Virologic failure [using CVR (NC = F)] occurred in similar numbers of patients in each group (Table 3). Overall, 11 patients taking atazanavir/ritonavir and 8 patients taking lopinavir/ritonavir who met criteria for virologic failure at week 48 were not virologic failures at week 96.
Among patients with virologic failure at week 48 or week 96 without baseline phenotypic resistance to their on-treatment PI, 3 developed major or minor PI substitutions through week 96. One patient in the atazanavir/ritonavir group had major and minor PI substitutions emerge and ultimately failed at week 67. This patient had baseline T12A/S, I13I/V, M36I, N37D, I62V, L63P, A71A/T, I72V, and I93L, with atazanavir fold-change of 0.78. In addition, 1 patient in the lopinavir/ritonavir group had minor PI substitutions emerge while on study. This patient had multiple major and minor substitutions (L10L/I, V32I, I54I/V, A71I, G73G/S and V82V/A, L89V, and L90M) without phenotypic resistance to lopinavir/ritonavir at baseline (LPV FC 6.09). An additional patient in the atazanavir/ritonavir group reported as a virologic failure at week 48 with an N88S substitution, associated with atazanavir resistance, subsequently achieved an HIV RNA <50 copies/mL at week 96 without a change in study regimen. No patient on either regimen with virologic failure that had a wild-type isolate at baseline developed genotypic or phenotypic resistance to atazanavir/ritonavir or lopinavir/ritonavir.
Patients in both the atazanavir/ritonavir and lopinavir/ritonavir treatment arms had similarly low rates of nonadherence (ie, <100% adherent) from week 4 to week 96 of the study. At study visits through week 96, across both treatment arms, 80% to 88% of patients were adherent to their treatment regimen (at week 96, adherence rates were 82% for atazanavir/ritonavir and 84% for lopinavir/ritonavir). For both regimens, the main reason for noncompletion of the MACS questionnaire was discontinuation of study medication [71/439 patients (16%) taking atazanavir/ritonavir and 90/433 patients (21%) taking lopinavir/ritonavir at week 96]. For patients who included reasons for nonadherence at week 96, the most common were “ran out of pills” in the atazanavir/ritonavir treatment group and “simply forgot” in the lopinavir/ritonavir treatment group.
The safety analysis was conducted on data from 878 treated patients (441 in the atazanavir/ritonavir group and 437 in the lopinavir/ritonavir group; 2 and 3 randomized patients on the atazanavir/ritonavir and lopinavir/ritonavir regimens, respectively, were never treated and 3 patients randomized to lopinavir/ritonavir received atazanavir/ritonavir). There were no unexpected safety events, adverse events were not treatment limiting in most cases, and the majority were mild to moderate in intensity.
There were no additional deaths after 48 weeks of the study. Serious adverse events were reported in 14% and 11% of patients on the atazanavir/ritonavir and lopinavir/ritonavir regimens, respectively, with an individual incidence of <1% in either regimen. Few were considered to be related to the study drugs.
The overall incidence of Grades 2-4 treatment-related adverse events was 30% and 32% in those patients on the atazanavir/ritonavir and lopinavir/ritonavir regimens, respectively (Table 4). Most of these were reported by 2% of patients or less on either regimen, and few were considered by the investigators to be related to the study drug (Table 4). More patients in the lopinavir/ritonavir treatment arm experienced gastrointestinal adverse events compared with the atazanavir/ritonavir arm. In addition, a larger proportion of subjects taking lopinavir/ritonavir (24%) compared with atazanavir/ritonavir (12%) required the use of antidiarrheal agents. Hepatobiliary adverse events were experienced by more patients in the atazanavir/ritonavir group than the lopinavir/ritonavir group. Three patients discontinued due to jaundice/hyperbilirubinemia through week 48 with no additional discontinuations due to hyperbilirubinemia occurring between weeks 48 and 96. Among patients who switched to the lopinavir/ritonavir tablet formulation (n = 39), the incidence of Grades 2-4 treatment-related adverse events after switch was 8%. There were no Grades 2-4 treatment-related adverse events of diarrhea after switch; diarrhea (all grades) was reported in 1/39 patients (3%) after switch.
The incidences of selected Grades 3-4 laboratory abnormalities are shown in Table 5. Elevations in total bilirubin were predictably higher in patients taking atazanavir/ritonavir than lopinavir/ritonavir (44% vs <1%). Grades 3-4 increases in alanine aminotransferase concentration were reported in 3% and 2% of patients taking atazanavir/ritonavir and lopinavir/ritonavir, respectively; Grades 3-4 elevations of aspartate aminotransferase were reported in 3% and 1% of patients taking atazanavir/ritonavir and lopinavir/ritonavir, respectively. Grades 3-4 elevations in serum creatinine were <1% in both regimens. Mean change from baseline to week 96 in serum creatinine was 0.04 mg/dL or less in both regimens, and substitution of tenofovir/emtricitabine for decline in renal function was <1% overall. The median calculated creatinine clearance percent change from baseline was −1% in patients in the atazanavir/ritonavir arm and −2% in the lopinavir/ritonavir arm. At week 96, the proportion of patients with >50% reduction from baseline in creatinine clearance was 0% in the atazanavir/ritonavir arm and <1% in the lopinavir/ritonavir arm.
Mean percent changes in lipids from baseline at week 96 were significantly higher (P < 0.0001) in patients taking lopinavir/ritonavir than atazanavir/ritonavir for fasting total cholesterol, non-high-density lipoprotein (HDL) cholesterol, and triglycerides (Fig. 5). Mean percent changes in low-density lipoprotein (LDL) cholesterol were similar between the 2 treatment groups. In addition, more patients on the atazanavir/ritonavir regimen than the lopinavir/ritonavir regimen had optimal lipids at week 96 as defined by the National Cholesterol Education Program Adult Treatment Panel III for total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol:HDL cholesterol ratio.17 Shifts up of 1 category or more in NCEP for total cholesterol occurred in 16% of patients taking atazanavir compared with 29% taking lopinavir/ritonavir; 32% vs 40%, respectively, for LDL cholesterol; and 23% vs 49%, respectively, for triglycerides. A total cholesterol:HDL cholesterol ratio >5 was recorded in 17% of patients in the atazanavir/ritonavir group at week 96 compared with 23% at baseline, and in 27% of patients in the lopinavir/ritonavir group (also 27% at baseline). Fewer patients taking atazanavir/ritonavir (2%) than lopinavir/ritonavir (9%) initiated lipid-reduction therapy after start of study therapy.
The 96-week data from this noninferiority study confirm the similar virologic efficacy of once-daily ritonavir-boosted atazanavir to twice-daily ritonavir-boosted lopinavir, both in combination with tenofovir/emtricitabine, for the treatment of antiretroviral-naive HIV-1 adults that was previously established at week 48.9 The difference in response between the regimens in the ITT analysis in favor of the atazanavir/ritonavir-based regimen at 96 weeks was driven by a similar virologic response rate with a higher rate of discontinuations among patients taking lopinavir/ritonavir. This was based on a combination of adverse events and withdrawal of consent, both of which were higher among the patients in the lopinavir/ritonavir group compared with those in the atazanavir/ritonavir group. Both atazanavir/ritonavir and lopinavir/ritonavir, in combination with tenofovir/emtricitabine, had similarly high rates of adherence in this trial, as measured by the MACS survey (>80%) throughout this study, and thus adherence differences cannot explain the differences in response between the 2 groups.
The CASTLE study is the first comparative study to confirm the durability of the once-daily atazanavir/ritonavir regimen in treatment-naive patients through 96 weeks, with noninferiority to, and higher response rates than, twice-daily lopinavir/ritonavir.
Response rates in this 96-week study were consistent with those seen in other studies of atazanavir/ritonavir18 and lopinavir/ritonavir7,8,19,20 in treatment-naive patients, after taking differences in study designs and populations into consideration. Similarly, the efficacy results are consistent with those reported for other long-term studies of PIs.21-24 Both the atazanavir/ritonavir and lopinavir/ritonavir regimens resulted in similar increases in CD4 cell counts over 96 weeks. Response rates of HIV RNA <50 copies/mL were achieved at consistent levels across all baseline CD4 cell counts in both treatment groups, with results that were higher in the atazanavir/ritonavir group than the lopinavir/ritonavir group due to a higher rate of discontinuations among patients taking lopinavir/ritonavir. In addition, both regimens were effective in patients with high baseline HIV RNA; response rates were somewhat lower in patients with higher baseline HIV RNA in both treatment groups. More patients with advanced disease (CD4 <50 cells/μL and HIV RNA 100,000 copies/mL or more) responded among those treated with atazanavir/ritonavir than with lopinavir/ritonavir. A poorer response to lopinavir/ritonavir in patients with more advanced disease compared with those with lower HIV RNA and CD4 cell counts has also been reported in other studies.8,25,26
As expected, there was a low rate of virologic failure during treatment with these boosted PI regimens. These findings are consistent with data from other studies.7,8,20 The rates of development of resistance to PIs over the course of the study were low, with only a single patient in each treatment group with virologic failure at 96 weeks developing phenotypic resistance to a study PI. The emergence of NRTI substitutions was also low, with 5 patients in each treatment group developing phenotypic resistance to emtricitabine and 2 patients on lopinavir/ritonavir with phenotypic resistance to tenofovir disoproxil fumarate.
The main difference between the regimens in this study was related to their safety and tolerability. Adverse events and toxicity are the most common causes of treatment failure, and among the PIs gastrointestinal tolerability is an established risk for this outcome.27 In this study, more patients in the lopinavir/ritonavir group than the atazanavir/ritonavir group withdrew consent, and more discontinued treatment due to adverse events. Furthermore, the patients in the lopinavir/ritonavir group experienced a higher rate of gastrointestinal intolerability than those in the atazanavir/ritonavir group. Of note, no patients in the atazanavir/ritonavir arm discontinued treatment due to diarrhea, and a greater proportion of patients given lopinavir/ritonavir who remained in the study required antidiarrheal medication compared with those given atazanavir/ritonavir. Although patients treated with atazanavir/ritonavir had a higher rate of bilirubin abnormalities, only few (3) patients discontinued treatment as a result, none of them between weeks 48 and 96.
As expected, lopinavir/ritonavir resulted in higher increases in lipids compared with atazanavir/ritonavir. Drug-related dyslipidemia is associated with increased cardiovascular risk in patients on PI-containing regimens.6,28-30 Some PIs are known to increase total cholesterol and LDL cholesterol levels,31 with a dose-response effect from ritonavir, although as seen in this study, the lipid profile changes are not consistent among different PIs. Although the ritonavir daily dose in the lopinavir/ritonavir arm was twice as high as in the atazanavir/ritonavir arm, total exposure to ritonavir was comparable between the treatment arms [geometric mean ratio for area under the concentration curve over 24 hours (AUC0-24) was 0.84; 90% CI, 0.61-1.15].32 The similarity in AUC0-24 for ritonavir with both treatment regimens suggests that the higher rates of metabolic and gastrointestinal abnormalities observed in the twice-daily lopinavir/ritonavir arm compared with the atazanavir/ritonavir arm must be in part related to the lopinavir component of the fixed-dose lopinavir/ritonavir regimen.
No new or unexpected safety concerns emerged between 48 and 96 weeks, and the gastrointestinal and lipid safety profiles of atazanavir/ritonavir remained more favorable than those of lopinavir/ritonavir at 96 weeks. Events leading to study drug discontinuation in both regimens were consistent with the known side-effect profiles of the study drugs and comparison/backbone treatments.
The open-label design of this study is a limitation. In addition, patients in the lopinavir/ritonavir treatment group were only allowed to switch from the capsule to the tablet formulation after 48 weeks. Although this allowed for a direct comparison between atazanavir/ritonavir and a single formulation of lopinavir/ritonavir for the first 48 weeks of the study, the lack of comparative data against the newer tablet formulation of lopinavir/ritonavir throughout the study may be relevant, particularly as the capsule formulation is no longer available. However, several factors argue against the significance of any possible effects of the lopinavir/ritonavir formulation: first, only 3 patients discontinued treatment before week 48 because of a preference for the lopinavir/ritonavir tablet, and second, the 2 formulations have been shown to have similar safety and tolerability profiles.19 Finally, the similarly high adherence rates for both the atazanavir/ritonavir and lopinavir/ritonavir regimens before and after week 48 also suggest that pill burden and tolerability were not limiting factors in these treatment-naive patients. It is unlikely, therefore, that study outcomes were affected as a result of the limited availability of the lopinavir/ritonavir tablet formulation.
The results of this long-term comparative study reinforce the use of once-daily atazanavir/ritonavir as a recommended first-line treatment option for HIV-1 infection. Atazanavir/ritonavir is noninferior to ritonavir-boosted twice-daily lopinavir, but with a more favorable overall safety profile, and, importantly, a better lipid profile than lopinavir/ritonavir in treatment-naive patients. This regimen is therefore an appropriate therapeutic option for antiretroviral-naive HIV-1-infected patients, and is highly effective in patients with advanced disease, as measured by baseline low CD4 and high HIV RNA levels.
We thank the investigators, study coordinators, site and data managers, and patients for their contributions. We also thank the Bristol-Myers Squibb team members: A. Rightmire, C. Day, M. Ricciuti, M. Mathew, R. Bertz, M. Child, C. Tasker, A. Gadoury, P. Mrowiec, M. DeGrosky, and A. Gopinathan. Editorial support was provided by Cheryl Jenkins and Jean Turner at PAREXEL and was funded by Bristol-Myers Squibb.
J.-M.M., J.A.-V., J.E., P.C., J.C., N.D., G.M., M.M., L.P., R.Y., V.W., M.L., D.M.G., and J.A. all provided scientific input into the study design and study protocol. J.A. assisted in writing the first draft of the manuscript. All authors assessed clinical data from the study and reviewed and edited the manuscript. All investigators were involved in enrollment of patients. R.Y. did all statistical analyses.
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CASTLE Study Team
Argentina-J. Benetucci, A. Casiro, I. Cassetti, J. Corral, J. Galindez, N. Luna, S. Lupo, E. Pallone, C. Rodriguez. Australia-D. Baker, N. Roth, C. Workman. Austria-N. Vetter. Belgium-J. Pelgrom. Brazil- J.L. Andrade, M. Da Eira, B. Grinsztejn, R. De Jesus Pedro, F. Rangel, R. Zajdenverg. Canada-J.-G. Baril, F. Crouzat, R. LeBlanc, C. Tremblay. Chile-L. Bavestrello Fernandez, P. Gaete Gutierrez, L. Noriega, C. Perez. Columbia-O. Sussmann. Costa Rica-G. Herrera. Dominican Republic- E. Koenig. France-J.-F. Bergmann, P. Dellamonica, C. Katlama, J.-M. Molina, D. Vittecoq, L. Weiss. Germany-K. Arasteh, G. Faetkenheuer, J. Rockstroh, A. Stoehr. Guatemala-E. Arathoon, J.-F. Garcia, C. Mejia-Villatoro. Hong Kong-P. Li. Indonesia-S. Djauzi. Italy- A. Antinori, A. Lazzarin, A. D'Arminio Monforte, G. Penco, V. Vullo. Mexico-M. Magana Aquino, G. Amaya, J. Andrade-Villanueva, D. Jorge, J. Sierra, J. Carlos Tinoco, I. Zavala. Netherlands-I.M. Hoepelman, S. Van Der Geest. Panama-C. Alfredo, N. Sosa. Peru-R. Cabello, J. Echevarria, A. La Rosa, R. Salazar. Portugal-F. Antunes. Puerto Rico-S. Saavedra, G. Sepulveda. Singapore-L. Lin. Spain-J. Arribas, B. Clotet, J. Gatell, P. Miralles, F. Pulido Ortega, A. Rivero, I. Santos Gil, J. Santos Gonzalez. South Africa-N. David, C. Firnhaber, D. Johnson, E. Krantz, G. Latiff, D. Malan, D. Martin, J. Pitt, M. Zeier. Thailand-P. Chetchotisakd, K. Supparatpinyo. Taiwan-S.-M. Hsieh, Y.-C. Liu, W.W. Wong. UK-J. Ainsworth, M. Johnson, G. Moyle, G. Scullard, I. Williams. USA-D. Brand, F. Cruickshank, E. DeJesus, C. McDonald, R. Myers, S. Reddy, M. Sension, D. Ward.
Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
combination antiretroviral therapy; HIV-1; atazanavir/ritonavir; treatment-naive patients; CASTLE study