Abstract
Background
Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including ...baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens.
Methods
We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations.
Results
We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio mHR, 2.2; 95% confidence interval CI, 1.3–3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1–3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3–.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2–.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6–.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0–1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome.
Conclusions
Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts.
Abstract Background Advancements in access to antiretroviral therapy (ART) and human immunodeficiency virus (HIV) care have led to a decline in AIDS-related deaths among people with HIV (PWH) in ...Switzerland. However, data on the ongoing changes in causes of death among PWH over the past 15 years are scarce. Methods We investigated all reported deaths in the Swiss HIV Cohort Study between 2005 and 2022. Causes of death were categorized using the Coding Causes of Death in HIV protocol. The statistical analysis included demographic stratification to identify time trends and logistic regression models to determine associated factors for the underlying cause of death. Results In total, 1630 deaths were reported, with 23.7% of individuals assigned female sex at birth. These deaths included 147 (9.0%) HIV/AIDS-related deaths, 373 (22.9%) due to non-AIDS, non-hepatic cancers, 166 (10.2%) liver-related deaths, and 158 (9.7%) cardiovascular-related deaths. The median age at death (interquartile range) increased from 45.0 (40.0–53.0) years in 2005–2007 to 61.0 (56.0–69.5) years in 2020–2022. HIV/AIDS- and liver-related deaths decreased, whereas deaths from non-AIDS, non-hepatic cancers increased and cardiovascular-related deaths remained relatively stable. Conclusions The proportionally decreasing HIV/AIDS and liver-related deaths showcase the effectiveness of ART, comprehensive HIV patient care, and interventions targeting hepatitis C virus coinfection. Future research should focus on managing cancer and cardiovascular-related conditions as the new leading causes of death among PWH. Comprehensive healthcare strategies focusing on non–AIDS-related comorbid conditions, cancer management, and sustaining liver and cardiovascular health are needed to bridge the ongoing health disparities between PWH and the general population.
CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. ...Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.
In the Swiss HIV Cohort Study, 61 of 222 (27%) HIV-suppressed persons with chronic hepatitis B virus (HBV) infection had HBV replication after 2 years on tenofovir, of whom 77% were suppressed ...thereafter. Self-reported adherence to therapy and HBV viral load at tenofovir initiation were predictors of persistent replication.
Abstract
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.
An individual polygenic risk score was associated with osteoporosis in people living with HIV. The genetic effect was robust, as it persisted after multivariable adjustment for established traditional and HIV-related osteoporosis risk factors, including tenofovir disoproxil fumarate and boosted protease inhibitor exposure.
We treated 122 human immunodeficiency virus/hepatitis C virus-infected individuals with grazoprevir/elbasvir ± ribavirin for 12-16 weeks and achieved a sustained virological response rate of 99%. In ...genotype 1a infected individuals, treatment duration was guided by presence of baseline resistance-associated substitutions.
Abstract
Background
This study was performed to investigate the efficacy and safety of grazoprevir-elbasvir guided by baseline resistance-associated substitutions (RASs) in the Swiss HCVree Trial.
Methods
We performed hepatitis C virus (HCV) RNA screening among all men who have sex with men (MSM) enrolled in the Swiss HIV Cohort Study. Individuals with replicating HCV genotype 1 or 4 infection were eligible for grazoprevir-elbasvir treatment. Genotype 1a-infected individuals with baseline RASs and genotype 4-infected individuals with prior failure of HCV treatment received 16 weeks of grazoprevir-elbasvir combined with ribavirin. All other individuals received 12 weeks of grazoprevir-elbasvir alone. Patients reporting unprotected sex with occasional partners were offered a HCV risk reduction-oriented behavioral intervention.
Results
We screened 3722 MSM and identified 177 (4.8%) with replicating infection. A total of 122 individuals (3.3%) were eligible for study treatment. Six of 76 patients infected with genotype 1a (7.3%) harbored baseline RASs. Sustained virological response after 12 weeks of follow-up was achieved in 121 patients (99%), including all with genotype 1a infection. Overall, 8 serious adverse events occurred, none of which was related to the study drug. Seventy-five percent of eligible MSM participated in the risk counseling program.
Conclusions
Grazoprevir-elbasvir for 12 or 16 weeks, with or without ribavirin, achieved high cure rates and had an excellent safety profile. Unique to other studies, the treatment duration was guided by the presence of baseline RASs among genotype 1a-infected individuals, and the treatment phase was accompanied by an HCV risk reduction-oriented behavioral intervention. This successful population-wide treatment approach lays the groundwork to achieve HCV elimination in coinfected MSM.
Clinical Trials Registration
NCT02785666
Abstract
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.
Despite effective prevention approaches, ongoing human immunodeficiency virus 1 (HIV-1) transmission remains a public health concern indicating a need for identifying its drivers.
We combined a ...network-based clustering method using evolutionary distances between viral sequences with statistical learning approaches to investigate the dynamics of HIV transmission in the Swiss HIV Cohort Study and to predict the drivers of ongoing transmission.
We found that only a minority of clusters and patients acquired links to new infections between 2007 and 2020. While the growth of clusters and the probability of individual patients acquiring new links in the transmission network was associated with epidemiological, behavioral, and virological predictors, the strength of these associations decreased substantially when adjusting for network characteristics. Thus, these network characteristics can capture major heterogeneities beyond classical epidemiological parameters. When modeling the probability of a newly diagnosed patient being linked with future infections, we found that the best predictive performance (median area under the curve receiver operating characteristic AUCROC = 0.77) was achieved by models including characteristics of the network as predictors and that models excluding them performed substantially worse (median AUCROC = 0.54).
These results highlight the utility of molecular epidemiology-based network approaches for analyzing and predicting ongoing HIV transmission dynamics. This approach may serve for real-time prospective assessment of HIV transmission.
Abstract
Objectives
Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s ...pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition.
Methods
A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions.
Results
A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively.
Conclusions
Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.
Abstract
Background
Bacterial pneumonia is a leading reason for hospitalization among people with HIV (PWH); however, evidence regarding its drivers in the era of potent antiretroviral therapy is ...limited.
Methods
We assessed risk factors for bacterial pneumonia in the Swiss HIV Cohort Study using marginal models. We further assessed the relationship between risk factors and changes in bacterial pneumonia incidence using mediation analysis.
Results
We included 12927 PWH with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100779 person-years. Bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 person-years in 2008 to 6.8 cases/1000 person-years in 2018. Older age, lower education level, intravenous drug use, smoking, lower CD4-cell count, higher HIV load, and prior pneumonia were significantly associated with higher bacterial pneumonia incidence. Notably, CD4 cell counts 350–499 cells/μL were significantly associated with an increased risk compared to CD4 ≥ 500 cells/µL (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01–1.89). Decreasing incidence over the last decade can be explained by increased CD4-cell counts and viral suppression and decreased smoking frequency.
Conclusions
Improvements in cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.
Bacterial pneumonia in people with HIV is associated with obstructive airway disease, proton pump inhibitors, CD4 cell count, viral load, smoking, and intravenous drug use. Improved HIV care and decreased smoking may have mediated reduced bacterial pneumonia incidence 2008–2018.
PDF
