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2003 HEPP Report: Infectious Diseases in Corrections, Vol. 6 No. 6 HIV & Hepatitis Education Prison Project

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Recommended Citation HIV & Hepatitis Education Prison Project, "HEPP Report: Infectious Diseases in Corrections, Vol. 6 No. 6" (2003). Infectious Diseases in Corrections Report (IDCR). Paper 46. http://digitalcommons.uri.edu/idcr/46

This Article is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Infectious Diseases in Corrections Report (IDCR) by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. HIV & HEPATITIS EDUCATION PRISON HEPJune 2003 Vol. 6, Issue 6 P REPORT PROJECT Infectious Diseases in Corrections SPONSOREDBYTHEBROWNMEDICALSCHOOLOFFICEOFCONTINUINGMEDICALEDUCATION. ABOUT HEPP Long-Term Toxicities Associated with HIV and HEPP Report, a forum for Antiretroviral Therapy correctional problem solving, targets correctional physicians, nurses, By Peter J. Piliero, M.D.*, Associate Professor of Medicine, Albany Medical College administrators, outreach workers, and Soon after the introduction of the first antiretroviraldine (3TC) have also been associated with pan- case managers. Published monthly (ARV) agent, (AZT), drug-related toxi-creatitis. There may be an added potential for pan- and distributed by email and fax, cities became recognized and well-characterized.creatitis when using combinations of these nucle- HEPP Report provides up-to-the Things have since become more complicated;oside reverse transcriptase inhibitors (NRTIs). moment information HIV/AIDS, there are now 17 ARV agents in four distinct class-Importantly, the concomitant use of alcohol hepatitis, and other infectious es. This has led to both decreased morbidity andincreases the risk of pancreatitis. In cases of acute diseases, as well as efficient ways mortality from HIV due to immune recon-pancreatitis, temporary interruption of ART is rec- to administer treatment in the correctional environment. Continuing stitution and viral suppression, and increasingommended. Subsequent resumption should avoid Medical Education credits are recognition of both acute and long-term toxicitiesthe likely causative agents the patient was taking provided by the Brown University of ARV therapy (ART). Most clinicians agree thatat the time he or she developed pancreatitis. Office of Continuing Medical the benefits of ART generally outweigh the risk; however, patients who experience significant sidePeripheral neuropathy Education. HEPP Report is Peripheral neuropathy usually occurs after pro- effects sometimes disagree with this. This can distributed to all members of the longed use of NRTIs.4This complication is most Society of Correctional Physicians lead to patient non-adherence or refusal to take often associated with the use of the "d-drugs" - (SCP) within the SCP publication, any ART at all for fear of toxicity. Drug toxicities (ddC), (d4T), and didano- CorrDocs (www.corrdocs.org). may have both acute and long-term implications to sine (ddI) (in decreasing order of likelihood). The the health of HIV-infected persons. combined use of two of these drugs has been CO-CHIEF EDITORS This report reviews common acute and long-termassociated with an even higher incidence of neu- Joseph Bick, M.D.toxicities of ART. Drug toxicities can be class-spe-ropathy. Recognizing neuropathic symptoms early Director, HIV Treatment Services, California Medical Facility, cific or ARV-agent specific. Having an under-on, and reducing or interrupting the offending California Department of Corrections standing of these complications allows cliniciansagent(s) usually leads to symptom resolution. If to anticipate potential toxicities, and to communi-patients are maintained on these drugs, progres- Anne S. De Groot, M.D.cate about them with their patients. Clinicianssive and often permanent neuropathy requiring Director, TB/HIV Research Lab, Brown Medical School should inform patients considering ART what com-narcotic analgesia may ensue. plications they may experience, how to recognize Lactic acidosis DEPUTY EDITORS these side effects, and what they should do about Lactic acidosis syndrome (LAS) was first reported Frederick L. Altice, M.D.them. This proactive approach is likely to lead to a in the early 1990s in association with zidovudine Director, HIV in Prisons Program, more trusting relationship and improved adher- (AZT) use, predominantly in obese African- Yale University AIDS Program ence.1 American women. In recent years, the greatest David P. Paar, M.D. Director, AIDS Care and Clinical Mitochondrial Toxicity association has been with the use of stavudine Research Program, In recent years, mitochondrial toxicity has been(d4T) with or without (ddI). The nucle- University of Texas, Medical Branch recognized as one of the most serious potentialoside and nucleotide analogues inhibit mitochon- side effects of ART.2Mitochondria are the energy-drial DNA production, which leads to an increased Stephen Tabet, M.D., M.P.H University of Washington and Northwest producing factories of our bodies; when mitochon-breakdown of fatty acids into lactic acid. Inhibition AIDS Education and Training Center drial production is decreased by inhibition of theis greatest for the "d-drugs" but also occurs with cellular DNA polymerase gamma, end-organ toxi-the other NRTIs.5 city can occur. Mitochondrial toxicity is associated SUPPORTERS Patients with LAS generally present with vague with the use of the nucleoside and nucleotide HEPP Report is grateful for constitutional complaints including fatigue, reverse transcriptase inhibitors, and may lead to a the support of the following malaise, abdominal pain, and nausea and vomit- companies through unrestricted number of clinical problems. These include pan- Continued on page 2 educational grants: creatitis, peripheral neuropathy, and increased production of lactic acid. Major Support:Abbott Laboratories, WHAT’S INSIDE Agouron Pharmaceuticals, and Pancreatitis Roche Pharmaceuticals. Pancreatitis can be an acute complication of ART, SARS Update pg 4 Sustaining:Boehringer Ingelheim even though it may occur after years of stable HIV 101 pg 5 Pharmaceuticals, Gilead Sciences, 3 Ask the Expert pg 6 Inc., GlaxoSmithKline, Merck & Co. treatment.This potential fatal complication has and Schering-Plough. been linked predominantly to the use of didano- Self-Assessment Test pg 9 sine (ddI); however, stavudine (d4T) and lamivu- Brown Medical School Providence, RI 02912 401.277.3651 fax: 401.277.3656 www.hivcorrections.org If you have any problems with this fax transmission please call 800.748.4336 or e-mail us at [email protected] June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 2

Long-Term Toxicities... use of protease inhibitors (PIs). SubsequentThe pathogenesis of fat maldistribution (continued from page 1) cohort studies have confirmed this associa-remains elusive. Retrospective cohort studies ing. Over the course of several weeks, thesetion, which is largely due to acquired insulinhave defined characteristics associated with 10 patients can develop tachypnea, pancreatitis,resistance.Patients with HCV co-infectiondevelopment of lipodystrophy: these include and/or hepatitis in the setting of progressiveappear to be at greater risk of developing thisan age >40 years, nadir CD4 cell count, acidemia. If unrecognized, death may occur.complication. Caucasian race, and antiretroviral use. More recently, a prospective study of ARV-naïve The clinician considering this diagnosis earlyDiagnosis is usually performed through peri- patients initiating therapy showed an associa- on in the setting of vague complaints shouldodic fasting glucose determinations or by a tion between development of lipoatrophy and obtain an arterial or venous lactate level. Atwo-hour oral glucose tolerance test. use of a stavudine-containing regimen, and mildly elevated level (2-5 mmol/L) is diagnos-Glycosylated hemoglobin levels are usually lipohypertrophy and the use of a PI-contain- tic of symptomatic hyperlactatemia, whereasnormal even in the setting of insulin resis- ing regimen. These investigators also defined a level >5 mmol/L in conjunction with atance. Treatment depends on the severity of a pattern to changes in body morphology reduced arterial pH confirms the diagnosis ofthe hyperglycemia, with mild cases respond- occurring after initiation of therapy. LAS. In both situations, interruption of ARTing to dietary intervention and exercise, mod- Specifically, patients gained fat and lean until resolution is necessary. Subsequenterate cases responding to insulin-sensitizing mass during the first 24 weeks of therapy, fol- therapy should, when possible, avoid thoseagents such as the glitazones, and severe lowed by progressive loss of extremity fat drugs most associated with LAS. cases responding to insulin therapy. while preserving gained central abdominal fat Modifying the regimen by replacing the PI 13 Metabolic Complications over the next 72 weeks of therapy. Various metabolic complications associatedwith a non-PI agent may also be successful. No definitive treatment for fat maldistribution with HIV have now been recognized. TheseDisorders of Bone include dyslipidemia, insulin resistance/dia- exists, though different approaches have Metabolism been tried. For lipoatrophy, several studies betes (dysglycemia), and osteopenia/osteo-More recently, disorders of bone metabolism have shown that substitution of either zidovu- porosis. have been recognized as another long-term dine (AZT) or (ABC) for stavudine complication seen in HIV-infected patients.11 Dyslipidemia (d4T) may be associated with increases Osteopenia and osteoporosis have both been Abnormal serum lipids have been noted since (albeit small) in subcutaneous fat, compared described in patients on ART, but predomi- the beginning of the HIV epidemic. In the pre- to continued declines in those remaining on nately in those on HAART. The etiology of ART era, patients commonly had hypocholes- stavudine (d4T). For lipohypertrophy, replace- these changes has not been delineated, terolemia and hypertriglyceridemia as a func- ment of the protease inhibitor with a reverse although there is a suggestion that the HIV-1 14 tion of their wasted hypercatabolic state, transcriptase inhibitor may be useful. combined with increased pro-inflammatoryprotease inhibitors may contribute to this cytokines.6However, the highly active ARTprocess by affecting osteoclast or osteoblastCosmetic surgical options to treat facial lipoa- (HAART) era has been associated with a dys-differentiation. Diagnosis is made by standardtrophy include a variety of methods of soft tis- lipidemic profile consisting of high total andDEXA scanning, although at this time routinesue augmentation. Although none of these LDL cholesterols, elevated triglycerides, andDEXA scanning of all HIV patients is not indi-procedures are specifically FDA-approved for a low HDL cholesterol. Although somecated. However, for those with other risk fac-this indication, some are FDA permissible as patients may exhibit all three of these abnor-tors for osteoporosis, such as family history,off-label use of approved agents. Bio- malities, many will only have abnormalities inhypogonadism, smoking, and corticosteroidabsorbale materials used for soft tissue aug- either the cholesterol or triglyceride fractions.use, screening DEXA scanning should bementation include Zyplast collagen, human The fraction most affected usually dependsconsidered. Preliminary studies have showncadaveric dermal tissue (Cymetra), or fascia on the ARV agent(s) used (for example, riton-that alendronate is effective at treating osteo-lata (Fascian) polylactic acid (Newfill), avir (RTV) predominantly affects triglyc-porosis in these patients. hyaluronic acid (Perlane) and fat transfers. erides). The effect on lipids is most pro- Permanent options include implants, liquid Lipodystrophy injectable medical grade silicone (Silikon- nounced with protease inhibitors (PIs), fol-One of the most disconcerting toxicities 1000), and polymethylmethacrylate (Artecoll). lowed by non-nucleoside and then nucleosideincreasingly recognized in the past three reverse transcriptase inhibitors. years is lipodystrophy, a disturbance in theFor buffalo humps that cause disfigurement, The dyslipidemic profile is associated with anway the body produces, uses, and distributesneck pain, or sleep apnea, liposuction may be 12 increased risk for atherogenesis, raising con-fat.Patients with long-term HIV infection,effective. Human growth hormone has also cern that as patients live longer due toespecially those treated with antiretroviralbeen shown to decrease buffalo hump and 15 HAART they may experience an increasedtherapy, may exhibit changes in body mor-excess abdominal fat.However, high cost risk for coronary or cerebral vascular morbid-phology due to changes in fat distribution.and tolerability issues have led few patients to ity and mortality.7Multiple cohort studies com-Although these changes are usually not asso-use this approach. Once ongoing research paring the frequency of coronary and/or cere-ciated with medical complications, the disfig-establishes the definitive cause of fat maldis- bral vascular disease in HIV-infected patientsurement can be psychologically disabling. tribution, more specific therapeutic options can be developed. with matched HIV-uninfected controls haveVarious cohort studies have estimated that up shown an increased incidence of disease into 50% of patients suffer from lipodystrophy.Hepatotoxicity Unrelated those with HIV infection. Identification andTwo patterns have emerged. Lipoatrophy, orto Chronic Viral management of individuals with dyslipidemiasubcutaneous fat loss, is seen most com-Hepatitis is now an essential part of HIV care. 8 monly in the face, extremities, and buttocks.Previous articles in HEPP Report have exten- Guidelines are now available. Lipohypertrophy, or increased fat deposition,sively covered the effects of chronic HBV and Dysglycemia is seen predominantly in the abdominalHCV in patients with HIV (go to www.hivcor- Disorders of glucose metabolism, or dysg-region ("paunch"), dorsocervical region ("buf-rections.org). However, hepatotoxicity occurs lycemia, were one of the first metabolic com-falo hump"), and breasts. Patients often havein HIV-infected patients even in the absence plications of ART identified.9Initial reports ofa combination of the two types of dysmorphicof chronic viral hepatitis. Some of these are new-onset hyperglycemia, including episodesfeatures. acute drug toxicities, such as those seen with of diabetic ketoacidosis, were linked to the Continued on page 7 June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 3

Faculty Disclosure Letter from the Editor In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, the faculty for this activity have Dear Correctional Colleagues: been asked to complete Conflict of Interest Disclosure forms. Disclosures are listed at the end of articles. All of the individual medications discussed In this month's main article, Dr. Peter Piliero discusses mitochondrial toxicity, which is in this newsletter are approved for treatment of HIV responsible for many of the long-term complications of antiretroviral therapy. These compli- and hepatitisunless otherwise indicated. For the cations, along with the development of viral resistance, are the primary reasons for treatment of HIV and hepatitis infection, many physi- cians opt to use combination antiretroviral therapy delaying the initiation of antiretroviral therapy in HIV-infected patients. This delay provides which is not addressed by the FDA. the opportunity and time to establish an effective provider-patient relationship and to edu- Senior Advisors cate patients about the risks and benefits of antiretroviral therapy. Such an approach will Karl Brown, M.D. lead to improved acceptance of and adherence to antiretroviral therapy, as well as earlier Rikers Island Jail recognition of complications that can be addressed by appropriate changes in antiretroviral John H. Clark, M.D., M.P.H., F.S.C.P. therapy. Los Angeles County Sheriff's Department Theodore M. Hammett, Ph.D. Abt Associates In this month's spotlight, Drs. Bhupinder Mann and Joseph Bick describe the sudden appearance of SARS and its effect on an unprepared public and health care system. Ned E. Heltzer, R.Ph., M.S. Heltzer Associates Although fear may be the first response to life-threatening emerging infectious diseases, Ralf Jürgens rational plans of response that are informed by facts are the only ways to respond to and Canadian HIV/AIDS Legal Network contain emerging pathogens. It is unclear what the magnitude of the SARS problem will be Joseph Paris, Ph.D., M.D. in the United States. But it is clear that all heath care facilities, including prisons and jails, CCHP Georgia Dept. of Corrections should develop a plan to contain and treat this infection if and when it appears at our Renee Ridzon, M.D. doorsteps. Bill & Melinda Gates Foundation Mary Sylla, J.D. After reading this issue, you should be familiar with toxicities associated with antiretroviral CorrectHELP: Corrections HIV Education and Law Project therapies, including common toxicities across drug classes and with specific agents. You David Thomas, M.D., J.D. should also be familiar with issues relating to the SARS virus, including how it is transmit- Division of Correctional Medicine, ted, symptoms, making a diagnosis, and what to think about when implementing a plan in a NovaSoutheastern University correctional facility. College of Osteopathic Medicine Louis C. Tripoli, M.D., F.A.C.F.E. As always, please contact us with your suggestions and comments. Correctional Medical Institute, Correctional Medical Services Lester Wright, M.D. Sincerely yours, New York State Department of Corrections Associate Editors Scott Allen, M.D. Rhode Island Department of Corrections David Paar Peter J. Piliero, M.D. Associate Professor of Medicine, Consultant, New York State Department of Corrections, Albany Medical College Subscribe to HEPP Report Dean Rieger, M.D. Faxto 617-770-3339for any of the following:(please print clearly or type) Indiana Department of Corrections Josiah Rich, M.D. ____ Yes, I would like to add/update/correct (circle one) my contact information for my complimentary Brown University School of Medicine, subscription of HEPP Report fax/email newsletter. The Miriam Hospital Steven F. Scheibel, M.D. ____ Yes, I would like to sign up the following colleague to receive a complimentary subscription of Regional Medical Director HEPP Report fax/email newsletter. Prison Health Services, Inc.

____ Yes, I would like my HEPPReport to be delivered in the future as an attached PDFfile in an David A. Wohl, M.D. email (rather than have a fax). University of North Carolina Managers Craig Grein NAME: FACILITY: Brown University Michelle Gaseau CHECK ONE: The Corrections Connection Physician Physician Assistant Nurse/Nurse Practitioner Nurse Administrator Layout Pharmacist Medical Director/Administrator HIV Case Worker/Counselor Other Kimberly Backlund-Lewis The Corrections Connection ADDRESS: CITY: STATE:ZIP: Distribution FAX: PHONE: Screened Images Multimedia Managing Editor EMAIL: Elizabeth Herbert HIV/Hepatitis Education Prison Project June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 4 A Correctional Perspective on Severe Acute Respiratory Syndrome (SARS) Bhupinder Mann*, M.D. and Joseph Bick*, M.D.

Editor's note:Bhupinder Mann, M.D., is a Mayo Clinic-trained hema- tologist/oncologist who spent several years working in correctional TABLE 1: SARS Case Definition health at the California Medical Facility in Vacaville, CA. Dr. Mann is Severe respiratory illness currently a Senior Consultant in Medical Oncology at the National wTemperature of >100.4º F (>38º C), and Cancer Centre of Singapore, and has firsthand experience with the wOne or more clinical findings of respiratory illness (e.g., cough, SARS epidemic. shortness of breath, difficulty breathing, or hypoxia), and wradiographic evidence of pneumonia, or The sudden global emergence of Severe Acute Respiratory Syndrome wrespiratory distress syndrome, or (SARS) has sickened over 8,000 individuals, crippled health care wautopsy findings consistent with pneumonia or respiratory delivery, and has had a devastating impact on the economy. The distress syndrome without an identifiable cause. causative agent, a novel Coronavirus, is not previously known to AND cause disease in humans. Thus far, no specific treatment, vaccination or reliable and readily available diagnostic tests are available. ExactlyEpidemiological criteria where we are in the course of this epidemic is not yet clear. wTravel (including transit in an airport) within 10 days of onset of symptoms to an area with current or previously documented or Transmission suspected community transmission of SARS, or Most have been acquired by close contact with a sympto-wClose contact* within 10 days of onset of symptoms with a per- matic individual. The virus has been cultured from nasopharyngealson known or suspected to have SARS secretions and stool, and has been shown to remain viable for sever-* Close contact is defined as having cared for or lived with a per- al hours outside the body on plastic and other surfaces. It appears thatson known to have SARS or having a high likelihood of direct con- respiratory droplets are the primary source of transmission. However,tact with respiratory secretions and/or body fluids of a patient large clusters have been documented to result from nebulizer-gener-known to have SARS. Examples of close contact include kissing ated aerosols and fecal-oral transmission (traced to damaged sewageor embracing, sharing eating or drinking utensils, close conversa- system in an apartment complex). tion (<3 feet), physical examination, and any other direct physical Symptoms contact between persons. Close contact does not include activi- The incubation period ranges from two to 16 days; the average is sixties such as walking by a person or sitting across a waiting room or office for a brief period of time. days. Common symptoms include fever (100%), chills, rigors, myal- gias, cough (>50%) and sputum, sore throat, coryza, nausea, vomit- exposed, and their caretakers, should have their temperature checked ing, diarrhea (20-30%). Seventy percent of patients have moderate regularly. lymphopenia, and 45% have mild thrombocytopenia. Clinicians and others who work in health care settings need to adhere At the time of initial presentation, 70-80% of patients demonstrate to strict respiratory and contact precautions. All individuals should varying patterns of air-space consolidation on CXR. Hypoxemia requir- undergo mask fit testing. Staff need to learn the proper methods for ing ICU care develops in 20-30% of cases. The mortality rate appears putting on, removing, and disposing of personal protection gear. Those to be dependent upon age, with an overall death rate of 14-15% and evaluating suspect cases should use standard precautions (hand as high as 55% in those over 60 years of age. washing), airborne precautions (N-95 respirator), and contact precau- Diagnosis tions (gowns and gloves). Hospital disinfectants including those based The initial diagnosis of SARS relies on suspicion based on a patient'son quaternary ammonium, phenol and alcohol, are highly active history. Specifically asking patients about their history of travel toagainst coronaviruses. affected areas, visits to an affected health care facility, or history of During an outbreak, patients and caretakers should remain separated casual social contact with a suspected or probable case is critical. from others in order to minimize the chance of spread to other patients Relying on initial symptoms alone, it is hard to differentiate SARS fromand health care workers. Also, the number of social visitors into the any other flu-like illness. Since a reliable, rapid diagnostic test is notfacility needs to be restricted, elective procedures should be delayed, presently available, clinicians must rely on symptoms, signs, andand the number of staff caring for SARS patients should be limited. exposure/travel history. Many patients develop an ARDS-like clinical SARS in the United States picture. Suspect cases should receive a chest x-ray, pulse oximetry, In the United States SARS has occurred in people with a history of and blood cultures. Gram stain of sputum and testing for other respi- travel to countries with SARS. In the U.S., casual contact with SARS ratory viruses such as influenza should be performed. patients has not resulted in transmission of the causative virus. Efforts RT-PCR can rapidly document the presence of coronavirus RNA.to prevent SARS in this country have focused primarily on screening Antibody response is now known to develop over time in serum; how-for illness in those arriving from areas with high rates of SARS. At this ever, the sensitivity and specificity of these tests has not yet beentime, the Centers for Disease Control and Prevention (CDC) does not established. Specimens from suspect cases should be saved for fur-recommend quarantine of persons arriving from areas with SARS. ther testing, and acute and convalescent serum samples should be Correctional Facilities obtained from individuals who meet the SARS case definition (see Currently, those of us working in correctional facilities might feel some- Table 1). what protected from the SARS epidemic. However, many believe that Infection Control this virus will continue to circulate, and that the number of cases Appropriate precautions need to be taken while evaluating suspected(including those in the U.S.) will increase. Respiratory viruses such as patients, starting from the point of triage. Patients with suspiciousinfluenza tend to wane in the warmer months and return with the cold- symptoms should be provided with a surgical mask upon arrival. Whener weather. The Directors of the National Institutes of Allergy and possible, suspect cases should be evaluated in a designated area. Infectious Diseases (NIAID) and the CDC have stated that they believe that SARS will persist and amplify in the years to come. Control of the epidemic relies on quarantining exposed individuals and tracing their contacts. Institutionalized individuals who may have been Continued on page 5 June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 5 Common Toxicities Among ARVs

AGENT POSSIBLE CLASS TOXICITIES ADDITIONAL TOXICITIES NRTI Abacavir (ABC; Ziagen) Mitochondrial toxicity (pancreatitis, peripheral neuropathy,Hypersensitivity reaction lactic acidosis) and lipodystrophy Didanosine (ddI; Videx) Mitochondrial toxicity (pancreatitis, peripheral neuropathy,Pancreatitis, peripheral neu- lactic acidosis) and lipodystrophy ropathy (3TC; Epivir)Mitochondrial toxicity (pancreatitis, peripheral neuropathy,Pancreatitis lactic acidosis) and lipodystrophy Stavudine (d4T; Zerit) Mitochondrial toxicity (pancreatitis, peripheral neuropathy,Peripheral neuropathy, pan- lactic acidosis) and lipodystrophy creatitis, hepatoxicity Zalcitabine (ddC; Hivid) Mitochondrial toxicity (pancreatitis, peripheral neuropathy,Pancreatitis, peripheral neu- lactic acidosis) and lipodystrophy ropathy, oral apthae Zidovudine (AZT; Mitochondrial toxicity (pancreatitis, peripheral neuropathy,Anemia, leukopenia, neu- Retrovir) lactic acidosis) and lipodystrophy tropenia, myositis NtRTI Tenofovir (TDF; Viread) Lactic acidosis NNRTI (DLV; Hepatotoxicity; potential to cause rash Rescriptor) (EFV; Sustiva)Hepatotoxicity; potential to cause rash Hyperlipidemia (NVP; Hepatotoxicity; potential to cause rash Viramune) PI (APV; Hyperglycemia, hyperlipidemia, and lipodystrophy. Agenerase) Increased risk for osteopenia and osteoporosis. (IDV; Crixivan) Hyperglycemia, hyperlipidemia, and lipodystrophy. Hepatitis Increased risk for osteopenia and osteoporosis. (NFV; Viracept)Hyperglycemia, hyperlipidemia, and lipodystrophy. Increased risk for osteopenia and osteoporosis. (RTV; Norvir) Hyperglycemia, hyperlipidemia, and lipodystrophy. Hepatitis Increased risk for osteopenia and osteoporosis. (SQV; Hyperglycemia, hyperlipidemia, and lipodystrophy. Invirase, Fortovase) Increased risk for osteopenia and osteoporosis. /Ritonavir Hyperglycemia, hyperlipidemia, and lipodystrophy. (LPV/RTV; Kaletra) Increased risk for osteopenia and osteoporosis.

Adapted from Bartlett, et al. 2001-2002 Medical Management of HIV Infection; and Sande, et al. The Sanford Guide to HIV/AIDS Therapy, 2002, Eleventh Edition.

SARs...(continued from page 4) wCan you obtain enough masks for all patients and staff who may need them? If this scenario unfolds, management of patients presenting with what wDo you have the ability to do fit testing? appears to be a routine viral syndrome or community-acquired pneu- monia will become much more problematic. Even now, the staff andwCan you isolate (or at a minimum cohort) all suspect cases? visitors of correctional facilities are a potential source for the introduc-wIs custodial staff prepared to control inmate movement? tion of SARS into a jail or prison. One can easily imagine how rapidly wDo you have adequate contracts with outside agencies to provide this illness might overwhelm a vulnerable population crowded togeth- appropriate medical services? er in a congregate living environment. wWill you be able to feed inmates and continue other necessary pro- Implementing a Plan grams in the event of controlled movement? The worldwide experience with SARS has allowed us to strategize for wDo you have enough health care staff to ensure the provision of the likely eventuality of SARS in our practice settings. The following necessary services in the event of an outbreak? questions should be kept in mind while preparing a plan to manage SARS in the correctional setting. *Disclosures: Nothing to disclose. June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 6 Ask the Expert Case Study: 38-year-old Woman With Persistent Flu-like Symptoms Case presentation and discussion by Stephen Tabet, MD, MPH, Assistant Professor of Medicine, University of Washington, and Director, Northwest Correctional Medicine Education Program. A collaboration with the Northwest AIDS Education and Training Center, with Stephen Tabet, MD, and Kate Willner, trainer.

CASE:A 38-year-old woman presents to the prison infirmary with flu-like complaints consisting of myalgias, abdominal pain, and nausea. Her medical history is significant for Class A2 HIV disease. She has had no HIV-related illnesses except for chronic, mild diarrhea. Her CD4 T-cell count is 512 (32%), and HIV RNA by bDNA is less than 50. Her antiretroviral regimen consists of stavudine (d4T), lamivudine (3TC), and indi- navir/ritonavir (IDV/RTV). Her only other illness is asymptomatic chronic hepatitis C virus (HCV) infection. She first reported to the infirmary one week ago, complaining of one week of flu-like illness. Total time since onset is two weeks. On examination today, the patient appears moderately ill. Her blood pressure is 112/64, pulse 105, respirations 22, and temperature 37.1 C. Her right upper abdomen is tender to palpa- tion. Because there has been no improvement in her symptoms, her medical care provider decides that further investigation is warranted. If this were your patient, what would you be concerned about right now, and how would you proceed to make the diagnosis?

DISCUSSION:It was fortunate for this woman that the alert infirmaryreplication mutations caused by the NRTIs. As the number of non- provider did not send her back to her room to wait a little longer for functioning mitochondria increases, the cell loses some of its ability to the "flu" to resolve. The provider in this case promptly checked a bat-produce energy from the non-lactate-producing respiration process. A tery of laboratory tests. The patient's urinary analysis was leukocyte"back-up" (lactate-producing) anaerobic energy production system is esterase trace-positive and positive for ketones. Serum AST (92 activated. Lactate, which is a by-product of anaerobic respiration, is units), ALT (118 units), total bilirubin 1.7 (units), and amylase normal.released from the cell into surrounding tissues and the bloodstream, BUN/creatinine were 27/1.6 units, and electrolytes were Na 139 where in healthy persons, it is cleared mainly by the liver. The anaer- units, Cl 104, K 4.3, and HCO3 12.; The anion gap (AG) was com- obic process is not intended by nature to be the cell's primary energy puted as follows: source; rather, it is for times when extra energy is required - during exercise, for example. A person with compromised mitochondria AG = (Na + K) - (Cl + HCO3) or AG = Na - (Cl + HCO3) seems to be using this reserve system for daily energy and may not be AG normal value < +/- 12mEq/L not clearing lactic acid sufficiently. Thus, NRTIs can precipitate abnor- or < 16 mEq/L if potassium concentration is used to calculate value malities, dysfunction, then toxicity, especially in someone with liver The result is 23. The correct diagnosis for this woman's illness is gapdamage. acidemia. Mitochondrial dysfunction leads to varied pathology and is not easy to The medical provider held the patient's medications and sent her to thepredict. HIV disease alone can cause a variety of abnormalities. This hospital for further evaluation and treatment. is a list of selected in vivomanifestations of NRTI-associated mito- chondrial toxicity: In the hospital, the medical team obtained a serum venous lactic acidwNeuromuscular - Myopathy: zidovudine (AZT); Polyneurophathy: level, following the ACTG Guidelines Protocol (http://aactg.s-zalcitabine (ddC), didanosine (ddI), stavudine (d4T) 3.com/members/psmet.htm). The reading was 6.1 mmol/L (normal iswHepatic/GI - Steatosis, lactic acidosis: zidovudine (AZT) didanosine 0.5 to 2.5 mmol/L at this institution). An ultrasound of her abdomen(ddI), stavudine (d4T), zalcitabine (ddC); Pancreatitis: didanosine revealed hepatomegaly with fatty infiltration. A diagnosis of severe(ddI), stavudine (d4T) nucleoside reverse transcriptase inhibitor (NRTI)-induced lacticwHematologic - Pancytopenias: zidovudine (AZT) acidemia with hepatic steatosis was confirmed and the patient's anti-wNephrologic - Proximal renal tubular dysfunction: adefovir retroviral medications were discontinued. (Hepsera) What is the most likely cause of anion gap acidosis in this wMetabolic - Lipodystrophy (new theory): stavudine (d4T) patient? Why are so many different tissues affected? An acidosis can be caused by several things. Medication-inducedSome thoughts are that 1) each tissue may have different NRTI kinet- renal tubular acidosis and chronic diarrhea can cause an acidosis, butics (tissue levels of drugs may differ); 2) each tissue may have differ- not a gap acidosis, as seen here. Sepsis can cause lactic with anent activation enzymes (levels of active drug may differ); 3) each tis- anion gap, but this patient did not appear to have sepsis clinically. Thissue may have different underlying proportion of mutant mtDNA; 4) it is patient's gap acidosis was caused by medication-induced lactic acad-known that NRTIs vary in their ability to inhibit mtDNA polymerase; 5) emia. the role of mitochondria may be more or less important in certain tis- Lactic academia and mitochondrial toxicity in HIV infection sues. The mitochondria are the body's battery packs, producing and storingThe Food and Drug Administration (FDA) reported 106 cases of lactic adenosine triphosphate (ATP) through a (non-lactate-producing)acidemia through June 1998. There were 46 cases associated with the process of cellular respiration and breaking it down when energy isuse of a single NRTI (mainly AZT) and 61 cases associated with a required. The number of mitochondria in cells of any particular tissuecombination of NRTIs including d4T, ddI, or AZT. In 69% of these varies, depending on tissue energy requirements. Cells of relativelycases, hepatic steatosis was present. There were 20 fatalities (85% quiescent tissue may contain only a few mitochondria; the cells of tis-female; 65% females obese). The French reported 11 cases in 867 sues with higher energy requirements - such as muscle, liver, and(0.84%) patients over 18 months: d4T/ddI (n=7); d4T/3TC (n=2); d4T nerves - may contain thousands of mitochondria. Mitochondria have(n=2). Hepatic steatosis was present in four of five biopsies. There was their own DNA strands (mtDNA) that are replicated by the enzymeone fatality. Four of the patients had HCV co-infection. They report polymerase gamma (pol gamma). Pol gamma is very similar to the HIVtreating lactic acidemia with riboflavin and carnitine. polymerase reverse transcriptase. Treating Mitochondrial Toxicities NRTIs that inhibit HIV reverse transcriptase may also interfere withEffective treatments still need to be evaluated. Current theories of polymerase gamma, apparently causing mutations in the replicating (Continued on page 7) mitochondria. Mitochondria do not have a mechanism for correcting June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 7

Ask the Expert...(continued from page 6) her labs were rechecked and results showed Na 137, Cl 106, and CO2 treatment focus on assisting the respiratory chain function with 1)21. At two months, post-discharge her electrolytes were normal, and Coenzyme Q - electron transfer with complex* III (portions of the ATPshe was no longer acidemic. However, the patient's HIV RNA electron transport chain in the mitochondria), 2) riboflavin - a cofactorincreased to 16,000 units (it had been undetectable) and her CD4 for electron transport complexes I and II, or 3) L-carnitine, a shuttlecount was 392 units (down from 512 units). The patient was hesitant mechanism for fatty acid transport across the mitochondria. Theseto restart antiretroviral therapy, and since her viral load and CD4 are at have shown varying efficacy in uncontrolled trials to date. Challengesacceptable levels for now, the bottom line for this patient is "wait and in studying mitochondrial toxicity (MT) include the lack of cell line orsee." When she does require therapy, NRTIs previously used in her animal model to reliably predict MT. In vitromodels may provide impor-treatment regimen will not be used and an NRT-sparing regimen will tant information but experience with fialuridine (FIAU) and recentlybe considered. with lodenosine (FddA) shows that clinical experience is the most reli-Summary able indictor. If lactic acidemia is not specifically looked for, it may not be diagnosed Hepatic Steatosis in time. The disease varies in presentation, and its common symptoms Hepatic steatosis is a frequent finding at biopsy, most often attributed- nausea, vomiting, fatigue, myopathy, abdominal pain, and recent to alcohol, obesity, diabetes, or drugs. If fatty acid oxidation in hepaticweight loss - are also symptomatic of HIV disease itself. There are cur- mitochondria is impaired, triglycerides may accumulate as small lipidrently limited diagnostic tests for toxicity and a serum specimen to vesicles in hepatocytes. Acute microvesicular steatosis can be verymeasure for lactic acid must be drawn carefully according to protocol. serious, leading to liver failure and death. Reference Resuming antiretroviral therapy AACTG Metabolic Guidelines for Hyperlactatemia and Lactic This patient improved after two days in the medicine intensive careAcidosis, http://aactg.s-3.com/metabolic/lactic.pdf unit, and an additional four days in the acute care ward. She returnedFor a list of references please email Kate Willner at to the facility and was seen in the infirmary for follow up. At one month,[email protected]

Long-Term Toxicities...(continued from page 2) *DISCLOSURES:Abbott (honoraria, consultant); Roche, Merck, GlaxoSmithKline, BMS (honoraria, research funding) hypersensitivity to nevirapine (NVP). One under-recognized toxicity is REFERENCES: non-alcoholic steatohepatitis (NASH). NASH may be seen in HIV-unin-1. Max B, Sherer R. Management of the adverse effects of antiretroviral fected patients and is usually associated with obesity, diabetes, or cer-therapy and medication adherence. Clin Infect Dis 2000; 30 (Suppl 2): tain medications, and can progress to cirrhosis if untreated. In HIV-S96-116. infected patients, NASH has been reported to occur in those with pro-2. Shikuma CM, Shiramizu B. Mitochondrial toxicity associated with longed hypertriglyceridemia and insulin resistance, usually secondarynucleoside reverse transcriptase inhibitor therapy. Current Inf Dis Reports to HAART. These patients present with sustained, mild-to-moderate2001; 3: 553-560. 3. Dassopoulos T, Ehrenpreis ED. Acute pancreatitis in HIV-infected elevations in serum transaminases (AST or ALT) with no serologic orpatients: A review. Am J Med 1999; 107: 78-84. virologic evidence of chronic HBV or HCV infection. Hepatic ultrasound4. Simpson DM, Tagliati M. -associated peripheral or CT scan will show a pattern consistent with fatty liver. Liver biopsyneuropathy in HIV infection. J Acquir Immune Defic Syndr 1995; 9: 153- will show steatosis with or without fibrosis or cirrhosis. Treatment161. involves therapy for the hypertriglyceridemia or insulin resistance,5. Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic lactatemia: an abstinence from any alcohol intake, use of antioxidants such as vita-emerging complication of antiretroviral therapy. AIDS 2000; 14: 2723- 2730. mins C and E, and in some cases alteration of the current ARV thera-6. Grunfeld C, Kotler DP, Hamadeh, et al. Hypertriglyceridemia in the py to remove the agents contributing to hypertriglyceridemia or insulinacquired immunodeficiency syndrome. Am J Med 1989; 86: 27-31. resistance.16 7. Stein JH. Dyslipidemia in the era of HIV protease inhibitors. Prog Cardiovasc Dise 2003 Jan-Feb. 293-304. Conclusion 8. Dube MP, Sprecher D, Henry WK. Preliminary guidelines for the evalu- The ART era has been a miraculous time for many patients with HIVation and management of dyslipidemia in adults infected with human infection and for those providing care. For patients with access to ARVimmunodeficiency virus and receiving antiretroviral therapy: therapy, HIV/AIDS has the potential to become a manageable, chron-Recommendation of the Adult AIDS Clinical Trials Group Cardiovascular ic disease. However, there are many prices to pay for this, including aDisease Focus. Clin Infect Dis 2000; 31: 1216-1224. 9. FDA. FDA Medical Bulletin 1997; 27(2). lifetime need for complex medical regimens associated with acute tox-10. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and icities. In the last few years, we have learned that there are chroniccardiovascular disease risk factors in adults with HIV infection and lipody- complications of both ARV therapy and prolonged survival with HIVstrophy. Clin Infect Dis 2001; 32: 130-139. infection. Some of these complications can be immediately life-threat-11. Mondy K, Yarasheski K, Powderly WG, et al. Longitudinal evolution of ening, whereas others have implications for patients' future morbiditybone mineral density and bone markers in HIV-infected individuals. Clin and mortality. In either case, patients and health care providers mustInfect Dis 2003; 36: 482-490. 12. Lichtenstein K, Armon C, Moorman A, et al. Clinical assessment of recognize that these long-term complications exist. Importantly, healthHIV-associated lipodystrophy in an ambulatory population. AIDS 2001; care providers need to understand how to diagnose and manage these15: 1389-98. complications in order to provide optimal long-term care to their13. Mallon PW, Miller J, Cooper DA, Carr A. Prospective evaluation of the patients with HIV infection. effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS. 2003 May 2;17(7):971-9. 14. Saag MS, Powderly WG, Schambelan M, et al. Switching antiretrovi- Suggested reading: ral drugs for treatment of metabolic complications in HIV-1 infection: sum- mary of selected trials. Topics HIV Med 2002; 10:47-51 M Schambelan, et al. Management of Metabolic Complications 15. Kotler D, Thompson M, Grunfeld C, et al. Growth hormone effectively Associated With Antiretroviral Therapy for HIV-1 Infection: reduces visceral adipose tissue accumulation and non-HDL cholesterol. Recommendations of an International AIDS Society-USA Panel. XIV International AIDS Conference 2002, Barcelona; LbOR18. JAIDS 2002, 31: 257-75. 16. Tien PC, Grunfeld C. The fatty liver in AIDS. Semin Gastrointest Dis 2002; 13(1): 47-54. June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 8 Save the Inside News Dates Save the Date: "Texas" Minifellowship authors concluded that fibrosis progression is Legal Issues in CorrectionalThe annual HIV Minifellowship for Correctionalvery slow in patients with mild chronic hepatitis C, Health Care Health Care Providers will be held in Providence,but that it appears to be accelerated in the later Sponsored by NCCHC and the Rhode Island, on September 22, 23, and 24,stages of disease. Increasing age and daily alco- American Bar Association Criminal2003. Sponsored by the University of Texashol consumption are the main factors associated Justice Section Medical Branch and HEPP Report, the confer-with significant fibrosis. Journal of Hepatology, June 27-28, 2003 ence will feature discussions by leading correc-2003;38(3):307-314 tional care providers and infectious disease spe- Chicago, Illinois Study: Methadone and Pegasys Interactions Call: 773-880-1460 cialists. Topics will include HIV epidemiology, opportunistic infections, HIV/HCV co-infection,and Safety Visit: www.ncchc.org/ Researchers from Johns Hopkins University pre- edu_legal2003/legal_conf.pdfmental health issues, guidelines for initiating and modifying ARV, and ethical issues. Call 409-747-sented results at the Digestive Disease Week 8769 or email [email protected] to register. (DDW) 2003 conference of a four-week study American Correctional evaluating interactions between methadone and Association Summer Number of Syphilis Cases in NJ Triples Pegasys. Methadone exposure increased by Conference The number of New Jersey men diagnosed with10%-15% during the first four weeks of taking August 9-13, 2003 syphilis has more than tripled in the last threeboth medications together, but the study found Nashville, Tennessee years, and the rise in numbers could be due tothat methadone did not have an impact on the Call: 800-222-5646, ext. 1922 increased risky behavior, ultimately leading topharmacokinetics or pharmacodynamics of Visit: www.aca.org/conventions/more HIV infections, according to the BergenPegagys. The authors concluded that dose mod- conventions_2003_summer.htm Record. The number of syphilis cases decreasedifications of Pegasys are not required and the throughout the 1990s but has spiked since 2000.combination of the drugs is safe and well tolerat- 3rd Annual Intensive Review in New Jersey Health Department officials reported. NATAP (www.natap.org), 5/20/03 Correctional Medicine that 121 men (mostly men who have sex with men) and 48 women were diagnosed withMan Has HIV Superinfection Sponsored by the Correctional syphilis in 2002. Bergen Record, 5/4/03 A man has been infected with two different strains Medicine Institute (CMI), of HIV, researchers report in the May 2, 2003 edi- the Society for CorrectionalMany Minorities With HIV Not Taking HAARTtion of AIDS. Although the immunological Physicians (SCP), and An analysis of 200 HIV-infected patients whoresponse to HIV-1 infection is believed to impede Johns Hopkins University died at a Texas hospital in between 1995 and"superinfection" with a second virus, study September 4-6, 2003 2000 found that more than half of them were notauthors report that this is not always the case. Baltimore, Maryland taking HAART. Despite the availability of HAART,About four months after infection with drug-resis- Baltimore Marriott Waterfront Hotel only 48% of patients who died in 1999-2000 weretant clade B virus, the patient was infected by a Call: 314-607-1565 taking HAART at the time of death, according tosecond drug-sensitive wild-type virus from the Email: [email protected] the authors. The main reasons the patients weresame subtype. His viral load then jumped from Visit: www.cm-institute.org not taking the drugs were an inability to adhere to34,000 copies/mL to almost 200,000 copies/mL. the regimen, an HIV diagnosis less than sixAIDS 2003; 17:F11-F16 and Reuters, 5/19/03 months prior to death, or an inability to tolerate 43rd Interscience Conference the drugs due to underlying liver disease. TheStudy: Evaluation of 24-Hour Viral Response on Antimicrobial Agents and study also found that many of the HIV-infectedto HCV Combination Therapy Chemotherapy (ICAAC) individuals who were not receiving HAART wereAt the DDW 2003 conference in Florida, September 14-17, 2003 minorities. Journal of Clinical Infectious researchers from the University of Vienna pre- Chicago, Illinois Diseases, 2003;36(8):1030-1038 sented results of a prospective evaluation of 24- Call: 202-737-3600 hour viral response in predicting outcome of treat- Email: [email protected] Study: How Often Should Liver Biopsy Be ment with Pegasys and ribavirin. While the 12 or Visit: www.icaac.org/ICAAC.asp Performed? 24 week response is more accurate at predicting A study in the Journal of Hepatology found thatETR and SVR, the authors concluded that the 24- The United States Conference an interval of at least four to five years is neededhour viral response rate is a sensitive predictor of on AIDS between liver biopsies to detect significantthe response to therapy, and may be useful in Sponsored by the Nationalchanges in patients with mild liver disease. Onecertain situations. hundred and eighty patients with histologicallyNATAP (www.natap.org), 5/21/03 Minority AIDS Council proven chronic hepatitis C were studied. The September 18-21, 2003 New Orleans, Louisiana Call: 202-483-6622 Visit: www.nmac.org Resources

HIV Minifellowship for New OHRP Guidance on the Involvement ofSARS Resources Correctional Health Care Prisoners in Research wCenters for Disease Control and Prevention: http://ohrp.osophs.dhhs.gov/humansubjects/guid- Providers www.cdc.gov/ncidod/sars/ ance/prisoner.htm Sponsored by the University of wWorld Health Organization: The Office for Human Research Protections Texas Medical Branch www.who.int/csr/sars/en/ (OHRP) on May 23,2003 posted a new guidance and HEPP Report, wNew England Journal of Medicine:(SARS document on the OHRP website: "OHRP content is posted free for all visitors) Brown University Guidance on the Involvement of Prisoners in http://content.nejm.org/early_release/sars.dtl September 22-24, 2003 Research." The new document replaces the pris- wCDC Public Health Training Network Providence, Rhode Island oner research guidance document titled "OPRR Satellite Broadcast & Webcast:Includes Call: 409-747-8769 Guidance on Approving Research Involving Email: [email protected] Prisoners" from May 19, 2000. archived webcast and presenters' slides. www.phppo.cdc.gov/PHTN/webcast/sarsII/ June 2003 Volume 6, Issue 6 visit HEPP Report online at www.hivcorrections.org 9

Self-Assessment Test for Continuing Medical Education Credit Brown Medical School designates this educational activity for 1 hour in category 1 credit toward the AMA Physician’s Recognition Award. To be eligible for CME credit, answer the questions below by circling the letter next to the correct answer to each of the questions. A minimum of 70% of the questions must be answered correctly. This activity is eligible for CME credit through December 31, 2003. The estimated time for completion of this activity is one hour and there is no fee for participation.

1. Mitochondrial toxicity has been primarily associated with: HEPP Report Evaluation (a) PIs (b) NRTIs 5 Excellent 4 Very Good 3 Fair 2 Poor 1 Very Poor (c) NNRTIs (d) NRTIs and NNRTIs 1. Please evaluate the following sections with respect to: 2. Mitochondrial toxicity can lead to: educational value clarity (a) Pancreatitis, peripheral neuropathy, and lactic acidosis (b) Pancreatitis, dyslipidemia, and hepatitis Main Article5 4 3 2 1 5 4 3 2 1 (c) Lactic acidosis, dyslipidemia, and pancreatitis (d) Lipodystrophy, peripheral neuropathy, and lactic acidosis Inside News5 4 3 2 1 5 4 3 2 1 Save the 3. Cohort studies have estimated that up to 70% of patients suf- Dates 5 4 3 2 1 5 4 3 2 1 fer from lipodystrophy. (a) True (b) False 2. Do you feel that HEPP Report helps you in your work? 4. HIV-infected patients with non-alcoholic steatohepatitis Why or why not? (NASH) can present with sustained, mild-to-moderate AST or ALT elevations, even in the absence of serologic evidence of chronic HBV or HCV. (a) True (b) False 3. What future topics should HEPP Report address?

5. Preliminary studies have shown that the following medication might be effective for the treatment of HIV-infected patients with osteoporosis: (a) Calcitonin (b) Alendronate 4. How can HEPPReport be made more useful to you? (c) Raloxifene (d) Calcium supplements

6. The dyslipidemic profile includes the following except: (a) High LDL cholesterol (b) Elevated triglycerides 5. Do you have specific comments on this issue? (c) Pancreatitis (d) Low HDL cholesterol

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