BACKGROUND:Although HIV is now a chronic condition with an excellent life expectancy, some personal aspects affecting people living with HIV (PLWH), such as parenting desire, are relatively understudied. This study aimed to explore parenting desire among PLWH in Switzerland. METHODS:From September 2022 until January 2024, PLWH (participants) enrolled in the Swiss HIV Cohort Study (SHCS) and followed up at seven university/cantonal hospitals were invited to complete a structured questionnaire co-designed with patient and public involvement. There were no exclusion criteria. The questionnaire covered parenting desire, the perceived influence of HIV on family planning and whether future parenthood had ever been discussed with an HIV physician. RESULTS:Of the 5038 PLWH attending SHCS clinic visits, 3006 (59.7%) completed the questionnaire (2974 (98.9%) complete datasets analysed). The median age was 54 years (IQR 44;61), 27% were female, 39% were men who have sex with men (MSM), 16% were of Black ethnicity, 94.5% had HIV RNA plasma viral loads <50 copies/ml. Overall, 515 participants (17.3%) expressed a desire for parenting, with a desire associated with being aged <45 years and of Black ethnicity, and 506 (17%) stated that HIV influenced family planning decisions. Discussing parenthood was associated with being female, Black, heterosexual and in a stable relationship. Among heterosexual male participants, 26.1% had ever had such discussions, compared to 6.8% of MSM. CONCLUSION:In this sample of PLWH, a minority expressed parenting desire, possibly due to high median participant age, and 17% felt HIV influenced family planning decisions. While female participants were more likely to have discussed future parenthood than male participants, there was a further disparity between heterosexual men and MSM. Whilst surrogacy is prohibited in Switzerland, MSM may have access to parenthood in other ways. Our findings suggest there is room for HIV physicians to proactively invite parenting discussions with all PLWH.

Abstract Background The interaction between HIV-1 and the host immune system plays a crucial role in the natural control and progression of the infection. Previous studies have identified APOBEC3G, Tetherin, SAMHD1, and SERINC5 as HIV-1 host restriction factors, which are counteracted by the viral proteins Vif, Vpu, and Nef, respectively. The blood expression levels of some of these host proteins are correlated with HIV load, suggesting that interindividual differences in the spontaneous control of HIV infection might lead to the identification of novel HIV restriction factors. Our study enrolled 150 participants from the Swiss HIV Cohort Study with human genome-wide genotyping data, pre-antiretroviral treatment peripheral blood mononuclear cells (PBMC) aliquots and HIV load measurements. Results Using BrB-seq, we quantified mRNA expression of all protein-coding genes and found significant associations between 792 genes and HIV load. Pathway analysis revealed that higher viral load associated with the upregulation of innate immune response, proteasome complex, mitochondrial and cell-cycle related activity, and with the downregulation of ribosomal transcripts and genes involved in cytokine-cytokine receptor interaction, including IL4R , IL7R , and TCF7 . Mendelian Randomization confirmed the viral restriction activity of TRABD2A and identified new candidates as potential restriction factors. Conclusions These findings provide novel insights into the host–virus interplay and suggest additional genes such as TNFSF10, TTC3 and GRAP that may contribute to the natural control of HIV-1 infection.

Background:Studies in Switzerland and other settings have reported minimal pretreatment integrase strand transfer inhibitor (INSTI) resistance, but many were conducted before widespread use of INSTIs or are limited regarding data availability and representativeness. Consequently, many questions remain regarding the transmissibility of INSTI drug resistance mutations (DRMs). Methods:In sequences predating antiretroviral therapy (ART) initiation collected in the Swiss HIV Cohort Study (SHCS) resistance database, we assessed INSTI DRMs using the Stanford HIV database algorithm. We use bayesian regression models to assess INSTI DRM trends, as well as epidemiological clustering. Models are adjusted for age, sex, HIV subtype, and time as a spline, with random effects for the SHCS center of registration and the sequencing laboratory. Results:In total, 3704 SHCS participants had an integrase sequence before ART initiation; 213 (5.8%) had INSTI DRMs, including 11 (0.3%) with major INSTI DRMs. The most common DRMs were the polymorphic accessory INSTI DRMs E157Q, T97A, and L74M. There was no change in the probability of detecting INSTI DRM(s) over the past 3 decades. Epidemiological clustering was similar between individuals with or without pre-ART INSTI DRMs; however, the clusters they formed were smaller, particularly before 2010. Conclusions:This study demonstrates that in Switzerland pre-ART INSTI DRMs are very rare, despite INSTIs being used for more than 10 years. In cases where pre-ART INSTI DRMs are detected, information on the context in which they emerged is rarely available, highlighting the need for continued genetic surveillance, particularly in the face of increasing numbers of individuals with INSTI resistance globally.

Summary Background Advanced 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. Methods 416 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, 8·08 years (IQR 4·83–11·09)) and 2 samples during suppressive ART (>3 years apart, median interval between samples, 9·81 years (7·16–11·01)). Findings In 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. Interpretations In 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. Funding Swiss HIV Cohort Study Research in context Evidence before this study Current 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 study To 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 evidence Our 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.

People with human immunodeficiency virus (PWH) exhibit accelerated aging and a higher prevalence of aging-related conditions, despite effective antiretroviral therapy. The biological mechanisms involved remain incompletely understood. Integrating genomic and metabolomic profiling may help uncover genes and pathways contributing to aging-related disease in this population. Using a genome-wide association study framework and untargeted metabolomic profiling, we searched for associations between human genetic variants and the plasma concentrations of 1,930 putative metabolites in 1,244 individuals enrolled in the Swiss HIV Cohort Study. We performed an expression quantitative trait locus (eQTL) colocalization analysis to explore biological links between genetic variants and metabolites and used Mendelian randomization to search for causal relationships between metabolites and agingrelated diseases. We identified 27 metabolites significantly associated with 12 genetic loci, including genes encoding the metabolic enzymes NAT8 and FUT2; 10 associations had been previously reported in general-population studies, of which eight were replicated in our analysis. The colocalization analyses provided evidence for a large overlap between genetic regulation of mRNA expression and metabolite levels, while Mendelian randomization suggested several causal effects. Our study uncovered genetic-metabolic associations observed in PWH and explored their biological relevance. These findings highlight the potential of integrated multi-omics profiling to deepen mechanistic understanding and inform future precision approaches to comorbidity management in this population.

INTRODUCTION:Tobacco smoking is an insufficiently addressed health burden among people living with HIV. The Reduce tobacco use in people living with HIV in Switzerland (RETUNE) trial tests the effectiveness of offering a menu of nicotine substitute products, including e-cigarettes, nicotine pouches, and nicotine patches, on tobacco smoking cessation rates. This a priori planned internal pilot aims to assess the trial processes, in particular the delivery of the intervention, and its acceptance by participants. METHODS:RETUNE is a pragmatic, randomized, multicenter trial using the 'Trials within Cohorts' (TwiCs) design embedded in the Swiss HIV Cohort Study. Participants are people living with HIV who are part of the cohort and smoke. Following the TwiCs design, participants can accept one of the offered intervention products or refuse all of them, after being randomized to the intervention group. This internal pilot study included the first 200 RETUNE participants randomized between February and September 2025. We report the acceptance rate and participants' experiences with the intervention products, based on trial data and additional questionnaires. RESULTS:Of the 98 participants randomized to the intervention group, 53 accepted a nicotine substitute product while 45 declined the intervention. The majority chose e-cigarettes (31/53; 59%), one-third chose nicotine patches (17/53; 32%), and four participants chose nicotine pouches (4/53; 8%). The most common reason for declining all offered products was no interest in quitting tobacco smoking (34/53; 64%). Overall, 37/53 (70%) intervention participants completed the pilot study survey. Most (27/37; 73%) continued the initially chosen product; the remaining changed the product, the nicotine concentration, or the flavor; however, no one stopped the smoking cessation intervention entirely. CONCLUSIONS:The results of this internal pilot support the feasibility of the RETUNE trial. The observed acceptance rate was similar to our estimate. E-cigarettes were the preferred product. We are continuing recruitment for the RETUNE trial. CLINICAL TRIAL REGISTRATION:The study is registered on the official website of ClinicalTrials.gov. IDENTIFIER:NCT06789692.

OBJECTIVES:To improve estimation of cohort coverage in the Swiss HIV Cohort Study (SHCS) using a data triangulation framework that compares SHCS data with multiple external data sources. DESIGN:Retrospective longitudinal analysis of the SHCS. METHODS:Cohort coverage of HIV diagnoses, AIDS diagnoses, and antiretroviral therapy (ART) uptake was triangulated across SHCS data (1985-2023), national HIV/AIDS surveillance (1985-2023), longitudinal antiretroviral therapy (ART) sales data (2017-2024), and a targeted literature comparison. Temporal trends in cohort coverage were assessed, and demographic representativeness was evaluated by sex, age, HIV acquisition mode, and region. Mean cohort coverage estimates were calculated for three outcomes: HIV and AIDS diagnoses (Step 1) and ART uptake (Step 2). RESULTS:Over 38 years, mean SHCS coverage was 62.4% for HIV diagnoses, 74.0% for AIDS, and 64.9% for ART uptake, consistent with literature-based estimates. Coverage of HIV diagnoses declined in recent years, and geographical heterogeneity was observed. The SHCS remained broadly representative across most subgroups; however, females, older adults, and people with heterosexually acquired HIV or using psychoactive substances were underrepresented, while people on single-tablet and salvage ART regimens were overrepresented. CONCLUSIONS:A data triangulation framework provides a practical approach for monitoring cohort coverage and representativeness. While the SHCS captures a broadly representative sample of diagnosed individuals, tailored strategies are needed to improve inclusion of underrepresented subgroups and maintain cohort coverage. Sustained monitoring is essential to ensure that cohort-based research remains generalizable and continues to inform clinical care and public health responses in Switzerland and beyond.

Abstract Background Among people living with HIV, there has been a shift of focus from HIV-related health issues to cardiovascular diseases and cancer. For both, tobacco smoking is a major but insufficiently addressed etiological factor. Evidence from randomized trials suggests that nicotine substitute products such as e-cigarettes and nicotine patches can reduce tobacco smoking and its associated health burden. However, most previous smoking cessation trials primarily included people who are motivated to quit smoking and focused on testing a single nicotine substitute product. The effectiveness of offering a menu of nicotine substitute products to tobacco smokers regardless of their willingness to quit smoking (“opt-out” approach) is unknown. Methods Reduce tobacco use in people living with HIV in Switzerland (RETUNE, NCT06789692) is a pragmatic, 1:1 randomized, multicenter, superiority clinical trial using the Trials within Cohorts (TwiCs) design within the Swiss HIV Cohort Study. RETUNE assesses the effectiveness of offering a menu of different nicotine substitute products, namely electronic cigarettes, nicotine pouches, and nicotine patches, versus usual care. Cohort participants are eligible if they smoke more than one tobacco cigarette per day, do not use any of the substitute products, and have signed the randomization consent following the TwiCs design. Participants randomized to the intervention may choose any of the offered substitutes to be used free of charge for 6 months or decline the offer. Overall, we plan to recruit 972 participants. The primary outcome is tobacco abstinence at 6 months measured as participant-reported past 7-day prevalence abstinence. The primary outcome will be assessed in the intention-to-treat set using a logistic regression model adjusted for region, men having sex with men, current drug users, and number of cigarettes per day at baseline. Secondary outcomes are long-term smoking cessation rates and tobacco-associated health outcomes. Discussion RETUNE started recruitment in February 2025 and is currently ongoing. RETUNE using the TwiCs design will clarify the effectiveness of a preference-based opt-out smoking cessation intervention among people living with HIV. Trial registration Clinicaltrials.gov NCT06789692. Registered on January 17th, 2025. The manuscript is aligned with the registry. https://clinicaltrials.gov/study/NCT06789692?cond=NCT06789692&rank=1

BACKGROUND:Clonal hematopoiesis (CH), defined by the expansion of hematopoietic cells with somatic mutations in leukemogenic genes (CH of indeterminate potential (CHIP)) or with mosaic chromosomal alterations (mCAs), is associated with aging and adverse health outcomes in the general population. CHIP prevalence is higher in People with HIV (PWH) than in controls. However, the full spectrum, prevalence, and clinical consequences of CH in PWH remain incompletely understood. METHODS:We assessed CHIP and mCAs in a large sample of PWH (N∼2,500) from the Swiss HIV Cohort Study. Using high-depth targeted sequencing of CHIP genes and genome-wide genotyping to call mCAs, we quantified the prevalence and clone size of both CH types and investigated an association of CH with clinical variables. RESULTS:CHIP (25% of individuals) and mCAs (16% of individuals) were common, positively correlated with age, often co-occurring (OR=1.7, p=0.02 for autosomal mCAs), and associated with various clinical outcomes, including all-cause mortality (HR=1.3, p=0.02 for CHIP) and hematologic malignancies (HR=9.4, p=0.01 for the effect of CHIP on the risk of myeloid cancer; HR>20, p<0.001 for the effect of co-occurring CHIP and mCAs on the risk of lymphoid cancer). We also observed associations of CH with several proxies of inflammatory status (CD4:CD8 ratio, HIV viral load, late initiation of antiretroviral therapy, and toxicity of antiretroviral drugs). CONCLUSION:The study provides a comprehensive assessment of the CH landscape in PWH, highlighting potential causes and consequences in this population and suggesting an interaction between CH and chronic immune activation.

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition linked to chronic inflammation, cardiovascular diseases, and hematological malignancies. People with HIV (PWH) show higher CHIP prevalence than the general population, but whether this is due to earlier emergence, altered clonal expansion dynamics, or differences in selective pressures is unclear. We reconstructed longitudinal CHIP trajectories in 52 PWH using serial blood samples spanning up to 25 years and identified patterns of CHIP dynamics consistent with known gene-specific fitness patterns. Larger clone size was associated with lower CD4 T-cell count and lower CD4/CD8 ratio. Compared with a general population cohort, PWH showed higher VAF across the observed age range and steeper early trajectory increases, while long-term expansion rates were broadly similar. These findings support a model in which HIV-associated immune dysregulation alters the hematopoietic fitness landscape, contributing to earlier clonal expansion and increased burden of CHIP in PWH. ### Competing Interest Statement HFG has been an advisor/consultant for Merck, Gilead, and ViiV and a DSMB member for Merck and has received honoraria. Furthermore, he has received research grants paid to his institution from the Swiss National Science Foundation, the Swiss HIV Cohort Study, the Yvonne Jacob Foundation, ViiV, and Gilead. Furthermore, he is a subcontractor of a grant by the Gates Foundation. ### Funding Statement This study has been financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #33FI-0_229621), by SHCS project #876, and by the SHCS research foundation. The data are gathered by the five Swiss University Hospitals, two Cantonal Hospitals, affiliated hospitals and private physicians. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The SHCS was approved by the ethics committees of the participating institutions, BASEC-Nr. 2023-02080: Kantonale Ethikkommission Zurich; Ethikkommission Nordwest- und Zentralschweiz EKNZ; Kantonale Ethikkommission Bern; Commission Cantonale d'ethique de la recherche sur l'etre humain CCER-GE; Commission cantonale d'ethique de la recherche sur l'etre humain, CER-VD; Comitato etico cantonale, Ticino; Ethikkommission Ostschweiz EKOS, and written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The SHCS data are available to researchers upon the project submission and review by the Scientific Board of the SHCS and the study team; the provision of data is subject to Swiss legal and ethical regulations. Swiss National Science Foundation, grant #33FI-0_229621

Background:People with human immunodeficiency virus type 1 (HIV-1; PWH) on antiretroviral therapy (ART) and suppressed viremia usually experience a decrease in HIV DNA over time, but about 25% experience an increase. Some also experience intermittent viremia. The reasons for and potential clinical implications of increases in the HIV reservoir remain unclear and a major concern. Methods:In this study, we longitudinally characterized the proviral landscape in 4 distinct groups of PWH (n = 40) successfully treated with ART over 10.4 years without any viral failure, presenting either an increase or decrease of total HIV DNA levels and experiencing or not experiencing intermittent viremia, by intact proviral DNA assay and near-full-length HIV proviral sequencing in bulk and on the single proviral level. Results:A decrease in intact proviruses was observed in all groups, independent of total HIV DNA level dynamics and viral load kinetics by both intact proviral DNA assay and single proviral sequencing. Genetic distances and diversities of individuals' proviral sequences did not increase over time in any group. Although new drug resistance mutations were occasionally observed in proviral DNA, numbers did not differ significantly between the groups. Conclusions:Our results show that the increase in HIV DNA levels is driven by an increase in defective proviruses, also in PWH experiencing intermittent viremia. Furthermore, we did not see evidence of evolution of the HIV reservoir, regardless of HIV reservoir size dynamics and viral load kinetics over a follow-up period of 10 years with ART. Nevertheless, PWH with intermittent viremia should be monitored frequently.

PURPOSE:Reducing the number of drugs in combined antiretroviral therapy (cART) likely reduces toxicity. We hypothesized that dual therapy (DT) with nevirapine (NVP) and lamivudine (3TC) would be non-inferior to a virtual control without treatment failure. METHODS:This multicenter study enrolled patients on cART with HIV plasma viral load (pVL) <50 cp/ml for ≥2 years and on NVP for ≥6 months. Patients were compared to a simulated virtual control group with an assumed failure rate of zero. Those with prior Non-Nucleoside Reverse Transcriptase Inhibitor failure or 3TC resistance were excluded. Treatment was simplified to DT with NVP/3TC for 48 weeks, with quarterly pVL-measurements. The primary endpoint was confirmed virologic failure (pVL ≥ 200 cp/mL). A 4% non-inferiority margin and sample size of 201 were set, with a stopping rule if three virologic failures occurred. RESULTS:From April 2019 to January 2023, 201 patients from five centers in Switzerland and Germany started DT, which 194 participants completed. Two patients (1.03%, 95% CI: -0.92% to 3.68%) reached the primary endpoint for failure due to adherence issues. No additional failures were observed during a 12-month post-study follow-up of 184 participants. CONCLUSIONS:Simplification to NVP and 3TC was as effective as the ideal virtual control. However, the results of NVP and 3TC maintenance therapy are only applicable to people living with HIV who meet the study's inclusion and exclusion criteria. Virtual controls could improve research efficiency and warrant further evaluation.

Background:Integrase strand transfer inhibitors (INSTIs) are highly effective components of antiretroviral therapy for HIV. Recent studies suggest increased cardiovascular disease (CVD) risk after INSTI initiation, but findings remain inconsistent. The Swiss HIV Cohort Study is nationally representative, collects high-quality data, and provides an ideal setting for independent evaluation using causal methods, avoiding participant overlap in multicountry HIV-cohort consortiums. Methods:We emulated sequential target trials from November 2011 to September 2025 to estimate the effect of switching from non-INSTI to INSTI-based treatment on 6-year CVD risk among treatment-experienced people with HIV. Eligible participants were ≥18 years old, INSTI-naive, virally suppressed, and without CVD history. For each trial, participants were assigned to remain on non-INSTI or switch to INSTI. Intention-to-treat (ITT) and per-protocol (PP) effects were estimated using pooled logistic regression with baseline adjustment (ITT) and inverse probability weighting (PP). Results:Among 8815 individuals contributing 539 017 person-trials, 5750 switched to INSTI, and 507 CVD events occurred. In ITT analyses, the adjusted risk ratio for switching versus remaining on non-INSTI was 1.34 (95% confidence interval 1.03-1.69) after 1 year, and 1.03 (0.88-1.16) after 6 years. Absolute risk differences were small, ranging from 0.20 percentage points (0.02-0.37) after 1 year to 0.13 (-0.49 to 0.58) after 6 years. Per-protocol estimates were similar. Conclusions:Switching to INSTI-based treatment did not substantially increase long-term CVD risk in treatment-experienced individuals with well-controlled HIV. The early increase in absolute risk was small and was not expected to be clinically meaningful. This further contextualizes results from multicountry analyses.

INTRODUCTION:As life expectancy among persons with HIV on antiretroviral therapy (ART) is increasing, comorbidities and polypharmacy increase. Drug-drug interactions (DDIs) are common among persons with HIV with a history of virological failure, since many are receiving boosted ART. We assessed the willingness of individuals with a history of virological failure on a boosted ART to participate in simplification trials and evaluated their expectations towards ART. METHODS:We conducted a cross-sectional survey among persons with HIV at five hospitals in Switzerland between October 2021 and July 2022. We collected data using quantitative paper-based questionnaires and analysed the data using descriptive statistics. Community representatives were involved in the study planning and conduct, and in the interpretation of findings. RESULTS:Overall, 143 (64%) of 223 eligible persons with HIV participated. Median age was 59 years (interquartile range [IQR] 52.5-63.5), 32 (22%) were female, median time on ART was 26 years (IQR: 20-27). Among participants, 104 (72%) would agree to participate in clinical trials aiming at evaluating simplified ART regimens with reduced DDI risks, or were still undecided. Of them, 92 (88%) were satisfied with their current treatment. Their main expectations about simplified ART were treatment efficacy (91%), fewer DDIs (83%), low pill number (78%) and forgiveness in case of missed doses (75%). CONCLUSIONS:Persons with HIV and a history of virological failure were motivated to participate in clinical research. This underlines the importance of including them in future trials. Furthermore, conducting feasibility surveys and including persons with HIV in the study design prior to trials ensures their relevance and alignment with people's needs and expectations.

Introduction: Little is known about the clinical status of persons with HIV (PWH) who re-engage in care after an interruption. We evaluated the immunological and clinical characteristics of individuals re-engaging in care within the Swiss HIV Cohort Study. Methods: Participants who re-engaged in care after an interruption >14 months with a viral load ≥100 copies/mL were classified as having interrupted ART. We defined late re-engagement as re-engaging with a CD4 cell count of <350 cells/µL or a new CDC stage C disease. Linear and logistic regression models with restricted cubic splines were used to estimate the mean CD4 cell count at re-engagement and the probability of late re-engagement as a function of care interruption duration. Results: Of 14,864 participants with a median follow-up of 10.2 years (IQR 4.7-17.2 years), 2,768 (18.6%) interrupted care, of whom 1,489 (53.8%) re-engaged. Among those re-engaging, 62.3% had interrupted ART. For participants who interrupted ART, the mean CD4 count declined from 374 cells/µL (95% CI 358-391 cells/µL) before the interruption to 250 cells/µL (95% CI 221-281 cells/µL) among those re-engaging after 14 months, and to 185 cells/µL (95% CI 160-212 cells/µL) among those re-engaging after 60 months. The estimated risk of late re-engagement in care was 68.6% (95% CI 62.3-74.4%) for participants who interrupted ART for 14 months and 75.2% (95% CI 68.9-80.6%) for those who interrupted ART for 60 months. Conclusion: Although HIV care interruptions are not very common in Switzerland, the majority of PWH re-engaging after interrupting ART return with late-stage HIV.

The interaction between HIV-1 and the host immune system plays a crucial role in the natural control and progression of the infection. Previous studies have identified APOBEC3G, Tetherin, SAMHD1, and SERINC5 as HIV-1 host restriction factors, which are counteracted by the viral proteins Vif, Vpu, and Nef, respectively. The blood expression levels of some of these host proteins are correlated with HIV load, suggesting that interindividual differences in the spontaneous control of HIV infection might lead to the identification of novel HIV restriction factors. Our study enrolled 150 participants from the Swiss HIV Cohort Study with human genome-wide genotyping data, pre-antiretroviral treatment peripheral blood mononuclear cells (PBMC) aliquots and HIV load measurements. Using BrB-seq, we quantified mRNA expression of all protein-coding genes and found significant associations between 792 genes and HIV load. Pathway analysis revealed that higher viral load associated with the upregulation of innate immune response, proteasome complex, mitochondrial and cell-cycle related activity, and with the downregulation of ribosomal transcripts and genes involved in cytokine-cytokine receptor interaction, including IL4R , IL7R , and TCF7 . Mendelian Randomization confirmed the viral restriction activity of TRABD2A and identified new candidates as potential restriction factors. These findings provide novel insights into the host–virus interplay and suggest additional genes that may contribute to the natural control of HIV-1 infection. ### Competing Interest Statement The authors have declared no competing interest. Swiss National Science Foundation, https://ror.org/00yjd3n13, 33FI-0_229621 Swiss HIV Cohort Study, #812 SHCS research foundation

BACKGROUND:Most individuals receiving combination antiretroviral therapy (ART) have human immunodeficiency virus (HIV) plasma viral loads below the limit of detection. However, episodes of low-level viremia (LLV) are observed in subsets of individuals, the risk factors and clinical significance of which remain debated. METHODS:We included participants enrolled in the Swiss HIV Cohort Study, starting ART between July 1999 and April 2023, with HIV RNA values <200 copies/mL 6 months after ART initiation. Using longitudinally collected data, we applied a time-updated Cox proportional hazards model to determine the association of LLV with the risk of subsequent viral failure, defined as ≥200 copies/mL. LLV was quantified by the time-updated area under the curve (AUC) of HIV RNA values, categorized as undetectable or, based on AUC tertiles, low, intermediate, or high. RESULTS:We included 8132 participants with a total of 49 579 person-years of follow-up. The median follow-up time was 4.7 years, and the median number of HIV RNA measurements was 16. Participants had a median age of 38 years, 75.9% were male, 74.4% were white, and 45.9% had HIV-1 subtype B. LLV was associated with an increased risk of subsequent viral failure, with the highest LLV category showing the strongest association (hazard ratio, 3.3 [for comparison with undetectable viral load]) among all included variables, including race/ethnicity, age, and ART. CONCLUSIONS:LLV was strongly associated with risk of subsequent viral failure, even after adjustment for demographic and clinical characteristics, including adherence and treatment regimen. The detection of LLV should prompt appropriate measures to decrease the risk of subsequent viral failure.

INTRODUCTION:Hepatitis B surface antigen (HBsAg) loss is a rare event among persons with hepatitis B virus (HBV) monoinfection but seems to happen more frequently in people with HIV (PWH). We assessed the proportion of PWH/HBV coinfection who experienced HBsAg loss during long-term tenofovir-therapy and evaluated its association with quantitative HBsAg (qHBsAg) levels at tenofovir start. METHODS:All Swiss HIV Cohort Study participants with two or more positive HBsAg measurements more than 6 months apart, and at least 4 years of tenofovir-containing antiretroviral therapy (ART), were considered. Our main outcomes were the loss of HBsAg during the first 2 years of tenofovir therapy and until the last available follow-up. We explored the association between qHBsAg levels at tenofovir start and HBsAg loss using multivariable logistic regression adjusted for potential confounders. RESULTS:A total of 272 PWH and HBV coinfection were included. Median age was 41 years (IQR 36-46) and 81% (221) were men. At tenofovir start, 62% (169/272) received prior HBV active therapy, 49% (110/224) were hepatitis B e antigen (HBeAg)-positive, 82% (222/272) had detectable HBV DNA (median 4.0 log10 IU/mL, IQR 2.1-7.5) and 19% (46/242) had low qHBsAg, defined as <1000 IU/mL. HBsAg loss was observed in 7% (19/272) of participants during the first 2 years of tenofovir-containing ART and in 16% (43/272) after a median follow-up time of 8.4 years (IQR 2.6-15.8). At the last follow-up, 59% (16/27) of those with HBsAg loss had seroconverted for detectable anti-HBs antibodies. In multivariable analyses, low qHBsAg at tenofovir start (OR 5.3, 95% CI 1.6-17.8) was a significant predictor of HBsAg loss. CONCLUSION:We found high rates of HBsAg loss in PWH and HBV coinfection on long-term tenofovir-containing ART, most of whom had low qHBsAg at tenofovir start.

Background:In Switzerland detailed individual patient data are lacking on trends in health care costs, major drivers of costs, and the contribution of breakthrough innovations, such as direct-acting agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection in people with HIV (PWH). Methods:We linked anonymized data of patients undergoing antiretroviral therapy (ART) or naive patients initiating ART between 2012 and 2017 in the Swiss HIV Cohort Study with claims data of health insurers covering 35% of Swiss residents. Trends in mean annual costs for overall care, ART, and hospitalizations were calculated with an adjustment of costs for censoring. Changes in costs over time in relation to patient characteristics, comorbidities, and treatment of HCV with DAAs were estimated by linear mixed models. Costs were reported in Swiss francs (CHF). Results:The final linked file contained 1830 individuals from 11 286 participants of the Swiss HIV Cohort Study and 5406 claims records (33.9%). The mean adjusted annual overall cost in 2012 was CHF 24 713 (SD, 14 107) and increased in 2017 by 1.2% to CHF 24 881 (SD, 14 523). Costs for ART contributed by far most to overall costs but decreased over time. Mean costs for hospitalizations increased with annual variation by 7.2% from CHF 8727 (SD, 10 473) in 2012 to CHF 9406 (SD, 9696) in 2017. Mean increases of costs for DAAs for 171 PWH coinfected with HCV (9.4%) were CHF 52 647 (95% CI, 50 862-54 431; P < .01). Conclusions:Increases in mean total costs for PWH in Switzerland from 2012 to 2017 were small. The contribution of DAAs for the treatment of chronic HCV to overall costs was marginal.

BackgroundThe pharmacokinetics of long-acting rilpivirine has mostly been studied in clinical trials, which do not fully address the uncertainties that arise in routine clinical situations.Aims and methodsOur population analysis aims to establish percentile curves for rilpivirine concentrations in people with HIV (PWH) followed-up in a routine clinical setting, while identifying patient-related factors that may influence rilpivirine exposure. A total of 238 PWH enrolled in our nationwide multicenter observational study contributed to 1038 concentrations (186 and 852 concentrations after oral and intramuscular injection, respectively).ResultsRilpivirine pharmacokinetics were best described by a two-compartment model with an oral to intramuscular relative bioavailability factor. A simple zero-order absorption process was retained for oral administration while a parallel first-order absorption was used for intramuscular administration, with 27.6% of the dose released via a fast absorption pathway and the remaining fraction via a slow absorption pathway. Our model estimated that long-acting rilpivirine reaches steady-state after 2.5 years and has an elimination half-life of 18 weeks, consistent with published estimates. In females, a 45.6% reduction in the proportion of the dose absorbed via the rapid absorption pathway was observed. However, this resulted in no more than 15% difference in trough concentrations (Ctrough) compared to males, which was not considered to be clinically relevant.ConclusionOverall, our model-based simulations showed that only approximately 50% of long-acting rilpivirine Ctrough would be above the 50 ng/mL threshold associated with optimal therapeutic response, while approximately 85% of Ctrough would be above the first quartile of concentrations observed in Phase III trials (32 ng/mL).