Trizivir versus Unboosted Atazanavir/AZT/3TC: The ACTION Study

There is ongoing controversy about the effectiveness of combination antiretroviral regimens that contain only nucleoside reverse transcriptase inhibitors (NRTIs). Studies to date indicate that triple-NRTI regimens may not provide adequate potency for treatment-naive individuals with high HIV viral loads; such regimens are not indicated for treatment-experienced patients.

As presented at the 46th ICAAC, held last week in San Francisco, Princey Kumar and colleagues conducted a multicenter, open-label study to evaluate the immunological and virological activity of the all-NRTI fixed-dose combination of abacavir, AZT, and 3TC (Trizivir) versus the AZT/3TC fixed-dose combination (Combivir) plus unboosted atazanavir (Reyataz) in treatment-naive patients.

The ACTION study included 279 subjects with plasma HIV viral loads of at least 5000 but less than 200,000 copies/mL (stratified as above or below 100,000 copies/mL), and CD4 cell counts of at least 100 cells/mm3.

Participants were randomly assigned to receive one of the following regimens for 48 weeks:

abacavir/AZT/3TC twice daily
AZT/3TC twice daily plus 400 mg atazanavir once daily

Patients were permitted to switch drugs if they developed abacavir hypersensitivity or complications related to hyperbilirubinemia (high bilirubin level, a know side effect of atazanavir).

Baseline characteristics were similar in the 2 arms. Overall, the median age was 37 years, 79% were men, 44% were white, 33% were black, and 20% were Hispanic. The median HIV viral load was 4.55 log copies/mL, 83% had viral loads below 100,000 copies/mL, and the median CD4 cell count was 270 cells/mm3; 85%, 11%, 4%, respectively, had CDC HIV disease stages A, B, and C.

Due to concerns about inadequate antiviral potency of triple-NRTI regimens, the researchers used strict criteria for virological failure, defined as any of the following:

Failure to have at least a 1 log drop in HIV RNA by Week 12;
Failure to achieve HIV RNA below 400 copies/mL by Week 24;
Confirmed HIV RNA below 50, then rebounded to 400 copies/mL or higher before Week 24;
Confirmed HIV RNA of 400 copies/mL or higher after Week 24.
Unconfirmed HIV RNA of 400 copies/mL or higher at Week 48.

Results

48-week virological response data are shown in the table below:

Table.  Abacavir/AZT/3TC BID versus Atazanavir + AZT/3TC BID

13% of patients in the abacavir/AZT/3TC arm and 12% in the atazanavir/AZT/3TC arm experienced virological failure.
Among patients with low baseline viral loads, more achieved undetectable HIV RNA in the abacavir/AZT/3TC arm.
In contrast, among patients with high baseline viral loads, more achieved undetectable HIV RNA in the atazanavir/AZT/3TC arm.
Both regimens were generally well-tolerated, with minimal lipid changes.
About 10 subjects in each arm had evidence of emergent resistance mutations at the time of virological failure, mostly M184V.

Conclusion

The researchers concluded that abacavir/AZT/3TC was non-inferior to atazanavir/AZT/3TC through 48 weeks of therapy and may be acceptable as initial therapy in a carefully selected group of patients with viral load below 100,000 copies.

They emphasized, however, that these results do not support triple-NRTI therapy for patients with higher baseline viral loads, and noted that neither regimen is currently listed as "first-line" in the U.S. DHHS treatment guidelines.

Georgetown University, Washington, DC; GlaxoSmithKline, Research Triangle Park, NC; Diversified Med. Practice, Houston, TX; Orlando Immunology Ctr., Orlando, FL; Therafirst Med. Ctr., Ft. Lauderdale, FL.

10/03/06

Reference
P N Kumar, P Patel, P Salvato, and others. ACTION Study: Efficacy and Safety of Abacavir/Lamivudine/Zidovudine [ABC/3TC/ZDV] BID Versus Lamivudine/Zidovudine [3TC/ZDV] BID + Atazanavir [ATV] QD in ART-Naive HIV-1 Infected Subjects. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract H-1058.

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