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BackgroundAntiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate.MethodsThis multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422.FindingsBetween Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of

BackgroundIntensified viral load monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies.MethodsWe used an individual Monte Carlo simulation to describe longitudinal ART adherence and viral load from conception until 2 years' postpartum. We applied national and international guidelines for viral load monitoring to the simulated data. We compared guidelines on the percentage of women receiving viral load monitoring and the percentage of women monitored at the time of elevated viral load.ResultsCoverage of viral load monitoring in pregnancy and breastfeeding varied markedly, with between 14% and 100% of women monitored antenatally and 38-98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved more than 95% testing in pregnancy but this was much lower (14-83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated viral load more than 1000 copies/ml were successfully detected by monitoring (range, 20-50%).DiscussionAlthough further research is needed to understand optimal viral load frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated viral load in pregnant and breastfeeding women.

Background In the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2010/VESTED study, pregnant women were randomized to initiate dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG + FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF. Methods We assessed red blood cell (RBC) folate concentrations at maternal study entry and delivery, and infant birth. RBC folate outcomes were (1) maternal change entry to delivery (trajectory), (2) infant, and (3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRTs) of each arm comparison in 340 mothers and 310 infants. Results Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/μL, and log10 HIV RNA was 3 copies/mL. Entry RBC folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG + FTC/TAF versus EFV/FTC/TDF arm (1.03 [95% confidence interval {CI}, 1.00–1.06]). The DTG + FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92 [95% CI,.78–1.09]) versus EFV/FTC/TDF. Conclusions Results are consistent, with no clinically meaningful differences between arms for all RBC folate outcomes, and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- versus EFV-based antiretroviral therapy. Clinical Trials Registration NCT03048422. [ABSTRACT FROM AUTHOR]

Introduction In resource-constrained settings, infant feeding decisions among women with HIV (WHIV) must balance the risk of infant HIV acquisition from breastfeeding with increased mortality associated with formula feeding. WHO guidelines recommend countries principally promote a single feeding method for WHIV, either breastfeeding or formula feeding. In 2016, Botswana revised its policy of formula feeding for infants born to WHIV, instead promoting exclusive breastfeeding during the first 6 months of life. Methods We sought to understand factors influencing infant feeding choices among WHIV by administering a questionnaire to pregnant and postpartum WHIV (2013-2015) participating in a clinical trial in Botswana (the Mpepu Study). Logistic regression analyses were used to identify factors associated with infant feeding choices. Results Of 810 surveyed participants, 24.0% chose breastfeeding and 76.0% chose formula feeding. Women were more likely to choose formula feeding if advised by a health worker to formula feed (aOR 1.90; 95% CI 1.02-3.57) or if they harboured doubts about the potency of antiretroviral treatment (ART) to prevent infant HIV acquisition (aOR 9.06; 95% CI 4.78-17.17). Women who reported lack of confidence in preparing infant formula safely (aOR 0.09; 95% CI 0.04-0.19) or low concerns about infant HIV acquisition (aOR 0.35; 95% CI 0.22-0.55) were significantly less likely to formula feed. Discussion Perceptions about ART effectiveness, social circumstances and health worker recommendations were key influencers of infant feeding choices among WHIV. Health system factors and maternal education interventions represent ideal targets for any programmatic actions aiming to shape informed decision-making towards HIV-free survival of infants., Author(s): Aamirah Mussa [sup.1] , Henock B. Taddese [sup.2] , Ekaterina Maslova [sup.2] , Gbolahan Ajibola [sup.1] , Joseph Makhema [sup.1] , Roger L. Shapiro [sup.1] [sup.3] , Shahin Lockman [...]

Introduction: Most African countries perform infant HIV testing at 6 weeks or later. The addition of targeted testing at birth may improve retention in care, treatment outcomes and survival for HIV-infected infants. Methods: HIV-exposed infants were screened as part of the Early Infant Treatment (EIT) study in Botswana. Screened infants were [greater than or equal to]35 weeks gestational age and [greater than or equal to]2000 g at birth. Risk factors for mother-to-child transmission (MTCT) were assessed by maternal obstetric card or verbally. Risk factors included 400 copies/mL, poor maternal ART adherence, lack of maternal zidovudine (ZDV) in labour, or lack of infant post-exposure prophylaxis. Infants underwent dried blood spot testing by Roche Cobas Ampliprep/Cobas Taqman HIV-1 qualitative PCR. Results: From April2015 to April2016, 2303 HIV-exposed infants were tested for HIV in the EIT study. Of these, 369 (16%) were identified as high risk for HIV infection by information available at birth, and 12 (0.5% overall, 3.25% of high risk) were identified as HIV positive at birth. All 12 positive infants were identified as high risk at the time of screening, and only 2 risk factors were required to identify all positive infants: either Conclusions: In utero MTCT occurred only among infants identified as high risk at delivery, using information available from the mother or obstetric record. Birth testing that targets high-risk infants based on maternal ART receipt is likely to identify the majority of in utero HIV transmissions, and allows early ART initiation for these infants. Keywords: HIV; mother-to-child transmission; children; paediatrics; vertical transmission; viral suppression, 1 | INTRODUCTION The World Health Organization (WHO) recommends HIV testing for all HIV-exposed infants at 4 to 6 weeks of age [1], based on studies demonstrating the benefits of [...]

: Introduction: Antiretrovirals such as dolutegravir (DTG) and tenofovir alafenamide (TAF) have been associated with excessive weight gain. The objective of this study was to understand the potential impact of ART‐associated weight gain on pregnancy outcomes among women living with HIV. Methods: Using data from the Tsepamo birth outcomes surveillance study in Botswana, we evaluated the relationship between maternal weight (and weight gain) and severe birth outcomes (very preterm delivery 4000 g) and maternal hypertension. We estimated the relative risk of each outcome by baseline weight (first weight in pregnancy Results: Of 22,828 women on ART at conception with singleton deliveries between August 2014 and April 2020, 16,300 (71.4%) had a weight measured 90 kg) was associated with increased risk of macrosomia (aRR 3.24, 95% CI 2.36, 4.44) and maternal hypertension (aRR 1.79, 95% CI 1.62, 1.97). Baseline weight was not associated with stillbirth or early neonatal death. For all outcomes, second trimester weight gain showed weaker associations than did baseline weight. Duration of pre‐pregnancy ART (years) was associated with higher baseline weight for DTG but not for EFV, and the risk of maternal hypertension by baseline weight category was higher for DTG than EFV for all strata. Conclusions: ART regimens associated with weight gain may reduce the number of women at risk for certain severe adverse pregnancy outcomes associated with low weight but increase the number at risk of macrosomia and maternal hypertension. Further research could determine whether weight‐based ART treatment strategies improve maternal and child health., INTRODUCTION Multiple studies have reported that tenofovir alafenamide (TAF) and dolutegravir (DTG) are associated with clinically significant weight gain, with risk of treatment‐emergent obesity (body mass index, or BMI, >30) [...]

Broadly neutralizing antibodies (bNAbs) may provide an alternative to standard antiretroviral treatment (ART) for controlling HIV-1 replication and may have immunotherapeutic effects against HIV-1 reservoirs. We conducted a prospective clinical trial with two HIV-1 bNAbs (VRC01LS and 10-1074) in children (n = 25) who had previously initiated small-molecule ART treatment before 7 days of age and who continued treatment for at least 96 weeks. Both bNAbs were dosed intravenously every 4 weeks, overlapping with ART for at least 8 weeks and then continued for up to 24 weeks or until detectable viremia of HIV-1 RNA rose above 400 copies per milliliter in the absence of ART. Eleven (44%) children maintained HIV-1 RNA below 400 copies per milliliter through 24 weeks of bNAb-only treatment; 14 (56%) had detectable viremia above 400 copies per milliliter at a median of 4 weeks. Archived HIV-1 provirus susceptible to 10-1074, lower birth HIV-1 DNA reservoir in peripheral blood mononuclear cells, sustained viral suppression throughout early life, and combined negative qualitative HIV-1 DNA polymerase chain reaction and negative HIV-1 serology at entry were associated with maintaining suppression on bNAbs alone. This proof-of-concept study suggests that bNAbs may represent a promising treatment modality for infants and children living with HIV-1. Future studies using newer bNAb combinations with greater breadth and potency are warranted. Editor's summary: Broadly neutralizing antibodies (bNAbs) have shown promise as a companion or alternative to antiretroviral treatment (ART) for HIV-1, although their efficacy in a pediatric population remains unclear. Here, Shapiro et al. report the results of a prospective clinical trial where children on ART from birth in Botswana were treated with two HIV-1 bNAbs, VRC01LS and 10-1074. The treatment was administered initially in combination with ART then alone. Eleven of 25 infants maintained viral suppression during the bNAb-only step; the authors found that these infants had more favorable HIV-1 reservoir characteristics, including a smaller initial proviral reservoir and susceptibility of those proviruses to bNAb neutralization. Together, these results highlight the potential of bNAb treatment for infants and children living with HIV-1.—Courtney Malo [ABSTRACT FROM AUTHOR]

: Introduction: Despite declining risk of vertical HIV transmission, prophylactic cotrimoxazole (CTX) remains widely used to reduce morbidity and mortality in the event of HIV infection among exposed infants, with an inherent risk of conferring commensal antimicrobial resistance. Using data from a randomized, placebo‐controlled trial of infant CTX prophylaxis, we sought to quantify emergence of antibiotic resistance. Methods: HIV‐exposed uninfected infants enrolled in the Botswana Mpepu study were randomized to prophylactic CTX or placebo between 14 and 34 days of life and continued through 15 months. Stool samples were collected from a subset of participating infants at randomization, three, and six months, and stored at −70°C prior to culture. Specimens that grew Escherichia coli (E. coli) or Klebsiella species (Klebsiella spp.) underwent antibiotic susceptibility testing by Kirby Bauer method using CTX (CTX 1.25/23.75 μg) and Amoxicillin (10 μg) in Mueller Hinton agar. Fisher's exact testing was used to compare prevalence of resistance by randomization arm (CTX/placebo). Results and Discussion: A total of 381 stool samples from 220 infants were cultured: 118 at randomization, 151 at three months, and 112 at six‐months. E. coli was isolated from 206 specimens and Klebsiella spp. from 138 specimens. Resistance to CTX was common in both E. coli and Klebsiella spp. at the randomization visit (52.2% and 37.7% respectively) and did not differ by study arm. E. Coli isolates from CTX recipients at three and six months had 94.9% and 84.2% CTX resistance, as compared with 51.4% and 57.5% CTX resistance in isolates from placebo recipients (p=0.01). Klebsiella spp. isolates from CTX recipients had 79.0% and 68.8% CTX resistance at three and six months, as compared with 19.1% and 14.3% in isolates from placebo recipients (p Conclusions: HIV‐exposed infants randomized to CTX prophylaxis had increased CTX‐resistant commensal gastrointestinal bacteria compared with placebo recipients. Additional research is needed to determine the longer‐term clinical, microbiologic, and public health consequences of antimicrobial resistance selected by infant CTX prophylaxis., Introduction The World Health Organization (WHO) recommends cotrimoxazole (CTX) prophylaxis for HIV‐exposed infants at risk of postnatal HIV transmission, continuing until six weeks after breastfeeding cessation (with confirmation of negative [...]

A prospective observational study was conducted to assess the virologic responses of women and infants to nevirapine-based antiretroviral treatment after previous exposure to a single dose of nevirapine or placebo in the setting of a short course of zidovudine. Results revealed that women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine.

The efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission is compared. It is observed that the formula feeding infants had a higher risk of early mortality and breast feeding infants had a higher risk of HIV transmission in sub-Saharan Africa.