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Maintaining high levels of adherence to antiretroviral therapy (ART) is a challenge across settings and populations. Understanding the relative importance of different barriers to adherence will help inform the targeting of different interventions and future research priorities. We searched MEDLINE via PubMed, Embase, Web of Science, and PsychINFO from 01 January 1997 to 31 March 2016 for studies reporting barriers to adherence to ART. We calculated pooled proportions of reported barriers to adherence per age group (adults, adolescents, and children). We included data from 125 studies that provided information about adherence barriers for 17,061 adults, 1,099 children, and 856 adolescents. We assessed differences according to geographical location and level of economic development. The most frequently reported individual barriers included forgetting (adults 41.4%, 95% CI 37.3%-45.4%; adolescents 63.1%, 95% CI 46.3%-80.0%; children/caregivers 29.2%, 95% CI 20.1%-38.4%), being away from home (adults 30.4%, 95% CI 25.5%-35.2%; adolescents 40.7%, 95% CI 25.7%-55.6%; children/caregivers 18.5%, 95% CI 10.3%-26.8%), and a change to daily routine (adults 28.0%, 95% CI 20.9%-35.0%; adolescents 32.4%, 95% CI 0%-75.0%; children/caregivers 26.3%, 95% CI 15.3%-37.4%). Depression was reported as a barrier to adherence by more than 15% of patients across all age categories (adults 15.5%, 95% CI 12.8%-18.3%; adolescents 25.7%, 95% CI 17.7%-33.6%; children 15.1%, 95% CI 3.9%-26.3%), while alcohol/substance misuse was commonly reported by adults (12.9%, 95% CI 9.7%-16.1%) and adolescents (28.8%, 95% CI 11.8%-45.8%). Secrecy/stigma was a commonly cited barrier to adherence, reported by more than 10% of adults and children across all regions (adults 13.6%, 95% CI 11.9%-15.3%; children/caregivers 22.3%, 95% CI 10.2%-34.5%). Among adults, feeling sick (15.9%, 95% CI 13.0%-18.8%) was a more commonly cited barrier to adherence than feeling well (9.3%, 95% CI 7.2%-11.4%). Health service-related barriers, including distance to clinic (adults 17.5%, 95% CI 13.0%-21.9%) and stock outs (adults 16.1%, 95% CI 11.7%-20.4%), were also frequently reported. Limitations of this review relate to the fact that included studies differed in approaches to assessing adherence barriers and included variable durations of follow up. Studies that report self-reported adherence will likely underestimate the frequency of non-adherence. For children, barriers were mainly reported by caregivers, which may not correspond to the most important barriers faced by children. Patients on ART face multiple barriers to adherence, and no single intervention will be sufficient to ensure that high levels of adherence to treatment and virological suppression are sustained. For maximum efficacy, health providers should consider a more triaged approach that first identifies patients at risk of poor adherence and then seeks to establish the support that is needed to overcome the most important barriers to adherence.

In 2006, WHO set forth its vision for a public health approach to delivering antiretroviral therapy. This approach has been broadly adopted in resource-poor settings and has provided the foundation for scaling up treatment to over 19·5 million people. There is a global commitment to end the AIDS epidemic as a public health threat by 2030 and, to support this goal, there are opportunities to adapt the public health approach to meet the ensuing challenges. These challenges include the need to improve identification of people with HIV infection through expanded approaches to testing; further simplify and improve treatment and laboratory monitoring; adapt the public health approach to concentrated epidemics; and link HIV testing, treatment, and care to HIV prevention. Implementation of these key public health principles will bring countries closer to the goals of controlling the HIV epidemic and providing universal health coverage.

World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings.

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.

Introduction Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. Methods Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, s from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post‐treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. Results and discussion In total, 3626 s and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single‐arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single‐arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second‐ or subsequent‐line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second‐ or subsequent‐line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. Conclusions These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer‐term outcomes, such as weight and metabolic changes.

Introduction Co‐trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale‐up of maternal antiretroviral therapy, most children remain HIV‐exposed uninfected (HEU) and the benefits of universal co‐trimoxazole are uncertain. We assessed the effect of co‐trimoxazole on mortality and morbidity of children who are HEU. Methods We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa‐Wide Information, SciELO and WHO Global Index Medicus for peer‐reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co‐trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity. Results We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co‐trimoxazole prophylaxis started at 2–6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub‐studies found that antimicrobial resistance was higher in infants receiving co‐trimoxazole. Two trials in Uganda investigating prolonged co‐trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence. Discussion Studies show no clinical benefit of co‐trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co‐trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non‐malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings. Conclusions In low‐mortality settings with few HIV transmissions and well‐performing early infant diagnosis and treatment programmes, universal co‐trimoxazole may not be required.

The specificity of nucleic acid amplification tests (NAATs) used for early infant diagnosis (EID) of HIV infection is <100%, leading some HIV-uninfected infants to be incorrectly identified as HIV-infected. The World Health Organization recommends that infants undergo a second NAAT to confirm any positive test result, but implementation is limited. Our objective was to determine the impact and cost-effectiveness of confirmatory HIV testing for EID programmes in South Africa. Using the Cost-effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, we simulated EID testing at age 6 weeks for HIV-exposed infants without and with confirmatory testing. We assumed a NAAT cost of US$25, NAAT specificity of 99.6%, NAAT sensitivity of 100% for infants infected in pregnancy or at least 4 weeks prior to testing, and a mother-to-child transmission (MTCT) rate at 12 months of 4.9%; we simulated guideline-concordant rates of testing uptake, result return, and antiretroviral therapy (ART) initiation (100%). After diagnosis, infants were linked to and retained in care for 10 years (false-positive) or lifelong (true-positive). All parameters were varied widely in sensitivity analyses. Outcomes included number of infants with false-positive diagnoses linked to ART per 1,000 ART initiations, life expectancy (LE, in years) and per-person lifetime HIV-related healthcare costs. Both without and with confirmatory testing, LE was 26.2 years for HIV-infected infants and 61.4 years for all HIV-exposed infants; clinical outcomes for truly infected infants did not differ by strategy. Without confirmatory testing, 128/1,000 ART initiations were false-positive diagnoses; with confirmatory testing, 1/1,000 ART initiations were false-positive diagnoses. Because confirmatory testing averted costly HIV care and ART in truly HIV-uninfected infants, it was cost-saving: total cost US$1,790/infant tested, compared to US$1,830/infant tested without confirmatory testing. Confirmatory testing remained cost-saving unless NAAT cost exceeded US$400 or the HIV-uninfected status of infants incorrectly identified as infected was ascertained and ART stopped within 3 months of starting. Limitations include uncertainty in the data used in the model, which we examined with sensitivity and uncertainty analyses. We also excluded clinical harms to HIV-uninfected infants incorrectly treated with ART after false-positive diagnosis (e.g., medication toxicities); including these outcomes would further increase the value of confirmatory testing. Without confirmatory testing, in settings with MTCT rates similar to that of South Africa, more than 10% of infants who initiate ART may reflect false-positive diagnoses. Confirmatory testing prevents inappropriate HIV diagnosis, is cost-saving, and should be adopted in all EID programmes.

The World Health Organization’s Model List of Essential Medicines for Children (EMLc) presents a list of the most efficacious, safe, and cost-effective medicines for priority conditions, intended for use in children up to 12 years of age. However, gaps in global availability and use of age-appropriate formulations of medicines for children still exist. To address these shortcomings, a comprehensive analysis of the appropriateness of formulations of essential medicines for children is being undertaken through the Global Accelerator for Paediatric Formulations (GAP-f) network, a WHO network launched in 2020 to respond to the paediatric treatment gap. This article describes the development and application of a paediatric Quality Target Product Profile (pQTPP) tool by WHO, to retrospectively evaluate the paediatric age-appropriateness of formulations on the EMLc and identify potential formulation gaps, to inform the review of the EMLc in 2023. A combination of paediatric-centric and global health-focused attributes and targets were defined, taking into consideration regulatory agency paediatric development guidelines and literature sources, and a qualitative scoring system was developed and tested. Example evaluations of paracetamol and clofazimine are provided, illustrating the tool’s use. The assessment of EMLc formulations is ongoing and shortcomings and gaps in EMLc formulations have already been identified. The pQTTP tool may also be applied to national lists and prospectively when designing new paediatric formulations.

Introduction Tenofovir alafenamide (TAF) is approved for paediatric use in fixed‐dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV. Methods We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009–March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0–19 years. Results and discussion Overall 3626 s and 371 full papers were screened. Four single‐arm, innovator‐funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment‐experienced and virally suppressed children or adolescents. One trial also included treatment‐naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment‐naïve participants were virally suppressed (one trial). Among treatment‐experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug‐related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug‐related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z‐score (height‐ and age‐adjusted) from baseline to 48 weeks was −0.12 (interquartile range [IQR] −0.46, 0.17) to 0.05 (IQR not reported) for spine, and −0.09 (IQR −0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight‐for‐age z‐scores increased by 0.25 from baseline to 48 weeks. Conclusions Four single‐arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF‐containing regimens over 24–48 weeks. However, further comparative and longer‐term safety data are needed in children and adolescents, including on weight and metabolic changes.

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.