The January 19, 2006 issue of the New England Journal of Medicine (NEJM) features 48-week results of a study (Gilead study 934) showing that the combination of the anti-HIV drugs Truvada (tenofovir and emtricitabine) plus Sustiva (efavirenz) taken once daily fulfilled the criteria for ^‘non-inferiority’ to Combivir (zidovudine and lamivudine) taken twice daily plus Sustiva once daily. The Truvada/Sustiva combination regimen also “proved superior” in terms of virologic suppression, CD4 response, and adverse events that resulted in discontinuation of the study drugs, according to the study authors.

The preliminary results of study 934 were first announced by Gilead Sciences in February 2005. More recently, Gilead and Bristol-Myers Squibb announced that the two companies have data supporting bioequivalence of a new formulation of the fixed-dose combination with the components that make up the combination.

If approved by the FDA, this 3-drug combination tablet would be the first and only complete HAART regimen for HIV in a fixed-dose combination tablet taken once daily. The companies are hoping that the demonstrated effectiveness of the 3 medications when used together plus the simplicity and ease of once daily administration of a single tablet will prove attractive to HIV HIV patients and their providers.

Study 934

Study 934 is a Phase III, multicenter, open-label clinical trial that enrolled 517 HIV-infected patients in the United States and Europe. The study’s primary endpoint was at 48 weeks. Participants in one arm of the study received Viread 300 mg, Emtriva 200 mg and Sustiva 600 mg, all dosed once daily. Patients in the comparator arm received Combivir twice daily and Sustiva 600 mg once daily. At study entry, patients had not previously received antiretroviral therapy and had HIV RNA (viral load) greater than 10,000 copies/mL.

Results

Through week 48, significantly more patients in the tenofovir–emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine–lamivudine group (84 percent vs. 73 percent, respectively).

This difference excludes the inferiority of the tenofovir, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen.

Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir–emtricitabine group vs. 70 percent in the zidovudine–lamivudine group)

Significant differences were also seen in increases in CD4 cell counts (190 cells per cubic millimeter in the tenofovir–emtricitabine group vs.158 in the zidovudine–lamivudine group).

More patients in the zidovudine–lamivudine group than in the tenofovir–emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P=0.02).

The K65R mutation (associated with resistance to Viread) did not develop in any of the patients.

Twenty-two patients with baseline NNRTI resistance were excluded from the analysis. There were no significant differences between the two treatment groups, and the most common resistance mutations that developed were associated with Sustiva.

Based on these findings, J E Gallant and the other study authors conclude, “Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs.”

01/20/06

Reference
J E Gallant and others (for the Study 934 Group). Tenofovir DF, Emtricitabine, and Efavirenz vs. Zidovudine, Lamivudine, and Efavirenz for HIV. The New England Journal of Medicine 354(3): 251-260. January 10, 2006.

Press Statement by Gilead Sciences on Study 934  

Following are selected statements on study 934 contained in a press release by Gilead Sciences:

The 48-week safety analysis for Study 934 is based on 511 patients who received any study medication. A significantly (p=0.02) greater percentage of patients in the Combivir group (9 percent) experienced adverse events that resulted in the discontinuation of study medications compared to the Viread/Emtriva arm (4 percent). The most common cause of discontinuation related to study drug for patients in the Combivir arm was anemia (14 patients, vs. 0 in the Viread/Emtriva arm; p<0.001) and in the Viread/Emtriva arm was NNRTI-associated rash, which occurred in 2 patients. Renal safety was similar in the two groups and no patient discontinued study medication due to renal events.

A significantly (p<0.001) greater percentage of patients in the Viread/Emtriva arm of the study had a lower mean increase from baseline in fasting total cholesterol levels (21 mg/dL) compared to patients in the Combivir arm (35 mg/dL). At week 48, total limb fat was significantly less in a subset of patients receiving Combivir (mean of 6.9 kg or 15.2 pounds; n=49) compared to a subset of patients receiving Viread and Emtriva (mean of 8.9 kg or 19.6 pounds; n=51; p=0.03).

Data from Study 934 have not been reviewed by the U.S. Food and Drug Administration (FDA).

Joint Venture to Develop Fixed-Dose Regimen of Truvada and Sustiva

On December 20, 2004, Gilead and Bristol-Myers Squibb (BMS) announced the establishment of a U.S. joint venture to develop and commercialize a once-daily fixed-dose combination of Truvada and Sustiva. Gilead and BMS announced on January 9, 2006 that the companies have obtained data supporting bioequivalence of a new formulation of the fixed-dose combination with the components that make up the combination and expect to file a new drug application with the FDA in the second quarter of this year.

01/20/06

Source
Gilead Sciences. DATA COMPARING VIREAD® AND EMTRIVA® TO COMBIVIR® AS PART OF COMBINATION HIV THERAPY PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE. January 19, 2006.

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