Disparities in access to Dolutegravir in West African children, adolescents and young adults aged 0-24 years living with HIV. A IeDEA Pediatric West African cohort analysis.

Introduction: We describe the 24-month incidence of Dolutegravir (DTG)-containing antiretroviral treatment (ART) initiation since its introduction in 2019 in the pediatric West African IeDEA cohorts. Methods: We included all patients aged 0-24 years on ART, from nine clinics in Côte d'Ivoire (n=4), Ghana, Nigeria, Mali, Benin, and Burkina Faso. Baseline varied by clinic and was defined as date of first DTG prescription; patients were followed-up until database closure/death/loss to follow-up (LTFU, no visit ≥ 7 months), whichever came first. We computed the cumulative incidence function for DTG initiation; associated factors were explored in a shared frailty model, accounting for clinic heterogeneity. Results: Since 2019, 3,350 patients were included; 49% were female;79% had been on ART ≥ 12 months. Median baseline age was 12.9 years (IQR: 9-17). Median follow-up was 14 months (IQR: 7-22). The overall cumulative incidence of DTG initiation reached 35.5% (95% CI: 33.7-37.2) and 56.4% (95% CI: 54.4-58.4) at 12 and 24 months, respectively. In univariate analyses, those aged <5 years and females were overall less likely to switch. Adjusted on ART line and available viral load (VL) at baseline, females >10 years were less likely to initiate DTG compared to males of the same age (aHR among 10-14 years: 0.62, 95% CI: 0.54-0.72; among ≥15 years: 0.43, 95% CI: 0.36-0.50), as were those with detectable VL (> 50 copies/mL) compared to those in viral suppression (aHR: 0.86, 95% CI: 0.77-0.97) and those on PIs compared to those on NNRTIs (aHR after 12 months of roll-out: 0.75, 95% CI: 0.65-0.86). Conclusion: Access to paediatric DTG was incomplete and unequitable in West African settings: children <5years, females ≥ 10 years and those with detectable viral load were least likely to access DTG. Maintained monitoring and support of treatment practices is required to better ensure universal and equal access. Key messages: What is already known on this topic?: Dolutegravir (DTG)-based ART regimens are recommended as the preferred first-line ART regimens recommended by the World Health Organisation in all people living with HIV since 2018, with a note of caution for pregnant women, then confirmed in all children with approved DTG dosing and adolescents since 2019.Deployment of universal DTG access in adults in West Africa has faced challenges such as infrastructure challenges, and healthcare system disparities, and was hindered by initial perinatal safety concerns affecting greatly women of childbearing age.Specific data on access to DTG in children, adolescents and young adults in West Africa is limited.What this study adds ?: This study describes the dynamic of the DTG roll-out over the first 24 months and its correlates since 2019 in a large West African multicentric cohort of children, adolescents and youth.We observed a rapid scale-up of DTG among children, adolescents and young adults living with HIV in West Africa, despite the COVID-19 pandemic.However, DTG access after 24 months was incomplete and unequitable, with adolescent girls and young women being less likely to initiate DTG compared to males, as were those with a detectable viral load (> 50 copies/mL) compared to those in success.Younger children < 5 years were also less likely to initiate DTG, explained by the later approval of paediatric formulations and their low availability.How this study might affect research, practice or policy?: Maintained monitoring, training and updating guidance for healthcare workers is essential to ensure universal access to DTG, especially for females, for whom inequity begins age 10 years.Efforts to improve access to universal DTG in West Africa require multifaceted interventions including healthcare infrastructure improvement and facilitation of paediatric antiretroviral forecasting and planification.

High Prevalence of Unconfirmed Positive HIV PCR Test Results among African Infants with HIV Exposure in the International epidemiology Databases to Evaluate AIDS (IeDEA) Consortium.

In a large, multi-regional cohort of African infants with HIV exposure, 44% of those with a positive HIV PCR lacked a confirmatory positive test. Efforts are needed to ensure high-fidelity implementation of HIV testing algorithms, so that all positive results are confirmed thereby reducing the risk of potentially false-positive results.

Potential for a large-scale newborn screening strategy for sickle cell disease in Mali: A comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood.

Sickle cell disease (SCD) is a life-threatening disease requiring reliable early diagnosis. We assessed the acceptability and diagnostic performances of two rapid diagnostic tests (RDTs) to identify SCD (HbSS, HbSC, HbS/ß-thalassaemia) or SCD carrier (HbS/HbC) in a pilot SCD newborn screening (NBS) strategy in Mali. All consenting delivering women were offered SCD NBS using cord blood sampling on two RDTs (SickleScan® and HemotypeSC®) compared to the high-performance liquid chromatography (HPLC) gold standard to detect SCD states. From April 2021 to August 2021, 4333 delivering women were eligible of whom 96.1% were offered NBS: 1.6% refused, 13.8% delivered before consenting and 84.6% consented; 3648 newborns were diagnosed by HPLC; 1.64% had SCD (0.63% HbSS, 0.85% HbSC, 0.16 HbS/ß-plus-thalassaemia); 21.79% were SCD carrier. To detect accurately SCD, SickleScan® had a sensitivity of 81.67% (95% confidence interval [CI]: 71.88-91.46) and a negative predictive value (NPV) of 99.69% (95% CI: 99.51-99.87); HemotypeSC® had a sensitivity of 78.33% (95% CI: 67.91-88.76) and a NPV of 99.64% (95% CI: 99.44-99.83). To detect SCD carrier: SickleScan® sensitivity was 96.10% (95% CI: 94.75-97.45) and NPV, 98.90% (95% CI: 98.51-99.29); HemotypeSC® sensitivity was 95.22% (95% CI: 93.74-96.70) and NPV, 98.66% (95% CI: 98.24-99.03). Routine SCD NBS was acceptable. Compared with HPLC, both RDTs had reliable diagnostic performances to exclude SCD-free newborns and to identify SCD carriers to be further confirmed. This strategy could be implemented in large-scale NBS programmes.

Cost-effectiveness of broadly neutralizing antibodies for infant HIV prophylaxis in settings with high HIV burdens: a simulation modeling study.

Introduction: Approximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings. Methods: We simulated infants in Côte d'Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth (HR-HIVE); b) with known HIV exposure at birth (HIVE); or c) with or without known HIV exposure (ALL). Modeled infants received 1-dose, 2-doses, or Extended (every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a ≤50% GDP per capita cost-effectiveness threshold). Results: The base case model projects that bNAb strategies targeting HIVE and ALL infants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach. HIVE-Extended would be cost-effective (cost-saving compared to standard-of-care) in Côte d'Ivoire and Zimbabwe; ALL-Extended would be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targeting HR-HIVE infants would result in greater lifetime costs and smaller life expectancy gains than HIVE-Extended. Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targeting HIVE infants would be cost-effective in Côte d'Ivoire and Zimbabwe, and targeting ALL infants would be cost-effective in South Africa. Discussion: Adding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.

Integration of HIV care into maternal and child health services in the global IeDEA consortium.

The WHO recommends the integration of routine HIV services within maternal and child health (MCH) services to reduce the fragmentation of and to promote retention in care for pregnant and postpartum women living with HIV (WWH) and their infants and children exposed to HIV (ICEH). During 2020-2021, we surveyed 202 HIV treatment sites across 40 low- and middle-income countries within the global International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. We determined the proportion of sites providing HIV services integrated within MCH clinics, defined as full [HIV care and antiretroviral treatment (ART) initiation in MCH clinic], partial (HIV care or ART initiation in MCH clinic), or no integration. Among sites serving pregnant WWH, 54% were fully and 21% partially integrated, with the highest proportions of fully integrated sites in Southern Africa (80%) and East Africa (76%) compared to 14%-40% in other regions (i.e., Asia-Pacific; the Caribbean, Central and South America Network for HIV Epidemiology; Central Africa; West Africa). Among sites serving postpartum WWH, 51% were fully and 10% partially integrated, with a similar regional integration pattern to sites serving pregnant WWH. Among sites serving ICEH, 56% were fully and 9% were partially integrated, with the highest proportions of fully integrated sites in East Africa (76%), West Africa (58%) and Southern Africa (54%) compared to ≤33% in the other regions. Integration was heterogenous across IeDEA regions and most prevalent in East and Southern Africa. More research is needed to understand this heterogeneity and the impacts of integration on MCH outcomes globally.

Global HIV prevention, care and treatment services for children: a cross-sectional survey from the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium.

OBJECTIVES: To assess access children with HIV have to comprehensive HIV care services, to longitudinally evaluate the implementation and scale-up of services, and to use site services and clinical cohort data to explore whether access to these services influences retention in care. METHODS: A cross-sectional standardised survey was completed in 2014-2015 by sites providing paediatric HIV care across regions of the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium. We developed a comprehensiveness score based on the WHO's nine categories of essential services to categorise sites as 'low' (0-5), 'medium', (6-7) or 'high' (8-9). When available, comprehensiveness scores were compared with scores from a 2009 survey. We used patient-level data with site services to investigate the relationship between the comprehensiveness of services and retention. RESULTS: Survey data from 174 IeDEA sites in 32 countries were analysed. Of the WHO essential services, sites were most likely to offer antiretroviral therapy (ART) provision and counselling (n=173; 99%), co-trimoxazole prophylaxis (168; 97%), prevention of perinatal transmission services (167; 96%), outreach for patient engagement and follow-up (166; 95%), CD4 cell count testing (126; 88%), tuberculosis screening (151; 87%) and select immunisation services (126; 72%). Sites were less likely to offer nutrition/food support (97; 56%), viral load testing (99; 69%) and HIV counselling and testing (69; 40%). 10% of sites rated 'low', 59% 'medium' and 31% 'high' in the comprehensiveness score. The mean comprehensiveness of services score increased significantly from 5.6 in 2009 to 7.3 in 2014 (p<0.001; n=30). Patient-level analysis of lost to follow-up after ART initiation estimated the hazard was highest in sites rated 'low' and lowest in sites rated 'high'. CONCLUSION: This global assessment suggests the potential care impact of scaling-up and sustaining comprehensive paediatric HIV services. Meeting recommendations for comprehensive HIV services should remain a global priority.

Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review.

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 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. 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.

Cost-effectiveness of broadly neutralizing antibody prophylaxis for HIV-exposed infants in sub-Saharan African settings.

INTRODUCTION: Infant HIV prophylaxis with broadly neutralizing anti-HIV antibodies (bNAbs) could provide long-acting protection against vertical transmission. We sought to estimate the potential clinical impact and cost-effectiveness of hypothetical bNAb prophylaxis programmes for children known to be HIV exposed at birth in three sub-Saharan African settings. METHODS: We conducted a cost-effectiveness analysis using the CEPAC-Pediatric model, simulating cohorts of infants from birth through death in Côte d'Ivoire, South Africa and Zimbabwe. These settings were selected to reflect a broad range of HIV care cascade characteristics, antenatal HIV prevalence and budgetary constraints. We modelled strategies targeting bNAbs to only WHO-designated "high-risk" HIV-exposed infants (HR-HIVE) or to all HIV-exposed infants (HIVE). We compared four prophylaxis approaches within each target population: standard of care oral antiretroviral prophylaxis (SOC), and SOC plus bNAbs at birth (1-dose), at birth and 3 months (2-doses), or every 3 months throughout breastfeeding (Extended). Base-case model inputs included bNAb efficacy (60%/dose), effect duration (3 months/dose) and costs ($60/dose), based on published literature. Outcomes included paediatric HIV incidence and incremental cost-effectiveness ratios (ICERs) calculated from discounted life expectancy and lifetime HIV-related costs. RESULTS: The model projects that bNAbs would reduce absolute infant HIV incidence by 0.3-2.2% (9.6-34.9% relative reduction), varying by country, prophylaxis approach and target population. In all three settings, HR-HIVE-1-dose would be cost-saving compared to SOC. Using a 50% GDP per capita ICER threshold, HIVE-Extended would be cost-effective in all three settings with ICERs of $497/YLS in Côte d'Ivoire, $464/YLS in South Africa and $455/YLS in Zimbabwe. In all three settings, bNAb strategies would remain cost-effective at costs up to $200/dose if efficacy is ≥30%. If the bNAb effect duration were reduced to 1 month, the cost-effective strategy would become HR-HIVE-1-dose in Côte d'Ivoire and Zimbabwe and HR-HIVE-2-doses in South Africa. Findings regarding the cost-effectiveness of bNAb implementation strategies remained robust in sensitivity analyses regarding breastfeeding duration, maternal engagement in postpartum care, early infant diagnosis uptake and antiretroviral treatment costs. CONCLUSIONS: At current efficacy and cost estimates, bNAb prophylaxis for HIV-exposed children in sub-Saharan African settings would be a cost-effective intervention to reduce vertical HIV transmission.

Adverse perinatal outcomes associated with prenatal exposure to protease-inhibitor-based versus non-nucleoside reverse transcriptase inhibitor-based antiretroviral combinations in pregnant women with HIV infection: a systematic review and meta-analysis.

BACKGROUND: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART. METHODS: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous. RESULTS: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I2 = 0%) compared to NNRTIs. CONCLUSIONS: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV. PROSPERO NUMBER: CRD42022306896.

Evaluation of the routine implementation of pulse oximeters into integrated management of childhood illness (IMCI) guidelines at primary health care level in West Africa: the AIRE mixed-methods research protocol.

BACKGROUND: The AIRE operational project will evaluate the implementation of the routine Pulse Oximeter (PO) use in the integrated management of childhood illness (IMCI) strategy for children under-5 in primary health care centers (PHC) in West Africa. The introduction of PO should promote the accurate identification of hypoxemia (pulse blood oxygen saturation Sp02 < 90%) among all severe IMCI cases (respiratory and non-respiratory) to prompt their effective case management (oxygen, antibiotics and other required treatments) at hospital. We seek to understand how the routine use of PO integrated in IMCI outpatients works (or not), for whom, in what contexts and with what outcomes. METHODS: The AIRE project is being implemented from 03/2020 to 12/2022 in 202 PHCs in four West African countries (Burkina Faso, Guinea, Mali, Niger) including 16 research PHCs (four per country). The research protocol will assess three complementary components using mixed quantitative and qualitative methods: a) context based on repeated cross-sectional surveys: baseline and aggregated monthly data from all PHCs on infrastructure, staffing, accessibility, equipment, PO use, severe cases and care; b) the process across PHCs by assessing acceptability, fidelity, implementation challenges and realistic evaluation, and c) individual outcomes in the research PHCs: all children under-5 attending IMCI clinics, eligible for PO use will be included with parental consent in a cross-sectional study. Among them, severe IMCI cases will be followed in a prospective cohort to assess their health status at 14 days. We will analyze pathways, patterns of care, and costs of care. DISCUSSION: This research will identify challenges to the systematic implementation of PO in IMCI consultations, such as health workers practices, frequent turnover, quality of care, etc. Further research will be needed to fully address key questions such as the best time to introduce PO into the IMCI process, the best SpO2 threshold for deciding on hospital referral, and assessing the cost-effectiveness of PO use. The AIRE research will provide health policy makers in West Africa with sufficient evidence on the context, process and outcomes of using PO integrated into IMCI to promote scale-up in all PHCs. TRIAL REGISTRATION: Trial registration number: PACTR202206525204526 retrospectively registered on 06/15/2022.

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review.

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, 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 DISCUSSION: In 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. 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.

Safety and efficacy of abacavir for treating infants, children, and adolescents living with HIV: a systematic review and meta-analysis.

BACKGROUND: Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first, second, or subsequent lines of treatment for infants, children, and adolescents living with HIV to inform 2021 WHO paediatric ART recommendations. METHODS: In this systematic review and meta-analysis, we included observational and experimental studies conducted in infants aged 0-1 year, children aged 1-10 years, and adolescents aged 10-19 years living with HIV; with data on safety or efficacy, or both, of abacavir-based antiretroviral therapy (ART); published in English or French between Jan 1, 2009, and Oct 1, 2020, plus an updated search to incorporate studies published between Oct 1, 2020, and May 15, 2022. Studies could be non-randomised or non-comparative and include patients who are treatment-naive or those who previously received abacavir (only if abacavir was combined with other ART). Case studies, studies in adults aged 18 years or older, and those assessing the effect of maternal ART exposure were excluded. We extracted data related to study identifier, study design, study period, setting, population characteristics, ART treatment, and safety (any hypersensitivity reaction, death, grade 3 or 4 adverse events, treatment discontinuation, any other morbidities, and serious adverse events), and efficacy outcomes (HIV viral load and CD4 counts reported at 6 and 12 months after ART initiation). Using random-effect models, we estimated weighted pooled incidence and relative risk (RR) of outcomes. The protocol is published in PROSPERO (CRD42022309230). FINDINGS: Of 1777 records identified, 1475 (83%) were screened after removing duplicates and a further 1421 (96%) were excluded. Of 54 full-text articles assessed for eligibility, 33 (61%) were excluded. Four records were identified from grey literature plus one duplicate from database searching, resulting in 24 studies included (two randomised controlled trials, one single-arm trial, 12 prospective cohorts, seven retrospective cohorts, and two cross-sectional studies). 19 studies described safety data and 15 described efficacy data. 18 (75%) studies were conducted in ART-naive participants. The risk of bias was considered moderate to high for most studies, and all outcomes had significant between-study heterogeneity. Data from 24 265 participants were included, of whom 7236 (30%) received abacavir. Abacavir hypersensitivity reaction was reported in nine (38%) studies, with an incidence ranging from 0·00% to 8·26% (I2=85%; p<0·0001). The incidence of death (reported in seven studies) following abacavir treatment varied from 0·00% to 5·49% (I2=58%; p=0·026). Viral suppression (<400 copies per mL) varied from 50% to 70% at 6 months (I2=92%, p<0·0001) and from 57% to 78% at 12 months (I2=88%, p<0·0001). INTERPRETATION: Toxic effects due to abacavir use remain rare and manageable. Despite scarce data on efficacy, this meta-analysis supports the use of abacavir as a preferred first-line regimen for infants and children living with HIV. FUNDING: WHO.

Clinical and programmatic outcomes of HIV-exposed infants enrolled in care at geographically diverse clinics, 1997-2021: A cohort study.

BACKGROUND: Although 1·3 million women with HIV give birth annually, care and outcomes for HIV-exposed infants remain incompletely understood. We analyzed programmatic and health indicators in a large, multidecade global dataset of linked mother-infant records from clinics and programs associated with the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS AND FINDINGS: HIV-exposed infants were eligible for this retrospective cohort analysis if enrolled at <18 months at 198 clinics in 10 countries across 5 IeDEA regions: East Africa (EA), Central Africa (CA), West Africa (WA), Southern Africa (SA), and the Caribbean, Central, and South America network (CCASAnet). We estimated cumulative incidences of DNA PCR testing, loss to follow-up (LTFU), HIV diagnosis, and death through 24 months of age using proportional subdistribution hazard models accounting for competing risks. Competing risks were transfer, care withdrawal, and confirmation of negative HIV status, along with LTFU and death, when not the outcome of interest. In CA and EA, we quantified associations between maternal/infant characteristics and each outcome. A total of 82,067 infants (47,300 EA, 10,699 CA, 6,503 WA, 15,770 SA, 1,795 CCASAnet) born from 1997 to 2021 were included. Maternal antiretroviral therapy (ART) use during pregnancy ranged from 65·6% (CCASAnet) to 89·5% (EA), with improvements in all regions over time. Twenty-four-month cumulative incidences varied widely across regions, ranging from 12·3% (95% confidence limit [CL], 11·2%,13·5%) in WA to 94·8% (95% CL, 94·6%,95·1%) in EA for DNA PCR testing; 56·2% (95% CL, 55·2%,57·1%) in EA to 98·5% (95% CL, 98·3%,98·7%) in WA for LTFU; 1·9% (95% CL, 1·6%,2·3%) in WA to 10·3% (95% CL, 9·7%,10·9%) in EA for HIV diagnosis; and 0·5% (95% CL, 0·2%,1·0%) in CCASAnet to 4·7% (95% CL, 4·4%,5·0%) in EA for death. Although infant retention did not improve, HIV diagnosis and death decreased over time, and in EA, the cumulative incidence of HIV diagnosis decreased substantially, declining to 2·9% (95% CL, 1·5%,5·4%) in 2020. Maternal ART was associated with decreased infant mortality (subdistribution hazard ratio [sdHR], 0·65; 95% CL, 0·47,0·91 in EA, and sdHR, 0·51; 95% CL, 0·36,0·74 in CA) and HIV diagnosis (sdHR, 0·40; 95% CL, 0·31,0·50 in EA, and sdHR, 0·41; 95% CL, 0·31,0·54 in CA). Study limitations include potential misclassification of outcomes in real-world service delivery data and possible nonrepresentativeness of IeDEA sites and the population of HIV-exposed infants they serve. CONCLUSIONS: While there was marked regional and temporal heterogeneity in clinical and programmatic outcomes, infant LTFU was high across all regions and time periods. Further efforts are needed to keep HIV-exposed infants in care to receive essential services to reduce HIV infection and mortality.

Surveillance of ARV safety in pregnancy and breastfeeding: towards a new framework.

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

Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: study protocol for a multicenter, open-label randomized controlled clinical trial.

BACKGROUND: Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35-40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia. METHODS: This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM. DISCUSSION: Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.

Effectiveness and Safety of Atazanavir Use for the Treatment of Children and Adolescents Living With HIV: A Systematic Review.

Background: Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed a systematic review to assess safety and effectiveness of atazanavir use in children and adolescents. Methods: We searched observational studies and clinical trials on Web of Science, Embase and Cochrane CENTRAL database between 2009/01/01 and 2020/10/01; as well as grey literature. We extracted safety (adverse events, grade 3 or 4 adverse events, treatment discontinuation) and effectiveness (CD4 cell counts and HIV viral load) outcomes. We estimated weighted summary pooled incidence with corresponding 95% confidence intervals. Results: Out of the 1,085 records screened, we included five studies (one comparative cohort, three single phase 2-3 trial arms, one retrospective cohort) reporting 975 children and adolescents, of whom 56% (544) received atazanavir. Three studies reported all-cause treatment discontinuation rates, yielding a pooled incidence of 19% [15-22] at 12 months. The comparative cohort compared atazanavir to darunavir, with few grade 3-4 adverse events, except transient hyperbilirubinemia, occurring in half (92/188) of the atazanavir patients. No death occurred (two studies reporting). Four studies described increased CD4 cell counts and decreased HIV viral load at 6 or 12 months. Conclusion: Few safety and effectiveness data were available for children and adolescents exposed to atazanavir. Transient grade 3-4 hyperbilirubinemia was the main adverse outcome reported. Immune and viral responses were descriptive. The use of atazanavir/ritonavir in children and adolescents needs further investigation, but remains a suitable option for a preferred second-line antiretroviral regimen. PROSPERO number: CRD42022309230.

Étude qualitative sur le vécu de l'annonce du statut VIH aux adolescents en Côte d'Ivoire.

INTRODUCTION: This qualitative study explores the experience of HIV-disclosure among adolescents living with HIV acquired during the perinatal period, followed in pediatric HIV care structures in Abidjan, Côte d’Ivoire. PURPOSE OF RESEARCH: Thirty adolescents and young adults living with HIV, ages 13 to 21, participated in a semi-structured interview about the conditions and consequences of the disclosure and asked for recommendations they would give. The interviews were analyzed using a thematic analysis procedure. RESULTS: We identified three types of illness and coping trajectories related to the HIV-disclosure : the trajectory of acceptance without prior crisis, the trajectory including a crisis before the HIV-disclosure, and the trajectory of crisis occurring after the disclosure. All three trajectories are impacted by the family context and the modalities of medical care. The results of the study show the importance of preparing the HIV-disclosure while including family members in an appropriate setting and confirm the importance of post-announcement follow-up. Peers appear to be an important resource for these young people, especially when they are adolescents living with HIV themselves and involved in the health care plan. CONCLUSIONS: This study contributes to the development of intervention strategies to improve the future of adolescents living with HIV, adapted to the local context of Ivory Coast.

In utero exposure to antiretroviral drugs and pregnancy outcomes: Analysis of the French ANRS pharmacovigilance database.

AIMS: In 2018, 1.07 million pregnant women received antiretroviral drugs, raising whether this affects pregnancy outcomes. We assessed the adverse pregnancy outcomes associated with prenatal antiretroviral drug exposure, notified to the French ANRS pharmacovigilance system. METHODS: An exhaustive case report series has been performed using the ANRS pharmacovigilance database. All ANRS-sponsored HIV clinical research studies using antiretroviral drugs either in pregnant women or women of childbearing age were eligible from 2004 to 2019. We analysed the following pregnancy outcomes: abortion, ectopic pregnancy, stillbirth, prematurity (<37 weeks of gestational age), low birth weight (<2500 g) and congenital abnormalities. A logistic regression was performed to assess the odds ratio (OR) for each outcome separately (if occurrence >50) compared to the outcome observed when exposed to non-nucleoside-reverse-transcriptase-inhibitor (NNRTI)-based regimen as the reference. RESULTS: Among the 34 studies selected, 918 deliveries occurred, of whom 88% had pregnancy outcomes documented. Pregnant women were mainly exposed to PI (n = 387, 48.6%), NNRTI (n = 331, 41.5%) and INI-based combinations (n = 40, 5.0%, 18 on dolutegravir). Compared to NNRTI-based combinations, there was no significant association observed with exposure to other antiretroviral combination for spontaneous abortion, prematurity or low birth weight, except an increased risk of low birth weight in new-born exposed to exclusive nucleoside-reverse-transcriptase-inhibitor (NRTI) combinations (n = 4; OR 7.50 [1.49-37.83]). CONCLUSIONS: Our study, mainly based on protease inhibitor (PI) and NNRTI-based regimens, is overall reassuring on the risk of adverse pregnancy outcomes, except for NRTI which should be interpreted cautiously (small number, indication bias). In this study, the number of integrase inhibitor (INI)-based combinations was too low to draw any conclusions.

Assessment of dietary diversity and nutritional support for children living with HIV in the IeDEA pediatric West African cohort: a non-comparative, feasibility study.

BACKGROUND: Nutritional care is not optimally integrated into pediatric HIV care in sub-Saharan Africa. We assessed the 6-month effect of a nutritional support provided to children living with HIV, followed in a multicentric cohort in West Africa. METHODS: In 2014-2016, a nutritional intervention was carried out for children living with HIV, aged under 10 years, receiving antiretroviral therapy (ART) or not, in five HIV pediatric cohorts, in Benin, Togo and Côte d'Ivoire. Weight deficiency was assessed using two definitions: wasting (Weight for Height Z-score [WHZ] for children<5 years old or Body-Mass-Index for Age [BAZ] for ≥5 years) and underweight (Weight for Age Z-score [WAZ]) (WHO child growth standards). Combining these indicators, three categories of nutritional support were defined: 1/ children with severe malnutrition (WAZ and/or WHZ/BAZ <-3 Standard Deviations [SD]) were supported with Ready-To-Use Therapeutic Food (RUTF), 2/ those with moderate malnutrition (WAZ and/or WHZ/BAZ = [-3;-2[ SD) were supported with fortified blended flours produced locally in each country, 3/ those non malnourished (WAZ and WHZ/BAZ ≥-2 SD) received nutritional counselling only. Children were followed monthly over 6 months. Dietary Diversity Score (DDS) using a 24h recall was measured at the first and last visit of the intervention. RESULTS: Overall, 326 children were included, 48% were girls. At baseline, 66% were aged 5-10 years, 91% were on ART, and 17% were severely immunodeficient (CD4 <250 cells/mL or CD4%<15). Twenty-nine (9%) were severely malnourished, 63 (19%) moderately malnourished and 234 (72%) non-malnourished. After 6 months, 9/29 (31%) and 31/63 (48%) recovered from severe and moderate malnutrition respectively. The median DDS was 8 (IQR 7-9) in Côte d'Ivoire and Togo, 6 (IQR 6-7) in Benin. Mean DDS was 4.3/9 (sd 1.2) at first visit, with a lower score in Benin, but with no difference between first and last visit (p=0.907), nor by intervention groups (p-value=0.767). CONCLUSIONS: This intervention had a limited effect on nutritional recovery and dietary diversity improvement. Questions remain on determining appropriate nutritional products, in terms of adherence, proper use for families and adequate energy needs coverage for children living with HIV. TRIAL REGISTRATION: PACTR202001816232398 , June 01, 2020, retrospectively registered.