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  • Speck, R  (9)
  • Pharmacy  (9)
  • 1
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    Online Resource
    Prevalence of HIV-1 drug resistance mutations in proviral DNA in the Swiss HIV Cohort Study, a retrospective study from 1995 to 2018
    Oxford University Press (OUP) ; 2023
    In:  Journal of Antimicrobial Chemotherapy Vol. 78, No. 9 ( 2023-09-05), p. 2323-2334
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 78, No. 9 ( 2023-09-05), p. 2323-2334
    Abstract: Genotypic resistance testing (GRT) is routinely performed upon diagnosis of HIV-1 infection or during virological failure using plasma viral RNA. An alternative source for GRT could be cellular HIV-1 DNA. Objectives A substantial number of participants in the Swiss HIV Cohort Study (SHCS) never received GRT. We applied a method that enables access to the near full-length proviral HIV-1 genome without requiring detectable viraemia. Methods Nine hundred and sixty-two PBMC specimens were received. Our two-step nested PCR protocol was applied to generate two overlapping long-range amplicons of the HIV-1 genome, sequenced by next-generation sequencing (NGS) and analysed by MinVar, a pipeline to detect drug resistance mutations (DRMs). Results Six hundred and eighty-one (70.8%) of the samples were successfully amplified, sequenced and analysed by MinVar. Only partial information of the pol gene was contained in 82/681 (12%), probably due to naturally occurring deletions in the proviral sequence. All common HIV-1 subtypes were successfully sequenced. We detected at least one major DRM at high frequency (≥15%) in 331/599 (55.3%) individuals. Excluding APOBEC-signature (G-to-A mutation) DRMs, 145/599 (24.2%) individuals carried at least one major DRM. RT-inhibitor DRMs were most prevalent. The experienced time on ART was significantly longer in DRM carriers (P = 0.001) independent of inclusion or exclusion of APOBEC-signature DRMs. Conclusions We successfully applied a reliable and efficient method to analyse near full-length HIV-1 proviral DNA and investigated DRMs in individuals with undetectable or low viraemia. Additionally, our data underscore the need for new computational tools to exclude APOBEC-related hypermutated NGS sequence reads for reporting DRMs.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkad240
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 2
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    Tenofovir Use is associated with a Reduction in Calculated Glomerular Filtration Rates in the Swiss HIV Cohort Study
    SAGE Publications ; 2007
    In:  Antiviral Therapy Vol. 12, No. 8 ( 2007-11), p. 1165-1174
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 12, No. 8 ( 2007-11), p. 1165-1174
    Abstract: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. Methods We compared treatment-naive patients or patients with treatment interruptions ≥12 months starting either a TDF-based combination antiretroviral therapy (cART) ( n=363) or a TDF-sparing regime ( n=715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. Results Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58–0.72) and 0.80 (95% CI 0.76–0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] =2.34 [95% CI 1.24–4.42]), higher baseline cGFR (HR=1.03 [95% CI 1.02–1.04] by 10 ml/min), TDF use (HR=1.84 [95% CI 1.35–2.51]) and boosted protease inhibitor use (HR=1.71 [95% CI 1.30–2.24] ) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. Conclusion There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350701200812
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2007
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  • 3
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    Real-life management of drug–drug interactions between antiretrovirals and statins
    Oxford University Press (OUP) ; 2020
    In:  Journal of Antimicrobial Chemotherapy Vol. 75, No. 7 ( 2020-07-01), p. 1972-1980
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 75, No. 7 ( 2020-07-01), p. 1972-1980
    Abstract: PIs cause drug–drug interactions (DDIs) with most statins due to inhibition of drug-metabolizing enzymes and/or the hepatic uptake transporter OATP1B1, which may alter the pharmacodynamic (PD) effect of statins. Objectives To assess the management of DDIs between antiretrovirals (ARVs) and statins in people living with HIV (PLWH) considering statin plasma concentrations, compliance with dosing recommendations and achievement of lipid targets. Methods PLWH of the Swiss HIV Cohort Study were eligible if they received a statin concomitantly with ARVs. HDL, total cholesterol (TC) and statin plasma concentration were measured during follow-up visits. Individual non-HDL and TC target values were set using the Framingham score and the 2018 European AIDS Clinical Society recommendations. Results Data were analysed for rosuvastatin (n = 99), atorvastatin (n = 92), pravastatin (n = 46) and pitavastatin (n = 21). Rosuvastatin and atorvastatin underdosing frequently led to suboptimal PD response. Insufficient lipid control was observed with PIs despite high atorvastatin concentrations, likely explained by inhibition of OATP1B1 resulting in less statin uptake in the liver. Target lipid values were more often achieved with unboosted integrase inhibitors due to both their favourable DDI profiles and neutral effect on lipids. Insufficient lipid control was common with pravastatin and pitavastatin regardless of co-administered ARVs and despite using maximal recommended statin doses. The latter suggests lower efficacy compared with rosuvastatin or atorvastatin. Conclusions Suboptimal management of DDIs with statin underdosing was observed in 29% of prescriptions. Integrase inhibitor-based regimens and/or treatment with rosuvastatin or atorvastatin should be favoured in patients with refractory dyslipidaemia.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkaa099
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 4
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    Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity
    Oxford University Press (OUP) ; 2021
    In:  Journal of Antimicrobial Chemotherapy Vol. 76, No. 3 ( 2021-02-11), p. 758-764
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 76, No. 3 ( 2021-02-11), p. 758-764
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkaa505
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 5
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    CD4 + T-Cell Count Increase in HIV-1-Infected Patients with Suppressed Viral Load Within 1 year after start of antiretroviral therapy
    SAGE Publications ; 2007
    In:  Antiviral Therapy Vol. 12, No. 6 ( 2007-08), p. 889-898
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 12, No. 6 ( 2007-08), p. 889-898
    Abstract: CD4 + T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4 + T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). Methods Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements 〈 50 copies/ml 〉 3 months apart during the 1st year of cART were included ( n=1,816 patients). We studied CD4 + T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2–3 and years 4–5 of suppression. Multiple median regression adjusted for repeated CD4 + T-cell measurements was used to study the dependence of CD4 + T-cell slopes on clinical covariates and drug classes. Results Median CD4 + T-cell increases following VL suppression were 87, 52 and 19 cells/μl per year in the three periods. In the multiple regression model, median CD4 + T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4 + T-cell 〈 650 cells/μ l at start of the period and low CD4 + T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4 + T-cell increases compared with stavudine. Conclusions In our observational study, long-term CD4 + T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4 + T-cell levels.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350701200602
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2007
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  • 6
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    Virological Outcome and Management of Persistent Low-Level Viraemia in HIV-1-Infected Patients: 11 Years of the Swiss HIV Cohort Study
    SAGE Publications ; 2015
    In:  Antiviral Therapy Vol. 20, No. 2 ( 2015-02), p. 165-175
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 20, No. 2 ( 2015-02), p. 165-175
    Abstract: Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS). Methods In this retrospective study (2000–2011), pLLV was defined as a VL of 21–400 copies/ml on ≥ three consecutive plasma samples with ≥8 weeks between first and last analyses, in patients undetectable for ≥24 weeks on cART. Control patients had ≥ three consecutive undetectable VLs over ≥32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL 〉 400 copies/ml. Results Among 9,972 patients, 179 had pLLV and 5,389 were controls. Compared to controls, pLLV patients were more often on unboosted protease inhibitor (PI)-based (adjusted odds ratio [aOR; 95% CI] 3.2 [1.8, 5.9] ) and nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-only combinations (aOR 2.1 [1.1, 4.2]) than on non-nucleoside reverse transcriptase inhibitor and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8, 315] ), unboosted PI-based (aOR 12.8 [1.7, 96]) or NRTI-only combinations (aOR 115 [6.8, 1,952] ), and VLs 〉 200 during pLLV (aOR 3.7 [1.1, 12]). No VF occurred in patients with persistent very LLV (21-49 copies/ml; n=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared with 19/74 (26%) without change ( P 〈 0.001). Conclusions Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL≥200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV 〉 200 copies/ml.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.3851/IMP2815
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2015
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  • 7
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    Long-Term Virological Response to Multiple Sequential Regimens of Highly Active Antiretroviral Therapy for HIV Infection
    SAGE Publications ; 2004
    In:  Antiviral Therapy Vol. 9, No. 2 ( 2004-02), p. 263-274
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 9, No. 2 ( 2004-02), p. 263-274
    Abstract: Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort. Design Retrospective analysis in an observational cohort. Methods 1140 individuals receiving uninterrupted HAART for 4.8 ±0.6 years were included. The virological response was classified as success ( 〈 400 copies/ml), low-level (LF: 400–5000 copies/ml) or high-level failure (HF: 〉 5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses. Results 40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67–3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72–0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes. Conclusion Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical. This study has been presented in part at the 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 2003. Abstract #571.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350400900212
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2004
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  • 8
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    Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting
    Oxford University Press (OUP) ; 2019
    In:  Journal of Antimicrobial Chemotherapy Vol. 74, No. 9 ( 2019-09-01), p. 2690-2697
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 74, No. 9 ( 2019-09-01), p. 2690-2697
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkz217
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 9
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    Emtricitabine and lamivudine concentrations in saliva: a simple suitable test for treatment adherence
    Oxford University Press (OUP) ; 2019
    In:  Journal of Antimicrobial Chemotherapy Vol. 74, No. 8 ( 2019-08-01), p. 2468-2470
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 74, No. 8 ( 2019-08-01), p. 2468-2470
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkz181
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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