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IAS 2009: ARIES Trial Shows Unboosted Atazanavir (Reyataz) Maintains Viral Suppression as well as Boosted Drug

The protease inhibitor atazanavir (Reyataz), taken with abacavir/lamivudine (Epzicom coformulation), was as likely to keep viral load undetectable after initial suppression as the same combination plus a boosting dose of ritonavir, researchers reported at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009) last month in Cape Town, South Africa. The unboosted regimen, however, was less likely to cause cholesterol and triglyceride elevations.

Kathleen Squires and colleagues conducted a large, open-label, non-inferiority trial, known as ARIES, to compare the efficacy, safety, tolerability, and durability of boosted versus unboosted atazanavir as a maintenance regimen in HIV patients with suppressed viral load.

More than 500 treatment-naive participants started on an induction regimen of 300/100 mg atazanavir/ritonavir plus the fixed-dose 600/300 mg abacavir/lamivudine pill once-daily.

Before starting abacavir, participants were screened using the HLA-B*5701 genetic test for hypersensitivity risk. ARIES was the first large North American study to use HLA-B*5701 screening to reduce the risk of abacavir hypersensitivity reactions, according to a press release issued by abacavir manufacturer GlaxoSmithKline. Out of 725 total patients screened, 41 (5.7%) tested HLA-B*5701 positive and were excluded from participation.

At week 36, those with confirmed viral load < 50 copies/mL and no virological failure were randomly assigned (1:1) to either remain on the same boosted regimen or drop ritonavir and continue on unboosted atazanavir for an additional 48 weeks. Participants then had an option to continue in an extension of the study through week 144.

Baseline characteristics were similar overall in the 2 arms. A majority of participants (84%) were men, the mean age was about 40 years, nearly two-thirds were white, and about one-third were black. Most patients (90%) in both arms had a low Framingham cardiovascular risk scores; 5% were coinfected with hepatitis C virus (HCV). The median CD4 cell count was 200 cells/mm³, but 13% had < 50 cells/mm³. However, patients in the unboosted atazanavir arm were twice as likely to have had a CDC class C AIDS diagnosis (16% vs 8%).

The primary endpoint was the proportion of participants with HIV RNA < 50 copies/mL at Week 84 using an intent-to-treat TLOVR (time to loss of virological response) analysis.

Results:

• In the week 84 intent-to-treat analysis, 86% of patients taking unboosted atazanavir had HIV RNA < 50 copies/mL, compared with 81% taking atazanavir/ritonavir.
• This difference was not statistically significant, thus demonstrating that unboosted atazanavir was non-inferior to the boosted drug (P = 0.140).
• With regard to viral load < 400 copies/mL, the corresponding rates were 92% and 86%, which did reach statistical significance favoring unboosted atazanavir (P = 0.036).
• Sub-analysis of participants with high and low baseline viral load also showed similar rates of continued virological suppression in the unboosted and boosted atazanavir arms:
  • HIV RNA < 100,000 copies/mL: 85% vs 79%, respectively;
  • HIV RNA ³100,000 copies/mL: 857 vs 82%, respectively.
• 1 patient in the unboosted atazanavir arm experienced confirmed virological failure (>400 copies/mL), compared with 7 in the boosted atazanavir arm.
• The single failing patient in the unboosted arm develop a reverse transcriptase resistance mutation, but no one developed any major protease inhibitor resistance mutations.
• Median CD4 cell count increases were similar, 240 cells/mm³ in the unboosted atazanavir arm and cells/mm³ atazanavir/ritonavir arms
• Treatment was generally well tolerated in both arms.
• Similar proportions of patients in the unboosted and boosted atazanavir arms withdrew early for any reason (8% vs 11%).
• Similar proportions in the unboosted and boosted arms experienced moderate-to-severe side effects (26% in both groups after the initial 36 weeks; 10% vs. 14% during the 48 week randomized period).
• Although about 13% of patients in both arms developed moderate or worse hyperbilirubinemia (elevated bilirubin, which can cause yellowing of the skin and whites of the eyes) during the induction phase, at week 84 fewer than half as many people in the unboosted atazanavir arm still had elevated bilirubin (4% vs 10%).
• Relative to the induction phase, median total and LDL ("bad") cholesterol fell during the randomized period in the unboosted atazanavir arm, while continuing to rise in the boosted arm, a significant difference.
• Triglycerides decreased in both arms, but more so in the unboosted arm.

Based on these findings, the researchers concluded that "[unboosted] atazanavir demonstrated similar efficacy to atazanavir/ritonavir," each in combination with abacavir/lamivudine, regardless of baseline viral load."

"Subjects in the simplification arm demonstrated a more favorable lipid profile and decreased bilirubin levels compared to those in the continuation arm," they added.

During discussion of the presentation, Squires noted that adherence was high (> 90%) in both arms, so improved adherence did likely did not explain the apparent slight advantage in the unboosted atazanavir arm.

Thomas Jefferson University, Philadelphia, PA; University of Colorado, Denver, CO; Orlando Immunology Center, Orlando, FL; SW Infectious Diseases Association, Dallas, TX; Clinique Medicale L'Actuel, Montreal, Canada; GlaxoSmithKline, Research Triangle Park, NC.

8/14/09

Reference

K Squires, B Young, E DeJesus, and others. Similar efficacy and tolerability of atazanavir (ATV) compared to ATV/ritonavir (RTV, r), each in combination with abacavir/lamivudine (ABC/3TC), after initial supression with ABC/3TC + ATV/r in HIV-1 infected patients: 84 week results of the ARIES trial. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract WELBB103.

Other source

GlaxoSmithKline. Epzicom + atazanavir regimen provided comparable efficacy to Epzicom + atazanavir/ritonavir regimen in treatment-naive HIV-infected patients. Press release. July 22, 2009.