Estimating the impact of alternative programmatic cotrimoxazole strategies on mortality among children born to mothers with HIV: A modelling study.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

COVID-19 and MIS-C treatment in children-results from an international survey.

Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. In addition, access to COVID-19 therapeutics remains limited. Collecting physicians' experiences with off-label use of therapeutics is important to inform global prioritization processes and better target pediatric research and development. A standardized questionnaire was designed to explore the use of therapeutics used to treat COVID-19 and multisystem inflammatory syndrome in children (MIS-C) in pediatric patients globally. Seventy-three physicians from 29 countries participated. For COVID-19, steroids were used by 75.6% of respondents; remdesivir and monoclonal antibodies were prescribed by 48.6% and 27.1% of respondents, respectively. For MIS-C, steroids were prescribed by 79.1% of respondents and intravenous immunoglobulins by 69.6%. The use of these products depended on their pediatric approval and the limited availability of antivirals and most monoclonal antibodies in Africa, South America, Southeast Asia, and Eastern Europe. Off-label prescription resulted widespread due to the paucity of clinical trials in young children at the time of the survey; though, based on our survey results, it was generally safe and led to clinical benefits.  Conclusion: This survey provides a snapshot of current practice for treating pediatric COVID-19 worldwide, informing global prioritization efforts to better target pediatric research and development for COVID-19 therapeutics. Off-label use of such medicines is widespread for the paucity of clinical trials under 12 years and 40 kg, though appears to be safe and generally results in clinical benefits, even in young children. However, access to care, including medicine availability, differs widely globally. Clinical development of COVID-19 antivirals and monoclonal antibodies requires acceleration to ensure pediatric indication and allow worldwide availability of therapeutics that will enable more equitable access to COVID-19 treatment. What is Known: • Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. • Access to care differs widely globally, so because of the diversity of national healthcare systems; the unequal availability of medicines for COVID-19 treatment represents an obstacle to the pediatric population's universal right to health care. What is New: • Off-label COVID-19 drug prescription is widespread due to the lack of clinical trials in children younger than 12 years and weighing less than 40 kg, but relatively safe and generally leading to clinical benefit. • The application of the GAP-f framework to COVID-19 medicines is crucial, ensuring widespread access to all safe and effective drugs, enabling the rapid development of age-appropriate formulations, and developing specific access plans (including stability, storage, packaging, and labeling) for distribution in low- and middle-income countries (LMICs). Antivirals and monoclonal antibodies may benefit from the acceleration to reach widespread and equal diffusion.

Importance of Prospective Studies in Pregnant and Breastfeeding Women Living With Human Immunodeficiency Virus.

Recently, the US Food and Drug Administration and European Medicines Agency issued warnings on the use of dolutegravir and darunavir/cobicistat for treatment of pregnant women living with human immunodeficiency virus (HIV). It took 3-5 years to identify the risks associated with the use of these antiretroviral drugs, during which time pregnant women were exposed to these drugs in clinical care, outside of controlled clinical trial settings. Across all antiretroviral drugs, the interval between registration of new drugs and first data on pharmacokinetics and safety in pregnancy becoming available is around 6 years. In this viewpoint, we provide considerations for clinical pharmacology research to provide safe and effective treatment of pregnant and breastfeeding women living with HIV and their children. These recommendations will lead to timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV, and are applicable to other chronic disease areas requiring medication during pregnancy.

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV.

INTRODUCTION: This review summarizes the current dosing recommendations for antiretroviral (ARV) drugs in the international pediatric guidelines of the World Health Organization (WHO), US Department of Health and Human Services (DHHS), and Pediatric European Network for Treatment of AIDS (PENTA), and evaluates the research that informed these approaches. We further explore the role of data generated through therapeutic drug monitoring in optimizing the dosing of ARVs in children. METHODS: A PubMed search was conducted for the literature on ARV dosing published in English. In addition, the registration documentation of European Medicines Agency and the US Food and Drug Administration for currently used ARVs and studies referenced by the WHO, DHHS, and EMA guidelines were screened. Resulting publications were screened for papers containing data on the area under the concentration-time curve, trough concentration, and peak concentration. Studies with enrolled participants with a median or mean age of ≥18 years were excluded. No restriction on publishing date was applied. DISCUSSION AND CONCLUSION: Pediatric ARV dosing is frequently based on data obtained from small studies and is often simplified to facilitate dosing in the context of a public health approach. Pharmacokinetic parameters of pediatric ARVs are subject to high interpatient variation and this leads to a potential risk of underdosing or overdosing when drugs are used in real life. To ensure optimal use of ARVs and validate dosing recommendations for children, it is essential to monitor ARV dosing more thoroughly with larger sample sizes and to include diverse subpopulations. Therapeutic drug monitoring data generated in children, where available and affordable, have the potential to enhance our understanding of the appropriateness of simplified pediatric dosing strategies recommended using a public health approach and to uncover suboptimal dosing or other unanticipated issues postmarketing, further facilitating the ultimate goal of optimizing pediatric ARV treatment.

Priorities for Decreasing Morbidity and Mortality in Children With Advanced HIV Disease.

Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV-infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed.

Managing Advanced HIV Disease in a Public Health Approach.

In 2017, the World Health Organization (WHO) published guidelines for the management of advanced human immunodeficiency virus (HIV) disease within a public health approach. Recent data suggest that more than a third of people starting antiretroviral therapy (ART) do so with advanced HIV disease, and an increasing number of patients re-present to care at an advanced stage of HIV disease following a period of disengagement from care. These guidelines recommend a standardized package of care for adults, adolescents, and children, based on the leading causes of morbidity and mortality: tuberculosis, severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. A package of targeted interventions to reduce mortality and morbidity was recommended, based on results of 2 recent randomized trials that both showed a mortality reduction associated with delivery of a simplified intervention package. Taking these results and existing recommendations into consideration, WHO recommends that a package of care be offered to those presenting with advanced HIV disease; depending on age and CD4 cell count, the package may include opportunistic infection screening and prophylaxis, including fluconazole preemptive therapy for those who are cryptococcal antigen positive and without evidence of meningitis. Rapid ART initiation and intensified adherence interventions should also be proposed to everyone presenting with advanced HIV disease.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis.

Human Immunodeficiency Virus (HIV) Drug Resistance in African Infants and Young Children Newly Diagnosed With HIV: A Multicountry Analysis.

BACKGROUND: Programs for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) have been scaled up in many low- and middle-income countries. However, HIV drug resistance (HIVDR) data among HIV-1-infected young children remain limited. METHODS: Surveys of pretreatment HIVDR among children aged <18 months who were diagnosed with HIV through early infant diagnosis were conducted in 5 sub-Saharan African countries (Mozambique, Swaziland, South Africa, Uganda, and Zimbabwe) between 2011 and 2014 following World Health Organization (WHO) guidance. Deidentified demographic and clinical data were used to explore risk factors associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. RESULTS: Among the 1450 genotypes analyzed, 1048 had accompanying demographic and clinical data. The median age of children was 4 months; 50.4% were female. HIV from 54.1% showed resistance to 1 or more antiretroviral (ARV) drugs, with 53.0% and 8.8% having resistance to 1 or more NNRTI or nucleoside reverse transcriptase inhibitors, respectively. NNRTI resistance was particularly high in children exposed to ARV drugs through PMTCT; adjusted odds ratios were 1.8 (95% confidence interval [CI], 1.3-2.6) for maternal exposure only and 2.4 (CI, 1.6-3.6) for neonatal exposure only. CONCLUSIONS: Protease inhibitor-based regimens in children aged <3 years are currently recommended by WHO, but the implementation of this recommendation is suboptimal. These results reinforce the urgent need to overcome barriers to scaling up pediatric protease inhibitor-based regimens in sub-Saharan Africa and underscore the need to accelerate the study and approval of integrase inhibitors for use in young children.

The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis.

BACKGROUND: 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. METHOD AND FINDINGS: 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. CONCLUSIONS: 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.

Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.

BACKGROUND: Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children. METHODS: Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets. RESULTS: The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target. CONCLUSIONS: According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population.

Clinical Impact and Cost-effectiveness of Diagnosing HIV Infection During Early Infancy in South Africa: Test Timing and Frequency.

BACKGROUND: Diagnosis of human immunodeficiency virus (HIV) infection during early infancy (commonly known as "early infant HIV diagnosis" [EID]) followed by prompt initiation of antiretroviral therapy dramatically reduces mortality. EID testing is recommended at 6 weeks of age, but many infant infections are missed. DESIGN/METHODS: We simulated 4 EID testing strategies for HIV-exposed infants in South Africa: no EID (diagnosis only after illness; hereafter, "no EID"), testing once (at birth alone or at 6 weeks of age alone; hereafter, "birth alone" and "6 weeks alone," respectively), and testing twice (at birth and 6 weeks of age; hereafter "birth and 6 weeks"). We calculated incremental cost-effectiveness ratios (ICERs), using discounted costs and life expectancies for all HIV-exposed (infected and uninfected) infants. RESULTS: In the base case (guideline-concordant care), the no EID strategy produced a life expectancy of 21.1 years (in the HIV-infected group) and 61.1 years (in the HIV-exposed group); lifetime cost averaged $1430/HIV-exposed infant. The birth and 6 weeks strategy maximized life expectancy (26.5 years in the HIV-infected group and 61.4 years in the HIV-exposed group), costing $1840/infant tested. The ICER of the 6 weeks alone strategy versus the no EID strategy was $1250/year of life saved (19% of South Africa's per capita gross domestic product); the ICER for the birth and 6 weeks strategy versus the 6 weeks alone strategy was $2900/year of life saved (45% of South Africa's per capita gross domestic product). Increasing the proportion of caregivers who receive test results and the linkage of HIV-positive infants to antiretroviral therapy with the 6 weeks alone strategy improved survival more than adding a second test. CONCLUSIONS: EID at birth and 6 weeks improves outcomes and is cost-effective, compared with EID at 6 weeks alone. If scale-up costs are comparable, programs should add birth testing after strengthening 6-week testing programs.

Patient-Reported Barriers to Adherence to Antiretroviral Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Viral suppression in adolescents on antiretroviral treatment: review of the literature and critical appraisal of methodological challenges.

OBJECTIVE: Medication adherence is often suboptimal for adolescents with HIV, and establishing correct weight-based antiretroviral therapy dosing is difficult, contributing to virological failure. This review aimed to determine the proportion of adolescents achieving virological suppression after initiating ART. METHODS: MEDLINE, EMBASE and Web of Science databases were searched. Studies published between January 2004 and September 2014 including ≥50 adolescents taking ART and reporting on the proportion of virological suppressed participants were included. RESULTS: From a total of 5316 potentially relevant citations, 20 studies were included. Only eight studies reported the proportion of adolescents that were virologically suppressed at a specified time point. The proportion of adolescents with virological suppression at 12 months ranged from 27 to 89%. CONCLUSION: Adolescent achievement of HIV virological suppression was highly variable. Improved reporting of virological outcomes from a wider range of settings is required to support efforts to improve HIV care and treatment for adolescents.

Choice of antiretroviral drugs for postexposure prophylaxis for children: a systematic review.

BACKGROUND: This systematic review aimed to assess the safety and efficacy of antiretroviral options for postexposure prophylaxis (PEP). Recognizing the limited data on the safety and efficacy of antiretroviral drugs for PEP in children, this review was extended to include consideration of data on the use of antiretroviral drugs for treatment of infants and children living with human immunodeficiency virus. METHODS: The PEP literature was assessed to identify studies reporting safety and completion rates for children given PEP, and this information was complemented by safety and efficacy data for drugs used in antiretroviral therapy. The proportion of patients experiencing each outcome was calculated and data were pooled using random-effects meta-analysis. RESULTS: Three prospective cohort studies reported outcomes of children given zidovudine (ZDV) plus lamivudine (3TC) as a 2-drug PEP regimen. The proportion of children completing the full 28-day course of PEP was 64.0% (95% confidence interval [CI], 41.2%-86.8%), whereas the proportion discontinuing due to adverse events was 4.5% (95% CI, .4%-8.6%). One randomized trial compared abacavir (ABC) plus lamivudine (3TC) and ZDV+3TC as part of a dual or triple first-line antiretroviral therapy regimen; this study showed better efficacy in the ABC-containing combinations and no difference in the time to first serious adverse event. Three randomized trials compared lopinavir/ritonavir (LPV/r) to nevirapine (NVP) for antiretroviral therapy and showed a lower risk of treatment discontinuations associated with LPV/r vs NVP (hazard ratio, 0.56 [95% CI, .41-.75]) but no difference in drug-related adverse events. The overall quality of the evidence was rated as very low. CONCLUSIONS: This review supports ZDV+3TC+LPV/r as the preferred 3-drug regimen for PEP in children.

Epstein-Barr virus load in children infected with human immunodeficiency virus type 1 in Uganda.

BACKGROUND: Epstein-Barr Virus (EBV) is involved in a wide range of malignancies, particularly in immunocompromised subjects. In Africa, EBV primary infection occurs during early childhood, but little is known about the EBV load in Human Immunodeficiency Virus type 1 (HIV-1)-infected children. METHODS: Blood samples from 213 HIV-1-infected children, 140 of whom were receiving antiretroviral therapy (ART), were collected at the Nsambya Hospital in Kampala, Uganda, and obtained for dried blood spot analysis. Nucleic acids were extracted and analyzed for quantification of EBV types 1 and 2; 16S ribosomal DNA (rDNA), a marker of microbial translocation; and HIV-1 RNA. RESULTS: Ninety-two of 140 children (66%) receiving ART and 57 of 73 ART-naive children (78%) had detectable EBV DNA levels. Coinfection with both EBV types was less frequent in ART-treated children than in ART-naive children (odds ratio, 0.54 [95% confidence interval {CI}, .30-.98]; P = .042). Mean EBV DNA levels (±standard deviation) were lower in the former (3.99 ± 0.59 vs 4.22 ± 0.54 log10 copies/mL; P = .006) and tended to be inversely associated with ART duration. EBV DNA levels were higher in children with an HIV-1 RNA load of > 3 log10 copies/mL of blood (regression coefficient, 0.32 [95% CI, .05-.59]; P = .020) and correlated with circulating 16S rDNA levels (rs = 0.25 [95% CI, .02-.46]; P = .031). CONCLUSIONS: These findings suggest that ART, by limiting HIV-1 replication, microbial translocation, and related immune activation, prevents superinfection with both EBV types and keeps EBV viremia down, thus potentially reducing the risk of EBV-associated lymphomas.

Viral load detection using dried blood spots in a cohort of HIV-1-infected children in Uganda: correlations with clinical and immunological criteria for treatment failure.

Correlations between clinical/immunological treatment failure and viral load (VL) detected by dried blood spot (DBS) sampling were explored in HIV-1-infected children in Uganda. Of 104 children on combined antiretroviral treatment (cART), 12.5% experienced clinical and/or immunological failure, while 28.8%, 44.2%, and 26.9% had VLs of <1,000, 1,000 to 5,000, and >5,000 copies/ml, respectively. Clinical/immunological failure poorly predicted virological failure.

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.

BACKGROUND: In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiation of ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to substitute drugs or interrupt therapy. This review, an update of a previous review, aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 3 years of age. OBJECTIVES: To evaluate 1) when to start ART in young children (less than 3 years); 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens; and 3) whether alternative strategies should be used to optimize antiretroviral treatment in this population: induction (initiation with 4 drugs rather than 3 drugs) followed by maintenance ART, interruption of ART and substitution of PI with NNRTI drugs once virological suppression is achieved on a PI-based regimen. SEARCH METHODS: Search methodsWe searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform). SELECTION CRITERIA: We identified RCTs that recruited perinatally HIV-infected children under 3 years of age without restriction of setting. We rejected trials that did not include children less than 3 years of age, did not provide stratified outcomes for those less than 3 years or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes. MAIN RESULTS: A search of the databases identified a total of 735 unique, previously unreviewed studies, of which 731 were excluded to leave 4 new studies to incorporate into the review. Four additional studies were identified in conference proceedings, for a total of 8 studies addressing when to start treatment (n=2), what to start (n=3), whether to substitute lopinavir/ritonavir (LPV/r) with nevirapine (NVP) (n=1), whether to use an induction-maintenance ART strategy (n=1) and whether to interrupt treatment (n=1).Treatment initiation in asymptomatic infants with good immunological status was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller pilot trial, median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure at 24 weeks was 1.79 (95%CI 1.33, 2.41) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0001) with no clear difference in the effect observed for children younger or older than 1 year. The hazard for virological failure at 24 weeks was overall 1.84 (95%CI 1.29, 2.63) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0008) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life.Infants starting a LPV/r regimen and achieving sustained virological suppression who then substituted LPV/r with NVP after median 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (>1000 copies/mL) was greater among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002).Children undergoing an induction-maintenance ART approach with a 4-drug NNRTI-based regimen for 36 weeks, followed by 3-drug ART, had significantly greater CD4 rise than children receiving a standard 3-drug NNRTI-based ART at 36 weeks (mean difference 1.70 [95%CI 0.61, 2.79] p=0.002) and significantly better viral load response at 24 weeks (OR 1.99 [95%CI 1.09, 3.62] p=0.02). However, the immunological and virological benefits were short-term.The one trial of treatment interruption that compared children initiating continuous ART from infancy with children interrupting ART was terminated early because the duration of treatment interruption was less than 3 months in most infants. Children interrupting treatment had similar growth and occurrence of serious adverse events as those in the continuous arm. AUTHORS' CONCLUSIONS: ART initiation in asymptomatic children under 1 year of age reduces morbidity and mortality, but it remains unclear whether there are clinical benefits to starting ART in asymptomatic children diagnosed with HIV infection between 1-3 years.The available evidence shows that a LPV/r-based first-line regimen is more efficacious than a NVP-based regimen, regardless of PMTCT exposure status. New formulations of LPV/r are urgently required to enable new WHO recommendations to be implemented. An alternative approach to long-term LPV/r is substituting LPV/r with NVP once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of routine viral load testing.A 4-drug induction-maintenance approach showed short-term virological and immunological benefits during the induction phase but, in the absence of sustained benefits, is not recommended as a routine treatment strategy. Treatment interruption following early ART initiation in infancy was challenging for children who were severely immunocompromised in the context of poor clinical immunological condition at ART initiation due to the short duration of interruption, and is therefore not practical in ART treatment programmes where close monitoring is not feasible.

Estimating age-based antiretroviral therapy costs for HIV-infected children in resource-limited settings based on World Health Organization weight-based dosing recommendations.

BACKGROUND: Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. METHODS: We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0-13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. RESULTS: The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. CONCLUSIONS: The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments.

Development of antiretroviral resistance in children with HIV in low- and middle-income countries.

With antiretroviral therapy (ART) recommended by the World Health Organization (WHO) for children aged <2 years with human immunodeficiency virus (HIV) and continuing global ART roll-out, ART coverage in children is rising. However ART coverage in children lags considerably behind that in adults (28% vs 58%). Long duration of therapy needed for HIV-infected children requires maximal efficacy, minimal toxicity, and prevention of development of drug resistance. This requires consideration of ways to improve sequencing of regimens during childhood to minimize development of resistance and treatment failure. We consider aspects of virological failure and development of resistance in vertically HIV-infected children in resource-limited settings. We review evidence guiding choices of first- and second-line ART, the impact of drugs given to prevent mother-to-child transmission, adherence issues and, availability of appropriate drug formulations. Recommendations made during the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)/WHO meeting (October 2012) are summarized.