Effect of Uridine or Pravastatin Treatment for HIV Lipoatrophy in Men
Effect of Uridine or Pravastatin Treatment for HIV Lipoatrophy in Men
Background Lipoatrophy can complicate thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI)-based antiretroviral therapy (ART). Lipoatrophy may be less likely with ART including ritonavir-boosted lopinavir (LPV/r). Small, placebo-controlled studies found that uridine (in tNRTI recipients) and pravastatin improved HIV lipoatrophy over 12 weeks. Today, most patients with lipoatrophy receive non-tNRTI-based ART; the effect of uridine in such patients is unknown.
Methods We performed a prospective, randomized trial in lipoatrophic adults with plasma HIV RNA<50 HIV-1 RNA copies/mL on tNRTI-sparing ART including LPV/r. Patients received uridine [36 g three times a day (tid) on 10 consecutive days per month; n=10], pravastatin [40 mg every night (nocte); n=12], uridine plus pravastatin (n=11) or neither (n=12) for 24 weeks. The primary endpoint was mean change in limb fat mass as assessed by dual-energy X-ray absorptiometry (DEXA). With 20 patients per intervention, the study had 80% power to detect a mean difference between a treatment and the control of 0.5 kg, assuming a standard deviation of 0.9 and an alpha threshold equal to 5% (two-sided).
Results Of 45 participants (all men, with median age 49.5 years and median limb fat 2.6 kg), two discontinued pravastatin and one participant stopped both pravastatin and uridine. The difference between the mean changes in limb fat mass for uridine vs. no uridine was 0.03 kg [95% confidence interval (CI) −0.35, +0.28; P=0.79]. The respective difference for pravastatin was −0.03 kg (95% CI −0.29, +0.34; P=0.84). Pravastatin slightly decreased total cholesterol (0.44 mmol/L; P=0.099). Visceral adipose tissue measured by computed tomography did not change significantly.
Conclusion In this population and at the doses used, neither uridine nor pravastatin for 24 weeks significantly increased limb fat mass.
HIV lipodystrophy is characterized by subcutaneous lipoatrophy in the face, arms, legs and buttocks and relative central fat accumulation (lipohypertrophy) in the neck, breasts and abdomen. Thymidine-based nucleoside reverse transcriptase inhibitor (tNRTI)-associated mitochondrial toxicity is implicated in lipoatrophy. Mitochondrial DNA polymerase-γ is inhibited by some NRTIs (mainly tNRTIs) and thus causes depletion of mtDNA-encoded enzymes, resulting in mitochondrial dysfunction. tNRTIs can also deplete adipose mitochondrial RNA. Lipoatrophy can be largely prevented through the use of drugs such as abacavir, lamivudine, tenofovir, emtricitabine and ritonavir-boosted lopinavir (LPV/r), but existing strategies for the treatment of lipodystrophy have produced disappointing results: switching from a tNRTI to a non-tNRTI produced only modest improvements in limb fat mass over 2 years; reconstructive surgery with poly-l-lactic acid is transiently effective but costly; and thiazolidinedione therapy failed to show efficacy in published, randomized trials.
Uridine is a pyrimidine precursor and so might replenish intracellular pyrimidine pools. In vitro, uridine abrogates the mitochondrial toxicity to adipocytes and hepatocytes of the tNRTIs stavudine (d4T) and zidovudine (ZDV), but not didanosine. Uridine supplementation increased limb fat by 0.9 kg relative to placebo over 12 weeks in lipoatrophic adults receiving a tNRTI, an increase far greater and more rapid than observed after replacement of the tNRTI with another drug. A small, nonrandomized study found that uridine supplementation for 32 weeks was well tolerated, did not affect HIV viral load, and was associated with a subjective improvement in lipoatrophy. However, the question of whether uridine increases limb fat mass in patients no longer receiving a tNRTI remains unanswered.
Another promising agent is pravastatin. Limb fat and subcutaneous abdominal fat increased significantly after 12 weeks of treatment with pravastatin 40 mg every night (nocte) in HIV-infected men with hypercholesterolaemia; the magnitude of the increase was not related to its cholesterol-lowering effect, suggesting a mechanism independent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This unexpected effect was not observed, however, in another randomized study.
We assessed the safety and efficacy of uridine and pravastatin in HIV-infected adults receiving an LPV/r-containing antiretroviral regimen with moderate-to-severe subcutaneous lipoatrophy despite cessation of tNRTI therapy.
Abstract and Introduction
Abstract
Background Lipoatrophy can complicate thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI)-based antiretroviral therapy (ART). Lipoatrophy may be less likely with ART including ritonavir-boosted lopinavir (LPV/r). Small, placebo-controlled studies found that uridine (in tNRTI recipients) and pravastatin improved HIV lipoatrophy over 12 weeks. Today, most patients with lipoatrophy receive non-tNRTI-based ART; the effect of uridine in such patients is unknown.
Methods We performed a prospective, randomized trial in lipoatrophic adults with plasma HIV RNA<50 HIV-1 RNA copies/mL on tNRTI-sparing ART including LPV/r. Patients received uridine [36 g three times a day (tid) on 10 consecutive days per month; n=10], pravastatin [40 mg every night (nocte); n=12], uridine plus pravastatin (n=11) or neither (n=12) for 24 weeks. The primary endpoint was mean change in limb fat mass as assessed by dual-energy X-ray absorptiometry (DEXA). With 20 patients per intervention, the study had 80% power to detect a mean difference between a treatment and the control of 0.5 kg, assuming a standard deviation of 0.9 and an alpha threshold equal to 5% (two-sided).
Results Of 45 participants (all men, with median age 49.5 years and median limb fat 2.6 kg), two discontinued pravastatin and one participant stopped both pravastatin and uridine. The difference between the mean changes in limb fat mass for uridine vs. no uridine was 0.03 kg [95% confidence interval (CI) −0.35, +0.28; P=0.79]. The respective difference for pravastatin was −0.03 kg (95% CI −0.29, +0.34; P=0.84). Pravastatin slightly decreased total cholesterol (0.44 mmol/L; P=0.099). Visceral adipose tissue measured by computed tomography did not change significantly.
Conclusion In this population and at the doses used, neither uridine nor pravastatin for 24 weeks significantly increased limb fat mass.
Introduction
HIV lipodystrophy is characterized by subcutaneous lipoatrophy in the face, arms, legs and buttocks and relative central fat accumulation (lipohypertrophy) in the neck, breasts and abdomen. Thymidine-based nucleoside reverse transcriptase inhibitor (tNRTI)-associated mitochondrial toxicity is implicated in lipoatrophy. Mitochondrial DNA polymerase-γ is inhibited by some NRTIs (mainly tNRTIs) and thus causes depletion of mtDNA-encoded enzymes, resulting in mitochondrial dysfunction. tNRTIs can also deplete adipose mitochondrial RNA. Lipoatrophy can be largely prevented through the use of drugs such as abacavir, lamivudine, tenofovir, emtricitabine and ritonavir-boosted lopinavir (LPV/r), but existing strategies for the treatment of lipodystrophy have produced disappointing results: switching from a tNRTI to a non-tNRTI produced only modest improvements in limb fat mass over 2 years; reconstructive surgery with poly-l-lactic acid is transiently effective but costly; and thiazolidinedione therapy failed to show efficacy in published, randomized trials.
Uridine is a pyrimidine precursor and so might replenish intracellular pyrimidine pools. In vitro, uridine abrogates the mitochondrial toxicity to adipocytes and hepatocytes of the tNRTIs stavudine (d4T) and zidovudine (ZDV), but not didanosine. Uridine supplementation increased limb fat by 0.9 kg relative to placebo over 12 weeks in lipoatrophic adults receiving a tNRTI, an increase far greater and more rapid than observed after replacement of the tNRTI with another drug. A small, nonrandomized study found that uridine supplementation for 32 weeks was well tolerated, did not affect HIV viral load, and was associated with a subjective improvement in lipoatrophy. However, the question of whether uridine increases limb fat mass in patients no longer receiving a tNRTI remains unanswered.
Another promising agent is pravastatin. Limb fat and subcutaneous abdominal fat increased significantly after 12 weeks of treatment with pravastatin 40 mg every night (nocte) in HIV-infected men with hypercholesterolaemia; the magnitude of the increase was not related to its cholesterol-lowering effect, suggesting a mechanism independent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This unexpected effect was not observed, however, in another randomized study.
We assessed the safety and efficacy of uridine and pravastatin in HIV-infected adults receiving an LPV/r-containing antiretroviral regimen with moderate-to-severe subcutaneous lipoatrophy despite cessation of tNRTI therapy.