Effectiveness

Atazanavir (Reyataz) is an effective antiretroviral agent with comparable efficacy to other protease inhibitors and to non-nucleoside reverse transcriptase inhibitors (NNRTIs). It should be given in combination with other antiretroviral drugs, except in certain limited circumstances.

In 2007, the 96-week results of the AI424-089 trial showed that atazanavir taken alone or boosted with ritonavir (atazanavir/r) once-daily as part of an antiretroviral regimen is safe and effective in treatment-naive, HIV-infected individuals, including those with advanced HIV disease.1 

The trial compared atazanavir/ritonavir 300/100mg once daily with atazanavir 400mg once daily in treatment-naive participants. In both study arms, once-daily lamivudine (3TC), and extended release stavudine were also given. At baseline, roughly half the participants had an average CD4 cell count around 200 cells/mm3 and a viral load above 100,000 copies/ml. 

At 96 weeks, boosted atazanavir showed a trend toward a higher rate of viral suppression, fewer virological rebounds, and less protease inhibitor or nucleoside analogue resistance. There was no statistically significant difference in the number of study participants achieving a viral load less than 50 copies/ml by intent-to-treat analysis. There were fewer virologic failures among people taking boosted atazanavir.

Five patients taking boosted atazanavir stopped treatment due to hyperbilirubinaemia, compared to none in the unboosted arm and there was a much higher rate of grade 3/4 bilirubin elevation in the boosted atazanavir group (66 vs 24%). Although participants taking boosted atazanavir experienced lipid elevations at a greater frequency (20 vs 7%), none required intervention.

The AI424-008 study has shown that atazanavir is of similar efficacy to the protease inhibitor nelfinavir (Viracept) in patients who are ARV-naive. After 48 weeks, similar numbers of patients had undetectable viral loads, with similar CD4 cell count increases.2 The A1424-007 study came to similar conclusions.3

In the United States, atazanavir, alone or boosted, is already licensed for first-line ART in therapy-naive or experienced patients and it is listed as a preferred regimen in the treatment guidelines. In Europe, it must be boosted with ritonavir.

The CASTLE study is a randomised, open-label, multicentre, study for ART-naive participants, assessing the non-inferiority of once-daily atazanavir (300mg) boosted with 100mg ritonavir compared to lopinavir/ritonavir (Kaletra) taken twice daily. Participants also receive once-daily Truvada (tenofovir + emtricitabine). In early 2008, the 48-week results were presented.4

Although designed as a 96-week trial, the study’s primary endpoint was the proportion of study participants with a viral load less than 50 copies/ml at week 48. That goal was met by 78% of participants in the atazanavir/r arm as compared to 76% in the lopinavir/r arm, a statistically insignificant difference.

The study enrolled over 800 participants who were evenly matched at baseline. The median CD4 count was just over 200 cells/mm3 and all patients had a baseline viral load greater than or equal to 5000 copies/ml. Thirty-one percent of the participants in both arms were female.

Responses in the two arms were also similar in participants who began with higher and with lower viral loads. Of the 435 participants with HIV RNA levels ≥100,000 copies/ml at baseline, 82% in the atazanavir/r arm and 81% in the lopinavir/r arm achieved suppression. Of the 448 with viral load <100,000, 74% and 72% achieved suppression respectively.

Mean CD4 increases from baseline were 203 cells/mm3 for atazanavir/ritonavir and 219 cells/mm3 for Kaletra. 

The investigators conclude that once-daily atazanavir/r is non-inferior to twice-daily lopinavir/r in treatment-naive individuals, with comparable antiviral efficacy, when combined with tenofovir and FTC. Boosted atazanavir appears to be better tolerated with a favourable lipid profile.

Seven percent of patients in the atazanavir/r arm vs 18% of patients in the lopinavir/r arm had total cholesterol greater than or equal to 240 mg/dL. In the atazanavir/r arm, 26% of patients experienced any grade 2-4 treatment-related adverse events as compared to 30% of patients in the other arm. Participants in the atazanivir/r arm also experienced fewer cases of diarrhoea and nausea.

Data on atazanavir in treatment-experienced patients are also available. Unsurprisingly, the AI424-043 study showed that atazanavir alone is not as potent as ritonavir-boosted lopinavir.5

However, study AI424-045 showed that once-daily, atazanavir/r was as effective as twice-daily lopinavir/r at suppressing viral load over two years when combined with tenofovir (Viread) and an NRTI in treatment-experienced patients. That study also suggested that atazanavir was better tolerated than Kaletra and resulted in a better lipid profile. More patients in the Kaletra arm experienced severe gastrointestinal side-effects, such as diarrhoea. The relative effects of the drugs in this study were unaffected by the number of baseline mutations.6 7

There is also evidence that dual boosted protease inhibitor drug combinations including atazanavir with Kaletra, ritonavir-boosted saquinavir (Invirase) are effective and safe in patients with substantial treatment experience.8 9

Recent evidence has suggested that ritonavir-boosted atazanavir-based therapy is safe and well tolerated in patients infected with hepatitis B or hepatitis C viruses. Similar rates of liver enzyme elevations were seen in a group of 180 hepatitis-co-infected patients and 124 patients who were not co-infected, with similar withdrawal rates in the two groups.10

Atazanavir is also safe and effective in HIV-positive patients with liver cirrhosis, according to a retrospective Spanish study presented in 2006. The investigators found that patients with cirrhosis who received atazanavir had both an immunological and virological response to the drug, but did not experience any clinically significant liver-related side-effects.11

Ritonavir-boosted atazanavir without any other anti-HIV drugs may also be a suitable 'maintenance' treatment for patients who have suppressed viral loads on combination therapy. One study of 36 patients found that 31 maintained viral suppression for at least 24 weeks. However, larger, randomised studies are required before this strategy can be recommended.12

References

  1. Malen N et al. Efficacy and safety of atazanavir-based therapy in antiretroviral naïve HIV-1 infected subjects both with and without ritonavir: 96-week results from AI424-089. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, abstract WEPEB024, 2007
  2. Murphy R et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS 17: 2603-2614, 2003
  3. Sanne I et al. Results of a phase 2 clinical trial at 48 weeks (A1424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 32: 18-29, 2003
  4. Molina J-M et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naïve HIV-1-infected subjects: the CASTLE study, 48-week results. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, Abstract 37, 2008
  5. Nieto-Cisneros L et al. Antiviral efficacy, metabolic changes and safety of atazanavir versus lopinavir / ritonavir in combination with NRTIs in patients who have experienced virological failure with prior PI-containing regimen(s): 24-week results from BMX A1424-043. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 117, 2003
  6. Johnson M et al. Atazanavir plus ritonavir or saquinavir, and lopinavir / ritonavir in patients experiencing multiple virological failures. AIDS 19: 685-694, 2005
  7. Johnson M et al. The influence of baseline protease inhibitor mutations on the efficacy of ritonavir-boosted atazanavir, atazanavir plus saquinavir, and lopinavir / ritonavir in patients who have experienced virologic failure on multiple HAART regimens. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 711, 2005
  8. Duvivier C et al. Dual boosted atazanavir / lopinavir / ritonavir containing regimen in HIV-1 infected pretreated patients: plasma trough concentration and efficacy results. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WePe3.2C10, 2005
  9. Boffito M et al. Atazanavir enhances saquinavir hard gel concentrations in a ritonavir-boosted once daily regimen. AIDS 18: 1291-1297, 2004
  10. Perez-Elias MJ et al. Effect of ritonavir-boosted atazanavir (Atv / R) in experienced HIV-infected patients regarding chronic hepatitis B / C status. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe1.1C25, 2005
  11. Hermida JM et al. Efficacy and safety of atazanavir in HIV-infected patients with liver cirrhosis. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, abstract MOPEB060, 2007
  12. Swindells S et al. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA 296: 806-814, 2006
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