Jeffrey Wiener

Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial.

BACKGROUND In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks. METHODS The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736. FINDINGS 676 mother-infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5-9) than in the maternal-antiretroviral (4%, 3-6; p=0·0273) or the infant-nevirapine (4%, 2-5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29-48 weeks than during the intervention phase (1·1 [95% CI 1·0-1·2] vs 0·7 [0·7-0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group). INTERPRETATION In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity. FUNDING US Centers for Disease Control and Prevention.

Dyslipidemia among perinatally HIV-infected children enrolled in the PACTS-HOPE cohort, 1999-2004: a longitudinal analysis.

Background: Protease inhibitor (PI)-containing regimens have led to improved survival among HIV-infected children. However, adverse effects, including dyslipidemia, may put children at risk for cardiovascular disease. Methods: Serum cholesterol and triglyceride levels were recorded on perinatally HIV-infected children participating in the PACTS-HOPE cohort (1999-2004). Hypercholesterolemia (HC) was defined as cholesterol ≥200 mg/dL and hypertriglyceridemia (HT) as triglycerides ≥150 mg/dL. HC and HT were modeled over time using generalized estimating equations. Results: For 178 children, 47% met criteria for HC and 67% for HT at least once during the study period. In generalized estimating equation models, PI use, undetectable viral load, and immunologic category 3 were independent predictors of HC. HT was significantly associated with PI use and body mass index (BMI) ≥90th percentile for age and gender. Among children on PI-containing regimens, HC was significantly associated with multiple PIs and undetectable viral load; HT was predicted by body mass index ≥90th percentile and ritonavir use. The prevalence of clinical lipodystrophy was 5.6% (10/178). Conclusions: Children on PI-containing regimens have a higher risk of both HC and HT. Lipid levels should be measured regularly in children on antiretroviral treatment. Interventions such as diet, exercise, or lipid-lowering drug therapy may benefit some children.

Bacterial Vaginosis and the Natural History of Human Papillomavirus

Objective. To evaluate associations between common vaginal infections and human papillomavirus (HPV). Study Design. Data from up to 15 visits on 756 HIV-infected women and 380 high-risk HIV-uninfected women enrolled in the HIV Epidemiology Research Study (HERS) were evaluated for associations of bacterial vaginosis, trichomoniasis, and vaginal Candida colonization with prevalent HPV, incident HPV, and clearance of HPV in multivariate analysis. Results. Bacterial vaginosis (BV) was associated with increased odds for prevalent (aOR = 1.14, 95% CI: 1.04, 1.26) and incident (aOR = 1.24, 95% CI: 1.04, 1.47) HPV and with delayed clearance of infection (aHR = 0.84, 95% CI: 0.72, 0.97). Whereas BV at the preceding or current visit was associated with incident HPV, in an alternate model for the outcome of incident BV, HPV at the current, but not preceding, visit was associated with incident BV. Conclusion. These findings underscore the importance of prevention and successful treatment of bacterial vaginosis.

Health outcomes of HIV-exposed uninfected African infants.

Objectives:To evaluate severe (grade 3/4) morbidity and mortality in HIV-exposed, uninfected infants. Design:Secondary data analysis of The Breastfeeding, Antiretrovirals, and Nutrition (BAN) clinical trial. Methods:BAN randomized 2369 mother–infant pairs to maternal, infant, or no extended antiretroviral prophylaxis during breastfeeding. Morbidity outcomes examined were pneumonia/serious febrile illness, diarrhea/growth faltering, and malaria. Infant death was defined as neonatal (⩽30 days of life), and postneonatal (31 days to 48 weeks of life). Cox proportional hazards models were used to evaluate the effect of covariates on infant morbidity and mortality. Results:The rate of pneumonia/serious febrile illness was highest in the first 12 weeks (0.83/100 person-weeks) before rapidly decreasing; rates of all morbidity outcomes increased after 24 weeks. Rates of pneumonia/serious febrile illness and diarrhea/growth faltering were higher during the rainy season. Prophylactic infant cotrimoxazole significantly decreased the rates of all morbidity outcomes. White blood cell (WBC) count less than 9000/&mgr;l at birth was associated with increased diarrhea/growth faltering [adjusted hazard ratio (aHR) 1.73, P = 0.04] and malaria (aHR 2.18, P = 0.02). Low birth weight (2000–2499 g) was associated with neonatal death (aHR 12.3, P < 0.001). Factors associated with postneonatal death included rainy season (aHR 4.24, P = 0.002), infant cotrimoxazole (aHR 0.48, P = 0.03), and low infant WBC count at birth (aHR 2.53, P = 0.02). Conclusion:Infant morbidity rates increased after 24 weeks, when BAN infants weaned. Introduction of prophylactic cotrimoxazole was associated with reduced rates of morbidity and mortality in HIV-exposed uninfected infants. Unexpectedly, a low WBC count at birth was significantly associated with later infant morbidity and mortality in this cohort.

Maternal viral load and rate of disease progression among vertically HIV-1-infected children: an international meta-analysis.

Objective: To evaluate whether maternal human immunodeficiency virus type 1 (HIV-1) RNA levels in the serum/plasma of mothers at or close to the time of delivery affects the rate of disease progression among vertically HIV-1-infected children and whether it correlates with other parameters affecting infant disease progression. Methods: International meta-analysis of eight studies with 574 HIV-1 infected infants with available maternal HIV-1 RNA measurements at or close to delivery and clinical follow-up. The primary outcome was disease progression (stage C disease or death, n = 178). Cohort-stratified Cox models were used. Results: Higher maternal HIV-1 RNA level at or close to delivery significantly increased disease progression risk [hazard ratio (HR), 1.25; 95% confidence interval (CI), 1.04–1.52 per 1 log10 increase; P = 0.02) with a borderline effect on mortality (HR, 1.26; 95% CI, 0.96–1.65; P = 0.10]. The association with disease progression risk was strong in the first 6 months of life (HR, 1.77; 95% CI, 1.28–2.45; P = 0.001), but not subsequently (HR, 1.03; 95% CI, 0.81–1.30). Maternal HIV-1 RNA, early infant HIV-1 RNA (at 30–200 days after birth) and infant CD4 were independent predictors of disease progression in the first 6 months. Maternal HIV-1 RNA at or close to delivery correlated with early infant HIV-1 RNA (r = 0.26, P < 0.001). Effects were independent of maternal and infant treatment. Conclusions: Higher maternal HIV-1 RNA at or close to delivery strongly predicts disease progression for HIV-1-infected infants, especially in their first 6 months of life and correlates with the early peak of viremia in the infected child.

A lipid-based nutrient supplement mitigates weight loss among HIV-infected women in a factorial randomized trial to prevent mother-to-child transmission during exclusive breastfeeding

BACKGROUND Breastfeeding increases metabolic demands on the mother, and excessive postnatal weight loss increases maternal mortality. OBJECTIVE We evaluated the efficacy of a lipid-based nutrient supplement (LNS) for prevention of excess weight loss in breastfeeding, HIV-infected women. DESIGN The BAN (Breastfeeding, Antiretrovirals, and Nutrition) Study was a randomized controlled trial in Lilongwe, Malawi. At delivery, HIV-infected mothers and their infants were randomly assigned according to a 2-arm (with and without LNS) by 3-arm (maternal triple-antiretroviral prophylaxis, infant-nevirapine prophylaxis, or neither) factorial design. The 28-wk LNS intervention provided daily energy (700 kcal), protein (20 g), and micronutrients (except for vitamin A) to meet lactation needs. Women were counseled to breastfeed exclusively for 24 wk and to wean by 28 wk. Weight change (0-28 wk) was tested in an intent-to-treat analysis by using 2-factor ANOVA and with longitudinal mixed-effects models. RESULTS At delivery, the LNS (n = 1184) and control (n = 1185) groups had similar mean weights and BMIs. Women receiving the LNS had less 0-28-wk weight loss (-1.97 compared with -2.56 kg, P = 0.003). This difference remained significant after adjustment for maternal antiretroviral drug therapy and baseline BMI. Women receiving antiretroviral drugs had more weight loss than did those not receiving antiretroviral drugs (-2.93 compared with -1.90 kg, P < 0.001). The benefit of the LNS for reducing weight loss was observed both in those receiving antiretroviral drugs (-2.56 compared with -3.32 kg, P = 0.019) and in those not receiving antiretroviral drugs (-1.63 compared with -2.16 kg, P = 0.034). CONCLUSIONS The LNS reduced weight loss among HIV-infected, breastfeeding women, both in those taking maternal antiretroviral prophylaxis to prevent postnatal HIV transmission and in those not receiving antiretroviral prophylaxis. Provision of an LNS may benefit HIV-infected, breastfeeding women in resource-limited settings. This trial was registered at clinicaltrials.gov as NCT00164762.

Ultrasensitive p24 antigen assay for diagnosis of perinatal human immunodeficiency virus type 1 infection.

ABSTRACT We evaluated an ultrasensitive p24 antigen enzyme immunosorbent assay on 802 plasma specimens from 582 infants and children of 0 to 180 days of age. Overall sensitivity and specificity were 91.7% and 98.5%, respectively. After exclusion of infants of less than 7 days of age, the sensitivity and specificity were 93.7% and 98.3%, respectively.

Role of Intestinal Mucosal Integrity in HIV Transmission to Infants Through Breast-feeding: The BAN Study

BACKGROUND Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS). METHODS We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study. RESULTS Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02). CONCLUSIONS These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV.

Detection of two biological markers of intercourse: prostate-specific antigen and Y-chromosomal DNA

BACKGROUND Although biological markers of womens exposure to semen from vaginal intercourse have been developed as surrogates for risk of infection or probability of pregnancy, data on their persistence time and clearance are limited. STUDY DESIGN During 2006-2008, 52 couples were enrolled for three 14-day cycles of abstinence from vaginal sex during which women were exposed in the clinic to a specific quantity (10, 100 or 1000 μL) of their partners semen. Vaginal swabs were collected before and at 1, 6, 12, 24, 48, 72 and 144 h after exposure for testing for prostate-specific antigen (PSA) and Y-chromosome DNA (Yc DNA). RESULTS Immediately after exposure to 1000 μL of semen, the predicted sensitivity of being PSA positive was 0.96; this decreased to 0.65, 0.44, 0.21 and 0.07 at 6, 12, 24 and 48 h, respectively. Corresponding predicted sensitivity of being Yc DNA positive was 0.72 immediately postexposure; this increased to 0.76 at 1 h postexposure and then decreased to 0.60 (at 6 h), 0.63 (at 12 h), 0.49 (at 24 h), 0.21 (at 48 h), 0.17 (at 72 h) and 0.12 (at 144 h). CONCLUSIONS Overall findings suggest that PSA may be more consistent as a marker of very recent exposure and that Yc DNA is more likely to be detected in the vagina after 12 h postexposure compared to PSA.

Addition of 7 days of zidovudine plus lamivudine to peripartum single-dose nevirapine effectively reduces nevirapine resistance postpartum in HIV-infected mothers in Malawi

Background:We assessed whether 7 days of zidovudine + lamivudine postpartum with single-dose nevirapine at labor decreases nevirapine resistance in HIV-infected women in Malawi. Methods:HIV-infected pregnant women receiving intrapartum single-dose nevirapine and 7 days of zidovudine + lamivudine (n = 132) and women receiving intrapartum single-dose nevirapine alone (n = 66) were followed from an antenatal visit through 6 weeks postpartum. Plasma specimens at 2 and 6 weeks postpartum were tested for genotypic resistance to nevirapine by population sequencing and sensitive real-time polymerase chain reaction. Poisson regression was used to determine predictors of postpartum nevirapine resistance. Results:Median HIV RNA was similar at entry (4.27 log vs. 4.35 log, P = 0.87), differed at 2 weeks postpartum (2.67 log vs. 3.58 log, P < 0.0001) but not at 6 weeks postpartum (4.49 log vs. 4.40 log, P = 0.79), between single-dose nevirapine/zidovudine + lamivudine and single-dose nevirapine groups, respectively. Nevirapine resistance, measured by population sequencing and sensitive real-time polymerase chain reaction, was significantly less common in those receiving single-dose nevirapine/zidovudine + lamivudine compared with single-dose nevirapine, respectively, at 2 weeks [10% (4 of 40) vs. 74% (31 of 42), P < 0.0001] and 6 weeks postpartum [10% (11 of 115) vs. 64% (41 of 64), P < 0.0001; adjusted relative risk = 0.18, 95% confidence interval (0.10 to 0.34)]. Conclusions:The significant decrease in nevirapine resistance conferred by 1 week of zidovudine + lamivudine should help policymakers optimize peripartum HIV prophylaxis recommendations.