EU Approves Boosted Reyataz(R) (Atazanavir Sulphate), In Combination With Other Antiretroviral Medicines, For Treating Naive HIV-1 Infected Adults

Main Category: HIV / AIDS
Also Included In: Regulatory Affairs / Drug Approvals
Article Date: 25 Jun 2008 - 1:00 PDT

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The European Commission has granted marketing authorization for REYATAZ® (atazanavir sulphate 300mg once daily), administered with ritonavir 100 mg once daily and taken in combination with other antiretroviral medicinal products, in antiretroviral treatment-naïve human immunodeficiency virus-1 (HIV-1) infected adults. The decision means that the use of atazanavir/r (atazanavir boosted with ritonavir) in antiretroviral treatment naïve patients is approved for marketing in the 27 countries of the European Union.

"The key factors for assessing a therapy for treatment naïve HIV patients include efficacy, safety and tolerability" said Graeme Moyle, Director of HIV Research Strategy, Chelsea and Westminster Hospital. "Boosted atazanavir is a protease inhibitor (PI) that offers once-daily dosing with a low pill burden with the new 300mg capsule, and has proven to be an effective and generally well tolerated treatment that is already used in treatment experienced patients. It is of great benefit to clinicians in the UK that we now have approval to use the first once-daily boosted PI in treatment naïve patients."

Similar efficacy with a difference in adverse event profile

The CASTLE study[1] provided the basis for registration filings for atazanavir/r in treatment-naïve patients. This large-scale, open-label, randomized study was designed to show the non-inferiority of atazanavir/r to lopinavir/r in previously untreated HIV-1 infected adult patients.

The results showed that efficacy was similar in both study arms; 78 percent of patients (n=343/440) taking once-daily atazanavir/r met the primary endpoint of achieving undetectable viral load (defined as less than 50 copies/mL) at 48 weeks, compared with 76 percent of patients (n=337/443) taking twice-daily lopinavir/r.

Safety events in the study were consistent with prior experience, and patients taking atazanavir/r experienced lower rates of Grade 2-4 adverse events such as diarrhoea (2%) and nausea (4%) than those taking lopinavir/r (11% and 8% respectively). Additionally, the atazanaivr/r arm was associated with significantly lower increases from baseline compared to the lopinavir/r arm in total cholesterol, triglycerides and non-HDL cholesterol at 48 weeks (all p<0.0001).

As with previous observation, 34% of the patients in the atazanaivr/r arm and less than 1% of patients in the twice-daily lopinavir/r arm experienced elevations in total bilirubin (hyperbilirubinaemia) greater than 2.5 times the upper limit of normal. This elevation was not associated with liver dysfunction as the rates of Grade 3-4 liver enzyme elevations were similar between treatment groups (2% in once-daily atazanaivr/r arm vs 1% in the twice-daily lopinavir/r arm).

Atazanavir 300mg boosted with 100mg ritonavir is now available in the UK for use in naive patients.

Bristol-Myers Squibb is a global biopharmaceutical and related health care products company whose mission is to extend and enhance human life.

REYATAZ® is a registered trademark of Bristol-Myers Squibb.

About the CASTLE study

The international, multi-centre, open-label, 96-week CASTLE study randomized 883 treatment-naive patients infected with HIV-1. Four hundred and forty patients were randomized to receive Atazanavir 300 mg and ritonavir 100 mg once daily and 443 patients were randomized to receive lopinavir/ritonavir 400/100 mg twice daily, each in combination with a once-daily, fixed-dose combination of emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg.

All patients had a baseline viral load of greater than or equal to 5,000 copies/mL; there was no CD4+ cell count restriction for study entry. The primary endpoint for the study was the proportion of patients with viral load of less than 50 copies/mL at 48 weeks.

Study results

- Efficacy was similar in both study arms; 78 percent of patients (n=343/440) taking once-daily atazanavir/ritonavir met the primary endpoint of achieving undetectable viral load (defined as less than 50 copies/mL) at 48 weeks, compared with 76 percent of patients (n=337/443) taking twice-daily lopinavir/ritonavir.

- Patients taking atazanaivr/ritonavir experienced lower rates of Grade 2-4 adverse events such as diarrhoea (2%) and nausea (4%) than those taking lopinavir/ritonavir (11% and 8% respectively), consistent with prior experience.

- The atazanavir/ritonavir arm was associated with significantly lower increases from baseline compared to lopinavir/ritonavir arm in total cholesterol, triglycerides and non-HDL cholesterol at 48 weeks (p<0.0001).

- As with previous observation, 34% of the patients in the atazanavir/ritonavir arm and less than 1% of patients in the twice-daily lopinavir/ritonavir arm experienced elevations in total bilirubin (hyperbilirubinaemia) greater than 2.5 times the upper limit of normal.

- The elevation in bilirubin was not associated with liver dysfunction as the rates of Grade 3-4 liver enzyme elevations were similar between treatment groups (2% in once-daily atazanavir/ritonavir arm vs 1% in the twice-daily lopinavir/ritonavir arm).

Important Information About Atazanavir

In the UK, atazanavir with ritonavir was previously indicated for the treatment of HIV-1 infected, antiretroviral treatment-experienced adults, in combination with other antiretroviral medicinal products2 In antiretroviral treatment-experienced patients, the demonstration of efficacy is based on study AI424-045 which compared atazanavir 300 mg once daily in combination with ritonavir 100 mg once daily with lopinavir/ritonavir, each regimen in combination with tenofovir and one NRTI. Based on available virological and clinical data, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). The choice of atazanavir should be based on individual viral resistance testing and the patient's treatment history2

[1] Molina, JM, Andrade-Villanueva, J, Echevarria, J. Et al. 'Efficacy and Safety of Once-Daily Atazanavir/Ritonavir (ATV/r) Compared to Twice-Daily Lopinavir/Ritonavir (LPV/r), Each in Combination with Tenofovir (TDF) and Emtricitabine (FTC), in Antiretroviral (ARV) Naive HIV-1 Infected Subjects. The CASTLE Study (AI424-138) 48 Week Results. Oral presentation. 15th Conference on Retroviruses and Opportunistic Infections, Boston, USA, 2008. References

1. Molina J-M. et al., CROI 2008, Boston, USA. Oral presentation 37
2. Reyataz Summary of Product Characteristics, June 2008 (accessible at http://www.medicines.org.uk)

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