Recent Findings on Metabolic Patterns With Efavirenz (Sustiva)

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Recent Findings on Metabolic Patterns With Efavirenz

Pablo Tebas, MD

The metabolic analysis of AIDS Clinical Trials Group (ACTG) A5095 compared changes in metabolism and body composition among treatment-naive patients initiating 3 different PI-sparing regimens and showed significant greater increases in lipid levels with efavirenz plus either 2 or 3 NRTIs than with the triple-NRTI regimen zidovudine/lamivudine/abacavir (Capsule Summary).[1] The triple-NRTI arm was discontinued at Week 24 because of virologic inferiority, and patients randomized to that arm were allowed to intensify their regimen with efavirenz or tenofovir. After intensification, the investigators observed significant lipid elevations only among those who added efavirenz. However, the 6 mg/dL (0.16 mmol/L) gain in high density lipoprotein (HDL) cholesterol associated with efavirenz may offset the 17 mg/dL (0.44 mmol/L) increase in total cholesterol. Because the differences in the absolute cholesterol changes were not very dramatic, they are potentially relevant only in patients with a highly significant preexisting risk of cardiovascular disease.

In my opinion, whether a triple-NRTI regimen of zidovudine/lamivudine/abacavir should be intensified with efavirenz or tenofovir is a moot clinical question because triple-NRTI combinations are no longer recommended for treatment-naive individuals as a result of this and other trials demonstrating worse virologic outcomes associated with such regimens. Although tenofovir intensification was associated with a better lipid profile in this analysis than efavirenz, I would still choose efavirenz over tenofovir if I were to prescribe one of these agents with 3 NRTIs, in view of data showing that an initial regimen of tenofovir plus abacavir and lamivudine resulted in very poor virologic outcomes.[2] I therefore would be concerned about combining those 3 drugs as part of a quadruple-NRTI regimen.The comparison of the 96-week metabolic data in the ACTG patients with the metabolic profiles of an HIV-negative population (National Health and Nutrition Examination Survey) is one of the most interesting parts of this study because it highlighted the similarity of the lipid profiles in these 2 groups. The HIV-infected patients (before and after HAART) had lower total and HDL cholesterol and higher triglyceride levels, but the proportion of HIV-infected individuals with metabolic syndrome was similar to the population at large. When interpreting these data, one should consider that the United States is currently experiencing an ongoing epidemic of cardiovascular disease. In fact, the “return to health†that many clinicians consider the result of starting antiretroviral therapy would probably better be described as a “return to nonhealth†that unfortunately characterizes developed countries.

The results of this ACTG substudy confirm a realization that has grown stronger in recent years―efavirenz is not a lipid-neutral drug. In this analysis patients taking efavirenz experienced increased triglyceride levels, as well as increases in total and HDL cholesterol, when compared with baseline levels. Recently presented results of ACTG 5142 also suggested that efavirenz was associated with peripheral lipoatrophy, which may be consistent with the statistically significant decrease in arm circumference in patients who intensified with efavirenz in A5905 (Capsule Summary).[3] However, I do not think this or other recently presented studies should change the current status of efavirenz as a component of preferred initial therapy.

I was struck by the high frequency of smoking, hypertension, and metabolic syndrome in this study population.[1] Interventions focusing on these problems, all of them well-known risk factors for cardiovascular disease, potentially will have a greater impact on overall cardiovascular risk than individual lipid changes associated with the antiretrovirals studied.A patient’s metabolic profile must remain one of several considerations when choosing an antiretroviral regimen. In my practice, I tend to select a regimen to which the patient and I think he or she can adhere—one that does not adversely affect quality of life and that fits the patient’s personal preferences. Most of the time, an NNRTI-based regimen fulfills these criteria and such regimens are my most frequently prescribed first-line therapy. If the patient or I have concerns about adherence, I usually select a boosted PI-containing regimen because failure of a boosted PI regimen rarely results in PI resistance.

References

1. Shikuma CM, Yang Y, Glesby MJ, et al. Metabolic effects of protease inhibitor-sparing antiretroviral regimens given as initial treatment of HIV-1 infection (AIDS Clinical Trials Group Study A5095). J Acquir Immune Defic Syndr. 2007; [Epub ahead of print].

2. Gallant JE, AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005;192:1921-1930.

3. Haubrich R, Riddler S, DiRienzo G, et al. Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 38.

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