OBJECTIVE:Primary 48-week analyses of the WISARD trial showed maintenance of virological suppression in most participants with K103N mutation when switched from standard regimens to dolutegravir plus rilpivirine (DTG/RPV). In this proof-of-concept pilot study we evaluate 96-week efficacy and safety of DTG/RPV. DESIGN:Open-label, parallel, two-arm, randomized trial across 32 sites in seven European countries. METHODS:Treatment-experienced HIV-1 participants with HIV RNA <50 copies/ml and documented prior K103N mutation, switched to DTG/RPV either immediately (DTG/RPV-I) or deferred after week 48 (DTG/RPV-D [control]; randomized 2 : 1). Endpoints were confirmed virological failure (CVF), virological suppression, safety, and changes in patient-reported outcomes from baseline to weeks 48/96. RESULTS:Of 140 randomized participants (95 DTG/RPV-I, 45 control), 4 had CVF by week 48 (3 DTG/RPV-I, 1 control) and 4 further patients had CVFs by week 96 (2 in each arm). Of the total 8 CVFs through week 96, HIV-1 RNA was ≥400 copies/ml in 4; only one sample amplified with no emergent DTG- or RPV-associated resistance mutations. The other three samples did not amplify due to insufficient sample. The week 96 proportion of subjects with virological suppression was 84.2% for DTG/RPV-I and 73.3% for DTG/RPV-D groups (difference +10.9%, 95% confidence interval -4 to +25.8; P = 0.168). Serious adverse events were infrequent in both groups, and none were considered related to study medication. HRQoL, participant satisfaction, and sleep quality were stable over time and similar in both groups. CONCLUSIONS:Week 96 data confirm that switching to DTG/RPV maintains virological suppression and is safe in most participants with a history of K103N.

The PROVENT study demonstrated the efficacy and safety of a single 300-mg dose of AZD7442 (tixagevimab/cilgavimab) for pre-exposure prophylaxis of COVID-19 in at-risk individuals. Here we report an analysis of repeat dosing of intramuscular AZD7442 300 and 600 mg from the PROVENT sub-study. The sub-study enrolled eligible participants from the parent study, creating four sub-study groups. Group 1 received AZD7442 300 mg in PROVENT followed by one 300-mg dose in the sub-study (10–14 months apart). Group 2 received placebo in PROVENT followed by two AZD7442 300-mg doses 6 months apart in the sub-study. Group 3a received AZD7442 300 mg in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. Group 3b received placebo in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-drug antibody (ADA) responses. Adverse events (AEs) and serious AEs (SAEs) were reported in 75.7–81.5

BACKGROUND:The World Health Organization recommends 2 doses of human papillomavirus (HPV) vaccine for adults without human immunodeficiency virus (HIV) but 3 doses in persons with HIV. There are no immunogenicity data on the 2-dose schedule in women with HIV (WWH). METHODS:This was a prospective study comparing 2 doses (months 0 and 6) versus 3 (months 0, 2, and 6) doses of 9-valent vaccine (Gardasil 9, Merck Sharp & Dohme) in WWH (15-40 years), on antiretrovirals with HIV RNA <400 copies/mL, enrolled during 2018-2021. After an open-label phase assessing safety (n = 45 receiving 3 doses), participants were randomized between 2 or 3 doses. Primary outcome was noninferiority of 2 doses compared to 3 doses for seroconversion against all vaccine genotypes. Due to the COVID-19 pandemic, 100 WWH, instead of initially planned 120, were randomized. The trial was further amended to give 2 doses to all participants enrolled thereafter (n = 22). Results were analyzed in modified intention-to-treat (mITT) on the randomized cohort (n = 100) and per protocol on the whole cohort (n = 167). RESULTS:Participants' median age was 35 years, median CD4 count was 649 cells/µL, and 16 missed the month 7 visit. In mITT, seroconversion was 97.7% for 2 doses and 97.9% for 3 doses, meeting the predefined noninferiority criteria. At month 7, antibodies titers against all vaccine genotypes were high in both groups (increase by 1.2-2.4 log10). There were no serious adverse events; participants with 3 doses experienced local reactions more frequently (82% vs 60% for 2 doses, P = .027) with more symptoms and longer duration. CONCLUSIONS:In women with well-controlled HIV, 2 doses of 9-valent HPV vaccine is noninferior to 3 doses in terms of seroconversion and is associated with less reactogenicity. CLINICAL TRIALS REGISTRATION:NCT03391921; EUDRACT 2018-000228-33; CTIS-EMA 2024-520419-42-00.

OBJECTIVES:This study assessed real-world effectiveness and safety of switching to dual therapy regimens consisting of an integrase inhibitor (INSTI), and reverse transcriptase inhibitor (RTI), among suppressed people living with HIV in Europe. METHODS:This observational cohort enrolled adults with HIV from 28 sites across Europe who were switching to a two-drug regimen of an INSTI plus a nucleoside reverse transcriptase inhibitor or non-nucleoside reverse transcriptase inhibitor while suppressed [viral load (VL) <50 copies/mL]. Participants were followed from regimen start date (baseline) until the earliest of 96 weeks, regimen discontinuation, loss to follow-up, or death. The primary endpoints were suppression, low-level viraemia (VL ≥50 to <200 copies/mL), and high-level viraemia (VL ≥200 copies/mL) at 24-, 48- and 96-weeks post-baseline, and virologic failure (VF) within 96 weeks (2 consecutive VLs ≥50 copies/mL or 1 VL ≥50 copies/mL followed by regimen discontinuation). Adverse events and discontinuations were also described. RESULTS:737 individuals switched to DTG + 3TC (536, 72.7%), DTG + RPV (186, 25.2%) and other INSTI+RTI regimens (15, 2.0%). At 24-,48-, and 96 weeks of follow up, >98% of individuals with VL data maintained suppression; among VLs ≥50 copies/mL, most (19/23; 82.6%) were low-level viraemia. Five individuals (<1%, DTG + 3TC:2; DTG + RPV:3) experienced VF. Forty-seven non-serious drug-related AEs were reported by 38 participants (5.4%); 2 people experienced serious AEs (0.3%). Regimen discontinuations were infrequent (n = 39, 5.3%) and most commonly attributed to tolerability issues (n = 17). CONCLUSIONS:Among suppressed people living with HIV in a real-world setting, INSTI+RTI two-drug regimens were highly effective and well tolerated over 96 weeks of follow-up.

HIV-1 persists in cellular reservoirs of latent virus that resist antiretroviral therapy (ART) and immune clearance, necessitating novel therapeutic strategies. While "shock-and-kill" approaches aim to reactivate latent virus under immune pressure, this strategy has demonstrated limited clinical efficacy. In contrast, "block-and-lock" strategies that reinforce and maintain HIV-1 quiescence represent a complementary approach to prevent reservoir expansion and enable long-term ART-free remission. We previously demonstrated that EGCG, the major phenolic compound of green tea, reverses HIV-1 latency by inhibiting UHRF1 expression, a key regulator involved in the epigenetic silencing of HIV-1. However, EGCG exhibits poor bioavailability and dose-dependent cytotoxicity, which severely limit its clinical use. Here, we evaluated (+)-catechin:lysine 1:2, a more stable and bioavailable polyphenol complex with unexplored anti-HIV properties. In J-Lat cell subclones, high concentrations (50-300 μg/mL) of (+)-catechin:lysine 1:2 induced HIV-1 reactivation to levels comparable to those induced by EGCG, but without dose-dependent cellular toxicity. Mechanistically, HIV-1 reactivation operated through UHRF1-independent pathways, distinguishing (+)-catechin:lysine 1:2 from EGCG. Additionally, sequential vitamin C pre-treatment at a 1:2 molar ratio significantly potentiated catechin-mediated reactivation, whereas concurrent co-treatment antagonized the effect, demonstrating that precise dosing time schedules critically determined efficacy. Strikingly, short-term exposure (24 h) of therapeutically achievable low doses of (+)-catechin:lysine 1:2 (10 μg/mL) paradoxically promoted HIV-1 quiescence, suppressing spontaneous viral reactivation. Importantly, this quiescence-promoting effect was confirmed in cells isolated from ART-treated people with HIV (PWH). These findings position of (+)-catechin:lysine 1:2 as a safely administrable and bioavailable molecule with promising potential for "block-and-lock" anti-HIV-1 cure strategies.

OBJECTIVE:To study the COVID-19 disease course in people living with HIV (PLWH) based on meaningful case numbers, information about comorbidities, antiretroviral and COVID-19 treatment and HIV disease-related variables. METHODS:Multi-centre, observational, retrospective study of people living with HIV with COVID-19 matched to HIV-uninfected individuals with COVID-19 (HUC) and a case-control study of people living with HIV with COVID-19 matched to COVID-19 negative people living with HIV. Kaplan-Meier estimates and Cox proportional-hazards models stratified on each matched pair were used for COVID-19 outcomes, and conditional logistic regression models were used to identify risk factors for COVID-19 infection. RESULTS:Five hundred people living with HIV and COVID-19, 1106 HUC and 992 people living with HIV without COVID-19 were included. Rates for chronic kidney disease, peripheral vascular disease, dementia, prior pneumonia and liver disease in people living with HIV with COVID-19 were significantly higher by 4.1-, 2.9-, 2.6-, 2.4- and 1.6-fold, respectively, compared to HIV seronegative COVID-19 patients. Chronic kidney disease, chronic obstructive pulmonary disease (COPD), body mass index (BMI) ≥30 kg/m2, Centers for Disease Control and Prevention stage B versus A and HIV viral load ≥50 copies/mL were significant risk factors for COVID-19 in people living with HIV. Critical care admission or death in people living with HIV was comparable to HUC, whilst people living with HIV stayed longer in hospital (11 vs. 9 days) and in intensive care unit (ICU) (18 vs. 7 days) and had a higher age-adjusted Charlson comorbidity index. CONCLUSIONS:Our study highlights the importance of a well-controlled HIV infection to prevent severe COVID-19-related outcomes. In people living with HIV and COVID-19, chronic kidney disease and a higher Charlson comorbidity index are risk factors that should prompt early treatment of COVID-19.

Abstract Background The SARS-CoV-2 antibody combination tixagevimab/cilgavimab (AZD7442) was efficacious in preventing COVID-19 over 6 months following a single 300 mg intramuscular (IM) dose in the PROVENT study. Participants included those that: (a) were immunocompromised and/or at increased risk for inadequate response to COVID-19 vaccination, or (b) were at increased severe COVID-19 risk. Following PROVENT, emergence of Omicron variants with reduced AZD7442 susceptibility prompted increase in the authorized dose and dosing frequency. Here, we report safety and pharmacokinetics (PK) of repeated doses of AZD7442 300–600 mg in participants who opted to continue in the PROVENT substudy. Methods Participants who entered the PROVENT open-label sub-study (NCT04625725) were assigned initially to 2 groups: Group 1 (n=234) received 1x AZD7442 300 mg in the parent study, then 1x 300 mg ∼10–14 months later (substudy Day 1). Group 2 (n=119) received placebo in the parent study, then 2x AZD7442 300 mg doses in the substudy. Group 3a (n=76) was a subset of Group 1 who received 2x 300 mg then 2x 600 mg doses. Group 3b (n=74) was a subset of Group 2 who received 1x 300 mg then 2x 600 mg doses (Table 1). The primary endpoint was safety; PK and antibodies to AZD7442 were also assessed. Results Baseline characteristics were overall similar across the groups. Adverse events (AEs) were reported in 75.7–81.5% and serious AEs in 13.2–16.8% of participants across the groups (Table 2). There were 14 deaths: 8 (3.4%) in Group 1, 5 (4.2%) in Group 2, and 1 (1.4%) in Group 3b. There was no clinically meaningful increase of AEs due to repeat doses of AZD7442 and no deaths were considered related to AZD7442. AZD7442 PK was consistent following redosing and between groups (Figure 1). The percentage of participants positive for treatment-emergent antibodies to AZD7442 was 10.5% (Group 1), 5.2% (Group 2), 10.7% (Group 3a), and 4.1% (Group 3b). Conclusion Safety and PK of AZD7442 were consistent after repeat dosing, regardless of whether participants initially received AZD7442 or placebo. These results will support future development of long-acting antibodies for pre-exposure prophylaxis against COVID-19. Disclosures Andrew Ustianowski, MD, PhD, AstraZeneca: Honoraria|Gilead: Honoraria|GSK: Honoraria|GSK: Speaker fees|Janssen: Honoraria|Janssen: Speaker fees|Merck: Honoraria|Merck: Speaker fees, Advisory Board|Pfiizer: Advisory Board|Sanofi: Honoraria|Sanofi: Speaker fees|ViiV Healthcare/GSK: Advisory Board Myron J. Levin, MD, CSL Seqirus USA: Advisor/Consultant|Curevo: Advisory Board|GSK: Grant/Research Support|GSK: Advisory Board|Moderna: Advisory Board|Pfizer: Advisory Board Stéphane De Wit, MD, AstraZeneca: Honoraria|AstraZeneca: Speaker fees|Gilead: Honoraria|Gilead: Speaker fees, Advisory Board|GSK: Honoraria|GSK: Speaker fees|Janssen: Honoraria|Janssen: Speaker fees|Merck: Honoraria|Merck: Speaker fees, Advisory Board|Pfizer: Advisory Board|Sanofi: Honoraria|Sanofi: Speaker fees|ViiV Healthcare/GSK: Advisory Board Odile Launay, MD, PhD, AstraZeneca: Principal investigator for the AstraZeneca-sponsored PROVENT study in France|AstraZeneca and other pharmaceutical companies: Honoraria|AstraZeneca and other pharmaceutical companies: Speaker fees Audrey Sharbaugh, PhD, AstraZeneca: Employee, holds or may hold stock Rohini Beavon, PhD, AstraZeneca: Employee, holds or may hold stock Jesse Thissen, MSc, AstraZeneca: Employee, holds or may hold stock Lauren Hirao, PhD, AstraZeneca: Employee, holds or may hold stock Vitalina Dzutseva, MD, PhD, AstraZeneca: Employee, holds or may hold stock Seth Seegobin, PhD, AstraZeneca: Employee, holds or may hold stock Katie Streicher, PhD, AstraZeneca: Employee of AstraZeneca and may own AstraZeneca stock or stock options. Alexandre Kiazand, MD, AstraZeneca: Employee, holds or may hold stock Mark T. Esser, PhD, AstraZeneca: Employee, holds or may hold stock Taylor Cohen, PhD, AstraZeneca: Employee, holds or may hold stock Lee-Jah Chang, MD, AstraZeneca: Employee of AstraZeneca John L. Perez, MD, AstraZeneca: Employee, holds or may hold stock

BACKGROUND:Current latency-reversing agents (LRAs) employed in the "shock-and-kill" strategy primarily focus on relieving epigenetic and transcriptional blocks to reactivate the latent HIV-1. However, their clinical efficacy is limited, partly due to their inability to fully reverse latency and the lack of LRAs specifically targeting post-transcriptional mechanisms. N6-methyladenosine (m6A) modification in HIV-1 RNA is emerging as an important post-transcriptional regulator of HIV-1 gene expression, yet its role in latency and reactivation remains largely unrecognized. Here, we explored the potential of small chemical compounds targeting the m6A pathway, specifically investigating the inhibition of ALKBH5 and its effect on latent HIV-1 reactivation mediated by the LRA romidepsin. METHODS:We used four in vitro cellular models of latency, primary model of CD4+ T cells HIV-1 infection and ex vivo cultures of CD8+-depleted PMBCs from ART-treated HIV+ patients. We measured latent viral reactivation by evaluating the expression of reporter protein GFP by flow cytometry, viral production by CA-p24 ELISA, and viral transcripts by RT-qPCR. CRISPR/Cas9 method was used to deplete ALKBH5. MeRIP and immuno-RNA FISH were used to address the m6A methylation levels on HIV-1 RNA upon ALKBH5 inhibition. RESULTS:We showed that ALKBH5 inhibitor 3 (ALKi-3) potentiated romidepsin-mediated viral reactivation in in vitro models of latency, primary model of CD4+ T cells infected with HIV-1 as well as in ex vivo cultures of CD8+-depleted PBMCs from ART-treated HIV+ patients. CRISPR/Cas9-mediated depletion of ALKBH5 mimicked the effects of ALKi-3. ALKi-3 increased levels of m6A-methylated HIV-1 RNA as shown by meRIP and immuno-RNA FISH. CONCLUSION:Our study provides a proof-of-concept for the modulation of the m6A pathway in enhancing HIV-1 reactivation. This approach represents a promising adjunct to existing reactivation protocols and provides a concept of "dual-kick", aiming to target transcriptional and post-transcriptional steps in HIV-1 reactivation from latency.

HIV-1 latency is mainly characterized at transcriptional level, and little is known about post-transcriptional mechanisms and their contribution to reactivation. The viral protein Rev controls the nucleocytoplasmic export of unspliced and singly-spliced RNA that is central to proviral replication-competence and is therefore a prerequisite for efficient viral reactivation during the "shock-and-kill" cure therapy. Here we show that during infection and reactivation, unspliced HIV-1 RNA is a subject to complex and dynamic regulation by the Rev cofactor MATR3 and the MTR4 cofactor of the nuclear exosome. MATR3 and MTR4 coexist in the same ribonucleoprotein complex functioning to either maintain or degrade the RNA, respectively, with Rev orchestrating this regulatory switch. Moreover, we provide evidence of nuclear retention of unspliced HIV-1 RNA in ex vivo cultures from 22 ART-treated people with HIV, highlighting a reversible post-transcriptional block to viral RNA nucleocytoplasmic export that is relevant to the design of curative interventions.

Objectives:The primary objective of this study was to characterize women living with HIV (WLWH) in Belgium. The secondary objective was an exploratory analysis comparing women and men living with HIV (MLWH). Methods:This was a cross-sectional, observational, multicenter study. Inclusion criteria for the primary objective were all adult treatment-naïve and experienced WLWH actively being treated at one of the participating centers. For the secondary objective, inclusion criteria were all adult naïve and experienced women and MLWH, actively being treated at a single participating center. Data were collected between December 2022 and March 2023. A multivariable analysis was performed on all women included to evaluate for associations with having hypertension (HTN) or being virologically nonsuppressed (HIV-1 VL ≥200 copies/mL). In the exploratory analysis of women and MLWH, a multivariable analysis was carried out to evaluate whether female gender was associated with having HTN or being virologically nonsuppressed. Results:Overall, 2797 WLWH were included. The majority were Black (73.5%) and 48.5% were aged ≥50 years. The most common comorbidity was HTN (17.3%) and most individuals were virologically suppressed (HIV-1 VL <50 copies/mL; 85.6%). Black race was associated with having HTN (p < 0.0001). Prior AIDS-defining illness (p = 0.02) and a CD4+ T-cell count <500 cells/µL (p < 0.0001) were associated with being nonsuppressed. A total of 1094 WLWH and 1878 MLWH were included in the exploratory analysis. HTN was higher among WLWH (20.2% vs. 12% MLWH). Female gender was not found to be associated with having HTN (p = 0.86) or being nonsuppressed (p = 0.14). Conclusion:In this analysis of WLWH in Belgium, the results depict an ageing population that is predominantly Black. The most common comorbidity observed was HTN. Women had a low rate of virologic nonsuppression, and female gender was not associated with being nonsuppressed.

Background:While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown. Methods:People with HIV enrolled in the RESPOND cohort who started an ARV after January 1, 2012 were included (baseline). The primary outcome was first cLEE individuals were censored at first of cLEE, last visit, death, or December 31, 2021. Incidence rates (IRs; events/1000 person-years) were calculated for each ARV overall and by ARV exposure (6-12 months, 1-2 years, and 2+ years). Poisson regression was used to estimate the incidence rate ratio (IRR) of cLEE and its association with individual ARVs and ARV class. Results:Of 17 106 individuals included contributing 87 924 person-years of follow-up, 1932 (11.3%) experienced cLEE (incidence rate [IR], 22.0; 95% CI, 21.0-23.0). There was no evidence of a cumulative ARV effect on cLEE incidence, (6-12 months: IR, 45.8; 95% CI, 41.4-50.19; 1-2 years: IR, 34.3; 95% CI, 31.5-37.4; and 2+ years: IR, 18.5; 95% CI, 17.4-19.7). Any use (vs no prior use) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class and tenofovir disoproxil fumarate (TDF) was independently associated with an increased IRR of cLEE, and any use of darunavir (DRV) was associated with a decreased risk of cLEE. Conclusions:cLEE is common and more frequent during the first year after initiating new ARVs. With a >5-year median follow-up, we found no short-term liver safety concerns with the use of INSTIs. Use of NNRTIs and TDF was associated with an increased cLEE risk, while DRV was associated with lower risk.

Background. With integrase strand transfer inhibitor (INSTI) use associated with increased body mass index (BMI) and BMI increases associated with higher diabetes mellitus (DM) risk, we explored the relationships between INSTI/non-INSTI regimens, BMI changes, and DM risk. Methods. RESPOND participants were included if they had CD4, human immunodeficiency virus (HIV) RNA, and >= 2 BMI measurements during follow-up. Those with prior DM were excluded. DM was defined as a random blood glucose >= 11.1 mmol/L, hemoglobin A1c >= 6.5%/48 mmol/mol, use of antidiabetic medication, or site-reported clinical diagnosis. Poisson regression was used to assess the association between natural log (ln) of time-updated BMI and current INSTI/non-INSTI and their interactions on DM risk. Results. Among 20 865 people with HIV included, most were male (74%) and White (73%). Baseline median age was 45 years (interquartile range [IQR], 37-52), with a median BMI of 24 kg/m(2) (IQR, 22-26). There were 785 DM diagnoses with a crude rate of 0.73 (95% confidence interval [CI], .68-.78)/100 person-years of follow-up. ln(BMI) was strongly associated with DM (adjusted incidence rate ratio [aIRR], 16.54 per log increase; 95% CI, 11.33-24.13; P < .001). Current INSTI use was associated with increased DM risk (IRR, 1.58; 95% CI, 1.37-1.82; P < .001) in univariate analyses and only partially attenuated when adjusted for variables including ln(BMI) (aIRR, 1.48; 95% CI, 1.29-1.71; P < .001). There were no interactions between ln(BMI), INSTI, and non-INSTI use and DM (P = .130). Conclusions. In RESPOND, compared with non-INSTIs, current use of INSTIs was associated with an increased DM risk, which partially attenuated when adjusted for BMI changes and other variables.

BACKGROUND:Women with HIV are globally underrepresented in clinical research. Existing studies often focus on reproductive outcomes, seldom focus on older women, and are often underpowered to assess sex/gender differences. We describe CD4, HIV viral load (VL), clinical characteristics, comorbidity burden, and use of antiretroviral therapy (ART) among women with HIV in the RESPOND study and compare them with those of the men in RESPOND. METHODS:RESPOND is a prospective, multi-cohort collaboration including over 34 000 people with HIV from across Europe and Australia. Demographic and clinical characteristics, including CD4/VL, comorbidity burden, and ART are presented at baseline, defined as the latter of 1 January 2012 or enrolment into the local cohort, stratified by age and sex/gender. We further stratify men by reported mode of HIV acquisition, men who have sex with men (MSM) and non-MSM. RESULTS:Women account for 26.0% (n = 9019) of the cohort, with a median age of 42.2 years (interquartile range [IQR] 34.7-49.1). The majority (59.3%) of women were white, followed by 30.3% Black. Most women (75.8%) had acquired HIV heterosexually and 15.9% via injecting drug use. Nearly half (44.8%) were receiving a boosted protease inhibitor, 31.4% a non-nucleoside reverse transcriptase inhibitor, and 7.8% an integrase strand transfer inhibitor. The baseline year was 2012 for 73.2% of women and >2019 for 4.2%. Median CD4 was 523 (IQR 350-722) cells/μl, and 73.6% of women had a VL <200 copies/mL. Among the ART-naïve population, women were more likely than MSM but less likely than non-MSM (p < 0.001) to have CD4 <200 cells/μL and less likely than both MSM and non-MSM (p < 0.001) to have VL ≥100 000 copies/mL. Women were also more likely to be free of comorbidity than were both MSM and non-MSM (p < 0.0001). CONCLUSION:RESPOND women are diverse in age, ethnicity/race, CD4/VL, and comorbidity burden, with important differences relative to men. This work highlights the importance of stratification by sex/gender for future research that may help improve screening and management guidelines specifically for women with HIV.

BackgroundMaternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) infants have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown.MethodsIn this observational study, humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation markers were quantified at baseline.FindingsOne month after vaccination, PWH had lower frequencies of MBC compared with HIV-uninfected PW. At delivery, PWH had attenuated pertussis-specific IgG levels and Fc-dependent effector functions. Reduced levels of maternal vaccine polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. After adjustment with ethnicity, maternal antibody levels and gestational age at vaccination, HIV infection was independently associated with decreased levels of PT specific-IgG in CB. Both maternal and neonatal pertussis-specific IgG responses as well as PT-specific IgG avidity were inversely correlated with maternal sCD14 levels before vaccination among PWH.InterpretationMaternal HIV infection is associated with attenuated humoral immune responses to Tdap vaccination that correlate with sCD14. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU infants.FundingThis work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre and has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under Award No. U19AI145825. N.D. is a clinical researcher and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIH NIAID 1U19AI14825. This article is published with the support of the Fondation Universitaire of Belgium.

Background:The events during acute HIV infection (AHI) set the stage for the subsequent course of the disease. Early initiation of antiretroviral therapy (ART) has been associated with favorable immunovirological outcomes, yet the precise impact of ART timing during AHI remains unclear, particularly on lymphoid tissues. Materials and methods:The ACS cohort is a prospective cohort study in Belgium, collecting longitudinal clinical data and human bodily material (HBM) from people diagnosed and treated during AHI. The aim of the cohort is to study the impact of ART initiation during AHI on HIV reservoir and immune dysfunction in peripheral blood and anatomical sanctuary sites, as well as its effect on the gut microbiome. The cohort consists of two HBM sampling trajectories: one limited (blood, stool and leukapheresis) and a more extensive one (blood, stool, leukapheresis, colonoscopy, inguinal lymph node excision and lumbar puncture). Here we describe the baseline characteristics, immunovirological outcomes, safety and tolerability of HBM sampling. Results:Between March 2016 and April 2024, 47 participants were enrolled, predominantly men who have sex with men (MSM), with a median age of 36 years [IQR 30-43.5]. Almost 90 % of participants initiated ART within 72 h after study inclusion, irrespective of HBM sampling trajectory. The timing of ART initiation according to the Fiebig stage did not significantly impact immune recovery (CD4/CD8 ratio ≥1) or the time to viral suppression. Approximately 40 % of participants opted for the extensive HBM sampling trajectory during AHI. However, the participation rate for the extensive trajectory decreased by nearly half at the longitudinal follow-up timepoint. In general, study-related procedures were safe and well-tolerated, with limited procedure-related adverse events (AEs). Inguinal lymph node excision was associated with the highest AE rate, in line with previous reports. Conclusions:Our findings reaffirm the beneficial effect of ART initiation during AHI on long term immunovirological outcomes, regardless of Fiebig stage at treatment initiation. Additionally, we demonstrate that the collection of HBM during and longitudinally after AHI is safe and feasible, without compromising time to ART initiation. Cohorts that integrate comprehensive clinical data with high-quality HBM samples are essential to longitudinally study the impact of early ART on reservoir dynamics and immune responses across various anatomical sites after AHI.

Background All-cause and AIDS-mortality in Europe has been decreasing between 1996 and 2020. However, regional differences as well as their drivers remain unclear. This study investigates mortality differences and their drivers, including usage of and response to antiretroviral therapy (ART) and active tuberculosis (TB), among people with HIV across Europe. Methods People with HIV enrolled in EuroSIDA were followed from 2001 through 2020. Immunologic-virologic status (IVS) was categorized as poor (CD4-cell count <= 350 cells/mm(3) and viral load (VL) > 200 copies/ml), good (CD4 >= 500 and VL < 200), or intermediate (remaining combinations). Participants missing either CD4-cell count or VL were categorized as unknown. Regional differences in mortality were analyzed using multivariable Poisson regression with interaction analyses between regions of Europe and IVS, ART, or TB status. Findings 20,364 people with HIV were included: 13,715/20,346 (67.3%) from Western, 3020/20,364 (14.8%) from Central Eastern, and 3629/20,364 (17.8%) from Eastern Europe. At enrolment, median age was 40 years (inter-quartile range (IQR): 33-48), median CD4-cell count 449 cells/mm(3) (IQR: 291-638), and most were male 14,993/20,346 (73.3%). A total of 2639 died during 192,591 person-years of follow-up (crude mortality rate 13.7/1000 person-years, 95% CI: 13.2-14.2), 519/2639 (19.7%) from AIDS (2.7/1000 person-years, 2.5-2.9). All-cause and AIDS-mortality rates decreased over time but remained higher in Eastern Europe after adjusting for confounders. Being off ART (aIRR 2.42; 95% CI 2.14-2.74), poor IVS (aIRR 4.2; 95% CI 3.39-5.20) and prior TB (aIRR 3.33; 95% CI 2.75-4.03) were associated with higher all-cause mortality. For all-cause mortality the effect of ART (test for interaction: p < 0.001) and IVS (p = 0.02), but not TB (p = 0.5) varied across regions. Interpretation Overall mortality and AIDS-mortality rates decreased over time, but remained higher in Eastern Europe. A poor IVS, being off ART and prior active TB were related to higher mortality. Eastern Europe had the highest proportion of people with poor or unknown IVS, emphasizing the continued need to improve HIV care with a focus on early diagnosis, ART initiation, and adherence.

Background. Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear.Methods. We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality.Results. CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/mu L were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies.Conclusions. In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.