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1.  Repeat pregnancy in women with HIV infection in Latin America and the Caribbean 
AIDS care  2015;27(10):1289-1297.
Intended and unintended pregnancies occur frequently among 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 6 months postpartum [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 (versus 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.
doi:10.1080/09540121.2015.1050987
PMCID: PMC4929011  PMID: 26288031
HIV; predictors of repeat pregnancy; pregnancy; Latin America
2.  Cost-Effectiveness of Pre-exposure HIV Prophylaxis During Pregnancy and Breastfeeding in Sub-Saharan Africa 
Supplemental Digital Content is Available in the Text.
Introduction:
Antiretroviral pre-exposure prophylaxis (PrEP) for the prevention of HIV acquisition is cost-effective when delivered to those at substantial risk. Despite a high incidence of HIV infection among pregnant and breastfeeding women in sub-Saharan Africa (SSA), a theoretical increased risk of preterm birth on PrEP could outweigh the HIV prevention benefit.
Methods:
We developed a decision analytic model to evaluate a strategy of daily oral PrEP during pregnancy and breastfeeding in SSA. We approached the analysis from a health care system perspective across a lifetime time horizon. Model inputs were derived from existing literature and local sources. The incremental cost-effectiveness ratio (ICER) of PrEP versus no PrEP was calculated in 2015 U.S. dollars per disability-adjusted life year (DALY) averted. We evaluated the effect of uncertainty in baseline estimates through one-way and probabilistic sensitivity analyses.
Results:
PrEP administered to pregnant and breastfeeding women in SSA was cost-effective. In a base case of 10,000 women, the administration of PrEP averted 381 HIV infections but resulted in 779 more preterm births. PrEP was more costly per person ($450 versus $117), but resulted in fewer disability-adjusted life years (DALYs) (3.15 versus 3.49). The incremental cost-effectiveness ratio of $965/DALY averted was below the recommended regional threshold for cost-effectiveness of $6462/DALY. Probabilistic sensitivity analyses demonstrated robustness of the model.
Conclusions:
Providing PrEP to pregnant and breastfeeding women in SSA is likely cost-effective, although more data are needed about adherence and safety. For populations at high risk of HIV acquisition, PrEP may be considered as part of a broader combination HIV prevention strategy.
doi:10.1097/QAI.0000000000001063
PMCID: PMC5043081  PMID: 27355502
pre-exposure prophylaxis; HIV prevention; pregnancy; breastfeeding; sub-Saharan Africa; cost-effectiveness
3.  CCR5 Expression Levels in HIV-Uninfected Women Receiving Hormonal Contraception 
The Journal of Infectious Diseases  2015;212(9):1397-1401.
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.
doi:10.1093/infdis/jiv233
PMCID: PMC4601918  PMID: 25895986
HIV-1; hormonal contraception; CCR5; medroxyprogesterone acetate; levonorgestrel; oral contraceptive pills; peripheral blood mononuclear cells; CD4; CXCR4
4.  Chlamydia and Gonorrhea in HIV-infected Pregnant Women and Infant HIV Transmission 
Sexually transmitted diseases  2015;42(10):554-565.
BACKGROUND
Sexually transmitted infections (STIs) such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) can lead to adverse pregnancy and neonatal outcomes. STI prevalence and its association with HIV mother-to-child transmission (MTCT) were evaluated in a sub-study analysis from a randomized, multi-center clinical trial.
METHODOLOGY
Urine samples from HIV-infected pregnant women collected at the time of labor and delivery were tested using polymerase chain reaction (PCR) testing for the detection of CT and NG (Xpert® CT/NG, Cepheid, Sunnyvale, CA). Infant HIV infection was determined by HIV DNA PCR 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 to 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 (OR 1.47, 95% CI 0.9–2.3, p=0.09).
CONCLUSION
This cohort of HIV-infected pregnant women are 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.
doi:10.1097/OLQ.0000000000000340
PMCID: PMC4571193  PMID: 26372927
maternal to child transmission; HIV; pregnancy; chlamydia; gonorrhea; sexually transmitted infections
5.  Cost-Effectiveness of Pre-exposure HIV Prophylaxis During Pregnancy and Breastfeeding in Sub-Saharan Africa 
Introduction
Antiretroviral pre-exposure prophylaxis (PrEP) for the prevention of HIV acquisition is cost-effective when delivered to those at substantial risk. Despite a high incidence of HIV infection among pregnant and breastfeeding women in sub-Saharan Africa (SSA), a theoretical increased risk of preterm birth on PrEP could outweigh the HIV prevention benefit.
Methods
We developed a decision analytic model to evaluate a strategy of daily oral PrEP during pregnancy and breastfeeding in SSA. We approached the analysis from a health care system perspective across a lifetime time horizon. Model inputs were derived from existing literature and local sources. The incremental cost-effectiveness ratio (ICER) of PrEP versus no PrEP was calculated in 2015 U.S. dollars per disability-adjusted life year (DALY) averted. We evaluated the effect of uncertainty in baseline estimates through one-way and probabilistic sensitivity analyses.
Results
PrEP administered to pregnant and breastfeeding women in SSA was cost-effective. In a base case of 10,000 women, the administration of PrEP averted 381 HIV infections but resulted in 779 more preterm births. PrEP was more costly per person ($450 versus $117), but resulted in fewer disability-adjusted life years (DALYs) (3.15 versus 3.49). The incremental cost-effectiveness ratio of $965/DALY averted was below the recommended regional threshold for cost-effectiveness of $6462/DALY. Probabilistic sensitivity analyses demonstrated robustness of the model.
Conclusions
Providing PrEP to pregnant and breastfeeding women in SSA is likely cost-effective, although more data are needed about adherence and safety. For populations at high risk of HIV acquisition, PrEP may be considered as part of a broader combination HIV prevention strategy.
doi:10.1097/QAI.0000000000001063
PMCID: PMC5043081  PMID: 27355502
pre-exposure prophylaxis; HIV prevention; pregnancy; breastfeeding; sub-Saharan Africa; cost-effectiveness
6.  A randomized safety and pharmacokinetic trial of daily tenofovir 1% gel in term and near-term pregnancy 
Introduction
Vaginal tenofovir (TFV) 1% gel may reduce incident HIV-1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near-term pregnancy.
Methods
Ninety-eight healthy pregnant women, stratified to a term cohort followed by a near-term cohort, were enrolled into a 2:1 randomized, double-blinded, placebo-controlled trial. Women received TFV or placebo gel for seven consecutive days with pharmacokinetic sampling on days 0 and 6. Maternal and cord blood were collected at delivery. Primary end points included laboratory and genital adverse events, adverse pregnancy and neonatal outcomes, and maternal TFV levels.
Results
Most adverse events were grade 1 and none of the grade 3 or 4 adverse events were related to study product. There was no significant difference in safety end points between the two pregnancy cohorts (p=0.18); therefore, their data were combined. Primary safety end point rates were similar for mothers randomized to the TFV gel vs placebo arm (72.7 and 68.8%, p=0.81). The same was true for newborns in the TFV gel vs placebo arms (4.5% vs 6.3%, p=0.66). All women randomized to TFV had quantifiable serum levels within eight hours of dosing, with low overall median (interquartile range) day 0 and day 6 peak values (3.8 (2.0 to 7.0) and 5.8 (2.6 to 9.4) ng/mL, respectively).
Conclusions
Daily TFV 1% vaginal gel use in term and near-term pregnancy appears to be safe and produces low serum drug levels.
doi:10.7448/IAS.19.1.20990
PMCID: PMC5034095  PMID: 27658440
HIV; pregnancy; prevention; pharmacokinetics; safety; tenofovir
7.  Pharmacokinetics of Tenofovir During Pregnancy and Postpartum 
HIV medicine  2015;16(8):502-511.
Objectives
Tenofovir disoproxol fumarate (TDF) is increasingly used in HAART regimens of pregnant women, but limited data exist on pregnancy pharmacokinetics of chronically-dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.
Methods
IMPAACT P1026s is a prospective, non-blinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at 2nd and 3rd trimester and postpartum, with maternal and umbilical cord samples at delivery. Tenofovir was measured by LC-MS. The target AUC was ≥ 1.99 mcg•hr/mL (non-pregnant historical control 10th percentile).
Results
Median tenofovir AUC was decreased during the 2nd (1.9 mcg•hr/mL) and 3rd (2.4 mcg•hr/mL, p=0.005) trimesters versus postpartum (3.0 mcg•hr/mL). Tenofovir AUC exceeded the target for 2/4 (50%) 2nd trimester; 27/37 (73%; 95% CI: 56%, 86%) 3rd trimester; and 27/32 (84%; 95% CI: 67%, 95%) postpartum women (p>0.05). Median 2nd/3rd trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median 3rd trimester weight was heavier for subjects below target AUC versus those above target (97.9 vs. 74.2 kg, p = 0.006). Median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected.
Conclusions
This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90kg) or inadequate HIV RNA response.
doi:10.1111/hiv.12252
PMCID: PMC4862736  PMID: 25959631
HIV; pregnancy; antiretrovirals; tenofovir; prevention of perinatal transmission
8.  Raltegravir Pharmacokinetics during Pregnancy 
Objective
We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum.
Methods
IMPAACT 1026s is an on-going prospective study of antiretroviral pk during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady state 12-hour pk profiles performed during pregnancy and at 6–12 weeks postpartum. Targets were trough concentration above 0.035 µg/mL, the estimated tenth percentile in non-pregnant historical controls.
Results
Median raltegravir AUC was 6.6 µg*hr/mL for second trimester (n= 16), 5.4 µg*hr/mL for third trimester (n=41), and 11.6 µg*hr/mL postpartum (n= 38) (p=0.03 pp vs 2nd trimester, p=0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester and postpartum subjects respectively, with wide variability (<0.010–0.917 µg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were < 400 copies/mL in 92% of women at delivery. Adverse events included elevated liver transaminases in one woman and vomiting in one. All infants with known status are HIV-uninfected.
Conclusions
Median raltegravir AUC was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.
doi:10.1097/QAI.0000000000000318
PMCID: PMC4213295  PMID: 25162818
HIV; pregnancy; raltegravir; pharmacokinetics
9.  Predictors of Adverse Pregnancy Outcomes in HIV infected Women in Latin America and the Caribbean: a Cohort Study 
Objectives
To examine maternal characteristics associated with adverse pregnancy outcomes (APOs) among HIV-infected women.
Design
Prospective cohort study
Setting
Multiple sites in Latin America and the Caribbean
Population
First on-study pregnancy among HIV-1-infected women enrolled in NISDI (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International Site Development Initiative) Perinatal (2002–2007) and LILAC (2008–2012) studies.
Methods
Frequencies of APOs assessed among pregnancies. Risk factors investigated by logistic regression analysis.
Main Outcome measures
APOs including preterm delivery (PT), low birth weight (LBW), small for gestational age (SGA), stillbirth (SB) and neonatal death.
Results
Among 1512 women, 1.9% (95% confidence interval [CI] 1.3–2.7%) of singleton pregnancies resulted in a stillbirth and 32.9% (30.6–35.4%) had at least one APO. Of 1483 singleton live births, 19.8% (17.8–21.9%) were PT, 14.2% (12.5–16.1%) were LBW, 12.6% (10.9–14.4%) were SGA, and 0.4% (0.2–0.9%) of infants died within 28 days after birth. Multivariable logistic regression modeling indicated that the following risk factors increased the probability of having one or more APOs: lower maternal body mass index (odds ratio [OR]=2.2; 95% CI: 1.4–3.5) at delivery, hospitalization during pregnancy (OR=3.3; 95% CI: 2.0–5.3), hypertension during pregnancy (OR=2.7; 95% CI: 1.5–4.8), antiretroviral use at conception (OR=1.4; 95% CI: 1.0–1.9) and tobacco use during pregnancy (OR=1.7; 95% CI: 1.3–2.2). Results of fitting multivariable logistic regression models for PT, LBW, SGA and SB are also reported.
Conclusions
HIV-infected women had relatively high occurrence of APOs and some maternal risk factors were associated with these APOs. Interventions targeting modifiable risk factors should be evaluated further.
doi:10.1111/1471-0528.12680
PMCID: PMC4157114  PMID: 24602102
HIV; pregnancy; pregnancy outcomes; prematurity; Latin America
10.  Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study 
The lancet HIV  2015;2(7):e279-e287.
Summary
Background
Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition.
Methods
We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679.
Findings
3141 South African women using injectable contraception were included in the present analysis: 1788 (56·9%) solely used DMPA, 1097 (34·9%) solely used NET-EN, and 256 (8·2%) used both injectable types at different times during follow-up. During 2733·7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7·57 per 100 person-years, 95% CI 6·61–8·68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8·62 per 100 person-years, 95% CI 7·35–10·11) than among NET-EN users (5·67 per 100 person-years, 4·35–7·38; hazard ratio 1·53, 95% CI 1·12–2·08; p=0·007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1·41, 95% CI 1·06–1·89; p=0·02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2·02 (95% CI 1·26–3·24) compared with 1·09 (0·78–1·52) for HSV-2-seronegative women (pinteraction=0·07).
Interpretation
Although moderate associations in observational analyses should be interpreted with caution, these findings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available.
Funding
National Institutes of Health, Mary Meyer Scholars Fund, and the Ruth Freeman Memorial Fund.
doi:10.1016/S2352-3018(15)00058-2
PMCID: PMC4491329  PMID: 26155597
11.  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
12.  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
13.  Congenital Anomalies and in utero Antiretroviral Exposure in HIV-exposed Uninfected Infants 
JAMA pediatrics  2015;169(1):48-55.
Importance
Most studies examining the association of prenatal antiretroviral exposures with congenital anomalies (CAs) in children born to HIV-infected women have been reassuring, but some suggest increased risk with specific antiretrovirals.
Objectives
To evaluate associations of in utero antiretroviral exposures with CAs in HIV-exposed uninfected children.
Design
prospective cohort study, the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study.
Setting
22 US medical centers
Participants
2580 HIV-exposed, uninfected children enrolled in SMARTT between 2007–2012.
Exposures
First trimester exposure to any antiretroviral and to specific antiretroviral medications.
Main Outcome
The primary endpoint was a CA, based on clinician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate associations of CAs with first trimester antiretroviral exposures, adjusting for demographic and maternal characteristics.
Results
CAs occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI: 5.85–7.82%); there were 242 confirmed major CAs (72 musculoskeletal, 55 cardiovascular). The prevalence of CAs increased significantly in successive birth cohorts (3.8% for children born <2002 up to 8.3% for 2008–2010). In adjusted models, there was no association of first trimester exposures to any antiretroviral, to combination antiretroviral regimens, or to any drug class with CAs. No individual antiretroviral in the reverse transcriptase inhibitor drug classes was associated with increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir (adjusted odds ratio (aOR)=1.93, 95% confidence interval (CI):1.23,3.03) and for ritonavir used as a booster (aOR=1.52, 95%CI: 1.08,2.14). With first trimester atazanavir, risks were highest for skin and musculoskeletal CAs (aORs=5.24 and 2.55, respectively).
Conclusions and Relevance
Few individual antiretrovirals and no drug classes were associated with increased risk of CAs after adjustment for calendar year and maternal characteristics. While the overall risk remained low, there was a relative increase in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV use during pregnancy still outweigh such risks, although further studies are warranted.
doi:10.1001/jamapediatrics.2014.1889
PMCID: PMC4286442  PMID: 25383770
14.  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
15.  Long-term cumulative detection of human papillomavirus among HIV seropositive women 
AIDS (London, England)  2014;28(17):2601-2608.
Objective
To estimate the effects of infection by human immunodeficiency virus (HIV) on the type-specific cumulative detection of cervicovaginal infection by human papillomavirus (HPV).
Design
Retrospective assessment of prospectively collected data in a multicenter U.S. cohort.
Methods
HIV seropositive and at-risk seronegative participants in the Women's Interagency HIV Study were followed semiannually for up to 11 years. HPV typing was determined from cervicovaginal lavage specimens by polymerase chain reaction; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 were considered carcinogenic.
Results
Among 3438 women enrolled, (2543 HIV seropositive, 895 seronegative), the cumulative detection of any HPV infection rose among HIV seropositive women from 53% at baseline to 92% at 8 years and among seronegative women from 22% to 66% (P < 0.0001 for HIV seropositive vs seronegative women). The 8-year cumulative detection of carcinogenic and noncarcinogenic HPV was 67% and 89% among HIV seropositive and 36% and 56% among seronegative women (P = 0.001 for both carcinogenic and noncarcinogenic HPV). The 8-year cumulative detection of HPV16 and HPV 18 was 15.2% and 15.0% in HIV seropositive and 6.7% and 6.1% in HIV seronegative women (P < 0.0001 for both). In multivariable regression analyses, lower CD4 count, age under 30 years, and smoking but not number of lifetime sexual partners were significant correlates of cumulative HPV detection.
Conclusion
More than 90% of HIV seropositive women have HPV detected during long follow-up. Rates are lower among at-risk HIV seronegative women, though most also develop HPV infections.
doi:10.1097/QAD.0000000000000455
PMCID: PMC4289460  PMID: 25188771
Human papillomavirus; HIV in women; immunodeficiency
16.  Heterogeneity of T Cell Responses to Pandemic pH1N1 Monovalent Vaccine in HIV-Infected Pregnant Women 
AIDS Research and Human Retroviruses  2015;31(11):1170-1177.
Abstract
We investigated the Th1 protective and regulatory T and B cell (Treg and Breg) responses to pH1N1 monovalent influenza vaccine (IIV1) in HIV-infected pregnant women on combination antiretroviral therapy (cART). Peripheral blood mononuclear cells (PBMCs) from 52 study participants were cryopreserved before and after vaccination and analyzed by flow cytometry. pH1N1-specific Th1, Treg, and Breg responses were measured in PBMCs after in vitro stimulation with pH1N1 and control antigen. The cohort analysis did not detect changes in pH1N1-Th1, Treg, or Breg subsets postvaccination. However, individual analyses distinguished subjects who mounted vigorous Th1 responses postvaccination from others who did not. Postvaccination, high pH1N1-Th1 correlated with high pH1N1-Treg and Breg responses, suggesting that low influenza effector responses did not result from excessive vaccine-induced immune regulation. High postvaccination pH1N1-Th1 responses correlated with baseline high PHA- and pH1N1-IFN-γ ELISpot and circulating CD4+CD39+% and CD8+CD39+% Treg, with low CD8+ cell numbers and CD19+FOXP3+% Breg, but not with CD4+ cell numbers or HIV viral load. These data highlight the heterogeneity of T cell responses to vaccines in HIV-infected individuals on cART. Predictors of robust Th1 responses to IIV include CD8+ cell numbers, T cell functionality, and circulating Breg and Treg.
doi:10.1089/aid.2015.0151
PMCID: PMC4651022  PMID: 26322930
17.  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.)
doi:10.1128/AAC.04701-14
PMCID: PMC4356823  PMID: 25624326
18.  High-Grade Cervical Disease in Adolescents With HIV 
Objective
To estimate the risk of high-grade squamous intraepithelial lesions (HSIL) in adolescents with HIV.
Materials and Methods
Review of cervical cytology and biopsy results from women aged 20 years and younger obtained within 3 years of enrollment in a prospective multicenter study.
Results
At enrollment, none of 132 adolescent participants (45 HIV seropositive and 87 seronegative) had HSIL or cervical intraepithelial neoplasia grade 2 or 3 (CIN 2,3). Eight (7%) of 123 women with follow-up developed high-grade disease after a median of 2.6 years of observation. The incidence of HSIL/CIN 2,3 was 2.7/100 person-years (4.8/100 person-years in HIV seropositive and 1.6/100 person-years in HIV seronegative women; relative risk = 3.1; 95% CI = 0.76–12.74; p = .13). No cancers were found in adolescents during the study.
Conclusions
The low incidence of HSIL or CIN 2,3 in adolescents suggests that optimal management is careful observation rather than preventive treatment of low-grade abnormalities.
doi:10.1097/LGT.0b013e318160b9a5
PMCID: PMC4507508  PMID: 18596461
HPV; adolescents; cervical cancer prevention; Pap test; HIV in women
19.  Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer 
Objective
Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.
Design/Methods
In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.
Results
Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.
Conclusion
These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis.
doi:10.1097/QAI.0000000000000157
PMCID: PMC4267467  PMID: 24694931
Genital tract HIV viral load; cervical neoplasia; HPV natural history
20.  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
21.  HYPERTENSION, PREECLAMPSIA AND ECLAMPSIA AMONG HIV-INFECTED PREGNANT WOMEN FROM LATIN AMERICA AND CARIBBEAN COUNTRIES 
The Journal of infection  2014;68(6):572-580.
Objectives
To evaluate the incidence of and risk factors for hypertensive disorders in a cohort of HIV-infected pregnant women.
Methods
Hypertensive disorders (HD) including preeclampsia/eclampsia (PE/E) and pregnancy-induced hypertension, and risk factors were evaluated in a cohort of HIV-infected pregnant women from Latin America and the Caribbean enrolled between 2002-2009. Only pregnant women enrolled for the first time in the study and delivered at ≥ 20 weeks gestation were analyzed.
Results
HD were diagnosed in 73 (4.8%, 95%CI: 3.8%-6.0%) of 1513 patients; 35(47.9%) had PE/E. HD was significantly increased among women with a gestational age-adjusted body mass index (gBMI) ≥ 25 kg/m2 (OR=3.1; 95%CI: 1.9-5.0), hemoglobin (Hg) ≥11 g/dL at delivery (OR=2.1; 95%CI: 1.2-3.6) and age ≥35 years (OR=1.8; 95%CI: 1.1-3.2). PE/E was increased among women with a gBMI ≥25 kg/m2 (OR=3.0; 95%CI: 1.5-6.0) and Hg ≥11 g/dL at delivery (OR=2.8; 95%CI: 1.2-6.5). A previous history of PE/E increased the risk of PE/E 6.7 fold (95%CI: 1.8-25.5). HAART before conception was associated with PE/E (OR=2.3; 95%CI: 1.1-4.9)
Conclusions
HIV-infected women, with a previous history of PE/E, a gBMI ≥25 kg/m2, Hg at delivery ≥11 g/dL and in use of HAART before conception are at an increased risk of developing PE/E during pregnancy.
doi:10.1016/j.jinf.2013.12.018
PMCID: PMC4046640  PMID: 24462561
22.  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 (CIN3+ 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 six 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 (1571 [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.
doi:10.1002/ijc.28523
PMCID: PMC3947413  PMID: 24170366
HIV in women; cervical intraepithelial neoplasia; Pap test
23.  Determinants of Vaccine Immunogenicity in HIV-Infected Pregnant Women: Analysis of B and T Cell Responses to Pandemic H1N1 Monovalent Vaccine 
PLoS ONE  2015;10(4):e0122431.
Influenza infections have high frequency and morbidity in HIV-infected pregnant women, underscoring the importance of vaccine-conferred protection. To identify the factors that determine vaccine immunogenicity in this group, we characterized the relationship of B- and T-cell responses to pandemic H1N1 (pH1N1) vaccine with HIV-associated immunologic and virologic characteristics.
pH1N1 and seasonal-H1N1 (sH1N1) antibodies were measured in 119 HIV-infected pregnant women after two double-strength pH1N1 vaccine doses. pH1N1-IgG and IgA B-cell FluoroSpot, pH1N1- and sH1N1-interferon γ (IFNγ) and granzyme B (GrB) T-cell FluoroSpot, and flow cytometric characterization of B- and T-cell subsets were performed in 57 subjects.
pH1N1-antibodies increased after vaccination, but less than previously described in healthy adults. pH1N1-IgG memory B cells (Bmem) increased, IFNγ-effector T-cells (Teff) decreased, and IgA Bmem and GrB Teff did not change. pH1N1-antibodies and Teff were significantly correlated with each other and with sH1N1-HAI and Teff, respectively, before and after vaccination. pH1N1-antibody responses to the vaccine significantly increased with high proportions of CD4+, low CD8+ and low CD8+HLADR+CD38+ activated (Tact) cells. pH1N1-IgG Bmem responses increased with high proportions of CD19+CD27+CD21- activated B cells (Bact), high CD8+CD39+ regulatory T cells (Treg), and low CD19+CD27-CD21- exhausted B cells (Bexhaust). IFNγ-Teff responses increased with low HIV plasma RNA, CD8+HLADR+CD38+ Tact, CD4+FoxP3+ Treg and CD19+IL10+ Breg.
In conclusion, pre-existing antibody and Teff responses to sH1N1 were associated with increased responses to pH1N1 vaccination in HIV-infected pregnant women suggesting an important role for heterosubtypic immunologic memory. High CD4+% T cells were associated with increased, whereas high HIV replication, Tact and Bexhaust were associated with decreased vaccine immunogenicity. High Treg increased antibody responses but decreased Teff responses to the vaccine. The proportions of immature and transitional B cells did not affect the responses to vaccine. Increased Bact were associated with high Bmem responses to the vaccine.
doi:10.1371/journal.pone.0122431
PMCID: PMC4395240  PMID: 25874544
24.  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
25.  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

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