Primary HPV and Molecular Cervical Cancer Screening in US Women Living With Human Immunodeficiency Virus.

BACKGROUND: Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH). METHODS: We enrolled n = 865 WLWH (323 from the Women's Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[-]/Pap[-] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry. RESULTS: Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). "PHS with reflex HPV16/18-genotyping and Pap testing" had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. "Concurrent oncHPV and Pap Testing" (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy. CONCLUSIONS: PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.

Incidence of cervical precancers among HIV-seropositive women.

OBJECTIVE: The objective of the study was to estimate the impact of human immunodeficiency virus (HIV) infection on the incidence of high-grade cervical intraepithelial neoplasia (CIN). STUDY DESIGN: HIV-seropositive and comparison seronegative women enrolled in a prospective US cohort study were followed up with semiannual Papanicolaou testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer) and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using a Cox analysis. Median follow-up (interquartile range) was 11.0 (5.4-17.2) years for HIV-seronegative and 9.9 (2.5-16.0) for HIV-seropositive women. RESULTS: CIN3+ was diagnosed in 139 HIV-seropositive (5%) and 19 HIV-seronegative women (2%) (P<.0001), with CIN2+ in 316 (12%) and 34 (4%) (P<.0001). The annual CIN3+ detection rate was 0.6 per 100 person-years in HIV-seropositive women and 0.2 per 100 person-years in seronegative women (P<.0001). The CIN3+ detection rate fell after the first 2 years of study, from 0.9 per 100 person-years among HIV-seropositive women to 0.4 per 100 person-years during subsequent follow-up (P<.0001). CIN2+ incidence among these women fell similarly with time, from 2.5 per 100 person-years during the first 2 years after enrollment to 0.9 per 100 person-years subsequently (P<.0001). In Cox analyses controlling for age, the hazard ratio for HIV-seropositive women with CD4 counts less than 200/cmm compared with HIV-seronegative women was 8.1 (95% confidence interval, 4.8-13.8) for CIN3+ and 9.3 (95% confidence interval, 6.3-13.7) for CIN2+ (P<.0001). CONCLUSION: Although HIV-seropositive women have more CIN3+ than HIV-seronegative women, CIN3+ is uncommon and becomes even less frequent after the initiation of regular cervical screening.

The effect of protease inhibitors on the cervical mucus of HIV-positive women taking norethindrone contraception.

OBJECTIVE: To compare cervical mucus score (CMS) with and without protease inhibitors (PI) before and after taking norethindrone (NET). STUDY DESIGN: This two-arm, researcher blinded, non-randomised, prospective study was conducted to evaluate cervical mucus quality in HIV-positive women taking progestin only pills. The study group was taking a PI, and compared to women taking ARV regimens that have demonstrated no significant interaction with NET in prior pharmacokinetic trials with combined oral contraceptives. The women had a cervical mucus score prior to NET administration. Mucus Scoring was repeated after 21 days of steady state exposure to oral NET 0.35 milligrams. Cervical mucus quality was quantified according to the World Health Organisation criteria, which include: volume, consistency, cellularity, spinnbarkeit, and ferning. RESULTS: Sixteen women took PI and 17 were controls. Baseline CMS were similar (p ≥ 0.1). After 21 days CMS were similar among the two groups (p = 1). CONCLUSIONS: HIV-positive women taking PI demonstrated thickened cervical mucus with oral norethindrone 0.35 mg and are similar to HIV-positive women taking no PI therapy. This may suggest no difference in contraceptive efficacy of progestin only pills in HIV-positive women taking PI.

Long-term cumulative incidence of cervical intraepithelial neoplasia grade 3 or worse after abnormal cytology: impact of HIV infection.

To estimate the long term cumulative risk for cervical intraepithelial neoplasia grade 3 or worse after an abnormal cervical Pap test and to assess the effect of HIV infection on that risk. Participants in the Women's Interagency HIV Study were followed semiannually for up to 10 years. Pap tests were categorized according to the 1991 Bethesda system. Colposcopy was prescribed within 6 months of any abnormality. Risk for biopsy-confirmed CIN3 or worse after abnormal cytology and at least 12 months follow-up was assessed using Kaplan-Meier curves and compared using log-rank tests. Risk for CIN2 or worse was also assessed, since CIN2 is the threshold for treatment. After a median of 3 years of observation, 1,947 (85%) women subsequently presented for colposcopy (1,571 [81%] HIV seropositive, 376 [19%] seronegative). CIN2 or worse was found in 329 (21%) of HIV seropositive and 42 (11%) seronegative women. CIN3 or worse was found in 141 (9%) of seropositive and 22 (6%) seronegative women. In multivariable analysis, after controlling for cytology grade HIV seropositive women had an increased risk for CIN2 or worse (H.R. 1.66, 95% C.I 1.15, 2.45) but higher risk for CIN3 or worse did not reach significance (H.R. 1.33, 95% C.I. 0.79, 2.34). HIV seropositive women with abnormal Paps face a marginally increased and long-term risk for cervical disease compared to HIV seronegative women, but most women with ASCUS and LSIL Pap results do not develop CIN2 or worse despite years of observation.

Accuracy of colposcopy in HIV seropositive and seronegative women with abnormal Pap tests.

OBJECTIVE: The aim of this study is to compare colposcopic findings and the accuracy of colposcopic impression in HIV seropositive and seronegative women with abnormal Pap tests. METHODS: HIV seropositive and seronegative women in a national cohort study had Pap tests collected every six months, with colposcopy for any abnormal result. Prospectively collected colposcopy and histology findings were analyzed retrospectively using Pearson Chi-square, t-test and Wilcoxon two-sample tests, logistic regression models, and Kappa coefficients. RESULTS: After adjusting for age and Pap result, 1618 eligible HIV seropositive women were more likely than 406 seronegative women to have inadequate colposcopic examinations, abnormal colposcopic findings, and large cervical lesions. However, among those with abnormal colposcopy, colposcopic characteristics and lesion size and number did not differ by HIV serostatus. Agreement between colposcopists' impressions and highest grade biopsy diagnoses was fair (kappa coefficient 0.35, 95% C.I. 0.31, 0.38). Agreement did not differ by HIV serostatus and did not improve with multiple biopsies (weighted kappa coefficient 0.35, 95% C.I. 0.32, 0.39) or after including all histology results over two years following colposcopy. CONCLUSION: Although HIV seropositive women with abnormal cytology are more likely to have colposcopic abnormality, the performance of colposcopy appears to be similar to that in HIV seronegative women. Biopsy is required to confirm colposcopic impression.

Abnormal pap tests and human papillomavirus infections among HIV-infected and uninfected women who have sex with women.

OBJECTIVE: To estimate the frequency of abnormal Pap and human papillomavirus (HPV) positivity among human immunodeficiency virus (HIV)-seropositive and -seronegative women who have sex with women (WSW). METHODS: Pap and HPV DNA polymerase chain reaction tests were obtained every 6 months from women in a US cohort of HIV-seropositive and -seronegative women. Women who have sex with women were women reporting no male and at least 1 female sex partner for 5 years. They were frequency matched 1:5 to women reporting sex only with men (WSM) and assessed using multivariable generalized estimating equation logistic regression models. RESULTS: Paps at study entry were abnormal in 12 (21%) of 49 HIV-seropositive WSW, 151 (64%) of 245 HIV-seropositive WSM, 3 (9%) of 24 HIV-seronegative WSW, and 16 (11%) of 120 HIV-seronegative WSM. Human papillomavirus was found at entry in 18 (42%) HIV-seropositive WSW, 109 (52%) HIV-seropositive WSM, 6 (27%) HIV-seronegative WSW, and 13 (13%) HIV-seronegative WSM. After controlling for HIV serostatus and CD4 count, WSW had marginally lower odds than WSM of Pap abnormality (odds ratio = 0.59, 95% confidence interval = 0.33-1.03) and of HPV (odds ratio = 0.53, 95% confidence interval = 0.32-0.89). After controlling for partner's gender, HIV seropositivity and lower CD4 count were associated with any HPV, oncogenic HPV, any abnormal Pap result, and high-grade squamous intraepithelial lesion or worse (p < .0001 for all). CONCLUSIONS: Although risks for abnormal Pap and HPV are modestly lower in WSW than in WSM, both are common in HIV-seropositive women regardless of sexual preference. Both WSW and WSM should be screened similarly.

Contraceptive use among U.S. women with HIV.

OBJECTIVE: To describe trends in and correlates of use of contraception and sterilization among women with the human immunodeficiency virus (HIV). METHODS: This was a longitudinal cohort study of HIV-infected and uninfected women at risk for pregnancy, including structured questions on contraceptive use every 6 months. Proportions of women using contraception were calculated. Multivariate generalized estimating equation models were applied, and correlates of use were determined using logistic regression. Sterilization was assessed using a Kaplan-Meyer plot. RESULTS: Across 26,832 visits among 2784 women from 1994 to 2005, barrier methods were used at 30.5%-36.3% of visits, sterilization at 21.8%-26.5%, hormones at <10%, and no contraception at >30%. Dual use of barrier and hormones or barrier and spermicide was uncommon. In multivariable analysis, HIV serostatus was not correlated with barrier use (OR 1.10, 95% CI 0.96-1.26, p = 0.18 compared with no method), but hormonal contraception was less likely in women with HIV (OR 0.73, 95% CI 0.60-0.89, p = 0.002). Among HIV-seropositive women, barrier use was more likely among women who had been pregnant (OR 1.37, 95% CI 1.03- 1.83, p = 0.03) and among those with higher CD4 lymphocyte counts (OR 1.10, 95% CI 1.04- 1.16, p = 0.0006), whereas hormone use was linked to higher CD4 counts (OR 1.12, 95% CI 1.03-1.23, p = 0.01). HAART use was not associated with barrier or hormone use. HIV serostatus was linked to sterilization in Cox analysis (HR 1.32, 95% CI 0.89-1.94, p = 0.17). CONCLUSIONS. Underuse of highly effective contraception and barriers leaves women with HIV at risk for unintended pregnancy and disease transmission.

Effect of human immunodeficiency virus infection on the prevalence and incidence of vaginal intraepithelial neoplasia.

OBJECTIVE: To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia (VAIN) in human immunodeficiency virus (HIV)-seropositive women. METHODS: Pap tests were done semiannually for 335 HIV-seropositive and 75 HIV-seronegative women with prior hysterectomy in the prospective Women's Interagency HIV Study cohort. End points included abnormal Pap test results after hysterectomy and VAIN regardless of hysterectomy. RESULTS: Over a median of 5.6 years of follow-up, vaginal Pap test results were abnormal at 1,076 (29%; 95% confidence interval [CI] 25-33%) of 3,700 visits among HIV-seropositive compared with 31 (4%; 95% CI 2-8%) of 763 visits among HIV-seronegative women (P<.001). Abnormal Pap test results included 641 atypical squamous cells of undetermined significance, 425 low-grade squamous intraepithelial lesions, and 10 high-grade squamous intraepithelial lesions in HIV-seropositive women and 28 atypical squamous cells of undetermined significance and three low-grade squamous intraepithelial lesions in HIV-seronegative women. The incidence of abnormal Pap test results after hysterectomy was 14 per 100 person-years among HIV-seropositive and two per 100 person-years among HIV-seronegative women (P<.001) and remained stable across time. The 5-year clearance rate of abnormal Pap test results was 34 per 100 person-years for HIV-seropositive and 116 per 100 person-years for HIV-seronegative women (P<.001). In multivariate regression models, women with lower CD4 counts were more likely to have and less likely to clear abnormal cytology when it occurred. The incidence of VAIN 2 or worse was 0.2 and 0.01 per 100 person-years for HIV-seropositive and HIV-seronegative women (P=.001). Two HIV-seropositive women developed stage II cancers with remission after radiotherapy. CONCLUSION: Vaginal Pap test results are often abnormal in HIV-seropositive women. Although more common than in HIV-seronegative women, VAIN 2 or worse and especially vaginal cancers are infrequent.

Trends in contraceptive use among women with human immunodeficiency virus.

OBJECTIVE: To estimate trends in contraceptive use, especially long-acting reversible contraceptives (LARCs) and condoms, among human immunodeficiency virus (HIV)-seropositive and HIV-seronegative women. METHODS: Human immunodeficiency virus-seropositive and HIV-seronegative women in a multicenter longitudinal cohort were interviewed semiannually between 1998 and 2010 about sexual behaviors and contraceptive use. Trends in contraceptive use by women aged 18-45 years who were at risk for unintended pregnancy but not trying to conceive were analyzed using generalized estimating equations. RESULTS: Condoms were the dominant form of contraception for HIV-seropositive women and showed little change across time. Less than 15% of these women used no contraception. Between 1998 and 2010, LARC use increased among HIV-seronegative women from 4.8% (6 of 126) to 13.5% (19 of 141, P=.02), but not significantly among seropositive women (0.9% [4 of 438] to 2.8% [6 of 213], P=.09). Use of highly effective contraceptives, including pills, patches, rings, injectable progestin, implants, and intrauterine devices, ranged from 15.2% (53 of 348) in 1998 to 17.4% (37 of 213) in 2010 (P=.55). Human immunodeficiency virus-seronegative but not HIV-seropositive LARC users were less likely than nonusers to use condoms consistently (hazard ratio 0.51, 95% confidence interval [CI] 0.32-0.81, P=.004 for seronegative women; hazard ratio 1.09, 95% CI 0.96-1.23 for seropositive women). CONCLUSION: Although most HIV-seropositive women use contraception, they rely primarily on condoms and have not experienced the increase in LARC use seen among seronegative women. Strategies to improve simultaneous use of condoms and LARC are needed to minimize risk of unintended pregnancy as well as HIV transmission and acquisition of sexually transmitted infections. LEVEL OF EVIDENCE: II.