV-1 disease not gone. N Engl J Med. 2010;362:967–970. progression in people dually infected with HIV-1 and herpes simplex 3. World Health Organization (WHO). World Health Statistics 2010. virus type 2: a randomised placebo-controlled trial. Lancet. 2010;375: Geneva, Switzerland: WHO; 2010. Available at: http://www.who.int/ 824–833. whosis/whostat/EN_WHS10_Full.pdf. Accessed October 15, 2010. 19. Abdool Karim, Q, Abdool Karim, SS, Frohlich, J, et al. Effectiveness 4. World Health Organization (WHO). The World Health Report 2006: and safety of tenofovir gel, an antiretroviral microbicide, for the Working Together for Health. Geneva, Switzerland: WHO; 2006. prevention of HIV infection in women. Science. 2010;329:1168–1174.

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A Way Forward: The National HIV/AIDS Strategy and Reducing HIV Incidence in the United States Gregorio A. Millett, MPH,*† Jeffrey S. Crowley, MPH,† Howard Koh, MD, MPH,‡ Ronald O. Valdiserri, MD, MPH,‡ Thomas Frieden, MD, MPH,§ Carl W. Dieffenbach, PhD,k Kevin A. Fenton, MD, PhD, FFPH,¶ Regina Benjamin, MD, MBA,# Jack Whitescarver, PhD,** Jonathan Mermin, MD, MPH,¶ Deborah Parham-Hopson, PhD, RN, FAAN,†† and Anthony S. Fauci, MD‡‡

In July 2010, the Obama Administration released Abstract: In July 2010, the Obama Administration released a National HIV/AIDS Strategy for the United States, which a National HIV/AIDS Strategy for the United States to refocus represents an effort to refocus national attention on ending the national attention on responding to the domestic HIV epidemic. The domestic HIV epidemic.3,4 The strategy is structured around 3 goals of the strategy are to reduce HIV incidence; to increase access key goals and is intended to identify a small number of action to care and optimize health outcomes among people living with HIV; steps to focus and align efforts across federal, state, local, and and to reduce HIV-related disparities. The strategy identifies a small tribal levels (Table 1). Although the nation initially succeeded number of action steps that will align efforts across federal, state, in reducing new HIV infections from 130,000 per year in the local, and tribal levels of government, and maximally impact the 1980s to 56,000 in the 1990s, overall HIV incidence in the domestic HIV epidemic. In this article, we outline key programmatic United States has remained stable for more than a decade and and research issues that must be addressed to accomplish the continues to increase among men who have sex with men. prevention goals of the National HIV/AIDS Strategy. while remaining stable or decreasing in other populations.1,5 Key Words: HIV/AIDS, National, Obama, President, strategy The National HIV/AIDS Strategy sets a goal of reducing annual incidence by 25% by 20156 and recently published (J Acquir Immune Defic Syndr 2010;55:S144–S147) mathematical models confirm that this goal is achievable.7 To achieve this result, we must refocus prevention efforts on those communities at greatest risk. The nation must also adopt a more strategic and coordinated approach that utilizes a combination INTRODUCTION of effective HIV prevention interventions and stimulates More than 1.1 million people are living with HIV in the innovation to develop additional effective scalable tools. United States, and more than 56,000 Americans become 1,2 infected with HIV each year. Notwithstanding our nation’s IMPROVING OUR PROGRAMMATIC RESPONSE significant achievements in caring for people with HIVand the TO REDUCE HIV INCIDENCE development of effective therapies, our ability to address the Analogous to antiretroviral therapy (ART), which is highly domestic epidemic depends on sustaining and expanding effective when multiple medications are combined, effective successful prevention strategies. prevention should involve multiple interventions to reduce risk behavior, reduce opportunities for transmission, and lower From the *Centers for Disease Control and Prevention, Atlanta, GA; †White biological susceptibility of transmitting or acquiring infection. House Office of National AIDS Policy, Washington, DC; ‡Office of Public Despite the availability of evidence-based behavioral and bio- Health and Science, Department of Health and Human Services, medical tools that reduce HIV transmission or HIV risk (Table Rockville, MD; §Office of the Director, Centers for Disease Control 2), the challenge for federal agencies and state and local partners and Prevention, Atlanta, GA; ||Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, responsible for delivering prevention services is understanding MD; {National Center for HIV/AIDS, Viral Hepatitis, STD, and TB which combinations of prevention interventions will produce the Prevention, Centers for Disease Control and Prevention, Atlanta, GA; most robust results in specific high-risk communities. #Office of the Surgeon General, Department of Health and Human There is significant potential to reduce HIV transmission Services, Rockville, MD; **Office of AIDS Research, Office of the by scaling up prevention interventions targeting people who Director, National Institutes of Health, Bethesda, MD; ††HIV/AIDS Bureau, Health Resources and Services Administration; and ‡‡Office of are diagnosed with HIV. Although studies show significant the Director, National Institute of Allergy and Infectious Diseases, reductions in the HIV transmission rate when people with HIV National Institutes of Health, Bethesda, MD. are tested and learn their status, some HIV-infected individuals The authors have no funding or conflicts of interest to disclose; and the article continue to engage in high-risk behaviors with partners who has never been presented in whole or in part. 7 Correspondence to: Gregorio Millett, MPH, Office of National AIDS Policy, The are HIV negative or of unknown status. For these HIV- White House, Washington, DC 20502 (e-mail: [email protected]). infected individuals, it is important to provide a tailored Copyright Ó 2010 by Lippincott Williams & Wilkins approach that promotes physical, emotional, and sexual health.

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TABLE 1. National HIV/AIDS Strategy Goals and Targets* Strategy Goal Recommended Action Steps Targets by 2015 Reduce HIV incidence 1. Intensify HIV prevention efforts in communities where 1. Lower the annual number of new infections by 25% HIV is most heavily concentrated (from 56,300 to 42,225) 2. Expand targeted efforts to prevent HIV infection using 2. Reduce the HIV transmission rate (a measure of annual a combination of effective, evidence-based approaches transmissions in relation to the number of people living 3. Educate all Americans about the threat of HIV and how with HIV) by 30%, from 5 persons infected each year to prevent it per 100 people with HIV to 3.5 persons infected each year per 100 people with HIV 3. Increase from 79% to 90% the percentage of people living with HIV who know their serostatus (from 948,000 to 1,080,000 people Increase access to care and 1. Establish a seamless system to immediately link people to 1. Increase the proportion of newly diagnosed patients optimize health outcomes continuous, coordinated quality care when they are linked to clinical care within 3 mo of their HIV for people living with HIV diagnosed with HIV diagnosis, from 65% to 85% (from 26,824 to 2. Take deliberate steps to increase the number and diversity 35,079 people). of available providers of clinical care and related services 2. Increase the proportion of Ryan White HIV/AIDS for people living with HIV Program clients who are in care (at least 2 visits for 3. Support people living with HIV with co-occurring health routine HIV medical care in 12 mo at least 3 mo conditions and those who have challenges meeting their apart) from 73% to 80% (or 237,924 people in basic needs, such as housing continuous care to 260,739 people in continuous care) 3. Increase the percentage of Ryan White HIV/AIDS Program clients with permanent housing from 82% to 86% (from 434,000 to 455,800 people) Reduce HIV-related disparities 1. Reduce HIV-related mortality in communities at high risk 1. Increase the proportion of HIV-diagnosed gay and for HIV infection bisexual men with undetectable viral load by 20% 2. Adopt community-level approaches to reduce HIV 2. Increase the proportion of HIV diagnosed blacks infection in high-risk communities with undetectable viral load by 20% 3. Reduce stigma and discrimination against people living 3. Increase the proportion of HIV-diagnosed Latinos with with HIV undetectable viral load by 20%

*The National Strategy identifies gay and bisexual men, black Americans, Latino Americans, and substance users as a primary focus for HIV prevention efforts. A presidential memorandum has identified the Department of Health and Human Services, Department of Justice, Department of Labor, Department of Housing and Urban Development, Department of Veterans Affairs, and Social Security Administration as lead agencies in implementing the strategy at the federal level.

In addition to promoting safer behaviors among people Canada, have found encouraging reductions in HIV incidence diagnosed with HIV, providing access to and improving the associated with the uptake of ART by the majority of known continuity of their care is critical. It is clear that ART both positives.11–13 However, an estimated 30% of people living provides clinical benefits for people living with HIV and with HIV in the United States who are clinically eligible for reduces the risk of transmission.8–10 Recent studies in ART are not receiving medical care and an additional 15% Denmark, San Francisco, California, and British Columbia, receiving medical care are not receiving ART.14 Individual

TABLE 2. HIV Prevention and Risk Reduction Tools for HIV-Negative and HIV-Positive Individuals Individual Interpersonal Community Structural Prevention with Screening for HIV and sexually Network-based methods to Availability of postexposure Policies that promote culturally HIV-negative transmitted infections get individuals in high-risk prophylaxis appropriate HIV education individuals Postexposure prophylaxis communities tested for HIV Access to condoms Policies, social marketing, and Risk reduction interventions Prevention services for Syringe services programs interventions to reduce HIV (sexual and alcohol and other partners of HIV-infected Social marketing efforts stigma and discrimination drug-related behaviors) individuals Prevention with Diagnosing undiagnosed Utilizing disease intervention Reducing community viral Instituting Affordable Care Act, HIV- positive positives specialists and peer advocates to load including access to care for HIV- individuals Linkage to continuous care link and keep diagnosed Syringe services programs infected individuals and Sexually transmitted infections individuals in care Access to condoms increasing the number of diagnosis and treatment Serosorting and safer sex Social marketing efforts providers Antiretroviral therapy counseling Policies, social marketing, and Prevention of mother-to-child For HIV-positive individuals in interventions to reduce HIV transmission serodiscordant partnerships stigma and discrimination Medication adherence support HIV status disclosure Accessibility to housing Risk reduction interventions Risk reduction counseling (sexual and alcohol and other Condom provision and drug-related behaviors) utilization q 2010 Lippincott Williams & Wilkins www.jaids.com | S145 Millett et al J Acquir Immune Defic Syndr Volume 55, Supplement 2, December 15, 2010 clinical outcomes and population-level outcomes can be Additional behavioral research and rigorous evaluation improved by increasing rates of ART usage when it is clinically is needed to minimize decay of behavioral intervention effects indicated, as well as ART adherence. Although the decision and to provide more viable adaptations of effective behavioral to start ART is a personal one that every individual with HIV interventions in clinic-based and community-based settings. should discuss with his or her clinician, all HIV-infected HIV prevention efforts must also continue to move beyond persons in the United States should have access to uninter- addressing individual HIV risk behavior. Individuals in some rupted health care that is coordinated and of high quality. disproportionately affected communities—particularly black There is also an opportunity to improve our program- gay men and black women—remain at greater risk for HIV matic response to identifying individuals with unrecognized infection, despite engaging in comparable or less risk than HIV infection. Approximately half of new sexually acquired individuals in other communities.22,23 Because individual- HIV infections in the United States are transmitted by 21% of level risk reduction interventions alone will not meaning- HIV-infected people who are unaware of their HIV status.2,15 fully reduce HIV incidence in some disproportionately Although guidelines for HIV testing in clinical settings have affected communities, there must be an improved un- been in place since 2006, these recommendations have not derstanding of network, social, and structural factors that been widely implemented.16 Routine HIV screening among place individuals in specific communities at elevated risk for targeted communities in reproductive health and sexually HIV infection.24,25 transmitted disease clinics, in emergency departments, in addiction treatment programs, and among partners of HIV- diagnosed individuals may reduce missed opportunities to NEXT STEPS identify and treat those with HIV. It is also important to Thirty years into the HIV epidemic in the United States, concentrate testing resources in communities where testing is it is unrealistic to expect that the National HIV/AIDS Strategy most likely to identify new, as well as chronic unrecognized or our recommendations for reducing new infections would be infections. Expanded HIV testing efforts targeted among composed entirely of new approaches to prevention. However, groups at highest risk for HIV infection in the District of the innovation of the national strategy lies in its commitment to Columbia was associated with a reduction in new AIDS building on an evolving evidence base of what works, in diagnoses.17 Achieving similar outcomes nationally will identifying common national goals toward which federal, require increasing provider awareness of HIV testing guide- state, local, and tribal governmental partners and community lines and addressing reimbursement disincentives for HIV partners can align their efforts, and in a renewed commitment testing services. to collaboration and coordination.

FUTURE RESEARCH TO REDUCE ACKNOWLEDGMENTS HIV INCIDENCE The authors would like to thank the members of the Additional research is also necessary to help improve the Federal Interagency Working Group for their contributions to nation’s response to the domestic HIV epidemic. The last 2 the process of creating the National HIV/AIDS Strategy. We years have been marked by significant advances in HIV 18–20 also thank Drs. Gary Marks and Gregory Folkers, as well as prevention, particularly in microbicide and vaccine research. Ms. Wendy Wertheimer for their comments during the drafting However, we must support further research to boost the of the manuscript. Last, we are grateful to the many effectiveness of promising microbicide and vaccine candidates individuals affected by or infected with HIVacross the country and bring newer candidates through Phase II and III trials. who shared their stories, convened meetings, and provided Should existing research studies investigating the effectiveness 21 recommendations that shaped the development of the National of preexposure prophylaxis (PrEP) yield positive results, HIV/AIDS Strategy. operational research must address how PrEP can best be integrated into comprehensive HIV prevention services for REFERENCES populations at greatest risk for HIV infection, and the provision of 1. Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the PrEP given existing resource constraints. We must also evaluate United States. JAMA. 2008;300:520–529. the degree to which behavioral disinhibition or inconsistent 2. Campsmith ML, Rhodes P, Hall HI, et al For the Centers for Disease adherence to medications or specific regimens may undercut Control. HIV prevalence estimates—United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;57:1073–1076. potential gains from these new prevention technologies. 3. White House Office of National AIDS Policy. National HIV/AIDS Research must also continue to test new, more effective, Strategy for the United States. Washington, DC: The White House; July and less costly HIV therapies and drug regimens that can 13, 2010. Available at: http://www.whitehouse.gov/sites/default/files/ reduce infectiousness with fewer side effects and clinical uploads/NHAS.pdf2. Accessed August 6, 2010. complications associated with long-term use among people 4. White House Office of National AIDS Policy. Federal Implementation Plan. Washington, DC: The White House. Available at: http://aids.gov/ living with HIV. These therapies, however, are effective only federal-resources/policies/national-hiv-aids-strategy/nhas-implementation.pdf3. if individuals are diagnosed and successfully access care. Accessed August 6, 2010. Additional research is necessary to identify best practices to 5. Centers for Disease Control. Trends in HIV/AIDS diagnoses among men reach undiagnosed HIV-infected individuals, to link them who have sex with men– 33 states, 2001–2006. MMWR Morb Mortal Wkly Rep. 2008;57;681–686. to care, and, when clinically indicated, to provide medications. 6. Holtgrave DR. On the epidemiologic and economic importance of the We must also develop and deploy better methods for National AIDS Strategy for the United States. Acquir Immune Defic diagnosing acute HIV infection. Syndr. 2010;55:139–142.

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7. Golden MR, Wood RW, Buskin SE, et al. Ongoing risk behavior among 16. CDC. Revised recommendations for HIV testing of adults, adolescents, persons with HIV in medical care. AIDS Behav. 2007;11:726–735. and pregnant women in health-care settings. MMWR 2006;55(No. 8. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus RR-14). Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/ deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009; rr5514a1.htm. 360:1815–1826. 17. Centers for Disease Control. Expanded HIV testing and trends in 9. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission diagnoses of HIV infection—District of Columbia, 2004–2008. MMWR after initiation of antiretroviral therapy: a prospective cohort analysis. Morb Mortal Wkly Rep. 2010;59;737–741. Lancet. 2010;375:2092–2098. 18. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and 10. Attia S, Egger M, Muller M, et al. Sexual transmission of HIV according safety of tenefovir gel, an antiretroviral microbicide, for the prevention of to viral load and antiretroviral therapy: systematic review and meta- HIV infection in women. Science. 2010;329:1168–1174. analysis. AIDS. 2009;23:1397–1404. 19. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with 11. Montaner JSG, Lima VD, Barrios R, et al. Association of highly active ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J antiretroviral therapy coverage, population viral load, and yearly new HIV Med. 2009;361:2209–2220. diagnoses in British Columbia, Canada: a population-based study. Lancet. 20. Zhou T, Georgiev I, Wu X, et al. Structural basis for broad and potent 2010;376:532–539. neutralization of HIV-1 by antibody VRC01. Science. 2010;329: 12. Cowan S, Christiansen AH, Haff J. New paradigm for positive prevention: 811–817. ‘‘test and treat’’—testing for and treating HIV has lowered transmission 21. Mayer KH, Venkatesh KK. Antiretroviral therapy as HIV prevention: rate in Denmark in spite of increased unsafe sex among MSM. Abstract status and prospects. Am J Public Health. 2010;100:1867–1876. MOAC0103. Presented at: XVIII International AIDS Conference; July 22. Millett GA, Flores SA, Peterson J, et al. Explaining disparities in HIV 18–23, 2010; Vienna, Austria. infection among black and white men who have sex with men: a meta- 13. Das M, Chu PL, Santos G-M, Scheer S, et al. Decreases in community analysis of HIV risk behaviors. AIDS. 2007;21:2083–2091. viral load are accompanied by reductions in new HIV infections in San 23. Hallfors DD, Iritani BJ, Miller WC, et al. Sexual and drug behavior Francisco. PLoS ONE. 2010;5(6):e11068. patterns and HIV/STD racial disparities: the need for new directions. Am J 14. Teshale E, Kamimoto N, Harris N, et al. Estimated number of HIV- Public Health. 2007;97:125–132. infected persons eligible for and receiving HIV antiretroviral therapy, 24. Dean HD, Fenton KA. Addressing social determinants of health in the 2003—United States. Abstract 167. Presented at: 12th Conference on prevention and control of HIV/AIDS, viral hepatitis, sexually trans- Retroviruses and Opportunistic Infections (CROI); February 22–25, 2005; mitted infections, and tuberculosis. Pub Health Rep. 2010;125(Suppl Boston, MA. 4):1–5. 15. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV 25. Kidder DP, Wolitski RJ, Campsmith ML, et al. Health status, health care from persons aware and unaware that they are infected with the virus in the use, medication use, and medication adherence in homeless and housed USA. AIDS. 2006;26;10:1447–1450. people living with HIV/AIDS. Am J Public Health. 2007;97:2238–2245.

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A Prevention Response That Fits America’s Epidemic: Community Perspectives on the Status of HIV Prevention in the United States Chris Collins, MPP* and Da´zon Dixon Diallo, MPH†

epidemic is characterized by ‘‘low prevalence in the general Abstract: HIV prevention services have succeeded in limiting HIV population, high prevalence among the disenfranchised and incidence in the United States but have not prevented HIV from socially marginalized, with a concentration in geographic becoming a devastating epidemic in the communities most affected. hotspots.’’ In many important ways, America’s prevention The National HIV/AIDS Strategy represents an important opportu- response is not designed to address this kind of epidemic. nity to improve domestic HIV prevention efforts and to begin to A more effective and strategic effort would be tailored to reduce HIV incidence over time. Elements that are essential to the dynamics of local epidemics, would target resources more improving HIV incidence outcomes include greater transparency and effectively, and would deliver services appropriate to accountability in use of HIV prevention funds; scaling up programing communities facing a range of health and other challenges. for those most at risk; fostering and evaluating community-based The National HIV/AIDS Strategy, issued by the White HIV prevention efforts; and looking beyond individual behavior House Office of National AIDS Policy in July 2010, provides change programming by putting a greater emphasis on structural, a critical opportunity to reform domestic HIV prevention network, and policy interventions. To overcome years of stagnation efforts and, ultimately, to begin to lessen HIV incidence over on HIV prevention outcomes, we need a response characterized by time. The strategy calls for targeting prevention resources accountability, appropriate targeting, and sufficient scale. where the epidemic is most acute, relying on evidence-based Key Words: accountability, community, prevention, policy, scale, approaches and improving coordination between public and structural private providers. Will the national strategy lead to concrete reforms in (J Acquir Immune Defic Syndr 2010;55:S148–S150) HIV prevention policy and programing that can accomplish President Obama’s goal of a 25% reduction in HIV incidence by 2015?5 At least 4 elements are essential to improving outcomes on HIV incidence and realizing the president’s goal, including the following: improved transparency and account- INTRODUCTION ability, scaling up programming for those most at risk, fostering indigenous efforts, and looking beyond individual Domestic HIV prevention efforts in the United States behavior change interventions. can claim important successes over the last 2 decades. HIV incidence has plummeted from its height in the mid 1980s, and the HIV transmission rate has fallen over the years.1 An evidence base of effective prevention interventions has been ADVANCING PREVENTION ACCOUNTABILITY established, and it has been estimated that HIV prevention Accountability for federal HIV program funds is often programs averted more than 350,000 new infections between conceptualized in terms of prudent administration of 1991 and 2006.2 resources. It is time to expand our notion of accountability Yet although delivery of HIV prevention services has to include strategic use of funding to reduce HIV infection helped limit HIV incidence, it has not prevented HIV from rates. Primary questions include whether local epidemic becoming a devastating epidemic in the communities most profiles closely inform the targeting of resources; whether affected. Progress in reducing incidence has stalled for more local prevention plans are designed with the clear aim of than a decade, with an estimated 56,000 new infections each reducing incidence; and whether outcomes are tracked and year.3 Wafaa El-Sadr et al4 point out that the US domestic reported regularly. Evidence to date suggests that use of federal HIV prevention funds by state and local entities is not well matched to the epidemic profile in many jurisdictions.6 From *amfAR, The Foundation for AIDS Research, Washington, DC; and Some examples of how prevention accountability could †SisterLove, Inc. be advanced 7 include: The authors have no funding or conflicts of interest to disclose; and no part has Having Centers for Disease Control and Prevention (CDC) been previously presented at any meeting. Correspondence to: Chris Collins, MPP, amfAR, 1150 17th Street, NW Suite play a more active role in supporting local and state 406, Washington, DC 20036 (e-mail: [email protected]). health authorities in use of federal HIV prevention funds. Copyright Ó 2010 by Lippincott Williams & Wilkins Particular attention would be placed on ensuring that local

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or state epidemiologic profiles closely inform resource a major role in translating knowledge and cultural competence allocation. In the past, CDC staff did periodic program among communities of color and other high-risk populations reviews with local and state health authorities. These into health promotion and behavior change. CBOs are in could be reinstated. a position to understand the unique circumstances that drive Asking health departments for ‘‘Statements of Alignment.’’ HIV infection in the communities they serve, to develop and These statements would accompany health departments’ deliver culturally appropriate HIV prevention and related annual reports to CDC, much as departments now must services to high-risk populations, and to form enduring provide a statement of concurrence from community partnerships with these populations.11 planning bodies. The statements of alignment would Since the beginning of the HIV/AIDS epidemic, CBOs either confirm that allocation of prevention funding have developed prevention interventions in the response to reasonably matches local epidemic conditions or explain HIV/AIDS, and among them are culturally competent programs why it does not. that address the unique needs of racial, ethnic, and sexual Improving transparency in the use of prevention funding. minority populations. These interventions were being developed CDC should annually publish its use of funds—both funds and implemented in the absence of widespread availability of utilized by local and state authorities and those spent by evidence-based HIV behavioral interventions.12 Most often, the CDC’s central office. This reporting would track CBOs developed their interventions in collaboration with allocations toward different activities and target communities they serve, incorporating innovative strategies and populations. approaches for prevention and demonstrating sensitivity to local Similar types of accountability approaches should also populations’ values and norms.13–15 be employed at other federal agencies engaged in HIV Although the CDC has long recognized the importance of prevention, including the Substance Abuse and Mental Health effective and evidence-based interventions with community- Services Administration. based indigenous (home-grown) prevention strategies and interventions and has recently given more attention to their development, greater support is needed for these efforts. Many GOING TO SCALE IN COMMUNITIES AT CBOs need assistance in building organizational capacity; they ELEVATED RISK also need additional resources to evaluate newly developed Intensive prevention services are not reaching many of interventions. Today, many CBO-led evaluations are limited to those at elevated risk of infection. For example, a 2006 survey determining participant satisfaction or are expressed simply as indicates that only a relatively small share of gay men and other basic outputs (eg, quantities of condoms distributed or numbers men who have sex with men (MSM) had participated in HIV of intervention sessions completed).16,17 To broaden the reach of prevention interventions during the previous 12 months.8 Amore locally developed interventions, CBOs need support to evaluate effective prevention effort will require interventions delivered and interventions within communities, demonstrate efficacy, and sustained at a scale that can have impact on incidence in the improve the effectiveness.18 communities at the center of the domestic epidemic. Perhaps most importantly, CBO-led evaluations will Although numerous studies have established the HIV enable the most vulnerable populations to hold their own prevention efficacy of some behavioral interventions, there is communities accountable and will help expand the impact scant evidence of the population-level impacts of many HIV of community-based, culturally appropriate, and effica- prevention approaches. Through the Diffusion of Evidence- cious HIV prevention interventions that can reach those Based Interventions program, CDC has identified a variety most at risk. of HIV prevention programs for which there is evidence of effectiveness. Yet as others have observed,9,10 many of these interventions are dated, do not adequately address some groups at elevated risk, and are difficult to deliver at scale. LOOKING BEYOND THE INDIVIDUAL Isolated small-scale prevention programs alone will not We know that context is key in the HIV epidemic. have a major impact in reducing infection rates. A much Individual behaviors are deeply influenced by social, greater emphasis is needed on developing, testing, and fielding economic, and other factors—a particularly relevant point in programs that can demonstrate measurable impact on in- this epidemic because many people at elevated risk are part of cidence. In many cases, this refocus of emphasis will mean communities facing multiple concerns. For them, interventions adopting approaches that combine multiple interventions that seek only to affect individual decisions may be insufficient tailored to those at elevated risk. Research portfolios at the to address the complex factors in personal vulnerability.19,20 As National Institutes of Health and CDC should be developed Fenton and Dean21 have written, ‘‘It is increasingly unacceptable with the goals of advancing knowledge about what will have for those planning and delivering prevention services to claim impact at a population level and expanding operations research that addressing SDH (social determinants of health) is outside that can guide delivery of these interventions in the field. their jurisdiction.’’ The task ahead is to create a system in which those active in health policy and programing are supported in working collaboratively to address social factors. We need FOSTERING COMMUNITY-BASED EFFORTS a system that fosters far more coordination across providers and Community-based organizations (CBOs) are the front establishes funding streams that support action on social line in HIV/AIDS prevention and service delivery. They play determinants. Community Transformation Grants, created by q 2010 Lippincott Williams & Wilkins www.jaids.com | S149 Collins and Diallo J Acquir Immune Defic Syndr  Volume 55, Supplement 2, December 15, 2010 health reform, are an important opportunity to address the 8. Sanchez T, Finlayson T, Drake A, et al. Human immunodeficiency community context of HIV and other health challenges. virus (HIV) risk, prevention, and testing behaviors—United States, National HIV Behavioral Surveillance System: men who have sex We also know that risk is not determined solely by the with men, November 2003–April 2005. MMWR Surveill Summ. 2006; behavior of an individual. Far more attention is needed to the 55:1–16. dynamics of sexual networks in the HIVepidemic. This is clear 9. Rietmeijer K. Deconstructing DEBI. Blog post. STDpreventiononline.org from work by Hallfors et al22 who found that although risk for [Web site]. Denver, CO: Internet and STD Center of Excellence; October HIV and STD acquisition is heightened among young white 3, 2008. Available at: http://www.stdpreventiononline.org/index.php/blog/ view/2619. Accessed August 8, 2010. adults who engage in high-risk behaviors, young adults who 10. Rietmeijer K. Deconstructing DEBI—Part Deux: Behavioral Science to are black are at elevated risk whether or not their personal the Rescue. Blog post. STDpreventiononline.org [Web Site]. Denver, CO: behaviors are ‘‘high risk.’’ Wohlfeiler and Ellen23 call for Internet and STD Center of Excellence; May 19, 2009. Available at: http:// a ‘‘new generation of structural interventions on sexual www.stdpreventiononline.org/index.php/blog/view/47310. Accessed August 8, 2010. networks,’’that reach people through Internet sex sites, gay sex 11. Chillag K, Bartholow K, Cordeiro J, et al. Factors affecting the delivery of clubs, and other venues with prevention and testing services HIV/AIDS prevention programs by community-based organizations. and, where appropriate, policy interventions. The authors point AIDS Educ Prev. 2002;14(Suppl A):27–37. out that policy interventions have been fundamental to success 12. Centers for Disease Control and Prevention, HIV/AIDS Prevention of injury and tobacco control and can play an important role in Research Synthesis Project. Compendium of HIV Prevention Interven- tions With Evidence of Effectiveness. Revised ed. Atlanta, GA: Centers for HIV. An example: regulations mandating that sex venues in Disease Control and Prevention; August 2001. Available at: http:// San Francisco remove doors from private rooms so that www.cdc.gov/hiv/resources/reports/hiv_compendium/12. Accessed monitors can ensure clients practice safer sex.24 Given August 10, 2010. mounting evidence of the prevention impact of HIV treatment, 13. Mayberry RM, Daniels P, Yancey EM, et al. Enhancing community-based organizations’ capacity for HIV/AIDS education and prevention. Eval wider access to and uptake of HIV treatment is another policy Program Plann. 2009;32:213–220. priority in the effort to lower HIV incidence. 14. Richter DL, Prince MS, Potts LH, et al. Assessing the HIV prevention The new National HIV/AIDS Strategy presents an capacity building needs of community-based organizations. J Public important opportunity to improve America’s HIV prevention Health Manag Pract. 2000;6:86–97. effort. But to overcome the years of stagnation in prevention 15. Chillag K, Bartholow K, Cordeiro J, et al. Factors affecting the delivery of HIV/AIDS prevention programs by community-based organizations. outcomes, we need a response characterized by accountability, AIDS Educ Prev. 2002;14(Suppl A):27–37. appropriate targeting, and sufficient scale. We also have to 16. Cashman SB, Adeky S, Allen AJ III, et al. 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