BOSTON — Elevations in inflammatory and coagulation biomarkers may explain the increased risk of cardiovascular disease and death in HIV-infected patients randomized to the treatment interruption arm of an international treatment strategy trial.
The Strategies for Management of Antiretroviral Therapies (SMART) trial was initiated in 2002 to compare CD4-cell-guided structured treatment interruptions with continuous antiretroviral therapy. The trial was halted in 2006 when interim data showed that patients randomized to intermittent therapy not only had significantly higher rates of AIDS-related opportunistic illnesses, but also of cardiovascular disease (CVD) and all-cause mortality, compared with patients on continuous therapy, Dr. Lewis Kuller said at the 15th Conference on Retroviruses and Opportunistic Infections.
To explore the possible mechanisms underlying the increased CVD risk, Dr. Kuller, of the University of Pittsburgh, and his colleagues in the SMART Study Group conducted a nested case-control analysis evaluating biomarkers that have been associated with mortality and CVD in the general population.
The investigators paired each of 85 SMART patients (55 in the treatment interruption group and 30 in the continuous therapy group) who died through 2006 with two age-, gender-, and country-matched controls from the remaining patient population. Estimating adjusted odds ratios for the fourth versus first quartile of each biomarker using logistic regression, they compared baseline and 1-month levels of four inflammatory makers (high-sensitivity C-reactive protein, interleukin-6, serum amyloid A, and amyloid P) and two coagulation markers (D-dimer and prothrombin fragment 1+2), Dr. Kuller said.
Compared with baseline, the 1-month D-dimer and interleukin-6 levels increased by 16% and 30%, respectively, among patients on intermittent treatment, and the progressive increases were directly related to increases in HIV viral load after treatment interruption. In contrast, the levels of both biomarkers remained stable in the continuous treatment arm. Mortality was strongly related both to baseline levels of these two biomarkers in the treatment interruption and continuous therapy groups, as well as to the progressive increases that occurred after treatment interruption, “with odds ratios greater than 12 for those in the fourth vs. first quartile,” Dr. Kuller said.
Calling the relationship between the increased levels of these two biomarkers and mortality risk “extraordinary,” Dr. Kuller noted that the association was far greater than that seen in general population studies of cardiovascular risk factors. “The findings indicate that elevated levels of D-dimer and interleukin-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups, and the increases in both markers may partly explain the increased risk of mortality and CVD in the treatment interruption group,” he said at the conference, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.
The associations between the biomarkers and CVD were modest but significant, Dr. Kuller said.