August 16, 2006
Metabolic complications remain among the most devastating, and even stigmatizing, side effects of antiretroviral medications. These complications, known alternatively as lipodystrophy, can consist of fat loss (lipoatrophy), fat accumulation (lipohypertrophy), or a combination of both. Fat loss is usually seen in the face, arms, legs and buttock area, while body fat gain occurs mainly in the abdominal region. In some patients, body fat changes can be quite devastating, with a dramatic effect on both the patient's self-image and the way others view him or her.
For health care providers, lipoatrophy is probably one of the important considerations we have to discuss with our patients before settling on a treatment regimen. Many factors -- such as age, race and sex -- can cause lipoatrophy. Medications such as stavudine (d4T, Zerit) have been associated with lipoatrophy, while others like tenofovir (TDF, Viread) and abacavir (ABC, Ziagen) are not linked to this condition.
Study A5005s,1 led by Michael Dubé and presented at the XVI International AIDS Conference, examines if there is a link between certain medications and lipoatrophy. It is a substudy of the well-known AIDS Clinical Trials Group (ACTG) 384 trial.
ACTG 384 was conducted mainly to compare the efficacy of:
ACTG 384 had six study arms: zidovudine + lamivudine + (efavirenz or nelfinavir or both) and stavudine + didanosine + (efavirenz or nelfinavir or both). The two four-drug arms were compared to the four three-drug arms. It enrolled 980 antiretroviral-naive patients in the United States and Italy. The results of ACTG 384 were previously reported at the XIV International AIDS Conference in Barcelona, Spain.2
The metabolic substudy A5005s was done to compare limb fat changes between the two nucleoside backbones (zidovudine + lamivudine versus stavudine + didanosine) and between the NNRTI- and PI-based regimens. The investigators followed a select group of 157 patients longitudinally over 144 weeks. DEXA (dual energy X-ray absorptiometry) scans were used to measure limb fat at baseline prior to starting medications and then repeated every 16 weeks. Patients who had any DEXA scans after baseline up to week 144 were included in the as-treated analysis. Data were censored 28 days after a regimen change. Sixty-five patients completed their DEXA scans at week 144, with 32 patients remaining on their initial regimen.
Patients had a median age of 36 years. Eighty-seven percent were male. Fifty-one percent of the patients were white, 29% were black and 19% were Hispanic. The median CD4+ cell count was 260 cells/mm3. The median viral load was 5.1 log. The median limb fat at baseline was 6.3 kg, which is considered normal.
The investigators first looked at the effect of the NRTI backbones, comparing zidovudine + lamivudine to stavudine + didanosine. In both groups, patients gained limb fat over the first 32 weeks, with a median gain of 8.5% and 4.3%, respectively. However, between week 32 and 144, patients in both groups lost limb fat. Patients on stavudine + didanosine lost a significant amount of limb fat (-19 %/year) compared to patients on zidovudine + lamivudine (-1.7%/year). Despite the loss, limb fat in the zidovudine + lamivudine group was still 1.4% above what they started with at baseline, while in the stavudine + didanosine group, limb fat had decreased from baseline by 32.5%.
The investigators next looked at the effect of the NNRTI efavirenz versus the PI nelfinavir versus efavirenz + nelfinavir. Since the results were similar for efavirenz + nelfinavir and nelfinavir alone, the data from both arms were pooled together for comparison with the efavirenz arm. After adjusting for the NRTI backbone, it was found that patients on nelfinavir had additional fat loss of 8.7%/year. Within the zidovudine + lamivudine group, those taking nelfinavir experienced limb fat loss of 7.9%/year, while those on efavirenz alone had a slight gain in fat (+2.7%/year). At the end of week 144, patients in the zidovudine + lamivudine + efavirenz group ended up with a total fat gain of 20% above baseline, while those on zidovudine + lamivudine + nelfinavir (with or without efavirenz) lost 18.8% of fat. This trend towards more fat loss with nelfinavir was also seen in those patients taking stavudine + didanosine as their nucleoside backbone.
In conclusion, when comparing the two nucleoside backbones, patients who were started on stavudine + didanosine lost more limb fat than did patients on zidovudine + lamivudine. This finding is probably not surprising and seems to be consistent with other previous studies that showed a link between lipoatrophy and thymidine analog NRTIs. The interesting result is the additional lipoatrophic effect from a PI (nelfinavir in this study). There are many different PIs available. Certain PIs may have less effect on lipid and glucose metabolism than others. Many studies are currently being conducted to determine differences in metabolic parameters and body habitus changes among PIs. It is probably assumptive to conclude that all PIs have the same effect on lipoatrophy.
The backbone combination of stavudine + didanosine is currently not recommended in the guidelines set forth by the U.S. Department of Health and Human Services. On the other hand, zidovudine + lamivudine (coformulated as Combivir) and tenofovir + (lamivudine or emtricitabine [FTC, Emtriva]) are the preferred initial backbones.
Many studies have shown an improvement in lipoatrophy when switching from a thymidine (stavudine or zidovudine) to a non-thymidine NRTI (such as tenofovir or abacavir). To avoid lipoatrophy, many physicians prefer to use non-thymidine backbones (such as Truvada [a coformulation of tenofovir + emtricitabine] or Epzicom [a coformulation of abacavir + lamivudine]) as part of initial therapy. For the third drug in an initial regimen, many still prefer an NNRTI in order to avoid metabolic side effects, while others choose a PI for its higher genetic barrier to resistance. Although there are many factors to consider when choosing an initial antiretroviral regimen for a patient, the most critical ones are probably to choose the medications that a patient accepts, tolerates and can adhere to.
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