BACKGROUND:HIV testing at birth supports timely infant HIV diagnosis and treatment. We evaluated the operational feasibility and effectiveness of facility-based, risk-stratified birth testing for newborns at high risk and moderate risk of vertical HIV transmission in Botswana. METHODS:We tested newborns at high risk or moderate risk of HIV acquisition at 35 delivery facilities selected based on delivery volume. At-risk newborns were identified by maternal delivery record review and tested after mothers provided verbal consent during brief interviews. Included infants were born to mothers 18 years and older, weighing 1·5 kg and over, and had one or more maternal risk factors; infants unlikely to survive 24 months were excluded. High-risk was defined as documented maternal HIV-1 viral load of 40 copies per mL or above during pregnancy, maternal CD4 count under 350 cells per μL during pregnancy, fewer than 12 weeks of maternal antiretroviral therapy (ART) use before delivery, or self-reported poor maternal adherence to ART (ie, more than three missed doses during pregnancy). Moderate risk included a new HIV diagnosis in pregnancy or other clinical concerns. Dried blood spots were evaluated using GeneXpert, with positive results confirmed by COBAS TaqMan. Children testing negative were retested at 6 weeks, per national guidelines. FINDINGS:From July 4, 2022, to July 4, 2024, 8844 total newborns were delivered to women living with HIV. Of these, 2737 newborns with any risk factor of concern to government midwives were identified, testing was offered to their mothers, and 96% accepted, yielding a total of 2627 newborns (30%) exposed to HIV who were tested at birth. HIV testing occurred at a median of 22 h of life (IQR 13-41). 1234 (14·0%) infants were high-risk and 1393 (15·8%) were moderate-risk by study-specific criteria; 1283 infants (48·8%) were female and 1344 (51·2%) were male; demographic data on race and ethnicity were not collected, although all participants were Black Africans. HIV was confirmed in 14 (0·5%) of 2627 newborns (13 classified as high-risk), with infant treatment-dose nevirapine-lamivudine-zidovudine started at a median of 2·7 days (IQR 2·0-3·3). Post-exposure prophylaxis for the 2613 newborns with negative birth testing results was zidovudine in 1037 (39·5%), nevirapine-lamivudine-zidovudine in 1497 (57·0%), and no prophylaxis documented in 79 (3·0%). 6-week follow-up testing was documented for 2211 infants (84·6%) with negative birth testing, with only three new infections (0·1%; one at high risk, two at moderate risk; and all were prescribed three-drug prophylaxis). INTERPRETATION:Near-point-of-care HIV testing at birth for high-risk newborns can identify the majority of HIV transmissions in early life. Simplified post-exposure prophylaxis may be appropriate in the setting of available maternal ART, even among infants at high risk. FUNDING:Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health. TRANSLATION:For the Setswana translation of the abstract see Supplementary Materials section.
BACKGROUND:Dolutegravir resistance is increasingly reported in treatment-experienced people with HIV in low-income and middle-income countries. Resistance testing resources are sparse, and viral rebound often reflects adherence lapses rather than resistance. Efficient strategies are needed to target testing to individuals at highest risk. We evaluated a reflex laboratory approach using plasma dolutegravir exposure to guide resistance testing in routine care. METHODS:In this prospective implementation study at two public-sector clinics in Johannesburg, South Africa, we analysed adults (aged ≥18 years) on dolutegravir-based antiretroviral therapy (ART) with viral rebound of 400 copies per mL or higher. From May 18, 2023, to Jan 10, 2025, we tested residual routine viral load samples for dolutegravir exposure using an enzyme immunoassay. If dolutegravir was detectable (≥20 ng/mL), we did reflex resistance testing on the same specimen; retrospective sequencing was done at study end for dolutegravir-undetectable samples. We modelled costs comparing the reflex approach with standard of care. FINDINGS:We analysed 400 samples from 288 individuals; 160 (56%) were female and 128 (44%) male, the median age was 44 years (IQR 35-50), and 240 (83%) had previous non-dolutegravir ART exposure. Plasma dolutegravir was detectable in 108 (38%) participants. Among those with successful sequencing, dolutegravir resistance occurred in 13 (13%) of 102 participants with detectable dolutegravir and three (2%) of 138 with undetectable dolutegravir, yielding an overall prevalence of 6·7% dolutegravir resistance and a negative predictive value for absence of dolutegravir resistance of 97·8% (95% CI 93·5-99·5). Dolutegravir resistance was associated with detectable dolutegravir (odds ratio [OR] 3 [95% CI 1-9], p=0·031), nucleoside reverse transcriptase inhibitor mutations (OR 33 [4-264], p=0·0009), non-nucleoside reverse transcriptase inhibitor mutations (OR 17 [2-135], p=0·0068), or M184V (OR 20 [4-92], p=0·0002). Cost modelling showed a 23% reduction in monitoring cost per person using the reflex strategy after confirmed viraemia versus current national guidelines. INTERPRETATION:Laboratory-initiated reflex plasma dolutegravir exposure testing provides an objective, cost-efficient strategy to predict the absence of dolutegravir resistance and supports adherence management, enabling timely, individualised treatment decisions. Reflex dolutegravir exposure testing could enhance clinical decision making, improve treatment outcomes, and strengthen HIV treatment and resistance monitoring algorithms in programmatic settings. FUNDING:The Amsterdam Dinner Foundation and Aidsfonds, the Netherlands Organisation for Scientific Research, ZonMw, and WOTRO.
HIV-2 remains a neglected component of the global HIV epidemic, predominantly affecting west Africa but also present in Europe and other regions through historical and migratory links. Although generally characterised by lower transmissibility and slower disease progression than HIV-1, HIV-2 poses distinct diagnostic, therapeutic, and programmatic challenges. Research, implementation, and advocacy efforts aimed at reducing HIV-2 infection must account for the limitations of available typing tools, the restricted access to validated viral load assays, the virus' intrinsic resistance to certain antiretroviral drug classes, and the gaps in retention in care that hinder progress towards global treatment targets. Strengthening collaborative research, improving diagnostic capacity, and integrating HIV-2 into broader HIV policy frameworks are essential to optimise patient outcomes and to advance the global HIV response.
BACKGROUND:Despite a general improvement in the HIV burden over the past two decades, gendered social determinants including intimate partner violence (IPV) continue to affect women's vulnerability to HIV, which could be further exacerbated as resources dwindle over the coming years. Our study aimed to quantify recent trends in the HIV burden, the magnitude of the HIV burden associated with IPV, and the potential impact of declining financial support globally. METHODS:Using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework, we estimated annual HIV incidence, prevalence, and mortality for 204 countries and territories from 1990 to 2023, disaggregated by age and sex. Input data included national HIV programme reports, population-based serosurveys, clinical and vital registration data, and systematically reviewed literature. Countries and territories were grouped according to the availability and completeness of HIV prevalence and mortality data, with tailored modelling approaches applied for each group. To characterise the potential contributions of IPV to the HIV burden, time series estimates of IPV prevalence by location and effect size estimates were combined to generate population attributable fractions of the HIV burden. To forecast future trends and assess the potential impact of reductions in development assistance for health, we used a non-parametric stochastic frontier approach to estimate how funding levels could affect antiretroviral therapy (ART) coverage. Adjustments in future ART coverage were integrated into our forecasts, altering projected rates of HIV-related incidence and mortality. We compared scenarios with and without funding cuts, quantifying the potential epidemiological effects of reduced ART availability by sex. FINDINGS:Between 2003 and 2023, the annual number of new HIV infections declined globally, from 2·85 million (95% uncertainty interval [UI] 2·76-2·96) to 2·06 million (1·88-2·29). Meanwhile, HIV-related deaths decreased from a peak of 1·71 million (1·61-1·83) in 2004 to 0·83 million (0·73-0·96) in 2023. The number of people living with HIV rose from 26·3 million (25·5-27·3) in 2003 to 42·4 million (40·3-44·4) in 2023, reflecting improved survival associated with ART expansion. Although females continued to have higher prevalence of HIV than males in 2023 (23·4 million [22·2-24·6] vs 19·1 million [17·6-20·5]), the gap in incidence between females and males has substantially declined. Regionally, sub-Saharan Africa had the greatest declines in both incidence (64·3%; 58·0-68·6) and mortality (74·6%; 70·4-78·5) between 2003 and 2023, while central Europe, eastern Europe, and central Asia recorded the highest increases in incidence rates (232·1%; 146·5-299·1) and mortality rates (37·8%; 31·2-45·5) during this period. IPV was associated with an estimated 10·7% (1·6-20·4) of HIV-related deaths among females aged 15 years and older globally in 2023, corresponding to 40 700 (6400-80 600) deaths, with the highest population attributable fractions observed in Oceania (17·4%; 2·8-33·1), central sub-Saharan Africa (14·2%; 2·1-29·4), and eastern sub-Saharan Africa (13·2%; 2·0-25·3). Forecasts indicate that funding reductions could decrease ART coverage by 8·1% globally between 2025 and 2030, resulting in approximately 1·6 million new HIV infections among females and 1·3 million new HIV infections among males, alongside 790 600 and 670 600 HIV-related deaths, respectively. These impacts are primarily concentrated in sub-Saharan Africa. INTERPRETATION:Despite two decades of substantial progress, the global HIV response remains highly sensitive to gendered social determinants and funding stability. The potential contribution of IPV to HIV-related mortality among women underscores the need for integrated interventions that address violence prevention and post-violence care alongside HIV treatment. The projected effects of funding cuts-millions of additional infections and deaths-highlight the fragility of the gains achieved and the urgent need to protect HIV financing. Achieving and sustaining the UNAIDS 2030 targets will require renewed investment, gender-responsive programming, and resilient health systems capable of providing equitable access to care. FUNDING:Gates Foundation and the US National Institute of Allergy and Infectious Diseases.
BACKGROUND:In randomised clinical trials (RCTs), tuberculosis preventive treatment (TPT) reduced tuberculosis incidence and mortality among people with HIV; however, real-world impact has not been evaluated since antiretroviral therapy (ART) was expanded to all people with HIV regardless of CD4 cell count. This study aimed to determine the programmatic effectiveness of TPT on reducing tuberculosis incidence and all-cause mortality among people with HIV initiating ART. METHODS:This prospective cohort study emulated six RCTs using individual-level data from electronic health records in Haiti, Kenya, Nigeria, Uganda, Ukraine, and Zimbabwe to estimate TPT effectiveness among people with HIV initiating ART between Jan 1, 2018, and Dec 31, 2021 (Haiti, Kenya, Nigeria, and Ukraine) or Dec 31, 2022 (Uganda and Zimbabwe). In each country, we created cohorts of newly enrolled people with HIV initiating ART, regardless of age. We excluded people diagnosed with tuberculosis 6 months before to 30 days after ART start. De-identified extracted data for each patient included visit-level data for selected study variables between the date of enrolment into HIV care and Dec 31, 2023 (Haiti, Kenya, Nigeria, and Ukraine) or Dec 31, 2024 (Uganda and Zimbabwe). Target trial emulation was used to define a hypothetical randomised trial of TPT initiation during an 8-week grace period compared with no TPT initiation. TPT effectiveness was summarised using adjusted hazard ratios (HRs) for tuberculosis and all-cause mortality estimated using an inverse propensity weighting approach, with weights adjusted for confounders including age and sex (time-fixed) and CD4 cell count, viral load, clinical stage, ART initiation, and ART adherence (time-varying). The six countries were pooled in a meta-analysis using inverse-variance weighting with effect heterogeneity assessed using I2. FINDINGS:We included 235 424 people with HIV: 69 936 people from Haiti, 65 936 from Uganda, 57 851 from Ukraine, 24 099 from Zimbabwe, 9549 from Kenya, and 8053 from Nigeria. In 235 424 people, 147 667 (62·7%) were aged 25-44 years, 133 582 (56·7%) were female, 101 842 (43·3%) were male, 104 277 (44·3%) had clinical stage 1, and 138 914 (59·0%) were on dolutegravir-based regimens. The adjusted HR for tuberculosis ranged from 0·35 (95% CI 0·28-0·43) in Haiti to 0·60 (0·36-0·91) in Kenya. The pooled HR for tuberculosis was 0·39 (0·34-0·43) with minimal variation across countries (I2=0%, 95% CI 0-75). The adjusted HR for mortality ranged from 0·25 (95% CI 0·20-0·30) in Uganda to 0·69 (0·53-0·96) in Zimbabwe. The pooled HR for mortality was 0·55 (0·51-0·58) with significant variation across countries (I2=96%, 95% CI 93-97). INTERPRETATION:TPT was effective in reducing tuberculosis incidence and mortality in people with HIV across various epidemiological contexts and risk groups. In an era of universal test-and-treat and new ART regimens, these data reinforce support for TPT as essential in HIV care. FUNDING:Gates Foundation. TRANSLATIONS:For the French and Ukrainian translations of the abstract see Supplementary Materials section.
BACKGROUND:A single dose of the replication-competent rVSVΔG-ZEBOV-GP vaccine is recommended by the WHO Strategic Advisory Group of Experts on Immunization during Ebola virus disease outbreaks. We aimed to assess the immunogenicity, safety, and tolerability of this vaccine in adults and adolescents with HIV. METHODS:In this phase 2, multicentre, double-blind, randomised, placebo-controlled trial, we enrolled participants aged 13-70 years who had laboratory-confirmed HIV infection, were on antiretroviral therapy (ART), had an undetectable viral load (<40 copies per mL), and had a CD4 count of 200 cells per μL or more at four ambulatory settings in Montreal and Ottawa (Canada), Dakar (Senegal), and Bobo-Dioulasso (Burkina Faso). Sequential enrolment of five study cohorts occurred over time at each study site according to CD4 counts: cohort 1 (adults [age 18-70 years] with a CD4 count ≥500 cells per μL), cohort 2 (adults with a CD4 count of >350 and <500 cells per μL), cohort 3 (adults with a CD4 count of 200-350 cells per μL), cohort 4 (adolescents [age 13-17 years] with a CD4 count ≥200 cells per μL), and cohort 5 (adults and adolescents with a CD4 count ≥200 cells per μL). Participants were randomly assigned 4:1 to receive one dose (cohorts 1-4) or two doses (56 days apart; cohort 5) of rVSVΔG-ZEBOV-GP or placebo, administered at day 0. An unmasked staff member at each site prepared the vaccine or placebo; all other study personnel and participants were masked to group assignments. Participants were followed up to day 365. The primary immunogenicity endpoints, assessed in the per-protocol population, were Ebola virus-specific antibody responses measured by glycoprotein ELISA (GP-ELISA; geometric mean titre ratio [GMTR]) and neutralisation (geometric mean fold increase [GMFI] of plaque reduction neutralisation test [PRNT]) on day 28 in cohorts 1-5 combined (combined cohort), and 28 days after the second dose of vaccine or placebo in cohort 5. The primary safety endpoints, assessed in the as-treated population, were: the occurrence of each solicited local and systemic adverse event during a 14-day follow-up period after each vaccination; fever, joint pain (arthralgia), joint swelling (arthritis), rash, and blisters or vesicular lesions during a 42-day follow-up period after vaccination; any haematological and biochemical laboratory abnormality at 0, 3, 7, 14, and 28 days after each vaccine; occurrence of any unsolicited adverse event during a 42-day follow-up period after each vaccination; and occurrence of vaccine-related serious adverse events up to day 365 of the study. The trial is registered at ClinicalTrials.gov (NCT03031912) and is complete. FINDINGS:Between Aug 1, 2017, and March 3, 2022, we assessed 647 individuals for eligibility, 251 of whom were enrolled. 120 (48%) participants were male, 130 (52%) were female, 225 (90%) were Black (Black African or African Canadian), and median age was 52·0 years (IQR 48·0-56·0). 51 participants were enrolled in cohort 1, 50 in cohort 2, 50 in cohort 3, 50 in cohort 4, and 50 in cohort 5. 202 (80%) participants were assigned to receive rVSVΔG-ZEBOV-GP and 49 (20%) were assigned to receive placebo. One dose of rVSVΔG-ZEBOV-GP elicited superior immune responses compared with placebo, with GP-ELISA antibodies in the combined cohort (per-protocol population) increasing over 40-fold (GMTR 42·90, 95% CI 31·49-58·43; p<0·0001). In cohort 5, the GP-ELISA geometric mean titre 28 days after the second dose was over 200-fold higher in the rVSV-ZEBOV-GP group than in the placebo group (GMTR 208·66, 95% CI 115·57-376·72; p<0·0001). GFMI of PRNT titres was 11·51 (95% CI 9·82-13·50) at day 28 for participants in the combined cohort who received one dose of rVSVΔG-ZEBOV-GP and 86·64 (95% CI 69·85-107·46) 28 days after a second dose in cohort 5. Solicited adverse events up to 42 days after vaccination were mild to moderate in severity and transient. In the 14 days after the first dose of vaccine, the most common adverse events were injection site pain (130 of 201 participants, 65%), headache (109 of 201, 54%), fatigue (91 of 201, 45%), and joint pain (50 of 201, 25%). Unsolicited adverse events to day 42 were not different between participants who received rVSVΔG-ZEBOV-GP (103 of 201, 51%) and those who received placebo (22 of 49, 45%; p=0·52). No clinically significant changes in CD4 cell counts, HIV viral load, or haematological and biochemical laboratory tests were observed. INTERPRETATION:A single dose of rVSVΔG-ZEBOV-GP is highly immunogenic in people living with HIV on ART with an undetectable viral load, with a tolerable safety profile. A two-dose regimen in a subset of participating adolescents and adults showed a significant boosting at day 28, with no increase in reactogenicity compared with the first dose. FUNDING:International Development Research Centre, US Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, and the Coalition for Epidemic Preparedness. TRANSLATION:For the French translation of the abstract see Supplementary Materials section.
Kaposi sarcoma (KS)-associated herpesvirus (KSHV), otherwise known as HHV-8, causes KS and several lymphoproliferative disorders including KSHV-associated multicentric Castleman disease, KSHV-associated inflammatory cytokine syndrome, primary effusion lymphoma, and KSHV-positive diffuse large B-cell lymphoma not otherwise specified. KS represents a substantial burden of disease in sub-Saharan Africa and in people with HIV worldwide. Diagnosis relies on pathology, but quantitative KSHV DNA measurements can help identify multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome and monitor treatment response. Alongside antiretroviral therapy, a stage-stratified approach to KS treatment indicates systemic therapy for advanced disease or to mitigate the risk of the related immune reconstitution inflammatory syndrome. The latter condition constitutes a therapeutic challenge, as do multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome, which are likely to be underdiagnosed. Research on novel treatment approaches, such as immunomodulatory regimens, as well as diagnostic and monitoring strategies, is underway.
BACKGROUND:In 2025, 78% of people living with HIV worldwide were on antiretroviral therapy 95% of people on treatment were virally suppressed. Suboptimal adherence, defined as not taking interventions as prescribed, threatens viral suppression and can lead to antiviral resistance, morbidity, mortality, and transmission. We updated a systematic review and network meta-analysis to estimate the effects of different adherence interventions on adherence and viral suppression. METHODS:In this systematic review and network meta-analysis, we searched MEDLINE, Embase, CENTRAL, and key conference proceedings for individually randomised trials of adherence interventions scalable in low-income and middle-income countries (LMICs) published from database inception to June 5, 2024. Trials were excluded if they were done among individuals receiving antiretroviral regimens associated with higher pill burden and toxicities or were assessing interventions reliant on costly technologies or highly specialised staff not scalable in LMICs. Two reviewers independently assessed all abstracts and subsequently full texts for inclusion. Discrepancies were resolved by consensus with a third reviewer. From the summary data, the initial reviewers then extracted the data, which included study characteristics, intervention types, and adherence. The primary outcome was adherence to antiretroviral therapy with different interventions, which was analysed in a network meta-analysis with fixed or random effects and in alignment with PRISMA guidelines. We assessed risk of bias using the Cochrane Risk of Bias 2 tool and evidence certainty using GRADE. FINDINGS:10 336 potentially eligible records were identified from the database search, of which 167 were eligible. Five additional records were added from manual searches, resulting in 172 records mapped to 164 unique trials. The studies focused on the effect of reminders (n=49 [30%]), supporters (n=47 [29%]), education (n=40 [24%]), counselling (n=47 [29%]), and complex interventions (n=4 [2%]) on adherence. For the network meta-analysis, across the eligible trials, reminders, supporters, counselling, and education had some effect on adherence. Overall, at 24 weeks, the only interventions that improved adherence compared with standard of care at 24 weeks were reminders (estimated odds ratio [OR] 1·53 [95% credible interval (CrI)]; risk difference [RD] 9·4% [95% CrI 2·5-16·0)] and supporters (1·82 [1·11-3·04]; 12·8% [2·5-21·4]). In LMICs, only counselling at 12 weeks (2·53 [1·03-6·75]; 18·8% [0·8-30·5]) and supporter at 24 weeks (2·11 [1·12-4·51]; 14·3% [2·4-23·7]) had improved effects. Subgroup patterns varied: adolescents benefited from reminders and supporters and education, and people with previous non-adherence benefited from counselling and supporters. Effects on viral suppression paralleled adherence; for example, supporters improved viral suppression at 48 weeks (1·34 [1·11-1·66]; 6·5% [2·3-10·8]). Reminders improved viral suppression at 24 weeks, whereas counselling showed modest benefit at 48 weeks. Most studies were rated at low risk of bias: low risk for randomisation, missing outcome data, and selective reporting (I2 range 0-92% across direct treatment comparisons). INTERPRETATION:Scalable adherence interventions-particularly reminders, counselling, and supporter-based approaches-improved adherence. Tailoring interventions to population needs could therefore strengthen HIV treatment outcomes and support global progress towards epidemic control. FUNDING:The Gates Foundation.
Whether undetectable equals untransmittable (U=U) applies during breastfeeding remains one of the most consequential unanswered questions in HIV prevention. Although sustained viral suppression eliminates sexual HIV transmission, evidence is insufficient to determine whether breastfeeding transmission risk reflects biological limits of U=U or failure to maintain viral suppression postpartum. Existing data suggest exceedingly low breastfeeding transmission risk with maternal viral suppression, but are limited by infrequent viral load monitoring, older antiretroviral therapy regimens, incomplete follow-up, and sparse breastmilk virology data. This uncertainty has important implications for women with HIV, clinicians, and policy makers, particularly in settings with high burden of HIV where breastfeeding is essential for infant health, survival, neurodevelopment, and nutrition, as well as maternal health. Rigorous prospective studies are urgently needed to answer the question of whether U=U applies during breastfeeding, using modern integrase inhibitor-based antiretroviral therapy, frequent plasma and breastmilk viral load testing, infant follow-up, and rights-based counselling frameworks. Regardless of whether future evidence demonstrates zero or very low residual risk, we strongly argue that women with HIV should be supported to make informed choices regarding infant feeding, grounded in autonomy, evidence, and shared decision making.
