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Once-Daily Atazanavir/Ritonavir Versus Twice-Daily

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Once-Daily Atazanavir/Ritonavir Versus Twice-Daily Articles 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 effi cacy and safety results of the CASTLE study Jean-Michel Molina, Jaime Andrade-Villanueva, Juan Echevarria, Ploenchan Chetchotisakd, Jorge Corral, Neal David, Graeme Moyle, Marco Mancini, Lisa Percival, Rong Yang, Alexandra Thiry, Donnie McGrath, for the CASTLE Study Team* Summary Lancet 2008; 372: 646–55 Background Atazanavir/ritonavir is as eff ective as lopinavir/ritonavir, with a more favourable lipid profi le and less Published Online gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations August 2, 2008 directly in treatment-naive patients. DOI:10.1016/S0140- 6736(08)61081-8 Methods In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were See Comment page 604 randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg *Members listed at end of paper twice daily (n=443), in combination with fi xed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation Department of Infectious was done with a computer-generated centralised randomisation schedule and was stratifi ed by baseline levels of HIV Diseases, Saint-Louis Hospital, AP-HP, Paris RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than (Prof J-M Molina MD); 50 copies per mL at week 48. The main effi cacy analysis was done by intention to treat. This trial is registered with University of Paris-Diderot, ClinicalTrials.gov, number NCT00272779. Paris 7, France (Prof J-M Molina); Hosp Civil De Guadalajara, Guadalajara, Mexico Findings At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving (J Andrade-Villanueva MD); lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (diff erence 1·7%, 95% CI –3·8 to 7·1). Mean Hospital Nacional Cayetano increases from baseline in CD4 cell count were similar (203 cells per µL in the atazanavir/ritonavir group vs 219 cells Heredia, Lima, Peru (J Echevarria MD); Department per µL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ of Medicine, Khonkaen ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had University, Khonkaen, Thailand non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance (Prof P Chetchotisakd MD); to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir Hospital Interzonal Gral De Agudos Oscar Alende, Buenos group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group Aires, Argentina (J Corral MD); than in the lopinavir/ritonavir group experienced grade 2–4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and Brooklyn Medical Centre, nausea (17 [4%] vs 33 [8%]). Grade 2–4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group Western Cape, South Africa versus none of 437 patients in the lopinavir/ritonavir group; grade 3–4 increases in total bilirubin were seen in (N David FCFP [SA]); Chelsea and Westminster Hospital, 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir. London, UK (G Moyle MD); and Research and Development, Interpretation In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral effi cacy to Bristol-Myers Squibb, lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia. Wallingford, CT, USA (M Mancini BS, L Percival MS, R Yang PhD, A Thiry PhD, Funding Bristol-Myers Squibb. D McGrath MD) Correspondence to: Introduction HAART in antiretroviral-naive patients.4–6 The choice of Prof Jean-Michel Molina, Since the introduction of combination highly active drugs is governed by consideration of effi cacy and Department of Infectious Diseases, Hopital Saint-Louis 1, antiretroviral therapy (HAART), there have been dramatic assessment of diff erences among treatment options in av C Vellefaux, reductions in HIV-1-related morbidity and mortality in terms of dosing convenience, tolerability, and 75475 Paris Cedex 10, France the developed world.1,2 While antiretroviral treatment longer-term safety concerns.7–9 For PI therapy, [email protected] strategies for HIV-infected patients continue to evolve, gastrointestinal tolerability and lipid profi le are key protease inhibitors (PIs) remain a cornerstone of HAART considerations. Gastrointestinal intolerability is an because of their recognised potency and high genetic established risk for treatment failure10 and PI-associated barrier to antiretroviral resistance.3 dyslipidaemia partly explains the increase in the risk Most current international guidelines recommend for myocardial infarction observed in patients on ritonavir-boosted PIs, including fi xed-dose lopinavir/ HAART.3,4,7,11–13 ritonavir and atazanavir, as preferred, or alternative Atazanavir is a potent once-daily PI with proven effi cacy third-agent HIV medications for the initiation of in both treatment-experienced and treatment-naive 646 www.thelancet.com Vol 372 August 23, 2008 Articles patients.14–18 It has a favourable impact on lipids in 19 treatment-naive patients and, even when boosted with 1057 assessed for eligibility ritonavir, results in better lipid profi les and improved gastrointestinal tolerability compared with lopinavir/ 174 excluded ritonavir in treatment-experienced patients.4,17 The aim of 133 no longer meet study criteria the 96-week CASTLE study (BMS AI424138) is to examine 17 withdrew consent the comparative clinical effi cacy of once-daily atazanavir/ 3 pregnancies 1 adverse event 883 randomised ritonavir and twice-daily lopinavir/ritonavir, both given 12 other in combination with once-daily, fi xed-dose tenofovir and 6 lost to follow-up 1 administrative reason emtricitabine, in treatment-naive HIV-1-infected patients. 1 non-compliance Here, we report the 48-week primary effi cacy and safety results of this study. Methods Participants 440 allocated to atazanavir/ritonavir 443 allocated to lopinavir/ritonavir 438 received intervention 440 received intervention* Patients were recruited from centres at 134 sites in 2 never received drug 3 never received drug 29 countries from November, 2005, through June, 2006, and were eligible for enrolment if they were infected with 39 discontinued by week 48 58 discontinued by week 48 HIV-1, aged 18 years or older, naive to antiretroviral 10 adverse event 14 adverse event therapy (<1 week previous antiretroviral exposure, except 4 death 4 death 5 lack of efficacy 8 lack of efficacy in setting of post-exposure prophylaxis or prevention of 6 lost to follow-up 6 lost to follow-up mother-to-child transmission, in which case <6 weeks of 6 poor/non-compliance 9 poor/non-compliance previous antiretroviral exposure was allowed), and had 4 withdrew consent 13 withdrew consent 2 pregnancy 2 pregnancy HIV-1 RNA of 5000 copies per mL or greater. 1 no longer met study criteria 2 other reasons The study was done in accordance with Good Clinical 1 other reason 14 discontinued on or after week 48 14 discontinued on or after week 48 1 adverse event Practice and the ethical principles in the Declaration of 1 adverse event 1 death Helsinki. At each study site, the protocol, amendments, 1 death 1 lack of efficacy and informed consent received approval by the 7 lack of efficacy 3 lost to follow-up 2 poor/non-compliance 2 poor/non-compliance institutional review board/independent ethics committee 1 pregnancy 2 withdrew consent before initiation. 2 no longer met study criteria 2 pregnancy 2 no longer met study criteria Procedures In this open-label, multicentre non-inferiority study, 385 continuing treatment 368 continuing treatment patients were randomly assigned in a one to one ratio to receive either atazanavir 300 mg (two 150 mg capsules) Figure 1: Trial profi le plus ritonavir 100 mg (one capsule) once daily, or *Three patients erroneously received atazanavir/ritonavir. fi xed-dose lopinavir/ritonavir 400/100 mg (three 133/33·3 mg capsules [fi xed-dose, soft-gel formulation]) Atazanavir/ritonavir Lopinavir/ritonavir Overall (N=440) (N=443) (N=883) twice daily, each given with tenofovir/emtricitabine 300/200 mg (one tablet) once daily. Throughout the fi rst Age (years) 34 (19–72) 36 (19–71) 35 (19–72) 48 weeks of the study, the protocol required patients to Sex (female) 138 (31%) 139 (31%) 277 (31%) receive the capsule formulation of lopinavir/ritonavir. CDC Class C AIDS 19 (4%) 24 (5%) 43 (5%) Randomisation was done with a computer-generated HIV RNA (log10 copies per mL) 5·01 (2·60–5·88) 4·96 (3·32–5·88) 4·98 (2·60–5·88) centralised randomisation schedule and was stratifi ed by HIV RNA ≥100 000 copies per mL 225 (51%) 208 (47%) 433 (49%) HIV RNA level at enrolment (<100 000 or ≥100 000 copies CD4 cell count (cells per µL) 205 (2–794) 204 (4–810) 205 (2–810) per mL) and geographic region (Africa, Asia, Europe, CD4 count <50 cells per µL 58 (13%) 48 (11%) 106 (12%) North America, South America). HBV positive 24 (5%) 20 (5%) 44 (5%) Patients were assessed at screening, at day 1 (baseline), HCV positive 40 (9%) 33 (7%) 73 (8%) and at weeks 2, 4, 12, 24, 36, and 48, or at early termination. HIV subtype B 280 (67%) 276 (65%) 556 (66%) Resistance testing was done at baseline and during the Data are n (%) or median (range).
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