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1.  Child Mortality Levels and Trends by HIV Status in Blantyre, Malawi: 1989-2009 
Continuous evaluation of child survival is needed in sub-Saharan Africa where HIV prevalence among women of reproductive age continues to be high. We examined mortality levels and trends over a period of ~20 years among HIV-unexposed and exposed children in Blantyre, Malawi.
Data from five prospective cohort studies conducted at a single research site from 1989-2009 were analyzed. In these studies, children born to HIV-infected and uninfected mothers were enrolled at birth and followed longitudinally for at least two years. Information on socio-demographic, HIV infection status, survival and associated risk factors was collected in all studies. Mortality rates were estimated using birth-cohort analyses stratified by maternal and infant HIV status. Multivariate Cox regression models were used to determine risk factors associated with mortality.
The analysis included 8,286 children. From 1989-1995, overall mortality rates (per 100 person-years) in these clinic-based cohorts remained comparable among HIV-uninfected children born to HIV-uninfected mothers (range 3.3-6.9) or to HIV-infected mothers (range 2.5-7.5). From 1989-2009, overall mortality remained high among all children born to HIV-infected mothers (range 6.3-19.3), and among children who themselves became infected (range 15.6-57.4, 1994-2009). Only lower birth weight was consistently and significantly (P<0.05) associated with higher child mortality.
HIV infection among mothers and children contributed to high levels of child mortality in the African setting in the pre-treatment era. In addition to services that prevent mother-to-child transmission of HIV, other programs are needed to improve child survival by lowering HIV-unrelated mortality through innovative interventions that strengthen health infrastructure.
PMCID: PMC3458133  PMID: 22692091
birth weight; child mortality; cohort effect; HIV; Malawi; Sub-Saharan Africa
2.  Trends in Birth Weight and Gestational Age for Infants Born to HIV-infected, Antiretroviral Treatment-Naïve Women in Malawi 
We analyzed birth outcomes among infants of treatment-naïve, HIV-infected women from a series of mother-to-child transmission of HIV studies in Blantyre, Malawi.
Data from six prospective studies at one research site were analyzed. Mean birth weight (BW) and gestational age (GA), and frequency of low birth weight (LBW; <2500 g) and preterm (PT) birth (GA<37 weeks) were estimated. We assessed risk factors for LBW and PT birth using mixed-effects logistic regression. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) from earlier studies (1989-94) and later studies (2000-07) are presented separately.
The analysis included 8874 HIV-exposed infants. Mean BW and GA ranged from 2793 to 3079 g, and 37.8 to 39.0 weeks. Greater maternal age was consistently (during both the early and late periods) associated with lower odds of LBW and PT birth; AOR (95% CI) for both outcomes in the early and late periods, respectively, were 0.98 (0.96-1.00) and 0.97 (0.95-0.99). Female infant gender was consistently associated with higher odds of PT birth during both periods and with higher odds of LBW during the later period. During the early period, higher maternal education was associated with lower odds of LBW (AOR 0.67 (0.48-0.95)) and PT birth (AOR 0.70 (0.51-0.95)) and later birth year was associated with lower odds of PT birth (AOR 0.35 (0.19-0.70)).
BW and GA remained stable within each time period. This analysis provides important baseline information for monitoring HIV treatment effects on birth outcomes. Modifiable factors affecting BW and GA should continue to be explored.
PMCID: PMC3329585  PMID: 22327871
antiretroviral therapy; pregnancy outcomes; HIV; Malawi; trends
3.  Bacterial vaginosis and the risk of Trichomonas vaginalis acquisition among HIV-1 negative women 
Sexually transmitted diseases  2014;41(2):123-128.
The vaginal microbiota may play a role in mediating susceptibility to sexually transmitted infections, including Trichomonas vaginalis (TV).
Data were analyzed from HIV-1 seronegative women participating in HIV Prevention Trials Network Protocol 035. At quarterly visits for up to 30 months, participants completed structured interviews and specimens were collected for genital tract infection testing. TV was detected by saline microscopy. BV was characterized by Gram stain using the Nugent score (BV=7-10; intermediate=4-6; normal=0-3 [reference group]). Cox proportional hazards models stratified by study site were used to assess the association between Nugent score category at the prior quarterly visit and TV acquisition.
In this secondary analysis, 2,920 participants from Malawi, South Africa, USA, Zambia and Zimbabwe contributed 16,259 follow-up visits. BV was detected at 5,680 (35%) visits and TV was detected at 400 (2.5%) visits. Adjusting for age, marital status, hormonal contraceptive use, unprotected sex in the last week and TV at baseline, intermediate Nugent score and BV at the prior visit were associated with an increased risk of TV (intermediate score: adjusted hazard ratio [aHR]=1.73, 95% confidence interval [CI] 1.21-2.19; BV: aHR=2.40, 95% CI 1.92-3.00). Sensitivity analyses excluding 211 participants with TV at baseline were similar to those from the full study population (intermediate score: aHR=1.54, 95% CI 1.10-2.14; BV: aHR=2.23, 95% CI 1.75-2.84)
Women with a Nugent score >3 were at an increased risk of acquiring TV. If this relationship is causal, interventions that improve the vaginal microbiota could contribute to reductions in TV incidence.
PMCID: PMC4128240  PMID: 24413493
Bacterial vaginosis; Trichomonas vaginalis; vaginal microbiota; sexually transmitted disease acquisition; prospective cohort
4.  Predictors of unstructured antiretroviral treatment interruption and resumption among HIV-positive individuals in Canada 
HIV medicine  2014;16(2):76-87.
Sustained optimal use of combination antiretroviral treatment (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration.
cART-naïve individuals ≥18 years of age who initiated cART between 2000–2011 were included. We defined TIs as ≥90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI.
7,633 participants were eligible, of whom 1,860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women (adjusted hazard ratio (aHR): 1.59, 95%CI: 1.33–1.92), younger individuals (aHR: 1.27, 95%CI: 1.15–1.37 per decade increase), earlier treatment initiators (CD4 count ≥350 versus <200 mm3, aHR: 1.46, 95%CI: 1.17–1.81), Aboriginal participants (aHR: 1.67, 95%CI: 1.27–2.20), injecting drug users (aHR: 1.43, 95%CI: 1.09–1.89), and users of zidovudine versus tenofovir in the initial cART regimen (aHR: 2.47, 95%CI: 1.92–3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 mm3 at cART initiation.
Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART.
PMCID: PMC4300259  PMID: 25174373
Treatment interruption; HIV; antiretroviral therapy; retention; Canada
5.  Effects of Cessation of Breastfeeding in HIV-1–Exposed, Uninfected Children in Malawi 
HIV-exposed, uninfected infants who do not breastfeed compared to those who breastfeed between 6 and 15 months experience substantially higher acute morbidity and cumulative mortality. Adequate monitoring of infant health and prolonged breastfeeding should be encouraged.
Background. We assessed morbidity rates during short intervals that accompanied weaning and cumulative mortality among HIV-exposed, uninfected infants enrolled in the postexposure prophylaxis of infants in Malawi (PEPI-Malawi) trial.
Methods. Women were counseled to stop breastfeeding (BF) by 6 months in the PEPI-Malawi trial. HIV-uninfected infants were included in this analysis starting at age 6 months. Breastfeeding and morbidity (illness and/or hospital admission and malnutrition [weight-for-age Z-score, ≤2]) were assessed during age intervals of 6–9, 9–12, and 12–15 months. BF was defined as any BF at the start and end of the interval and no breastfeeding (NBF) was defined as NBF at any time during the interval. The association of NBF with morbidity at each mutually exclusive interval was assessed using Poisson regression models controlling for other factors. Cumulative mortality among infants aged 6–15 months with BF and NBF was assessed using an extended Kaplan–Meier method.
Results. At age 6 months, 1761 HIV-uninfected infants were included in the study. The adjusted rate ratios for illnesses and/or hospital admission for NBF, compared with BF, was 1.7 (P < .0001) at 6–9 months, 1.66 (P = .0001) at 9–12 months, and 1.75 (P = .0008) at 12–15 months. The rates of morbidity were consistently higher among NBF infants during each age interval, compared with BF infants. The 15 months cumulative mortality among BF and NBF children was 3.5% and 6.4% (P = .03), respectively.
Conclusions. Cessation of BF is associated with acute morbidity events and cumulative mortality. Prolonged BF should be encouraged, in addition to close monitoring of infant health and provision of support services.
PMCID: PMC3202326  PMID: 21810754
6.  Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial 
The Lancet. Infectious diseases  2014;14(4):281-290.
Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.
The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with, number NCT00074581.
1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373–522) cells per μL in patients assigned to the early treatment group and 428 (357–522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197–249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52–1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43–0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28–0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5–27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5–32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.
Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.
US National Institute of Allergy and Infectious Diseases.
PMCID: PMC4144040  PMID: 24602844
7.  Pooled Individual Data Analysis of 5 Randomized Trials of Infant Nevirapine Prophylaxis to Prevent Breast-Milk HIV-1 Transmission 
A pooled analysis of individual data from >5000 human immunodeficiency virus type 1 (HIV-1)–infected mothers and their infants from Africa and India who participated in 5 randomized trials shows that extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection.
Background. In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission.
Methods. Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks.
Results. The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%–7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%–5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%–6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%–3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%–80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%–69%; P < .001).
Conclusions. Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.
PMCID: PMC3518881  PMID: 22997212
breast milk; HIV; nevirapine
8.  Development of Methods for Cross-Sectional HIV Incidence Estimation in a Large, Community Randomized Trial 
PLoS ONE  2013;8(11):e78818.
Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment.
Methods and Findings
Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept.
In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation.
PMCID: PMC3827276  PMID: 24236054
9.  Placental Malaria and Mother-to-Child Transmission of Human Immunodeficiency Virus-1 
There are few studies of the association between placental malaria (PM) and mother-to-child transmission (MTCT) of human immunodeficiency virus-1 (HIV-1), and the results of published studies are inconsistent. To determine the association between PM and MTCT of HIV-1, we performed a secondary analysis of data from a clinical trial of antibiotics to reduce chorioamnionitis. Data regarding 1,662 HIV-1–infected women with live born singleton and first-born twin infants with information regarding PM and infant HIV-1 infection status at birth were analyzed. At the time of the study, women did not have access to antiretroviral drugs for treatment of acquired immunodeficiency syndrome but had received nevirapine prophylaxis to reduce the risk of MTCT of HIV-1. Placental malaria was not associated with the infant HIV-1 infection status at birth ( P = 0.67). Adjustment for maternal plasma viral load and CD4+ cell count did not change these results (odds ratio = 1.06, 95% confidence interval = 0.51–2.20, P = 0.87). Placental malaria was more likely to be related to HIV-1 infection at birth among women with low viral load at baseline (P for interaction = 0.08). In conclusion, PM was not associated with infant HIV-1 infection status at birth. The interaction of maternal plasma viral load, PM, and MTCT of HIV-1 warrants further studies.
PMCID: PMC3775571  PMID: 19346367
10.  Stavudine (d4T) concentrations in women receiving post-partum antiretroviral treatment and their breastfeeding infants 
First-line antiretroviral treatment regimens in resource-limited settings used in breastfeeding mothers often include stavudine (d4T). Limited data describing d4T concentrations in breast milk are available. We analyzed d4T concentrations in 52 mother-infant pairs using ultra-performance liquid chromatography-tandem mass spectrometry (lower limit of quantification: 5 ng/ml in plasma, 20 ng/ml in breast milk). Median (interquartile range) d4T concentrations were 86 (36–191) ng/ml in maternal plasma, 151 (48–259) ng/ml in whole milk, 190 (58–296) ng/ml in skim milk, and <5 (<5-<5) ng/ml in infant plasma. While d4T is concentrated in breast milk relative to maternal plasma, the infant d4T dose received from breast milk is very small and not clinically significant.
PMCID: PMC3404155  PMID: 22614899
stavudine concentrations; breast milk; mother-to-child transmission; HIV
11.  Antibody Maturation and Viral Diversification in HIV-Infected Women 
PLoS ONE  2013;8(2):e57350.
The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women.
Samples collected at enrollment (N = 2,561) and 12–24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67).
In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection.
Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.
PMCID: PMC3583828  PMID: 23460842
12.  Distribution of haematological and chemical pathology values among infants in Malawi and Uganda 
Data on paediatric reference laboratory values are limited for sub-Saharan Africa.
To describe the distribution of haematological and chemical pathology values among healthy infants from Malawi and Uganda.
A cross-sectional study was conducted among healthy infants, 0–6 months old, born to HIV-uninfected mothers recruited from two settings in Blantyre, Malawi and Kampala, Uganda. Chemical pathology and haematology parameters were determined using standard methods on blood samples. Descriptive analyses by age-group were performed based on 2004 Division of AIDS Toxicity Table age categories. Mean values and interquartile ranges were compared by site and age-group.
A total of 541 infants were included altogether, 294 from Malawi and 247 from Uganda. Overall, the mean laboratory values were comparable between the two sites. Mean alkaline phosphatase levels were lower among infants aged ≤21 days while aspartate aminotransferase, creatinine, total bilirubin and gamma-glutamyl transferase were higher in those aged 0–7 days than in older infants. Mean haematocrit, haemoglobin and neutrophil counts were higher in the younger age-groups (<35 days) and overall were lower than US norms. Red and white blood cell counts tended to decrease after birth but increased after ~2 months of age. Mean basophil counts were higher in Malawi than in Uganda in infants aged 0–1 and 2–7 days; mean counts for eosinophils (for age groups 8–21 or older) and platelets (for all age groups) were higher in Ugandan than in Malawian infants. Absolute lymphocyte counts increased with infant age.
The chemical pathology and haematological values in healthy infants born to HIV-uninfected mothers were comparable in Malawi and Uganda and can serve as useful reference values in these settings.
PMCID: PMC3571100  PMID: 23164296
Chemical pathology; Haematology; Infant; Malawi; Reference laboratory value; Uganda
13.  The role of transplacental microtransfusions of maternal lymphocytes in HIV transmission to newborns 
AIDS (London, England)  2008;22(17):2251-2256.
Perinatal HIV transmission could occur via microtransfused maternal blood during delivery. If so, detecting maternal cells in umbilical cord blood should correlate with infection risk.
To develop sensitive assays for maternal DNA in infant's blood stored as dried blood spots (DBS) and examine the correlation between microtransfusion and perinatal HIV infection risk.
Blood-in-blood serial dilutions were prepared as DBS. Extracted DNA was amplified for unique minor-population sequences using 24 allele-specific polymerase-chain-reaction (AS-PCR) assays. Using newborns born to HIV+ mothers, paired mother-infant samples were similarly examined to identify unique maternal sequences targeted by AS-PCR of DNA extracted from cord blood DBS. Cord-blood PCR-negative infants were categorized as uninfected or perinatally infected by HIV PCR on samples collected 4–8 weeks after birth.
Sequences from added cells were detected at ≤1:1000 dilutions in 19 of 20 aliquots, and ≤1:10,000 dilutions in 7 of 20 aliquots; the median limit of detection (probit analysis) was 1 added genomic sequence in 9500 background sequences of amplifiable DNA. Maternal sequences were detected in cord-blood DBS of 50% of infected infants (N=18) and 44% of uninfected infants (N=43). Infection did not correlate with more frequent detection of maternal sequences.
This semi-quantitative assay reliably detected maternal DNA sequences in DBS at levels of less than 1:1000 cells. Maternal sequences were frequently detected but did not correlate infection risk with detection or level of maternal DNA in umbilical cord blood. Therefore we could not demonstrate that microtransfusions at parturition were responsible for perinatal HIV transmission.
PMCID: PMC3509793  PMID: 18981764
14.  Association of recent HIV infection and in utero HIV-1 transmission: Findings from the PEPI-Malawi trial 
AIDS (London, England)  2011;25(11):1357-1364.
We previously developed a multi-assay algorithm (MAA) to identify recent HIV infection that includes the BED-Capture Enzyme Immunoassay, an avidity assay based on the Genetic Systems HIV-1/HIV-2+O Enzyme Immunoassay, CD4 cell count, and HIV viral load. We used this MAA to evaluate the association between recent maternal HIV infection and in utero transmission of HIV.
Plasma samples were collected at delivery from 2,561 HIV-infected women in the PEPI-Malawi trial. The MAA described above was used to identify women with recent HIV infection. Logistic regression models assessed association between recent HIV infection and in utero HIV transmission (defined as a positive infant HIV DNA test at birth).
Seventy-three women were identified as recently infected using the MAA. Those women were younger and had lower parity than women who were identified as not recently infected using the MAA (P<0.0001 for age and parity). The frequency of in utero HIV transmission was 17.8% among women identified as recently infected, compared to 6.7% among women identified as not recently infected (13/73 vs. 166/2488, P=0.001). In a multivariate model, three factors were independently associated with in utero HIV transmission: recent infection (adjusted odds ratio [AOR]: 2.49, 95% CI: 1.30–4.78, P=0.006), log10 HIV viral load at delivery (AOR: 2.01, 95% CI: 1.60–2.51, P<0.0001), and younger age (per 10 year increase, AOR: 0.66, 95% CI: 0.43–0.93, P=0.02).
Results obtained using a MAA suggest that recent maternal HIV acquisition is strongly associated with in utero HIV transmission, independent of HIV viral load at delivery.
PMCID: PMC3263827  PMID: 21572305
HIV; incidence; multiassay algorithm; mother-to-child transmission; Malawi
15.  Efavirenz Conceptions and Regimen Management in a Prospective Cohort of Women on Antiretroviral Therapy 
Use of the antiretroviral drug efavirenz (EFV) is not recommended by the WHO or South African HIV treatment guidelines during the first trimester of pregnancy due to potential fetal teratogenicity; there is little evidence of how clinicians manage EFV-related fertility concerns. Women on antiretroviral therapy (ART) were enrolled into a prospective cohort in four public clinics in Johannesburg, South Africa. Fertility intentions, ART regimens, and pregnancy testing were routinely assessed during visits. Women reporting that they were trying to conceive while on EFV were referred for regimen changes. Kaplan-Meier estimators were used to assess incidence across ART regimens. From the 822 women with followup visits between August 2009–March 2011, 170 pregnancies were detected during study followup, including 56 EFV conceptions. Pregnancy incidence rates were comparable across EFV, nevirapine, and lopinavir/ritonavir person-years (95% 100/users (P = 0.25)); incidence rates on EFV were 18.6 Confidence Interval: 14.2–24.2). Treatment substitution from EFV was made for 57 women, due to pregnancy intentions or actual pregnancy; however, regimen changes were not systematically applied across women. High rates of pregnancy on EFV and inconsistencies in treatment management suggest that clearer guidelines are needed regarding how to manage fertility-related issues in. women on EFV-based regimens.
PMCID: PMC3384948  PMID: 22778534
16.  High Incidence of Unplanned Pregnancy after Antiretroviral Therapy Initiation: Findings from a Prospective Cohort Study in South Africa 
PLoS ONE  2012;7(4):e36039.
Increased fertility rates in HIV-infected women receiving antiretroviral therapy (ART) have been attributed to improved immunological function; it is unknown to what extent the rise in pregnancy rates is due to unintended pregnancies.
Non-pregnant women ages 18–35 from four public-sector ART clinics in Johannesburg, South Africa, were enrolled into a prospective cohort and followed from August 2009–March 2011. Fertility intentions, contraception and pregnancy status were measured longitudinally at participants' routine ART clinic visits.
Of the 850 women enrolled, 822 (97%) had at least one follow-up visit and contributed 745.2 person-years (PY) at-risk for incident pregnancy. Overall, 170 pregnancies were detected in 161 women (incidence rate [IR]: 21.6/100 PY [95% confidence interval (CI): 18.5–25.2]). Of the 170 pregnancies, 105 (62%) were unplanned. Unmet need for contraception was 50% higher in women initiating ART in the past year as compared to women on ART>1 year (prevalence ratio 1.5 [95% CI: 1.1–2.0]); by two years post-ART initiation, nearly one quarter of women had at least one unplanned pregnancy. Cumulative incidence of pregnancy was equally high among recent ART initiators and ART experienced participants: 23.9% [95% CI: 16.4–34.1], 15.9% [12.0–20.8], and 21.0% [16.8–26.1] for women on ART 0–1 yr, >1 yr–2 yrs, and >2 yrs respectively (log-rank, p = 0.54). Eight hormonal contraceptive failures were detected [IR: 4.4 [95% CI: 2.2–8.9], 7/8 among women using injectable methods. Overall 47% (80/170) of pregnancies were not carried to term.
Rates of unintended pregnancies among women on ART are high, including women recently initiating ART with lower CD4 counts and higher viral loads. A substantial burden of pregnancy loss was observed. Integration of contraceptive services and counselling into ART care is necessary to reduce maternal and child health risks related to mistimed and unwanted pregnancies. Further research into injectable contraceptive failures on ART is warranted.
PMCID: PMC3338622  PMID: 22558319
17.  Initiation of Antiretroviral Treatment in Women After Delivery Can Induce Multiclass Drug Resistance in Breastfeeding HIV-Infected Infants 
HIV-infected breastfeeding infants acquired multi-class drug resistance (MCR) after their mothers started highly active antiretroviral therapy (HAART). MCR was more frequent in infants whose mothers started HAART by 6 months post-partum or were exclusively breastfeeding when they reported HAART use.
Background. The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)–infected lactating women with CD4+ cell counts <350 cells/μL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis.
Methods. We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests.
Results. Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P = .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P = .003).
Conclusions. postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.
PMCID: PMC3070029  PMID: 21460326
18.  Prevention of HIV-1 Infection with Early Antiretroviral Therapy 
The New England journal of medicine  2011;365(6):493-505.
Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples.
In nine countries, we enrolled 1763 couples in which one partner was HIV-1–positive and the other was HIV-1–negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1–infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1–related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1–negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death.
As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P = 0.01).
The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy.
PMCID: PMC3200068  PMID: 21767103
19.  Population Attributable Fractions for Late Postnatal Mother-to-Child Transmission of HIV-1 in Sub-Saharan Africa 
Assess population attributable fractions (PAFs) for late postnatal transmission (LPT) of human immunodeficiency virus-1 (HIV-1) in a cohort of HIV-1-exposed infants.
We used data established from a risk factor analysis of LPT (negative HIV-1 results through the 4-6 week visit, but positive assays thereafter through the 12-month visit) from a perinatal clinical trial conducted in three sub-Saharan countries. PAFs were calculated as the proportions of excess LPTs attributed to identified risk factors.
For the cohort of 1317 infants, 206 (15.6%) had only low maternal CD4+ counts (< 200 cells/mm3), 332 (25.2%) had only high maternal plasma viral loads (VLs) (> 50 000 copies/mL), and 81 (6.2%) had both low CD4+ counts and high VLs. Their PAFs were 26.0% [95% confidence interval (CI), 12.0%-36.0%], 37.0% (95% CI, 22.0%-51.0%) and 16.0% (95% CI, 6.0%-25.0%), respectively.
Our PAF analysis illustrates the public health impact of the substantial proportion of LPTs accounted for by high-risk women with both low CD4+ counts and high VLs. In light of these results, access to and use of antiretroviral therapy (ART) by high-risk HIV-1-infected pregnant women is essential. Additional strategies to reduce LPT for those not meeting criteria for ART should be implemented.
PMCID: PMC3086731  PMID: 20224418
Breast feeding; late postnatal transmission; prevention of mother to child transmission/vertical transmission; risk factors; viral load
20.  Effect of prenatal and perinatal antibiotics on maternal health in Malawi, Tanzania, and Zambia 
We assessed the effect of prenatal and peripartum antibiotics on maternal morbidity and mortality among HIV-infected and uninfected women.
A multicenter trial was conducted at clinical sites in 4 Sub-Saharan African cities: Blantyre and Lilongwe, Malawi; Dar es Salaam, Tanzania; and Lusaka, Zambia. A total of 1558 HIV-infected and 271 uninfected pregnant women who were eligible to receive both the prenatal and peripartum antibiotic/placebo regimens were enrolled. Pregnant women were interviewed at 20–24 weeks of gestation and a physical examination was performed. Women were randomized to receive either antibiotics or placebo. At the 26–30 week visit, participants were given antibiotics or placebo to be taken every 4 hours beginning at the onset of labor and continuing after delivery 3 times a day until a 1-week course was completed. Logistic regression and Cox proportional hazards models were used.
There were no significant differences between the antibiotic and placebo groups for medical conditions, obstetric complications, physical examination findings, puerperal sepsis, and death in either the HIV-infected or the uninfected cohort.
Administration of study antibiotics during pregnancy had no effect on maternal morbidity and mortality among HIV-infected and uninfected pregnant women.
PMCID: PMC2783250  PMID: 19716560
Antibiotics; HIV; Maternal morbidity; Maternal mortality; Pregnancy
21.  Primary HIV-1 Infection among Infants in Sub-Saharan Africa: HPTN 024 
Our objectives were to assess clinical signs and diagnoses associated with primary HIV-1 infection among infants.
We analyzed data from a clinical trial (HPTN 024) in sub-Saharan Africa. Study visits were conducted at birth, at 4–6 weeks, and at 3, 6, 9, and 12 months. The study population comprised live born, singleton, first born infants of HIV-1-infected women, with negative HIV-1 RNA assays who were still breastfeeding at 4–6 weeks.
Of 1317 HIV-1-exposed infants, 84 became HIV-1-infected after 4–6 weeks and 1233 remained uninfected. There were 102 primary and 5650 non-primary infection visits. The most common signs were cough and diarrhea, and the most common diagnoses were malaria and pneumonia. Primary infection was associated with significantly increased odds of diarrhea [odds radio (OR)=2.4], pneumonia (OR=3.5), otitis media (OR=3.1), and oral thrush (OR=2.9). For the clinical signs and diagnoses evaluated, sensitivity was low (1ȃ16.7%) and specificity was high (88.2%–99%). Positive predictive values ranged from 0.1–1.4%. Negative predictive values ranged from 28.0–51.1%.
Certain clinical signs and diagnoses, although more common during primary HIV-1 infection, had low sensitivity and high specificity. Efforts to expand access to laboratory assays for the diagnosis of primary HIV-1 infection among infants of HIV-1-infected women should be emphasized.
PMCID: PMC2753468  PMID: 19367174
HIV-1; infant; primary infection
22.  Determining an Optimal Testing Strategy for Infants at Risk for Mother-to-child Transmission of HIV-1 During the Late Postnatal Period 
AIDS (London, England)  2008;22(17):2341-2346.
To determine the optimal time for a second HIV-1 nucleic acid amplification assay to detect late postnatal transmission of HIV-1 (first negative test at 4–8 weeks of age) in resource limited settings.
A longitudinal analysis of data from HPTN 024
Children born to HIV-1 infected mothers enrolled in the HIV Prevention Trial Network trial 024 (HPTN 024) were tested for HIV-1 infection at six intervals within the first year of life. Mothers and infants received nevirapine prophylaxis. We estimated the probability of being alive and having a positive test in each interval after 4–8 weeks and at 30 days post-weaning, conditional on having acquired HIV during the late postnatal period. The interval with the highest probability was taken to be the optimal visit interval.
A total of 1609 infants from HPTN 024 had at least one HIV-1 diagnostic test and were included in the analysis. We found that testing at one month after weaning or 12 months of age (whichever comes first), identified 81% of those infected during the late postnatal period (after 4–8 weeks) through breastfeeding. In total, 93% (95% CI: 89,98) of all infected infants would be detected if tests were performed at these two time points.
In resource-limited settings, HIV-1 PCR testing at 4–8 weeks followed by a second test at one month after weaning or at one year of age (whichever comes first), led to the identification of the vast majority of HIV-1 infected infants.
PMCID: PMC2760032  PMID: 18981773
HIV infant diagnosis; late postnatal transmission; breast feeding
23.  Intrapartum Antibiotic Exposure and Early Neonatal Morbidity and Mortality in Africa 
Pediatrics  2009;124(1):e137-e144.
Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants.
To determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality.
Secondary analysis of data from a multi-site randomized placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intent-to-treat (ITT) analysis, infants born to women randomized to antibiotics or placebo were compared. Additionally, non-ITT analysis was performed because some women received non-study antibiotics for various clinical indications.
Overall, 2659 pregnant women were randomized. Of these, 2466 HIV-1-infected and -uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs. 8.6%, p=0.03) and more admissions to the Special Care Baby Unit (12.6% vs. 9.8%, p = 0.04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Further analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received non-study antibiotics than of mothers who received study antibiotics.
There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive non-study antibiotics.
PMCID: PMC2764263  PMID: 19564260
Antibiotic resistance; Antibiotics; Neonatal morbidity; Neonatal mortality; Neonatal sepsis
24.  Nevirapine Resistance in Human Immunodeficiency Virus Type 1-Positive Infants Determined Using Dried Blood Spots Stored for Up to Six Years at Room Temperature▿  
Journal of Clinical Microbiology  2009;47(4):1209-1211.
Dried blood spots that had been stored ambiently for 3 to 6 years lost approximately 1 log10 of human immunodeficiency virus type 1 (HIV-1) RNA, but the majority could still be genotyped for resistance. Nevirapine resistance was found in 7/16 (43.5%) HIV-1-positive HIVNET 024 infants at 4 to 6 weeks, but no resistance was found at other time points.
PMCID: PMC2668311  PMID: 19225101
25.  Risk Factors for Late Postnatal Transmission of Human Immunodeficiency Virus Type 1 in Sub-Saharan Africa 
We conducted secondary data analyses of a clinical trial (HIVNET 024) to assess risk factors for late postnatal transmission (LPT) of HIV-1 through breastfeeding.
Data regarding live born, singleton infants of HIV-1-infected mothers were analyzed. The timing of HIV-1 transmission through 12 months after birth was defined as: in utero (positive HIV-1 RNA results at birth), perinatal/early postnatal (negative results at birth, positive at 4–6 week visit), or LPT (negative results through the 4–6 week visit, but positive assays thereafter through the 12 month visit). HIV-1-uninfected infants were those with negative HIV-1 enzyme immunoassay results at 12 months of age, or infants with negative HIV-1 RNA results throughout follow-up.
Of 2292 HIV-1-infected enrolled women, 2052 mother/infant pairs met inclusion criteria. Of 1979 infants with HIV-1 tests, 404 were HIV-1-infected, and 382 had known timing of infection (LPT represented 22% of transmissions). Further analyses of LPT included infants who were breastfeeding at the 4–6 week visit (with negative HIV-1 results at that visit) revealed 6.9% of 1317 infants acquired HIV-1 infection through LPT by 12 months of age. More advanced maternal HIV-1 disease at enrollment (lower CD4+ counts, higher plasma viral loads) were the factors associated with LPT in adjusted analyses.
In this breastfeeding population, 6.9% of infants uninfected at 6 weeks of age acquired HIV-1 infection by 12 months. Making interventions to decrease the risk of LPT of HIV-1 available and continuing research regarding the mechanisms of LPT (so as to develop improved interventions to reduce such transmission) remain essential.
PMCID: PMC2730543  PMID: 18277935
Breast feeding; mother-to-child transmission of HIV-1; risk factors; Sub-Saharan Africa

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