North-South collaboration in clinical pharmacological research of HIV treatment.

Abstract

This thesis presents the first output of a North-South (Europe-Africa) collaboration in clinical pharmacological research of HIV treatment. Pharmacokinetics of antiretroviral drugs are highly variable in the paediatric population as children mature and grow rapidly and individually until they are adults. Generic fixed dose combination tablets for HIV-infected adults are not well suited for children. It was demonstrated that recently developed generic paediatric tablets with an adjusted ratio of antiretroviral drugs are appropriate for HIV-infected children in Africa. Future efforts should be made to expand the development of affordable generic paediatric formulations. A simple and inexpensive thin layer chromatography assay was developed for the detection of subtherapeutic nevirapine concentrations in saliva of African HIV-infected adults. It is an attractive alternative to high-performance liquid chromatography for therapeutic drug monitoring of nevirapine in resource-limited settings. Single-dose nevirapine to prevent mother-to-child transmission of HIV is associated with the development of nevirapine resistance, probably due to its long elimination half-life. Three regimens with enzyme inducers (single 400-mg dose of carbamazepine, 184mg phenytoin once daily for 3 or 7 days) significantly reduced nevirapine half-life in healthy non-pregnant women. These interventions should be tested in the African setting of single-dose nevirapine for the prevention of mother-to-child transmission of HIV to reduce the development of nevirapine resistance. A high incidence of adverse events was reported in 11 healthy volunteers treated with a higher than standard dose of the new lopinavir/ritonavir tablets in combination with rifampicin. An adequately powered prospective study in HIV-tuberculosis co-infected patients is needed to investigate the consequence of inferior lopinavir exposure due to non-adjusted doses of lopinavir/ritonavir and to determine the tolerability of recommended increased doses