Initial antiretroviral therapy regimen and risk of heart failure.

OBJECTIVES: Heart failure risk is elevated in people with HIV (PWH). We investigated whether initial antiretroviral therapy (ART) regimens influenced heart failure risk. DESIGN: Cohort study. METHODS: PWH who initiated an ART regimen between 2000 and 2016 were identified from three integrated healthcare systems. We evaluated heart failure risk by protease inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTI), and integrase strand transfer inhibitor (INSTI)-based ART, and comparing two common nucleotide reverse transcriptase inhibitors: tenofovir disoproxil fumarate (tenofovir) and abacavir. Follow-up for each pairwise comparison varied (i.e. 7 years for protease inhibitor vs. NNRTI; 5 years for tenofovir vs. abacavir; 2 years for INSTIs vs. PIs or NNRTIs). Hazard ratios were from working logistic marginal structural models, fitted with inverse probability weighting to adjust for demographics, and traditional cardiovascular risk factors. RESULTS: Thirteen thousand six hundred and thirty-four PWH were included (88% men, median 40 years of age; 34% non-Hispanic white, 24% non-Hispanic black, and 24% Hispanic). The hazard ratio (95% CI) were: 2.5 (1.5-4.3) for protease inhibitor vs. NNRTI-based ART (reference); 0.5 (0.2-1.8) for protease inhibitor vs. INSTI-based ART (reference); 0.1 (0.1-0.8) for NNRTI vs. INSTI-based ART (reference); and 1.7 (0.5-5.7) for tenofovir vs. abacavir (reference). In more complex models of cumulative incidence that accounted for possible nonproportional hazards over time, the only remaining finding was evidence of a higher risk of heart failure for protease inhibitor compared with NNRTI-based regimens (1.8 vs. 0.8%; P  = 0.002). CONCLUSION: PWH initiating protease inhibitors may be at higher risk of heart failure compared with those initiating NNRTIs. Future studies with longer follow-up with INSTI-based and other specific ART are warranted.

Towards depersonalized abacavir therapy: chemical modification eliminates HLA-B*57 : 01-restricted CD8+ T-cell activation.

OBJECTIVE: Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57 : 01 and activate T cells. DESIGN: An interdisciplinary laboratory study using samples from human donors expressing HLA-B57 : 01. Researchers were blinded to the analogue structures and modelling data. METHODS: Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive CD8 clones were generated to study the association between HLA-B57 : 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed. RESULTS: Major histocompatibility complex class I-restricted CD8 clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B57 : 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding and the T-cell response. CONCLUSION: These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.

Macrocytosis is a predictor of resting lactate concentrations in persons on dideoxynucleoside therapy for HIV infection.

OBJECTIVES: Mitochondrial toxicity is an important toxicity of antiretroviral therapy and may manifest as elevated blood lactate. Macrocytosis has been hypothesized to act as a marker of mitochondrial toxicity in persons with HIV infection. As part of a larger study on markers of mitochondrial toxicity we evaluated the relationship between resting lactate and erythrocyte mean corpuscular volume (MCV). METHODS: We studied the effect of micronutrient supplementation on lactate metabolism in three groups: those with HIV on and not on dideoxynucleoside-containing antiretroviral therapy and those without HIV. As part of the study we measured resting lactate and erythrocyte MCV after a 14-h fast. RESULTS: Erythrocyte MCV was significantly higher among the 11 participants on antiviral therapy (109.3 femtoliters (fl)) compared to five controls without HIV (89.3 fl) and four controls with HIV not on antiviral therapy (88.3 fl). In addition a strong predictive relationship was seen between MCV and resting lactate (R(2)=0.548, p<0.01). CONCLUSIONS: Macrocytosis may be a marker of treatment-related mitochondrial dysfunction in persons on treatment for HIV. Evaluating patients for early evidence of mitochondrial dysfunction in resource-constrained settings could be facilitated by this marker.

HLA-B*5701 screening for susceptibility to abacavir hypersensitivity.

The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.