Comparison of oxidative stress markers in HIV‐infected patients on efavirenz or atazanavir/ritonavir‐based therapy

Abstract

IntroductionChronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies.Materials and MethodsCohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests.Results145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference −16.3 [CI 95%: −31.4, −1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference −21.8 [−38.0, −5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated.ConclusionsIn virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.

Changes in Plasma Levels of Oxidized Lipoproteins and Lipoprotein Subfractions with Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy and Associations with Common Carotid Artery Intima-Media Thickness: ACTG 5260s

“…We found that LDLox increased in all three-treatment regimens (even in the ATV/r group) after 96 weeks of ART. As previously noted, patients on ATV/r have been shown to have lower increase in LDLox relative to those on EFV[29]. These data and our findings that ATV/r did not reduce plasma LDLox (despite that elevated bilirubin may have a beneficial role in counteracting oxidative stress[29]), suggest that the differential effects of ART on LDLox may be more complex than initially thought.…”

“…Notably, in placebo-controlled trial that evaluated the effect of rosuvastatin in HIV-infected adults on stable ART with LDL less than 130 mg/dl and increased inflammation, LDLox levels increased after initially declining and were not different from placebo at week 48, suggesting that LDLox was influenced by some unclear mechanism in treated and suppressed patients with HIV[28]. A prospective cohort of virologically suppressed HIV-infected patients on stable ATV/r versus efavirenz (EFV)-based first-line therapies also found an increase (compared to baseline before ART) in LDLox in both ATV/r- and EFV- based regimens[29]. In addition, it has been shown that LDLox levels are increased in HIV Infection and may drive monocyte activation[17].…”

Serum activities of oxidative burst enzymes in HIV infected subjects

“…The observation of significantly lower activities of CAT (p < 0.02) and MPO (p < 0.05) in HIV positive HAART naïve subjects compared with the control subjects is consistent with previous studies [12,27,28]. Ibeh et al [12] reported that superoxide dismutase (SOD) and CAT activities were significantly lower (p < 0.05) in HAART naïve subjects than the subjects on HAART and controls.…”

Atazanavir and Cardiovascular Risk Among Human Immunodeficiency Virus-Infected Patients: A Systematic Review

“…Multiple studies have shown that individuals with Gilbert syndrome, a genetic deficiency in UGT1A1 resulting in chronic low level hyperbilirubinemia, have a reduced risk for CV events compared with the general population [35–38]. ATV has been shown to increase bilirubin levels and reduce levels of oxidative stress in HIV-infected patients compared with non-ATV-based treatment [23, 39]. Additional studies have also linked increasing bilirubin levels with slower atherosclerosis progression (as measured by cIMT) [14, 40], which suggests that there may be a relationship between ATV therapy, bilirubin levels and improvements in oxidative stress, atherosclerosis, and CV risk.…”