The European Union’s Committee for Proprietary Medicinal Products yesterday gave the go-ahead for the licensing of the new protease inhibitor atazanavir (Reyataz) in Europe – but only when boosted with ritonavir and only for treatment-experienced patients. Marketing approval for Reyataz is due at the end of February 2004.
Atazanavir was approved in the United States earlier this year, with no restriction on its use in treatment-naïve patients and no recommendation for boosting with ritonavir.
The atazanavir decision follows a pattern of EU/US discordance that began with tenofovir, which was initially approved in Europe only for treatment-experienced patients in late 2001. In October 2001 the US Food and Drug Administration approved tenofovir for treatment in any patient with HIV, despite the lack of data at that time to support its use in first-line therapy.
In the case of atazanavir, manufacturer Bristol Myers Squibb had submitted data from a 48 week study, and the decision appears to reflect increasing reluctance on the part of the CPMP to approve new antiretrovirals for first-line treatment without at least 96 weeks of randomised follow-up.
The decision to discourage atazanavir dosing without ritonavir boosting in treatment-experienced patients is likely to have been influenced by two considerations. Atazanavir performed less well than lopinavir/ritonavir in the 034 study, in which patients who had experienced failure of one protease inhibitor-containing regimen were randomised to receive either atazanavir or lopinavir/ritonavir (with two nucleoside analogues they had not taken before). Also, concern has been expressed over the margin of comfort when atazanavir is dosed alone, since trough levels of the drug may not be high enough in some patients. Ritonavir boosting substantially increases trough levels, and a comparison of atazanavir/ritonavir and lopinavir/ritonavir in more heavily protease inhibitor-experienced patients showed no difference after 24 weeks in viral suppression.
However, a strict interpretation of the data gives no information about what happens in patients who have experienced failure of a NNRTI-containing first-line regimen (the typical pattern of treatment in Europe) and who then switch to atazanavir. Supporters of the drug will argue that this is unnecessarily cautious, but with an increasing number of antiretroviral drugs on the market, the CPMP appears to be returning to a traditionally cautious approach to the licensing of new medications, in part because of growing concern in some countries over the volume of patients with resistance to multiple classes of drugs.
However, the CPMP has approved Reyataz in the form of 100, 150 and 200mg capsules, so the potential will exist for doctors to prescribe atazanavir without ritonavir at a dose of 400mg, off label, if they believe this is appropriate.
Further information
Further information on this website
Atazanavir/ritonavir comparable to lopinavir/ritonavir in PI-experienced
Atazanavir in treatment-experienced people: boosted looks better