The Antiretroviral Pregnancy Registry: Three decades of prospective monitoring for birth defects.

PURPOSE: Antiretrovirals (ARVs) are life-saving drugs used for the treatment and prevention of HIV infection and antiviral drugs (AVs) for the treatment of chronic HBV infection. ARVs have proven highly effective in reducing perinatal HIV transmission, however the risk of birth defects from prenatal exposure to ARVs/AVs is an ongoing concern. The Antiretroviral Pregnancy Registry (APR), an international, prospective exposure-registration cohort study, monitors ARV and AV use in pregnancy for early signals of teratogenicity. This communication reports results of 30-years' experience of ARV/AV exposure during pregnancy and lessons learned through continuous quality improvement. METHODS AND RESULTS: Birth defect prevalence is estimated and compared to internal and external groups. Statistical inference is based on exact methods for binomial proportions. Between 2006 and 2023, cumulative enrollment more than tripled from 6893 to 25 960 pregnancies and ARVs/AVs monitored increased from 29 to 222. Through January 2023, there were 21 636 live births and 631 outcomes with birth defects, for overall prevalence of 2.9/100 live births (95% CI 2.7, 3.2). The birth defect prevalence was 3.0% (95% CI 2.7%, 3.3%) among first trimester exposures and 2.8% (95% CI 2.5%, 3.2%) among second/third trimester exposures (prevalence ratio 1.04 [95% CI 0.89, 1.21]). CONCLUSIONS: Birth defect prevalence is not statistically significantly different between first trimester ARV/AV pregnancy exposures compared to second/third trimester exposures and is also not different from two population-based surveillance systems: 2.72/100 live births reported in the Metropolitan Atlanta Congenital Defects Program (MACDP); and 4.17/100 live births from the Texas Birth Defects Registry (TBDR).

New HIV infections from blood transfusions averted in 28 countries supported by PEPFAR blood safety programs, 2004-2015.

BACKGROUND: To quantify the impact of the US President's Emergency Plan for AIDS Relief (PEPFAR) on the risk of HIV transmission through infected blood donations in countries supported by PEPFAR blood safety programs. METHODS: Data reported to the World Health Organization Global Database on Blood Safety were analyzed from 28 countries in sub-Saharan Africa (SSA), Asia, and the Caribbean during 2004-2015. We used the Goals model of Spectrum Spectrum System Software, version 5.53, to perform the modeling, assuming laboratory quality for HIV testing had 91.9% sensitivity and 97.7% specificity irrespective of testing method based on results of two external quality assurance and proficiency testing studies of transfusion screening for HIV in SSA blood centers. We calculated the number of new HIV infections from the number of transfusions and the prevalence of HIV infection acquired from blood transfusions with infected blood donations. We determined the impact of laboratory testing programs by estimating the number of new HIV infections averted since PEPFAR implementation. RESULTS: Assuming that HIV testing would not be performed in any of these countries without PEPFAR funding, the number of new HIV infections acquired from blood transfusions averted by laboratory testing increased over time in all 28 countries. The total number of HIV infections averted was estimated at 229 278 out of 20 428 373 blood transfusions during 2004-2015. CONCLUSION: Our mathematical modeling suggests a positive impact achieved over 12 years of PEPFAR support for blood safety. Standardized HIV testing of donated blood has reduced the risk of HIV transmission through blood transfusions in SSA, Asia, and the Caribbean.

Reducing cervical cancer deaths in women living with HIV: PEPFAR and the Go Further partnership.

Women with HIV bear a significant burden of Human Papillomavirus (HPV) related cervical disease, and a have a higher risk of dying from cervical cancer should it occur. WLH have increased acquisition of HPV and decreased clearance, leading to persistent HPV infection: a risk for cervical cancer. The greatest burden of HIV in women occurs in sub-Saharan Africa where diagnostic and treatment services for cervical disease are limited. This paper will describe the epidemiology of HPV related cervical disease in women living with HIV (WLH) and the efforts to treat precursor lesions in HIV treatment programs supported by the President's Emergency Plan for AIDS Relief (PEPFAR.

Urethrocutaneous fistulas after voluntary medical male circumcision for HIV prevention-15 African Countries, 2015-2019.

BACKGROUND: Voluntary medical male circumcision (VMMC) is an HIV prevention strategy recommended to partially protect men from heterosexually acquired HIV. From 2015 to 2019, the President's Emergency Plan for AIDS Relief (PEPFAR) has supported approximately 14.9 million VMMCs in 15 African countries. Urethrocutaneous fistulas, abnormal openings between the urethra and penile skin through which urine can escape, are rare, severe adverse events (AEs) that can occur with VMMC. This analysis describes fistula cases, identifies possible risks and mechanisms of injury, and offers mitigation actions. METHODS: Demographic and clinical program data were reviewed from all reported fistula cases during 2015 to 2019, descriptive analyses were performed, and an odds ratio was calculated by patient age group. RESULTS: In total, 41 fistula cases were reported. Median patient age for fistula cases was 11 years and 40/41 (98%) occurred in patients aged < 15 years. Fistulas were more often reported among patients < 15 compared to ≥ 15 years old (0.61 vs. 0.01 fistulas per 100,000 VMMCs, odds ratio 50.9 (95% confidence interval [CI] = 8.6-2060.0)). Median time from VMMC surgery to appearance of fistula was 20 days (interquartile range (IQR) 14-27). CONCLUSIONS: Urethral fistulas were significantly more common in patients under age 15 years. Thinner tissue overlying the urethra in immature genitalia may predispose boys to injury. The delay between procedure and symptom onset of 2-3 weeks indicates partial thickness injury or suture violation of the urethral wall as more likely mechanisms of injury than intra-operative urethral transection. This analysis helped to inform PEPFAR's recent decision to change VMMC eligibility policy in 2020, raising the minimum age to 15 years.

Case series of glans injuries during voluntary medical male circumcision for HIV prevention - eastern and southern Africa, 2015-2018.

BACKGROUND: Male circumcision confers partial protection against heterosexual HIV acquisition among men. The President's Emergency Plan for AIDS Relief (PEPFAR) has supported > 18,900,000 voluntary medical male circumcisions (VMMC). Glans injuries (GIs) are rare but devastating adverse events (AEs) that can occur during circumcision. To address this issue, PEPFAR has supported multiple interventions in the areas of surveillance, policy, education, training, supply chain, and AE management. METHODS: Since 2015, PEPFAR has conducted surveillance of GIs including rapid investigation by the in-country PEPFAR team. This information is collected on standardized forms, which were reviewed for this analysis. RESULTS: Thirty-six GIs were reported from 2015 to 2018; all patients were < 15 years old (~ 0·7 per 100,000 VMMCs in this age group) with a decreasing annual rate (2015: 0.7 per 100,000 VMMCs; 2018: 0.4 per 100,000 VMMC; p = 0.02). Most (64%) GIs were partial or complete amputations. All amputations among 10-14 year-olds occurred using the forceps-guided (FG) method, as opposed to the dorsal-slit (DS) method, and three GIs among infants occurred using a Mogen clamp. Of 19 attempted amputation repairs, reattached tissue was viable in four (21%) in the short term. In some cases, inadequate DS method training and being overworked, were found. CONCLUSION: Following numerous interventions by PEPFAR and other stakeholders, GIs are decreasing; however, they have not been eliminated and remain a challenge for the VMMC program. Preventing further cases of complete and partial amputation will likely require additional interventions that prevent use of the FG method in young patients and the Mogen clamp in infants. Improving management of GIs is critical to optimizing outcomes.

Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother-Infant Pairs Enrolled in a Large Perinatal Study.

Background: The presence of antiretroviral drug-associated resistance mutations (DRMs) may be particularly problematic in human immunodeficiency virus (HIV)-infected pregnant women as it can lead to mother-to-child transmission (MTCT) of resistant HIV strains. This study evaluated the prevalence and the effect of antiretroviral DRMs in previously untreated mother-infant pairs. Methods: A case-control design of 1:4 (1 transmitter to 4 nontransmitters) was utilized to evaluate DRMs as a predictor of HIV MTCT in specimens obtained from mother-infant pairs. ViroSeq HIV-1 genotyping was performed on mother-infant specimens to assess for clinically relevant DRMs. Results: One hundred forty infants acquired HIV infection; of these, 123 mother-infant pairs (88%) had specimens successfully amplified using ViroSeq and assessed for drug resistance genotyping. Additionally, 483 of 560 (86%) women who did not transmit HIV to infants also had samples evaluated for DRMs. Sixty-three of 606 (10%) women had clinically relevant DRMs; 12 (2%) had DRMs against >1 drug class. Among 123 HIV-infected infants, 13 (11%) had clinically relevant DRMs, with 3 (2%) harboring DRMs against >1 drug class. In univariate and multivariate analyses, DRMs in mothers were not associated with increased HIV MTCT (adjusted odds ratio, 0.8 [95% confidence interval, .4-1.5]). Presence of DRMs in transmitting mothers was strongly associated with DRM presence in their infants (P < .001). Conclusions: Preexisting DRMs were common in untreated HIV-infected pregnant women, but did not increase the risk of HIV MTCT. However, if women with DRMs are not virologically suppressed, they may transmit resistant mutations, thus complicating infant management.

Trends and Gaps in National Blood Transfusion Services - 14 Sub-Saharan African Countries, 2014-2016.

Ensuring availability of safe blood products through recruitment of voluntary, nonremunerated, blood donors (VNRDs) and prevention of transfusion-transmissible infections (TTIs), including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis, is important for public health (1,2). During 2004-2016, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) provided approximately $468 million in financial support and technical assistance* to 14 sub-Saharan African countries† with high HIV prevalence to strengthen national blood transfusion services (NBTSs)§ and improve blood safety and availability. CDC analyzed these countries' 2014-2016 blood safety surveillance data to update previous reports (1,2) and summarize achievements and programmatic gaps as some NBTSs begin to transition funding and technical support from PEPFAR to local ministries of health (MOHs) (2,3). Despite a 60% increase in blood supply since 2004 and steady declines in HIV prevalence (to <1% among blood donors in seven of the 14 countries), HIV prevalence among blood donors still remains higher than that recommended by the World Health Organization (WHO) (4). PEPFAR support has contributed to significant reductions in HIV prevalence among blood donors in the majority of PEPFAR-supported countries, and linking donors who screen HIV-positive to confirmatory testing and indicated treatment, as well as further reducing TTIs, remains a public health priority (5).

Acceptability of and Adherence to an Antiretroviral-Based Vaginal Microbicide among Pregnant Women in the United States.

The MTN-008 trial was the first multi-dose study conducted to evaluate the safety of a microbicide gel (2:1 randomized to tenofovir 1% or hydroxycellulose (HEC) placebo gel) during pregnancy. The study aim was to evaluate safety, tolerability and pharmacokinetics of the study products. Procedures included daily gel administration, with Day 0 and Day 6 in clinic, and Days 1-5 at home. Because pregnancy may pose unique challenges to consistent gel use and acceptability, evaluation of adherence and acceptability was a secondary objective of the trial. The study enrolled healthy, HIV-negative, pregnant women aged 18-40 in Pittsburgh, PA and Birmingham, AL, USA in 2 consecutive groups: cohort 1 was 37-39 weeks gestation, cohort 2 was 34-36 weeks. Ninety-one women completed the study (45 and 46 in each cohort, respectively) and were evaluable per protocol. Adherence was evaluated using self-reports: participants completed a web-based computer-assisted self-interview (CASI) at Days 0 and 6 about gel attitudes and behaviors. At Day 6 trained research staff conducted a short interviewer-administered questionnaire with both structured and open-ended questions. Frequencies of quantitative data were tabulated in SAS and descriptive statistics are presented; open-ended textual data were summarized by a behavioral scientist experienced in qualitative analysis. Participants reported generally neutral perceptions of gel characteristics. A small number of women (7-8%) reported pain (6/90), other physical discomfort (7/90), or mental discomfort (7/90) associated with the process of applicator insertion. About 5% reported the same for the gel itself. Two-thirds (61/90) thought the gel was runny, many complained of bothersome gel leakage and several cited this reason for not inserting a full dose. The majority were not worried the gel would cause problems for their pregnancy or babies. Ninety-seven percent (83/86) said they would use the gel in the future if they were pregnant, and 90% (81/90) when nonpregnant. Self-reported adherence was high with 88% (79/90) reporting daily gel use on both the computerized and interviewer-administered questionnaires. The majority (67/90) reported no difficulty with daily use. However, drug was undetectable (<0.31 ng/mL) among 45% (27/60; 95% CI 32-58%) of the women on active product prior to observed dosing at Day 6. The most common reason for reported nonuse (N = 6) was forgetting. Study gel was generally acceptable, but many complained of a runny consistency (61/90) and leakage (83/90). No frequent or strong concerns about the effects of the study gel on the pregnancy/fetus were reported. Self-reported adherence to study gel self-administered at home for 5 days was high, however plasma drug levels suggest actual use may have been considerably lower. Findings from this study can provide insights relevant to use of other antiretroviral-based, vaginally-inserted HIV prevention methods during pregnancy.

Cytomegalovirus Urinary Shedding in HIV-infected Pregnant Women and Congenital Cytomegalovirus Infection.

BACKGROUND: Cytomegalovirus (CMV) urinary shedding in pregnant women infected with human immunodeficiency virus (HIV) was evaluated to determine whether it poses an increased risk for congenital CMV infection (cCMV). METHODS: A subset of mother-infant pairs enrolled in the perinatal NICHD HPTN 040 study (distinguished by no antiretroviral use before labor) was evaluated. Maternal and infant urines were tested by qualitative real-time polymerase chain reaction (RT-PCR) for CMV DNA with quantitative RT-PCR performed on positive specimens. RESULTS: Urine specimens were available for 260 women with 85.4% from the Americas and 14.6% from South Africa. Twenty-four women (9.2%) had detectable CMV viruria by qualitative PCR. Maternal CMV viruria was not associated with mean CD4 cell counts or HIV viral load but was associated with younger maternal age (P = .02). Overall, 10 of 260 infants (3.8%) had cCMV. Women with detectable peripartum CMV viruria were more likely to have infants with cCMV than those without: 20.8% (5/24) versus 2.1% (5/236), (P = .0001). Women with CMV viruria had significantly higher rates of HIV perinatal transmission (29.2% vs. 8.1%, P = .002). They were 5 times (adjusted odds ratio [aOR] = 5.6, 95% confidence interval [CI] 1.9-16.8) and nearly 30 times (aOR, 29.7; 95% CI, 5.4-164.2) more likely to transmit HIV and CMV to their infants, respectively. Maternal gonorrhea (aOR, 19.5; 95% CI, 2.5-151.3) and higher maternal HIV log10 viral load (OR, 2.8; 95% CI, 1.3-6.3) were also significant risk factors for cCMV. CONCLUSION: In this cohort of HIV-infected pregnant women not on antiretrovirals, urinary CMV shedding was a significant risk factor for CMV and HIV transmission to infants. CLINICAL TRIALS REGISTRATION NUMBER: NCT00099359.

Pregnant and breastfeeding women: A priority population for HIV viral load monitoring.

Landon Myer and colleagues discuss viral load monitoring for pregnant HIV-positive women and those breastfeeding; ART treatments can suppress viral load and are key to preventing transmission to the child.

Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel.

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.

Detectable Tenofovir Levels in Breast-Feeding Infants of Mothers Exposed to Topical Tenofovir.

Lactation studies are necessary evaluations of medications for reproductive-age women. We evaluated pharmacokinetics (PK), pharmacodynamics, safety, and adherence profiles associated with 7 days of 1% tenofovir (TFV) vaginal gel use during lactation. Tenofovir levels (maternal/infant serum, milk) and anti-HIV activity (milk), adverse events (AEs), and adherence were measured for 17 HIV-1-seronegative breast-feeding mother-infant pairs. Tenofovir use was well-tolerated and detected at low levels in maternal serum, milk, and infant serum but demonstrated no anti-HIV activity in milk.

CCR5 Expression Levels in HIV-Uninfected Women Receiving Hormonal Contraception.

Human immunodeficiency virus (HIV) infectivity increases as receptor/coreceptor expression levels increase. We determined peripheral CD4, CCR5, and CXCR4 expression levels in HIV-uninfected women who used depot medroxyprogesterone acetate (DMPA; n = 32), the levonorgestrel-releasing intrauterine device (LNG-IUD; n = 27), oral contraceptive pills (n = 32), or no hormonal contraception (n = 33). The use of LNG-IUD increased the proportion of CD4(+) and CD8(+) T cells that expressed CCR5; increases in the magnitude of T-cell subset CCR5 expression were observed with DMPA and LNG-IUD use (P < .01 for all comparisons). LNG-IUD and, to a lesser extent, DMPA use were associated with increased peripheral T-cell CCR5 expression.

Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug-drug interactions between depot medroxyprogesterone acetate (DMPA) and twice-daily lopinavir (LPV) plus low-dose ritonavir (RTV) (LPV/r) among 24 HIV-infected women and compared the results to those for HIV-infected women receiving DMPA while on no antiretroviral therapy or on nucleosides only (n = 14 subjects from the control arm of AIDS Clinical Trials Group [ACTG] study 5093). The objectives of the study were to address the effect of LPV/r on DMPA and to address the effect of DMPA on LPV/r therapy. PK parameters were estimated using noncompartmental analysis with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of LPV and RTV PKs before and 4 weeks after DMPA dosing. Plasma progesterone concentrations were measured every 2 weeks after DMPA dosing through week 12. Although the MPA area under the concentration-time curve and maximum concentration of drug in plasma were statistically significantly increased in the study women on LPV/r compared to those in the historical controls, these increases were not considered clinically significant. There were no changes in LPV or RTV exposure after DMPA. DMPA was well tolerated, and suppression of ovulation was maintained. (This study has been registered at ClinicalTrials.gov under registration no. NCT01296152.).

Three postpartum antiretroviral regimens to prevent intrapartum HIV infection.

BACKGROUND: The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants. METHODS: Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth. RESULTS: A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan-Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups). CONCLUSIONS: In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.).

Chlamydia and Gonorrhea in HIV-Infected Pregnant Women and Infant HIV Transmission.

BACKGROUND: Sexually transmitted infections (STIs) such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) can lead to adverse pregnancy and neonatal outcomes. The prevalence of STIs and its association with HIV mother-to-child transmission (MTCT) were evaluated in a substudy analysis from a randomized, multicenter clinical trial. METHODOLOGY: Urine samples from HIV-infected pregnant women collected at the time of labor and delivery were tested using polymerase chain reaction testing for the detection of CT and NG (Xpert CT/NG; Cepheid, Sunnyvale, CA). Infant HIV infection was determined by HIV DNA polymerase chain reaction at 3 months. RESULTS: Of the 1373 urine specimens, 249 (18.1%) were positive for CT and 63 (4.6%) for NG; 35 (2.5%) had both CT and NG detected. Among 117 cases of HIV MTCT (8.5% transmission), the lowest transmission rate occurred among infants born to CT- and NG-uninfected mothers (8.1%) as compared with those infected with only CT (10.7%) and both CT and NG (14.3%; P = 0.04). Infants born to CT-infected mothers had almost a 1.5-fold increased risk for HIV acquisition (odds ratio, 1.47; 95% confidence interval, 0.9-2.3; P = 0.09). CONCLUSIONS: This cohort of HIV-infected pregnant women is at high risk for infection with CT and NG. Analysis suggests that STIs may predispose to an increased HIV MTCT risk in this high-risk cohort of HIV-infected women.

Repeat pregnancy in women with HIV infection in Latin America and the Caribbean.

Intended and unintended pregnancies occur frequently among human immunodeficiency virus (HIV)-infected women. We evaluated the occurrence of repeat pregnancy and characteristics associated with this outcome among HIV-infected women in Latin America and the Caribbean who were participating in the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI). Of the 1342 HIV-infected pregnant women enrolled in NISDI, 124 (9.2%) had one or more repeat pregnancies on study. Median time between the index delivery and date of conception of the subsequent pregnancy was 1.4 years (range 0.1-5.7). Younger age (odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.04-1.11 per one year decrease in age), hospitalization during the index pregnancy or up to six months post-partum [OR = 2.0, 95% CI: 1.2-3.4], and poor index pregnancy outcome (stillbirth or spontaneous/therapeutic abortion; OR = 3.4, 95% CI: 1.4-8.4) were associated with increased occurrence of repeat pregnancy in multivariable analysis. Among women with repeat pregnancies, the proportion receiving antiretroviral treatment (vs. prophylaxis) increased from 39.4% at the time of the index pregnancy to 81.8% at the time of the repeat pregnancy (p < 0.001). These results can help identify women most likely to benefit from reproductive counseling in order to assist with healthy pregnancy planning and prevention of unintended pregnancies.

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.

Safety of pediatric HIV elimination: the growing population of HIV- and antiretroviral-exposed but uninfected infants.

Lynne Mofenson and Heather Watts discuss the context and implications of the study by J. Sibuide and colleagues, which provides a detailed analysis of birth defects in infants with in utero antiretroviral drug exposure in the French Perinatal Cohort. Please see later in the article for the Editors' Summary.

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.