On May 13 an FDA advisory committee gave backing to the full approval of Bristol-Myers Squibb's new protease inhibitor, atazanavir (Reyataz). The regulatory body now has until June 20 to make its final decision on the application, explains TAG's Antiviral Project Director, Rob Camp. While the drug is welcomed by activists, patients and clinicians alike, there is growing concern in some quarters over issues that BMS is said to have glossed over in its race to approval. A study presented at the hearing called into question the much touted lipid profile of the new PI on the block: atazanavir-treated people showed body fat changes no different from those treated with nelfinavir-implying that a favorable lipid profile does not necessarily translate into a lack of lipodystrophy. Further red flags were raised over cardiac abnormalities, potential liver toxicity and the drug's contested resistance profile.

Members of the AIDS Treatment Activist Coalition (ATAC) went so far as to draft a letter of protest to Antiviral Drug Products director Dr. Debra Birnkrant, expressing fears that the FDA's granting of full approval so quickly would leave BMS little incentive to more clearly define important long-term safety and efficacy issues in a variety of clinical settings. Excerpts from TAG's position paper, which recommended full approval contingent upon completion of follow-up studies to address these issues, appear below.

Overview
Atazanavir is the first protease inhibitor that can be dosed once daily without using ritonavir or other cytochrome P450 inhibitors as boosters. There may, however, be situations (e.g., second-line regimens, high viral loads) where boosting atazanavir with 100 mg of ritonavir may be necessary or useful. Current data support atazanavir's use only as a first-line protease inhibitor in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Data on the combination of atazanavir + ritonavir in second-line and subsequent regimens (and its supposed lipid effects) need to be generated and made available.

The 48-week virologic efficacy of atazanavir is similar to that of nelfinavir, and in one large study atazanavir showed comparable efficacy to that of efavirenz (although in most previous studies efavirenz appeared more potent than it did in this particular study). While atazanavir can thus be approved as a first-line protease inhibitor, data are insufficient to recommend use of atazanavir as a sole protease inhibitor in HIV-infected individuals who have already failed another protease inhibitor-containing regimen. The atazanavir label should clearly state that unboosted, atazanavir has only been studied as a first-line protease inhibitor.

So far the safety profile for atazanavir has not been alarming, although concerns about hyperbilirubinemia and hepatic issues need to be more clearly addressed in ongoing studies. Examples: For those with mild liver impairment, are dose reductions to 300 mg QD recommended? What about the recommended atazanavir dose for more serious liver problems? Although there may be no difference between hepatitis co-infected and non-co-infected people with hyperbilirubinemia, atazanavir should be used with caution (i.e., more visits and laboratory analyses) by people with abnormal liver function tests (LFTs) at baseline, including those with chronic hepatitis. Sadly, the serious adverse events data collected in the expanded access program have not been categorized or published in order to help us define the risks of atazanavir use. This should be done immediately.

Another study showed that switching from nelfinavir to atazanavir is a viable strategy to reduce elevated lipids, suggesting that the change from any non-virologically failing regimen to atazanavir can be made safely. Contrary to initial findings, atazanavir shares cross-resistance with most other protease inhibitors. It is unlikely to be of any use when more than five common protease gene mutations are present.

Interaction studies show that efavirenz lowers atazanavir absorption by 70%, so this combination is only recommended with a ritonavir booster. But what are the effects on lipids of atazanavir + ritonavir 100 mg? For absorption, atazanavir is best taken with "food." What kinds of food were used, and how much was recommended? Absorption was less with a high-fat meal. During studies, how were patients advised? Food studies and guidelines are needed.

Atazanavir's development was aided by substantial participation of study volunteers hailing from South Africa, five countries in South America, and two in Asia. Bristol will need to assure that it is made as accessible in these countries as in developed nations-but at an affordable price.

In summary, atazanavir has both pros (the lipid profile) and cons (hyperbilirubinemia), and with the right clinical use it is clearly a welcome addition to the armamentarium of antiretroviral drugs currently available.

Efficacy
Phase II: Comparison to nelfinavir. Bristol-Myers Squibb studies 007 and 008 compared 693 people on atazanavir to 194 on nelfinavir. There was no significant difference in the proportion of patients achieving <400 or <50 HIV-RNA copies/mL at week 48. CD4 lymphocyte increases were similar, approximately 300 CD4 cells from baseline.

Phase III, Study 034: Comparison to efavirenz. In the 034 study, treatment-naïve patients treated with atazanavir- or efavirenz- based regimens plus 3TC + AZT achieved comparable efficacy at 48 weeks. Of the 805 patients, 82% completed 48 weeks of treatment. Switching was not permitted. An intent-to-treat analysis showed that 70% of atazanavir and 64% of efavirenz patients had viral loads below 400 copies/mL; and, 32% of atazanavir and 37% of efavirenz patients had viral loads below 50 copies/mL. The rise in CD4 counts was 176 for atazanavir- and 160 for efavirenz-treated patients.

Atazanavir in Salvage Regimens
The Puzzle study. Individuals with HIV-RNA >10,000 copies/mL, after failure of two protease inhibitors and one NNRTI, were treated with atazanavir (300 mg QD) + ritonavir (100 mg QD), tenofovir (300 mg QD) and reverse transcriptase inhibitors. Tenofovir decreased atazanavir AUC by 25.2% and ritonavir AUC by 25.6% after four-weeks of tenofovir. One explanation offered was that tenofovir lowers ritonavir, which lowers atazanavir. As tenofovir is a widely used new drug, better studies are needed to confirm this and ascertain its clinical significance. Clearly, when the combination of atazanavir + tenofovir is used, the atazanavir should be boosted by ritonavir.

Atazanavir + saquinavir QD. BMS study 009 evaluated the safety, tolerability, and efficacy of dual protease inhibitor therapy with atazanavir (400 or 600 mg QD) + saquinavir (1,200 mg QD), or ritonavir + saquinavir (400/400 BID) + two nucleoside reverse transcriptase inhibitors after virologic failure on a prior regimen. This was a randomized, blinded study in 85 adults with HIV RNA 1,000-100,000 copies/mL and CD4 <150 cells/mm³. The ritonavir + saquinavir regimen was more potent, but had more discontinuations for treatment-related adverse events.

Resistance Profile
While earlier pre-clinical work suggested that atazanavir might demonstrate a distinct resistance profile, the amino acid changes associated with atazanavir resistance turn out to overlap those of other protease inhibitors (with the exception of the I50L and N88S mutations). The pathways to atazanavir resistance vary, but appear to involve the N88S. As such, broad cross-resistance is expected. A better sense of the resistance profile in antiretroviral-experienced people could have been achieved through a closer look at the virologic outcome of atazanavir use in the expanded access program.

Resistance in Protease Inhibitor Naïve Individuals
The I50L mutation does not confer cross-resistance to other protease inhibitors as assessed by in vitro changes in susceptibility. Indeed, susceptibility to other protease inhibitors may be increased ("hypersusceptibility") by the presence of the I50L substitution. At this time, however, no clinical relevance can be extrapolated because only a handful of samples have been isolated and phenotyped. More studies here are clearly needed. This proposed I50L hypersusceptibility differs from what is seen with mutations I50V or D30N associated with amprenavir and nelfinavir.

Resistance in Protease Inhibitor Experienced Individuals
Seven amino acid substitutions have been identified that correlated with decreased susceptibility to atazanavir: two primary (82 and 90) and five secondary (10, 20, 46, 54 and 73) residues. While no single substitution was uniquely predictive of reduced atazanavir susceptibility, the presence of at least five of the seven key substitutions correlated strongly with an atazanavir fold change greater than four-fold among protease inhibitor resistant clinical isolates which, as previously stated, is detrimental to a constant maintenance of drug above the IC90. One possible combination to study would be atazanavir + ritonavir + amprenavir in salvage settings, as only either the I50L or I50V will be selected. This may force the virus down a pathway that will make it susceptible to the other protease inhibitor(s).

Expanded Access
The program started in May 2002 and now has approximately 3,000 people enrolled in more than 25 countries. serious adverse events have not been reviewed. Once again, an expanded access program has been under-utilized as far as getting useful real-life information.

Follow-Up Studies
Follow-up studies that need to be done include the following:

Dosing. Is the chosen dose the optimum dose? 400 mg QD provides a low inhibitory quotient. It is not altogether clear why Bristol chose the 400 mg QD dose for its Phase III trials. Other studies needed: dosing of 600 mg vs. 800 mg vs. dual protease inhibitor (atazanavir 400 mg + ritonavir 100 mg) as initial therapy.

Switch studies. Because many people with high lipids are going to be interested in switching to atazanavir, it should be clearly demonstrated that this can be done safely and with no loss to efficacy of the regimen in the long term.

Drug-drug interaction/pharmacokinetic studies. Interaction studies need to be done with methadone, H2 blockers, rifampin, statins, fibrates, ribavirin, efavirenz, nevirapine, tenofovir, fos-amprenavir, saquinavir (Invirase and Fortovase), and pegylated interferon.

Pediatrics. No data have been generated for pediatric use. PACTG 020 is presently accruing patients.

Cardiovascular safety. Atazanavir affects the QT interval, like lopinavir + ritonavir. The clinical significance of atazanavir-associated changes in cardiac electrical impulses should be defined, especially with multi-protease inhibitor regimens.

Liver safety. Atazanavir may be contraindicated in people with a history of hyperbilirubinemia or other hepatic abnormalities. Further studies need to be undertaken to characterize atazanavir's side effects in these people, and where and when atazanavir may be contraindicated.

Long-Term Safety
Metabolics. A study is needed which measures the effect of atazanavir on cardiovascular risk factors (with or without concomitant ritonavir) as well as insulin resistance and body shape changes.

Resistance. Does the I50L substitution lead to clinically meaningful hypersusceptibility to other protease inhibitors? Or is this merely an interesting laboratory phenemenon? Under what circumstances? A study is needed.

Protease inhibitor-experienced persons. Bristol recommends the combination of atazanavir + ritonavir after any protease inhibitor failure. We need a clinical study similar to the lopinavir + ritonavir vs. atazanavir study, in single or multi-failure people with atazanavir + ritonavir before this can be recommended clinically for protease inhibitor failures.

Based on data from ongoing and completed studies, specifically the 008, 009, and 034 studies, TAG believes that the FDA should approve the Bristol-Myers Squibb application for accelerated approval of atazanavir (Reyataz) for the treatment of HIV infection in combination with other antiretroviral agents in adults, provided that the follow-up studies recommended within its report are commenced and successfully completed in a timely fashion. ¤