Suchergebnisse

AbstractIntroductionMost clinical trials for new antiretroviral (ARV) agents are conducted among narrowly defined adult populations. Only after safety and efficacy have been clearly demonstrated among adults living with HIV are trials including adolescents, children and infants conducted. This approach contributes to significant delays in the availability of optimal new ARV regimens for infants, children and adolescents. This commentary discusses issues related to the inclusion of adolescents aged 12 to 18 years in initial HIV clinical phase 3 trials of novel antiretrovirals (ARVs) or conducting parallel phase 3 clinical trials among adolescents.DiscussionThe absorption, metabolic and excretion or elimination pathways for drugs do not significantly differ between adolescents and adults. In fact, dosing recommendations for ARVs are the same for adults and adolescents who meet the age and weight criteria. Although conducting clinical trials among adolescents present special challenges (e.g. consenting minors and concerns about trial completion and contraception), these challenges can be addressed to obtain high‐quality trial results. Importantly, new agents and optimized combinations have more favourable dosing schedules and side‐effect profiles and are more effective ARV agents with higher HIV drug resistance thresholds, which would be extremely beneficial to improve outcomes among HIV‐positive adolescents.ConclusionsAdolescents may not present with significantly different pharmacokinetic characteristics from those in adults. Including HIV‐positive adolescents in phase 3 ARV clinical trials, either with adults or in specific adolescent studies conducted in parallel, would allow adolescents to access promising, more effective treatment for HIV years earlier than with the current stepwise approach.

IntroductionDespite significant gains in access to early infant diagnosis (EID) over the past decade, most HIV‐exposed infants still do not get tested for HIV in the first two months of life. For those who are tested, the long turnaround time between when the sample is drawn and when the results are returned leads to a high rate of loss to follow‐up, which in turn means that few infected infants start antiretroviral treatment. Consequently, there continues to be high mortality from perinatally acquired HIV, and the ambitious goals of 90% of infected children identified, 90% of identified children treated and 90% of treated children with sustained virologic suppression by 2020 seem far beyond our reach. The objective of this commentary is to review recent advances in the field of HIV diagnosis in infants and describe how these advances may overcome long‐standing barriers to access to testing and treatment.DiscussionSeveral innovative approaches to EID have recently been described. These include point‐of‐care testing, use of SMS printers to connect the central laboratory and the health facility through a mobile phone network, expanding paediatric testing to other entry points where children access the health system and testing HIV‐exposed infants at birth as a rapid way to identify in utero infection. Each of these interventions is discussed here, together with the opportunities and challenges associated with scale‐up. Point‐of‐care testing has the potential to provide immediate results but is less cost‐effective in settings where test volumes are low. Virological testing at birth has been piloted in some countries to identify those infants who need urgent treatment, but a negative test at birth does not obviate the need for additional testing at six weeks. Routine testing of infants in child health settings is a useful strategy to identify exposed and infected children whose mothers were not enrolled in programmes for the prevention of mother‐to‐child transmission. Facility‐based SMS printers speed up the return of laboratory results and may be of value for other testing services apart from HIV infant diagnosis.ConclusionsNew tools and strategies for HIV infant diagnosis could have a significant positive impact on the identification and retention of HIV‐infected infants. In order to be most effective, national programmes should carefully consider which ideas to implement and how best to integrate novel strategies into existing systems. There is no single solution that will work everywhere. Rather, a number of approaches need to be considered and should be linked in order to achieve the greatest impact on the continuum of care from testing to treatment.

AbstractIntroduction: In 2013, an estimated 2.1 million adolescents (age 10–19 years) were living with HIV globally. The extent to which health facilities provide appropriate treatment and care was unknown. To support understanding of service availability in 2014, Paediatric‐Adolescent Treatment Africa (PATA), a non‐governmental organisation (NGO) supporting a network of health facilities across sub‐Saharan Africa, undertook a facility‐level situational analysis of adolescent HIV treatment and care services in 23 countries.Methods: Two hundred and eighteen facilities, responsible for an estimated 80,072 HIV‐infected adolescents in care, were surveyed. Sixty per cent of the sample were from PATA's network, with the remaining gathered via local NGO partners and snowball sampling. Data were analysed using descriptive statistics and coding to describe central tendencies and identify themes.Results: Respondents represented three subregions: West and Central Africa (n = 59; 27%), East Africa (n = 77, 35%) and southern Africa (n = 82, 38%). Half (50%) of the facilities were in urban areas, 17% peri‐urban and 33% rural settings. Insufficient data disaggregation and outcomes monitoring were critical issues. A quarter of facilities did not have a working definition of adolescence. Facilities reported non‐adherence as their key challenge in adolescent service provision, but had insufficient protocols for determining and managing poor adherence and loss to follow‐up. Adherence counselling focused on implications of non‐adherence rather than its drivers. Facilities recommended peer support as an effective adherence and retention intervention, yet not all offered these services. Almost two‐thirds reported attending to adolescents with adults and/or children, and half had no transitioning protocols. Of those with transitioning protocols, 21% moved pregnant adolescents into adult services earlier than their peers. There was limited sexual and reproductive health integration, with 63% of facilities offering these services within their HIV programmes and 46% catering to the special needs of HIV‐infected pregnant adolescents.Conclusions: Results indicate that providers are challenged by adolescent adherence and reflect an insufficiently targeted approach for adolescents. Guidance on standard definitions for adherence, retention and counselling approaches is needed. Peer support may create an enabling environment and sensitize personnel. Service delivery gaps should be addressed, with standardized transition and quality counselling. Integrated, comprehensive sexual reproductive health services are needed, with support for pregnant adolescents.

AbstractBackground: The 2016 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommended to start all HIV‐infected children on antiretroviral therapy (ART). Here, we explore the possible benefits and risks of implementing universal ART for all HIV‐infected children and adolescents and outline some of the key considerations that led to the 2016 revision of WHO guidelines.Methods: We conducted a review of the published data from 2000 to 2016, to ascertain the clinical and programmatic benefits, as well as the risks of implementing universal ART for all children.Results and discussion: Universal ART for all children has the potential to increase treatment coverage, which in 2015 was only 51% globally, as well as providing several biological benefits, by preventing: premature death/loss to follow‐up, progressive destruction of the immune system, poor growth and pubertal delay, poor neuro‐cognitive outcomes and future burden to the health care system with complications of untreated HIV‐infection. However, the strategy could be associated with risks, notably development of HIV drug resistance, antiretroviral drug toxicities and increased costs to an already stretched health system.Conclusion: Overall, our findings suggest that the benefits could outweigh the risks and support universal ART for all HIV‐infected children, but recognize that national programmes will need to put measures in place to minimize the risks if they choose to implement the strategy.

IntroductionAs the global community makes progress towards the 90‐90‐90 targets by 2020, a key challenge is ensuring that antiretroviral drugs for children and adolescents are suitable to the context of resource‐limited settings. Drug optimization aims to support the expanded use of more simplified, less toxic drug regimens with high barriers to drug resistance that require minimal clinical monitoring while maintaining therapeutic efficacy. This manuscript summarizes the progress made and outlines further critical steps required to ensure that the right drugs are available to start children and adolescents on treatment and to keep them virologically suppressed.DiscussionBuilding upon previous work in drug optimization, several important steps were taken in 2014 to ensure alignment between WHO dosing recommendations and the requirements of regulatory bodies, to accelerate drug development, to reduce intellectual property barriers to generic production of combined formulations and rationalize drug selection in countries. The priority for the future is to improve access to antiretroviral therapy (ART) at the two ends of the paediatric age spectrum – infants and adolescents – where the treatment gap is greatest, and optimize drug sequencing with better use of available medicines for second‐ and third‐line ART. Future efforts in this area will require continuous collaboration and coordination, and the promotion of innovative approaches to accelerate access to new drugs and formulations.ConclusionsWhile significant progress has been made, additional efforts are needed to ensure that treatment targets are reached by 2020.

AbstractIntroductionCo‐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.MethodsWe 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.ResultsWe 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.DiscussionStudies 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.ConclusionsIn low‐mortality settings with few HIV transmissions and well‐performing early infant diagnosis and treatment programmes, universal co‐trimoxazole may not be required.

AbstractIntroductionMany children and adolescents living with HIV still present with severe immunosuppression with morbidity and mortality remaining high in those starting antiretroviral therapy (ART) when hospitalized.DiscussionThe major causes of morbidity and mortality in children living with HIV are pneumonia, tuberculosis, bloodstream infections, diarrhoeal disease and severe acute malnutrition. In contrast to adults, cryptococcal meningitis is rare in children under 5 years of age but increases in adolescence. In 2021, the World Health Organizations (WHO) consolidated guidelines for managing HIV disease and rapid ART included recommendations for children and adolescents. In addition, a WHO technical brief released in 2020 highlighted the various interventions that are specifically related to children and adolescents with advanced HIV disease (AHD). We discuss the common clinical presentations of children and adolescents with AHD with a focus on diagnosis, prevention and treatment, highlight some of the challenges in the implementation of the existing package of care, and emphasize the importance of additional research to address the needs of children and adolescents with AHD.ConclusionsThere are limited data informing these recommendations and an urgent need for further research on how to implement optimal strategies to ensure tailored approaches to prevent and treat AHD in children and adolescents. Holistic care that goes beyond a simple choice of ART regimen should be provided to all children and adolescents with AHD.

AbstractIntroductionTenofovir 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.MethodsWe 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 discussionOverall 3626 abstracts 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.ConclusionsFour 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.

AbstractIntroductionGlobally 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.MethodsSources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts 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 discussionIn total, 3626 abstracts 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.ConclusionsThese 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.

AbstractIntroductionDespite the coordinated efforts by several stakeholders to speed up access to HIV treatment for children, development of optimal paediatric formulations still lags 8 to 10 years behind that of adults, due mainly to lack of market incentives and technical complexities in manufacturing. The small and fragmented paediatric market also hinders launch and uptake of new formulations. Moreover, the problems affecting HIV similarly affect other disease areas where development and introduction of optimal paediatric formulations is even slower. Therefore, accelerating processes for developing and commercializing optimal paediatric drug formulations for HIV and other disease areas is urgently needed.DiscussionThe Global Accelerator for Paediatric Formulations (GAP‐f) is an innovative collaborative model that will accelerate availability of optimized treatment options for infectious diseases, such as HIV, tuberculosis and viral hepatitis, affecting children in low‐ and middle‐income countries (LMICs). It builds on the HIV experience and existing efforts in paediatric drug development, formalizing collaboration between normative bodies, research networks, regulatory agencies, industry, supply and procurement organizations and funding bodies. Upstream, the GAP‐f will coordinate technical support to companies to design and study optimal paediatric formulations, harmonize efforts with regulators and incentivize manufacturers to conduct formulation development. Downstream, the GAP‐f will reinforce coordinated procurement and communication with suppliers. The GAP‐f will be implemented in a three‐stage process: (1) development of a strategic framework and promotion of key regulatory efficiencies; (2) testing of feasibility and results, building on the work of existing platforms such as the Paediatric HIV Treatment Initiative (PHTI) including innovative approaches to incentivize generic development and (3) launch as a fully functioning structure.ConclusionsGAP‐f is a key partnership example enhancing North‐South and international cooperation on and access to science and technology and capacity building, responding to Sustainable Development Goal (SDG) 17.6 (technology) and 17.9. (capacity‐building). By promoting access to the most needed paediatric formulations for HIV and high‐burden infectious diseases in low‐and middle‐income countries, GAP‐f will support achievement of SDG 3.2 (infant mortality), 3.3 (end of AIDS and combat other communicable diseases) and 3.8 (access to essential medicines), and be an essential component of meeting the global Start Free, Stay Free, AIDS Free super‐fast‐track targets.

AbstractIntroductionMaternal 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.DiscussionWHO 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.ConclusionsTailoring 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.

AbstractIntroductionTo improve the diagnosis and survival of children living with HIV (CLWH), the World Health Organization recommends testing approaches beyond traditional infant HIV testing programmes. Information about undiagnosed HIV prevalence among children of varying ages in the general population is needed to guide innovative national/subnational case‐finding and testing approaches.MethodsWe used the Cost‐Effectiveness of Preventing AIDS Complications (CEPAC)‐Pediatric model to estimate the prevalence of undiagnosed HIV in 2‐, 5‐ and 10‐year‐old children in South Africa, Côte d'Ivoire and Zimbabwe in 2018. We simulated cohorts of children born in 2008 (10‐year‐olds), 2013 (5‐year‐olds) and 2016 (2‐year‐olds). Country‐/year‐specific inputs for pregnant/breastfeeding women included: HIV prevalence (4.2–32.3%), HIV incidence (0.03–0.24%/month), knowledge of HIV status (27–89%) and antiretroviral drug coverage (36–95%). Paediatric inputs included early infant testing coverage (6–95%) and breastfeeding duration (0–20 months). We projected the proportion of surviving CLWH in whom HIV remained undiagnosed and the undiagnosed HIV prevalence among surviving children of each age in the general population. For children born in 2016, we projected survival and diagnosis of all CLWH through 2026. We conducted sensitivity analyses on model parameters.ResultsIn 2018, the projected proportion of surviving CLWH whose HIV remained undiagnosed in South Africa/Côte d'Ivoire/Zimbabwe was 44.2%/55.8%/52.9% among 2‐year‐old CLWH; 29.0%/37.8%/33.2% among 5‐year‐old CLWH; and 18.3%/25.4%/23.1% among 10‐year‐old CLWH. Projected general population undiagnosed HIV prevalence in South Africa/Côte d'Ivoire/Zimbabwe was 0.44%/0.32%/0.68% among 2‐year‐olds; 0.25%/0.17%/0.41% among 5‐year‐olds; and 0.24%/0.14%/0.38% among 10‐year‐olds. Among all CLWH born in 2016, 50–54% were projected to die without HIV diagnosis (and subsequently without treatment) within 10 years after birth; 80–85% of these deaths occurred in the first 2 years.ConclusionsProjected population‐level undiagnosed HIV prevalence is low and sharply decreases after age 2, with more CLWH dying than being diagnosed. Despite low undiagnosed prevalence in the general population of older children, we project that a large proportion of CLWH remain undiagnosed, suggesting that innovative strategies targeting untested children of all ages outside of health facility settings should be prioritized. Programmes could consider routine testing of the general population of children below 2 in all settings and children of all ages in high‐prevalence settings.