Efficacy and adverse outcomes of combination antiretroviral therapy in HIV-1-infected adults

Abstract

Current estimates of combination antiretroviral therapy (cART) efficacy are founded upon randomised studies typically of less than two yearsâ duration, and do not mark long-term, non-AIDS morbidities (e.g. cardiovascular, renal, and liver disease, diabetes, cancer), which remain more common in HIV-infected persons and are associated with chronic exposure to some antiretroviral drugs.

This thesis reviews existing knowledge of cART efficacy and non-AIDS morbidities, with two broad aims for its original research components: (1) evaluate the evidence for efficacy and adequacy of harms reporting amongst studies of initial cART; and (2) investigate novel toxicities for the current â Preferredâ antiretrovirals atazanavir, darunavir, and raltegravir.

A meta-analysis of initial cART studies showed improved mean efficacy between 1994 and 2010 (43% to 78%), but durability remains a concern, with participant decision and adverse events responsible for treatment interruption in almost 20% of patients. Drug selection (favouring integrase strand transfer inhibitors and tenofovir-emtricitabine) is a key determinant of greater efficacy, as is lower pre-treatment plasma viral load. A second meta-analysis of published initial cART studies showed inadequate harms reporting by published cART studies: deaths, AIDS, serious non-AIDS and serious adverse events were reported by 83%, 53%, 25%, and 42% of studies, respectively â frequencies which remain mostly unchanged over time.

In a randomised study of HIV-negative adults, no difference was found between the post-prandial lipid effects of atazanavir/ritonavir and darunavir/ritonavir, suggesting it is not a mechanism for greater cardiovascular risk. Atazanavir/ritonavir elicited lower post-prandial arterial stiffness, which may contribute to its cardiovascular-neutral risk profile. In contrast, a cross-sectional assessment of cART-experienced patients found raltegravir to be associated with greater prevalence of skeletal muscle toxicity. Proximal myopathy was a newly-identified toxicity seen with raltegravir, but was relatively uncommon (4%).

Clinical events remain relevant â and necessary â to providing a true assessment of cART benefits and harms. Recording reasons for why patients elect to interrupt treatment and reporting all clinical harms will improve cART durability. Organ-specific toxicities may not become evident for years post-approval, and are unaccounted for by current methods of determining efficacy. New cART drugs require continuing evaluation for their contribution to long-term harmful outcomes.