Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review

Background: The integrase strand transfer inhibitor dolutegravir (DTG) is being introduced into low- and middle-income countries (LMICs) as an alternative to first-line treatment with non-nucleoside reverse transcriptase inhibitors. However, DTG is not yet widely recommended for use in pregnant women. The aim of this systematic review was to analyse all available data on birth outcomes and congenital anomalies in the infants of pregnant women treated with DTG. Methods: A PubMed and Embase search was conducted using the terms "dolutegravir" or "DTG" and "pregnancy" or "pregnant" from the earliest available date on the database to 26 July 2017. Any reports involving women who were pregnant, HIV positive and taking DTG were included. The percentage of pregnant women with adverse birth outcomes or congenital anomalies in their infants after taking dolutegravir was compared with five historical control databases. Results: There were six databases included in the main analysis of birth outcomes and congenital anomalies, with a total of 1200 pregnant women. The percentage of pregnant women taking DTG with adverse birth outcomes and congenital abnormalities was similar to results from historical control studies of HIV-positive women. However, there was significant heterogeneity among the six databases - the percentage of infants with congenital anomalies ranged from 0.0% in Botswana (0/116 infants) to 13.3% in IMPAACT P1026S (2/15 infants). Conclusions: Up to 15 million people could be on treatment with DTG in LMICs within the next 5 years, of whom a substantial percentage is likely to be women of child-bearing potential. In many countries with large HIV epidemics, unplanned pregnancies are common and access to antenatal clinic facilities may be limited. Continued pharmacovigilance is essential, but it is reassuring that no clear safety signals have been detected, to date, for pregnant women treated with DTG in terms of birth outcomes or congenital anomalies

HIV treatment in pregnancy

Almost 25 years since antiretroviral therapy (ART) was first shown to prevent mother-to-child transmission of HIV, 76% of pregnant women living with HIV (over 1 million women) receive ART annually. This number is the result of successes in universal ART scale-up in low-income and middle-income countries. Despite unprecedented ART-related benefits to maternal and child health, challenges remain related to ART adherence, retention in care, and unequal access to ART. Implementation research is ongoing to understand and to address obstacles that lead to loss to follow-up. The biological mechanisms that underlie observed associations between antenatal ART and adverse outcomes in pregnancy and birth are not completely understood, with further research needed as well as strengthening of the systems to assess safety of antiretroviral drugs for the mother and HIV-exposed child. In the treat-all era, as duration of treatment and options for ART expand, pregnant women will remain a priority population for treatment optimisation to promote their health and that of their ART-exposed children

Audit of Early Mortality among Patients Admitted to the General Medical Ward at a District Hospital in Botswana

Background: Mortality among adult general medical admissions has been reported to be high across sub-Saharan Africa, yet there is a paucity of literature on causes of general medical inpatient mortality and quality-related factors that may contribute to the high incidence of deaths. Based on a prior study at our hospital as well as our clinical experience, death early in the hospitalization is common among patients admitted to the adult medical wards. Objective: Quantify early inpatient mortality and identify factors contributing to early in-hospital mortality of medical patients in a resource-limited hospital setting in Botswana. Methods: Twenty-seven cases of patients who died within 48 hours of admission to the general medical wards at Scottish Livingstone Hospital in Molepolole, Botswana from December 1, 2015–April 25, 2016 were retrospectively reviewed through a modified root cause analysis. Findings: Early in-hospital mortality was most frequently attributed to septic shock, identified in 20 (74%) of 27 cases. The most common care management problems were delay in administration of antibiotics (15, 56%), inappropriate fluid management (15, 56%), and deficient coordination of care (15, 56%). The most common contributing factors were inadequate provider knowledge and skills in 25 cases (93%), high complexity of presenting condition in 20 (74%), and inadequate communication between team members in 18 (67%). Conclusions: Poor patient outcomes in low-and middle-income countries like Botswana are often attributed to resource limitations. Our findings suggest that while early in-hospital mortality in such settings is associated with severe presenting conditions like septic shock, primary contributors to lack of better outcomes may be healthcare-provider and system-factors rather than lack of diagnostic and therapeutic resources. Low-cost interventions to improve knowledge, skills and communication through a focus on provider education and process improvement may provide the key to reducing early in-hospital mortality and improving hospitalization outcomes in this setting

Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.

CAPRISA, 2019.Abstract available in PDF

Maternal weight and birth outcomes among women on antiretroviral treatment from conception in a birth surveillance study in Botswana.

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. 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 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. 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. [Abstract copyright: © 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.

Review article: Direct-acting antivirals for the treatment of HCV during pregnancy and lactation: implications for maternal dosing, foetal exposure, and safety for mother and child

BACKGROUND: With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct-acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended. AIM: To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation METHODS: A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation. RESULTS: Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy-induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester. CONCLUSIONS: Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination

Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000-2021.

OBJECTIVE: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000-2021. POPULATION: Liveborn infants. METHODS: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. RESULTS: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). CONCLUSIONS: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs

Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000–2021

Objective: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. Design: Descriptive multi-country secondary data analysis. Setting: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000–2021. Population: Liveborn infants. Methods: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. Results: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). Conclusions: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs.The Children's Investment Fund Foundation, grant 2004-04670. The funders had no role in the study design, data collection, analysis or interpretation of the paper