Switching nucleoside reverse transcriptase inhibitors?

Evidence from several small studies has suggested some benefit from switching away from d4T treatment, but the numbers treated in these studies were small, with no matched control groups or randomisation .

Well-controlled studies looking at the strategy of changing nucleosides are very thin on the ground. Current evidence suggests that switching from d4T (stavudine, Zerit) to another NRTI seems to produce minimal benefits in fat wasting.

The prospective Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study compared 477 HIV-positive patients and 211 HIV-negative controls. HIV-positive participants had significantly lower levels of subcutaneous fat than the HIV-negative comparison group. This difference persisted over the five years of the study, and those with HIV were more likely to lose both subcutaneous fat (35 vs 27%) and visceral fat (17 vs 5%). Discontinuing treatment with d4T had minimal impact on limb fat, with an average annual increase of fat in the leg of only 1%.1

In the MITOX study, 111 patients were randomised to switch from d4T or AZT (zidovudine, Retrovir) to abacavir (Ziagen) or stay on these drugs, and no-one changed any of their other drugs. People who switched to abacavir had a mean increase in limb fat at week 104 of 1.26kg (+/- 2.02kg) compared to 0.46kg (+/-1.38kg) for the patients who remained on a thymidine analogue. This difference was statistically significant, but there was no difference between the groups in self-assessed degree of improvement.[ref] 2

In a second Australian study, 37 patients taking d4T/3TC plus nelfinavir or indinavir or AZT/3TC/indinavir were randomised to switch d4T and their protease inhibitor for AZT and abacavir, or to stay on existing therapy, so that everyone who switched ended up taking AZT/3TC/abacavir. After 48 weeks on the new regimen, intent-to-treat analysis showed that leg fat in the control group had continued to decline by an average of 10g a month, whereas it increased by an average of 7g a month in the switch group (p = 0.05). The change in leg fat percentage was not statistically significant. Arm fat increased in the switch group (+12g/per month), but did not change substantially in the control group.3 The extreme modesty of the fat gains recorded in this study was underlined by the on-treatment analysis of percentage fat changes. Patients who switched to abacavir gained just 95g (0.23%) in fat mass per leg after 48 weeks. Abdominal fat did not change significantly over the 48 week period.

The authors point out that two processes appeared to be at work after the switch, depending on the baseline regimen. In those whose baseline regimen did not include d4T, the effect of a switch to abacavir appeared to be the sparing of further fat loss. However, in individuals receiving d4T and a protease inhibitor at baseline, fat restoration was the predominant effect of a switch, perhaps due to more substantial fat loss prior to the switch.

A second observation in this study concerned the timing of fat restoration: the larger fat gain occurred after week 24, leading the authors to suggest that the rate of fat restoration may pick up speed as time goes on. Fat restoration occurs more quickly in the arms, they say, than in the legs.

In an American study with no control group, 118 people replaced d4T with either abacavir or AZT. After 48 weeks, those who switched showed much greater improvements than those seen in the three studies above. Fat levels in the arms had increased by 35.3% from baseline, whilst trunk fat and leg fat had increased by 16.4% and 12% respectively. CT scans indicated that the total increase in subcutaneous fat was 4%, whilst visceral fat declined by 2%. Seventy nine per cent of participants experienced an increase in subcutaneous fat, and 54% experienced a decrease in visceral fat. 4 Five out of 86 patients experienced abacavir hypersensitivity reactions.

A British study conducted by Graeme Moyle randomised 30 people with high cholesterol and lipoatrophy to switch from d4T to abacavir. Body fat changes were monitored by DEXA scan at baseline and weeks 12, 24, 36 and 48. Leg fat increased significantly in patients who switched from d4T to abacavir (+1.08kg, or +52%) after 48 weeks, but declined slightly in those who continued d4T treatment or switched to AZT and abacavir. These moderate changes were not noticed by patients, who reported no significant changes in several measures of body fat including leg fat. 5

CPCRA 058, a 36-month study, looked at changes in subcutaneous fat when ARV-naive patients started on one of three NRTI-containing regimens: AZT, d4T, or abacavir. All three arms also included 3TC plus either a PI or NNRTI. Use of AZT or d4T resulted in subcutaneous fat loss in the triceps, abdomen, and thighs. Long-term abacavir use resulted in significant subcutaneous fat gain in the abdomen.6

References

  1. Grunfeld C et al. Regional adipose tissue measured by MRI over 5 years in HIV-infected and control participants indicates persistence of HIV-associated lipoatrophy. AIDS 24: online edition, DOI: 10. 1097/QAD.0b013e32833ac7a2, 2010
  2. Carr A et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 288: 207-215, 2002
  3. John M et al. Randomized, controlled, 48 week study of switching stavudine and / or protease inhibitors to Combivir / abacavir to prevent or reverse lipoatrophy in HIV-infected patients. J Acquir Immune Defic Syndr 33: 29-33, 2003
  4. McComsey GA et al. Effect of ritonavir-boosted protease inhibitor regimens on lipid profiles. 14th International AIDS Conference, Barcelona, abstract ThPeB7319, 2002b
  5. Moyle G et al. A 48 week, randomized, open label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr 33: 22-28, 2003
  6. Shlay JC et al. Long-term subcutaneous tissue changes among antiretroviral-naive persons initiating stavudine, zidovudine, or abacavir with lamivudine. J Acquir Immune Defic Syndr 48(1): 53-62, 2008
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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