AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit) begin to cause damage to fat cells (adipose cells) long before physical signs of fat wasting appear, according to findings presented today at the Sixth International Workshop on Lipodystrophy and Adverse Drug Reactions in HIV in Washington DC, USA.
In contrast, patients treated with a nucleoside backbone of abacavir (Ziagen) and 3TC (lamivudine, Epivir) showed no evidence of damage to fat cells.
The thymidine analogues AZT and d4T have been linked to fat loss in several clinical trials and in cohort studies. They are believed to cause fat loss through damage to mitochondria, the structures within cells that generate energy for cellular processes. Specifically, they can reduce mitochondrial function and DNA levels by inhibiting the activity of polymerase gamma.
Recapping on findings presented at last year’s workshop, David Nolan of the Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Australia, said that levels of mitochondrial DNA in adipose tissue biopsies correlated closely with the percentage of leg fat in individuals receiving antiretroviral treatment, and that mitochondrial DNA depletion occurred in the first three to twelve months of treatment.
Updating his group’s findings, David Nolan reported on what is now a substantial cohort of patients who have undergone fat biopsies. One hundred and three patients have contributed 147 fat biopsies. Forty-one treatment-naïve patients have been studied, together with 38 AZT-treated patients and 30 d4T-treated patients. The cohort has also gathered data from 24 patients who have started treatment with nucleoside analogue backbones that do not include AZT or d4T, reflecting a growing trend towards avoidance of thymidine analogues in first line HIV treatment.
The mean mitochondrial DNA level at baseline in treatment-naïve patients was 1427 copies per cell, with no significant difference according to race, CD4 percentage or gender.
Amongst patients treated with AZT or d4T, mitochondrial DNA levels in adipose tissue declined by at least 60% within six to twelve months and this change was statistically significant in comparison to treatment-naïve patients (d4T, p = 0.005; AZT, p = 0.02).
In contrast, patients who commenced treatment with an abacavir-containing regimen that excluded AZT (n = 17) showed no significant reduction in mitochondrial DNA levels compared to treatment-naïve patients. Similarly, three patients who commenced tenofovir-containing regimens showed no evidence of mitochondrial DNA reduction.
Discussing the relevance of the results for the development of clinically evident fat loss, David Nolan said, “the mitochondrial DNA change is the triggering event, but the clinical pathology [of fat loss] is a much longer term trend.”
Other data on abacavir and fat loss were also presented to the workshop. Data from the SOLO study of fosamprenavir (Telzir) / ritonavir (Norvir) with abacavir and 3TC show that after 120 weeks of treatment, 170 previously treatment-naïve patients showed an average weight gain of 4kg and a 3.5cm increase in waist circumference but no median change in waist-hip ratio. Eight patients of 161 (5%) reported fat wasting at week 120 and 19% reported fat accumulation.
Nolan D et al. Differential effects of nucleoside reverse transciptase inhibitor (NRTI) regimens on adipocyte mitochondrial DNA depletion in HIV-infected patients. Antivir Ther 9: L11, 2004.
Walmsley S et al. The proportion of patients reporting body fat redistribution was unchanged between week 48 and week 120 in subjects receiving fosamprenavir/ritonavir in Study APV 3005. Antivir Ther 9: L32, 2004.