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Steven van Lelyveld

Tuesday 12 March 2013

New insights into complications and treatment of HIV-1 infection

Promotor: Prof. dr. Andy Hoepelman
Defence: 12 March 2013

In this thesis the complications and treatment of HIV-1 infection in the current era was studied. Life expectancy of HIV-infected patients has increased enormously with the introduction of combination antiretroviral therapy (cART). In line with this observation, we found that the outcome of patients admitted to the intensive care unit has improved accordingly. However, in a nationwide cohort study we found that patients with an inadequate immunological response on cART have a worse clinical outcome, despite viral suppression. Furthermore, clinical, immunological and virological aspects of treatment with maraviroc, a CCR5-antagonist registered for R5-tropic HIV-1 virus, were studied. It was found that this antiretroviral drug is a useful alternative in clinical practice, and initial data point out that maraviroc may even be of benefit in patients infected with a dual-tropic viral population. The CCR5 coreceptor is present on the surface CD4+ T cells and various other cells of the immune system and is suggested to be important in processes such as T cell activation and leucocyte trafficking, next to inhibition of entry of HIV virus in the cell. We therefore investigated whether addition (intensification’) of maraviroc tot the antiretroviral regimen of patients with a suboptimal immunological response on cART despite viral suppression, might have additional immunological effects, such as an increase in CD4 cell count. In the ‘Maraviroc Immune Recovery Study’, a multicenter placebo-controlled trial, no effect of maraviroc intensification of cART on CD4 cell count was found. However, slight effects on CD8+ T cell activation and apoptosis were found, and an observed increase in T cell lifespan in the maraviroc arm was found in a labeling study using D2O. Therefore, further investigations are necessary into the possible immunological effects of maraviroc intensification of cART.