Changing highly active antiretroviral therapy (HAART) regimen from one containing nucleoside analogues (NRTIs) to one that lacks this drug class can lead to a reversal of drug-induced fat loss from the limbs, according to the results of two studies presented on Wednesday at the Twelfth Annual Retrovirus Conference in Boston.
Fat loss in the limbs and face (lipoatrophy) is a disturbing side-effect of antiretroviral therapy, which often has a negative impact on quality of life and drug adherence. ACTG 5125s was a metabolic substudy of ACTG 5116, which randomised individuals with advanced HIV disease to switch from their existing stable therapy to either ritonavir-boosted lopinavir (Kaletra) with efavirenz (Sustiva) or efavirenz plus two NRTIs.
The aim of the study was to determine whether a switch to an NRTI-sparing regimen was effective and if it resulted in improvements in fat distribution and lipid measures. The study also examined bone mineral density and glucose metabolism over 48 weeks of follow-up.
Sixty-two participants with a previous lowest-ever CD4 cell count below 200 cells/mm3 or pre-treatment viral load above 80,000 copies/ml were enrolled. All participants had received highly active antiretroviral therapy (HAART) for at least 18 months and had viral load below 200 copies/ml at the time of the treatment switch.
At baseline the median total limb fat was 6kg, measured by dual energy X-ray absorpiometry (DEXA) scans. This increased by a median of 562g in those who switched to Kaletra / efavirenz, compared with a median loss of 246g in those who continued to receive NRTIs in their regimen (p = 0.097).
Among 46 patients who had been followed for a median of 104 weeks, those in the non-NRTI arm gained a median of 782g of limb fat, whilst those in the NRTI arm had lost a median of 900g of limb fat compared to baseline (p = 0.002).
The study was not powered to detect differences between NRTI combinations or the contribution of individual NRTIs, such as d4T (stavudine, Zerit) towards limb fat loss.
Triglyceride levels increased by a median of 85mg/ml in the Kaletra group compared to an increase of 11mg/ml in the NRTI group by week 48 (p = 0.001). Total cholesterol also increased significantly in the NRTI-sparing group (+19 vs. -7 mg/ml, p
There were no differences in trunk fat levels, bone mineral density or glucose metabolism between the treatment groups after 48 weeks.
The researchers suggest that the switch to an NRTI-sparing regimen is a therapeutic option for people with lipoatrophy, although it should be noted that the degree of fat restoration was relatively modest in the NRTI-sparing group, with a median of 13% fat gain over two years.
However, Pablo Tebas, presenting, warned that the benefits of NRTI-sparing regimens on fat redistribution must be balanced against their inferior virological potency.
These findings were mirrored in a late breaker presentation of 24-week results from study AACTG 5110 by Robert Murphy. The research group randomised 77 patients with viral loads below 500 copies/ml on a d4T or AZT (zidovudine, Retrovir)-containing regimens to switch this NRTI to abacavir (Ziagen), or to discontinue their current drug regimen and begin the NRTI-sparing combination of Kaletra and nevirapine (Viramune).
After 24 weeks, computed tomography (CT) scans showed that the 37 patients receiving the NRTI-sparing regimen had experienced a median increase of 8% in subcutaneous thigh fat (p = 0.06). This was compared to no change in the abacavir group.
Subcutaneous abdominal fat tissue increased in both groups (p
The switch to the NRTI-sparing regimen was found to be immunologically safe, leading to a significant increase in CD4 cell count (8 cells/mm3, p = 0.03) after 24 weeks. Similar proportions of both groups also maintained undetectable viral loads (93 vs. 92%).
The study also included a third group that remained on the original HAART regimen for 24 weeks before being randomised to one of the two treatment arms. This allowed the investigators to increase the power of their study without compromising the potential benefits to the study participants.
AACTG 5110 is the first study to detect an improvement in lipoatrophy after only 24 weeks. However, the researchers warn that an 8% increase in limb fat from a very low baseline is modest, and unlikely to be detected by the patient. However, follow-up of the three groups is continuing, and the full 48-week results, including quality of life measurements, should be available later this year.
Tebas P et al. Switch to a protease inhibitor containing/nucleoside reverse transcriptase inhibitor-sparing regimen increases appendicular fat and serum lipid levels without affecting glucose metabolism or bone mineral density. The results of a prospective randomised trial, ACTG 5125s. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 40, 2005.
Murphy R et al. Switching to thymidine analog-sparing or a nucleoside-sparing regimen improves lipoatrophy: 24-week results of a prospective randomized clinical trial, AACTG 5100. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 45LB, 2005.