AIDS

BackgroundDespite effective antiretroviral therapy, HIV-1 remains a global health challenge. Most people living with HIV (PWH) are diagnosed in the chronic stage and around half globally are diagnosed late. Within the group with a chronic diagnosis, insight into the effect of time of therapy initiation on reservoir dynamics and immune reconstitution from diagnosis onwards is limited. MethodsIn this prospective cohort study of PWH diagnosed during the chronic stage (from Fiebig VI) were stratified into late (<350 CD4+ T cells/mm3 or an AIDS-defining illness) or non-late diagnosis groups. We analyzed the viral reservoir by IPDA, SQuHIVLa and FISH-Flow, and the immune compartment with the AIM assay and a 45-color spectral flow cytometry panel in the first year after ART initiation. FindingsAlthough proviral DNA decreased in the first year of ART, the inducible reservoir remained stable. PWH with a late diagnosis had a significantly higher inducible reservoir and lower CD4+ T-cell counts than the non-late HIV diagnosis group. A year after ART initiation, the group with a late diagnosis showed a higher abundance of exhausted CD8+ T cells, higher expression of activation/exhaustion markers, and a lower naive CD4+ T-cell abundance than the non-late diagnosis group. Moreover, activation and exhaustion marker expression on T cells correlated significantly with CD4+ T cell count pre-ART. InterpretationOur results show that late diagnosis is associated with a persistently higher inducible viral reservoir and impaired immune recovery. These findings underline the importance of early diagnosis and treatment, and rationalize the use of late diagnosis as a covariate in future studies. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrior research has demonstrated that initiation of antiretroviral therapy (ART) during the acute stage of HIV-1 infection limits reservoir seeding, reduces immune activation and preserves immune function. Therefore, studies have focused on reservoir and immune dynamics in this acutely diagnosed group. However, only 8,4% of diagnoses in Europe are made at an acute stage. Despite the fact that the far majority of diagnoses are made at chronic infection, heterogeneity within this group has been overlooked. In clinical settings, late HIV-1 diagnosis, defined as CD4+ T cell count <350 or AIDS-defining illness, has been shown to lead to more opportunistic infections, slower time to viral suppression and increased mortality when compared to a non-late (but still chronic) diagnosis. Yet, the reservoir and immune dynamics in these groups remains poorly characterized. Added value of this studyIn this study, PBMCs from a prospective cohort of people with a chronic HIV diagnosis in the first year after ART initiation were analyzed using integrated approaches - reservoir quantification and in depth immunophenotyping to simultaneously characterize reservoir dynamics and the immune compartment. We show a significant decrease in the intact viral reservoir for all participants within the first year of ART, whereas the inducible reservoir remained stable. A comparison was performed between the group with late and non-late (but still chronic) diagnosis, shedding light on the heterogeneity within the chronic diagnosis group. The late diagnosis group had a significantly higher inducible reservoir and immune exhaustion, both in marker expression as well as exhausted T cell abundance. All but four of these activation and exhaustion markers differentially expressed between the two groups correlate with CD4+ T cell count pre-ART, highlighting the large heterogeneity in this group. Implications of all the available evidenceTogether, these findings provide insight into the reservoir and immune dynamics within the first year after ART initiation. The data can especially inform both reservoir-targeting strategies that intervene at or shortly after ART initiation, as well as strategies that aim to harness the immune system. Moreover, these results reinforce the importance of early diagnosis, even after the acute stage. The differences in the reservoir and immune compartments between the late and non-late diagnosis groups underscore the need for the use of late diagnosis or time to diagnosis as a covariate in future cure studies.

Background: Despite the success of combination antiretroviral therapy (cART), vascular comorbidities, including cerebrovascular disease, are more prominent in people living with HIV (PLWH) compared to people without HIV (PWOH). However, quantitative assessments of cerebrovascular morphometry and their associations with cognitive outcomes in the context of HIV are still limited. In this study, we explore this missing link. Methods: Magnetic Resonance Angiography (MRA) data, blood markers, and neurocognitive assessments were collected from 73 PWOH subjects (male: 57, female: 16; age: 53 {+/-} 16) and 99 PLWH subjects (male: 66, female: 30, age: 53 {+/-} 11). Vessel morphometric features were quantified using intraCranial Artery Feature Extraction (iCafe) to investigate associations between vessel morphometry, markers of monocytes, endothelial cell activation, and cognitive performance. Results: HIV status predicted a lower total number of branches ({beta} = -0.224, p = 0.001, d = -0.517) and shorter total distal length ({beta} = -0.173, p = 0.021, d = -0.370) with a moderate effect size. Total branch number was found to be negatively associated with plasma levels of monocyte markers (sCD14: r = -0.167, p = 0.033; sCD163: r = -0.157, p = 0.045) and positively correlated with white matter cerebral blood flow (r = 0.550; p [&le;] 0.05). HIV status was the strongest predictor of overall cognitive performance in ANCOVA model ({beta} = -0.219, p = 0.006, d = -0.453). Conclusions: Our results suggest that cognitive impairment in PLWH is associated with vessel morphology metrics. Monocyte immune activation may contribute to changes in vessel morphology.

Introduction: People with long-term virologically suppressed HIV (PWH) experience chronic inflammation. Beneficial effects such as lower levels of inflammation were reported for cannabis-based medicine but data on the safety of standardized low-dose full-spectrum cannabidiol (CBD) are limited. Methods: This double-blind randomized placebo-controlled trial (NCT05306249) included 80 ART-treated PWH with undetectable viremia (median time on efficient ART 14 years, median age 54 years), encompassing 30% women. Participants received 1 mg/kg CBD oil twice daily (full-spectrum, THC <0.3%) or placebo for 12 weeks plus a 4 week follow-up. Primary trial endpoint (autophagy gene expression) will be described elsewhere; here we evaluate the treatment impact on prespecified safety outcomes such as hemodynamic with electrocardiograms, HIV immunovirological parameters and comprehensive assessments of liver and kidney functions, performed using standard blood tests. Mixed-effects models adjusted for baseline age, sex, BMI, CD4 count and duration of viral suppression assessed longitudinal changes. Results: Of 80 randomized participants, 35 PWH in CBD and 37 in placebo groups completed week 12. No clinically meaningful differences emerged in creatinine, aminotransferases (ALT, AST), or conjugated bilirubin. Total bilirubin decreased in the CBD arm vs placebo (mixed effect model considering time, group and time*group, adjusted for covariates p=0.046). In exploratory sex-stratified analysis, a significant difference starting at week 12 (-8.0 bpm [95% CI -15.6; -0.4], p=0.0425) and persisting at week 16 (-7.9 bpm [95% CI -14.6; -1.3], p=0.0191) evidences a lower heart rate in men belonging to the CBD group compared to the placebo group; no change in females. There was no change in plasma viral load, cell-associated HIV-DNA levels and CD4/CD8 ratio. Discussion: Low-dose full-spectrum GMP-certified CBD was well tolerated over 12 weeks in virally suppressed people with HIV. Observed reductions in total bilirubin and male heart rate are exploratory and warrant confirmation in adequately powered trials incorporating inflammatory biomarkers and pharmacokinetics.

BackgroundRecent multiomic analyses identify metformin-inducible genes, such as DDIT4, as predictors of delayed HIV rebound, suggesting a "cell-extrinsic" role for low systemic inflammation in viral control. We sought to validate this inflammatory "cooling" in a large-scale human population. MethodsUsing Olink proteomics from the UK Biobank (N = 502,493), we evaluated associations between metformin use and inflammatory markers (IL-6, CXCL10, GZMB) in a diabetic cohort (N = 18,548). Stepwise regression was used to adjust for co-medications (statins) and glycemic control (HbA1c). ResultsMetformin use was associated with significantly lower levels of IL-6 (p = 0.0049) and CXCL10 (p < 0.001) after adjusting for age, BMI, and statin use. In exploratory analyses of participants with HIV (N = 61), metformin users showed directionally lower mean IL-6 and CXCL10. However, associations in the primary cohort were attenuated upon adjustment for HbA1c, indicating that metformins systemic anti-inflammatory effect is largely mediated by its metabolic efficacy. ConclusionsMetformin use is associated with a reduction in master regulators of inflammation, independent of common co-medications. These findings suggest that metformin promotes the systemic "cell-extrinsic" environment required for HIV control via its metabolic effects, providing a population-level substrate for the "block-and-lock" mechanisms observed in clinical cohorts.

IntroductionDolutegravir-based first-line antiretroviral therapy (tenofovir disoproxil fumarate, lamivudine, and dolutegravir; TLD) has delivered substantial clinical and public health benefits. However, sharply decreasing funding for HIV programmes necessitates cost reduction within current treatment guidelines. We evaluated whether replacing tenofovir disoproxil fumarate with tenofovir alafenamide (TAFLD), a drug with equivalent effectiveness and side effect profile, could reduce HIV treatment costs in South Africa. MethodsWe conducted a budget-impact analysis over 2026-2030 from the provider-perspective. The cost of antiretroviral treatment (ART) provision with either TLD or TAFLD was estimated using ingredients-based costing, including the cost of drugs, laboratory monitoring, staff, consumables, equipment and overheads. Costs are reported in 2025 USD, are undiscounted and not inflated. Population estimates for adults on first-line therapy were derived from Thembisa 4.8. We modelled a phased transition from TLD to TAFLD over two years, and explored sensitivity to TAFLD price variation ({+/-}15%) and inclusion of creatinine monitoring. ResultsTAFLD reduced per-patient annual costs by 4-5% compared with TLD (from US$178 to US$169, and US$287 to US$277, for first and follow-up years, respectively). At full replacement, total programme savings were approximately US$54 million per year (-5%). Even with continued creatinine monitoring, TAFLD remained cost-saving, reducing annual costs by around 4%. Savings increased to 8% if TAFLD prices were 15% lower than base-case assumptions. ConclusionsReplacing TDF with TAF in first-line antiretroviral therapy could generate meaningful cost savings for South Africa with minimal programme disruption. While long-term metabolic effects require consideration, TAFLD represents a feasible interim cost-reduction strategy while awaiting next-generation HIV therapies.

BackgroundUndetectable HIV-specific antibodies in early-treated children with confirmed infection correlate with low viral reservoir and may identify those eligible for future HIV remission strategies. The neonatal immune systems unique characteristics, combined with impairments resulting from exposure to maternal HIV and antiretroviral treatment (ART), may affect antibody responses to HIV. Yet immune competence remains understudied in the context of negative HIV serology. The ANRS-EP59-CLEAC study included 76 children and adolescents with HIV. We measured plasma HIV antibodies by enzyme immunoassay, other analytes by ELISA or multiplex assays, and blood cell phenotypes and functions by flow cytometry. We used Fishers and Mann-Whitneys tests and logistic regression to analyze variables associated with negative HIV serology. Nine participants tested negative for HIV-specific antibodies, eight children and one adolescent. Negative HIV serology occurred exclusively in participants who had initiated ART early and had HIV RNA < 50 copies/mL at evaluation. Among 17 early-treated children with sustained viral suppression, only 7 had negative HIV serology. In this subgroup, negative HIV serology associated with higher nadir CD4 counts, lower plasma IgM levels, higher frequencies of circulating follicular CD8 T lymphocytes, and higher expression of the costimulatory molecule CD86 on myeloid dendritic cells. We found no evidence of B or T lymphocyte deficits associated with negative HIV serology. Low antigenic exposure was necessary but insufficient to explain negative HIV serology. Beyond its association with low HIV reservoir, negative HIV serology correlated with less severe prior CD4 T-lymphocyte depletion and higher frequencies of follicular CD8 T lymphocytes. SummaryIn HIV-infected infants, starting antiretroviral therapy (ART) very early dramatically improves health outcomes. An important phenomenon observed in some of these children is that, despite being HIV-infected, they show no detectable antibodies against the virus -- a profile referred to as negative HIV serology. This feature could help identify patients most likely to benefit from future strategies aimed at achieving long-term virus control without treatment. To better understand this phenomenon, we studied HIV-infected children and adolescents enrolled in the ANRS-EP59-CLEAC trial, which compares the effects of ART initiated early (before 6 months of age) versus late (after 24 months). We showed that negative HIV serology is associated with early treatment, but also with a better-preserved immune system: less depletion of CD4 T cells, which are critical immune cells, and a higher abundance of specific T lymphocytes with potent antiviral activity. Importantly, we found no evidence of defects in the mechanisms responsible for antibody production. These findings suggest that negative HIV serology reflects a favorable immunological profile and could serve as a useful marker to select children as candidates for HIV remission trials.

BackgroundHuman immunodeficiency virus (HIV) infection in pregnancy is associated with preterm birth (PTB), low birthweight (LBW), and perinatal death (PND). Although antiretroviral therapy (ART) suppresses viral load it does not prevent HIV-associated adverse pregnancy outcomes or resolve inflammation. As circulating maternal immune factors may not fully capture maternal-fetal interface immune dysregulation, this observational cohort study aimed to identify localized and systemic immune factors associated with PTB, LBW and PND in ART-treated pregnant people living with HIV (PPLWH). MethodsWe enrolled 118 PPLWH in Kinshasa, Democratic Republic of the Congo, during the second or third trimester. We collected maternal peripheral plasma (at enrollment, 1-3 days post-delivery, and postpartum) alongside umbilical cord and placental plasma at delivery. Concentrations of 45 immune factors were measured via LegendPlex and ELISAs and associations analyzed using Kruskal-Wallis tests with Dunns correction or Mann-Whitney tests. ResultsPlacental plasma exhibited the highest overall concentrations of immune factors, highlighting a distinct localized microenvironment. Among 118 pregnancies, 35 (30%) resulted in PTB, 10 (9%) in PND, and 9 (8%) in LBW. Compared to term births, PTB was associated with higher levels of the chemokines CCL20, CXCL9, and CXCL10 in cord and/or postdelivery plasma (p<0.01), while placental CCL20 levels were lower (p<0.05). Compared to live births, PND was associated with higher postdelivery CXCL1, cord IL-8, placental MPO and NGAL (p<0.05); higher postdelivery CXCL5 (p<0.01); and higher S100A8/A9 levels in cord and postdelivery plasma (p<0.01 and p<0.001, respectively). Finally, LBW was associated with higher enrollment IL-18 and S100A8/A9 levels (p<0.05 and p<0.01, respectively); as well as higher SAA levels in postdelivery and postpartum plasma (p<0.05). ConclusionsIn ART-treated PPLWH, distinct adverse birth outcomes are driven by time- and compartment-specific immune pathways. PTB is associated with localized T-cell chemokine responses, PND with neutrophil recruitment and activation, and LBW with pro-inflammatory cytokine and acute-phase protein responses. These pathways provide mechanistic insights into pregnancy complications in PPLWH and highlight potential compartment-specific biomarkers for risk stratification.

IntroductionViral load (VL) testing is the recommended approach for monitoring antiretroviral therapy (ART) effectiveness, while guidelines recommend targeted CD4 testing after ART initiation. This study examined trends in VL and CD4 testing frequencies, as well as the relationship with AIDS diagnosis and mortality among people with HIV in the Asia-Pacific region. MethodsWe included adults enrolled in the Treat Asia HIV Observational Database (TAHOD) between 2003-2018 who had been on ART for [&ge;]1 year. VL and CD4 testing rates were analysed using Poisson regression models. Associations between testing frequency and AIDS diagnosis or mortality were evaluated using Fine and Gray competing risk regression. ResultsAmong 8,446 patients, VL testing rates remained steady at 1 per person-year (PYS) between 2003-2018. Increased VL testing was associated with more frequent CD4 testing (>2 tests in the previous year; IRR=1.57, 95%CI 1.53-1.60), later follow-up years (2008-2012: IRR=1.15, 95%CI 1.12-1.18; 2013-2015: IRR=1.07, 95%CI 1.04-1.10), older age (31-40 years: IRR=1.06, 95%CI 1.03-1.08; 41-50 years: IRR=1.08, 95%CI 1.05-1.11; >50 years: IRR=1.07, 95%CI 1.03-1.11), higher current VL (401-1000 copies/mL: IRR=1.16, 95%CI 1.09-1.24; >1000 copies/mL: IRR=1.07, 95%CI 1.04-1.11), initial ART regimen (NRTI+PI: IRR=1.07, 95%CI 1.04-1.10; other combinations: IRR=1.11, 95%CI 1.05-1.17), and higher country income levels (upper-middle: IRR=2.17, 95%CI 2.11-2.23; high: IRR=3.14, 95%CI 3.03-3.26). CD4 testing rates decreased from 2.04 to 1.06/PYS over the same period. Lower CD4 testing frequency was associated with HIV exposure mode (MSM: IRR=0.94, 95%CI 0.92-0.96; IDU: IRR=0.93, 95%CI 0.90-0.97; other/unknown: IRR=0.90, 95%CI 0.87-0.93), higher current CD4 (201-350 cells/{micro}L: IRR=0.95, 95%CI 0.93-0.97; 351-500 cells/{micro}L: IRR=0.89, 95%CI 0.87-0.91; >500 cells/{micro}L: IRR=0.85, 95%CI 0.83-0.87) and receiving an NRTI+PI first-line combination (IRR=0.96, 95% CI 0.94-0.98). VL and CD4 testing frequencies were not significantly associated with AIDS diagnosis. However, having > 2 CD4 tests in the previous year was associated with higher mortality risk. ConclusionThe trends in the rates for CD4 and VL testing in the region between 2003-2018 were significantly affected by demographic, clinical and socio-economic factors. Recognizing these factors is critical to optimizing differentiated monitoring strategies and improving outcomes for PWH in the region.

Human immunodeficiency virus (HIV) infection promotes considerable bioenergetic, spatially heterogenous strain to the brain that is incompletely ameliorated through viral suppression afforded by antiretroviral therapy (ART). Disrupted homeostasis of brain lipids after HIV in humans or simian immunodeficiency virus (SIV) infection in rhesus macaques occurs due to elevated energetic demands, neuroinflammation, reactive oxygen species, and barrier leakiness. Brain lipids are particularly vulnerable to HIV-associated dysregulation due to their high abundance, unique composition, and specialized functional roles. Using rhesus macaques exposed to SIV and ART (tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG), we investigated the spatial distribution and abundance of lipids across brain regions and metabolically relevant peripheral tissues using mass spectrometry imaging. When comparing lipid abundance, individual lipids representing a multitude of species were more varied across tissues than by treatment condition. Further, we discerned either solely SIV infection or ART outweighed one another in altering phospholipids in different tissues Presence of ART had a greater influence on phospholipid homeostasis in the temporal cortex and hippocampus than in the midbrain, possibly due to differences in penetrance and turnover of ART across brain regions. Overall, these data demonstrate ART robustly increased phospholipids across brain regions while SIV infection had a varied impact depending on the brain region. These findings inform the need to further evaluate the neurologic consequences that may result in the brain due to disrupted lipid homeostasis across ART regimens.

IntroductionSustaining long-term viral suppression among people living with HIV (PLHIV) remains a major public health challenge in sub-Saharan Africa, despite widespread access to antiretroviral therapy (ART). Evidence on time to first-line ART failure and its predictors at a national scale remains limited, particularly for dolutegravir (DTG)-based regimens. We aimed to estimate the time to first-line ART failure and identify associated predictors among PLHIV in Tanzania using national programmatic data. MethodsWe conducted a retrospective cohort study using routinely collected data from the National Care and Treatment Clinic database (CTC-2) in Tanzania. The analysis included PLHIV aged [&ge;]11 years who initiated first-line ART between January 2017 and December 2021 and had at least six months of follow-up. Time to first-line ART failure was defined as the duration from ART initiation to the first documented virological failure (viral load [&ge;]1,000 copies/mL). Kaplan-Meier methods were used to estimate failure-free survival, and Cox proportional hazards models were used to identify predictors of failure. Non-proportional hazards for DTG-based regimens were addressed using an extended Cox model with a time-varying coefficient. ResultsThe final analytic cohort comprised 36,764 individuals and 789 first-line treatment failure events. Median follow-up time varied across regimen groups. Failure-free survival differed significantly by regimen anchor (log-rank p<0.001). In multivariable Cox models, age and gender were significantly associated with treatment failure. DTG-based regimens demonstrated a time-varying effect: compared with non-DTG regimens, DTG was associated with a substantially lower hazard of failure early after initiation, with the protective effect attenuating over time. Estimated hazard ratios for DTG versus non-DTG regimens were 0.37, 0.67, and 1.22 at 6, 12, and 24 months of follow-up, respectively. ConclusionsIn this large national cohort, the risk of first-line ART failure varied by regimen and patient characteristics. DTG-based regimens showed strong early protection against failure, but this effect diminished over time, highlighting the importance of continued virological monitoring after ART initiation. Time-to-event analyses using routine programmatic data provide important evidence for optimizing ART delivery and informing HIV programme decisions in Tanzania and similar settings.

Background: Advanced HIV disease (AHD) remains a major contributor to HIV-related morbidity and mortality despite widespread antiretroviral therapy (ART) access in sub-Saharan Africa. Although treatment-related adverse drug reactions (ADRs) may compromise treatment outcomes, evidence on the relationship between AHD and ADR occurrence remains limited. This study aimed to determine the prevalence and identify factors associated with AHD, characterize treatment-related ADR and assess the association between AHD and ADR occurrence among people living with HIV receiving ART in Dar es Salaam, Tanzania. Methods: We conducted a multicenter cross-sectional study among 1,513 people living with HIV receiving ART at selected HIV care and treatment clinics in Dar es Salaam, TanzaniaFor this adolescent/adult cohort, AHD was operationally defined as WHO clinical stage III/IV disease and/or baseline CD4 count <200 cells/mm3. Treatment-related ADRs were defined as participant-reported and/or clinically documented ART-related adverse events identified during routine HIV care, including both current and retrospectively reported events. Modified Poisson regression with robust standard errors was used to estimate crude and adjusted risk ratios (RRs) with 95% confidence intervals (CIs). Results: Among 1,508 participants with sufficient information for classification, 961 (63.7%) had AHD. Factors independently associated with AHD included age [&ge;]50 years (aRR 1.10, 95% CI 1.01-1.20), underweight nutritional status (aRR 1.17, 95% CI 1.00-1.35), and concomitant medication use (aRR 1.19, 95% CI 1.03-1.37), while DTG-based ART was associated with lower AHD prevalence (aRR 0.78, 95% CI 0.68-0.90). Overall, 569 participants (38.0%) reported at least one ADR. Composite AHD was not independently associated with ADR occurrence (aRR 0.95, 95% CI 0.82-1.11), but baseline CD4 <200 cells/mm3 was associated with increased ADR risk (aRR 1.20, 95% CI 1.02-1.41). Comorbidity (aRR 1.66, 95% CI 1.42-1.93) was the strongest correlate of ADR occurrence. Conclusion: AHD remains highly prevalent among people living with HIV receiving ART in Tanzania. While composite AHD was not independently associated with ADR occurrence, severe immunosuppression, comorbidity burden, and concomitant medication exposure were associated with increased ADR risk. These findings suggest that immunologic severity and broader clinical complexity may be more informative predictors of ART-related toxicity than composite syndromic AHD classification alone. Strengthened early diagnosis, differentiated advanced HIV care, integrated pharmacovigilance strategies, and routine medication risk assessment are needed.

BackgroundAlthough Kenyas HIV programme has long prioritized high-burden counties for intensified paediatric interventions, a critical evidence gap remains in developing integrated analytic frameworks that can objectively predict and validate paediatric HIV burden using data-driven models. We therefore developed and tested a framework that combines machine-learning (ML) prediction with geostatistical hotspot analysis, where a hotspot denotes a statistically significant spatial cluster of elevated paediatric HIV cases to strengthen data-driven surveillance and resource targeting. MethodsNational HIV testing data for children aged 0-14 years were analysed together with indicators from the 2022 Kenya Demographic and Health Survey. Multiple supervised ML algorithms were trained to predict the number of children living with HIV (CLHIV) across Kenyas 47 counties. Model performance was evaluated using root-mean-square and mean-absolute error. The tuned Lasso-regression model demonstrated the best predictive accuracy and generated county-level estimates for October 2022 to June 2023. These predictions were subsequently assessed for spatial autocorrelation (Morans I) and validated using Getis-Ord Gi* statistics. FindingsThe model predicted 3160 newly identified CLHIV during the study period, compared with 3092 cases reported nationally. To account for differences in county population size, paediatric HIV incidence was calculated as cases per 10,000 children aged 0-14 years using 2023 census projections as the denominator. Incidence-based choropleth maps revealed that the highest reported burden was concentrated in Isiolo (11{middle dot}2 per 10,000) and western Kenya (Homa Bay 7{middle dot}7, Kisumu 3{middle dot}6, Siaya 3{middle dot}5), while model predictions identified additional high-incidence counties in eastern and northern regions. Significant spatial clustering was confirmed for both reported (z = 3{middle dot}23, Morans I = 0{middle dot}22, p = 0{middle dot}001) and predicted (z = 4{middle dot}92, Morans I = 0{middle dot}37, p < 0{middle dot}001) distributions. Thirteen counties, predominantly in western Kenya, were identified as statistically significant hotspots. InterpretationThis study presents a validated methodological framework integrating ML prediction with geostatistical analysis for paediatric HIV surveillance. By expressing model outputs as population-adjusted incidence, the framework enables equitable comparison of paediatric HIV burden across counties of differing size, strengthening the evidence base for geographic prioritization and resource allocation. FundingThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The global ambition to end the human immunodeficiency virus (HIV) epidemic requires understanding which system-level policy levers, enacted under the framework of Universal Health Coverage (UHC), are most effective in achieving both transmission reduction and diagnostic coverage. This study addresses an important evidence gap by quantifying the within-country association between measurable UHC policy indicators and the estimated rate of new HIV infections across nine Southeast Asian countries between 2013 and 2022. Employing a Fixed-Effects panel data methodology, the analysis controls for time-invariant national heterogeneity, ensuring reliable estimates of policy impact. We found that marginal changes in total current health expenditure (CHE) as a percentage of gross domestic product (GDP) were not statistically significantly associated with changes in HIV incidence. However, increases in the UHC Infectious Disease Service Coverage Index were statistically significantly associated with concurrent reductions in HIV incidence (p < 0.001), suggesting the efficacy of targeted service implementation as the principal driver of curbing new HIV infections. In addition, the UHC Reproductive, Maternal, Newborn, and Child Health Service Coverage Index exhibited a statistically significant positive association with changes in HIV incidence (p < 0.01), which is interpreted as a vital surveillance artefact resulting from expanded detection and reporting of previously undiagnosed HIV cases. Furthermore, out-of-pocket (OOP) health expenditure as a percentage of CHE showed a counter-intuitive negative association with changes in HIV incidence (p < 0.01), suggesting this metric primarily shows ongoing indirect cost burdens on the established patient cohort, or, alternatively, presents a diagnostic access barrier that results in lower case finding. These findings suggest that policymakers should prioritise investment in targeted infectious disease service efficacy over aggregate fiscal commitment and utilise integrated sexual health platforms for strengthened HIV surveillance and case identification.

IntroductionHIV testing for children of women living with HIV (WLHIV) is an efficient method of diagnosing HIV in children. We analyzed pooled data from 13 Population-based HIV Impact Assessments (PHIA) conducted from 2015 through 2019 to determine the gap in diagnosing HIV in children of WLHIV. MethodsIn each PHIA, children younger than 15 years in a subset of households were sampled for HIV testing. Mother-reported responses on childs status were linked to maternal interviews and biomarker data. Analysis was restricted to children whose mothers were alive, older than 15 years and aware of their HIV-positive status prior to the survey. We calculated weighted proportions of children who were never previously tested and proportion of children living with HIV (CLHIV) with no evidence of antiretroviral treatment (ART) use (categorized as newly diagnosed). Survey weights were pooled across all PHIAs to account for survey design and nonresponse. ResultsOf 4,234 WLHIV, 3,436 were aware of their HIV status and had at least one child (n=6,173) for whom responses were obtained. Of the 6,173 children, 43.5% (n=2,371) were reported as never been tested. Overall, 5,500 children provided blood for HIV testing during the survey. Newly diagnosed test positivity was 1.7% (90/5,191); 2.9% (61/2,120) among those with reported unknown HIV status and 0.9% (29/3,071) among those with reported HIV negative status. Among children with reported HIV positive status, 94.5% were confirmed by survey testing and of these, 91% had antiretrovirals (ARVs) detected. ConclusionsOver 40% of children of WLHIV who were aware of their HIV positive status had never been tested for HIV. HIV positivity ranged between 0.9% to 2.9% while 9.0% of children known to be HIV positive were not on ART. The study calls for renewed efforts to enhance testing of children and treatment linkage for those diagnosed with HIV.

BackgroundAdvanced ageing has been associated with an increased risk of serious disease endpoints in people with HIV (PWH). We conducted a longitudinal analysis to assess advanced proteomic ageing during untreated HIV infection and the effect of antiretroviral therapy (ART) on it by comparing the plasma proteome before and after ART initiation. Methods416 protein abundance estimates were used to train a linear regression model predicting chronological age on 727 samples from Swiss HIV Cohort Study (SHCS) participants on long-term suppressive ART (median ART duration, 11.7 years). Advanced ageing was defined as age predicted by the proteomic ageing clock (PAC) minus chronological age. We evaluated the effect of successful ART on advanced proteomic ageing in an independent set of 80 PWH who had 4 longitudinal samples available, that is 2 samples during untreated HIV infection (>3 years apart, median interval between samples, 8{middle dot}08 years (IQR 4{middle dot}83-11{middle dot}09)) and 2 samples during suppressive ART (>3 years apart, median interval between samples, 9{middle dot}81 years (7{middle dot}16-11{middle dot}01)). FindingsIn the longitudinal test cohort, participants showed significantly higher proteomic age during untreated HIV infection than during suppressive ART, with a mean difference of 5.99 years (95% CI 4.25, 7.72), p = 0.0001. Thus, ART was associated with a marked reduction in proteomic advanced ageing. Although proteomic age remained higher than chronological age at all time points, linear interpolation of per-participant advanced ageing showed progressive normalisation towards chronological age during long-term suppressive ART. We validated these findings with our previously published epigenetic ageing study in the same cohort and extended those observations to the functional proteome, showing that proteomic data can capture acute immune signatures. Further, mediation analysis suggests that reversal of advanced ageing under ART is not driven by CD4+ or CD8+ T cell counts, indicating that the proteome captures ageing signals beyond immune reconstitution. InterpretationsIn a longitudinal study spanning more than 17 years, the advanced proteomic ageing observed during untreated HIV infection showed immediate and persistent deceleration under suppressive ART, demonstrating the importance of minimising the duration of untreated HIV infection. FundingSwiss HIV Cohort Study Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCurrent guidelines recommend prompt antiretroviral therapy (ART) initiation after HIV diagnosis, making it now difficult to quantify the potential effects of untreated HIV on advanced ageing. Biological ageing clocks serve as proxies for individual-level disease impact and are associated with serious disease endpoints in people with HIV (PWH). We searched PubMed for English-language reports from database inception to February 24, 2026, using combinations of the terms "HIV infection," "antiretroviral therapy," "proteomic ageing," "proteomic clocks," "proteomic advanced ageing," and "age advancement." We identified one study reporting that virally suppressed HIV infection is associated with a significant increase in proteomic ageing. We have previously shown in the well established longitudinal SHCS cohort with blood samples spanning >17 years and available both pre-ART and post-ART, that telomere length attrition and epigenetic ageing is accelerated during untreated HIV infection and that initiation of successful ART is associated with a significant reduction in accelerated ageing. Added value of this studyTo our knowledge, this is the first study to examine the impact of untreated HIV on the proteome using a proteomic ageing clock. Our results demonstrate that proteomic age is elevated before ART initiation and decreases significantly following successful viral suppression on ART. This reduction was not mediated by standard immunological markers (CD4+ and CD8+ T-cell counts,CD4:8 ratio). Compared with our previous epigenetics study, the proteome appears more responsive: advanced ageing increases more sharply during untreated HIV infection and is faster to decrease after ART initiation. Implications of all the available evidenceOur findings demonstrate the importance of prompt ART initiation for PWH and reveal HIV-related ageing signals in the proteome that extend beyond immune reconstitution. Further, given the established association between advanced ageing and serious disease endpoints, this evidence motivates future studies into persistent advanced ageing to enable identification and stratification of high-risk PWH.

Objectives: This systematic review and meta-analysis (2010 - 2025) examines changes in uptake and retention rates among pregnant and postpartum women with HIV in sub-Saharan Africa as countries adopted Option B+ for preventing vertical transmission. Design and data sources: We searched PubMed, Embase, Cochrane Library, Scopus, and African Index Medicus from 10/2021 - 05/2025 for eligible studies that measured HIV care uptake or retention for pregnant/postpartum women under prevention policies before or during Option B+. Study designs were limited to cohort, case-control, cross-sectional, or interventional studies. Exclusions were white papers, commentaries, modeling, cost-effectiveness, and qualitative studies. Data extraction and synthesis: Outcomes were (i) HIV care uptake defined as initiation of ART during pregnancy or prior to initial antenatal care (ANC) visit and (ii) proportion of women retained in HIV care as defined by study authors after ART initiation (or entry to antenatal care). These were synthesized in meta-analyses stratified by policy era (pre-Option B+ vs. Option B+) at different times for different countries. Comparisons between policy eras were made using relative risk with a 95% confidence interval. Pooled retention estimates at 6- and 12-months post ART initiation used crude relative risks (RR) with 95% confidence intervals (CI). Results: Among 4,752 articles, 82 from 17 countries were included; 60 reported HIV care uptake, 31 reported retention outcomes. Pooled HIV uptake rose by 8% (RR=1.08; 95% CI:1.06-1.09) and pooled retention in HIV care rose by 46% (RR=1.46; 95% CI:1.41-1.51) after Option B+ implementation. Pooled estimates of retention in care were 36.9% (95% CI: 13.9%, 59.9%) at 6 months post ART initiation before the implementation of Option B+ and 72.7% (95% CI: 66.3%, 79.1%) after implementation. Conclusion: HIV care uptake and retention improved after Option B+ implementation in 15 countries reporting results, but retention remains suboptimal for meeting UNAIDS 95-95-95 targets.

BackgroundAlthough the number of new HIV diagnoses among men who have sex with men (MSM) in the Netherlands has declined considerably, the recent plateau suggests ongoing transmission. In 2024, 29% of new diagnoses among MSM were in a late HIV stage, showing that the time between infection and diagnosis can still be substantially reduced. In low-incidence settings, infections introduced through immigration are increasingly important in sustaining transmission, highlighting the need to re-evaluate current testing guidelines. We assess targeted testing strategies among MSM in the Netherlands addressing these considerations. MethodsWe used an agent-based model of HIV transmission among MSM in the Netherlands, incorporating infections acquired domestically and abroad. For 2024 - 2040, we simulated testing interventions targeting different subgroups, including offering an HIV test to immigrants upon entry, increasing testing rates among MSM residing in the Netherlands, and combinations of these approaches. ResultsOffering HIV testing to immigrating MSM at the entry averted up to 94 (95-th % quantile interval, 95% QI -128 - 328) new infections over 15 years if at least 50% take the test. Increasing testing to every 7 months in the general MSM population achieved the largest reduction, with up to 508 (95% QI 292 - 900) infections averted. The same testing rate in MSM with more than 5 partners within the previous six months resulted in 340 (95% QI 132-592) infections averted. Combining testing at entry with 7-months testing among general resident MSM averted the most infections, 534 (95% QI 308 - 884). ConclusionsCombination of offering HIV test to immigrating MSM at the entry with 7-month testing frequency in the general resident MSM population can substantially reduce HIV infections. The difference in impact between targeting general MSM and those with relatively high recent partner numbers suggests that criteria for being at risk of having HIV need to expand. 1 Author summaryWhile HIV transmission among MSM in the Netherlands has decreased substantially over the last decade, it is still ongoing. In 2024, 29% of new HIV diagnoses in MSM were in individuals in late-stage of HIV infection, suggesting that the time between HIV acquisition and diagnosis should be shortened further. Additionally, in a low-incidence setting such as MSM in the Netherlands, introduction of HIV infections through immigration becomes more important. We evaluated several HIV testing strategies for this context, considering both immigrating MSM and resident MSM. While offering HIV test at entry point can avert many HIV infections, increasing testing rate in resident MSM to on average every seven months can avert substantially more HIV infections. The greatest impact is achieved when these approaches are combined: targeting both immigrating MSM and those already living in the country. This combined strategy requires the fewest additional tests per infection averted. Importantly, our simulations show that there are MSM living with undiagnosed HIV who do not necessarily meet the traditional criteria for being at risk. Improved testing strategies can help reach these individuals earlier, benefiting both public and their personal health.

Delayed diagnosis and poor antiretroviral therapy (ART) adherence remain primary drivers of HIV-related morbidity in low-resource settings, yet real-world AI validation at scale is lacking. We conducted a retrospective validation study using two publicly available, de-identified datasets: a Quality of Care cohort of 27,288 HIV-positive patients on ART across multiple healthcare facilities, and the CEPHIA multi-country assay database comprising 165,444 specimen records from six countries. Four machine learning classifiers were evaluated using 10-fold stratified cross-validation with SMOTE applied strictly to training folds. Explicit data leakage prevention, ablation analysis, calibration assessment, and bootstrap confidence intervals were applied. Economic projections used one-way sensitivity analysis. This study adheres to TRIPOD reporting guidelines. Random Forest achieved AUC-ROC of 0.9753 (95% CI: 0.970-0.975), sensitivity 87.3% (95% CI: 86.4-88.2%), specificity 95.7% (95% CI: 95.2-96.2%), and Brier score 0.079. Ablation testing confirmed robustness (AUC 0.963 without the primary predictor). Temporal validation on held-out future patients yielded AUC 0.772 (95% CI: 0.744-0.802), confirming generalisation across time. Real-world analysis revealed median diagnosis-to-ART delay of 74 days, with 47.3% of patients exceeding 90 days and 36.7% presenting with CD4 below 200 cells per microlitre. Multi-country CEPHIA analysis identified 18.6% HIV recency within the 130-day early-intervention window. Decision curve analysis confirmed net clinical benefit across threshold probabilities 0.03-0.45. Subgroup analysis demonstrated consistent AUC across sex, age, CD4 strata, and WHO staging (max difference 0.051). Economic modelling projected base-case savings of USD 415 per patient (USD 2.07 million per 5,000-patient cohort). These findings provide large-scale empirical evidence that AI-driven informatics can predict ART adherence failure and quantify systemic care gaps, offering a scalable framework for equitable HIV care delivery in resource-limited settings. Prospective external validation is required before clinical deployment.

BackgroundRoutine viral load monitoring is central to assessing treatment effectiveness in HIV care, and dolutegravir (DTG)-based regimens are now preferred in many treatment programmes. However, national routine data analyses comparing 48-week viral load suppression across antiretroviral therapy initiation regimens in Tanzania remain limited. MethodsWe conducted a retrospective cohort analysis using routinely collected HIV programme data from Tanzanias National AIDS, STIs and Hepatitis Control Programme database. After de-duplication and data processing, the working analysis warehouse contained 49,547 patients and 1,008,137 visits. The primary analysis included 6,991 patients with a valid viral load measured 48 weeks after initiation of antiretroviral therapy. Viral suppression was defined as a viral load <1,000 copies/mL. We compared suppression between DTG-based and non-DTG-based initiation groups and across individual initiation regimens. Treatment change episodes and early DTG switching patterns were summarized as secondary analyses. ResultsOf the 6,991 included patients, 6,113 (87.4%) achieved viral load suppression at 48 weeks. Suppression was higher among DTG initiators than non-DTG initiators (917/1,000, 91.7% vs. 5,196/5,991, 86.7%). TDF+3TC+EFV was the most common non-DTG initiation regimen, whereas TDF+3TC+DTG was the most common regimen among DTG initiators. ConclusionsViral suppression at 48 weeks was high overall but was higher among patients initiated on DTG-based regimens than among those initiated on non-DTG regimens. By anchoring outcomes to a fixed post-initiation time point, this study complements existing Tanzanian evidence on viral load testing uptake and geographic variation. It provides regimen-specific insights into the effectiveness of early treatment under routine programme conditions.

Objectives: Quantify hazardous alcohol consumption prevalence among individuals at risk of acquiring HIV infection and its association with high-risk sexual behaviors and incident HIV in 11 Eastern and Southern African countries. Design: Secondary analysis of 16 nationally-representative household surveys (2015-2023). Methods: The study included sexually active individuals aged [&ge;]15 years. Alcohol use patterns were classified using the AUDIT-C (non-drinkers/low-risk drinkers/hazardous non-binge drinkers/hazardous binge drinkers). Outcomes included high-risk sexual behaviors, recent HIV infection, and undiagnosed HIV infection. Survey-weighted alcohol use prevalence and logistic regression were estimated by gender, adjusting for sociodemographic covariates. Model outputs were used to estimate change in incident infections when removing excess risks associated with alcohol use patterns. Results: Analyses included 251,931 participants. Across countries, 5.8%-21.1% reported hazardous binge drinking, and 3.7%-15.7% reported hazardous non-binge drinking, with large gender differences. Sexual risk behaviors increased with drinking severity among men and women. Compared with non-drinkers, alcohol use was associated with higher odds of undiagnosed HIV infection; adjusted odds ratios ranged from 1.32 (1.16-1.50) for low-risk drinkers to 1.52 (1.34-1.72) for hazardous binge drinkers among men, and 1.28 (1.13-1.46) to 1.55 (1.31-1.82) among women. Simulated removal of alcohol-associated excess risk reduced undiagnosed HIV by 15.1% (10.9%-19.4%) among men and 5.8% (4.0%-7.9%) among women. Estimates for recent HIV infection followed a similar pattern but with larger uncertainty. Conclusions: Hazardous alcohol use was associated with sexual risk and HIV infection in Eastern and Southern Africa. Reaching individuals who use alcohol with effective HIV prevention may reduce HIV acquisition risk across the region.