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In countries with high human immunodeficiency virus (HIV) prevalence, up to 30% of pregnant women are living with HIV, with fetal exposure to both HIV and antiretroviral therapy during pregnancy. In addition, pregnant women without HIV but at high risk of HIV acquisition are increasingly receiving HIV preexposure antiretroviral prophylaxis (PrEP). Investments are being made to establish and follow cohorts of children to evaluate the long-term effects of in utero HIV and antiretroviral exposure. Agreement on a key set of definitions for relevant exposures and outcomes is important both for interpreting individual study results and for comparisons across cohorts. Harmonized definitions of in utero HIV and antiretroviral drug (maternal treatment or PrEP) exposure will also facilitate improved classification of these exposures in future observational studies and clinical trials. The proposed definitions offer a uniform approach to facilitate the consistent description and estimation of effects of HIV and antiretroviral exposures on key child health outcomes.

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study’s standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the “PROMISE” (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study’s standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

IntroductionPregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies.DiscussionPregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias.ConclusionsPregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.

As new antiretrovirals (ARVs), including long-acting ARVs for treatment and prevention, are approved and introduced, surveillance during pregnancy must become the safety net for evaluating birth outcomes, especially those that are rare and require large numbers of observations. Historically, drug pharmacovigilance in pregnancy has been limited and fragmented between different data sources, resulting in inadequate data to assess risk. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network and World Health Organization convened a Workshop which reviewed strengths and weaknesses of existing programs and discussed an improved framework to integrate existing safety data sources and promote harmonization and digitalization.This paper highlights that although robust sources of safety data and surveillance programs exist, key challenges remain, including unknown denominators, reporting bias, under-reporting (e.g. in voluntary registries), few data sources from resource-limited settings (most are in North America and Europe), incomplete or inaccurate data (e.g. within routine medical records). However, recent experiences (e.g. with safety signals) and current innovations (e.g. electronic record use in resource-limited settings and defining adverse outcomes) provide momentum and building blocks for a new framework for active surveillance of ARV safety in pregnancy. A public health approach should be taken using data from existing sources, including registries of pregnancy ARV exposure and birth defects; observational surveillance and cohort studies; clinical trials; and real-world databases. Key facilitators are harmonization and standardization of outcomes, sharing of materials and tools, and data linkages between programs. Other key facilitators include the development of guidance to estimate sample size and duration of surveillance, ensuring strategic geographic diversity, bringing partners together to share information and engaging the community of women living with HIV.Looking ahead, critical steps to safely introduce new ARVs include (1) adopting harmonized standards for measuring adverse maternal, birth and infant outcomes; (2) establishing surveillance centres of excellence in areas with high HIV prevalence with harmonized data collection and optimized electronic health records linking maternal/infant data; and (3) creating targets and evaluation goals for reporting progress on implementation and quality of surveillance in pregnancy. The platform will be leveraged to ensure that appropriate contributions and strategic actions by relevant stakeholders are implemented.

Background: Without treatment, HIV infection in pregnant women is associated with adverse pregnancy outcomes. We compared adverse pregnancy outcomes among HIV-positive women on antiretroviral therapy (ART) and HIV-negative women who enrolled for antenatal care in selected health facilities in Maseru district, Lesotho. Methods: We enrolled a cohort of HIV-positive and HIV-negative women at their first antenatal visit and followed them through delivery. Study data on miscarriage, stillbirth, preterm birth, low birth weight and birth defects were collected through participant interviews and medical record abstraction. We used the Rao-Scott χ2 test and the t test to assess differences in characteristics and outcomes between HIV-positive and HIV-negative women and generalized estimating equations for multivariable analysis. Results: A total of 614 HIV-positive and 390 HIV-negative pregnant women were enrolled in the study with delivery information on 571 (93.1%) and 352 (90.3%) respectively. In the delivery cohort, the median age at enrolment was 28 years for HIV-positive women and 23 years for HIV-negative women with median gestational ages of 20 and 21 weeks, respectively. A total of 149 singleton pregnancies had documented adverse pregnancy outcomes; 33 (9.6%) HIV-negative pregnancies and 116 (20.6%) HIV-positive pregnancies. Compared with their HIV-negative counterparts, HIV-positive women were more likely to experience an adverse pregnancy outcome, adjusted odds ratio (AOR) 2.6 [95% confidence interval (CI): 1.71–3.97]; an intrauterine death (miscarriage or stillbirth), AOR 2.64 [95% CI: 1.25–5.49]; or a low birth weight delivery, AOR 1.89 [95% CI: 1.16–3.09]. Conclusion: Adverse pregnancy outcomes remained 2–3 times higher among HIV-positive women compared with HIV-negative women despite universal ART. publishedVersion

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.

This study is a comprehensive review with the purpose of collecting the most relevant data in several sections including current treatment guidelines in the paediatric population.Literature was systematically searched in different databases. Results were limited to 2019+ and English, French and Spanish language.Children can exhibit mild and less severe COVID-19 disease than adults and also have asymptomatic carriage of SARS-CoV-2, while severe disease is more frequently noted during infancy (1 year). SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE-2) receptor; age-, racial-, and gender-specific differences in ACE-2 expression need to be elucidated in order to explain the differential clinical profiles between children and adults. Multisystem inflammatory syndrome in children (MIS-C) is an important condition to recognise in children. The decision to use antiviral or immunomodulatory therapy in a child or adolescent should be individualised based on the clinical scenario. Remdesivir is the only FDA-approved therapy available for children older than 12 years old who require hospitalisation for COVID-19.Further studies are urgently required to address prevention and treatment in at-risk and infected children, especially with underlying comorbidities. The chapter on the overall impact of COVID-19 in children has not yet been written. Nevertheless, SARS-CoV-2 has now joined a long list of human pandemics, which may forever change the world's history.

Scaling Up Covid-19 Vaccination in Africa In the mid-1990s and early 2000s, highly active antiretroviral treatment was accessible in high-income countries but had limited availability in African co...

Little is known about the clinical features and outcomes of SARS-CoV-2 infection in Africa. We conducted a retrospective cohort study of patients hospitalized for COVID-19 between March 10, 2020 and July 31, 2020 at seven hospitals in Kinshasa, Democratic Republic of the Congo (DRC). Outcomes included clinical improvement within 30 days (primary) and in-hospital mortality (secondary). Of 766 confirmed COVID-19 cases, 500 (65.6%) were male, with a median (interquartile range [IQR]) age of 46 (34–58) years. One hundred ninety-one (25%) patients had severe/critical disease requiring admission in the intensive care unit (ICU). Six hundred twenty patients (80.9%) improved and were discharged within 30 days of admission. Overall in-hospital mortality was 13.2% (95% CI: 10.9–15.8), and almost 50% among those in the ICU. Independent risk factors for death were age < 20 years (adjusted hazard ratio [aHR] = 6.62, 95% CI: 1.85–23.64), 40–59 years (aHR = 4.45, 95% CI: 1.83–10.79), and ≥ 60 years (aHR = 13.63, 95% CI: 5.70–32.60) compared with those aged 20–39 years, with obesity (aHR = 2.30, 95% CI: 1.24–4.27), and with chronic kidney disease (aHR = 5.33, 95% CI: 1.85–15.35). In marginal structural model analysis, there was no statistically significant difference in odds of clinical improvement (adjusted odds ratio [aOR] = 1.53, 95% CI: 0.88–2.67, P = 0.132) nor risk of death (aOR = 0.65, 95% CI: 0.35–1.20) when comparing the use of chloroquine/azithromycin versus other treatments. In this DRC study, the high mortality among patients aged < 20 years and with severe/critical disease is of great concern, and requires further research for confirmation and targeted interventions.

Emergency response to emerging threats with the potential for vertical transmission, such as the 2015 to 2017 response to Zika virus, presents unique clinical challenges that underscore the need for better communication and care coordination between obstetric and pediatric providers to promote optimal health for women and infants. Published guidelines for routine maternal-infant care during the perinatal period, and models for transitions of care in various health care settings are available, but no broad framework has addressed coordinated multidisciplinary care of the maternal-infant dyad during emergency response. We present a novel framework and strategies to improve care coordination and communication during an emergency response. The proposed framework includes (1) identification and collection of critical information to inform care, (2) key health care touchpoints for the maternal-infant dyad, and (3) primary pathways of communication and modes of transfer across touchpoints, as well as practical strategies. This framework and associated strategies can be modified to address the care coordination needs of pregnant women and their infants with possible exposure to other emerging infectious and noninfectious congenital threats that may require long-term, multidisciplinary management. KEY POINTS: · Emerging congential threats present unique coordination challenges for obstetric and pediatric clinicians during emergency response.. · We present a framework to help coodinate care of pregnant women/infants exposed to congenital threats.. · The framework identifies critical information to inform care, health care touchpoints, and communication/information transfer pathways..

Supplemental Digital Content is available in the text, Background: The Spectrum/AIM model is used by national programs and UNAIDS to prepare annual estimates of the status of the HIV epidemic in 170 countries. The model and assumptions are updated regularly under the guidance of the UNAIDS Reference Group on Estimates, Modelling and Projections in response to new data, studies and program needs. This article describes the most recent updates for the 2018 round of estimates. Methods: New data on AIDS-related mortality from Europe and Brazil have been used to update mortality rates of those not on antiretroviral therapy (ART). Household survey data and new studies of pregnant women, mothers, and children have been used to improve estimates of the number of HIV-positive pregnant and breastfeeding women and pediatric ART initiation. New tools to estimate geographic variation in HIV prevalence have been used to prepare district estimates of key indicators. Results: The 2018 version of Spectrum includes: new estimates of non-ART AIDS-related mortality by CD4+ count that depend on ART coverage; a procedure to estimate country-specific patterns of HIV incidence by age by fitting to prevalence by age from household surveys; an updated estimate of postpartum transmission with ART started before pregnancy of 0.023% per month; an updated estimate of retention on treatment at delivery of 80% for all women on ART; a somewhat older pattern of ART initiation by age that has 26% of new pediatric patients initiating ART at 10–14 years of age, 18% at 2–4 years of age, and 26% at 5–9 years of age; and a new tool for estimating key HIV indicators at the district level. Conclusion: The new methods and data implemented in the 2018 version of Spectrum allow national programs more flexibility in describing their programs and are intended to improve the estimates of adult mortality and pediatric HIV indicators.

BackgroundThe Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs.MethodsFour pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class “congenital or familial disorders” were searched for NTDs.ResultsNTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators.ConclusionsPharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.

BACKGROUND Global pediatric treatment goals are for 90% of known children living with HIV to be on antiretroviral therapy (ART), with 90% having viral suppression. We used enrollment data from a study evaluating a family-centered HIV care program in Eswatini to describe the ART histories and virologic outcomes of enrolled children living with HIV and identify factors associated with viral suppression (

Objectives We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. Design IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). Methods IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir–maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. Results Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value Conclusions Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis.

Item does not contain fulltext BACKGROUND: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants. SETTING: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10-12, 2018, in Geneva, Switzerland. METHODS: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices. RESULTS: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely-under certain conditions-allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data. CONCLUSION: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy.

In the African context, there is a paucity of data on SARS-CoV-2 infection and associated COVID-19 in pregnancy. Given the endemicity of infections such as malaria, HIV, and tuberculosis (TB) in sub-Saharan Africa (SSA), it is important to evaluate coinfections with SARS-CoV-2 and their impact on maternal/infant outcomes. Robust research is critically needed to evaluate the effects of the added burden of COVID-19 in pregnancy, to help develop evidence-based policies toward improving maternal and infant outcomes. In this perspective, we briefly review current knowledge on the clinical features of COVID-19 in pregnancy; the risks of preterm birth and cesarean delivery secondary to comorbid severity; the effects of maternal SARS-CoV-2 infection on the fetus/neonate; and in utero mother-to-child SARS-CoV-2 transmission. We further highlight the need to conduct multicountry surveillance as well as retrospective and prospective cohort studies across SSA. This will enable assessments of SARS-CoV-2 burden among pregnant African women and improve the understanding of the spectrum of COVID-19 manifestations in this population, which may be living with or without HIV, TB, and/or other coinfections/comorbidities. In addition, multicountry studies will allow a better understanding of risk factors and outcomes to be compared across countries and subregions. Such an approach will encourage and strengthen much-needed intra-African, south-to-south multidisciplinary and interprofessional research collaborations. The African Forum for Research and Education in Health’s COVID-19 Research Working Group has embarked upon such a collaboration across Western, Central, Eastern and Southern Africa.

IntroductionRapid, robust and continually updated evidence synthesis is required to inform management of COVID-19 in pregnant and postpartum women and to keep pace with the emerging evidence during the pandemic.Methods and analysisWe plan to undertake a living systematic review to assess the prevalence, clinical manifestations, risk factors, rates of maternal and perinatal complications, potential for mother-to-child transmission, accuracy of diagnostic tests and effectiveness of treatment for COVID-19 in pregnant and postpartum women (including after miscarriage or abortion). We will search Medline, Embase, WHO COVID-19 database, preprint servers, the China National Knowledge Infrastructure system and Wanfang databases from 1 December 2019. We will supplement our search with studies mapped by Cochrane Fertility and Gynaecology group, Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre), COVID-19 study repositories, reference lists and social media blogs. The search will be updated every week and not be restricted by language. We will include observational cohort (≥10 participants) and randomised studies reporting on prevalence of COVID-19 in pregnant and postpartum women, the rates of clinical manifestations and outcomes, risk factors in pregnant and postpartum women alone or in comparison with non-pregnant women with COVID-19 or pregnant women without COVID-19 and studies on tests and treatments for COVID-19. We will additionally include case reports and series with evidence on mother-to-child transmission of SARS-CoV-2 in utero, intrapartum or postpartum. We will appraise the quality of the included studies using appropriate tools to assess the risk of bias. At least two independent reviewers will undertake study selection, quality assessment and data extraction every 2 weeks. We will synthesise the findings using quantitative random effects meta-analysis and report OR or proportions with 95% CIs and prediction intervals. Case reports and series will be reported as qualitative narrative synthesis. Heterogeneity will be reported as I2 and τ2 statistics.Ethics and disseminationEthical approval is not required as this is a synthesis of primary data. Regular updates of the results will be published on a dedicated website (https://www.birmingham.ac.uk/research/who-collaborating-centre/pregcov/index.aspx) and disseminated through publications, social media and webinars.PROSPERO registration numberCRD42020178076.

BACKGROUND Breastfeeding mothers with HIV infection not qualifying for antiretroviral therapy (ART) based on country-specific guidelines at the time of the Promoting Maternal-Infant Survival Everywhere trial and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) postpartum. HIV transmission proportions were similar (

Background To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. Methods We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework. Findings We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92). Interpretation The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable. Funding WHO.

Summary box In December 2019, a novel coronavirus, SARS-CoV-2, emerged in Wuhan City, China, causing a cluster of cases of severe pneumonia (COVID-19), and becoming a global pandemic. Individuals of all ages are susceptible to SARS-CoV-2, but older age and underlying comorbidities are known to be associated with increased risk of disease severity and mortality. However, despite the rapidly increasing amount of data on SARS-CoV-2 infection and COVID-19, data on how SARS-CoV-2 affects children and adolescents remain limited and conflicting, with an increased spectrum of disease manifestations emerging (eg, multisystem inflammatory syndrome). Critical research needs have emerged with important public policy implications. In initial data from China, children had significantly lower rates and severity of COVID-19 than adults; 2% of cases were aged 0–19 years, 0.9%

Introduction Findings from biomedical, behavioural and implementation studies provide a rich foundation to guide programmatic efforts for the prevention of mother‐to‐child HIV transmission (PMTCT). Methods We summarized the current evidence base to support policy makers, programme managers, funding agencies and other stakeholders in designing and optimizing PMTCT programmes. We searched the scientific literature for PMTCT interventions in the era of universal antiretroviral therapy for pregnant and breastfeeding women (i.e. 2013 onward). Where evidence was sparse, relevant studies from the general HIV treatment literature or from prior eras of PMTCT programme implementation were also considered. Studies were organized into six categories: HIV prevention services for women, timely access to HIV testing, timely access to ART, programme retention and adherence support, timely engagement in antenatal care and services for infants at highest risk of HIV acquisition. These were mapped to specific missed opportunities identified by the UNAIDS Spectrum model and embedded in UNICEF operational guidance to optimize PMTCT services. Results and discussion From May to November 2019, we identified numerous promising, evidence‐based strategies that, properly tailored and adopted, could contribute to population reductions in vertical HIV transmission. These spanned the HIV and maternal and child health literature, emphasizing the importance of continued alignment and integration of services. We observed overlap between several intervention domains, suggesting potential for synergies and increased downstream impact. Common themes included integration of facility‐based healthcare; decentralization of health services from facilities to communities; and engagement of partners, peers and lay workers for social support. Approaches to ensure early HIV diagnosis and treatment prior to pregnancy would strengthen care across the maternal lifespan and should be promoted in the context of PMTCT. Conclusions A wide range of effective strategies exist to improve PMTCT access, uptake and retention. Programmes should carefully consider, prioritize and plan those that are most appropriate for the local setting and best address existing gaps in PMTCT health services.

BackgroundAlthough mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission.MethodsA Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis.ResultsForty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1–6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding.ConclusionsSubcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.

The first step in improving morbidity and mortality among children living with HIV is the timely and early identification of HIV infection, which must be followed by rapid engagement in care and provision of antiretroviral therapy. However, in 2018, only 59% of HIV-exposed infants received an infant nucleic acid diagnostic test by age 2 months and only 54% of children living with HIV received treatment. Because infant diagnosis requires molecular techniques to detect viral nucleic acid, programs for early diagnosis of infection in infants are more complex than those in adults and often require coordination and management of multiple health facilities as well as logistic, financial, and human resource challenges. This article will discuss challenges at each step in the early infant diagnosis cascade and innovations that may help overcome these challenges.

Background HIV-positive children have lagged adults on retention in HIV care and viral suppression. To address this gap, Eswatini’s Ministry of Health started a pilot family-centered HIV care model (FCCM) targeting HIV-positive children under 20 years old and their families. Methods We conducted semi-structured in-depth interviews with 25 caregivers and 17 healthcare workers (HCWs) to assess acceptability of FCCM in four pilot FCCM health facilities in Hhohho region of Eswatini. Thematic analysis with inductive and deductive codes was used to identify salient themes. Results Caregivers and HCWs reported FCCM benefits including strengthening the family bond, encouragement for family members to disclose their HIV status and supporting each other in taking antiretroviral drugs. Caregivers reported that they spent fewer days in clinic, experienced shorter waiting times, and received better counseling services in FCCM compared to the standard-of-care services. FCCM implementation challenges included difficulty for families to attend clinic visits together (e.g., due to scheduling conflicts with weekend Teen Support Club meetings and weekday FCCM appointments). Both HCWs and caregivers mentioned difficulty in sharing sensitive health information in the presence of other family members. HCWs also had challenges with supporting caregivers to disclose HIV status to children and managing the larger group during clinic visits. Conclusions FCCM for HIV-positive children was acceptable to both caregivers and HCWs, and they supported scaling-up FCCM implementation nationally. However, special considerations should be made to address the challenges experienced by participants in attending clinic visits together as a family in order to achieve the full benefits of FCCM for HIV positive children.

Pregnancy is a period of high HIV acquisition risk for African women, and pregnant women who become acutely infected with HIV account for up to one-third of vertical HIV transmissions. To protect women and eliminate vertical transmission, the World Health Organization recommends offering oral tenofovir-based pre-exposure prophylaxis (PrEP) to HIV-negative pregnant and postpartum women with substantial HIV acquisition risk. PrEP implementation for pregnant and postpartum women lags behind other high-risk populations. Unique considerations for PrEP implementation arise during pregnancy and postpartum, including integration of provider training, clinical delivery, and monitoring PrEP exposure and outcomes within existing maternal health systems, yet few implementation data are available to generate evidence in this context. In this Viewpoint, we examine current PrEP delivery among pregnant and postpartum African women, identify gaps in evidence according to the RE-AIM framework, and offer recommendations to guide the implementation science research agenda to optimize PrEP for these populations.

Author(s): Joseph Davey, Dvora L; Pintye, Jillian; Baeten, Jared M; Aldrovandi, Grace; Baggaley, Rachel; Bekker, Linda-Gail; Celum, Connie; Chi, Benjamin H; Coates, Thomas J; Haberer, Jessica E; Heffron, Renee; Kinuthia, John; Matthews, Lynn T; McIntyre, James; Moodley, Dhayendre; Mofenson, Lynne M; Mugo, Nelly; Myer, Landon; Mujugira, Andrew; Shoptaw, Steven; Stranix-Chibanda, Lynda; John-Stewart, Grace; PrEP in Pregnancy Working Group | Abstract: IntroductionHIV incidence is high during pregnancy and breastfeeding with HIV acquisition risk more than doubling during pregnancy and the postpartum period compared to when women are not pregnant. The World Health Organization recommends offering pre-exposure prophylaxis (PrEP) to pregnant and postpartum women at substantial risk of HIV infection. However, maternal PrEP national guidelines differ and most countries with high maternal HIV incidence are not offering PrEP. We conducted a systematic review of recent research on PrEP safety in pregnancy to inform national policy and rollout.MethodsWe used a standard Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) approach to conduct a systematic review by searching for completed, ongoing, or planned PrEP in pregnancy projects or studies from clinicaltrials.gov, PubMed and NIH RePORTER from 2014 to March 2019. We performed a systematic review of studies that assess tenofovir disoproxil fumarate (TDF)-based oral PrEP safety in pregnant and breastfeeding HIV-uninfected women.Results and discussionWe identified 14 completed (n = 5) and ongoing/planned (n = 9) studies that evaluate maternal and/or infant outcomes following PrEP exposure during pregnancy or breastfeeding. None of the completed studies found differences in pregnancy or perinatal outcomes associated with PrEP exposure. Nine ongoing studies, to be completed by 2022, will provide data on g6200 additional PrEP-exposed pregnancies and assess perinatal, infant growth and bone health outcomes, expanding by sixfold the data on PrEP safety in pregnancy. Research gaps include limited data on (1) accurately measured PrEP exposure within maternal and infant populations including drug levels needed for maternal protection; (2) uncommon perinatal outcomes (e.g. congenital anomalies); (3) infant outcomes such as bone growth beyond one year following PrEP exposure; (4) outcomes in HIV-uninfected women who use PrEP during pregnancy and/or lactation.ConclusionsExpanding delivery of PrEP is an essential strategy to reduce HIV incidence in pregnancy and breastfeeding women. Early safety studies of PrEP among pregnant women without HIV infection are reassuring and ongoing/planned studies will contribute extensive new data to bolster the safety profile of PrEP use in pregnancy. However, addressing research gaps is essential to expanding PrEP delivery for women in the context of pregnancy.

This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyl-tert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despite the increased dose, M8 AUC was lower during the third trimester compared to postpartum (0.53, IQR [0.38-0.75]), as was the M8/NFV AUC ratio (0.51, IQR [0.42-0.63]). NFV AUC0-12 was above target in 15 of 18 (83%) of participants during the third trimester compared to 14 of 16 (88%) postpartum. No major safety concerns were noted. Increasing the NFV dose to 1875 mg twice daily during the third trimester achieved similar concentrations postpartum compared to standard dosing (1250 mg twice daily). Increased NFV dose regimens may still have some benefit to human immunodeficiency virus (HIV)-positive pregnant women living in countries where novel protease inhibitors are currently unavailable or in individuals who are intolerant to ritonavir-boosted HIV medications.

Observational data characterizing the pediatric and adolescent HIV epidemics in real-world settings are critical to informing clinical guidelines, governmental HIV programs, and donor prioritization. Global expertise in curating and analyzing these data has been expanding, with increasingly robust collaborations and the identification of gaps in existing surveillance capacity. In this commentary, we describe existing sources of observational data for children and youth living with HIV, focusing on larger regional and global research cohorts, and targeted surveillance studies and programs. Observational data are valuable resources to cross-validate other research and to monitor the impact of changing HIV program policies. Observational studies were among the first to highlight the growing population of children surviving perinatal HIV and transitioning to adolescence and young adulthood, and have raised serious concerns about high rates of treatment failure, loss to follow-up, and death among older perinatally infected youth. The use of observational data to inform modeling of the current global epidemic, predict future patterns of the youth cascade, and facilitate antiretroviral forecasting are critical priorities and key end products of observational HIV research. Greater investments into data infrastructure are needed at the local level to improve data quality and at the global level to faciliate reliable interpretation of the evolving patterns of the pediatric and youth epidemics. Although this includes harmonized data forms, use of unique patient identifiers to allow for data linkages across routine data sets and electronic medical record systems, and competent data managers and analysts are essential to make optimal use of the data collected.

Introduction A family-centered care model (FCCM) providing family-based HIV services, rather than separate adult/pediatric services, has been proposed to increase pediatric retention and treatment adherence. Materials and methods Eight health-care facilities in the Hhohho region of Eswatini were randomized to implement FCCM (n = 4) or continue standard-of-care (SOC) separate adult/pediatric clinics (n = 4). HIV-positive children and caregivers were enrolled; caregiver interview and child/caregiver chart abstraction were done at enrollment and every three months; pediatric viral load was evaluated at enrollment and every six months through 12 months. Because of study group differences in 12-month viral load data availability (89.4% FCCM and 72.0% SOC children had 12-month viral load), we used three separate analyses to evaluate the effects of FCCM on children’s viral suppression ( Results We enrolled 379 HIV-positive children and 363 caregivers. Among all children at enrollment, viral suppression and undetectability was 78.4% and 73.9%, respectively, improving to 90.2% and 87.3% at 12 months. In mITT and weighted mITT analyses, there was no significant difference in children’s 12-month viral suppression between FCCM and SOC groups (89.2% and 91.6%, respectively). Using imputed ITT, there was a modest increase in 12-month viral suppression in FCCM versus SOC children (79.7% and 69.8%, respectively, p = 0.051) and 12-month undetectability (78.7% and 65.7%, respectively, p = 0.015). Among the 255 children suppressed at enrollment, more FCCM versus SOC children (98.0% versus 95.3%) were suppressed at 12-months, but this was not statistically significant in mITT or weighted mITT analyses, with a marginally significant difference using imputed mITT analysis (p = 0.042). A higher proportion of children suppressed at enrollment had undetectable viral load at 12 months in FCCM versus SOC children (98.0% versus 92.5%), a statistically significant difference across analytical methods. Among the 61 children unsuppressed at enrollment, achieving suppression was higher among SOC versus FCCM children, but this difference was not statistically significant and included only 38 children; and there were no significant differences in detectable viral load at 12 months. There were no significant differences between study groups in retention or ART adherence at 12 months for children or caregivers. Factors associated with lack of viral suppression/detectability at 12 months included lack of viral suppression at enrollment and having a younger caregiver (age Conclusions FCCM in Eswatini was associated with a modest increase in viral suppression/undetectability at 12-months; 12-month retention and adherence did not differ by study group for children or caregivers. High levels of suppression and retention in both groups may have limited our ability to detect a difference. Trial registration NCT03397420; ClinicalTrials.gov.

Introduction The incidence and treatment of cancer in HIV-infected children from resource-limited settings has not been extensively studied. Objectives Develop and implement a cross-sectional survey to evaluate pediatric cancer burden, diagnostic modalities in use, and treatment availability as perceived by HIV clinic staff at regional International Epidemiology Databases to Evaluate AIDS (IeDEA) sites. Methods IeDEA regional investigators developed a cross-sectional clinical site survey which included questions on the numbers and types of pediatric cancers observed, modalities used to treat identified cancers, and treatment options available at individual sites in the Asia-Pacific, Latin America, Central Africa, East Africa, West Africa, and Southern Africa regions. Results Kaposi sarcoma, non-Hodgkin lymphoma, and Burkitt lymphoma were reported by site personnel to be the most prevalent types of cancer in the pediatric HIV population. Survey results indicate that access to comprehensive cancer treatment modalities is very limited for children in these regions despite HIV care and treatment sites reporting that they diagnose pediatric cancers. Responses also showed that evaluating cancer in the pediatric HIV population is a challenge due to a lack of resources and varying treatment availability within regions. Conclusions Further study is needed to increase our understanding of the changing epidemiology of cancer in HIV-infected pediatric populations. Increased financial and technical resources are critical to aid in the advancement of health services to support treatment of these children in resource-constrained settings.

Background The importance of youth engagement in designing, implementing and evaluating programs has garnered more attention as international initiatives seek to address the HIV crisis among this population. Adolescents, however, are not often included in HIV implementation science research and have not had opportunities to contribute to the development of HIV-related research agendas. Project Supporting Operational AIDS Research (SOAR), a United States Agency for International Development-funded global operations research project, involved youth living with HIV in a meeting to develop a strategic implementation science research agenda to improve adolescent HIV care continuum outcomes, including HIV testing and counseling (HTC) and linkage to care. Methods Project SOAR convened a 2-day meeting of 50 experts, including four youth living with HIV. Participants examined the literature, developed research questions, and voted to prioritize these questions for the implementation science research agenda. This article presents the process of involving youth, how they shaped the course of discussions, and the resulting priority research gaps identified at the meeting. Results Youth participation influenced working group discussions and the development of the implementation science agenda. Research gaps identified included how to engage vulnerable adolescents, determining the role that stigma, peers, and self-testing have in shaping adolescent HTC behaviors, and examining the costs of different HTC and linkage to care strategies. Conclusion The meeting participants developed the research agenda to guide future implementation science research to improve HIV outcomes among adolescents in sub-Saharan Africa. This process highlighted the importance of youth in shaping implementation science research agendas and the need for greater youth engagement.

Cytomegalovirus (CMV) urinary shedding in pregnant women infected with human immunodeficiency virus (HIV) was evaluated to determine whether it poses an increased risk for congenital CMV infection (cCMV).A subset of mother-infant pairs enrolled in the perinatal NICHD HPTN 040 study (distinguished by no antiretroviral use before labor) was evaluated. Maternal and infant urines were tested by qualitative real-time polymerase chain reaction (RT-PCR) for CMV DNA with quantitative RT-PCR performed on positive specimens.Urine specimens were available for 260 women with 85.4% from the Americas and 14.6% from South Africa. Twenty-four women (9.2%) had detectable CMV viruria by qualitative PCR. Maternal CMV viruria was not associated with mean CD4 cell counts or HIV viral load but was associated with younger maternal age (P = .02). Overall, 10 of 260 infants (3.8%) had cCMV. Women with detectable peripartum CMV viruria were more likely to have infants with cCMV than those without: 20.8% (5/24) versus 2.1% (5/236), (P = .0001). Women with CMV viruria had significantly higher rates of HIV perinatal transmission (29.2% vs. 8.1%, P = .002). They were 5 times (adjusted odds ratio [aOR] = 5.6, 95% confidence interval [CI] 1.9-16.8) and nearly 30 times (aOR, 29.7; 95% CI, 5.4-164.2) more likely to transmit HIV and CMV to their infants, respectively. Maternal gonorrhea (aOR, 19.5; 95% CI, 2.5-151.3) and higher maternal HIV log10 viral load (OR, 2.8; 95% CI, 1.3-6.3) were also significant risk factors for cCMV.In this cohort of HIV-infected pregnant women not on antiretrovirals, urinary CMV shedding was a significant risk factor for CMV and HIV transmission to infants.NCT00099359.

Author(s): Osorio, Luiz Eduardo; Boechat, Maria Ines; Mirochnick, Mark; Kumwenda, Newton; Kreitchmann, Regis; Emel, Lynda; Pinto, Jorge; Joao, Esau; Santos, Breno; Swenson, Molly; George, Kathleen; Sato, Paul; Mofenson, Lynne; Nielsen-Saines, Karin; HIV Prevention Trials Network (HPTN) 057 Protocol Team | Abstract: BackgroundTenofovir 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.MethodsHand/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.ResultsAcross 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.ConclusionBone 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.

Pregnant/lactating women in some sub-Saharan Africa settings are at substantial risk of HIV acquisition and could benefit from preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF), but safety data in pregnancy/lactation are limited.Systematic data review through August 2016.We reviewed research reports/conference abstracts with maternal/child adverse outcome data in HIV-infected and HIV-uninfected pregnant/lactating women receiving TDF alone or in combination with other drugs compared with non-TDF regimens.In total, 26 articles in HIV-infected and seven in HIV-uninfected women were identified. No statistically significant differences were observed between TDF and comparison non-TDF regimens in pregnancy incidence, stillbirth/pregnancy loss, preterm delivery less than 37 weeks, low birth weight2500/1500 g, small for gestational age, birth defects, or infant (14 days) or maternal mortality. One study reported significantly higher very preterm delivery (34 weeks) and neonatal mortality with TDF versus non-TDF antiretroviral therapy (ART), but no significant difference between TDF ART and zidovudine/single-dose nevirapine. Most studies report normal infant linear growth; one study showed slightly lower, and one higher 1-year length-for-age z-score in TDF ART-exposed infants. No significant differences were reported in abnormal laboratory values or bone markers between TDF and non-TDF-exposed infants in four studies. Lower maternal bone mineral density was observed at 74 weeks postpartum in breastfeeding women on TDF ART compared with no ART in one study.Given available safety data, there does not appear to be a safety-related rationale for prohibiting PrEP during pregnancy/lactation or for discontinuing PrEP in HIV-uninfected women receiving PrEP who become pregnant and are at continuing risk of HIV acquisition.

Summary Background Although lifelong combination antiretroviral therapy (ART) is recommended for all individuals with HIV, few data exist for pregnancy outcomes associated with ART initiation before conception. We assessed adverse pregnancy outcomes associated with ART initiated before conception compared with that of ART started after conception. Methods We did a systematic review of studies from low-income, middle-income, and high-income countries by searching the Cochrane Central Register of Controlled Trials, Embase, LILACS, MEDLINE, Toxline, Web of Knowledge, and WHO Global Index Medicus and trials in progress (International Clinical Trials Registry Platform) for randomised trials, quasi-randomised trials, and prospective cohort studies done between Jan 1, 1980, and June 1, 2016, in which timing of ART initiation in pregnant women living with HIV was reported. We used the risk ratio (RR) and corresponding 95% CIs as the primary measure to assess the association between the selected outcomes and ART initiation before conception versus after conception. We used a random-effects model to pool risk ratios. Findings We included 11 studies with 19 189 mother–infant pairs. Women who started ART before conception were significantly more likely to deliver preterm (pooled RR 1·20, 95% CI 1·01−1·44) or very preterm (1·53, 1·22−1·92), or to have low-birthweight infants (1·30, 1·04−1·62) than were those who began ART after conception. Few data exist for neonatal mortality. The risk of very low birthweight, small for gestational age, severe small for gestational age, stillbirth, and congenital anomalies did not differ significantly between women who were taking ART before conception and those who began ART after conception. Interpretation The benefits of ART for maternal health and prevention of perinatal transmission outweigh risks, but data for the extent and severity of these risks are scarce and of low quality. As use of ART before conception rapidly increases globally, monitoring for potential adverse pregnancy outcomes will be crucial. Funding WHO.

SETTING International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis (TB) prevention trial conducted among children enrolled from 2004 to 2008 during South Africa's roll-out of combination antiretroviral therapy (ART). OBJECTIVE To estimate TB incidence and mortality and the effect of ART. DESIGN Children were pre-screened to exclude TB disease and exposure, actively screened 3-monthly for TB exposure and symptoms, and provided post-exposure isoniazid prophylaxis therapy (IPT). TB diagnoses were definite, probable, or possible, and mortality all-cause. Testing was at the 5% significance level. RESULTS In 539 children (aged 3-4 months) followed up for a median of 74 weeks (interquartile range [IQR] 48-116), incidence/100 person-years (py) was 10.67 (95%CI 8.47-13.26) for any TB and 2.89 (95%CI 1.85-4.31) for definite/probable TB. Any TB incidence was respectively 9.39, 13.59, and 9.83/100 py before

Introduction The unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk‐benefit messaging when a safety signal is identified. Discussion The Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll‐out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high‐quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified. Conclusions The response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk‐benefit trade‐offs in a variety of contexts; guidance to transform this risk‐benefit balance into effective and agreed‐upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.

BACKGROUND Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration. METHODS In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks. FINDINGS At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6-6·9) and 82 885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9-52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20-57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0-3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5-7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6-1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p

BackgroundRandomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking.MethodsWe randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety.ResultsThe median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P