Comparison of adverse birth outcomes among HIV-infected and HIV-uninfected women delivering in high and low risk settings in the era of universal ART in Malawi: a registry study.

Background: Recent studies show that ART is associated with an adverse birth outcome in HIV-infected women.Aim: To compare rates of low birthweight (LBW) and preterm birth (PTB) between HIV-infected women receiving lifelong ART and HIV-uninfected women giving birth in low- and high-risk settings in Malawi.Methods: This observational, registry study was conducted from January 2016 to August 2017 in one large, tertiary referral hospital and four primary healthcare (PHC) facilities in Blantyre, Malawi. Women who delivered singleton live births or stillbirths of ≥20 weeks gestation were included in the analysis. Descriptive and stratified analyses were conducted using χ2 tests and multivariable logistic models to control for maternal age, gravidity and health facility.Results: A total of 14,233 births were included in the analysis (7715 from the tertiary hospital and 6518 from PHC facilities). In the univariable analysis, there were no differences in rates of LBW (6.7% vs 6.4%) and PTB (42.5% vs 42.0%) between HIV-infected and -uninfected women delivering in PHC facilities. However, differences in LBW were significantly higher in HIV-infected women in multivariable analysis (LBW aOR 1.40, 95% CI 1.01-1.95). Rates of LBW and PTB were significantly higher in HIV-infected women than in uninfected women delivering at the tertiary hospital (LBW 17.6% vs 13.2%, aOR 1.53, 95% CI 1.27-1.85; PTB 28.2% vs 24.9%, aOR 1.37, 95% CI 1.17-1.60)Conclusion: Rates of adverse birth outcomes are significantly higher in HIV-infected women than in HIV-uninfected women, and this is more apparent in high-risk hospital settings than in low-risk PHC settings.

Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092.

BACKGROUND: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. MATERIALS AND METHODS: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0-12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. RESULTS: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) -3.4 (IQR -4.0, -3.0) and 27 non-SAM had median WHZ -1.0 (IQR -1.8, -0.1). No significant differences in mean AUC0-12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0-12h (GMR, 0.60; 95% CI, 0.4-1.0; P = 0.047) at week 12, higher ZDV AUC0-12h (GMR, 1.52; 1.2-2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). CONCLUSION: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.

Resumption of postpartum sexual activity and menses among HIV-infected women on lifelong antiretroviral treatment compared to HIV-uninfected women in Africa.

OBJECTIVE: To determine time from delivery to resumption of sexual activity and menses among HIV-infected women on antiretroviral treatment (ART) and HIV-uninfected women. METHODS: HIV-infected women on ART and HIV-uninfected women were recruited from five health facilities at delivery and followed prospectively for a maximum of 1 year in Blantyre, Malawi from January 2016 to September 2017. Sociodemographic, clinical, and laboratory data were collected at delivery and 1.5, 3, 6, 9, and 12 months. Descriptive, time to event Kaplan-Meier, and multivariable Cox proportional hazards analyses were conducted. RESULTS: Data on 878 women (460 [52.4%] HIV-uninfected and 418 [47.6%] HIV-infected, P=0.156) who attended at least one follow-up visit were analyzed. Among HIV-uninfected compared to HIV-infected women, respectively, the median number of days to resumption of sexual activity was 180 vs 181; to irregular menses was 82 vs 71; and to regular menses was 245 vs 366. In multivariable models, being married was associated with early resumption of sexual activity (hazard ratio [HR] 1.91, P<0.001), and being HIV-infected and use of an effective method of family planning were associated with later start of regular menses (HR<1.0, P<0.050). CONCLUSION: Counseling of women on reproductive intentions should start early irrespective of HIV infection or use of ART.

Decreased growth among antiretroviral drug and HIV-exposed uninfected versus unexposed children in Malawi and Uganda.

OBJECTIVE: To compare growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) versus age-matched and sex-matched HIV-unexposed uninfected (HUU) children. DESIGN: Prospective cohort of AHEU children identified from the PROMISE trial (NCT01061151: clinicaltrials.gov registry) and age-matched and sex-matched HUU controls from child-wellness clinics, enrolled (September 2013 to October 2014) in Malawi and Uganda. METHODS: Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head-circumference-for-age (HCAZ) z-scores were derived at 12 months and 24 months of age. Wilcoxon Rank-Sum and Fisher's exact tests were used for unadjusted exposure group comparisons. Generalized Estimating Equations models estimated adjusted relative risks (aRR) for poor growth outcomes. RESULTS: Overall, 471 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared with HUU children had significantly lower mean LAZ (P < 0.001) and WAZ (P < 0.001) at 12 and 24 months of age and HCAZ (P = 0.016) at 24 months, with similar but not significant differences among Malawian AHEU and HUU children. The risk of stunting (more than two standard deviations below the WHO population LAZ median) was increased among AHEU versus HUU children: aRR = 2.13 (95% confidence interval (CI): 1.36-3.33), P = 0.001 at 12 months, and aRR = 1.67 (95% CI 1.16-2.41), P = 0.006 at 24 months of age in Uganda; and aRR = 1.32 (95% CI 1.10-1.66), P = 0.018, at 24 months of age in Malawi. The risk of HCAZ below WHO median was increased among AHEU versus HUU children at 24 months of age, aRR = 1.35 (95% CI 1.02-1.79), P = 0.038 in Uganda; and aRR = 1.35 (95% CI 0.91-2.02), P = 0.139 in Malawi. CONCLUSION: Perinatal exposures to maternal HIV and antiretroviral drugs were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months of age compared with HUU children.

Neurodevelopmental effects of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children versus HIV-unexposed and uninfected children in Uganda and Malawi: a prospective cohort study.

BACKGROUND: Antiretroviral medication during pregnancy and breastfeeding substantially decreases the risk of HIV transmission from mothers to infants, but its effects on the child's neurodevelopment are unknown. This study compared neurodevelopmental outcomes of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children with HIV-unexposed and uninfected children at ages 12, 24, 48, and 60 months. METHODS: For this study, a prospective cohort of HIV-exposed and uninfected children was identified from two research sites in the PROMISE-BF trial (at Blantyre, Malawi, and Kampala, Uganda), in which pregnant HIV-infected mothers were randomly assigned to triple antiretroviral prophylaxis (lopinavir-ritonavir plus either lamivudine and zidovudine or emtricitabine and tenofovir), versus zidovudine alone. Post partum, the mother-infant pairs were randomly assigned to maternal triple antiretroviral treatment or infant nevirapine during breastfeeding. HIV-unexposed and uninfected children matched for age, sex, and socioeconomic background were enrolled at vaccination and well-child clinics at the study sites. We included only children without a history of documented brain infection or injury or substantial malnutrition, and whose mothers were randomly assigned and maintained within their assigned ante-partum and post-partum phases throughout their treatment arm periods. Primary outcomes were the Mullen Scales of Early Learning (MSEL) cognitive composite score at age 12 months, 24 months, and 48 months; and the mental processing index for the Kaufman Assessment Battery for Children, second edition (KABC-II) global score at 48 months and 60 months. Repeated measures were analysed using a linear mixed-effects model controlling for data collection site. FINDINGS: Between Aug 23, 2013, and Dec 17, 2014, we co-enrolled 861 children. For MSEL assessments, 738 were eligible for inclusion at age 12 months, 790 at age 24 months, and 692 at age 48 months. For KABC-II assessments, 685 were eligible for inclusion at age 48 months and 445 at age 60 months. There were no differences in MSEL cognitive composite scores according to exposure at age 12 and 24 months (p=0·19 and 0·24, respectively, for comparison of all groups). At 48 months, MSEL cognitive composite scores were worse for children of mothers who did not remain on triple antiretroviral treatment throughout both the ante-partum and post-partum treatment phases (adjusted means 80·64 [95% CI 77·74-83·54] and 81·34 [78·19-84·48], respectively), compared with those who did remain on triple treatment (adjusted mean 85·93, 95% CI 83·05-88·80; p=0·0486 for the comparison of all groups). The KABC-II composite scores (mental processing index) did not differ at 48 or 60 months according to exposure (p=0·81 and 0·89, respectively, for comparison of all groups). Scores for MSEL and KABC-II for children of mothers on triple antiretrovirals in both the ante-partum and post-partum treatment phases were similar to those for children in the HIV-unexposed and uninfected reference group at all timepoints. INTERPRETATION: Maternal triple antiretroviral exposure during both the ante-partum and post-partum phases did not result in greater developmental risks for the mothers' HIV-exposed and uninfected children through age 60 months, compared with children who were HIV-unexposed and uninfected. This might be because ante-partum triple antiretroviral protection of the health of mothers with HIV during pregnancy might be neuroprotective for the child, and when continued post partum, could enhance the quality of caregiving for the child through better clinical care for the mother. FUNDING: National Institutes of Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Pregnancy Outcomes in the Era of Universal Antiretroviral Treatment in Sub-Saharan Africa (POISE Study).

BACKGROUND: Adverse pregnancy outcomes such as preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) remain major global problems. We compared pregnancy outcomes among HIV-infected women receiving antiretroviral treatment (ART) and with CD4 ≥350 cells, and HIV-uninfected women to assess whether disparities associated with HIV infection have been eliminated through use of ART. SETTING: Observational study conducted at 5 health facilities in Blantyre, Malawi, during 2016-2017. METHODS: HIV-infected women receiving the national ART regimen (efavirenz + lamivudine + tenofovir) and HIV-uninfected women were consented and enrolled at delivery. Data collected included sociodemographic and clinical; gestational age; BW; infant/maternal anthropometry; and laboratory results. We defined PTB as GA <37 weeks; LBW as BW <2·5 kg; and SGA as BW <10th percentile of GA. SGA infants were classified into proportionate and disproportionate based on ponderal index. Descriptive, stratified, and multivariate logistic and linear regression analyses were used. RESULTS: Of 5423 women approached, 614 HIV-infected and 685 HIV-uninfected women were enrolled. Rates of PTB, LBW, and SGA were 10.6%, 7.2%, and 17.1% among HIV-infected women on ART and 9.5%, 5.0%, and 18.4% among HIV-uninfected women, respectively. None of these differences were statistically significant in univariate- or multivariate-adjusted analyses (P > 0.05). Of 231 SGA infants, 78.8% were proportionate and 21% were disproportionate. Of the 614 HIV-infected women on ART, 75% had undetectable virus at delivery. CONCLUSIONS: ART use has reduced the high rates of adverse pregnancy outcomes among HIV-infected women. However, the rates remain high irrespective of HIV infection and require appropriate interventions.