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1.  HIV Disease Progression in the First Year after Delivery among African Women followed in the HPTN 046 Clinical Trial 
Background
Starting lifelong antiretroviral therapy (ART) in HIV-infected pregnant women may decrease HIV progression and transmission but adherence after delivery may be difficult, especially for asymptomatic women. We evaluated disease progression among HIV-infected women not on ART with CD4+ lymphocyte counts above 200 cells/uL at delivery.
Methods
We analysed risk of death, progression to AIDS (stage IV or CD4 < 200 cells/uL), or to CD4+ count < 350 one year after delivery among postpartum women enrolled to a prevention of breastfeeding transmission trial using Kaplan-Meier methods. In the primary analysis, women were censored if ART was initiated.
Results
Among 1285 women who were < WHO stage IV at 6 weeks postpartum, 49 (4.3%) progressed to stage IV/CD4 < 200 cells/uL or death by one year. Progression to CD4 < 200 or death occurred among 16 (4.3%) of 441 women with CD4 count of 350–549 and 10 (1.6%) of 713 with CD4 counts > 550 at delivery. CD4 < 350 by 12 months postpartum occurred among 116 (37.0%) of 350 women with CD4 count 400–549 and 48 (7.4%) of 713 > 550 at delivery.
Conclusions
Progression to AIDS or CD4 count < 350 is uncommon through one year postpartum for women with CD4 counts over 550 at delivery, but occurred in over one third of those with CD4 counts under 550. ART should be continued after delivery or breastfeeding among women with CD4 counts < 550 if follow up and ARV adherence can be maintained.
doi:10.1097/QAI.0b013e3182a2123a
PMCID: PMC3800257  PMID: 23846568
HIV; postpartum; disease progression
2.  Combination Antiretroviral Use and Preterm Birth 
The Journal of Infectious Diseases  2012;207(4):612-621.
Background. Use of antiretroviral drugs (ARVs) during pregnancy has been associated with higher risk of preterm birth.
Methods. The Pediatric HIV/AIDS Cohort Study network's Surveillance Monitoring for ART Toxicities study is a US-based cohort of human immunodeficiency virus (HIV)–exposed uninfected children. We evaluated maternal ARV use during pregnancy and the risk of any type of preterm birth (ie, birth before 37 completed weeks of gestation), the risk of spontaneous preterm birth (ie, preterm birth that occurred after preterm labor or membrane rupture, without other complications), and the risk of small for gestational age (SGA; ie, a birth weight of <10th percentile for gestational age). Multivariable logistic regression models were used to evaluate the association of ARVs and timing of exposure, while adjusting for maternal characteristics.
Results. Among 1869 singleton births, 18.6% were preterm, 10.2% were spontaneous preterm, and 7.3% were SGA. A total of 89% used 3-drug combination ARV regimens during pregnancy. In adjusted models, the odds of preterm birth and spontaneous preterm birth were significantly greater among mothers who used protease inhibitors during the first trimester (adjusted odds ratios, 1.55 and 1.59, respectively) but not among mothers who used nonnucleoside reverse-transcriptase inhibitor or triple-nucleoside regimens during the first trimester. Combination ARV exposure starting later in pregnancy was not associated with increased risk. No associations were observed between SGA and exposure to combination ARV regimens.
Conclusions. Protease inhibitor use early in pregnancy may be associated with increased risk for prematurity.
doi:10.1093/infdis/jis728
PMCID: PMC3549601  PMID: 23204173
preterm birth; antiretrovirals; pregnancy; small for gestational age
3.  Antiretrovirals in Pregnancy: A Note of Caution 
The Journal of Infectious Diseases  2012;206(11):1639-1641.
doi:10.1093/infdis/jis581
PMCID: PMC3499111  PMID: 23066163
4.  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 HIV seropositive and seronegative women who have sex with women (WSW).
Methods
Pap and HPV DNA PCR tests were obtained every six months from women in a U.S. cohort of HIV seropositive and seronegative women. WSW were women reporting no male and at least one female sex partner over five years. WSW 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 seronegative WSM. HPV 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 (O.R. 0.59, 95% C.I. 0.33, 1.03) and of HPV (O.R. 0.53, 95% C.I. 0.32, 0.89). After controlling for partner gender, HIV seropositivity and lower CD4 count were associated with any HPV, oncogenic HPV, any abnormal Pap result, and HSIL or worse (P < 0.0001 for all).
Conclusion
While risks for abnormal Pap and HPV are modestly lower in WSW than WSM, both are common in HIV seropositive women regardless of sexual preference. WSW and WSM should be screened similarly.
doi:10.1097/LGT.0b013e3182942733
PMCID: PMC3905442  PMID: 23959300
Human papillomavirus; HIV in women; women who have sex with women
5.  Infant Growth Outcomes After Maternal Tenofovir Disoproxil Fumarate Use During Pregnancy 
Journal of acquired immune deficiency syndromes (1999)  2013;64(4):10.1097/QAI.0b013e3182a7adb2.
OBJECTIVE
To determine whether maternal use of tenofovir disoproxil fumarate (TDF) for treatment of HIV in pregnancy predicts fetal and infant growth.
METHODS
The study population included HIV-uninfected liveborn singleton infants of mothers enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 (born 2002-2011) in the United States and exposed in utero to a combined (triple or more) antiretroviral (ARV) regimen. Infant weight at birth and 6 months was compared between infants exposed and unexposed to tenofovir in utero using two-sample T- and Chi-square tests and multivariable linear and logistic regression models including demographic and maternal characteristics.
RESULTS
Among 2025 infants with measured birth weight, there was no difference between those exposed (N=630, 31%) versus unexposed to tenofovir in mean birth weight (2.75 vs. 2.77 kg, p=0.64), or mean gestational age- and sex-adjusted birth weight z-score (WASZ) (0.14 vs. 0.14, p=0.90). Among 1496 infants followed for 6 months, there was no difference in mean weight at 6 months between tenofovir-exposed (N=457, 31%) and tenofovir-unexposed infants (7.64 vs. 7.59 kg, p= 0.52), or in mean WASZ (0.29 vs. 0.26, p= 0.61). Tenofovir exposure during the 2nd/3rd trimester, relative to no exposure, significantly predicted under-weight (WASZ < 5%) at age 6 months (OR [95% CI]: 2.06 [1.01, 3.95], p=0.04). Duration of tenofovir exposure did not predict neonatal or infant growth.
CONCLUSIONS
By most measures, in utero exposure to tenofovir did not significantly predict infant birth weight or growth through 6 months of age.
doi:10.1097/QAI.0b013e3182a7adb2
PMCID: PMC3818710  PMID: 24169122
tenofovir; mother-to-child transmission; infant growth; TDF; HIV; pregnancy
6.  Plasma and Mucosal HIV Viral Loads Are Associated with Genital Tract Inflammation In HIV-Infected Women 
Background
Systemic and mucosal inflammation may play a role in HIV control. A cross-sectional comparison was conducted among women in the Women’s Interagency HIV Study (WIHS) to explore the hypothesis that compared to HIV-uninfected participants, women with HIV and in particular, those with high plasma viral load (PVL) have increased levels of mucosal and systemic inflammatory mediators and impaired mucosal endogenous antimicrobial activity.
Methods
19 HIV-uninfected, 40 HIV-infected on antiretroviral therapy (ART) with PVL ≤ 2600 copies/ml (low viral load) (HIV+-LVL), and 19 HIV-infected on or off ART with PVL >10,000 (high viral load) (HIV+-HVL) were evaluated. Immune mediators and viral RNA were quantified in plasma and cervicovaginal lavage (CVL). CVL antimicrobial activity was also determined.
Results
Compared to HIV-uninfected, HIV+-HVL women had higher levels of mucosal, but not systemic pro-inflammatory cytokines and chemokines, higher Nugent scores, and lower E. coli bactericidal activity. In contrast, there were no significant differences between HIV+-LVL and HIV-uninfected controls. After adjusting for PVL, HIV genital tract shedding was significantly associated with higher CVL concentrations of IL-6, IL-1β, MIP-1α, and RANTES and higher plasma concentrations of MIP-1α. High PVL was associated with higher CVL levels of IL-1β and RANTES, as well as with higher Nugent scores, lower E. coli bactericidal activity, smoking and lower CD4 counts; smoking and CD4 count retained statistical significance in a multivariate model.
Conclusion
Further study is needed to determine if the relationship between mucosal inflammation and PVL is causal and to determine if reducing mucosal inflammation is beneficial.
doi:10.1097/QAI.0b013e3182961cfc
PMCID: PMC3706034  PMID: 23591635
HIV; HSV; mucosal immunity; inflammation; female genital tract; WIHS
7.  Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication 
Journal of perinatal medicine  2010;39(2):163-170.
Objective
To determine rate of and risk factors for birth defects in infants born to HIV-infected women receiving nucleoside and protease inhibitor antiretroviral (ARV) therapy.
Methods
Birth defects were evaluated among infants on the Pediatric AIDS Clinical Trials Group 316 trial that studied addition of peripartum nevirapine to established ARV regimen for prevention of mother-to-child transmission. Maternal therapy was categorized by trimester of earliest exposure. Birth defects were coded using conventions of the Antiretroviral Pregnancy Registry.
Results
Birth defects were detected in 60/1414 (4.2%; 95% CI 3.3–5.4%) infants including 30/636 (4.7%; 95% CI 3.2–6.7%) with first trimester ARV exposure and 30/778 (3.9%; 95% CI 2.6–5.5%) with exposure only after the first trimester (P=0.51). Rates of classes of defects were similar between first trimester compared to later exposure groups except heart defects which occurred in 16 (2.5%; 95% CI 1.4–4.1%) with first trimester ARV exposure and in six (0.8%; 95% CI 0.3–1.7%) infants with later exposure (P=0.02). Exposure to ARV was not associated with specific types of heart defects. Two cases of cardiomyopathy were noted.
Conclusion
ARV use in early pregnancy was not associated with an increased risk of birth defects overall. The possible association of ARV exposure with heart defects requires further surveillance.
doi:10.1515/JPM.2010.139
PMCID: PMC3068472  PMID: 21142844
Antiretrovirals; birth defects; HIV
8.  Safety and Immunogenicity of 2009 pH1N1 Vaccination in HIV-Infected Pregnant Women 
Two 30-μg doses of unadjuvanted pH1N1 vaccine were moderately immunogenic in human immunodeficiency virus–infected pregnant women, and no serious vaccine-related adverse events were observed. Seroprotection persisted in most women postpartum. Efficient transplacental antibody transfer occurred, but seroprotection in infants waned rapidly.
Background. Pregnant women infected with human immunodeficiency virus (HIV) may have particular vulnerability to 2009 pandemic H1N1 influenza (pH1N1) infection. The safety and immunogenicity of pH1N1 vaccination in HIV-infected pregnant women are unknown.
Methods. HIV-infected women 18–39 years of age and 14–34 weeks’ gestation on antiretroviral therapy received two 30-μg doses of unadjuvanted, inactivated pH1N1 vaccine 21 days apart. Hemagglutination inhibition titers were measured at entry, 21 days after dose 1, and 10 and 21 days after dose 2, and, in mothers and infants, at delivery and 3 and 6 months postdelivery.
Results. No severe vaccine-related adverse events were observed among 127 subjects. At entry, 21% had seroprotective (≥1:40) titers. Seroprotection and seroresponse (≥4-fold rise) occurred in 73% and 66% after dose 1 and 80% and 72% after dose 2, respectively. Of women lacking seroprotection at entry, 66% attained seroprotection after dose 1 and 75% after dose 2. Seroprotective titers were present in 67% of mothers and 65% of infants at delivery (median 66 days after dose 2), 60% of mothers and 26% of infants at 3 months postdelivery, and 59% of mothers and 12% of infants at 6 months postdelivery.
Conclusions. Two 30-μg doses were moderately immunogenic in HIV-infected pregnant women. No concerning vaccine-related safety signals were observed. Seroprotection persisted in most women postpartum. Efficient transplacental antibody transfer occurred, but seroprotection in infants waned rapidly. Vaccination to protect HIV-infected pregnant women and their newborns from new influenza strains is feasible, but more immunogenic platforms should be evaluated.
Clinical Trials Registration. NCT00992017.
doi:10.1093/cid/cit057
PMCID: PMC3634309  PMID: 23378284
pH1N1; vaccine; HIV-infected; pregnancy; immunogenicity
9.  Pharmacokinetics of an Increased Atazanavir Dose with and without Tenofovir During the Third Trimester of Pregnancy 
Background
Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy.
Methods
IMPAACT 1026s is a prospective, non-blinded pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including two cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the 2nd trimester (2nd trim), 400/100 mg during the 3rd trimester (3rd trim) and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by HPLC. Pharmacokinetic targets were the 10th percentile atazanavir AUC (29.4 mcg*hr/mL) in non-pregnant adults on standard dose and 0.15 mcg/mL, minimum trough concentration.
Results
Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; Median (range) pharmacokinetic parameters are presented for 2nd, 3rd trim and PP and number who met target/total. * indicates p<0.05 compared to PP.
Atazanavir without tenofovir
AUC 30.5 (9.19–93.8), 45.7 (11–88.3), and 48.8 (9.9–112.2) mcg-hr/mL, and 8/14, 29/37 and 27/34 met target. C24h was 0.49 (0.09–4.09), 0.71 (0.14–2.09), and 0.90 (0.05–2.73) mcg/mL; 13/14, 36/37 and 29/34 met target.
Atazanavir with tenofovir
AUC 26.2 (6.8–60.9)*, 37.7 (0.72–88.2)*, and 58.6 (6–149) mcg-hr/mL, and 7/17, 23/32 and 27/29 met target. C24h was 0.44 (0.12–1.06)*, 0.57 (0.02–2.06)*, and 1.26 (0.09–5.43) mcg/mL; 7/17, 23/32 and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events.
Conclusions
Atazanavir/ritonavir increased to 400/100mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.
doi:10.1097/QAI.0b013e318289b4d2
PMCID: PMC3625451  PMID: 23392467
atazanavir; tenofovir; pharmacokinetics; pregnancy; HIV; mother to child transmission
10.  Safety of Pediatric HIV Elimination: The Growing Population of HIV- and Antiretroviral-Exposed but Uninfected Infants 
PLoS Medicine  2014;11(4):e1001636.
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
doi:10.1371/journal.pmed.1001636
PMCID: PMC4004531  PMID: 24781352
11.  Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093 
Contraception  2007;77(2):84-90.
Background
Concomitant use of antiretrovirals (ARV) and hormonal contraceptives may change the metabolism of each and the resulting safety profiles. We evaluated the safety and tolerability of depot medroxyprogesterone acetate (DMPA) among women on ARV.
Study Design
HIV-infected women on selected ARV regimens or no ARV were administered DMPA 150 mg intramuscularly and evaluated for 12 weeks for adverse events, changes in CD4+ count and HIV RNA levels, and ovulation.
Results
Seventy evaluable subjects were included, 16 on nucleoside only or no ARV, 21 on nelfinavir-containing regimens, 17 on efavirenz-containing regimens, and 16 on nevirapine-containing regimens. Nine grade 3 or 4 adverse events occurred in 7 subjects; none were judged related to DMPA. The most common findings possibly related to DMPA were abnormal vaginal bleeding (9, 12.7%), headache (3, 4.2%), abdominal pain, mood changes, insomnia, anorexia, and fatigue, each occurring in 2 (2.9%) subjects. No significant changes in CD4+ count or HIV RNA levels occurred with DMPA. No evidence of ovulation was detected, and no pregnancies occurred.
Conclusions
The clinical profile associated with DMPA administration in HIV-infected women, most on ARV, appears similar to that seen in HIV-uninfected women. DMPA prevented ovulation and did not affect CD4+ counts or HIV RNA levels. In concert with previously published DMPA/ARV interaction data, these data suggest that DMPA can be used safely by HIV-infected women on the ARV studied.
doi:10.1016/j.contraception.2007.10.002
PMCID: PMC2424313  PMID: 18226670
HIV; women; depotmedroxyprogesterone; antiretrovirals; contraception 1
12.  Prevalence of HIV among women entering labor who accepted or declined voluntary counseling and testing 
Objective
To assess whether there was a difference in HIV seroprevalence between eligible women who declined and those who agreed to participate in a study of voluntary counseling and testing among women entering labor with unknown HIV status in South Africa.
Methods
Anonymous cord blood specimens were collected—as dried blood spots—from all women approached for participation in a cluster-randomized trial. No patient identifiers were included on the cord blood specimens. The dried blood spots were analyzed for HIV antibody via enzyme immunoassay and western blotting.
Results
Of 7238 women screened for study participation, 1041 (14.4%) had undocumented HIV status; of these women, 542 were eligible for inclusion and 343 enrolled. Based on 513 evaluable samples, the overall seroprevalence was 13.3% (95% confidence interval [CI], 10.4–16.5), which was similar to the 13.1% (95% CI, 9.7–17.2) seroprevalence among the 343 enrolled women.
Conclusion
Seroprevalence among eligible women was similar to that among enrolled women, which indicates that study participation did not select for a group with an HIV seroprevalence substantially different from that among women who declined to enroll.
doi:10.1016/j.ijgo.2012.07.029
PMCID: PMC3553312  PMID: 23141415
Anonymous testing; HIV prevalence; Study participation; Voluntary counseling and testing
13.  Negative Predictive Value of Pap Testing: Implications for Screening Intervals for Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2012;120(4):791-797.
Objective
To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value.
Methods
Participants in the Women’s Interagency HIV Study were followed with conventional Pap smears every 6 months. After excluding those with abnormal Pap tests before study, cervical disease, or hysterectomy, women with negative enrollment Pap results were followed for development within 15 or within 39 months of precancer, defined as a Pap read as high grade squamous intraepithelial lesion, atypical glandular cells favor neoplasia, or adenocarcinoma in situ, or a cervical biopsy read as cervical intraepithelial neoplasia 2+. Correlations between one or more consecutive negative Pap results and subsequent precancer were assessed using Cox proportional hazards models.
Results
Among 942 HIV infected women with negative baseline Pap tests, 8 (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap tests, precancer was rare, with no cases within 15 months and 10/539 (2%) within 39 months. No women developed precancer or cancer within 39 months after 10 consecutive negative Pap tests. Risks for precancer within 15 months after negative Pap included current smoking (aHR 1.5, 95% CI 1.2, 2.0 vs nonsmokers), younger age (aHR=1.5, 95% CI 1.1, 2.1 for women aged younger than 31 years vs older than 45 years) and lower CD4 count (aHR 11.8, 95% CI 1.3, 2.3 for CD4 200–500, aHR 2.2, 95% CI 1.6, 2.9 for CD4 <200/cmm, vs CD4 >500/cmm).
Conclusion
Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate.
doi:10.1097/AOG.0b013e31826a8bbd
PMCID: PMC3448928  PMID: 22996096
14.  Trends in Contraceptive Use Among Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2012;120(4):783-790.
Objective
To estimate trends in contraceptive use, especially long-acting reversible contraceptives (LARC) and condoms, among human immunodeficiency virus (HIV)-seropositive and HIV-seronegative women.
Methods
HIV-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. Fewer than 15% of these women used no contraception. Between 1998 and 2010, LARC use rose among HIV-seronegative women from 4.8% (6/126) to 13.5% (19/141, p=0.02), but not significantly among seropositive women (0.9% (4/438) to 2.8% (6/213, p = 0.09). Use of highly effective contraceptives, including pills, patches, rings, injectable progestin, implants and intrauterine devices, ranged from 15.2% (53/348) in 1998 to 17.4% (37/213) in 2010 (p = 0.55). HIV-seronegative but not seropositive LARC users were less likely than nonusers to use condoms consistently (HR=0.51, 95% C.I. 0.32–0.81, p = 0.004 for seronegative women; HR = 1.09, 95% C.I. 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.
doi:10.1097/AOG.0b013e318269c8bb
PMCID: PMC3449062  PMID: 22996095
15.  Cervicovaginal HPV Infection Before and After Hysterectomy: Evidence of Different Tissue Tropism for Oncogenic and Non-Oncogenic HPV Types in a Cohort of HIV-positive and HIV-negative Women 
Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of non-oncogenic HPV types in the vagina. In the current investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by PCR. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison group – before versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% versus 12%; P<0.001) and after hysterectomy (56% versus 6%; P<0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence (odds ratio [OR]=0.71; 95% confidence interval [CI]=0.59-0.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR=0.48; 95%CI=0.35-0.66) than non-oncogenic HPV types (OR=0.89; 95%CI=0.71-1.11; Pinteraction=0.002). Overall, we observed greater reductions in oncogenic than non-oncogenic HPV prevalence following hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared with vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer.
doi:10.1002/ijc.27363
PMCID: PMC3321069  PMID: 22120980
vaginal; HPV; hysterectomy; viral tropism; HIV
16.  Correlating knowledge of cervical cancer prevention and human papillomavirus with compliance after colposcopy referral 
Objective
To assess the impact of knowledge of cervical cancer biology and prevention as well as noncognitive measures on compliance with colposcopy referral in a high risk population.
Methods
Participants in a U.S. cohort of women with human immunodeficiency virus (HIV) and at risk comparison women completed behavior questionnaires and instruments measuring knowledge of cervical cancer prevention, depressive symptoms, trust in doctors, and perceived stress. Examinations including Pap tests also were conducted. Associations with compliance with resulting indicated colposcopy were assessed in multivariable models.
Results
Of 326 women with indicated colposcopy, 222 (68%) were compliant with colposcopy referral and 104 (32%) noncompliant. In multivariable analysis, better colposcopy compliance was associated with less education (O.R. for compliance 2.24, 95% C.I. 1.12–4.51 vs more than high school), prior abnormal Pap (O.R. per prior abnormal Pap 1.08 95% C.I. 1.01–1.15), study site (O.R. for site with best vs worst compliance 16.1, 95% C.I. 2.91–88.6), and higher stress (O.R. for Perceived Stress Scale-10 score >16 vs lower 3.25, 95% C.I. 1.45–7.26).
Conclusion
Noncognitive factors and how sites manage abnormal Pap testing affect colposcopy compliance. Educational interventions alone are unlikely to improve colposcopy compliance in similar high-risk populations.
doi:10.1097/LGT.0b013e318238e83d
PMCID: PMC3760241  PMID: 22227841
HPV; cervical cancer prevention; Pap test; health education; perceived stress; HIV in women
17.  Safety of Tenofovir Use During Pregnancy: Early Growth Outcomes in HIV-Exposed Uninfected Infants 
AIDS (London, England)  2012;26(9):1151-1159.
Objective
To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants.
Design
US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure.
Methods
We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5kg); weight-for-age z-scores (WAZ), length-forage z-scores (LAZ) and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age one year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ and HCAZ by TDF exposure.
Results
Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with versus without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age one year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: −0.17 vs. −0.03, p=0.04; HCAZ: 0.17 vs. 0.42, p=0.02).
Conclusions
TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age one year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.
doi:10.1097/QAD.0b013e328352d135
PMCID: PMC3476702  PMID: 22382151
Tenofovir disoproxil fumarate; perinatal HIV exposure; infant growth; antiretroviral drugs; pregnancy
18.  Three Postpartum Antiretroviral Regimens to Prevent Intrapartum HIV Infection 
The New England journal of medicine  2012;366(25):2368-2379.
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. Intra-partum 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.)
doi:10.1056/NEJMoa1108275
PMCID: PMC3590113  PMID: 22716975
19.  Effect of Human Immunodeficiency Virus Infection on the Prevalence and Incidence of Vaginal Intraepithelial Neoplasia 
Obstetrics and Gynecology  2012;119(3):582-589.
Objective
To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia 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. Endpoints included abnormal Pap tests after hysterectomy and vaginal intraepithelial neoplasia regardless of hysterectomy.
Results
Over a median of 5.6 years of follow-up, vaginal Pap tests were abnormal at 1,076 (29%, 95% C.I. 25%, 33%) of 3,700 visits among HIV seropositive vs. 31 (4%, 95% C.I. 2%, 8%) of 763 visits among seronegative women (P < 0.001). Abnormal Pap tests included 641 atypical squamous cells of undetermined significance (ASC-US), 425 low-grade squamous intraepithelial lesions (LSIL), and 10 high-grade squamous intraepithelial lesions in HIV-seropositive women, and 28 ASC-US and three LSIL in HIV-seronegative women. The incidence of abnormal Pap tests after hysterectomy was 14/100 person-years among HIV-seropositive and 2/100 person-years among HIV-seronegative women (P < 0.001) and remained stable across time. The 5-year clearance rate of abnormal Pap tests was 34/100 person-years for HIV-seropositive and 116/100 person-years for HIV-seronegative women (P < 0.001). 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 vaginal intraepithelial neoplasia 2+ was 0.2 and 0.01 per 100 person-years for HIV-seropositive and HIV-seronegative women (P = 0.001). Two HIV-seropositive women developed Stage II cancers, with remission after radiotherapy.
Conclusion
Vaginal Pap tests are often abnormal in HIV-seropositive women. Though more common than in HIV-seronegative women, vaginal intraepithelial neoplasia 2+ and especially vaginal cancers are infrequent.
doi:10.1097/AOG.0b013e318244ee3d
PMCID: PMC3285255  PMID: 22353957
20.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
Context
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
Objective
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
Results
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
Conclusion
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
doi:10.1001/jama.2012.5664
PMCID: PMC3556987  PMID: 22820789
21.  Pharmacokinetics and Placental Transfer of Single-Dose Tenofovir 1% Vaginal Gel in Term Pregnancy 
The Journal of Infectious Diseases  2011;204(10):1527-1531.
Tenofovir (TFV) 1% vaginal gel has been found to decrease sexual transmission of human immunodeficiency virus. To initiate investigations during pregnancy, 16 healthy pregnant women scheduled for cesarean delivery received a single application of TFV gel preoperatively. Maternal serum drug concentrations were determined and fetal cord blood, amniotic fluid, placental tissue, and endometrial tissue specimens were collected. The median maternal peak concentration and cord blood TFV concentrations were 4.3 and 1.9 ng/mL, respectively (∼100- and 40-fold lower than after TFV oral dosing, respectively). No adverse events were related to the use of TFV gel. These findings support ongoing and future investigations of TFV gel in pregnancy.
Clinical Trial Registration: NCT00572273. http://www.clinicaltrials.gov/ct2/show/NCT00540605?term=mtn-002&rank=1.
doi:10.1093/infdis/jir562
PMCID: PMC3192189  PMID: 21930612
22.  Relative time to pregnancy among HIV-infected and uninfected women in the Women’s Interagency HIV Study, 2002–2009 
AIDS (London, England)  2011;25(5):707-711.
Objectives
To determine the incidence rate of, and the relative time to pregnancy by HIV status in US women between 2002 and 2009.
Design
The Women’s Interagency HIV Study (WIHS) is an ongoing, multicenter prospective cohort study of the natural and treated history of HIV infection and related outcomes among women with and without HIV.
Methods
Eligible participants were ≤45 years of age; sexually active with male partner(s) or reported a pregnancy outcome within the past year; and never reported hysterectomy, tubal ligation, or oopherectomy. Poisson regression was conducted to compare pregnancy incidence rates over time by HIV status. Relative time to pregnancy was ascertained via Kaplan-Meier plots and generalized gamma survival analysis.
Results
Adjusting for age, number of male sex partners, contraception, parity, exchanging sex, and alcohol use, HIV infection was associated with a 40% reduction in the incidence rate of pregnancy (incidence rate ratio=0.60, 95% confidence interval: [C.I.] 0.46–0.78). The time for HIV-infected women to become pregnant was 73% longer relative to HIV-uninfected women (relative time=1.73, 95% C.I.: 1.35–2.36). In addition to HIV infection, decreased parity and older age were independent predictors of lower pregnancy incidence.
Conclusions
Despite the beneficial effects of modern antiretroviral therapy on survival and prevention of maternal-to-child transmission, our findings suggest that pregnancy incidence remains lower among HIV-infected women. Whether this lower incidence is due to behavioral differences or reduced biologic fertility remains an area worthy of further study.
doi:10.1097/QAD.0b013e3283445811
PMCID: PMC3496791  PMID: 21297418
women; HIV; pregnancy; time to pregnancy; parity
23.  Genital Warts and Vulvar Intraepithelial Neoplasia: Natural History and Effects of Treatment and Human Immunodeficiency Virus Infection 
Obstetrics and gynecology  2011;118(4):831-839.
Objective
To describe the natural history of genital warts and vulvar intraepithelial neoplasia (VIN) in women with human immunodeficiency virus (HIV).
Methods
A cohort of 2,791 HIV infected and 953 uninfected women followed for up to 13 years had genital examinations at 6-month intervals, with biopsy for lesions suspicious for VIN.
Results
The prevalence of warts was 4.4% (5.3% for HIV seropositive women and 1.9% for seronegative women, P < 0.0001). The cumulative incidence of warts was 33% (95% C.I. 30, 36%) in HIV seropositive and 9% (95% C.I. 6, 12%) in seronegative women (P < 0.0001). In multivariable analysis, lower CD4 lymphocyte count, younger age, and current smoking were strongly associated with risk for incident warts. Among 501 HIV seropositive and 43 seronegative women, warts regressed in 410 (82%) seropositive and 41 (95%) seronegative women (P = 0.02), most in the first year after diagnosis. In multivariable analysis, regression was negatively associated with HIV status and lower CD4 count as well as older age. Incident VIN of any grade occurred more frequently among HIV seropositive than seronegative women: 0.42 (0.33 – 0.53) vs 0.07 (0.02 – 0.18)/100 person-years (P < 0.0001). VIN2+ was found in 58 women (55 with and 3 without HIV, P < 0.001). Two women with HIV developed stage IB squamous cell vulvar cancers.
Conclusion
While genital warts and VIN are more common among HIV seropositive than seronegative women, wart regression is common even in women with HIV, and cancers are infrequent.
doi:10.1097/AOG.0b013e31821a0f4d
PMCID: PMC3178036  PMID: 21934446
24.  Maternal Outcomes after Highly Active Antiretroviral Therapy for the Prevention of Mother-to-Child Transmission in HIV-infected Women in Brazil 
Antiviral therapy  2011;16(3):349-356.
Background
Information is lacking on outcomes in HIV-infected Brazilian women with CD4+ counts > 200 cells/mm3 who initiate HAART for the prevention of mother-to-child transmission and discontinue after delivery.
Methods
Clinical event rates after postpartum HAART discontinuation were calculated for all WHO 2–3 events as well as for HIV progression warranting HAART re-initiation, defined by a WHO 4 event and/or CD4+ decline to ≤ 200 cells/mm3. Predictors of the WHO 2–3 events and HIV progression outcomes were evaluated with Cox`s proportional hazards models.
Results
One hundred and twenty women were followed for a mean of 1.5 years after delivery. Twenty-six women had 30 events as follows: 20 developed WHO stage 2–3 events, yielding an incidence rate of 13/100 PY (95% CI 8–20 per 100 PY); 10 developed HIV progression requiring HAART re-initiation (IR: 6/100 PY; 95% CI: 3–11 per 100 PY). Among progressors, a single woman developed a WHO 4 clinical event and the remainder had CD4+ declines. Women who had baseline CD4+ cell counts between 200–500 cells/mm3 had a hazard ratio for WHO 2–3 events of 2.5 compared to women with baseline ≥ 500 cells/mm3 (95%CI: 1.0–6.3; p=0.05). The only significant predictor of HIV progression was baseline CD4+ cell count (HR=0.99, CI: 0.98–0.99; p=0.02).
Conclusions
In this observational study, a baseline CD4+ cell count below 500 cells/mm3 was associated with an increased risk of postpartum WHO 2–3 clinical events and HIV disease progression. Randomized studies are needed to further evaluate the impact of postpartum treatment discontinuation on maternal health.
doi:10.3851/IMP1779
PMCID: PMC3437753  PMID: 21555817
HIV; pregnancy; mother-to-child transmission; Brazil; maternal health
25.  Nelfinavir and Lamivudine Pharmacokinetics during the First Two Weeks of Life 
Background
There are no previous data describing nelfinavir and lamivudine pharmacokinetics in neonates treated with weight band dosing regimens.
Design
Pharmacokinetic study of nelfinavir and lamivudine pharmacokinetics in infants during the first 2 weeks of life treated with weight band dosing regimens.
Methods
Intensive 12 hour pharmacokinetic profiles were performed between either days 4–7 or days 10–14 of life in 26 Brazilian infants.
Results
Pharmacokinetic data were obtained from 26 infants who received median (range) per kg doses of 58.8 (48.4–79.0) mg/kg for nelfinavir and 2.0 (1.5 – 3.2) mg/kg for lamivudine. Median nelfinavir AUC0-12 was 25.5 (1.7 – 183.5) μg*hr/mL and median C12h was 1.09 (<0.04 – 14.44) μg/mL. AUC0-12 was less than 15 μg*hr/mL (the 10% percentile for adults) in 12 infants (46%). Median lamivudine AUC0-12 was 7.8 (2.7–15.6) μg*hr/mL and median C12h was 0.23 (<0.04 – 0.74) μg/mL.
Conclusions
Lamivudine pharmacokinetic parameters observed in this study were consistent with those seen in other studies of neonates. While median nelfinavir AUC and C12h in these neonates were above the exposure targets, interindividual variability in nelfinavir exposure was large and nelfinavir exposure failed to meet the exposure targets in 46% of infants.
doi:10.1097/INF.0b013e3182242950
PMCID: PMC3158246  PMID: 21666540
Nelfinavir; Lamivudine; Pharmacokinetics; Newborns

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