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
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.
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.
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.
Abstract
Background
The rate of acquired human immunodeficiency virus type 1 (HIV-1) drug resistance (ADR) has fallen dramatically since introduction of combined antiretroviral therapy (cART) in ...Switzerland. However, clinical experience indicates that there are still patients at risk of newly acquiring drug resistance despite having access to cART. Here, we characterized risk factors for ADR, to improve patient care and prevent emergence of drug resistance and treatment failure.
Methods
We performed a case-control study to identify risk factors for ADR in all patients starting their first cART in the Swiss HIV Cohort Study (SHCS) since 1996. The SHCS is highly representative and includes >75% of patients receiving ART in Switzerland. To this end, we implemented a systematic medical chart review to obtain more detailed information on additional parameters, which are not routinely collected in the SHCS. The collected data were analyzed using univariable and multivariable conditional logistic regression.
Results
We included in our study 115 cases and 115 matched controls. Unemployment (multivariable odds ratio mOR, 2.9 95% confidence interval {CI}, 1.3–6.4; P = .008), African origin (mOR, 3.0 95% CI, 1.0–9.2; P = .047), comedication with anti-infectives (mOR, 3.7 95% CI, 1.0–12.6; P = .045), and symptoms of mental illness (mOR, 2.6 95% CI, 1.2–5.5; P = .012) were associated with ADR in the multivariable model.
Conclusions
Although ADR has become very rare with cART due to new potent therapies, patients in socially challenging life situations or presenting with mental health issues are at higher risk for drug resistance. Prompt identification and adequate support of these patients before ADR will prevent treatment failure and HIV-1 transmission.
In a case-control study, we were able to identify specific risk factors for acquired drug resistance in all patients starting their first combination antiretroviral therapy regimen in the Swiss HIV Cohort Study since 1996.
Abstract
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.
In this prospective coronary computed tomography angiography study among human immunodeficiency virus–positive participants, noncalcified/mixed plaque was only positively associated with abacavir. Emtricitabine, tenofovir disoproxil fumarate, and efavirenz were negatively associated with noncalcified/mixed plaque, any plaque, and calcified plaque, respectively.
Objectives
To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals ...according to age, ≥50 years or <50 years.
Methods
All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database.
Results
Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups.
Conclusions
The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and response.
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).
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.
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).
An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors.
Abstract
Background
Scale-up of direct-acting antiviral therapy is expected to abate hepatitis C virus (HCV) incidence among human immunodeficiency virus (HIV)-positive men who have sex with men ...(MSM). International transmission could influence this process. We classified HCV infections in HIV-positive MSM as either domestically or internationally acquired, and estimated how this classification changed over time.
Methods
HCV subtype 1a (the most frequent subtype among MSM) genomes from 99 persons enrolled in the Swiss HIV Cohort Study and diagnosed with replicating HCV infections, were sequenced. Sixty-six of these sequences were from MSM. We inferred maximum-likelihood phylogenetic trees and time trees containing a fragment of the NS5B region of these and 374 circulating strains. We inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission.
Results
Of HCV transmissions, 50% to 80% were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54% (range 0–75%). It increased to 85% (range 67%–100%) between 2008 and 2016.
Conclusions
International and domestic transmission have played major roles in this epidemic. While international transmission persists, local transmission has established as the main source of infections.
We used phylogenetics and phylodynamics to classify over time HCV infections in HIV-positive MSM as either domestically or internationally acquired. We found that while international transmission dominated initially and persists, local transmission has established as the main source of infections.
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