Other studies – nucleosides and switching to abacavir; importance of lipoatrophy and buffalo hump
Simon Collins, HIV i-Base
Several Australian research groups that have reported on studies of switching to abacavir continued to show interesting results. Switching d4T to abacavir has previously been reported to reverse limb fat loss and even lead to slight fat increase (approx +10%).
Thompson and colleagues from Melbourne, Australia in a GlaxoSmithKline-supported study, looked at the effect on fat apoptosis in 12 patients who switched to abacavir (and one who switched to AZT) after >two years use of d4T. Increases in arm, leg and trunk fat of 25%, 15% and 23% respectively were reported from DEXA results 48 weeks after the switch. Adipose mitochondrial (mT) DNA/fat cell levels increased from 214 at baseline to 462 at week 48 in the eight patients measured, and this compared to 863 for a control group of 20 HIV-negative individuals. Median adipocyte apoptosis, assessed semi-quantitatively by terminal deoxynucleotidyl transferase dUTP-digoxigenin nick end labeling (TUNEL), decreased from 2.0 (IQR 1-2.5) at baseline to 1.25 (IQR 0.5-2.5) at week 48. Although one patient in this study switched to AZT, and given that AZT has also been implicated in lipoatrophy, it is more appropriate the study be mainly observed as the result of the abacavir switch. 
A second study from Hoy and colleagues assessed mitochondrial DNA cells/copy in PBMCs from 39 patients in the MITOX study who switched to abacavir and 55 controls who remained on d4T or AZT. Mean (SD) changes in mT DNA copy number at four, 12 and 24 weeks were 54.8 (350.4), 76.6 (414.2) and 48.8 (431.61) for the switch group compared to –38.0 (267.7), -15.3 (344.7) and –85.3 (390.4) in those who continued on d4T or AZT. There was a trend to increased mt/DNA in the switch group but there was no correlation between change in mT DNA and change in peripheral fat measured by DEXA and the study concluded that there is currently limited utility in quantifying mT DNA in PBMCs to access nucleoside toxicity. 
To add further weight to the contribution nucleosides play in lipodystrophy, limb and VAT fat were found not to change significantly over two years in 45 male patients who switched from a PI containing regimen but who continued using nucleosides. Lifetime duration of d4T or AZT use independently and significantly correlated with reduction in limb fat at week 120 with a decrease of 0.72kg (CI –1.18 to –0.26) and 0.29kg (CI –0.52 to –0.06) with d4T and AZT respectively. 
Finally, Boyd and colleagues reported improvements in lipoatrophy in 61 patients (38 male, 23 female) who switched to nuke-sparing indinavir/ritonavir (800/100 BID) plus efavirenz combinations and increases in percentage body fat by DEXA, increases in thigh and abdominal subcutaneous fat (p=0,04) and abdominal visceral fat (p=0.05) at 48 weeks after the switch. 
The finding that buffalo hump was not in itself an HIV-associated condition statistically related to lipodystrophy syndrome was, together with a similar suggestion for abdominal fat accumulation, one of the controversial conclusions presented by Carl Grunfeld in the preliminary data from the FRAM study last summer at the Barcelona International AIDS Conference. Posters 732 and 733 from this study at CROI further elaborated on the finding that compared to matched controls, lipoatrophy (fat loss) in both limbs and/or abdomen were the predominant link to HIV-related fat loss, and maintained that fat accumulation was not statistically associated with the same syndrome. [5, 6]
A more detailed analysis of buffalo hump from the same study (BH was found in 8% of HIV-positive men and 11.3% of HIV-negative controls in the US population) revealed, as many people suspected at the time, the importance of a qualitative analysis, finding that NH averaged 2.5 times higher in HIV+ (9.0×8.2cm) compared to controls (5.5×5.4cm); each dimension p<0.001. 
Unless stated otherwise, all references are to the Programme and Abstracts of the 10th Conference on Retroviruses and Opportunisitc Infections (CROI), 10–14 February 2003, Boston.
- Thompson K, McCormsey G, Ross L et al. Improvements in body fat and mitochondrial DNA levels are accompanied by decreased adipose tissue cell apoptosis after replacement of stavudine therapy with abacavir or zidovudine. Poster 728
- Hoy J, Gahan M, Carr A et al. Changes in mitochondrial DNA in PBMCs from patients with lipoatrophy randomized to switch or continue thymidine analogue-containing ARV regimens. Abstract 729.
- Martin A, Carr A, Smith D et al. Progression of lipodystrophy with long-term thymidine analogue usage despite stopping protease inhibitors. Poster 727
- Boyd M, Bien D, Reiss P et al. Lipodystrophy in patients switched to indinavir/ritonavir 800/100mg BID anf efavirenz 600mg QD after failing nucleoside combinations therapy: a prospective, 48-week observational substudy of HIV-NAT 009. Poster 738
- Gripshover B, Tien PC, Saag M et al. Lipoatrophy is the dominant feature of the lipodystrophy syndrome in HIV-infected men. Abstract 732
- Saag M, Gripshover B, Tien PC et al. Body composition in HIV+ men with and without peripheral lipoatrophy is different than controls. Abstract 733.
- Zolopa A, Benson C, Bacchetti P et al. Buffalo hump in men with HIV infection: larger, but not more common. Abstract 734.