Lead author Joel E. Gallant, M.D., M.P.H., of the The Johns Hopkins University School of Medicine, Baltimore, presented the findings of the study at a JAMA media briefing at the International AIDS Conference in Bangkok, Thailand.
Highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV) infection into a chronic manageable disease, according to background information in the article. The article also indicates that although many regimens lower plasma viral load to below the limit of detection in most patients, maintaining a durable response remains challenging because of adverse effects, long-term toxicity, and complex dosing schedules, all of which can lead to nonadherence, virologic failure, and drug resistance.
To evaluate the safety and efficacy of tenofovir disoproxil fumarate (DF) treatment in patients who have not had antiretroviral therapy, Dr. Gallant and colleagues conducted a randomized, double-blind trial comparing tenofovir DF with stavudine, both given in combination with lamivudine and efavirenz. The study was conducted in 81 centers in the United States, South America, and Europe from June 9, 2000, to January 30, 2004. A total of 753 patients infected with HIV were screened and 602 patients entered the study. Patients were randomized to receive either tenofovir DF (n=299) or stavudine (n=303), with corresponding placebo, in combination with lamivudine and efavirenz. Efficacy was measured as the proportion of patients with an HIV viral load (plasma HIV RNA) of less than 400 copies/mL at week 48.
The researchers found that the proportion of patients with a viral load of less than 400 copies/mL at week 48 was 239 (80 percent) of 299 in patients receiving tenofovir DF and 253 (84 percent) of 301 in patients receiving stavudine. Equivalence was demonstrated in the secondary analyses (HIV RNA <50 copies/mL) at week 48 and through 144 weeks. Virologic failure was most often associated with efavirenz and lamivudine resistance.
Concerning safety, tenofovir DF was associated with a significantly lower average increase from baseline in fasting triglycerides, total cholesterol, directly measured low-density lipoprotein cholesterol, and a higher increase in high-density lipoprotein cholesterol. More patients required the addition of lipid-lowering agents in the stavudine group. Peripheral neuropathy (which includes pain or numbness in the feet or legs) and investigator-reported lipodystrophy (a condition characterized by changes in body fat distribution) were less common in the tenofovir DF group.
"This is to our knowledge the first large 3-year, randomized, double-blind trial of antiretroviral therapy in treatment-naive patients," the researchers write. "The high proportion of patients achieving HIV RNA level below limit of quantification through 144 weeks in both regimens is presumed to be due to a combination of the potency of the drugs used and the tolerability and simplicity of the regimens."
"These data support the use of tenofovir DF as a component of initial therapy for HIV infection. They also provide further support for the use of efavirenz-based regimens in this patient population. Although both tenofovir DF and stavudine performed equally well with respect to antiviral potency, the 3-year results indicate that tenofovir DF was associated with less toxicity than stavudine," the authors conclude. (JAMA. 2004; 292:191-201. Available post-embargo at JAMA.com)
Editor's Note: This study was supported entirely by Gilead Sciences Inc., Foster City, Calif. For the financial disclosures of the authors, please see the JAMA article.
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