Download full-text

Full-text

Available from: Huldrych F Günthard, Jan 26, 2015
    • "Study Population. A total of 71 plasma samples, 10 CSF samples, and 8 urine samples from 71 participants were obtained from four study population subsets: • Swiss HIV Cohort Study (SHCS) (Schoeni-Affolter F et al., 2010) participants under EFV included in our previous study to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of antiretroviral therapy. A total of 39 plasma samples were selected according to their genotype (Lubomirov et al., 2011 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). Most metabolites profile analyses have been so far restricted to 8OH-EFV, 7OH-EFV and EFV-N-gln even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolites profiles analyses by tandem mass spectrometry of plasma, CSF and urine samples in 71 HIV patients under efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-Glucuronide, and 8OH-EFV-sulfate (identified for the first time) in humans were found 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6 and CYP3A metabolic pathways, the 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (p < 0.0001) which was also reflected by phase II metabolites 8OH-EFV-gln/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of CNS toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV - gln, 8OH-EFV-sulfate and 7OH-EFV - gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of these previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz need to be further examined in larger cohort studies.
    No preview · Article · Nov 2015 · Drug metabolism and disposition: the biological fate of chemicals
  • Source
    • "This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. regional hospitals, and private practices, since 1988[9]. Demographic, clinical and laboratory data are collected at registration and every six months thereafter using a standard protocol. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). Methods: We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). Results: SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. Conclusion: In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.
    Full-text · Article · Jul 2015 · PLoS ONE
  • Source
    • "Established in 1988, the SHCS is one of the longest running HIV cohort studies worldwide[16]. About 70% of patients living with AIDS are enrolled in the SHCS and 70% of the antiretroviral drugs sold in the country are prescribed within the study[16,27]. We had to exclude patients seen in private practices who were better educated and more likely to be in salaried work than the patients included in our study. "
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES: Inequalities and inequities in health are an important public health concern. In Switzerland, mortality in the general population varies according to the socio-economic position (SEP) of neighbourhoods. We examined the influence of neighbourhood SEP on presentation and outcomes in HIV-positive individuals in the era of combination antiretroviral therapy (cART). METHODS: The neighbourhood SEP of patients followed in the Swiss HIV Cohort Study (SHCS) 2000-2013 was obtained on the basis of 2000 census data on the 50 nearest households (education and occupation of household head, rent, mean number of persons per room). We used Cox and logistic regression models to examine the probability of late presentation, virologic response to cART, loss to follow-up and death across quintiles of neighbourhood SEP. RESULTS: A total of 4489 SHCS participants were included. Presentation with advanced disease [CD4 cell count <200 cells/μl or AIDS] and with AIDS was less common in neighbourhoods of higher SEP: the age and sex-adjusted odds ratio (OR) comparing the highest with the lowest quintile of SEP was 0.71 [95% confidence interval (95% CI) 0.58-0.87] and 0.59 (95% CI 0.45-0.77), respectively. An undetectable viral load at 6 months of cART was more common in the highest than in the lowest quintile (OR 1.52; 95% CI 1.14-2.04). Loss to follow-up, mortality and causes of death were not associated with neighbourhood SEP. CONCLUSION: Late presentation was more common and virologic response to cART less common in HIV-positive individuals living in neighbourhoods of lower SEP, but in contrast to the general population, there was no clear trend for mortality.
    Full-text · Article · Nov 2014 · AIDS (London, England)
Show more