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.

Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naive/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/709579v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@15fb1adorg.highwire.dtl.DTLVardef@189d79corg.highwire.dtl.DTLVardef@aa6a89org.highwire.dtl.DTLVardef@3852f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

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.

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.

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.

ObjectiveTo evaluate risk of dementia after cancer diagnosis among Medicaid beneficiaries with HIV. DesignLongitudinal observational study of Medicaid enrollment, inpatient, and outpatient claims data from 14 states, 2001-2015. MethodsBeneficiaries aged 18-64 with HIV and [&ge;]6 months of enrollment were matched 1:1 on cancer status by age, sex, race, year, and state. We estimated the weighted cumulative incidence functions (CIFs) of dementia at 1, 2, and 5 years after cancer diagnosis using the Aalen-Johansen estimator to account for the competing risk of death and cluster stratified analyses to account for matching. We calculated the corresponding risk differences (RD) and 95% confidence intervals (CI) using nonparametric bootstrap. ResultsAt 5 years, the CIF of dementia was 9.6% (95%CI: 8.2, 11.6) and 4.7% (95%CI: 3.7, 6.1) among those with and without AIDS-defining cancer, respectively (RD: 4.9%; 95%CI: 2.9, 7.0). At 5 years, the CIF of dementia was 7.1% (95%CI: 5.9, 7.8) and 5.3% (95%CI: 4.2, 6.2) among those with and without non-AIDS-defining cancer, respectively (RD: 1.8%; 95%CI: 0.34, 2.9). Dementia incidence appeared higher among beneficiaries with lung cancer (2yr RD: 1.9%; 95%CI: 0.01, 5.2) and beneficiaries [&le;]50 with colon cancer (2yr RD: 4%; 95%CI: 0.3, 10.5), but lower among beneficiaries [&le;]50 with prostate cancer (2yr RD: -1.9%; 95%CI: -2.3, -1.6). Dementia incidence did not differ among beneficiaries with and without breast cancer. ConclusionsDementia risk may be increased among people with HIV with certain cancers, including AIDS-defining cancers. Dementia risk appears to vary by cancer type and age at diagnosis.

BackgroundMaintaining viral suppression among people who inject drugs (PWID) living with HIV in sub-Saharan Africa remains critical to minimize drug resistance for dolutegravir (DTG)-based regimens. We evaluated PWID taking DTG to assess longitudinal rates of viral non-suppression and emergence of drug resistance mutations in Kenya. MethodsWe enrolled Kenyan PWID who had transitioned from an efavirenz (EFV) based regimen to tenofovir+lamivudine+DTG (TLD) [&ge;]6 months prior, and measured plasma HIV RNA viral load (VL) every 6 months for 2 years. We used univariable Cox proportional hazards to assess longitudinal risk for viremia (VL >200 copies/ml). Plasma specimens with viremia were genotyped for HIV drug resistance, including minority variants, using a lab-developed PacBio sequencing assay, and referenced by the Stanford HIVdb program. ResultsAmong 250 participants, 125 were receiving methadone, 199 (79.6) reported heroin use, 70% were male, and median age was 39 years. 194 (77.6%) participants completed all five study visits, 41 (16.4%) were lost to follow-up and 15 (6.0%) died. Across all study visits, 166 (66.0%) of the 250 participants were always suppressed, and 84 (33.6%) were viremic at least once during follow-up, including 8 (3.2%) who were always viremic and 76 (30.4%) who were intermittently suppressed. Living in an improvised shelter or outdoors was significantly associated with a higher risk of viremia (HR=4.35, 95% CI: 1.52-12.53). 93 specimens had drug resistance genotyping, 27 (29%) of which were from participants with incomplete follow-up. NNRTI resistance was frequent (37-41% across visits), whereas major resistance mutations were infrequent to tenofovir (4.3%), lamivudine (7.5%), and DTG (1%, minority variant S153F detected at 1% frequency). Accessory DTG mutations, which do not independently reduce susceptibility, were more common, observed in 41% (38/93) of genotyped specimens, most often T97A, E138K, and L74M. ConclusionAmong PWID living with HIV on TLD in Kenya, one-third had intermittent or sustained viral non-suppression across two years of follow-up. While NNRTI resistance was common, DTG resistance mutations were rare. Improving viral suppression among PWID living with HIV will reduce transmission risks and improve clinical outcomes.

BackgroundAbrupt cessation of USAID and CDC resources to KwaZulu Natal province in South Africa, threatens the progress over decades to address HIV. MethodsWe used a previously developed validated HIV transmission model with input from the KZN Department of Health and local stakeholders to estimate impact of funding cuts on HIV incidence and mortality at 12-months and through 2030. We applied the model to estimate the impact of restoring funds on HIV incidence and mortality. ResultsHIV incidence increased at 12 months and through 2030 by 3.4% and 22.8%, leading to 35,300 and 116,100 additional infections, and 12,800 and 42,300 additional deaths, respectively. Restoring funding after a 12-month pause, reallocated to focus on long-acting PrEP, would avert 12,600 new infections. ConclusionThis model application demonstrates that the sudden cessation of USAID and CDC commitments in the largest HIV epidemic in the world leads to increased incidence and mortality and threatens decades of progress in KZN, South Africa. Restoring funding within 12 months and increasing efficiency of HIV interventions can reestablish KwaZulu Natal province, South Africas trajectory toward EHE goals.

BackgroundLoss to follow-up (LTFU) undermines the success of antiretroviral therapy (ART) programs, especially in high HIV prevalence regions like Njombe, Tanzania. Understanding factors influencing LTFU is critical to enhance patient retention. AimTo assess the prevalence and predictors of LTFU among people living with HIV (PLHIV) receiving ART in Njombe, Tanzania, from 2017 to 2021 MethodsWe conducted a retrospective cohort study using the National Care and Treatment Clinic (CTC2) database, defining LTFU as absence from care for 180 days or more. Logistic regression identified factors associated with LTFU. Data were cleaned using Microsoft Excel and analyzed using IBM SPSS Statistics version 26. Descriptive statistics were used to summarize demographic and clinical characteristics, and logistic regression was used to identify independent predictors of LTFU ResultsOf the 37,642 PLHIV initiated on ART, 13,411 (35.6%) were LTFU during the five-year study period. The highest annual incidence of LTFU occurred in 2020 (n = 4,069), coinciding with the onset of the COVID-19 pandemic. District-level disparities were substantial: Wangingombe recorded the highest disengagement prevalence (46.7%), while Makete recorded the lowest (23.7%). Multivariable analysis revealed that gender and age were not independent predictors of attrition (p > 0.05). However, significant associations with LTFU were observed for lower pharmacy refill adherence, marital status (single and divorced), and district of residence. Notably, patients in Wangingombe had more than double the odds of LTFU compared to those in Njombe (AOR 2.09; 95% CI: 1.95-2.24), whereas the 2021 initiation cohort demonstrated a significantly lower risk of disengagement (AOR 0.25; 95% CI: 0.22-0.28). ConclusionLTFU remains a critical challenge in the Njombe Region. Targeted interventions, including strengthened pharmacy refill monitoring, district-specific strategies, and psychosocial support for PLHIV, are essential to improve retention and sustain progress toward national HIV treatment goals.

The advent of antiretroviral therapy (ART) has led to substantial increases in life expectancy among persons with diagnosed HIV (PWDH), and in turn, an increasingly older population. This represents a public health challenge, as older PWDH are more susceptible to age-related health morbidities compared to the general population. In this study, we triangulate diverse data sources to reconstruct the Italian PWDH age structure over the past decade to better-understand recent trends, and provide demographic projections through 2035. We find that the PWDH population grew from approximately 112,000 persons in 2012, to 140,000 in 2024, and forecasted to reach 155,000 by 2035. This is primarily driven by decreased PWDH mortality, with such decreases forecast to continue. Persons over 60, estimated as 8.6% of the PWDH population in 2012, had increased to over 20% by 2020, and are projected to reach 47.2% by 2035. By 2030, over 10% of PWDH in Italy are projected to be over 75, compared to less than 1% in 2012. Our results demonstrate that the Italian HIV care infrastructure must prepare for a dramatic shift from managing a predominantly young-adult disease to caring for a majority-elderly population within the next decade, representing an unprecedented transformation in the nature and scope of required services.

ObjectiveTo quantify trends in annual mean healthcare costs per person living with HIV from 2003 to 2018 from a publicly funded healthcare system perspective. DesignWe conducted a retrospective population-based study using administrative health data in Ontario, Canada, including 25,842 people living with HIV diagnosed and entering care between 1992 and 2018. A nested cohort from the Ontario HIV Treatment Network Cohort Study (n=3,516) provided additional HIV-related characteristics. MethodsAnnual mean healthcare costs per person were estimated using a validated costing algorithm and inflated to 2025 Canadian dollars. Trends were examined overall and stratified by sociodemographic factors (age, sex, rurality, neighbourhood income, immigration status) and year of entry into HIV care. Within the nested cohort, trends were stratified by nadir CD4 count and any antiretroviral therapy use since diagnosis. ResultsAnnual mean cost per person increased from $11,963 in 2003 to $16,721 in 2018. Medication costs remained the largest cost component throughout (47.4-61.7%) and closely mirrored overall trends. Higher annual mean costs were consistently observed among individuals diagnosed at older ages, lower-income neighbourhood residents, long-term Ontario residents (Canadian-born or immigrated before 1985), and individuals with nadir CD4<200cells/{micro}L. ConclusionMedication expenditures continue to drive healthcare costs for people living with HIV. Cost containing strategies, including expanded generic substitution and strengthened price negotiation, may reduce costs without compromising outcomes. Persistent cost disparities highlight the need to address delayed treatment initiation and broader social determinants shaping HIV treatment access and sustained engagement in care.

People who inject drugs (PWID) in India continue to experience high HIV incidence while coverage of HIV and harm reduction services within this population remains suboptimal in many settings, highlighting the need to identify novel service delivery points. To evaluate the effectiveness of spatially focused upscaling of interventions at observed venues where PWID injected drugs together, we developed an individual-based dynamic transmission model of HIV informed by detailed injection network, service engagement, and injection venue attendance data collected in a sociometric study of PWID (n = 2512) in New Delhi, India. HIV incidence was simulated for different spatial targeting strategies and with increasing service coverage at injection venues according to UNAIDS/UNODC goals. We identified significant decreases in predicted HIV incidence when deploying interventions at frequently visited injection venues (from 6.8 cases/100 person-years to 2.7/100PY for full service coverage at the most-visited venue, and further down to 1.3/100PY for 12 most-visited venues). Prioritizing the most visited venues stratified by spatial clusters provided services to a larger number of individuals versus prioritizing the overall most visited venues, suggesting that service expansion at venues that are spatially distinct with minimal population overlap has a slightly larger impact on reducing HIV incidence.

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.

BackgroundHIV-specific broadly neutralising antibodies (bNAbs) can maintain viral control after interrupting antiretroviral therapy (ART). We investigated the duration and efficacy of Fc-engineered long-acting bNAbs (LS-bNAbs) in maintaining ART-free HIV control compared with placebo. MethodsRIO is a 1:1 randomised double-blind placebo-controlled trial of two LS-bNAbs (3BNC117-LS & 10-1074-LS) in individuals virally suppressed on ART initiated since early-stage HIV. Eligible participants interrupted ART after receiving blinded infusions of either both LS-bNAbs (Arm-A) or placebo (Arm-B). A second optional blinded infusion was offered after 20 weeks for participants who remained virally suppressed without ART. The primary outcome was time to viral rebound 20 weeks after ART interruption, defined as either the first of six consecutive plasma HIV RNA >1,000 copies/mL, or two measurements >100,000 copies/mL. Secondary outcomes included adverse events, long-term viral control and bNAb pharmacokinetics. FindingsSixty-eight participants were randomised, thirty-four to each arm. By week 20, viral rebound had occurred in 8 Arm-A and 30 Arm-B participants; 75% (95% CI, 61 - 92) of Arm-A participants had not rebounded, compared to 11% (95% CI, 4-29) participants in Arm-B. Arm-A participants were 91% less likely to rebound compared to Arm-B participants (hazard ratio of rebound (HR): 0.09; 95% confidence interval (CI) 0.04 - 0.21, P < 0.001). ART-free viral control using the above endpoints beyond 96 weeks was evident in 7 (25%, 95% CI 13 - 48) Arm-A participants compared to 2 (11%, 95% CI 4 - 29) Arm-B participants (HR: 0.22, 95% CI 0.12 - 0.40, P < 0.001). These seven participants had predicted serum bNAb concentrations below the presumed therapeutic threshold of 10 g/mL at 96 weeks. Of nine serious adverse events, none were study-related. ConclusionLong-acting bNAbs can sustain extended ART-free viral control in people treated during early-stage HIV and represent a promising step towards achieving ART-free HIV remission. FundingThe RIO trial was funded by the Bill & Melinda Gates Foundation (grant ref. OPP1210792). Infrastructure support in the UK for this research was provided by the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC), the NIHR Imperial Clinical Research Facility (ICRF) and the Oxford NIHR BRC. O_LIStudy/trial registration numbers and date of registration: {circ}UK Research Ethics Committee reference: 19/LO/1669 (11 Sep 2019) {circ}EudraCT: 2019-002129-31 (12 Dec 2019) {circ}EU CTR: 2024-514564-13-00 (02 Jan 2025) {circ}ClinicalTrials.gov Identifier: NCT04319367 (02 Mar 2020) {circ}UK IRAS: 266322 {circ}Sponsor Protocol Number: 19IC5249 {circ}Funder Reference: OPP1210792 C_LI Evidence in contextWe systematically searched Medline, Embase, and Web of Science databases until April 2024 with additional searches updated until January 2026. Combination therapy of HIV-specific broadly neutralising antibodies (bNAbs) has demonstrated periods of viral control for people living with HIV who interrupt their antiretroviral treatment. The development of long-lasting LS-bNAbs with Fc-receptor modifications has been shown to increase the serum half-lives by up to four-fold. To date, the clinical efficacy and duration of ART-free HIV control with LS-bNAbs has not been evaluated in a sufficiently powered human trial. Added value of this studyThe RIO trial; a prospective double blind randomised controlled study for the first time demonstrates that a single dose of two bNAbs 10-1074-LS and 3BNC117-LS was 91% more effective in maintaining ART-free viral control to twenty weeks compared to placebo. The long-term follow up to 96 weeks adds new data on the duration and frequency (25%) of viral control conferred by two doses of LS-bNAbs beyond the expected frequencies of post-treatment control in an early treated cohort of people living HIV. ART-free viral control beyond 96 weeks is likely due to post-bNAb induced mechanisms as modelled bNAb concentrations past this time were below presumed therapeutic thresholds. Administration of LS-bNAbs was safe and not associated with any Severe Adverse Events. Implications of all the available evidenceLS-bNAbs represent a major advance towards ART-free HIV control and remission as an achievable goal. These findings will inform future combination strategies to enhance the mechanisms of post-bNAb HIV control.

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.

Female sex workers (FSW) in sub-Saharan Africa experience disproportionately high risks of HIV infection. Mathematical models are widely used to assess the contribution of sex workers and other key populations to HIV transmission dynamics and to inform targeted programmes. However, many rely on simplifying assumptions, such as stable sex worker characteristics and constant HIV transmission risk over time. These assumptions may be unrealistic and could bias modelled estimates. We used the South African Thembisa model to assess how alternative assumptions about FSW age, duration of sex work, and client-to-FSW transmission risk affect modelled HIV outcomes. We compared six scenarios that combined constant and increasing FSW age and sex work duration with constant and early-epidemic declining (exponentially or exposure-dependent) transmission risk. Each scenario was calibrated to HIV prevalence data from population-based and sex worker-specific surveys. Scenarios that allowed both FSW characteristics and transmission risk to vary over time showed the best agreement with external data, most closely reproducing HIV incidence, prevalence, and viral suppression estimates from a 2019 national sex worker survey (incidence [~]5 per 100 person-years, prevalence 61-62%, viral suppression [~]60%), and producing incidence rate ratios more consistent with estimates from the broader eastern and southern Africa region. By contrast, the scenario assuming constant FSW characteristics and transmission risk overestimated HIV incidence and underestimated prevalence and viral suppression. At the same time, this time-invariant specification attributed a much larger share of new HIV infections to sex work, with commercial sex work accounting for more than 20% of new infections in 2025, compared with 9-13% under time-varying assumptions. Overall, our findings show that HIV model estimates for sex workers are highly sensitive to modelling assumptions. Incorporating time-varying FSW parameters yields estimates that are more consistent with empirical data and support more reliable programme planning and evaluation. Author SummaryFemale sex workers in sub-Saharan Africa face much higher risks of HIV infection than other women. Mathematical models are often used to understand why and to guide prevention programmes. Yet many of these models make simple assumptions about sex workers - for example, that their average age stays the same over time, that they spend a fixed number of years in sex work, or that the chance of HIV passing from a client to a sex worker never changes. In reality, these factors changed over time. In this study, we used South Africas national HIV model to test how changing these assumptions affects the results. We compared different versions of the model and checked which ones best matched national sex worker survey data. We found that the model worked better when we allowed sex workers to become older over time, to spend longer in sex work, and the risk of passing on HIV to decline. Our findings show that mathematical models can give very different answers depending on how they represent the lives and experiences of sex workers. More realistic assumptions lead to more accurate estimates and can help ensure that programmes focus support where it is most needed.

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.