HIV Lipodystrophy Workshop: d4T/ddI cause more fat loss than AZT/3TC

Clear clinical evidence that the combination of ddI/d4T is associated with greater fat loss than AZT/3TC was presented on Wednesday at the Fourth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, in San Diego.

Didanosine and stavudine (ddI/d4T) were associated with a significantly greater loss of fat in the arms and legs amongst participants in the ACTG 384 study after 48 and 60 weeks on treatment, when compared with zidovudine/lamivudine (AZT/3TC).

The findings led Dr. Judith Currier of the University of California to state that “ddI/d4T should be taken off the [US] list of nucleoside pairs that are recommended for initial therapy”.

One hundred and fifty six patients were randomly selected for a sub-study in which DEXA scans (a form of X-ray designed to assess body composition) were carried out at baseline and during the 80 week follow-up of the larger study. Participants in ACTG 384 were randomised to one of two nucleoside analogue backbones, AZT/3TC or d4T/ddI, and also randomised to add either nelfinavir, efavirenz or both to that backbone. If the first combination failed, individuals in the triple therapy arms switched to the remaining drugs (e.g from ddI/d4T/nelfinavir to AZT/3TC/efavirenz).

The impact of these combinations on viral load and time to treatment failure was reported at the XIV International Conference in Barcelona earlier this year. That analysis showed that the combination of AZT/3TC/efavirenz resulted in a longer time to failure of the second regimen and longer time to failure of the first regimen.

The fat loss analysis is the first time that a randomised comparison of nucleoside analogue backbones has used a relatively objective measurement of lipoatrophy to compare the effect of different drugs on fat wasting. Previous studies have used physician report, and have not reported on trends over time to the same extent.

In the ACTG 384 sub-study, individuals randomised to ddI/d4T had lost 7.5% of their baseline limb fat by week 48, despite an initial increase in fat levels during the first 16-32 weeks of treatment. In comparison, the AZT/3TC group still had median fat levels above baseline (+4.7%). This difference was statistically significant (P=0.027). This difference became more pronounced at week 64 (-13% vs +2%). Despite a higher proportion of Caucasians in the ddI/d4T group, there was no difference when the results were analysed by racial group.

The analysis also looked at trunk fat, but did not distinguish between subcutaneous and visceral fat. Levels of trunk fat remained above baseline in both groups at week 64, but trunk fat levels were significantly higher in the AZT/3TC group.

The sub-study was not powered to look at differences between triple regimens in effects on limb fat. At the time the study was designed (1998), the suggestion that protease inhibitors and nucleoside analogues might have additive influences on the development of lipodystrophy had not surfaced. Instead, the sub-study was designed to compare the effects of the most commonly prescribed protease inhibitor of the day (nelfinavir) with the new drug in town (efavirenz).

Loss of limb fat only became apparent at week 60 in the nelfinavir group and at week 80 in the efavirenz group. At week 80, limb fat had declined by 18% in the nelfinavir group and 10.7% in the efavirenz group (p=0.019).

A number of limitations of this study were highlighted by Michael Dube of the University of Indiana, who presented the eagerly awaited data. He notde that the results were still relatively short-term in comparison to the time that patients can expect to remain on treatment, and that the findings relating to ddI/d4T may not be generalisable to other d4T-containing combinations (but see a related news story from the same meeting).

He also noted that some treatment switching took place. Since this was an intent to treat analysis, patients who switched to their second regimen after treatment failure would still be analysed as if they were taking their first-line regimen. Might this muddy the waters?

In ACTG 384, a major factor driving the superiority of AZT/3TC/efavirenz as first line regimen appears to have been superior tolerability. One of the main reasons for switching from ddI/d4T was the development of neuropathy, a sign of mitochondrial toxicity that might suggest such individuals were more prone to such toxicity, and might therefore suffer accelerating fat loss regardless of their regimen. Did adverse event-driven switches introduce bias, asked Dr Graeme Moyle of the Chelsea and Westminster Hospital, London?

Not in this study, apparently. The analysis censored data at the point at which individuals switched due to adverse events, and only 9 patients were lost for this reason. Excluding these patients entirely from the analysis made no difference to the final results, said study statistician Robert Zackin.

Together with results presented by the Western Australia group in the same session, these findings are likely to further restrict the use of d4T/ddI, and make clinicians more cautious about the use of d4T. They will also increase pressure for large randomised studies comparing AZT/3TC with tenofovir-containing nucleoside backbones, to establish the safety and efficacy of alternatives to AZT/3TC and d4T/3TC, the most commonly used nucleoside backbones.