Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229

Abstract

BACKGROUND Lipoatrophy is prevalent on thymidine NRTIs (tNRTI). A pilot trial showed that uridine (NucleomaxX®) increased limb fat. METHODS A5229 was a multicenter trial in which HIV-infected individuals with lipoatrophy on tNRTI-regimens were randomized to NucleomaxX or placebo. Primary endpoint was change in limb fat from baseline to week-48. The study was powered to detect 400-gram difference between arms at week-48. A stratified Wilcoxon rank-sum test was used to assess between-arm differences. RESULTS The 165 subjects were 91% male, 62% white; median age 49 years, CD4 506 cells/mm3, and limb fat 3037 grams; 81% had HIV-1 RNA ≤50 copies/mL; 76% were on AZT. Baseline characteristics were similar between groups. Only 59% completed 48-weeks of treatment, however only 3 subjects (1 on uridine) discontinued due to toxicity (diarrhea). In intent-to-treat, there was no difference for changes in limb fat between treatments at week-24 or week-48. On as-treated analysis, uridine resulted in an increase in %limb fat vs. placebo (3.4% vs. −0.8%, p=0.01) at week-24 but not at week-48 (1.8% vs.3.8%, p=0.93). Similar results were seen when limiting the analysis to subjects with ≥80% adherence. The results were not related to severity of lipoatrophy or type of tNRTI. No changes were found in facial-anthropometrics, fasting lipids, trunk-fat, CD4, or HIV-RNA. CONCLUSIONS We found a modest transient improvement in limb fat after 24 weeks of uridine. The lack of sustained efficacy at week-48 was not due to changes in adherence or reduction in sample size. Uridine was safe and did not impair virologic control.

Management of the metabolic effects of HIV and HIV drugs

“…38 Despite these results and positive pilot data, 39 two large, randomized clinical trials have shown no benefit of a uridine-rich supplement for the treatment of lipoatrophy in HIV-infected individuals. 40,41 Similarly, the unexpected benefits of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, pravastatin, on extremity fat recovery in a small, randomized clinical trial 42 were not confirmed in two more recent randomized clinical trials. 40,43 Neither uridine nor pravastatin can, therefore, be recommended for the treatment of lipoatrophy.…”

New and emerging agents in the management of lipodystrophy in HIV-infected patients

“…Furthermore, in contrast to in vitro data, NucleomaxX supplementation did not lead to changes in fat or blood mitochondrial DNA levels 148. These promising data on lipoatrophy improvement are not fully confirmed in a larger prospective, randomized, placebo-controlled multicenter trial (ACTG study A5229) 149. In this study, the results demonstrate that in HIV lipoatrophy, despite a small increase in limb fat after 24 weeks with as-treated analysis, the effect was not sustained through 48 weeks of uridine 111,149…”

Quality of life outcomes associated with treatment of human immunodeficiency virus (HIV) facial lipoatrophy

“…The median DLQI score at baseline was 16 (range: [13][14][15][16][17][18][19]. After 12 months of treatment, the median DLQI score was 9 (range: [6][7][8][9][10][11][12][13][14], corresponding with a reduction in impairment of 43.75% (P < 0.05). 26…”

“…Various in vitro studies of cultured adipocytes demonstrated that uridine prevented the adverse effects of pyrimidine analogs, such as mitochondrial DNA depletion and resulting adipocyte apoptosis . However, although uridine has been shown to transiently improve limb fat, it has not been shown to affect facial fat …”

“…9 However, although uridine has been shown to transiently improve limb fat, it has not been shown to affect facial fat. 10 Given the significant effect of FLA on QoL, surgical reconstruction and injectable fillers are often used for cosmetic improvement. Poly-L-lactic acid (PLLA) (Sculptra â ; Dermik Laboratories, Inc., Bridgewater, NJ, USA) and calcium hydroxylapatite (CaHA) (Radiesse â ; BioForm Medical, Inc., San Mateo, CA, USA) are currently the only Food and Drug Administration (FDA)-approved fillers for HIV-associated FLA (HIV FLA).…”