Long-acting antiretroviral products have the potential to transform human immunodeficiency virus (HIV) prevention and treatment approaches in pediatric populations. Broadly neutralizing antibodies and/or long-acting antiretroviral formulations by injection could dramatically improve provision of HIV prophylaxis and/or early treatment to newborns and infants at risk of HIV infection. Challenges in daily oral antiretroviral administration to toddlers and school age children living with HIV may be relieved by use of long-acting formulations, but the pharmacokinetics and safety of these products in children must be studied before they can enter routine clinical use. Although some initial studies of broadly neutralizing antibodies and injectable long-acting agents in infants and young children are underway, more studies of these and other long-acting products are needed. For many adolescents, compliance with daily medication administration is especially challenging. Long-acting products hold particular promise for adolescents living with HIV as well as those at high risk of HIV acquisition, and adolescents can usually be included in the drug development pipeline simultaneously with adults. Long-acting products have the potential to provide alternatives to lifelong daily oral drug administration across the pediatric age spectrum, leading to more effective prevention and treatment of HIV infection in infants, children, and adolescents.

Medication use during pregnancy in the absence of pharmacokinetic and safety data is common, particularly for antiretrovirals, as pregnant women are not usually included in clinical trials leading to drug licensure. To date, data are typically generated through opportunistic pregnancy studies performed in the postmarketing setting, leading to a substantial time-lag between initial regulatory approval of a drug and availability of essential pregnancy-specific pharmacokinetic and safety data. During this period, health care providers lack key information on human placental transfer, fetal exposure, optimal maternal dosing in pregnancy, and maternal and fetal drug toxicity, including teratogenicity risk. We discuss new approaches that could facilitate the acquisition of these critical data earlier in the drug development process, aiding clinicians and patients in making informed decisions on drug selection and dosing during pregnancy. An integrated approach utilizing multiple novel methodologies (in vitro, ex vivo, in silico and in vivo) is needed to accelerate the availability of pharmacology data in pregnancy and lactation.

In settings with a high burden of HIV, pregnant women often experience a cluster of risk factors, including alcohol use and intimate partner violence (IPV). These interrelated risks are poorly understood among pregnant women at risk of HIV in sub-Saharan Africa. We aim to determine cross-sectional associations between pregnant women's alcohol use and victimization due to IPV in the HIV-Unexposed-Uninfected Mother-Infant Cohort Study in Cape Town, South Africa. Women who tested HIV-negative at first antenatal care (ANC) visit were followed to delivery. Trained interviewers collected demographic and psychosocial information, including recent alcohol use and experiences of IPV victimization. We assess the prevalence of alcohol use and associations with IPV using multivariable logistic regression. In 406 HIV-uninfected pregnant women (mean age = 28 years; mean gestational age = 21 weeks), 41 (10%) reported alcohol consumption in the past 12 months; 30/41 (73%) of these at hazardous levels. Any and hazardous alcohol use were associated with greater odds of reporting past year IPV (adjusted odds ratio [aOR] for hazardous use: 3.24, 95% CI = 1.11, 7.56; aOR for any alcohol use: 2.97, 95% CI = 1.19, 7.45). These data suggest the occurrence of overlapping HIV risk factors among pregnant women and may help design improved health interventions in this population.

Background

Intensified 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.

Methods

We 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.

Results

Coverage 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%).

Discussion

Although 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

Studies in adults and children suggested that starting antiretroviral therapy (ART) soon after infection positively influences early events in HIV infection raising the possibility that remission may be achieved in some.

Methods

We designed an analytic treatment interruption (ATI) trial to test the hypothesis that a sizable minority of HIV-infected neonates who initiated ART <14 days of birth and maintained on ART would be able to maintain viral suppression when ART was withdrawn. To yield the target cohort for this trial, 73 HIV-infected neonates identified at one hospital in Johannesburg, South Africa, were initiated on ART <14 days of birth and maintained on ART tracking viral load (VL) decline and immune recovery (clinicaltrials.gov # NCT02431975).

Findings

Three HIV-infected infants (4.1%) died and nine (12.3%) were lost to follow-up before 48 weeks of age. Of those surviving on study, 52.5% attained and sustained VL <50 copies/ml and half of these sustained CD4+ T-cell percentage >30% which were the primary entry criteria for the ATI trial. Proportions achieving ATI eligibility criteria were similar in the 46 infants starting ART <48 h (19.6%) to 27 infants starting 2-14 days (25.9%) (p = 0.567).

Interpretation

Very early ART on its own, using regimens available when the trial was designed, is insufficient to attain minimum entry criteria needed to justify our trial of ART interruption. Decisions about how quickly to start ART should be based on optimizing standard clinical outcomes rather than with the expectation that remission can be attained.

Funding

NICHD/NIAID (U01HD080441), South African Research Chairs Initiative of DST and NRF (South Africa).

Despite considerable progress in paediatric HIV treatment and timely revision of global policies recommending the use of more effective and tolerable antiretroviral regimens, optimal antiretroviral formulations for infants, children, and adolescents remain limited. The Paediatric Antiretroviral Drug Optimization group reviews medium-term and long-term priorities for antiretroviral drug development to guide industry and other stakeholders on formulations most needed for low-income and middle-income countries. The group convened in December, 2018, to assess progress since the previous meeting and update the list of priority formulations. Issues relating to drug optimisation for neonatal prophylaxis and paediatric treatment, and those relating to the investigation of novel antiretrovirals in adolescents and pregnant and lactating women were also discussed. Continued focus on identifying, prioritising, and providing access to optimal antiretroviral formulations suitable for infants, children, and adolescents is key to ensuring that global HIV treatment targets can be met.

: In 2015, only 53 infants born in the United States acquired HIV - the lowest recorded number of perinatal HIV infections. Recognizing this significant achievement, we must acknowledge that the United States has not yet reached the goal of eliminating perinatal HIV transmission. This analysis describes different approaches to perinatal HIV preventive services among five states and the District of Columbia as case studies. Continuous focus on improving identification, surveillance and prevention of HIV infection in pregnant women and their infants is necessary to reach the goal of eliminating perinatal HIV transmission in the United States.

Introduction

Maternal antiretroviral therapy (ART) with viral suppression prior to conception, during pregnancy and throughout the breastfeeding period accompanied by infant postnatal prophylaxis (PNP) forms the foundation of current approaches to preventing vertical HIV transmission. Unfortunately, infants continue to acquire HIV infections, with half of these infections occurring during breastfeeding. A consultative meeting of stakeholders was held to review the current state of PNP globally, including the implementation of WHO PNP guidelines in different settings and identifying the key factors affecting PNP uptake and impact, with an aim to optimize future innovative strategies.

Discussion

WHO PNP guidelines have been widely implemented with adaptations to the programme context. Some programmes with low rates of antenatal care attendance, maternal HIV testing, maternal ART coverage and viral load testing capacity have opted against risk-stratification and provide an enhanced PNP regimen for all infants exposed to HIV, while other programmes provide infant daily nevirapine antiretroviral (ARV) prophylaxis for an extended duration to cover transmission risk throughout the breastfeeding period. A simplified risk stratification approach may be more relevant for high-performing vertical transmission prevention programmes, while a simplified non-risk stratified approach may be more appropriate for sub-optimally performing programmes given implementation challenges. In settings with concentrated epidemics, where the epidemic is often driven by key populations, infants who are found to be exposed to HIV should be considered at high risk for HIV acquisition. All settings could benefit from newer technologies that promote retention during pregnancy and throughout the breastfeeding period. There are several challenges in enhanced and extended PNP implementation, including ARV stockouts, lack of appropriate formulations, lack of guidance on alternative ARV options for prophylaxis, poor adherence, poor documentation, inconsistent infant feeding practices and in inadequate retention throughout the duration of breastfeeding.

Conclusions

Tailoring PNP strategies to a programmatic context may improve access, adherence, retention and HIV-free outcomes of infants exposed to HIV. Newer ARV options and technologies that enable simplification of regimens, non-toxic potent agents and convenient administration, including longer-acting formulations, should be prioritized to optimize the effect of PNP in the prevention of vertical HIV transmission.

Despite progress in providing antiretroviral therapy to pregnant women living with HIV, a substantial number of vertical transmissions continue to occur. Novel approaches leveraging modern potent, safe, and well-tolerated antiretroviral drugs are urgently needed.