Switch & simplification of antiretroviral therapy

Abstract

The advent of combined antiretroviral therapy (cART) has transformed HIV care such that most individuals can expect a normal or near normal life expectancy. Managing HIV is increasingly focused on the prevention and treatment of non-infectious co-morbidities and dealing with drug-related side effects and toxicities, the main reasons for switching cART. Switching cART can be complicated by pharmacokinetic (PK) interactions and modern, potent agents may allow us to move away from the standard ‘three active drugs’ mantra. This thesis examines the pharmacokinetic impact of switching directly from efavirenz, widely used for initial therapy, to etravirine and to maraviroc. The impact of efavirenz to etravirine switch on central nervous system side effects was also investigated in a double-blind trial. In addition the value of pre-treatment tropism testing to guide susceptibility to maraviroc is explored. Finally a large cohort analysis explored the importance of active nucleoside analogues in a boosted protease inhibitor based, second line regimen for patients who had failed first line non-nucleoside reverse transcriptase inhibitor therapy. The pharmacokinetic studies confirmed a prolonged induction effect of efavirenz and a novel finding that this induction effect varies according to which agent is used. The tropism analysis showed that tropism switch during suppressive therapy is uncommon thus supporting the use of pre-treatment testing as a guide to future switch. Individuals with ongoing central nervous symptoms on efavirenz experienced significant improvement in switch to etravirine, the first time this has been proven in a randomised, blinded trial; furthermore significant lipid improvements were observed. Finally the cohort analysis suggested that the number of new or active nucleosides in a second line boosted PI-based combination does not affect virological outcomes; simpler second line regimens should be considered and could provide several advantages over more complex choices.