An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response.
Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA.
30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.
ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
Diet is a modifiable factor that can contribute to the health of pregnant women. In a sample of 577 HIV-positive pregnant women who completed baseline interviews for the Breastfeeding, Antiretrovirals, and Nutrition Study in Lilongwe, Malawi, cluster analysis was used to derive dietary patterns. Multiple regression analysis was used to identify associations between the dietary patterns and mid-upper arm circumference (MUAC), arm muscle area (AMA), arm fat area (AFA), and hemoglobin at baseline. Three key dietary patterns were identified: animal-based, plant-based, and grain-based. Women with relatively greater wealth were more likely to consume the animal-based diet, which had the highest intake of energy, protein, and fat and was associated with higher hemoglobin levels compared to the other diets. Women with the lowest wealth were more likely to consume the grain-based diet with the lowest intake of energy, protein, fat, and iron and were more likely to have lower AFA than women on the animal-based and plant-based diets, but higher AMA compared to women on the animal-based diet. Pregnant, HIV-infected women in Malawi could benefit from nutritional support to ensure greater nutrient diversity during pregnancy, when women face increased nutrient demands to support fetal growth and development.
maternal diet; nutrition; pregnancy; HIV; anthropometry; Malawi; cluster analysis
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.
HIV; infant; breast-feeding; microbial translocation; immune activation; intestinal permeability
There are potential health risks associated with the use of early weaning to prevent mother-to-child transmission of HIV in resource-poor settings. Our objective was to examine growth and nutrient inadequacies among a cohort of children weaned early. Children participating in the Breastfeeding Antiretrovirals and Nutrition (BAN) Study in Lilongwe, Malawi, had HIV-infected mothers, were weaned at 6 months and fed LNS until 12 months. 40 HIV-negative, BAN-exited children were compared to 40 HIV-negative, community children matched on age, gender and local health clinic. Nutrient intake was calculated from 24-hour dietary recalls collected from BAN-exited children. Anthropometric measurements were collected from BAN-exited and matched community children at 15-16 months, and 2 months later. Longitudinal random effects sex-stratified models were used to evaluate anthropometric differences between the 2 groups. BAN-exited children consumed adequate energy, protein, and carbohydrates but inadequate amounts of fat. The prevalence of inadequate micronutrient intakes were: 46% for vitamin A; 20% for vitamin B6; 69% for folate; 13% for vitamin C; 19% for iron; 23% for zinc. Regarding growth, BAN-exited girls gained weight at a significantly lower rate (0.02g/kg/day [95%CI: 0.01, 0.03] than their matched comparison (0.05g/kg/day [95%CI: 0.03, 0.07]); BAN girls grew significantly slower (0.73cm/month [95%CI: 0.40,1.06]) than their matched comparison (1.55cm/month [95%CI: 0.98, 2.12]). Among this sample of BAN-exited children, early weaning was associated with dietary deficiencies and girls experienced reduced growth velocity. In resource-poor settings, HIV prevention programs must ensure that breastfeeding stop only once a nutritionally adequate and safe diet without breastmilk can be provided.
LNS; early breastfeeding cessation; HIV; Malawi; child growth
The World Health Organization guidelines recommend cotrimoxazole prophylactic treatment (CPT) for all HIV-exposed infants from age 6 weeks to the cessation of breastfeeding and the exclusion of HIV infection. There are limited data about the effects of CPT among this population of infants. We examined the effects of CPT on adverse health outcomes among HIV-exposed infants during the first 36 weeks of life by using data from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study, a large clinical trial of antiretroviral drugs given to the mother or infant for prevention of HIV transmission during breastfeeding.
For the analysis, we assigned a status of CPT-exposed to infants who were participating in the study after the CPT program started. We estimated unadjusted and adjusted hazard ratios (HRs) for the effect of CPT status on time to incident malaria, severe illness or death, anemia, and weight-for-age Z score < −2.0. Participation in the study was limited to focus exclusively on HIV-exposed, uninfected infants.
The HR for the effect of CPT on incident malaria was 0.35 (95% confidence interval [CI]: 0.21, 0.57) during the first 10 weeks of CPT exposure, and 0.93 (95% CI: 0.67, 1.29) for the remaining 20 weeks. CPT was not associated with the other outcomes examined.
CPT offered temporary protection against malaria among HIV-exposed, uninfected infants. However, CPT offered no protection against anemia, low weight for age, or the collapsed outcome of severe illness or death.
HIV; malaria; cotrimoxazole; infants
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.
breast milk; HIV; nevirapine
Background. Limited data exist on cotrimoxazole prophylactic treatment (CPT)
in pregnant women, including protection against malaria versus standard intermittent preventive
therapy with sulfadoxine-pyrimethamine (IPTp). Methods. Using observational
data we examined the effect of CPT in HIV-infected pregnant women on malaria during pregnancy,
low birth weight and preterm birth using proportional hazards, logistic, and log binomial regression,
respectively. We used linear regression to assess effect of CPT on CD4 count.
Results. Data from 468 CPT-exposed and 768 CPT-unexposed women
were analyzed. CPT was associated with protection against malaria versus
IPTp (hazard ratio: 0.35, 95% Confidence Interval (CI): 0.20, 0.60). After
adjustment for time period this effect was not statistically significant (adjusted hazard
ratio: 0.66, 95% CI: 0.28, 1.52). Among women receiving and not receiving CPT,
rates of low birth weight (7.1% versus 7.6%) and preterm birth (23.5% versus 23.6%) were similar.
CPT was associated with lower CD4 counts 24 weeks postpartum in women
receiving (−77.6 cells/μL, 95% CI: −125.2, −30.1) and not
receiving antiretrovirals (−33.7 cells/μL, 95% CI: −58.6, −8.8).
Conclusions. Compared to IPTp, CPT provided comparable protection against malaria in HIV-infected
pregnant women and against preterm birth or low birth weight. Possible implications of CPT-associated lower CD4 postpartum warrant further examination.
We describe change in weight, midupper arm circumference (MUAC), arm muscle area (AMA) and arm fat area (AFA) in 1130 pregnant HIV-infected women with CD4 counts > 200 as part of the BAN Study (www.thebanstudy.org), a randomized, controlled clinical trialto evaluate antiretroviral and nutrition interventions to reducemother-to-child transmission of HIV during breast feeding. In a longitudinal analysis, we found a linear increase in weight with a mean rate of weight gain of 0.27 kgs/wk, from baseline (12 to 30 wks gestation) until the last follow-up visit (32 to 38 wks). Analysis of weight gain showed that 17.1% of the intervals between visits resulted in a weight loss. In unadjusted models, MUAC and AMA increased and AFA declined during late pregnancy. Based on multivariable regression analysis, exposure to the famine season resulted in larger losses in AMA [−0.08, 95%CI: −0.14, −0.02; p=0.01] while AFA losses occurred irrespective of season [−0.55, 95%: −0.95, −0.14, p=0.01]. CD4 was associated with AFA [0.21, 95%CI: 0.01, 0.41, p=.04]. Age was positively associated with MUAC and AMA. Wealth index was positively associated with MUAC, AFA, and weight. While patterns of anthropometric measures among HIV-infected, pregnant women were found to be similar to those reported for uninfected women in sub-Saharan Africa, effects of the famine season among undernourished, Malawian women are of concern. Strategies to optimize nutrition during pregnancy for these women appear warranted.
We examined the relationship of maternal anthropometry to fetal growth and birth weight among 1005 HIV-infected women in Lilongwe, Malawi, who consented to enrollment in the Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study (www.thebanstudy.org). Anthropometric assessments of mid-upper arm circumference (MUAC), arm muscle area (AMA), and arm fat area (AFA) were collected at the baseline visit between 12 and 30 weeks gestation and in up to 4 follow-up prenatal visits. In longitudinal analysis, fundal height increased monotonically at an estimated rate of 0.92 cm/week and was positively and negatively associated with AMA and AFA, respectively. These latter relationships varied over weeks of follow-up. Baseline MUAC, AMA, and AFA were positively associated with birth weight [MUAC: 31.84 grams per cm increment, 95% CI: 22.18, 41.49 (p<0.01); AMA: 6.88 g/cm2, 95% CI: 2.51, 11.26 (p<0.01); AFA: 6.97 g/cm2, 95% CI: 3.53, 10.41 (p<0.01)]. In addition, MUAC and AMA were both associated with decreased odds for LBW (<2500 g) [MUAC: OR=0.85, 95% CI: 0.77, 0.94 (p<0.01); AMA: OR=0.95, 95% CI: 0.91, 0.99 (p<0.05)]. These findings support the use of MUAC as an efficient, cost effective screening tool for LBW in HIV-infected women, as in HIV-uninfected women.
Although the Malawian government recommends HIV-exposed infants receive early infant diagnosis of HIV (EID) at “under-five” pediatric clinics (U5Cs), most never enroll. Therefore, we evaluated the integration of EID testing into an immunization clinic (IC) compared to the current standard of EID testing at an U5C.
Prospective observational study.
Using routine provider initiated HIV testing and counseling (PITC) registers, we prospectively studied 1757 children offered PITC at a government IC and U5C. Infants tested by HIV DNA polymerase chain reaction (PCR) were followed until PCR result disclosure or defaulting.
We sampled 877 and 880 consecutive PITC recipients at U5C and IC, respectively. Overall, a 7 fold greater proportion received PITC at IC (84.2% vs 11.4%, p<0.001). PITC recipients at IC were more than 14 months younger (2.6 vs 17.0, p<0.001), with greater proportions HIV-exposed (17.6% vs 5.3%, p<0.001) and PCR eligible (7.9% vs 3.5%, p<0.001).
A higher percentage of IC infants accepted PCR testing (100.0% vs 90.3%, p=0.03). Additionally, IC PCR recipients were 2.5 months younger (3.1 vs 5.6, p<0.001) with 4 times less testing PCR positive (7.1% vs 32.1%, p<0.001). Importantly, a more than 3 fold greater proportion of HIV-exposed infants at IC returned for their PCR result and enrolled into care (78.6% vs 25.0%, p<0.001).
Compared to an U5C, integrating EID testing into an IC is more acceptable, more feasible, enrolls more infants into EID at younger ages, and would likely strengthen Malawi's EID services if expanded.
Africa; pediatrics; prevention of mother-to-child transmission; early infant diagnosis of HIV; HIV DNA PCR; provider initiated HIV testing and counseling
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.
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.
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).
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
US Centers for Disease Control and Prevention.
In Sub-Saharan Africa, prevalence estimates of hepatitis C virus (HCV) vary widely.
To assess the prevalence of HCV infection among HIV-infected, pregnant women screened for a large clinical trial in Lilongwe, Malawi.
Plasma from 2041 HIV-infected, pregnant women was screened for anti-HCV IgG using a chemiluminiscent immunometric assay (CIA). Specimens with a signal-cut-off ratio ≥ 1.00 were considered reactive and those with S/Co ratio < 1.00 non-reactive. All CIA-reactive specimens were tested by a recombinant immunoblot assay (RIBA) for anti-HCV and by PCR for HCV RNA.
Of 2041 specimens, 110 (5.3%, 95% CI: 4.5–6.5%) were CIA reactive. Of the 109 CIA reactive specimens available for RIBA testing, 2 (1.8%) were positive, 28 (25.7%) were indeterminate, and 79 (72.5%) were negative. All CIA-reactive specimens were HCV RNA negative (n = 110). The estimated HCV prevalence based on the screening assay alone was 5.3%; based on supplemental RIBA testing, the status of HCV infection remained indeterminate in 1.4% (28/2040, 95% CI: 0.1–2.0) and the prevalence of confirmed HCV infections was 0.1% (2/2040, 95% CI: 0–0.4%).
HCV seroprevalence among HIV-infected, pregnant women in Malawi confirmed by supplemental RIBA HCV 3.0 is low (0.1%); CIA showed a high false-reactivity rate in this population.
HIV; HCV; Pregnant women; Malawi
The Data and Safety Monitoring Board (DSMB) for the Breastfeeding, Antiretrovirals, and Nutrition study, a clinical trial aimed to prevent postnatal HIV transmission, recommended halting randomization to the enhanced standard-of-care (control) arm. The 67 mother-infant pairs on the control arm and less than 21 weeks postpartum at the time of the DSMB recommendation were read a script informing them of the DSMB decision and offering them the the maternal or infant antiretroviral interventions for the remainder of the 28-week breastfeeding period. This paper describes the BAN study response to the DSMB decision and what the women on the control arm chose, when given a choice to start the maternal or infant antiretroviral interventions.
Postnatal HIV transmission; breastfeeding; antiretorival prophylaxis
We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.
We randomly assigned 2369 HIV-1–positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan–Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1–negative 2 weeks after birth. Rates were compared with the use of the log-rank test.
Among mother–infant pairs, 5.0% of infants were HIV-1–positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P = 0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P = 0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.
The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)
The Malawian government recently changed its prevention of mother-to-child transmission (PMTCT) regimen and plans to change its first-line antiretroviral therapy (ART) regimen to Tenofovir(TDF)/Lamivudine/Efavirenz as a fixed-dose combination tablet. Implementation could be challenging if baseline creatinine clearance (CrCl) screening were required to assess renal function prior to TDF therapy. Our goal is to determine predictors of CrCl<50 ml/min among HIV-infected, ART-naïve individuals.
Data on HIV-infected, ART-naïve adults screened for enrollment into 5 HIV clinical trials in Lilongwe, Malawi were combined for a pooled analysis of predictors for CrCl<50 ml/min. CrCl was derived from the Cockroft-Gault equation. Multivariable logistic regression modeled the association of age, body mass index (BMI), hemoglobin, CD4 cell count <350 cells/mm3, gender, and pregnancy with CrCl<50 ml/min.
The analysis included 3508 patients with values for creatinine clearance. Most subjects were female (90.6%) with a median age of 26 years (IQR 22–29). The median CD4 cell count was 444 (IQR 298.0–561.0), and 85.2% percent of women in our study were pregnant. Few patients had CrCl<50 ml/min (n = 38, 1.1%). A BMI less than 18.5 in non-pregnant females (OR = 8.87, 95% CI = 2.45–32.09)) was associated with CrCl<50 ml/min. Hemoglobin level higher than 10 g/dL in males (OR = 0.69, 95% CI = 0.56–0.86) and non-pregnant females (OR = 0.21, 95% CI = 0.04–0.97) was protective against CrCl<50 ml/min.
Our findings indicate few patients would be excluded from a TDF-based antiretroviral regimen, suggesting baseline creatinine clearance assessment may not be necessary for implementation. However, in ART settings individuals with low BMI or anemia could potentially be at increased risk for lower CrCl.
International guidelines recommend exclusive breastfeeding to 6 months among HIV-infected mothers choosing to breastfeed and cessation thereafter if replacement feeding is acceptable, feasible, affordable, sustainable and safe. When mothers wean they are challenged to provide an adequate replacement diet. This study investigates the use and acceptability of a lipid-based nutrient supplement (LNS) as a breastmilk substitute when provided to infants (6-12mo) of HIV-positive mothers, as part of the Breastfeeding, Antiretroviral, and Nutrition (BAN) Study. A sub-sample of mothers (n=45) participated in interviews that explored exclusive breastfeeding, weaning, and strategies to feed LNS. Mothers reported several weaning strategies, including gradual reduction of breastfeeding, expressing breastmilk into a cup, and separation of mother and child. LNS, a peanut-based micronutrient fortified paste, was highly accepted and incorporated into the traditional diet. Weaning is a feasible HIV prevention method among this population in Malawi when supported by the provision of LNS as a breastmilk substitute.
HIV; infant feeding; breastfeeding; weaning; LNS
We assessed whether 7 days of zidovudine+lamivudine postpartum with single-dose nevirapine at labor decreases nevirapine resistance in HIV-infected women in Malawi.
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 PCR. Poisson regression was used to determine predictors of postpartum nevirapine resistance.
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 PCR, was significantly less common in those receiving single-dose nevirapine/zidovudine+lamivudine compared to single-dose nevirapine, respectively, at 2 weeks (10% (4/40) vs. 74% (31/42), p<0.0001) and 6 weeks postpartum [10% (11/115) vs. 64% (41/64), p<0.0001; adjusted relative risk=0.18, 95% confidence interval (0.10–0.34)].
The significant decrease in nevirapine resistance conferred by one week of zidovudine+lamivudine should help policymakers optimize peripartum HIV prophylaxis recommendations.
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.
Breast feeding; late postnatal transmission; prevention of mother to child transmission/vertical transmission; risk factors; viral load
A process evaluation of nurses’ implementation of an infant-feeding counseling protocol was conducted for the Breastfeeding, Antiretroviral and Nutrition (BAN) Study, a prevention of mother-to-child transmission of HIV clinical trial in Lilongwe, Malawi. Six trained nurses counseled HIV-infected mothers to exclusively breastfeed for 24 weeks postpartum and to stop breastfeeding within an additional four weeks. Implementation data were collected via direct observations of 123 infant feeding counseling sessions (30 antenatal and 93 postnatal) and interviews with each nurse. Analysis included calculating a percent adherence to checklists and conducting a content analysis for the observation and interview data. Nurses were implementing the protocol at an average adherence level of 90% or above. Although not detailed in the protocol, nurses appropriately counseled mothers on their actual or intended formula milk usage after weaning. Results indicate that nurses implemented the protocol as designed. Results will help to interpret the BAN Study’s outcomes.
In order to evaluate strategies to reduce HIV transmission through breast milk and optimize both maternal and infant health among HIV-infected women and their infants, we designed and implemented a large, randomized clinical trial in Lilongwe, Malawi. The development of protocols for large, randomized clinical trials is a complicated and lengthy process often requiring alterations to the original research design. Many factors lead to delays and changes, including study site-specific priorities, new scientific information becoming available, the involvement of national and international human subject committees and monitoring boards, and alterations in medical practice and guidance at local, national, and international levels. When planning and implementing a clinical study in a resource-limited setting, additional factors must be taken into account, including local customs and program needs, language and socio-cultural barriers, high background rates of malnutrition and endemic diseases, extreme poverty, lack of personnel, and limited infrastructure. Investigators must be prepared to modify the protocol as necessary in order to ensure participant safety and successful implementation of study procedures. This paper describes the process of designing, implementing, and subsequently modifying the Breastfeeding, Antiretrovirals, and Nutrition, (BAN) study, a large, ongoing, randomized breastfeeding intervention trial of HIV-infected women and their infants conducted at a single site in Lilongwe, Malawi. We highlight some of the successes, challenges, and lessons learned at different stages during the conduct of the trial.
Mother-to-child transmission of HIV; breastfeeding; HIV/AIDS; nutrition; study design and management; antiretroviral drugs
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.
Breast feeding; mother-to-child transmission of HIV-1; risk factors; Sub-Saharan Africa
Poor nutrition may be associated with mother-to-child transmission (MTCT) of HIV and other adverse pregnancy outcomes.
The objective was to examine the relation of nutritional indicators with adverse pregnancy outcomes among HIV-infected women in Tanzania, Zambia, and Malawi.
Body mass index (BMI; in kg/m2) and hemoglobin concentrations at enrollment and weight change during pregnancy were prospectively related to fetal loss, neonatal death, low birth weight, preterm birth, and MTCT of HIV.
In a multivariate analysis, having a BMI < 21.8 was significantly associated with preterm birth [odds ratio (OR): 1.82; 95% CI: 1.34, 2.46] and low birth weight (OR: 2.09; 95% CI: 1.41, 3.08). A U-shaped relation between weight change during pregnancy and preterm birth was observed. Severe anemia was significantly associated with fetal loss or stillbirth (OR: 3.67; 95% CI: 1.16, 11.66), preterm birth (OR: 2.08; 95% CI: 1.39, 3.10), low birth weight (OR: 1.76; 95% CI: 1.07, 2.90), and MTCT of HIV by the time of birth (OR: 2.26; 95% CI: 1.18, 4.34) and by 4−6 wk among those negative at birth (OR: 2.33; 95% CI: 1.15, 4.73).
Anemia, poor weight gain during pregnancy, and low BMI in HIV-infected pregnant women are associated with increased risks of adverse infant outcomes and MTCT of HIV. Interventions that reduce the risk of wasting or anemia during pregnancy should be evaluated to determine their possible effect on the incidence of adverse pregnancy outcomes and MTCT of HIV.