Reversibility of lipoatrophy in HIV patients 2 years after switching from a thymidine analogue to abacavir
The HIV-associated lipodystrophy syndrome affects approximately 50% of HIV-positive patients, particularly those receiving antiretroviral therapy based on nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs).
The selection of an optimal treatment regimen for HIV infection is influenced by increasing evidence that particular antiretroviral drugs may exacerbate lipoatrophy and associated metabolic abnormalities.
However, because of cross-resistance among antiretroviral drug classes and other treatment toxicities, it is likely that, in a lifetime, HIV patients will have to take drugs that are associated with the development of the lipodystrophy syndrome.
A number of cohort studies have suggested that long-term exposure to thymidine-based analogues results in lipoatrophy that is associated with mitochondrial toxicity and lactic acidemia.
The PIILR extension study examined lipoatrophic patients on a protease inhibitor-sparing antiretroviral regimen for at least 12 months, who then ceased stavudine (d4T) or zidovudine (AZT, ZDV). This study resulted in significant improvements in lipoatrophy but an unacceptable rate of HIV virological rebound.
More recently, replacement of d4T or ZDV with abacavir (ABC) in randomised controlled trials has been shown to lead to modest improvements in fat mass over a relatively short period of time.
The initial MITOX (mitochondrial toxicity) study reported a significant increase of 0.4 kg (11%) in limb fat in the ABC-treated subjects at 24 weeks, as well as significant relative increases in subcutaneous thigh and abdominal fat mass. However, this difference in limb fat was not apparent clinically.
The objective of the current study was to determine if long-term improvement in HIV lipoatrophy can be attained by substitution of the thymidine analogues ZDV or d4T with ABC. Long-term follow-up (104 weeks) of this randomised, open-label study (MITOX) appears in the 30 April issue of AIDS.
Seventeen HIV clinics in Australia and London enrolled 85 patients with HIV lipodystrophy who were randomised to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43).
At week 24, all control patients could switch to ABC. Of the original 111 patients randomised, 85 had long-term follow-up data, with 77 having imaging data available at 104 weeks.
The primary endpoint was time-weighted change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA).
At week 104, the mean increase in limb fat for the ABC and ZDV/d4T group was 1.26 +/- 2.02 kg and 0.49 +/- 1.38 kg, respectively. The time-weighted change for limb fat was significantly different between the two arms (0.43 kg; P = 0.008).
On-treatment analysis demonstrated a trend for increased limb fat in patients in the ABC arm.
Interestingly, visceral fat accumulation, buffalo hump, self-assessed lipodystrophy or the lipodystrophy case definition score (LCDS) did not improve.
The authors conclude: “In patients with moderate-to-severe lipodystrophy, significant improvements in subcutaneous fat continued over 104 weeks after switching from a thymidine analogue to ABC. Nevertheless, the lipodystrophy syndrome was still evident, indicating additional strategies need evaluating.”
The increase in subcutaneous fat seemed to be linear over time in this study, which may point at a continuous biological effect. This may be the good news, because the gain itself although statistical significant was clinically not relevant. A severely wasted leg may have lost 4-5 kg of fat which means that the gain of 1.2 kg is about 20% needed to return to normal.
These results were presented at the 2003 Workshop on Lipodystrophy and included in the reports from that meeting in the August/September 2003 issue of HTB:
It is to be hoped that the high profile already given to the results from this study, and the caution against use of d4T in the 2003 BHIVA guidelines should mean that few patients with lipoatrophy are still using d4T. The publication of the full results in AIDS is therefore welcomed.
Martin A et al (for the Mitochondrial Toxicity (MITOX) Study Group). Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 18(7): 1029-1036. April 30, 2004.
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