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Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study.
Lancet. 2008 Aug 23; 372(9639):646-55.Lct

Abstract

BACKGROUND

Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients.

METHODS

In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779.

FINDINGS

At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1.7%, 95% CI -3.8 to 7.1). Mean increases from baseline in CD4 cell count were similar (203 cells per muL in the atazanavir/ritonavir group vs 219 cells per muL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2-4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2-4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3-4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir.

INTERPRETATION

In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia.

Authors+Show Affiliations

Department of Infectious Diseases, Saint-Louis Hospital, AP-HP, Paris; University of Paris-Diderot, Paris 7, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18722869

Citation

Molina, Jean-Michel, et al. "Once-daily Atazanavir/ritonavir Versus Twice-daily Lopinavir/ritonavir, Each in Combination With Tenofovir and Emtricitabine, for Management of Antiretroviral-naive HIV-1-infected Patients: 48 Week Efficacy and Safety Results of the CASTLE Study." Lancet (London, England), vol. 372, no. 9639, 2008, pp. 646-55.
Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646-55.
Molina, J. M., Andrade-Villanueva, J., Echevarria, J., Chetchotisakd, P., Corral, J., David, N., Moyle, G., Mancini, M., Percival, L., Yang, R., Thiry, A., & McGrath, D. (2008). Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet (London, England), 372(9639), 646-55. https://doi.org/10.1016/S0140-6736(08)61081-8
Molina JM, et al. Once-daily Atazanavir/ritonavir Versus Twice-daily Lopinavir/ritonavir, Each in Combination With Tenofovir and Emtricitabine, for Management of Antiretroviral-naive HIV-1-infected Patients: 48 Week Efficacy and Safety Results of the CASTLE Study. Lancet. 2008 Aug 23;372(9639):646-55. PubMed PMID: 18722869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. AU - Molina,Jean-Michel, AU - Andrade-Villanueva,Jaime, AU - Echevarria,Juan, AU - Chetchotisakd,Ploenchan, AU - Corral,Jorge, AU - David,Neal, AU - Moyle,Graeme, AU - Mancini,Marco, AU - Percival,Lisa, AU - Yang,Rong, AU - Thiry,Alexandra, AU - McGrath,Donnie, AU - ,, PY - 2008/8/30/pubmed PY - 2008/9/3/medline PY - 2008/8/30/entrez SP - 646 EP - 55 JF - Lancet (London, England) JO - Lancet VL - 372 IS - 9639 N2 - BACKGROUND: Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients. METHODS: In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779. FINDINGS: At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1.7%, 95% CI -3.8 to 7.1). Mean increases from baseline in CD4 cell count were similar (203 cells per muL in the atazanavir/ritonavir group vs 219 cells per muL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2-4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2-4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3-4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir. INTERPRETATION: In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/18722869/Once_daily_atazanavir/ritonavir_versus_twice_daily_lopinavir/ritonavir_each_in_combination_with_tenofovir_and_emtricitabine_for_management_of_antiretroviral_naive_HIV_1_infected_patients:_48_week_efficacy_and_safety_results_of_the_CASTLE_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)61081-8 DB - PRIME DP - Unbound Medicine ER -