Predicting adverse events during therapy for HIV and hepatitis C : the role of ITPase activity and ITPA genotype

The general aim of this thesis is to investigate the influence of the ITPA genetic SNPs 94C>A and 124+21A>C and the activity of the enzyme ITPase on the occurrence of adverse events during treatment for the infectious diseases HCV and HIV. While ITPA SNPs were previously found to be protective against hemolytic anemia during therapy with ribavirin for HCV, it is not clear to what extent other SNPs contribute to ITPase activity. Therefore, in Chapter 2, ITPase activity is compared with ITPA genotype for prediction of anemia during ribavirin use for HCV. In HIV-infected patients the ITPase activity in erythrocytes was found to be decreased compared to a population not infected with HIV. As leukocytes are the main target cells for HIV-infection, in Chapter 3 the expression of the ITPase protein in leukocytes and leukocyte subpopulations is explored in association with ITPA genotype. The results in HIV-infected patients are compared to a non-HIV infected population. As the current therapy for HIV is highly effective, the main obstacle for treatment nowadays is adverse events during cART. In Chapter 4, we investigate the association of ITPase activity and ITPA genotype with the occurrence of adverse events during combination antiretroviral therapy for HIV. One of the most important adverse drug events during tenofovir use is nephrotoxicity. In order to test if ITPase activity and ITPA genotype could be used as a biomarker to predict nephrotoxicity during tenofovir use for HIV,these parameters are determined and compared in HIV-infected patients with and without nephrotoxicity, in Chapter 5. Other important aspects brought on by the current effective HIV therapy, are long term consequences of cART and increasing diseases of older age, one of them being cardiovascular diseases. The association of ITPase activity and ITPA genotype with the occurrence of cardiovascular diseases and metabolic events during cART for HIV-infection is further explored in Chapter 6. To further unravel effects caused by HIV-infection itself and effects caused by cART, in Chapter 7, basic cell metabolomics of untreated HIV-infected patients are compared to a control population (the effect of HIV-infection). In addition metabolomics data prior to start of cART were compared to 12 months of therapy successfully suppressing HIV replication (the effect of cART). In Chapter 8 the results of these studies are discussed with respect to future perspectives.

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