Atazanavir: positive opinion in EU, but only for treatment-experienced and only when boosted

21 November 2003

Estimated reading time 3 minutes

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.

Glossary

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

first-line therapy

The regimen used when starting treatment for the first time.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

off label

Use of a drug for a condition other than that for which it received regulatory approval.

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.