Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.

Genetic diversity from proviral DNA as a proxy for time since HIV-1 infection.

HIV-1 RNA genetic diversity predicts time since infection which is important for clinical care and research. It's unclear, however, whether proviral DNA genetic diversity sampled under suppressive antiretroviral therapy can be used for this purpose. We tested whether proviral genetic diversity from NGS sequences predicts time since infection and recency in 221 people with HIV-1 with known infection time. Proviral diversity was significantly associated with time since infection (p<5*10-07, R2 up to 25%) and predictive of treatment initiation during recent infection (AUC-ROC up to 0.85). This shows the utility of proviral genetic diversity as a proxy for time since infection.

Antibody and T-cell response to bivalent booster SARS-CoV-2 vaccines in people with compromised immune function (COVERALL-3).

BACKGROUND: Bivalent mRNA vaccines, designed to combat emerging SARS-CoV-2 variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months post vaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/ml (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a five-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with HIV or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare.

Deciphering factors linked with reduced SARS-CoV-2 susceptibility in the Swiss HIV Cohort Study.

BACKGROUND: Factors influencing susceptibility to SARS-CoV-2 remain to be resolved. Using data of the Swiss HIV Cohort Study (SHCS) on 6,270 people with HIV (PWH) and serologic assessment for SARS-CoV-2 and circulating-human-coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection. METHODS: We analyzed SARS-CoV-2 PCR-tests, COVID-19 related hospitalizations, and deaths reported to the SHCS between January 1, 2020 and December 31, 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in pre-pandemic (2019) and pandemic (2020) bio-banked plasma and compared to HIV-negative individuals. We applied logistic regression, conditional logistic regression, and Bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and Ab responses to SARS-CoV-2 in PWH. RESULTS: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High pre-pandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses upon infection. We observed a robust protective effect of smoking on SARS-CoV-2-infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14), which occurred even in previous smokers, and was highest for heavy smokers. CONCLUSIONS: Our findings of two independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2.

Antiretroviral Drug Exposure and Response in Obese and Morbidly Obese People With Human Immunodeficiency Virus (HIV): A Study Combining Modelling and Swiss HIV Cohort Data.

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS: Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and nonobese individuals. RESULTS: The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with nonobese (BMI: 18.5-25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than nonobese PWH. CONCLUSIONS: The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs.

Weight, anthropometric and metabolic changes after discontinuing antiretroviral therapy containing tenofovir alafenamide (TAF) in people with HIV.

BACKGROUND: Antiretroviral therapy (ART)-related weight gain is of particular concern in people with HIV (PWH). While weight gain was observed among PWH receiving tenofovir alafenamide (TAF), little is known about the potential reversibility after TAF discontinuation. We evaluated weight and metabolic changes 12 months after TAF discontinuation in the Swiss HIV Cohort Study. METHODS: We included participants who received at least six months of TAF-containing ART between January 2016 and March 2023. Using multivariable mixed-effect models, changes in weight and lipid levels were compared between individuals who continued TAF and those who switched to one of the following TAF-free regimens: TDF-based ART, dolutegravir/lamivudine (DTG/3TC), or long-acting cabotegravir/rilpivirine (CAB/RPV). RESULTS: Of 6555 participants (median age 54 years, 24.3% female, 13% Black), 5485 (83.7%) continued and 1070 (16.3%) stopped TAF. Overall, discontinuing TAF was associated with an adjusted mean weight change of -0.54 kg (95% CI -0.98 to -0.11) after 12 months. In stratified analyses, switching from TAF to TDF led to an adjusted mean weight decrease of -1.84 kg (CI -2.72 to -0.97), and to a decrease in mean total cholesterol (-0.44 mmol/L) and triglycerides (-0.38 mmol/L) after 12 months. Switching from TAF-based ART to DTG/3TC (-0.17 kg, CI -0.82 to 0.48) or long-acting CAB/RPV (-0.64 kg, CI -2.16 to 0.89) did not lead to reductions in weight. CONCLUSIONS: Replacing TAF with TDF in PWH led to a decrease in body weight and an improved lipid profile within one year. Weight changes were not observed among individuals who switched to DTG/3TC or long-acting CAB/RPV.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

External validation of the Dat'AIDS score: A risk score for predicting 5-year overall mortality in people living with HIV aged 60 years or older.

OBJECTIVE: To perform an external validation of the Dat'AIDS score for predicting 5-year overall mortality among people with HIV (PWH) aged 60 years or older. METHODS: This was a multi-centre prospective cohort study at all sites participating in the Swiss HIV Cohort Study (SHCS). We calculated the Dat'AIDS score in PWH aged 60 years or older at their first visit between 1 January 2015 and 1 January 2020. People living with HIV-2 and those whose Dat'AIDS score could not be calculated were excluded. Patients were followed until 1 January 2020. The primary endpoint was all-cause mortality. Vital status was collected throughout the study period. We obtained population and score descriptive statistics and assessed the score's discrimination and calibration. RESULTS: We included 2205 participants (82% male) of median [interquartile range (IQR)] age 62.0 (60.3-67.0) years, mostly with viraemia <50 copies/mL (92.7%). Median follow-up time was 15.9 years and median (IQR) CD4 cell count at enrolment was 586 (420-782) cells/µL. In all, 152 deaths were recorded during a total follow-up period of 7147 patient-years. The median (IQR) observed Dat'AIDS score was 3 (0-8). Discriminative capacities were good as the C-statistic was 0.73 (95% CI: 0.69-0.77) and consistent across all subgroups. Comparison of observed and expected survival probabilities showed good calibration. CONCLUSIONS: External validation of the Dat'AIDS score in patients aged 60 years or older showed that it could be a useful tool not only for research purposes, but also to identify older patients at a higher mortality risk and to tailor the most appropriate interventions.

Incidence of sexually transmitted infections and association with behavioural factors: Time-to-event analysis of a large pre-exposure prophylaxis (PrEP) cohort.

OBJECTIVES: Our objective was to obtain long-term data on the incidence of sexually transmitted infections (STIs) and their association with behavioural factors after widespread pre-exposure prophylaxis (PrEP) implementation. METHODS: This was a time-to-event analysis of a national PrEP cohort in Switzerland (SwissPrEPared study). Participants were people without HIV interested in taking PrEP with at least two STI screening visits. Primary outcomes were incidence rate of gonorrhoea, chlamydia, and syphilis. The association between behavioural factors and STI diagnosis was expressed using hazard ratios. We adjusted for testing frequency and calendar year. RESULTS: This analysis included 3907 participants enrolled between April 2019 and April 2022, yielding 3815.7 person-years of follow-up for gonorrhoea (15 134 screenings), 3802.5 for chlamydia (15 141 screenings), and 3858.6 for syphilis (15 001 screenings). The median age was 39 years (interquartile range [IQR] 32-47), 93.8% (n = 3664) identified as men who have sex with men (MSM). The incidence was 22.8 (95% confidence interval [CI] 21.3-24.4) per 100 person-years for gonorrhoea, 26.3 (95% CI 24.7-28.0) for chlamydia, and 4.4 (95% CI 3.8-5.1) for syphilis. Yearly incidence rates decreased between 2019 (all bacterial STIs: 81.6; 95% CI 59.1-109.9) and 2022 (all bacterial STIs: 49.8; 95% CI 44.6-55.3). Participants reporting chemsex substance use were at higher risk of incident STIs, as were those reporting multiple sexual partners. Younger age was associated with a higher risk of gonorrhoea and chlamydia. CONCLUSIONS: Incidence rates of bacterial STIs decreased over time. Young MSM, those with multiple partners, and those using chemsex substances were at increased risk of STIs.

Multicentric evaluation of a specific intrathecal anti-Treponema pallidum IgG index as a diagnostic biomarker of neurosyphilis: results from a retro-prospective case-control study.

BACKGROUND AND OBJECTIVES: The diagnosis of neurosyphilis (NS) lacks a true 'gold standard', making the diagnosis challenging while consequences of a misdiagnosis are potentially severe. The aim of this study was to evaluate the diagnostic performance of measuring an antibody index (AI) for the intrathecal synthesis of specific anti-Treponema pallidum (T. pallidum) IgG for the diagnosis of NS. METHODS: Specific anti-T. pallidum IgG were measured simultaneously in paired cerebrospinal fluid (CSF)-serum samples collected retrospectively and prospectively between 2007 and 2022, from patients suspected of NS, in Switzerland. An AI was calculated to account for blood-brain barrier integrity. Area under the receiver operating characteristic curve, sensitivity/specificity and positive/negative predictive values of AI test were estimated. Two NS definitions were used: NS1 included patients with NS suspicion presenting with neurological symptoms and/or acute neurosensory signs, and positive T. Pallidum Hemagglutinations Assay (TPHA)/T. pallidum particle agglutination assay (TPPA) serology and CSF-TPHA/TPPA ≥320, and either CSF-leucocytes >5 cells/mm3 and/or CSF-protein >0.45 g/L and/or a reactive CSF-venereal disease research laboratory (VDRL)/rapid plasma reagin (RPR) test. NS2 included patients with suspected NS presenting with acute ocular and/or otologic symptoms, and positive TPHA/TPPA serology, and a favourable response to NS treatment. Controls were patients diagnosed with any other central nervous system (CNS) pathologies and with positive TPHA/TPPA serology. RESULTS: The study included 71 NS (43 NS1 and 28 NS2) and 110 controls. With a threshold of ≥1.7, sensitivity and specificity of the specific AI test were 90.7% (CI 77.7 to 97.4) and 100% (CI 96.7 to 100.0), respectively, for NS1 and 14.3% (CI 4 to 32.7) and 100% (CI 96.7 to 100.0) for NS2. In patients suspected of NS with a CNS involvement (NS1 group), NS could be confirmed by the positivity of this specific AI. CONCLUSIONS: Measurement of an intrathecal synthesis index of specific anti-T. pallidum IgG in patients with CSF inflammatory signs appears to be a valuable diagnostic test. However, in otic or ocular syphilis, presenting few CSF abnormalities, AI is not sufficient alone to confirm NS diagnosis. TRIAL REGISTRATION: Swiss Association of Research Ethics Committees number 2019-00232.

De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay.

The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.

Long-term trends in hepatitis C prevalence, treatment uptake and liver-related events in the Swiss HIV Cohort Study.

BACKGROUND AND AIMS: Treatment for chronic hepatitis C virus (HCV) infections changed dramatically in the last decade. We assessed changes in the prevalence of replicating HCV infection, treatment uptake and liver-related morbidity and mortality in persons with HIV (PWH) and hepatitis C in the Swiss HIV cohort study. METHODS: We included all cohort participants between 2002 and 2021. We assessed yearly prevalence of replicating HCV infection, overall and liver-related mortality, as well as the yearly incidence of liver-related events in persons with at least one documented positive HCV-RNA. RESULTS: Of 14 652 participants under follow-up, 2294 had at least one positive HCV-RNA measurement. Of those, 1316 (57%) ever received an HCV treatment. Treatment uptake increased from 8.1% in 2002 to a maximum of 32.6% in 2016. Overall, prevalence of replicating HCV infection declined from 16.5% in 2004 to 1.3% in 2021. HCV prevalence declined from 63.2% to 7.1% in persons who inject drugs, and from 4.1% to 0.6% in men who have sex with men. Among the 2294 persons with replicating HCV infection, overall mortality declined from a maximum of 3.3 per 100 patient-years (PY) to 1.1 per 100 PY, and incidence of liver-related events decreased from 1.4/100 PY to 0.2/100 PY. CONCLUSIONS: The introduction of DAA therapy was associated with a more than 10-fold reduction in prevalence of replicating HCV infection in PWH, approaching the estimates in the general population. Overall mortality and liver-related events declined substantially in persons living with HIV and hepatitis C.

Exploring group differences in the response to a sexual risk reduction intervention to prevent hepatitis C virus reinfection in HIV-infected MSM: a mixed-methods study.

To prevent hepatitis C virus (HCV) reinfection, within the Swiss HCVree Trial, a preventive risk reduction intervention was implemented alongside curative treatment. Formative qualitative research identified three response patterns to the intervention. This mixed-methods study's aim was to cross-validate group differences in (a) the content of sexual risk reduction goals set during intervention and (b) the extent of their behavioural change in condomless anal intercourse with non-steady partners (nsCAI), sexualised and intravenous drug use at start and six-month post-intervention. Qualitative thematic analysis was used to summarise goal setting domains. Quantitative descriptive analysis was used to evaluate group differences based on assumptions of the group descriptions. Results largely confirmed assumptions on inter-group response differences in goal setting and behaviour: as expected group 1 Avoid risks showed the lowest HCV risk profile with changes in nsCAI. Group 2 Minimize-risks and Group 3 Accept-risks showed unchanged nsCAI. Group 3 had the highest HCV risk profile. Differences in their goal preferences (1: condom use; 2 reduction blood exposure; 3 safer dating) highlight diversity in attitudes to behavioural change. Our results improve understanding of variability in intervention responses such as changes in attitudes and behaviour. This provides evidence for intervention tailoring and outcome measurement.

Immune response to the recombinant herpes zoster vaccine in people living with HIV over 50 years of age compared to non-HIV age-/gender-matched controls (SHINGR'HIV): a multicenter, international, non-randomized clinical trial study protocol.

BACKGROUND: The burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH - even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR'HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls. METHODS: We will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls. DISCUSSION: The SHINGR'HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).

Tracing HIV-1 strains that imprint broadly neutralizing antibody responses.

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Absence of Proviral Human Immunodeficiency Virus (HIV) Type 1 Evolution in Early-Treated Individuals With HIV Switching to Dolutegravir Monotherapy During 48 Weeks.

Human immunodeficiency virus type 1 (HIV-1) infection is treated with antiretroviral therapy (ART), usually consisting of 2-3 different drugs, referred to as combination ART (cART). Our recent randomized clinical trial comparing a switch to dolutegravir monotherapy with continuation of cART in early-treated individuals demonstrated sustained virological suppression over 48 weeks. Here, we characterize the longitudinal landscape of the HIV-1 reservoir in these participants, with particular attention to potential differences between treatment groups regarding evidence of evolution as a proxy for low-level replication. Near full-length HIV-1 proviral polymerase chain reaction and next-generation sequencing was applied to longitudinal peripheral blood mononuclear cell samples to assess proviral evolution and the potential emergence of drug resistance mutations (DRMs). Neither an increase in genetic distance nor diversity over time was detected in participants of both treatment groups. Single proviral analysis showed high proportions of defective proviruses and low DRM numbers. No evidence for evolution during dolutegravir monotherapy was found in these early-treated individuals.

Polygenic Risk Scores for Prediction of Subclinical Coronary Artery Disease in Persons With Human Immunodeficiency Virus (HIV): The Swiss HIV Cohort Study.

BACKGROUND: In people with human immunodeficiency virus (HIV) (PWH), individual polygenic risk scores (PRSs) are associated with coronary artery disease (CAD) events. Whether PRSs are associated with subclinical CAD is unknown. METHODS: In Swiss HIV Cohort Study participants of European descent, we defined subclinical CAD as presence of soft, mixed, or high-risk plaque (SMHRP) on coronary computed tomography (CT) angiography, or as participants in the top tertile of the study population's coronary artery calcium (CAC) score, using noncontrast CT. We obtained univariable and multivariable odds ratios (ORs) for subclinical CAD endpoints based on nongenetic risk factors, and validated genome-wide PRSs built from single nucleotide polymorphisms associated with CAD, carotid intima-media thickness (IMT), or longevity in the general population. RESULTS: We included 345 genotyped participants (median age, 53 years; 89% male; 96% suppressed HIV RNA); 172 and 127 participants had SMHRP and CAC, respectively. CAD-associated PRS and IMT-associated PRS were associated with SMHRP and CAC (all P < .01), but longevity PRS was not. Participants with unfavorable CAD-PRS (top quintile) had an adjusted SMHRP OR = 2.58 (95% confidence interval [CI], 1.18-5.67), and a CAC OR = 3.95 (95% CI, 1.45-10.77) vs. bottom quintile. Unfavorable nongenetic risk (top vs. bottom quintile) was associated with adjusted SMHRP OR = 24.01 (95% CI, 9.75-59.11), and a CAC-OR = 65.07 (95% CI, 18.48-229.15). Area under the receiver operating characteristic curve increased when we added CAD-PRS to nongenetic risk factors (SMHRP: 0.75 and 0.78, respectively; CAC: 0.80 and 0.83, respectively). CONCLUSIONS: In Swiss PWH, subclinical CAD is independently associated with an individual CAD-associated PRS. Combining nongenetic and genetic cardiovascular risk factors provided the most powerful subclinical CAD prediction.

Sustained Viral Suppression With Dolutegravir Monotherapy Over 192 Weeks in Patients Starting Combination Antiretroviral Therapy During Primary Human Immunodeficiency Virus Infection (EARLY-SIMPLIFIED): A Randomized, Controlled, Multi-site, Noninferiority Trial.

BACKGROUND: Starting combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection results in a smaller HIV-1 latent reservoir, reduced immune activation, and less viral diversity compared to starting cART during chronic infection. We report results of a 4-year study designed to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir (DTG) monotherapy. METHODS: EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. People with HIV (PWH) who started cART <180 days after a documented primary HIV-1 infection with suppressed viral load were randomized (2:1) to DTG monotherapy with 50 mg daily or continuation of cART. The primary endpoints were the proportion of PWH with viral failure at 48, 96, 144, and 192 weeks; noninferiority margin was 10%. After 96 weeks, randomization was lifted and patients were permitted to switch treatment groups as desired. RESULTS: Of 101 PWH randomized, 68 were assigned to DTG monotherapy and 33 to cART. At week 96 in the per-protocol population, 64/64 (100%) showed virological response in the DTG monotherapy group versus 30/30 (100%) in the cART group (difference, 0.00%; upper bound of 95% confidence interval 6.22%). This demonstrated noninferiority of DTG monotherapy at the prespecified level. At week 192, the study end, no virological failure occurred in either group during 13 308 and 4897 person weeks of follow-up for the DTG monotherapy (n = 80) and cART groups, respectively. CONCLUSIONS: This trial suggests that early cART initiation during primary HIV infection allows sustained virological suppression after switching to DTG monotherapy.

Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study.

BACKGROUND: People with human immunodeficiency virus (HIV; PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count. RESULTS: We included 536 cases with a first CAD event (2000-2021; median age, 56 years; 87% male; 84% with suppressed HIV RNA) and 1464 event-free controls. Cases had higher latest leukocyte count before CAD event than controls (median [interquartile range], 6495 [5300-7995] vs 5900 [4910-7200]; P < .01), but leukocytosis (>11 000/µL) was uncommon (4.3% vs 2.1%; P = .01). In the highest versus lowest leukocyte quintile at latest time point before CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years before the event were significantly associated with CAD events. CONCLUSIONS: PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors.

Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland.

BACKGROUND: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear. METHODS: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures. RESULTS: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease. CONCLUSIONS: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.