European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142

Abstract

Background: Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants.

Methods: Seven hundred and fifty-seven ART-naive patients were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Nonrandomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white individuals. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup.

Results: Median age was 39 years, 9% were women, and 37, 32, and 30 were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen, respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N = 10) had higher baseline non-HDL cholesterol [160 mg/dl (interquartile range 137-171) vs. 120 mg/dl (104-136); P = 0.005], a decrease in non-HDL cholesterol over 96 weeks [-14% (-20 to 6) vs. +25% (8 to 51); P < 0.001], tended to have more baseline extremity fat, and had more extremity fat loss by DEXA [-13% (-13 to 12) vs. +9% (-13 to 26); P = 0.08] and lipoatrophy (50 vs. 20%; P = 0.04). Haplogroup W (N = 5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat [+35.5% (26.8 to 54.9); P = 0.02].

Conclusions: Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART.

Trial registration: ClinicalTrials.gov NCT00050895.

Figure 1. Median percent changes in (a) extremity fat by DEXA and (b) fasting non-HDL cholesterol from baseline to 48 and 96 weeks after randomization, by mtDNA haplogroup

Dark horizontal line indicates no change. Individual lines represent different haplogroups. Thick lines denote changes within haplogroup I (dashed lines) and combined non-I haplogroups (solid lines). For Figure 1a: P=0.08 for 96-week difference in median percent changes in extremity fat between I and non-I groups; P=0.02 for haplogroup W versus combined non-W haplogroups. Baseline and 96-week DEXA data are also shown in Table 3. For Figure 1b: P<0.001 for 96-week difference in median percent changes in non-HDL cholesterol between I and non-I groups. Sample sizes with available data at each time point are shown above the horizontal axis; individual haplogroup sample sizes with data available at 96 weeks are shown in the haplogroup legend. Note: the total non-I haplogroup sample sizes shown include a single subject belonging to haplogroup V.

Figure 1. Median percent changes in (a) extremity fat by DEXA and (b) fasting non-HDL cholesterol from baseline to 48 and 96 weeks after randomization, by mtDNA haplogroup

Dark horizontal line indicates no change. Individual lines represent different haplogroups. Thick lines denote changes within haplogroup I (dashed lines) and combined non-I haplogroups (solid lines). For Figure 1a: P=0.08 for 96-week difference in median percent changes in extremity fat between I and non-I groups; P=0.02 for haplogroup W versus combined non-W haplogroups. Baseline and 96-week DEXA data are also shown in Table 3. For Figure 1b: P<0.001 for 96-week difference in median percent changes in non-HDL cholesterol between I and non-I groups. Sample sizes with available data at each time point are shown above the horizontal axis; individual haplogroup sample sizes with data available at 96 weeks are shown in the haplogroup legend. Note: the total non-I haplogroup sample sizes shown include a single subject belonging to haplogroup V.

Figure 2. Proportion of subjects with lipoatrophy defined as ≥20% loss of extremity fat by DEXA at 96 weeks (a) overall, and (b) among those who received thymidine analogue NRTIs zidovudine or stavudine, by mtDNA haplogroup

Individual haplogroup sample sizes with DEXA data available at 96 weeks are shown beneath the horizontal axis labels. Total N=178 for (a), N=91 for (b). Note: the total non-I haplogroup sample sizes shown include a single subject belonging to haplogroup V.

Figure 2. Proportion of subjects with lipoatrophy defined as ≥20% loss of extremity fat by DEXA at 96 weeks (a) overall, and (b) among those who received thymidine analogue NRTIs zidovudine or stavudine, by mtDNA haplogroup

Individual haplogroup sample sizes with DEXA data available at 96 weeks are shown beneath the horizontal axis labels. Total N=178 for (a), N=91 for (b). Note: the total non-I haplogroup sample sizes shown include a single subject belonging to haplogroup V.