By Liz Highleyman

Atazanavir (Reyataz)

Lopinavir/ ritonavir (Kaletra)

Long-term clinical trial data show that modern HAART regimens offer continued antiviral efficacy over time, although toxicities remain a concern.

The international CASTLE trial compared 2 protease inhibitors, ritonavir-boosted atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra), as first-line therapy for treatment-naive patients. According to the latest U.S. HIV treatment guidelines, both are considered "preferred" options for people starting therapy for the first time.

As previously reported, similar proportions of patients taking atazanavir/ritonavir and lopinavir/ritonavir achieved HIV viral load < 50 copies/mL at 48 weeks (78% vs 76%, respectively), but rates of side effects differed. More recently, researchers reported that side effects among CASTLE participants differed somewhat by race/ethnicity and by gender.

In a late-breaker session at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in Washington, DC, the CASTLE investigators presented 96 week efficacy and safety data.

CASTLE is a randomized, open label, prospective study comparing once-daily 300/100 mg atazanavir/ritonavir vs twice-daily 400/100 mg lopinavir/ritonavir, both in combination with fixed-dose tenofovir/emtricitabine (Truvada) in 883 treatment-naive patients.

More than two-thirds (69%) were men and the mean age was 35 years. About half (48%) were white and 18% were black, with the remainder being "other" or mixed race/ethnicity. The mean baseline viral load was about 5.0 log10 copies/mL, about half had HIV RNA > 100,000 copies/mL, and the median CD4 count was about 200 cells/mm3.

Results

• In an intent-to-treat "non-completer = failure" analysis at 96 weeks, 327 of 440 patients (74%) in the atazanavir/ritonavir arm achieved HIV RNA < 50 copies/mL, compared with 302 of 443 (68%) in the lopinavir/ritonavir arm (P < 0.05).

• Among those with baseline viral load ? 100,000 copies/mL, the corresponding rates were 74% and 66%, respectively.

• Among those with baseline viral load < 100,000 copies/mL, the rates were 75% and 70%, respectively.

• Among those with baseline CD4 count < 50 cells/mm3, the respective rates were 78% and 58%.

• Mean CD4 cell increases from baseline were comparable: 268 in the atazanavir/ritonavir arm and 290 in the lopinavir/ritonavir arm (a non-significant difference).

• Rates of virological failure were low in both arms, at 7%.

• 16% of participants in the atazanavir/ritonavir arm and 21% in the lopinavir/ritonavir group discontinued the study before week 96.

• 3% and 5%, respectively, discontinued due to adverse events.

• 14% taking atazanavir/ritonavir and 11% taking lopinavir/ritonavir experienced serious adverse events.

• 30% and 32%, respectively, experienced any moderate to severe (grade 2-4) adverse events.

• Grade 2-4 hyperbilirubinemia (elevated blood bilirubin) was more frequent in the atazanavir/ritonavir arm (4% vs 0%).

• Grade 2-4 diarrhea (2% vs 12%) and nausea (4% vs 8%) were less common in the atazanavir/ritonavir arm compared with the lopinavir/ritonavir arm (most patients started with the older, less well-tolerated capsule formulation of lopinavir/ritonavir)

• Mean percent increases in fasting triglycerides were significantly smaller among patients taking atazanavir/ritonavir compared with those taking lopinavir/ritonavir (13% vs 50%).

• The same was true for total cholesterol (13% vs 25%, respectively), though the cholesterol breakdown was comparably favorable in both arms:

• Low-density lipoprotein (LDL or "bad") cholesterol: increases of 14% and 17%, respectively;

• High-density lipoprotein (HDL or "good") cholesterol: increases of 21% and 29%, respectively;

• Emergence of drug resistance mutations was infrequent in both arms.

Based on these findings, the investigators stated that "Non-inferiority of atazanavir/ritonavir vs lopinavir/ritonavir was confirmed at week 96."

"In the [intent-to-treat] analysis, atazanavir/ritonavir had higher response rates than lopinavir/ritonavir," they continued. "This difference, not observed in the on-treatment analysis, was driven by similar virologic efficacy and a higher rate of discontinuations among patients receiving lopinavir/ritonavir."

They added that "Atazanavir/ritonavir continues to demonstrate a better lipid profile and fewer GI adverse events" compared with lopinavir/ritonavir.

Once-daily atazanavir/ritonavir plus [tenofovir/emtricitabine] demonstrated durable antiviral efficacy and safety," they concluded. "This regimen is an appropriate therapeutic option for antiretroviral-naive HIV-1-infected patients."

Dept. of Infectious Diseases, Saint-Louis Hosp., Paris, France; Hosp Civil De Guadalajara, Guadalajara, Mexico; Hosp. Natl. Cayetano Heredia, Lima, Peru; Dept. of Med., Khonkaen Univ., Khonkaen, Thailand; Hosp. Interzonal Gral De Agudos Oscar Alende, Buenos Aires, Argentina; Brooklyn Med. Ctr., Western Cape, South Africa; Bristol-Myers Squibb, Research and Devel., Wallingford, CT.

10/31/08

Reference

J Molina, J Andrade-Villanueva, J. Echevarria, and others. CASTLE: Atazanavir-Ritonavir vs Lopinavir-Ritonavir in Antiretroviral-Naïve HIV-1 Infected Patients: 96 Week Efficacy & Safety. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1250d.

Other source

Bristol Myers-Squibb. 96-Week Data From CASTLE Study Continue to Show Similar Efficacy Between Once-Daily REYATAZ (atazanavir sulfate)/Ritonavir and Twice-Daily Lopinavir/Ritonavir in Previously Untreated HIV-1 Infected Adult Patients. Press release. October 26, 2008.