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.

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.

Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

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.

Impact of Integrase Inhibitors on Cardiovascular Disease Events in People With Human Immunodeficiency Virus Starting Antiretroviral Therapy.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with human immunodeficiency virus using a target trial framework, which reduces the potential for confounding and selection bias. METHODS: We included Swiss HIV Cohort Study participants who were ART-naïve after May 2008, when INSTIs became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights. RESULTS: Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (interquartile range, 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increased risk for CVD events (adjusted hazard ratio, 0.80; 95% confidence interval [CI], .46-1.39). Adjusted risk differences between individuals who started INSTIs and those who started other ART were -0.17% (95% CI, -.37 to .19) after 1 year, -0.61% (-1.54 to 0.22) after 5 years, and -0.71% (-2.16 to 0.94) after 8 years. CONCLUSIONS: In this target trial emulation, we found no difference in short- or long-term risk for CVD events between treatment-naïve people with human immunodeficiency virus who started INSTI-based ART and those on other ART.

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.

Impact of Latent Tuberculosis on Diabetes.

While an increased risk of active and latent tuberculosis infection (LTBI) in people with type-2 diabetes (DM) has been demonstrated, it is less well characterized whether LTBI is associated with an increased risk of developing DM. We investigated the link between LTBI and DM in people living with HIV in the Swiss HIV Cohort Study via time-dependent Cox proportional hazards models. We found that LTBI significantly increased the risk of developing DM (HR = 1.47), which was robust across different adjustment and censoring techniques. Our results thus suggest that LTBI may be associated with an increased risk of developing DM.

Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over >17 Years.

BACKGROUND: In people with human immunodeficiency virus (PWH), long-term telomere length (TL) change without/with suppressive antiretroviral therapy (ART) and the contribution of genetic background to TL are incompletely understood. METHODS: We measured TL change in peripheral blood mononuclear cells by quantitative polymerase chain reaction in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. We applied mixed-effects multilevel regression to obtain uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4/CD8 ratio. We assessed the effect of (1) individual antiretrovirals and (2) an individual TL-polygenic risk score ([TL-PRS] based on 239 single-nucleotide polymorphisms) on TL in 798 additional participants from our previous longitudinal studies. RESULTS: During untreated human immunodeficiency virus (HIV) infection (median observation, 7.7; interquartile range [IQR], 4.7-11] years), TL declined significantly (median -2.12%/year; IQR, -3.48% to -0.76%/year; P = .002). During suppressive ART (median observation, 9.8; IQR, 7.1-11.1 years), there was no evidence of TL decline or increase (median + 0.54%/year; IQR, -0.55% to + 1.63%/year; P = .329). The TL-PRS contributed to TL change (global P = .019) but particular antiretrovirals did not (all P > .15). CONCLUSIONS: In PWH, TL is associated with an individual PRS. Telomere length declined significantly during untreated chronic HIV infection, but no TL change occurred during suppressive ART.

Women with HIV transitioning through menopause: Insights from the Swiss HIV Cohort Study (SHCS).

OBJECTIVES: We aimed to assess prevalence and age at menopause, identify factors associated with early menopause and explore the provision and utilization of healthcare in women living with HIV in Switzerland. METHODS: This was a retrospective Swiss HIV Cohort Study analysis from January 2010 to December 2018. Descriptive statistics to characterise the population and menopause onset. Logistic regression analysis to identify risk factors for early menopause. RESULTS: Of all women in the SHCS, the proportion of postmenopausal women tripled from 11.5% (n = 274) in 2010 to 36.1% (n = 961) in 2018. The median age at menopause was 50 years. Early menopause (< 45 years) occurred in 115 (10.2%) women and premature ovarian insufficiency (POI) (< 40 years) in 23 (2%) women. Early menopause was associated with black ethnicity (52.2% vs. 21.6%, p < 0.001), but not with HIV acquisition mode, CDC stage, viral suppression, CD4 cell count, hepatitis C, smoking or active drug use. While 92% of the postmenopausal women underwent a gynaecological examination during the 36 months before menopause documentation, only 27% received a bone mineral density measurement within 36 months after the last bleed and 11% were on hormone replacement therapy at the time of menopause documentation. CONCLUSIONS: The median age of women living with HIV at menopause is around 2 years lower than that reported for HIV-negative women in Switzerland. HIV care providers need to adapt their services to the requirements of the increasing number of women living with HIV transitioning through menopause. They should be able to recognize menopause-associated symptoms and improve access to bone mineral density measurement as well as hormone replacement therapy.

Weight and Metabolic Changes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living With HIV : A Cohort Study.

BACKGROUND: Tenofovir-based antiretroviral therapy (ART) has become first-line in all major HIV treatment guidelines. Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has a favorable renal and bone safety profile, but concerns about metabolic complications remain. OBJECTIVE: To assess weight changes, the development of overweight/obesity, and changes in lipid levels 18 months after replacing TDF with TAF. DESIGN: Cohort study. SETTING: 5 university hospitals, affiliated hospitals, and private physicians in Switzerland. PARTICIPANTS: 4375 adults living with HIV who received TDF-containing ART for 6 months or longer. MEASUREMENTS: Changes in weight and lipid levels were assessed using mixed-effect models. Differences in proportions of newly overweight/obese participants were calculated using 2-proportions Z tests. RESULTS: 4375 individuals were included, with follow-up between 1 January 2016 and 31 July 2019. Median age was 50 years (interquartile range, 43 to 56 years), 25.9% were female, and 51.7% had a normal body mass index (BMI); 3484 (79.6%) switched to TAF and 891 (20.4%) continued TDF. After 18 months, switching to TAF was associated with an adjusted mean weight increase of 1.7 kg (95% CI, 1.5 to 2.0 kg), compared with 0.7 kg (CI, 0.4 to 1.0 kg) with the continued use of TDF (between-group difference, 1.1 kg [CI, 0.7 to 1.4 kg]). Among individuals with a normal BMI, 13.8% who switched to TAF became overweight/obese, compared with 8.4% of those continuing TDF (difference, 5.4 percentage points [CI, 2.1 to 8.8 percentage points]). Switching to TAF led to increases in adjusted mean total cholesterol (0.25 mmol/L [9.5 mg/dL]), high-density lipoprotein cholesterol (0.05 mmol/L [1.9 mg/dL]), low-density lipoprotein cholesterol (0.12 mmol/L [4.7 mg/dL]), and triglyceride (0.18 mmol/L [16.1 mg/dL]) levels after 18 months. LIMITATION: Short follow-up, small subgroup analyses, and potential residual confounding. CONCLUSION: Replacing TDF with TAF is associated with adverse metabolic changes, including weight increase, development of obesity, and worsening serum lipid levels. PRIMARY FUNDING SOURCE: Swiss National Science Foundation.

Trust, affect, and choice in parents' vaccination decision-making and health-care provider selection in Switzerland.

This article examines the relationships between biomedicine, complementary and alternative medicine (CAM) and parents' vaccination decision-making in Switzerland. Our empirical evidence sheds light on an understudied phenomenon-parents switching from one doctor to another provider (often one offering CAM services) around issues that arise during vaccination consultations. This is important to understand since CAM is used by 25%-50% of the Swiss population and is integrated into the Swiss health-care system when offered by biomedically trained medical doctors with additional CAM training. Qualitative data gathered from in-depth semi-structured interviews with parents (N = 30) and ethnographic observations of vaccination consultations (N = 16 biomedical consultations, N = 18 CAM consultations) demonstrate how there was not always a clear-cut, direct relationship between (non)vaccination and parents' use of CAM and/or biomedicine. Borrowing from Hirschman (Exit, voice, and loyalty: Responses to decline in firms, organizations, and states, Harvard Univ. Press, 1970), we frame our analysis by using the concepts of exit, voice and loyalty to describe parents' provider selection and vaccination decision-making process, although only four families in the sample described switching solely because of vaccination-related issues. Findings add to vaccine decision-making literature by describing and analysing the underdiscussed provider-switching phenomenon and by demonstrating the importance of parents' experiences of trust, affect and choice in vaccination consultations as they pursue the best health outcomes for their children.

Impact of Delaying Antiretroviral Treatment During Primary Human Immunodeficiency Virus Infection on Telomere Length.

BACKGROUND: Telomere length (TL) shortens during aging, HIV seroconversion, and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI). METHODS: We measured TL in peripheral blood mononuclear cells by quantitative polymerase chain reaction in participants of the Zurich PHI Study with samples available for ≥6 years. We obtained univariable/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL. RESULTS: In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the first (shortest), second, and third (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (P for trend = .034), and longer TL over 6 years, but only with continuous ART (P < .001), not if ART was interrupted ≥12 months (P = .408). In multivariable analysis, participants in the second and third ART delay tertile had 17.6% (5.4%-29.7%; P = .004) and 21.5% (9.4%-33.5%; P < .001) shorter TL, after adjustment for age, with limited effect modification by clinical variables. CONCLUSIONS: In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.

Rapid Progression of Kidney Dysfunction in People Living With HIV: Use of Polygenic and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Risk Scores.

BACKGROUND: In people with human immunodeficiency virus (PWH), it is unknown whether genetic background associates with rapid progression of kidney dysfunction (ie, estimated glomerular filtration rate [eGFR] decrease of >5mL/min/1.73m2 per year for ≥3 consecutive years). METHODS: We obtained univariable and multivariable hazard ratios (HR) for rapid progression, based on the clinical D:A:D chronic kidney disease (CKD) risk score, antiretroviral exposures, and a polygenic risk score based on 14 769 genome-wide single nucleotide polymorphisms in white Swiss HIV Cohort Study participants. RESULTS: We included 225 participants with rapid progression and 3378 rapid progression-free participants. In multivariable analysis, compared to participants with low D:A:D risk, participants with high risk had rapid progression (HR =  1.82 [95% CI, 1.28-2.60]). Compared to the first (favorable) polygenic risk score quartile, participants in the second, third, and fourth (unfavorable) quartiles had rapid progression (HR = 1.39 [95% CI, 0.94-2.06], 1.52 [95% CI, 1.04-2.24], and 2.04 [95% CI, 1.41-2.94], respectively). Recent exposure to tenofovir disoproxil fumarate was associated with rapid progression (HR = 1.36 [95% CI, 1.06-1.76]). DISCUSSION: An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors.

Coronary Artery Disease-Associated and Longevity-Associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living With Human Immunodeficiency Virus: The Swiss HIV Cohort Study.

BACKGROUND: Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with human immunodeficiency virus (HIV) (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRSs) and by considering genetic variants associated with successful aging and longevity. METHODS: In the Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (ORs) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRSs. PRSs were built from CAD-associated single-nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. RESULTS: We included 269 patients with CAD events between 2000 and 2017 (median age, 54 years; 87% male; 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (ie, traditional and HIV-related) risk factors and PRSs, built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (P < .001). Participants with the most unfavorable clinical risk factor profile (top quintile) had an adjusted CAD-OR of 17.82 (95% confidence interval [CI], 8.19-38.76), compared with participants in the bottom quintile. Participants with the most unfavorable CAD-PRSs (top quintile) had an adjusted CAD-OR of 3.17 (95% CI, 1.74-5.79), compared with the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had an adjusted CAD-OR of 3.67 (95% CI, 2.00-6.73), compared with the bottom quintile. CONCLUSIONS: In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related, and genetic risk factors provided the most powerful CAD prediction.

Telomere Length, Traditional Risk Factors, Factors Related to Human Immunodeficiency Virus (HIV) and Coronary Artery Disease Events in Swiss Persons Living With HIV.

BACKGROUND: Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with human immunodeficiency virus (HIV; PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH. METHODS: We measured TL by quantitative polymerase chain reaction (PCR) in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 1 January 2000 to 31 December 2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses. RESULTS: We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR = 0.56 (95% confidence interval [CI], .35-.91) and OR = 0.54 (95% CI, .31-.96). Multivariable OR for current smoking was 1.93 (95% CI, 1.27-2.92), dyslipidemia OR = 1.92 (95% CI, 1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR = 1.82 (95% CI, 1.27-2.59), OR = 2.02 (95% CI, 1.34-3.04), OR = 3.42 (95% CI, 2.14-5.45), and OR = 1.66 (95% CI, 1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use. CONCLUSIONS: In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.

Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity.

BACKGROUND: The extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study. METHODS: Retrospective review of medical records was performed to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug-drug interactions (DDIs) database. RESULTS: For 175 included individuals, the median age was 78 years (IQR 76-81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5-10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3-4.7), renal impairment (OR: 2.7; 95% CI: 1.4-5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1-3.8) and female sex (OR: 8.3; 95% CI: 2.4-28.1). CONCLUSIONS: Polypharmacy and inappropriate prescribing are highly prevalent in elderly people living with HIV. Women are at higher risk than men, partly explained by sex differences in the occurrence of non-HIV comorbidities and medical care. Medication reconciliation and periodic review of prescriptions by experienced physicians could help reduce polypharmacy and inappropriate prescribing in this vulnerable, growing population.

Antiretroviral Drugs Associated With Subclinical Coronary Artery Disease in the Swiss Human Immunodeficiency Virus Cohort Study.

BACKGROUND: Coronary artery disease (CAD) events have been associated with certain antiretroviral therapy (ART) agents. In contrast, the influence of ART on subclinical atherosclerosis is not clear. The study objective was to assess the association between individual ART agents and the prevalence and extent of subclinical CAD. METHODS: Coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) were performed in ≥45-year-old Swiss Human Immunodeficiency Virus Cohort Study participants. The following subclinical CAD endpoints were analyzed separately: CAC score >0, any plaque, calcified plaque, noncalcified/mixed plaque, segment involvement score (SIS), and segment severity score (SSS). Logistic regression models calculated by inverse probability of treatment weights (IPTW) were used to explore associations between subclinical CAD and cumulative exposure to the 10 most frequently used drugs. RESULTS: There were 403 patients who underwent CCTA. A CAC score >0 was recorded in 188 (47%), any plaque in 214 (53%), calcified plaque in 151 (38%), and noncalcified/mixed plaque in 150 (37%) participants. A CAC score >0 was negatively associated with efavirenz (IPTW adjusted odds ratio per 5 years 0.73, 95% confidence interval [CI] 0.56-0.96), tenofovir disoproxil fumarate (0.68, 95% CI 0.49-0.95), and lopinavir (0.64, 95% CI 0.43-0.96). Any plaque was negatively associated with tenofovir disoproxil fumarate (0.71, 95% CI 0.51-0.99). Calcified plaque was negatively associated with efavirenz (0.7, 95% CI 0.57-0.97). Noncalcified/mixed plaque was positively associated with abacavir (1.46, 95% CI 1.08-1.98) and negatively associated with emtricitabine (0.67, 95% CI 0.46-0.99). For SSS and SIS, we found no association with any drug. CONCLUSIONS: An increased risk of noncalcified/mixed plaque was only found in patients exposed to abacavir. Emtricitabine was negatively associated with noncalcified/mixed plaque, while tenofovir disoproxil fumarate and efavirenz were negatively associated with any plaque and calcified plaque, respectively.

Self-reported Neurocognitive Impairment in People Living With Human Immunodeficiency Virus (HIV): Characterizing Clusters of Patients With Similar Changes in Self-reported Neurocognitive Impairment, 2013-2017, in the Swiss HIV Cohort Study.

BACKGROUND: Self-reported neurocognitive impairment (SRNI) in people living with human immunodeficiency virus type 1 (HIV-1) infection is frequent. We use longitudinal information on SRNI in the Swiss HIV Cohort Study (SHCS) to identify and characterize groups of patients with persisting SRNI over time. METHODS: We included all SHCS patients who were assessed for SRNI during at least 5 visits spanning at least 2.5 years in 2013-2017. We first compared patients with SRNI to those without SRNI over the whole study period. Second, we used a hierarchical cluster algorithm to identify groups of patients with similar changes of SRNI over time. In both analyses, we studied clinical and demographic factors potentially influencing SRNI. RESULTS: In total, 79 683 questionnaires of 11 029 patients contained information about SRNI, and 8545 of 11 029 (77.5%) patients had longitudinal information. The overall percentage of patients with SRNI decreased from 19.6% in 2013 to 10.7% in 2017. Compared to patients in the cluster with low-level SRNI over time, patients in the cluster with high-level persisting SRNI more often had a prior opportunistic infection of the central nervous system (CNS) (odds ratio [OR], 3.7; P < .001), imperfect adherence to antiretroviral therapy (ART) (OR, 2.8; P < .001), and depression (OR, 1.9; P < .001). CONCLUSIONS: Although overall SRNI is decreasing in the SHCS, there is a group of patients with persisting SRNI over time. Past opportunistic infections of the CNS, imperfect adherence to ART, and depression were associated most with persisting SRNI. Patients with these characteristics should be preferentially tested for neurocognitive impairment.Although overall self-reported neurocognitive impairment (SRNI) is decreasing in the Swiss HIV Cohort Study, there is a group of patients with persisting SRNI over time, characterized by more past opportunistic infections of the central nervous system, imperfect adherence to antiretroviral therapy, and depression.

Contribution of Genetic Background and Data Collection on Adverse Events of Anti-human Immunodeficiency Virus (HIV) Drugs (D:A:D) Clinical Risk Score to Chronic Kidney Disease in Swiss HIV-infected Persons With Normal Baseline Estimated Glomerular Filtration Rate.

BACKGROUND: In human immunodeficiency virus (HIV), the relative contribution of genetic background, clinical risk factors, and antiretrovirals to chronic kidney disease (CKD) is unknown. METHODS: We applied a case-control design and performed genome-wide genotyping in white Swiss HIV Cohort participants with normal baseline estimated glomerular filtration rate (eGFR >90 mL/minute/1.73 m2). Univariable and multivariable CKD odds ratios (ORs) were calculated based on the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) score, which summarizes clinical CKD risk factors, and a polygenic risk score that summarizes genetic information from 86 613 single-nucleotide polymorphisms. RESULTS: We included 743 cases with confirmed eGFR drop to <60 mL/minute/1.73 m2 (n = 144) or ≥25% eGFR drop to <90 mL/minute/1.73 m2 (n = 599), and 322 controls (eGFR drop <15%). Polygenic risk score and D:A:D score contributed to CKD. In multivariable analysis, CKD ORs were 2.13 (95% confidence interval [CI], 1.55-2.97) in participants in the fourth (most unfavorable) vs first (most favorable) genetic score quartile; 1.94 (95% CI, 1.37-2.65) in the fourth vs first D:A:D score quartile; and 2.98 (95% CI, 2.02-4.66), 1.70 (95% CI, 1.29-2.29), and 1.83 (95% CI, 1.45-2.40), per 5 years of exposure to atazanavir/ritonavir, lopinavir/ritonavir, and tenofovir disoproxil fumarate, respectively. Participants in the first genetic score quartile had no increased CKD risk, even if they were in the fourth D:A:D score quartile. CONCLUSIONS: Genetic score increased CKD risk similar to clinical D:A:D score and potentially nephrotoxic antiretrovirals. Irrespective of D:A:D score, individuals with the most favorable genetic background may be protected against CKD.