Toxicities associated with antiretroviral treatment of HIV-1

Abstract

Background: Despite the success of antiretroviral treatment (ART) in human immunodeficiency virus (HIV), the associated toxicities are complex to manage and compromise treatment benefits. Prevention and treatment of chronic toxicities such as cardiovascular disease (CVD), metabolic disorders, lipodystrophy, and osteoporosis are essential to ensure patient well being. This thesis aimed to provide more information on these toxicities in two clinical trial settings. Methods: Three sub-studies of the STEAL clinical trial examined the toxicities associated with ABC/3TC and TDF/FTC. The first study compared cardiovascular safety profiles of the two ART by examining CVD biomarkers. The second identified baseline predictors of limb fat recovery. A final study identified specific HLA genotypes associated with body composition changes. The final chapters of the thesis examined ART toxicities in HIV participants failing their first-line therapy in the SECONDLINE study. Lipodystrophy, metabolic disturbances, cardiovascular risk and bone mineral density were examined in participants randomised to either 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) plus lopinavir/ritonavir (LPV/r) or to raltegravir plus LPV/r. Results: The primary STEAL study was the first randomised controlled trial to support the finding that ABC was associated with adverse cardiovascular affects. We found there were no consistent differences in biomarker levels of immune activation, coagulopathic disorders or endothelial dysfunction as a biological explanation for this adverse effect. Limb fat gain was similar with both ABC/3TC and TDF/FTC treatment and the baseline predictors of greater limb fat gain were thymidine N(t)RTI use, high glucose, high interleukin 6 and low limb fat. The HLA analysis demonstrated that participants carrying one or more of the HLA supertypes A01, B08 and DQ2 may be resistant to thymidine analogue-induced lipoatrophy. SECONDLINE study participants switching to LPV/r plus raltegravir improved limb fat similar to the N(t)RTI plus LPV/r regimen, but worsened total:HDL cholesterol ratio over 48 weeks. In addition, LPV/r plus raltegravir was associated with less bone loss that the LPV/r plus 2-3 N(t)RTI. Thereby demonstrating that raltegravir may be a safe alternative to standard second-line therapy. Conclusion: Endeavours to understand treatment-related toxicities are important initiatives to assist with long-term, effective use of ART in HIV infected individuals.