Case

A 30 year-old female inmate, G4P2, presents to the prison diagnostic intake clinic with a history of A2 HIV infection, last approximate CD4 count 350 cells/µl and HIV-1 quantitative viral load (VL) 50,000 copies/ml, for which she is taking no medications and is antiretroviral therapy (ART)-naive. She has a four-year sentence and a history of heroin dependence. Her last Pap was performed approximately four years ago when she was diagnosed with HIV, and she thinks it was normal. She reports being treated for chlamydia when diagnosed with HIV. Her ex-husband was HIV-infected and is now deceased. She reports no sex partners for at least 12 months.

On physical exam, vital signs are normal, and she appears well nourished. She has no evidence of oral thrush or lymphadenopathy, her skin is normal, and her chest, breast, and abdominal examinations are normal. Pelvic exam is notable for watery, grayish vaginal discharge with a fishy odor, though on gross examination her cervix and vaginal wall appear normal. Cells are collected from her cervix using a spatula and cytobrush and a slide for conventional Pap test is prepared. A swab of the discharge from her vaginal wall is also collected. The vaginal pH is 6.0, and the wet mount shows few lactobacilli. Laboratory tests to confirm her T cell count, HIV-1 viral load, electrolytes, and renal/hepatic function, and to screen for hepatitis A,B,C, syphilis, chlamydia, gonorrhea, toxoplasmosis, and CMV are obtained.

Q: What is the cause of her vaginal discharge and how should it be treated?

A: She has bacterial vaginosis (BV), in which an overgrowth of bacterial species (such as Gardnerella, Bacteroides, Mycoplasma, Mobiluncus, and Peptostreptococcus) normally present in the vagina occurs. BV correlates with loss of protective (peroxide-producing) lactobacilli normally present in the vagina, thereby raising the vaginal pH above normal (>4.5). In non-pregnant women, BV is usually treated with metronidazole at 500 mg po twice daily for seven days (250 mg po three times daily for seven days in pregnancy). Of note, in a recently published observational cohort study by Watts, et al., the authors report that BV and Trichomonas vaginalis infection may increase the risk of acquisition (or reactivation) of HPV infection among HIV-infected and high-risk HIV-uninfected women.

She returns to clinic for follow-up of test results three weeks later. Her CD4 count is 334 cells/µl with HIV-1 VL of 85,000 copies/ml. Her Pap report states that it is "satisfactory for evaluation" and shows "atypical squamous cells of undetermined significance (ASC-US)". Other tests ordered are normal and show no evidence of hepatitis, syphilis, gonorrhea, or chlamydia.

Q: How should her cervical cytology (ASC-US Pap) be managed? Would ordering an HPV test be helpful?

A: This inmate should be referred for colposcopic examination since she is HIV-infected and has an abnormal Pap, even if it is only mildly abnormal. Also, even if the colposcopy is normal, she should have a repeat Pap in six months since she has had only one Pap since her diagnosis of HIV, and this was at least four years ago. Women at highest risk of cervical cancer in the U.S. are those who are not properly screened for cervical cancer. Because cervical cytology is only, on average, 60% sensitive in detecting moderate to severe cervical intraepithelial neoplasia (CIN grade 2/3) or cancer, other screening strategies, such as HPV DNA testing, are recommended for use in some specific clinical scenarios relating to immunocompetent women. However, studies, though limited, have shown that HPV DNA testing in HIV-infected women may not be cost-effective or as clinically meaningful compared to testing in immunocompetent women. Therefore, in the 2001 ASCCP guidelines for the management of women with cytological abnormalities, it was recommended that all HIV-infected women (regardless of CD4 count or HIV-1 VL) with any cytological abnormality, including ASC-US, be referred for colposcopy, in order to ensure accurate and timely detection of CIN 2/3 or cancer. Detection of DNA for oncogenic HPV types among HIV-infected women with ASC-US is more common than among HIV-uninfected women, and therefore, does not appear to be a cost-effective strategy for determining who in this population should go to colposcopy.

Q: Should this patient, who is largely asymptomatic from HIV infection, be treated with ART?

A: According to the recently revised 2004 DHHS ART guidelines, treatment for this ART-naive, asymptomatic inmate with a CD4 count that is now <350 cells/µl should be offered. If her CD4 count was >350 cells/µl, treatment could be deferred since her VL is <100,000 copies/ml. It is unclear whether initiation of ART would aid in regression of cervical disease, by way of decreasing HIV-1 viral load and increasing CD4 count. Prospective or randomized trials properly designed to address this issue have not been published, and the data that exists is conflicting. Of note, moderate to severe cervical dysplasia is considered a symptomatic condition of HIV since it may indicate a defect in cell-mediated immunity and has a clinical course that may be complicated by HIV (AIDS surveillance case definition 1993). If the inmate described in the case has cervical intraepithelial neoplasia (CIN) grade 2 or CIN 3 detected on colposcopy, she would meet the case definition for Stage B HIV infection and should then be offered ART.

Discussion

Human papillomavirus (HPV), which is the most common sexually transmitted infection, causes cervical dysplasia and squamous cell cancer. In 1999, Massad, et al. reported the prevalence of abnormal cervical screening cytology among HIV-infected women to be approximately 38%. Published reports on ASC-US cytology among HIV-infected women suggest a 14-15% risk for CIN 2/3, and a more recent study showed that HPV DNA testing in this population may not be sensitive enough to use as a triage strategy for detecting CIN 2/3.

Cervical cancer screening guidelines for HIV-infected women have not been revised since 1995 and only state that these women should have two Pap tests performed six months apart in the first year of the initial HIV diagnosis. If Pap results for both are normal, they can then go to annual cytological screening. A published report by Goldie, et al. suggests that HPV DNA testing may be cost effective if performed in conjunction with primary cervical cytological screening of women in the first year of HIV diagnosis and then, if either is positive, used to triage women who undergo more intensive screening thereafter (e.g. six month intervals verses annually). However, this published report was a cost modeling study and has not been tested in a prospective or randomized clinical trial. In a recent observational cohort study by Harris, et al., the authors showed there to be a similar cumulative incidence of any cytological abnormalities, over three or more years, among HIV-seronegative and HIV-seropositive women (CD4 counts greater than 500 cells/µl) who had normal cytology and negative HPV DNA tests at baseline. These findings suggest that among HIV-infected women with relatively preserved immune function (i.e. CD4 counts >500 cells/µl), cervical cancer screening guidelines for immunocompetent women, may apply. However, these findings need to be confirmed in a properly designed formal clinical trial. Therefore, until more evidence is available to suggest otherwise, HIV-infected women with ASC-US or other cytological abnormalities should be referred for colposcopy.

Just as little is known about the proper cervical cancer screening strategies for HIV-infected women, the same is true for the management of mild dysplasia, or CIN 1, in these women. In immunocompetent women, CIN1 is often observed and not treated, particularly in younger women, since CIN 1 will often regress without treatment. In a published prospective cohort study by Massad et al., the authors show that CIN 1 infrequently progresses to more severe disease, including cancer, in women with HIV infection. They concluded that observation appears safe for these women (with the assumption that they will be followed carefully and not lost to follow-up in the system). In adult women, regardless of immune function, CIN 2/3 or worse disease should always be treated.

**Based largely on these data discussed above and the 2001 American Society for Colposcopy & Cervical Cytology (ASCCP) Consensus Guidelines, Dr. Weaver provides in this issue a suggested algorithm for HIV-infected women with cytological abnormalities.

Bethany Weaver, D.O., M.P.H., , Acting Instructor of Medicine, University of Washington Center for AIDS & STD Research (CFAR), has nothing to disclose.

References

1. Goldie SJ et al. Cost effectiveness of HPV testing to augment cervical cancer screening in women infected with the HIV. Am J Med 2001;111:140-9.
   

2. Harris TG et al. Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and HPV test results. JAMA 2005 (23/30 March);293(12):1471-6.
   

3. Holcomb K et al. The significance of ASCUS cytology in HIV-positive women. Gynecol Oncol 1999;75:118.
   

4. Massad LS et al. HPV testing for triage of HIV-infected women with Papanicolau smears read as atypical squamous cells of uncertain significance. J of Women's Hlth 2004 (2 November);13:147-53.
   

5. Massad LS et al. Natural history of grade 1 cervical intraepithelial neoplasia in women with HIV. Obstet Gynecol 2004 (November);104(5):1077-85.
   

6. Massad LS et al. Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. J Acquir Immune Defic Syndr 1999;21:33.
   

7. Solomon et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114-9.
   

8. USPHS/IDSA Prevention of opportunistic infections working group. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV: disease-specific recommendations. Clin Infect Dis 1995;21(suppl 1):532-43.
   

9. Watts DH, et al. Effects of bacterial vaginosis and other genital infections on the natural history of HPV infection in HIV-1-infected and high-risk HIV-1-uninfected women. J Inf Dis 2005 (1 April);191:1129-39.

10. Wright TC Jr et al. Interim guidance for the use of HPV DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004 (Feb);103(2):304-9.

11. Wright TC Jr et al. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002 (24 April);287(16):2120-9.

12. Wright TC et al. Significance of mild cytologic atypia in women infected with HIV. Obstet Gynecol 1996;87:515.

13. For American Society for Colposcopy & Cervical Pathology 2001 Consensus Guidelines, visit www.asccp.org/consensus.shtml.

14. For Department of Health & Human Services 2004 HIV Treatment Guidelines, visit www.cdc.gov/hiv/treatment.htm#treatment.