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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.  Adherence and acceptability in MTN 001: A randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women 
AIDS and behavior  2013;17(2):737-747.
We compared adherence to and acceptability of daily topical and oral formulations of tenofovir (TFV) used as pre-exposure prophylaxis (PrEP) for HIV prevention among women in South Africa, Uganda and the United States. 144 sexually active, HIV-uninfected women participated in a cross-over study of three regimens: oral tablet, vaginal gel, or both. We tested for differences in adherence and evaluated product acceptability. Self-reported adherence for all regimens was high (94%), but serum TFV concentrations indicated only 64% of participants used tablets consistently. Most women in the U.S. (72%) favored tablets over gel; while preferences varied at the African sites (42% preferred gel and 40% tablets). Findings indicate a role for oral and vaginal PrEP formulations and highlight the importance of integrating pharmacokinetics-based adherence assessment in future trials. Biomedical HIV prevention interventions should consider geographic and cultural experience with product formulations, partner involvement, and sexual health benefits that ultimately influence use.
doi:10.1007/s10461-012-0333-8
PMCID: PMC3562423  PMID: 23065145
anti-infective agents; HIV; patient compliance; sexual behavior; vaginal creams, foams and jellies; administration, oral; PrEP; microbicide
3.  Suboptimal Nevirapine Steady-State Pharmacokinetics During Intrapartum Compared With Postpartum in HIV-1–Seropositive Ugandan Women 
Background
Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa.
Methods
This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring.
Results
The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipant’s C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients.
Conclusions
Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.
doi:10.1097/QAI.0b013e3181e9871b
PMCID: PMC3594885  PMID: 20622674
antiretroviral agents; HIV; pregnancy; pharmacokinetics; Sub-Saharan Africa
4.  MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments 
PLoS ONE  2013;8(1):e55013.
Background
Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.
Objective
MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.
Methods and Findings
We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).
Conclusions
Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir’s antiviral effect substantially influence PrEP efficacy.
Trial Registration
ClinicalTrials.gov NCT00592124
doi:10.1371/journal.pone.0055013
PMCID: PMC3559346  PMID: 23383037
5.  Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial 
Lancet  2011;379(9812):221-228.
Summary
Background
Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months.
Methods
In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primaryefficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412.
Findings
Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1.1% (95% CI 0.3–1.8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2.4% (1.3–3.6) of controls (difference 1.3%, 95% CI 0–2.6), equating to a 54% reduction in transmission (p=0.049). However, mortality (1.2% for nevirapine vs 1.1% for placebo; p=0.81) and combined HIV infection and mortality rates (2.3% vs 3.2%; p=0.27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.
Interpretation
Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age.
Funding
US National Institutes of Health.
doi:10.1016/S0140-6736(11)61653-X
PMCID: PMC3539769  PMID: 22196945
6.  Safety and Efficacy of HIV Hyperimmune Globulin (HIVIGLOB) for Prevention of Mother-to-Child HIV Transmission in HIV-1 infected Pregnant Women and their Infants in Kampala, Uganda (HIVIGLOB/NVP STUDY) 
Background
This phase III randomized clinical trial compared single dose nevirapine (sdNVP) plus HIV immunoglobulin (HIVIGLOB) to sdNVP alone for preventing maternal-to-child transmission (PMTCT) of HIV.
Primary objectives were to determine rates of HIV infection among infants, and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants.
Methods
Mother-infant pairs were randomized to receive 200mg of NVP to women in labor and 2mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240ml dose of HIVIGLOB given to women at 36-38 weeks gestation and a single intravenous 24ml dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6 and 12 months of age.
Results
Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm versus the sdNVP arm (18.7% vs.15.0%; RR =1.240 [95% CI: 0.833-1.846]; p= 0.290). Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively for mothers (18.9% vs. 19.3%; p= 0.91) and infants (62.6% vs. 59.5%; p=0.51), were not significantly different.
Conclusion
Giving mother-infant pairs an infusion of peripartum HIV hyperimmunoglobulin in addition to sdNVP for PMTCT was as safe as sdNVP alone, but was no more effective than sdNVP alone in preventing HIV transmission.
doi:10.1097/QAI.0b013e31822f8914
PMCID: PMC3204156  PMID: 21826009
HIV; HIVIGLOB; sdNVP; breastfeeding; PMTCT; Uganda
7.  Analysis of HIV tropism in Ugandan infants 
Current HIV research  2010;8(7):498-503.
HIV-infected infants may have CXCR4-using (X4-tropic) HIV, CCR5-using (R5-tropic) HIV, or a mixture of R5-tropic and X4-tropic HIV (dual/mixed, DM HIV). The level of infectivity for R5 virus (R5-RLU) varies among HIV-infected infants. HIV tropism and R5-RLU were measured in samples from HIV-infected Ugandan infants using a commercial assay. DM HIV was detected in 7/72 (9.7%) infants at the time of HIV diagnosis (birth or 6–8 weeks of age, 4/15 (26.7%) with subtype D, 3/57 (5.3 %) with other subtypes, P=0.013). A transition from R5-tropic to DM HIV was observed in only two (6.7%) of 30 infants over 6–12 months. Six (85.7%) of seven infants with DM HIV died, compared to 21/67 (31.3%) infants with R5-tropic HIV (p=0.09). Higher R5-RLU at 6–8 weeks was not associated with decreased survival. Infants with in utero infection had a higher median R5-RLU than infants who were HIV-uninfected at birth (p=0.025).
PMCID: PMC3075545  PMID: 21073438
CCR5; CXCR4; HIV-1; infant; survival; transmission; tropism
8.  Analysis of HIV Diversity Using a High-Resolution Melting Assay 
Abstract
HIV viruses are usually genetically homogeneous shortly after infection, and become more heterogeneous over time. We developed a high-resolution melting (HRM) assay to analyze HIV diversity without sequencing. Plasma samples from the HIVNET 012 trial were obtained from nine Ugandan mother–infant pairs. DNA amplified from the HIV gag region was analyzed to determine the number of degrees over which the DNA melted (HRM score). HRM gag DNA was also cloned and sequenced (50 clones/mother; 20 clones/infant). The median HRM score for infants (4.3, range 4.2–5.3) was higher than that for control plasmids (3.4, range 3.2–3.8, p < 0.001) and lower than that for mothers (5.7, range 4.4–7.7, p = 0.005, exact Wilcoxon rank sum test). The intraclass correlation coefficient reflecting assay reproducibility was 94% (95% CI: 89–98%). HRM scores were also compared to sequenced-based measures of HIV diversity; higher HRM scores were associated with higher genetic diversity (p < 0.001), complexity (p = 0.009), and Shannon entropy (p = 0.022), but not with length variation (p = 0.111). The HRM assay provides a novel, rapid method for assessing HIV diversity without sequencing. This assay could be applied to any region of the HIV genome or to other genetic systems that exhibit DNA diversity.
doi:10.1089/aid.2009.0259
PMCID: PMC2920076  PMID: 20666583
9.  Association of HIV Diversity and Survival in HIV-Infected Ugandan Infants 
PLoS ONE  2011;6(4):e18642.
Background
The level of viral diversity in an HIV-infected individual can change during the course of HIV infection, reflecting mutagenesis during viral replication and selection of viral variants by immune and other selective pressures. Differences in the level of viral diversity in HIV-infected infants may reflect differences in viral dynamics, immune responses, or other factors that may also influence HIV disease progression. We used a novel high resolution melting (HRM) assay to measure HIV diversity in Ugandan infants and examined the relationship between diversity and survival through 5 years of age.
Methods
Plasma samples were obtained from 31 HIV-infected infants (HIVNET 012 trial). The HRM assay was used to measure diversity in two regions in the gag gene (Gag1 and Gag2) and one region in the pol gene (Pol).
Results
HRM scores in all three regions increased with age from 6–8 weeks to 12–18 months (for Gag1: P = 0.005; for Gag2: P = 0.006; for Pol: P = 0.016). Higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with an increased risk of death by 5 years of age (for Pol: P = 0.005; for Gag1/Gag2 (mean of two scores): P = 0.003; for Gag1/Gag2/Pol (mean of three scores): P = 0.002). We did not find an association between HRM scores and other clinical and laboratory variables.
Conclusions
Genetic diversity in HIV gag and pol measured using the HRM assay was typically low near birth and increased over time. Higher HIV diversity in these regions at 6–8 weeks of age was associated with a significantly increased risk of death by 5 years of age.
doi:10.1371/journal.pone.0018642
PMCID: PMC3077388  PMID: 21533179
10.  Short Communication: In Utero HIV Infection Is Associated with an Increased Risk of Nevirapine Resistance in Ugandan Infants Who Were Exposed to Perinatal Single Dose Nevirapine 
Use of single dose nevirapine (sdNVP) to prevent HIV mother-to-child transmission is associated with the emergence of NVP resistance in many infants who are HIV infected despite prophylaxis. We combined results from four clinical trials to analyze predictors of NVP resistance in sdNVP-exposed Ugandan infants. Samples were tested with the ViroSeq HIV Genotyping System and a sensitive point mutation assay (LigAmp, for detection of K103N, Y181C, and G190A). NVP resistance was detected at 6–8 weeks in 36 (45.0%) of 80 infants using ViroSeq and 33 (45.8%) of 72 infants using LigAmp. NVP resistance was more frequent among infants who were infected in utero than among infants who were diagnosed with HIV infection after birth by 6–8 weeks of age. Detection of NVP resistance at 6–8 weeks was not associated with HIV subtype (A vs. D), pre-NVP maternal viral load or CD4 cell count, infant viral load at 6–8 weeks, or infant sex. NVP resistance was still detected in some infants 6–12 months after sdNVP exposure. In this study, in utero HIV infection was the only factor associated with detection of NVP resistance in infants 6–8 weeks after sdNVP exposure.
doi:10.1089/aid.2009.0003
PMCID: PMC2752753  PMID: 19552593
11.  Short Communication: In Utero HIV Infection Is Associated with an Increased Risk of Nevirapine Resistance in Ugandan Infants Who Were Exposed to Perinatal Single Dose Nevirapine 
Abstract
Use of single dose nevirapine (sdNVP) to prevent HIV mother-to-child transmission is associated with the emergence of NVP resistance in many infants who are HIV infected despite prophylaxis. We combined results from four clinical trials to analyze predictors of NVP resistance in sdNVP-exposed Ugandan infants. Samples were tested with the ViroSeq HIV Genotyping System and a sensitive point mutation assay (LigAmp, for detection of K103N, Y181C, and G190A). NVP resistance was detected at 6–8 weeks in 36 (45.0%) of 80 infants using ViroSeq and 33 (45.8%) of 72 infants using LigAmp. NVP resistance was more frequent among infants who were infected in utero than among infants who were diagnosed with HIV infection after birth by 6–8 weeks of age. Detection of NVP resistance at 6–8 weeks was not associated with HIV subtype (A vs. D), pre-NVP maternal viral load or CD4 cell count, infant viral load at 6–8 weeks, or infant sex. NVP resistance was still detected in some infants 6–12 months after sdNVP exposure. In this study, in utero HIV infection was the only factor associated with detection of NVP resistance in infants 6–8 weeks after sdNVP exposure.
doi:10.1089/aid.2009.0003
PMCID: PMC2752753  PMID: 19552593
12.  Predictors of Early and Late Mother-to-Child Transmission of HIV in a Breastfeeding Population: HIV Network for Prevention Trials 012 Experience, Kampala, Uganda 
Objective:
To determine the predictors for early versus later (breastfeeding) transmission of HIV-1.
Methods:
Secondary data analysis was performed on HIV Network for Prevention Trials 012, a completed randomized clinical trial assessing the relative efficacy of nevirapine (NVP) versus zidovudine in reducing mother-to-child transmission (MTCT) of HIV-1. We used Cox regression analysis to assess risk factors for MTCT. The ViroSeq HIV genotyping and a sensitive point mutation assay were used to detect NVP resistance mutations.
Results:
In this subset analyses, 122 of 610 infants were HIV infected, of whom 99 (81.1%) were infected early (first positive polymerase chain reaction ≤56 days). Incidence of MTCT after 56 days was low [0.7% per month (95% confidence interval, CI: 0.4 to 1.0)], but continued through 18 months. In multivariate analyses, early MTCT “factors” included NVP versus zidovudine (hazard ratio (HR) = 0.57, 95% CI: 0.38 to 0.86), pre-entry maternal viral load (VL, HR = 1.76, 95% CI: 1.28 to 2.41), and CD4 cell count (HR = 1.16, 95% CI: 1.05 to 1.28). Maternal VL (6–8 weeks) was associated with late MTCT (HR = 3.66, 95% CI: 1.78 to 7.50), whereas maternal NVP resistance (6–8 weeks) was not.
Conclusions:
Maternal VL was the best predictor of both early and late transmission. Maternal NVP resistance at 6–8 weeks did not predict late transmission.
doi:10.1097/QAI.0b013e3181afd352
PMCID: PMC2767188  PMID: 19617849
early/late postnatal; MTCT; HIV-1

Results 1-12 (12)