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Humoral immunity is considered a key component of effective vaccines against HIV‐1. Hence, an enormous effort has been put into investigating the neutralizing antibody response to HIV‐1 over the ...past 20 years which generated key information on epitope specificity, potency, breadth and in vivo activity of the neutralizing antibodies. Less clear is still the role of antibody‐mediated effector functions (antibody‐dependent cellular cytotoxicity, phagocytosis, complement system) and uncertainty prevails whether Fc‐mediated mechanisms are largely beneficial or detrimental for the host. The current knowledge on the manifold functions of the humoral immune response in HIV infection, their underlying mechanisms and potential in vaccine‐induced immunity will be discussed in this review.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of ...indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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
Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) improves renal tubular markers in HIV-infected individuals but the impact on estimated glomerular ...filtration rate (eGFR) remains unclear.
Methods
In all participants from the Swiss HIV Cohort Study who switched from TDF to TAF-containing antiretroviral regimen or continued TDF, we estimated changes in eGFR and urine protein-to-creatinine ratio (UPCR) after 18 months using mixed-effect models.
Results
Of 3520 participants (26.6% women, median age 50 years), 2404 (68.5%) switched to TAF. Overall, 1664 (47.3%) had an eGFR <90 mL/min and 1087 (30.9%) an UPCR ≥15 mg/mmol. In patients with baseline eGFR ≥90 mL/min, eGFR decreased with the use of TDF and TAF (−1.7 mL/min). Switching to TAF was associated with increases in eGFR of 1.5 mL/min (95% confidence interval CI, .5–2.5) if the baseline eGFR was 60–89 mL/min, and 4.1 mL/min (95% CI, 1.6–6.6) if <60 mL/min. In contrast, eGFR decreased by 5.8 mL/min (95% CI, 2.3–9.3) with continued use of TDF in individuals with baseline eGFR <60 mL/min. UPCR decreased after replacing TDF by TAF, independent of baseline eGFR.
Conclusions
Switching from TDF to TAF improves eGFR and proteinuria in patients with renal dysfunction.
We assessed changes in renal function after replacing TDF with TAF in a national cohort of HIV-infected individuals. Among patients with established renal dysfunction, urinary protein-to-creatinine ratio and eGFR improved after the switch to TAF.
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.
We assessed changes in sexual behavior among people with human immunodeficiency virus (HIV) over 20 years. Condom use with stable partners steadily declined from over 90 to 29 since the Swiss U U ...statement, with similar trajectories between men who have sex with men (MSM) and heterosexuals. Occasional partnership remained higher among MSM compared to heterosexuals even during coronavirus disease 2019 (COVID-19) social distancing.
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.
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