Background:  Switch studies have demonstrated that lipoatrophy improves modestly when the thymidine analogue NRTI (tNRTI) is removed. Pilot short trials showed that uridine supplementation (as NucleomaxX^®) improves lipoatrophy, but the pathogenesis and sustainability of these findings remain uncertain. We compared uridine supplementation in the form of NucleomaxX^® to tNRTI switch to TDF in subjects with lipoatrophy on tNRTI.

Methods:  All subjects at baseline had lipoatrophy and were on a d4T or AZT-containing regimen with HIV-1 RNA <400 copies/mL. A randomized, open-label, 48-week study switched patients from the tNRTI to TDF or added uridine (while continuing tNRTI). Baseline and 48 week endpoints were limb fat by DEXA scan, subcutaneous abdominal fat mtDNA and mtRNA, peripheral blood mononuclear cell mtDNA, plasma inflammation markers (sTNF receptors, hsCRP, and IL-6), bone mineral density of the hip and lumbar spine, HIV-1 RNA, CD4 counts, and fasting metabolic parameters.

Results:  Fifty subjects enrolled (n = 24 TDF-switch; 26 uridine). Median age was 48 years; 50% white; 80% males; median limb fat 4494 grams; 80% were receiving AZT at entry. Baseline characteristics were similar between groups. In TDF-switch arm, fat mtDNA, PBMC mtDNA, and inflammation markers did not change, although significant increases in mtRNAs (ND1/L13, ND6/L13, CTYB/L13; all P <0.001), limb fat +409 g (IQR -59 to 1155), CD4 count (P =0.03) and decreases in total-and hip-BMD (median -3.3%; IQR -5.1 to 0; P =0.005) were seen. In the uridine arm, mtRNAs increased (all < 0.001), hsCRP and IL-6 increased (both P =0.02), while fat mtDNA decreased without changes in limb fat or PBMC mtDNA. Between-group changes were significant for fat mtDNA (P =0.02), hsCRP (P =0.02), IL-6 (P =0.02), limb fat (P =0.04), and total- and hip- BMD (P =0.002). On the TDF-switch, changes in limb fat negatively correlated with baseline fat mtDNA, tNRTI duration, and with changes in insulin, and positively with baseline insulin, baseline CD4 and changes in fat mtDNA. No correlation was found between changes in limb fat and those of fat mtRNA, PBMC mtDNA, inflammation markers or PI, or NNRTI duration.   

Conclusions:  In subjects with lipoatrophy, switching from a tNRTI to TDF for 48 weeks led to significant increases in limb fat and fat mtRNA. Uridine supplementation did improve mtRNA, but worsened inflammation markers and fat mtDNA and did not change limb fat. Large decreases in total- and hip BMD were seen after TDF switch.