Atazanavir equal to efavirenz: new PI proves its potency, but leaves some questions

Kate Squires of the University of Southern California reported some surprising results today at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, from a comparative study of atazanavir versus efavirenz. Both are once daily drugs produced by Bristol Myers Squibb. Efavirenz has replaced nelfinavir as the gold standard against which new agents need to measure up if they are to have credibility.

In this study, 805 treatment-naïve individuals were randomized to receive atazanavir (400mg qd) or efavirenz (600mg qd) with AZT/3TC as Combivir. The mean baseline viral load was approximately 80,000 copies/ml, and the mean CD4 counts were 286 and 280 cells/mm3 respectively.

After 48 weeks, 70% of the atazanavir group and 64% of the efavirenz group had viral load below 400 copies/ml by intent to treat analysis (which counts all patients who started treatment, whether or not they are still receiving the study drugs at week 48), but only 32% and 37% respectively had viral load below 50 copies.

Efavirenz recipients were significantly more likely to experience LDL cholesterol and triglyceride increases; whilst fasting LDL cholesterol levels rose an average of 1% in atazanavir group, levels rose by 18% in the efavirenz group at week 24 (p

Six per cent of the atazanavir group discontinued treatment due to adverse events, compared to 10% of the efavirenz group, a significant difference. Individuals who were forced to change treatment due to nucleoside analogue intolerance were counted as treatment failures; substitution of nucleoside analogues was not permitted.

Less than one per cent of the atazanavir group discontinued treatment due to bilirubin elevations. Bilirubin, the liver enzyme associated with the appearance of jaundice, can become elevated on atazanavir.

What does this study show?

This study has been eagerly awaited, and shows that atazanavir is comparable to efavirenz in potency. The low levels of viral suppression below 50 copies at week 48 in comparison to other studies are not fully explained however; presenting the study, Kate Squires suggested that use of the Roche 1.5 assay (intended to measure non-B HIV subtypes more accurately) may have contributed somewhat to this result, presumably through greater sensitivity. The study was conducted at 91 sites worldwide, the majority outside Europe and North America.

Kate Squires also noted that whilst suppression below 50 copies in the efavirenz group was anomalously low in the efavirenz group compared with other studies, the rates of viral suppression in patients with baseline viral load above 100,000 copies/ml were broadly comparable with other studies of efavirenz. No significant difference was found in rates of viral suppression below 400 copies between patients with baseline viral load above or below 100,000 copies/ml.

Seventeen per cent of patients in each group had viral load rebound above 400 copies/ml at week 24, or failed to experience viral suppression below this level by that time point, and genotypic resistance testing in these patients revealed that nearly two thirds of the efavirenz-treated patients had the K103N mutation, a sign of efavirenz resistance.

In the atazanavir group, protease mutations were largely concentrated at codon I50L (in three of five genotypeable subjects; the I50I/L mutant being detectable in one other). The I50L mutation is characteristic of atazanavir resistance. This mutation does not appear to confer cross-resistance to other protease inhibitors.

Atazanavir is also less likely to lead to any metabolic disturbances; in fact, it is the first protease inhibitor or NNRTI that doesn’t cause increases in triglyceride and cholesterol levels, and the triglyceride reduction seen in the atazanavir group should be considered in the context of a tendency for triglyceride levels to rise as HIV disease progresses. “This could be considered as a sign that patients are getting well”, Dr Mike Youle of London’s Royal Free Hospital told aidsmap.