Hepatitis C virus (HCV) treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV-coinfected patients.

The efficacy of current hepatitis C therapy in HIV/HCV-coinfected patients is largely dependent on HCV genotype. The annual prevalence of HCV genotypes/subtypes and their influence on HCV clearance with antiviral treatment were examined in a dynamic cohort of HIV/HCV-coinfected patients followed up in Madrid since 2000. Patients entered the cohort at first visit and left the cohort when HCV clearance was achieved with HCV therapy or when follow-up was interrupted for any reason, including death. A total of 672 HIV/HCV-coinfected patients constituted the cohort. The mean follow-up time was 5.5 years, corresponding to 4108 patient-years. Mean age at entry was 37 years, and 73% were men and 86% were intravenous drug users. Overall distribution of HCV genotypes was as follows: 57.1% HCV-1 (1a: 29.2%, 1b: 20.4%, unknown: 7.6%), 1.3% HCV-2, 25.4% HCV-3 and 15.9% HCV-4. A total of 274 (40.8%) patients were treated with peginterferon-ribavirin, of whom 116 (42.3%) achieved HCV clearance following 1-3 courses of therapy. The proportion of HCV-1/4 rose from 71.7% in 2000 to 76.8% in 2008, whereas the proportion of HCV-2/3 fell from 28.1% in 2000 to 23.2% in 2008. The yearly prevalence increased for HCV-1 (R(2) : 0.92, b: 0.59, P < 0.001) and HCV-4 (R(2) : 0.77, b: 0.33, P < 0.005) and conversely diminished for HCV-3 (R(2) : 0.94, b: -0.82, P < 0.001). In summary, the prevalence of HCV-1 and HCV-4 has increased over the last decade in HIV/HCV-coinfected patients, whereas conversely it has declined for HCV-3, in association with the wider use of HCV therapy (41%) in this population.

Overview of the pharmacogenetics of HIV therapy.

The administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, influencing antiviral activity as well as incidence of drug-related toxicities. The reasons for this large inter-individual variability in drug levels are multifactorial, and involve differences in metabolism related to gender, concomitant medications, drug compliance, underlying diseases and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the inter-individual variation in the body disposition of drugs. One of its main goals is to give grounds to individualized treatment. The majority of pharmacogenetic traits so far have involved drug metabolism. This is the case for the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid, which is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which allows splitting the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretroviral drugs have focussed on metabolizer enzymes at the liver and on transporter proteins on cell membranes. Herein, we review the most relevant metabolizer enzymes and protein transporters, along with the genetic polymorphisms, which seem to influence the pharmacokinetics of antiretroviral drugs, ultimately determining its efficacy and toxicity.