Pathogenesis and Treatment of HIV Infection

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Increased D-dimer concentrations are associated with poor cardiovascular and other clinical outcomes in people with treated HIV infection. Proteinase activated receptor-1 (PAR-1) is activated by thrombin and overexpressed by immune cells from HIV-infected people. We studied the efficacy of vorapaxar, a licensed inhibitor of PAR-1, in reducing HIV-associated hypercoagulation and inflammation in the ADVICE (Vorapaxar for HIV-associated inflammation and coagulopathy) trial. We randomly assigned 65 participants (1:1) with HIV-1 infection on stable antiretroviral therapy and with D-dimer levels greater than 200 ng/ml to receive vorapaxar or matched placebo for 12 weeks. The primary endpoint was treatment group difference in changes from baseline D-dimer concentrations after 8-12 weeks of treatment. D-dimer concentrations after 8-12 weeks of treatment did not differ significantly between groups (difference -002 log10 ng/mL, 95% CI -010 to 005; p=056). Vorapaxar treatment was safe and well tolerated in this cohort. Thus, despite being an attractive hypothesis, vorapaxar had no effect on D-dimer concentrations in HIV-infected patients receiving stable antiretroviral therapy but at risk of poor outcomes. Alternative approaches are needed to reduce hypercoagulation, inflammation, and adverse long-term outcomes in patients with treated HIV infection. Among 20 highly treatment experienced people with HIV with extensive antiretroviral drug resistance and high levels of self-reported adherence, an inpatient 8-day directly observed therapy confirmed nonadherence as the major cause of virologic failure for 9/20 (45%) participants, preventing unnecessary regimen changes that could jeopardize future treatment options. The impact of variation in host genetics on replication of HIV-1 in demographically diverse populations remains uncertain. We performed a genome-wide screen for associations of single nucleotide polymorphisms (SNP) to viral load (VL) in antiretroviral therapy-nave participants (n=2,440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed human leukocyte antigen (HLA) alleles and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex (MHC) class I region with effect sizes ranging between 0.14-0.39 log10 VL. Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the MHC I region is a major host determinant of HIV-1 control with shared genetic variants across diverse populations.