Background

In some patients, lipoatrophy is a significant complication of antiretroviral therapy (ART). It has been associated with nucleoside analogue (NRTI) therapy, particularly with exposure to stavudine, and has proved difficult to treat. Prior studies have demonstrated modest improvements in peripheral fat with the substitution of abacavir or zidovudine for stavudine or for thymidine analogues (stavudine or zidovudine).(1, 2) Other studies have suggested that abacavir and tenofovir may be less likely than thymidine analogues to cause lipoatrophy.(3) Three new "switch studies" examined the effect on lipoatrophy of replacing thymidine analogues with abacavir or tenofovir, or of discontinuing all NRTIs via a switch to a nucleoside-sparing regimen.

RAVE Study Examines Abacavir or Tenofovir Versus Thymidine Analogues

Abstract: A 48-week, Randomized, Open-label Comparative Study of Tenofovir DF vs Abacavir as Substitutes for a Thymidine Analog in Persons with Lipoatrophy and Sustained Virological Suppression on HAART. Graeme Moyle, C Sabin, J Cartledge, M Johnson, E Wilkins, D Churchill, P Hay, A Fakoya, M Murphy, G Scullard, C Leen, G Reilly, and The Rave Study Group. Abstract 44LB.

Description: The RAVE study examined the effect of substituting abacavir or tenofovir for thymidine analogues in patients with lipoatrophy. One hundred and five patients with moderate-to-severe lipoatrophy who were receiving stavudine or zidovudine as part of a stable ARV regimen were randomized to substitute abacavir or tenofovir for the thymidine analogue. The primary endpoint was the change in change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA), at 48 weeks. At baseline, all patients had HIV RNA levels of < 50 copies/mL. Their median CD4 count was 500 cells/µL (nadir < 200 cells/µL). Limb fat mass, subcutaneous abdominal fat, visceral fat, and lipid levels were similar in both groups. Of the patients, 71 had been receiving stavudine, while 34 were receiving zidovudine.

Subjects were well matched at baseline for most fat measurements (the ABC group had greater median visceral fat than the others), and for metabolic, CD4, and demographic parameters. The median CD4 count was approximately 600 cells/µL (nadir > 200 cells/µL); Seventy six percent of patients were on stavudine, and 24% were on zidovudine.

Results: At 48 weeks, by intent-to-treat analysis, limb fat mass had increased significantly from baseline in both treatment groups (0.3-0.4 kg), with no significant difference between the groups. The increase was greater in patients who had switched from stavudine. Changes in visceral fat and subcutaneous abdominal fat, measured by computed tomography (CT) scan, also were not significantly different between groups. The tenofovir group experienced modest decreases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, while the abacavir group showed no significant changes from baseline. Virologic suppression was maintained similarly in both groups, but drug discontinuation was more frequent in the abacavir group, with 3 patients experiencing hypersensitivity reactions. There were no observed differences between groups in changes in creatinine or bone mineral density.

Switching to a Thymidine Analogue-Sparing or a Nucleoside-Sparing Regimen Improves Lipoatrophy

Abstract: Switching to a Thymidine Analog-sparing or a Nucleoside-sparing Regimen Improves Lipoatrophy: 24-Week Results of a Prospective Randomized Clinical Trial, AACTG 5110. Robert Murphy, J Zhang, R Hafner, A Shevitz, K Tashima, K Yarasheski, J Forand, B Berzins, S Owens, S Evans, P Tebas, and AACTG 5110 Study Team. Abstract 45LB.

Description: The RAVE study examined the effect of substituting abacavir or tenofovir for thymidine analogues in patients with lipoatrophy. One hundred and five patients with moderate-to-severe lipoatrophy who were receiving stavudine or zidovudine as part of a stable ARV regimen were randomized to substitute abacavir or tenofovir for the thymidine analogue. The primary endpoint was the change in change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA), at 48 weeks. At baseline, all patients had HIV RNA levels of < 50 copies/mL. Their median CD4 count was 500 cells/µL (nadir < 200 cells/µL). Limb fat mass, subcutaneous abdominal fat, visceral fat, and lipid levels were similar in both groups. Of the patients, 71 had been receiving stavudine, while 34 were receiving zidovudine.

Results: At 48 weeks, by intent-to-treat analysis, limb fat mass had increased significantly from baseline in both treatment groups (0.3-0.4 kg), with no significant difference between the groups. The increase was greater in patients who had switched from stavudine. Changes in visceral fat and subcutaneous abdominal fat, measured by computed tomography (CT) scan, also were not significantly different between groups. The tenofovir group experienced modest decreases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, while the abacavir group showed no significant changes from baseline. Virologic suppression was maintained similarly in both groups, but drug discontinuation was more frequent in the abacavir group, with 3 patients experiencing hypersensitivity reactions. There were no observed differences between groups in changes in creatinine or bone mineral density.

PI-Based/NRTI-Sparing Regimen Increases Appendicular Fat and Serum Lipid Levels

Abstract: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 Randomized Trial, ACTG 5125s. Pablo Tebas, J Zhang, K Yarasheski, S Evans, M Fischl, A Shevitz, J Feinberg, A Collier, C Shikuma, B Brizz, F Sattler, and Adult AIDS Clinical Trials Group (AACTG). Abstract 40.

Description: ACTG 5125s, a substudy of A5116, compared the effects on fat distribution of an NRTI-sparing regimen compared with a protease inhibitor-sparing regimen. Sixty two subjects with HIV RNA < 200 copies/mL, nadir CD4 counts < 200 cells/µL, and on ART for at least 18 months (in study ACTG 388) were randomized to switch their regimen to LPV/r + efavirenz or to efavirenz + 2 NRTIs. Patients were not required to have lipoatrophy, but baseline median limb fat was somewhat low (6 kg). The median CD4 count was 440 cells/µL, and > 60% of patients had received stavudine. Fat was measured by whole body and regional DEXA.

Results: At 48 weeks, limb fat increased by a median of 562 grams in the NRTI-sparing group and decreased by 246 grams in the NRTI-containing group (p = .097). At time of last observation (median 104 weeks; 46 patients), limb fat had increased by a median of 782 grams, or 10%, in the NRTI-sparing group, and had decreased by 900 grams (15%) in the NRTI-containing arm (p = .002). There were no significant changes in trunk fat. The study was not powered to differentiate between NRTIs.

The NRTI-sparing group had statistically significant increases in total cholesterol and triglycerides compared with the NRTI-containing group. There were no differences between groups, and no changes from baseline, in glucose measurements or bone mineral density.

Comment: These studies demonstrate that lipoatrophy may improve with discontinuation of certain NRTIs (eg, thymidine analogues), and that improvement may be greater with elimination of all NRTIs. Thus, they support previous findings that the different NRTIs affect fat metabolism to different degrees and that NRTIs as a class may cause or perpetuate lipoatrophy. Thus stavudine (and perhaps zidovudine) may confer a higher risk of lipoatrophy than abacavir or tenofovir, and switching to the latter agents (as in RAVE and AACTG 5110) may improve peripheral fat loss. However, discontinuation of all NRTIs may improve lipoatrophy to a greater degree (as in AACTG 5110) than switches to abacavir or tenofovir.

Unfortunately, these studies do not address the effects of these interventions on facial lipoatrophy, which is the aspect of this condition that is most disturbing to patients. In addition, while the studies show that peripheral fat loss can improve over the course of 24-48 weeks, it is not clear that the improvements noted have clinical significance, or that they will continue over time. Additional research and extended follow-up of these and other cohorts is needed to determine effective ways to prevent and reverse lipodystrophy.

References

1. McComsey GA, Ward DJ, Hessenthaler SM, Sension MG, Shalit P, Lonergan JT, Fisher RL, Williams VC, Hernandez JE; Trial to Assess the Regression of Hyperlactatemia and to Evaluate the Regression of Established Lipodystrophy in HIV-1-Positive Subjects (TARHEEL; ESS40010) Study Team. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Clin Infect Dis. 2004 Jan 15;38(2):263-70. PMID: 14699460

2. Martin A, Smith DE, Carr A, Ringland C, Amin J, Emery S, Hoy J, Workman C, Doong N, Freund J, Cooper DA; Mitochondrial Toxicity Study Group. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS. 2004 Apr 30;18(7):1029-36. PMID: 15096806

3. Gallant J, Staszewski S, Pozniak AL, Suleiman JMA, De Jesus E, Lu B, Yale K, Miller MD, Cheng AK. Long-term efficacy and safety of tenofovir disoproxil fumarate (TDF): A 144-week comparison versus stavudine (d4T) in antiretroviral-naive patients. XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4538.