Lay summary

Antiretroviral drug (ARV) therapy has dramatically improved the prognosis of HIV infection converting it from a deadly disease into a chronic manageable condition. Nevertheless, despite the impressive therapeutic benefit of ARVs, the currently available molecules suppress, but do not eliminate the infection. This is due to the persistence of minimal residual viral replication or of viral latency, such that relapse is an inevitable consequence of therapy interruption, and thus long-term therapy is necessary. Unfortunately, treatment intolerance is observed in approximately one third of HIV-infected patients receiving first line ARVs, leading to treatment modification or interruption. Coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetic and pharmacodynamic aspects of HIV therapeutics remain therefore a high priority because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy. Genetic and non-genetic factors influence drug exposure, toxicity and clinical response to therapy. The important interindividual pharmacokinetic variability observed for antiretroviral agents is not only explained by pharmacogenetic predisposition affecting drug’s transport and metabolism, but also by patho-physiological conditions and by environmental influences, including co-administered drugs.

The present research project aims at studying the complex gene-drug-environmental interplay relevant to antiviral treatment in HIV-infected patients. Specifically, co-infection with the Hepatitis C Virus (HCV) is common in HIV-infected individuals and chronic hepatitis C is a leading cause of morbidity and death in HIV/HCV coinfected patients. Therefore, eradication of HCV through therapeutic interventions is of particular importance in this population. HIV/HCV co-infected patients will be increasingly treated by the novel HCV protease inhibitors (HCV-PI) that allow cure rates never encountered so far in HCV genotype-1 infected patients. However, these new molecules have a high potential of drug interactions, notably with ARVs, and the influence of patients’ pharmacogenetic background on the intensity of these drug interactions remains to be investigated.

The exploitation of the Swiss HIV Cohort Study (SHCS) Pharmacology database from the National Therapeutic Drug Monitoring Service focusing on new ARVs and anti-HCV drugs will be reinforced by prospective clinical studies realized within the framework of the SHCS, integrating the clinical pharmacokinetics/dynamics and (pharmaco)genetics analysis of first-line antiretroviral regimen in treatment-naïve HIV patients, and of the novel HCV-PI-based therapy in HIV/HCV co-infected patients.

The project aims at responding to clinically relevant therapeutic issues such as the importance of new pharmacogenetics and pharmacokinetics tools for improving the long-term tolerability and response to antiviral treatment, and should open the way to personalized prescription of antiviral drugs. The ultimate goal is the selection of first-line regimens according to patients’ genetic background, and the careful drug dosage adjustment through population pharmacokinetics-based therapeutic drug monitoring.