Human Papillomavirus (HPV) and Trichomonas: Common, Concerning, and Challenging Sexually Transmitted Infections Erna Milunka Kojic, MD  Hu m a n papillomavirus (HPV) a n d terest in using a combination of high-risk types 6, 11, 16, or 18. The bivalent vaccine Trichomonas are two of the most common HPV type testing and cytology for screen- is directed against HPV types 16 and 18 to sexually transmitted infections (STIs) in ing. The combined approach increases the prevent cervical cancer and precancerous the Unites States and worldwide, with sensitivity substantially compared with lesions. Recommendations from the ACIP prevalences exceeding those of Chlamydia either test alone, and has a negative predic- and the ACS are shown in Table 1. and N. gonorrhea infections. Both infec- tive value of 99% to 100%.4 Studies with the HPV vaccine have tions have epidemiologic associations and demonstrated safety with relatively few can have serious health consequences. Studies with the adverse events reported. The protective element of the vaccine is the high con- Hu m a n Papillomavirus (HPV) HPV vaccine have centration of HPV type-specific neutral- In f e c t i o n demonstrated izing antibody. In the Females United to HPV is the major cause of cervical and Unilaterally Reduce Endo/Ectocervical anal cancers, as well as oral and anogenital safety with Disease (FUTURE I/II) study, almost condylomas. HPV is a DNA virus of which relatively few all women who received the quadrivalent over 90 types have been identified. Ap- HPV vaccine became anti-HPV 6, 11, 16, proximately 30 types are sexually transmit- adverse events and 18 seropositive one month after the ted and infect the anogenital area of both reported. third vaccine dose (99.8%, 99.8%, 99.8%, men and women. Data from the National and 99.5% seropositive, respectively).7 Health and Nutrition Examination Survey1 The study also showed that the vaccine have provided the first national estimate of Most women clear newly acquired prevented 98-100% of CIN grades 1 to the prevalence of HPV infection among HPV infection spontaneously, and the 3 or adenocarcinoma in situ, and vaginal, women in the United States aged 14 to prevalence of HPV DNA positivity drops vulvar, perineal, and perianal intraepithelial 59. Overall, 26.8 percent of women tested with age from a peak in adolescence and lesions associated with vaccine-type HPV positive for one or more strains of HPV. the early 20s.5 Current guidelines have when administered to subjects who had not Prevalence of HPV was highest in women therefore incorporated testing for high- been previously exposed to HPV. The vac- ages 20-24. Among all participating risk HPV only for women 30 years of age cine also reduced the rate of vulvar, vaginal, women, the prevalence of high-risk types and older, and triaging cervical cytology and perianal lesions by 34% and cervical of HPV was 15.2 percent. The prevalence management based on HPV test results. lesions by 20% regardless of the type of of HPV types 6, 11, 16, and 18—the types In the absence of cervical lesions, treat- HPV infection. The FUTURE II study targeted by Quadrivalent HPV vaccine was ment is not recommended for subclinical showed that the efficacy of the vaccine in 3.4 percent overall. genital HPV infection or low grade lesions preventing HPV-16 and -18-related CIN Persistence of high-risk types of HPV such as cervical intraepithelial neoplasia 2 and 3 and adenocarcinoma in situ was (16, 18, 31, 33, 35, 45) causes cervical 1 (CIN1).6 In clinical care, no anti HPV lower (44%) for those women with previ- dysplasia and cancer. Worldwide, types 16 treatment is available, only treatment of le- ous exposure to the vaccine types.7 and 18 account for the majority of cervical sions caused by HPV infection. Preventing In Rhode Island, state-supplied vac- cancers, and one or more of these types can HPV infection is therefore important. cine is available for routine vaccination at be found in 90% of high grade intraepi- Currently, there are two prophylactic 11-12 years of age and catch-up vaccina- thelial precursor lesions.2 Non-oncogenic vaccines approved by the US Food and tion for females 13-18 years of age. As of types 6 and 11 are the etiologic agents for Drug Administration (FDA) for prevent- July 2010, the state also began supplying the majority of genital warts. Currently, ing HPV infection. These vaccines are a the vaccine for permissive use in males nine cytology is used to screen for HPV related quadrivalent HPV vaccine (made by Merck through 18 years of through the universal diseases. However, cytology as a cervical and Co, and approved in June 2006) and state-supplied vaccine program. Vaccine cancer screening method has a number a bivalent HPV vaccine (made by Glaxo- recommendations from both the ACIP and of limitations, including the sensitivity to SmithKline, and approved in October the American Cancer Society are shown detect histologically significant disease. 2009). The quadrivalent vaccine is directed in Table 1. The sensitivity and specificity of cervical against HPV types 6, 11, 16, and 18 and cytology ranges from 57% to 90% and is FDA-approved for preventing cervical HPV a n d HIV c o -infection from 65% to 97%, respectively.3 These cancer, genital warts, and precancerous or Highly active antiretroviral regimens limitations have led to a considerable in- dysplastic genital lesions caused by HPV have revolutionized the treatment of 255 Volume 95 No. 8 Au g u s t 2012 decrease the vaccine’s efficacy. One study, Table 1. Comparison of Advisory Committee on Immunization Practices evaluating 767 HIV-infected and 390 and American Cancer Society Recommendations for Human Papilloma uninfected women, the DNA prevalence Virus (HPV) Vaccination of one or more of HPV types 6, 11, 16, and 18 was 15.9%; specifically, type 6 was Advisory Committee on Immunization American Cancer Society 3.1%, 11 was 0.9%, 16 was 5.7%, and Practices 18 was 6.1% (6.7% in HIV- uninfected 10 Quadrivalent HPV vaccine: Routine Quadrivalent or bivalent HPV women). Thus, although HIV-infected HPV vaccination with 3 doses of vaccine: Routine HPV vaccination women have a much higher prevalence vaccine is recommended for girls with 3 doses of vaccine is recom- of these four types than HIV- uninfected AND boys 11 and 12 years of age mended for girls 11 and 12 years women, the majority of them (84-89%) with catch-up for females and males of age with catch-up for girls aged did not have the types contained in the aged 13 to 26 years if not vaccinated 13 to 18 years if not vaccinated vaccine. Preventing infection of the four previously or have not completed the previously or have not completed vaccine HPV types could decrease the series. the series. impact of HPV infection among HIV- Bivalent HPV vaccine: Routine HPV infected individuals. The immunogenicity vaccination with 3 doses of vaccine and safety of an HPV vaccine in HIV- is recommended for girls 11 and 12 infected women is being evaluated. years of age with catch-up for girls In terms of managing HPV related and women aged 13 to 26 years if diseases in HIV infected women, the not vaccinated previously. American Society for Colposcopy and Quadrivalent or bivalent HPV vac- Quadrivalent or bivalent HPV vac- Cervical Pathology (ASCCP) guidelines cine: Girls as young as 9 years of cine: Girls as young as 9 years of recommend that HIV-infected women be age can be vaccinated. age can be vaccinated. managed in the same manner as women in the general population.6 At present, Quadrivalent HPV vaccination is Quadrivalent or bivalent HPV vac- insufficient data are available to sup- recommended for all female and cine: HPV vaccination is recom- port the use of HPV testing for triage of male individuals.13 through 26 years mended for all females 13 through HIV-seropositive women aged 30 years of age. 18 years of age. and older. Based on the lack of sufficient

data, the DHHS guidelines recommend Bivalent HPV vaccine is recommend- The American Cancer Society has ed for all girls and women 13 through no recommendation regarding the a referral for colposcopy for any cervical 26 years of age. use of either HPV vaccine in men cytologic abnormality found in HIV-sero- and boys. positive women, regardless of the presence or absence of high-risk HPV types. Quadrivalent or bivalent HPV vac- Data are insufficient to recom- cine: The vaccine is not licensed for mend for or against universal vac- Tr i c h o m o n a s v a g i n a l i s use in girls younger than 9 years of cination of women 19 to 26 years In f e c t i o n age or women older than 26 years of age. HPV vaccination is not Trichomonas vaginalis (T. vaginalis) of age. recommended for women older is a sexually transmitted protozoan para- Quadrivalent HPV vaccine is than 26 years of age. site. In the United States, an estimated contraindicated for persons with a 3.7 million people have the infection, history of immediate hypersensitivity to yeast. but only a third develops any symp- toms of trichomoniasis. In a nationally Bivalent HPV vaccine in prefilled sy- representative sample, the prevalence of ringes is contraindicated for persons trichomoniasis among 14–49-year-old with anaphylactic latex allergy. women in the United States was 3.1%, corresponding to 2.3 million women individuals infected with HIV and have HIV-infected women have been reported with trichomoniasis compared with a resulted in dramatic reductions in morbid- to have a higher prevalence and persis- prevalence of 0.33% and 2.5% for Neis- ity and mortality.8 While mortality due to tence of HPV infection and to have an seria gonorrhea and Chlamydia trachomatis HIV infection or AIDS declined, mortal- increased risk for abnormal Papanicolaou infections respectively (NHANES).12 ity due to malignancies has increased and (Pap) smears as well as cervical cancer.11 Infection is more common in women now represents an increasing proportion Therefore, the burden of HPV infection than in men, especially non-Hispanic of overall deaths among persons with HIV is greater among HIV-infected rather than black women, and older women are more infection.9 HPV infections are more preva- HIV-uninfected women. likely than younger women to have been lent and persistent in HIV-infected wom- A concern in HIV-infected women infected.12 The prevalence is likely to be en, with a prevalence of 64% compared is that the high prevalence of previous underestimated as the infection is not to 28% in HIV-uninfected women.10 exposure to HPV 6, 11, 16 and 18 would reportable like many other STIs, available 256 Medicine & Health/Rhode Island diagnostic methods are often insensitive, Re f e r e n c e s 11. Ellerbrock TV, Chiasson MA, Bush TJ, et al. and the clinical awareness of the infec- 1. Dunne EF, Unger ER, Sternberg M, et al. Incidence of cervical squamous intraepithe- lial lesions in HIV-infected women. JAMA. tion is often limited to women and not Prevalence of HPV infection among females in the United States. JAMA. 2007;297:813–9. 2000;283:1031–7. their male partners. The symptoms of T. 2. Clifford GM, Smith JS, Aguado T, Franceschi 12. Sutton M, Sternberg M, Koumans EH, vaginalis infection are less pronounced S. Comparison of HPV type distribution in McQuillan G, Berman S, Markowitz L. The in men, and the detection of infection is high-grade cervical lesions and cervical cancer: prevalence of Trichomonas vaginalis infec- tion among reproductive-age women in the more complicated. Studies of male STD a meta-analysis. Br J Cancer. 2003;89:101–5. 3. Arbyn M, Bergeron C, Klinkhamer P, Martin- United States, 2001-2004. Clin Infect Dis. clinic patient populations have reported Hirsch P, Siebers AG, Bulten J. Liquid com- 2007;45:1319–26. prevalences between 11 and 17%. The pared with conventional cervical cytology: a 13. http://www.trichomoniasis.org/Prevalence/ systematic review and meta-analysis. Obstet Index.aspx. prevalence of T. vaginalis among male 14. Sorvillo F, Smith L, Kerndt P, Ash L. Trichomo- sexual partners of infected women is over Gynecol. 2008;111:167–77. 4. Kaplan JE, Benson C, Holmes KH, Brooks JT, nas vaginalis, HIV, and African-Americans. 13 73%. Males with T. vaginalis infections Pau A, Masur H. Guidelines for prevention Emerg Infect Dis. 2001;7:927–32. are often untreated, both because of lack and treatment of opportunistic infections in 15. Hobbs MM, Lapple DM, Lawing LF, et al. Methods for detection of Trichomonas vagi- of symptoms and due to lack of treatment HIV-infected adults and adolescents: recom- mendations from CDC, the National Institutes nalis in the male partners of infected women: as male partners of women with known T. of Health, and the HIV Medicine Association implications for control of trichomoniasis. J vaginalis. T. vaginalis re-infection among of the Infectious Diseases Society of America. Clin Microbiol. 2006;44:3994–9. women is therefore common. MMWR Recomm Rep. 2009;58:1–207; quiz 16. Andrea SB, Chapin KC. Comparison of Aptima Trichomonas vaginalis transcription- T. vaginalis causes vaginitis, pelvic CE1–4. 5. Ho GY, Bierman R, Beardsley L, Chang CJ, mediated amplification assay and BD affirm inflammatory disease, and several adverse Burk RD. Natural history of cervicovaginal VPIII for detection of T. vaginalis in symp- obstetric sequelae (e.g. premature rupture papillomavirus infection in young women. N tomatic women: performance parameters and of membranes, low birth weight, preterm Engl J Med. 1998;338:423–8. epidemiological implications. J Clin Microbiol. 2011;49:866–9. labor). Recent advances in TV diagnostics 6. Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus have led to an improved understanding of guidelines for the management of women with Erna Milunka Kojic, MD, is an As- the epidemiology of this pathogen. T. vagi- abnormal cervical cancer screening tests. Am J sociate Professor of Medicine at the Warren nalis is also associated with prolonged HPV Obstet Gynecol. 2007;197:346–55. Alpert Medical School of Brown University, carriage and increased risk of acquiring 7. Quadrivalent vaccine against human papillo- mavirus to prevent high-grade cervical lesions. and Director of the Immunology Center in HIV infection. Studies have suggested that N Engl J Med. 2007;356:1915–27. the Division of Infectious Diseases at The T. vaginalis may increase the rate of HIV 8. Palella FJ, Jr., Delaney KM, Moorman AC, et Miriam Hospital. transmission by approximately twofold.14 al. Declining morbidity and mortality among This fact can translate into a significant patients with advanced human immunodefi- ciency virus infection. HIV Outpatient Study Disclosure of Financial Interests problem in light of the high T. vaginalis Investigators. N Engl J Med. 1998;338:853– The author and/or their spouse/sig- prevalence globally. 60. nificant other have no financial interests Until recently, lack of sufficiently 9. Louie JK, Hsu LC, Osmond DH, Katz MH, Schwarcz SK. Trends in causes of death among to disclose. sensitive and specific diagnostic tests persons with acquired immunodeficiency syn- has limited the accurate diagnosis and drome in the era of highly active antiretroviral Corresponden c e recognition of this infection. Diagnosis therapy, San Francisco, 1994-1998. J Infect Dis. Erna Milunka Kojic, MD of vaginal trichomoniasis can be done 2002;186:1023–7. 10. Jamieson DJ, Duerr A, Burk R, et al. Char- Immunology Center by microscopy of vaginal secterions (wet acterization of genital human papillomavirus 1125 North Main Street mount), culture, rapid antigen detection, infection in women who have or who are at risk Providence RI, 02906 and nucleic amplification tests (NAAT). of having HIV infection. Am J Obstet Gynecol. phone: (401) 793-5961 Microscopy detection is highly insensitive 2002;186:21–7. fax: (401) 793-4779 in detecting T vaginalis and culture is time e-mail: [email protected] consuming. There are several nucleic acid tests available although only one, the Af- firm VP III hybridization assay, has been FDA approved.15 Other commercially available tests like the Gen-Probe Aptima T vaginalis transcription-mediated am- plification (TMA) tests are being evalu- ated and may be even more sensitive in detecting T. vaginalis.16 With increasing evidence of compli- cations associated with trichomonas infec- tions, screening for T. vaginalis should be encouraged, especially as treatment with metronidazole 2 gm or tinidazole 2 gm in single doses is easy and highly effective.

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