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ART Reduces Inflammation Overall, but Tenofovir and Abacavir Have Different Effects

Some inflammation-associated biomarkers decreased among people with HIV who started combination antiretroviral therapy (ART) regardless of regimen, but others -- including CRP and IL-6 -- were affected differently by different drug regimens, researchers reported in the July 17, 2012, issue of AIDS.

Ever since the SMART treatment interruption trial showed in 2006 that HIV positive people who stop ART have a higher risk of non-AIDS cardiovascular, liver, and kidney disease, scientists have extensively studied how HIV and its treatment can influence chronic inflammation.

Some researchers have suggested that inflammation might help explain the greater risk of heart attacks among people taking abacavir (Ziagen, also in the Epzicom coformulation) that has seen in some -- but far from all -- studies.

Grace McComsey from Case Western Reserve University and colleagues looked at the effects of specific antiretroviral drugs on inflammation biomarkers in ACTG A5224, a sub-study of the larger A5202 trial.

In A5202, previously untreated HIV positive participants were randomly assigned to receive abacavir/lamivudine (the drugs in Epzicom) or tenofovir/emtricitabine (the drugs in Truvada), both with either open-label efavirenz (Sustiva) or ritonavir-boosted atazanavir (Reyataz).

This sub-analysis included 244 participants. Most (85%) were men, about half were white, and median age was 39 years. At baseline the median HIV RNA level was 4.6 log copies/mL and the median CD4 T-cell count was 240 cells/mm³.

The sub-study compared changes in the abacavir/lamivudine and tenofovir/emtricitabine arms from baseline to weeks 24 and 96 in various markers associated with inflammation, coagulation (blood clotting), and immune response, including tumor necrosis factor-alpha (TNF-alpha), soluble tumor necrosis factor receptor (sTNFR) I and II, soluble vascular cell adhesion molecule 1 (sVCAM-1), solubleintercellular adhesion molecule 1 (sICAM-1), high-sensitivityC-reactive protein (hsCRP), and interleukin 6 (IL-6).

Results

• Levels of TNF-alpha, sTNFR-, sTNFR-II, sVCAM-1, and sICAM-1 decreased significantly at weeks 24 and 96 across the board, with no significant differences between drug regimens.
• At week 24, people taking abacavir/lamivudine had a greater mean increase in hsCRP levels compared with those taking tenofovir/emtricitabine (1.43 vs 0.88, respectively); similar results were seen at week 96.
• At week 24, people taking efavirenz had a greater mean rise in hsCRP than those taking boosted atazanavir (1.41 vs 0.88, respectively), though the difference was no longer significant at week 96.
• At week 24, IL-6 levels decreased significantly among patients taking tenofovir/emtricitabine, but not among those taking abacavir/lamivudine; by week 96, IL-6 had decreased significantly in people taking both NRTI combinations.
• IL-6 changes were not significantly different between participants taking efavirenz or boosted atazanavir at either time point.

"Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens," the study authors concluded. "Differences were seen on hsCRP and IL-6 changes with [abacavir/lamivudine] vs [tenofovir/emtricitabine] and on hsCRP with efavirenz vs [atazanavir/ritonavir].

"Our study supports the findings of earlier studies that initiation of effective ART results in an overall decrease in inflammation markers, with the exception of hsCRP, which remains unchanged or even increases," they elaborated in their discussion. "The reason hsCRP behaves differently from other markers remains elusive, with one potential explanation being HIV-associated subclinical hepatocyte [liver cell] dysfunction, as CRP is mainly produced by hepatocytes in response to IL-6."

The study was too small to meaningfully compare clinical outcomes, but the 2 participants who had myocardial infarctions were taking tenofovir/emtricitabine plus efavirenz, which some experts assume to be the more heart-healthy regimen.

7/6/12

Reference

GA McComsey, D  Kitch, ES Daar, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir: ACTG A5224s, A5202 substudy. AIDS 26(11):1371-1385. July 17, 2012.