Newton Kumwenda

Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350–550 cells/mm³. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.

Background: Tenofovir disoproxil fumarate (TDF) use during pregnancy has been increasing, and studies linking bone toxicity with exposure to TDF have raised concern for its use in infants. Methods: Hand/wrist and spine radiographs were obtained at 3 days and 12 weeks of age in infants born to HIV-infected pregnant women enrolled in the HIV Prevention Trials Network 057 pharmacokinetic study of TDF conducted in Malawi and Brazil assigned to 3 TDF dosing cohorts. In cohort 1, mothers received 600 mg of TDF during labor. In cohort 2, infants received 4 mg/kg dose on days 0, 3 and 5. In cohort 3, a 900 mg maternal dose was given during labor, followed by a 6 mg/kg infant dose on days 0, 3 and 5 of life. Results: Across all 3 cohorts, 89 infants had radiographs performed at either time point, and 85 had radiographs performed at both time points. Metaphyseal lucency was present in 1 case in Brazil and 2 in Malawi. Fifteen percent of infants from Brazil and 9% of infants from Malawi presented bone age discrepancies. No other abnormalities were identified in Brazil, whereas in Malawi, there were 7 more cases of wrist osteopenia, 2 of spine osteopenia and 3 other abnormalities. Conclusion: Bone abnormalities were not uncommon in the overall cohort of HIV-exposed infants. Because of very limited study drug exposure at the time of birth, it is unlikely that TDF was associated with these findings. Untreated maternal HIV disease and/or maternal nutritional status could potentially be related to fetal bone development. This association should be explored in future cohort studies.

Objectives Highly active antiretroviral therapy (HAART) provision to eligible HIV-infected pregnant and post-partum women is critical for optimizing maternal health. We assessed the impact of maternal HAART on HIV-free survival of breastfed infants in Malawi. Methods The post-exposure prophylaxis of infants-Malawi trial (2004–2009) enrolled mothers/infants during labor or immediately post-partum to evaluate 14-week extended infant antiretroviral prophylaxis for preventing HIV transmission through breastfeeding. Mothers meeting national HAART guidelines were referred for therapy. Child HIV-free survival—survival without HIV infection—was compared by maternal HAART status. Results Overall, 3022 mother-infant pairs contributed 4214 infant/person-years (PY) at-risk for HIV infection or death, with 532 events (incidence 12.6/100 PY, 95 % confidence interval [CI] 11.6–13.7). During follow-up, 349 mothers were HAART initiated; 581 remained HAART naïve with CD4 cell counts 3, and 2092 were never HAART-eligible. By 3 months, 11 % of infants with HAART naïve mothers (CD4 < 250) were infected with HIV or died versus 7 % of infants of HAART-initiated mothers and 4 % of infants of HAART-ineligible mothers. Maternal HAART was associated with a 46 % reduction in infant HIV infection or death as compared to infants with HAART naïve mothers (CD4 < 250) (adjusted hazards ratio 0.54, 95 % CI 0.36–0.81). Among HIV-exposed, uninfected infants, breastfeeding, but not HAART, was significantly associated with decreased child mortality. Conclusions HIV infection and mortality are high during the first 3 months post-partum in infants of mothers with advanced HIV, and rapid maternal HAART initiation can significantly improve HIV-related infant outcomes. Clinical Trials Registration This study is registered at http://clinicaltrials.gov/ under trial number NCT00115648.

Objective: This study examined HIV superinfection in HIV-infected women postpartum, and its association with mother-to-child transmission (MTCT). Design: Plasma samples were obtained from HIV-infected women who transmitted HIV to their infants after 6 weeks of age (transmitters, n = 91) and HIV-infected women who did not transmit HIV to their infants (nontransmitters, n = 91). These women were originally enrolled in a randomized trial for prevention of MTCT of HIV in Malawi (Post-Exposure Prophylaxis of Infants trial in Malawi). Methods: Two HIV genomic regions (p24 and gp41) were analyzed by next-generation sequencing for HIV superinfection. HIV superinfection was established if the follow-up sample contained a new, phylogenetically distinct viral population. HIV superinfection and transmission risk were examined by multiple logistic regression, adjusted for Post-Exposure Prophylaxis of Infants study arm, baseline viral load, baseline CD4⁺ cell count, time to resumption of sex, and breastfeeding duration. Results: Transmitters had lower baseline CD4⁺ cell counts (P = 0.001) and higher viral loads (P < 0.0001) compared with nontransmitters. There were five cases of superinfection among transmitters (rate of superinfection = 4.7/100 person-years) compared with five cases among the nontransmitters (rate of superinfection = 4.4/100 person-years; P = 0.78). HIV superinfection was not associated with increased risk of postnatal MTCT of HIV after controlling for maternal age, baseline viral load, and CD4⁺ cell count (adjusted odds ratio = 2.32, P = 0.30). Longer breastfeeding duration was independently associated with a lower risk of HIV superinfection after controlling for study arm and baseline viral load (P = 0.05). Conclusion: There was a significant level of HIV superinfection in women postpartum, but this was not associated with an increased risk of MTCT via breastfeeding.

Data on prevalence of hepatitis E virus (HEV) in Malawi is limited. We tested blood samples from HIV-uninfected and -infected populations of women and men enrolled in research studies in Malawi during 1989–2008 to determine the seroprevalence of HEV, hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Samples were tested for IgG against HEV, total antibodies against HAV and HCV, and presence of HBV surface antigens. Of 800 samples tested, 16.5% were positive for HEV IgG, 99.6% were positive for HAV antibodies, 7.5% were positive for HBV surface antigen, and 7.1% were positive for HCV antibodies. No clear trends over time were observed in the seroprevalence of HEV, and HIV status was not associated with hepatitis seroprevalence. These preliminary data suggest that the seroprevalence of HEV is high in Malawi; the clinical effects may be unrecognized or routinely misclassified.

Background: Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. Methods: The HIV Prevention Trials Network 057 protocol was a phase 1, open-label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV-infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses on days 0, 3, and 5; maternal 900 mg doses/infant 6 mg/kg doses on days 0, 3, and 5; maternal 600 mg doses/infant 6 mg/kg daily for 7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid, and breast milk tenofovir concentrations were determined by liquid chromatographic–tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. Results: One hundred twenty-two mother–infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 and 900 mg exceeded that in nonpregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults, and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74%–97% of infants receiving daily dosing. Conclusions: A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in the studies of TDF efficacy for HIV prevention of mother-to-child transmission and early infant treatment.

The need to develop capacity for health services and systems research (HSSR) in low and middle income countries has been highlighted in a number of international forums. However, little is known about the level of HSSR training in Sub-Saharan Africa (SSA). We conducted an assessment at four major East and Southern African universities to describe: a) the numbers of HSSR PhD trainees at these institutions, b) existing HSSR curricula and mode of delivery, and c) motivating and challenging factors for PhD training, from the trainees’ experience.

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. 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.

Use of HIV prevention methods may vary for women by types of sexual partners. In a microbicide safety and effectiveness trial (HPTN 035) differences in adherence to a microbicide study gel were compared between women with new versus ongoing partnerships over time. 1,757 women in the three HPTN 035 trial’s arms completed the Follow-up Partner Status (FPS) questionnaire at their last study visit. Women married at baseline were asked if they had the same husband, new husband or new partner. Unmarried women were asked if they had changed partners or married. Self-reported gel adherence during the last sex act was compared at each quarterly visit between women with ongoing versus new partners. High gel adherence was compared with low gel adherence (85–100 vs. n = 123) reported a new partner and 41 % (51) of those reported a new husband. Median gel adherence was reported to be 100 % in women with ongoing partners and 75 % for women with new partners (p < 0.001). In women reporting no gel use in their last sex act, only 12.5 % of the women with a new partner and none of those with an ongoing partner reported using condoms (p < 0.001). Fewer women with new partners reported using both the gel and condom during the last sex act as compared to women with ongoing partners (median 50 vs. 71.4 %, p < 0.001). After adjusting for age, site, education level, and sexual frequency, women with ongoing partners were more likely to report high gel adherence than those with new partners (AOR 2.5, 95 % CI 1.6, 3.9). This pattern persisted when gel use over time was compared between women with new versus ongoing partners. In the HPTN 035 trial, women with new partners had higher HIV incidence and reported less gel use and higher condom use. Specific counseling and support are needed to help women use potential HIV prevention methods, including microbicides, when they are changing partners.

Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4⁺ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log₁₀ copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log₁₀ copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.