Gloria Mayondi

Comparative Safety of Antiretroviral Treatment Regimens in Pregnancy

Importance Maternal antiretroviral treatment (ART) started before conception may increase the risk for adverse birth outcomes among women with human immunodeficiency virus (HIV) infection, but whether the risk differs by ART regimen is unknown. Objective To compare the risk for selected birth outcomes by maternal ART regimen. Design, Setting, and Participants This observational birth outcomes surveillance study compared all live births and stillbirths with a gestational age of at least 24 weeks in 8 geographically dispersed government hospitals throughout Botswana (approximately 45% of births nationwide). Data were collected from August 15, 2014, through August 15, 2016. Exposures Births among HIV-infected women who started 3-drug ART regimens before their last menstrual period and did not switch or stop ART in pregnancy were considered to be ART exposed from conception. Main Outcomes and Measures The primary outcomes were any adverse birth outcome, including stillbirth, preterm birth (<37 weeks), small size for gestational age (SGA; <10th percentile of weight for gestational age) or neonatal death (<28 days from delivery), and any severe adverse outcome, including very preterm birth (<32 weeks), very SGA (<3rd percentile of weight for gestational age), stillbirth, and neonatal death. Results Information was available for 47 027 of 47 124 births (99.8%) at surveillance maternity hospitals (mean [SD] age of mothers, 26.86 [6.45] years). Among 11 932 HIV-exposed infants, 5780 (48.4%) were ART exposed from conception. Adverse birth outcomes were more common among HIV-exposed infants than HIV-unexposed infants (39.6% vs 28.9%; adjusted relative risk [ARR], 1.40; 95% CI, 1.36-1.44). The risk for any adverse birth outcome was lower among infants exposed from conception to tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TDF-FTC-EFV) (901 of 2472 [36.4%]) compared with TDF-FTC and nevirapine (NVP) (317 of 760 [41.7%]; ARR, 1.15; 95% CI, 1.04-1.27); TDF-FTC and lopinavir-ritonavir (TDF-FTC–LPV-R) (112 of 231 [48.5%]; ARR, 1.31; 95% CI, 1.13-1.52); zidovudine, lamivudine, and NPV (ZDV-3TC-NVP) (647 of 1365 [47.4%]; ARR, 1.30; 95% CI, 1.20-1.41); or ZDV-3TC–LPV-R (75 of 167 [44.9%]; ARR, 1.21; 95% CI, 1.01-1.45). The risk for any severe adverse outcome was also lower among infants exposed from conception to TDF-FTC-EFV (303 of 2472 [12.3%]) compared with TDF-FTC-NVP (136 of 760 [17.9%]; ARR, 1.44; 95% CI, 1.19-1.74), TDF-FTC–LPV-R (45 of 231 [19.5%]; ARR, 1.58; 95% CI, 1.19-2.11), ZDV-3TC-NVP (283 of 1365 [20.7%]; ARR, 1.68; 95% CI, 1.44-1.96), or ZDV-3TC–LPV-R (39 of 167 [23.4%]; ARR, 1.93; 95% CI, 1.43-2.60) from conception. Compared with TDF-FTC-EFV, all other regimens were associated with higher risk for SGA; ZDV-3TC-NVP was associated with higher risk of stillbirth, very preterm birth, and neonatal death; and ZDV-3TC-LPV-R was associated with higher risk for preterm birth, very preterm birth, and neonatal death. Conclusions and Relevance Among infants exposed to ART from conception, TDF-FTC-EFV was associated with a lower risk for adverse birth outcomes than other ART regimens.

Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study

Summary Background Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana. Methods In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks’ gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks’ gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs). Findings Our analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88–1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81–1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA. Interpretation Adverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy. Funding National Institutes of Health.

Neurodevelopment of HIV-Exposed and HIV-Unexposed Uninfected Children at 24 Months

Through comparison of HEU and HUU children’s neurodevelopment, we examine the effect of in-utero HIV exposure on neurodevelopment among 24-month-old uninfected children. BACKGROUND: We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana. METHODS: HIV-infected and uninfected mothers enrolled in a prospective observational study (“Tshipidi”) in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics. RESULTS: We evaluated 670 children (313 HEU, 357 HUU) with ≥1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small. CONCLUSIONS: HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring.

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women in Botswana. Samples from 752 pregnant women were tested for hepatitis B surface antigen (HBsAg), and HBsAg-positive samples were tested for hepatitis B e antigen (HBeAg) and HBV DNA load. Samples that were HBsAg negative were screened for occult HBV infection by determining the HBV DNA load. HBV genotypes were determined based on a 415-base-pair fragment of the surface gene. Among the 752 women tested during pregnancy or early postpartum, 16 (2.1%) (95% confidence interval (CI): 2.0–2.2) were HBsAg-positive. The prevalence of chronic HBV infection was higher (3.1%) among HIV-infected (95% CI: 3.0–3.2) compared with HIV-uninfected women (1.1%) (95% CI: 1.07–1.1, p = 0.057). Among the 622 HBsAg-negative women, the prevalence of occult HBV infection was 6.6% (95% CI: 6.5–6.7). Three of thirteen HBsAg-positive participants were HBeAg-positive, and all were HIV-negative. Of the 11 maternal samples successfully genotyped, five (45.5%) were genotype D3, five (45.5%) were genotype A1, and one was genotype E (9%). Low and similar proportions of HIV-infected and -uninfected pregnant women in Botswana had occult or chronic HBV infection. We identified a subset of HIV-negative pregnant women who had high HBV DNA levels and were HBeAg-positive, and thus likely to transmit HBV to their infants.

Hypertensive disease in pregnancy in Botswana: Prevalence and impact on perinatal outcomes

OBJECTIVES Perinatal morbidity in sub-Saharan Africa has been attributed to infection, obstetric emergencies, and preterm birth, but less is known about hypertension in pregnancy. Our objective was to characterize the prevalence of hypertension in pregnancy and the impact of hypertension on perinatal outcomes in sub-Saharan Africa. STUDY DESIGN We performed surveillance of obstetric records at eight of the largest public hospitals in Botswana. Women were included in this analysis if they were HIV-uninfected and had singleton gestations and at least one prenatal blood pressure measurement. MAIN OUTCOME MEASURES We measured stillbirth, preterm birth, small for gestational age, and neonatal death in women with and without hypertension in pregnancy. RESULTS We included 14,170 pregnancies. Hypertension occurred in 3156 (22.2%) women, with 602 (19.1%) defined as severe. Severe hypertension increased risk of stillbirth (RR 4.4; 95% CI 3.2-6.2), preterm birth (RR 2.5; 95% CI 2.2-2.8), small for gestational age (RR 2.7; 95% CI 2.3-3.1) and neonatal death (RR 5.1; 95% CI 2.9-5.6). Non-severe hypertension increased risk of stillbirth (RR 2.0; 95% CI 1.5-2.7), preterm birth (RR 1.2; 95% CI 1.1-1.3), and small for gestational age (RR 1.6; 95% CI 1.4-1.8). Perinatal outcomes were worse in women with hypertension who had spontaneous preterm birth compared to those who underwent iatrogenic preterm delivery. CONCLUSIONS Hypertension in pregnancy is common in Botswana and leads to a large number of adverse outcomes. Improved management of hypertension in pregnancy may improve perinatal morbidity and mortality.

HIV Exposure and Formula Feeding Predict Under-2 Mortality in HIV-Uninfected Children, Botswana

Objectives To prospectively assess rates and detailed predictors of morbidity and mortality among HIV‐exposed uninfected children and HIV‐unexposed children in Botswana in a more recent era. Study design We enrolled HIV‐infected and HIV‐uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010‐July 2012. Live‐born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling. Results A total of 893 live‐born HIV‐uninfected children (436 HIV‐exposed uninfected, 457 HIV‐unexposed) were followed. HIV‐infected mothers had a median CD4 count of 410 cells/mm3, 32% took 3‐drug antiretroviral treatment during pregnancy, 67% took only zidovudine, and 1% took <2 weeks of any antiretrovirals antepartum. Twenty four‐month vital status was available for 888 (99.4%) children. HIV‐exposed uninfected children had a significantly higher risk of death compared with children of HIV‐uninfected mothers (5.0% vs 1.8%) (adjusted hazard ratio 3.27, 95% CI 1.44‐7.40). High collinearity between maternal HIV status and child feeding method precluded analysis of these factors as independent predictors of mortality. Preterm birth, low birth weight, and congenital anomaly were also associated with mortality (in separate analyses), but maternal socioeconomic factors, depression, substance use, and social support were not significant predictors. Conclusions The strongest predictors of 24‐month mortality among children in Botswana were HIV exposure and formula feeding, although the relative contribution of these factors to child health could not be separated.

Effect of Gestational Age at Tenofovir-Emtricitabine-Efavirenz Initiation on Adverse Birth Outcomes in Botswana

Among human immunodeficiency virus-positive women in Botswana on the recommended first-line antiretroviral therapy regimen, tenofovir-emtricitabine-efavirenz, initiated within the first or early second trimester, we found no increased risk of stillbirth, neonatal death, preterm/very preterm delivery, or the infant being born small or very small for gestational age. Treatment with tenofovir-emtricitabine-efavirenz <1 year before conception increased the risk of preterm delivery slightly over late-second-trimester treatment initiation (adjusted risk ratio, 1.33 [95% confidence interval, 1.04-1.70]).