BMS experimental PI atazanavir shows potency comparable to NNRTI efavirenz among treatment-naïve HIV patients

13 November 2002. Related: Conference reports, Antiretrovirals, ICAAC 42nd San Diego 2002.

Brian Boyle MD and Ronald Baker PhD , for HIVandhepatitis.com

A HAART regimen containing the experimental protease inhibitor (PI) atazanavir produces an anti-HIV effect comparable to an efavirenz -based HAART regimen, according to data presented at the 42nd ICAAC in San Diego in September.

Atazanavir (ATV) is a once-daily protease inhibitor (PI) that has low pill burden (two pills once daily), a favourable lipid profile with virtually no effect on lipids, and a favourable resistance profile with 150L, a mutation that does not appear to affect the other PIs, being the signature mutation in PI-naïve patients treated with ATV.

More details on the metabolic effects at week 24 of the study

In a double-blind, multinational, randomised trial, 810 ARV-naïve patients (mean viral load ~4.85 log10 copies/mL; mean CD4 ~320 cells/mm3) the potency of ATV was compared to efavirenz (EFV, Sustiva, Stocrin) in combination with fixed-dose AZT (zidovudine, ZDV, Retrovir) + 3TC (lamivudine, Epivir). The efficacy results at week 48 are depicted below

* ITT (NC=F)

There was no significant difference in either arm between patients of different gender or with a viral load higher or lower than 100,000 copies/mL at baseline.

“These results are promising and important in that atazanavir, if approved, may provide physicians with another first-line treatment option for individuals with HIV and AIDS,” said Kathleen Squires MD, associate professor of medicine, Keck School of Medicine at the University of Southern California, in a press release from Bristol-Myers Squibb. Dr Squires presented the data at the ICAAC meeting in San Diego.

Both medications appeared safe and relatively well tolerated. Rash was more common in the efavirenz arm and jaundice (5%) more common in the ATV arm. In the ATV arm, 33% of patients experienced a grade 3 or 4 bilirubin increase, but only 5% dose reduced and only 1% discontinued ATV due to this side effect.

The study authors concluded: “ATV once daily has similar antiviral efficacy to a standard of care regimen with efavirenz through [48 weeks]. Both were safe, well tolerated. ATV was associated with decreases or minimal increases in lipid parameters.”

While the results for the efavirenz arm are lower than seen in some prior studies, there are several potential explanations for this. These include the multinational nature of the study, the disallowance of nucleoside analogue switches (which led to more patient discontinuations), the use of a very strict analysis of the data (with treatment failure defined as any noncompleter, any disease progression to CDC category C, 2 sequential HIV RNA levels >50, or 1 HIV RNA level >50 if no subsequent value available or if present at the 48 week time point), and the use of a more sensitive viral assay (Amplicor 1.5) than has been used in prior studies.

Still, the net effect of this trial is to find that ATV did just as well as efavirenz in combination with AZT and 3TC.

In May 2002, Bristol-Myers Squibb filed for the registration of atazanavir with the European Medicines Evaluation Agency. The company plans to file for the registration of atazanavir with the United States Food and Drug Administration later this year.

Comment

These results are still somewhat disappointing considering a success rate of 70-80% (<50 copies) in the recent efavirenz containing studies (TDF 903, FTC both presented as late breaker at ICAAC).

Both studies were multinational and both studies used Amplicor with <50 copies.

An intent to treat analysis which includes patients switching or discontinuing the study drug would be interesting, because if the above explanations are true the success rate should be much higher in this approach.

Sources:

K Squires and others. Atazanavir (ATV) QD and Efavirenz (EFV) QD with Fixed-Dose ZDV+3TC: Comparison of Antiviral Efficacy and Safety Through Wk 24 (AI424-034).  Abstract 1076. 42nd ICAAC Abstracts, September 27 – 30, 2002, San Diego, CA.

Bristol-Myers Squibb. Data show Bristol-Myers Squibb’s investigational protease inhibitor atazanavir provided antiviral effect comparable to Sustiva in treatment-naïve HIV/AIDS patients. Press Release. September 28, 2002.

Personal Communication. David Rosen. September 29, 2002.