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HIV Regimens Similar but Not Equivalent - ACTG5202 efavirenz vs Reyataz/r + TDF/FTC or abacavir/3TC
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Primary source: Annals of Internal Medicine
Source reference:
Daar ES, et al "Atazanavir plus ritonavir or efavirenz as part of a three drug regimen for initial treatment of HIV-1: A randomized trial " Ann Intern Med 2011.
MedPage Today
Published: February 14, 2011
Action Points
* Explain that a large randomized trial found that ritonavir-boosted atazanavir and efavirenz produced similar virologic and adverse effects outcomes when used with abacavir/lamivudine or tenofovir/emtricitabine as initial HIV treatment.
* Note that the study did not achieve the prespecified equivalence outcome.
A large clinical trial fell short of showing that two commonly used approaches to a first anti-HIV treatment regimen are formally equivalent.
But the two -- based on either the ritonavir-boosted protease inhibitor atazanavir (Reyataz) or the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva) -- still appeared to have similar efficacy, according to Eric Daar, MD, of Harbor-UCLA Medical Center in Torrance, Calif., and colleagues.
The failure to reach formal equivalence -- as defined before the study started -- was probably the result of a lower than expected rate of virologic failure two years into the study, Daar and colleagues reported online in Annals of Internal Medicine.
But a post-hoc analysis of the data suggested the probability of remaining free of failure differed by less than 10%, a threshold commonly used for defining equivalence, the researchers argued.
Treatment guidelines for initial HIV therapy suggest two nucleoside reverse transcriptase inhibitors combined with either a non-NRTI, a ritonavir-boosted protease inhibitor, or an integrase inhibitor, the researchers noted.
But there are limited data comparing atazanavir/ritonavir with efavirenz, they noted.
To help fill the gap, they conducted a randomized trial, in which the two lead compounds were added to common, once-daily combinations of nucleoside reverse transcriptase inhibitors -- either abacavir/lamivudine (Kivexa) or tenofovir/emtricitabine (Truvada).
The trial ran from September 2005 to November 2007, with a median of 138 weeks of follow-up, and the primary outcomes were time to virologic failure, safety, and tolerability.
All told, 1,857 patients were randomly assigned to one of the four treatment regimens and 1,331 completed the follow-up.
The primary efficacy hypothesis was that, within each of the NRTI arms, boosted atazanavir would be equivalent to efavirenz, Daar and colleagues noted.
The drugs were specified to be equivalent if a Cox proportional hazards model, using efavirenz as the reference, found the two-sided 95% confidence interval for the hazard ratio to be between 0.71 and 1.40.
But analysis showed:
* Among those randomized to the abacavir/lamivudine arms, the hazard ratio for time to virologic failure was 1.13 with a 95% confidence interval from 0.82 to 1.56. The difference was not statistically significant, at P=0.147.
* For those assigned to the tenofovir/emtricitabine arms, the hazard ratio was 1.01 with a 95% confidence interval from 0.70 to 1.46, which again was not significant, at P=0.37.
Although neither hazard ratio showed a significant difference, "neither met prespecified equivalence boundaries," the researchers reported.
However, analysis also showed that the probability of remaining free of virologic failure at week 96 was 83.4% for boosted atazanavir and 85.3% for efavirenz when they were combined with abacavir/lamivudine. The difference was -1.9 with a 95% confidence interval from -6.8 to 2.9, or 9.7 percentage points.
Values in the tenofovir/emtricitabine arms were 89% for boosted atazanavir and 89.8% for efavirenz, with a difference of -0.8 and a 95% confidence interval from -4.9 to 3.3, or 8.2 percentage points, the researchers reported.
Although the results did not meet the specified equivalence mark, the results suggest "for the first time in a large randomized study" that the two drugs have similar efficacy, the researchers argued.
They also found that safety and tolerability were slightly better for atazanavir than efavirenz when combined with abacavir/lamivudine, but there were no differences when they were combined with tenofovir/emtricitabine.
Daar and colleagues cautioned that when the study started it was not routine practice to test for HLA-B*5701 before using abacavir -- something that might have affected safety and tolerability results.
They also noted that study limitations include baseline drug resistance testing in only 40% to 50% of patients because of changing practices over time, premature unblinding of the NRTIs in the group of patients with high baseline viral loads, and change or discontinuation of the third drug in almost a third of patients.
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Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV Type-1 A Randomized Trial
Our analyses showed, for the first time in a large, randomized study, that a ritonavir-boosted protease inhibitor had similar virologic efficacy as an efavirenz-based regimen with either abacavir-lamivudine or tenofovir DF-emtricitabine. Rates of safety and tolerability end points were lower among persons assigned to atazanavir plus ritonavir than efavirenz with abacavir-lamivudine, with no differences when combined with tenofovir DF-emtricitabine......Results from A5202 provide useful information for clinicians and patients making decisions about the initial treatment of HIV-1 infection. Atazanavir plus ritonavir and efavirenz provide similar antiviral activity when used with either of the NRTI pairs. There were, however, differences between regimens in CD4 cell increases, frequency of emergent resistance, rates of safety and tolerability events, and changes in fasting lipid and in renal parameters. These factors should be considered when selecting initial treatment of patients with HIV-1 infection.
A total of 83 patients switched from the assigned efavirenz to atazanavir plus ritonavir; 6 before and 40 at or after virologic failure, and 37 without virologic failure. Forty-five switched from atazanavir plus ritonavir to efavirenz, 2 before and 16 at or after virologic failure, and 27 without having virologic failure.
A prespecified sensitivity analysis included potential virologic failures without confirmation (n = 34) and suggested that third-drug treatment effect differed by screening viral load stratum (P for interaction = 0.096). In the high viral load stratum, persons assigned to abacavir-lamivudine with atazanavir plus ritonavir had a higher rate of virologic failure compared with persons assigned efavirenz (HR, 1.68 [CI, 1.08 to 2.60]; P = 0.019), a difference not seen in low viral load stratum (HR, 0.99 [CI, 0.64 to 1.54]; P = 0.97). For comparison of the third drugs with tenofovir DF-emtricitabine, this sensitivity analysis was similar to primary results. In another prespecified sensitivity analysis that classified unconfirmed virologic failure, death, and discontinued follow-up as failures, results were similar to the primary efficacy analysis. Additional prespecified sensitivity analyses included censoring at first modification of the third drug, censoring at first modification of any assigned drugs, and censoring persons in the high viral load stratum at the time of the data safety monitoring board action; all had similar results as the primary analyses (Appendix Table 2)
There are few comparisons of once-daily treatment regimens for HIV type 1 (HIV-1)......This randomized trial in antiretroviral-naïve patients with HIV-1 showed that a once-daily ritonavir-boosted protease inhibitor regimen had similar virologic efficacy to a once-daily efavirenz-based regimen when combined with either abacavir-lamivudine or tenofovir DF-emtricitabine. The ritonavir-boosted protease inhibitor regimen seemed safer and more tolerable than the efavirenz regimen when combined with abacavir-lamivudine but not when combined with tenofovir DF-emtricitabine.
Treatment guidelines for initial HIV type 1 (HIV-1) therapy recommend 2 nucleoside reverse transcriptase inhibitors (NRTIs) with either a non-NRTI (NNRTI), ritonavir-boosted protease inhibitor or integrase inhibitor (1, 2). Abacavir-lamivudine and tenofovir disoproxil fumarate (DF)-emtricitabine are efficacious, once-daily NRTIs (3-5). The preferred NNRTI is efavirenz, and atazanavir plus ritonavir is 1 of the preferred protease inhibitors (1, 6, 7).
The AIDS Clinical Trials Group (ACTG) A5202 study compared efficacy, safety, and tolerability of abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir plus ritonavir or efavirenz. After scheduled interim data review, the data and safety monitoring board noted inferior virologic efficacy of abacavir-lamivudine compared with tenofovir DF-emtricitabine among patients with HIV-1 RNA of 100 000 copies/mL or more at screening (8). We now report the final results of the primary study objectives comparing atazanavir plus ritonavir versus efavirenz.
Eric S. Daar, MD; Camlin Tierney, PhD; Margaret A. Fischl, MD; Paul E. Sax, MD; Katie Mollan, MS; Chakra Budhathoki, PhD; Catherine Godfrey, MD; Nasreen C. Jahed, MPH; Laurie Myers, MS; David Katzenstein, MD; Awny Farajallah, MD; James F. Rooney, MD; Keith A. Pappa, PharmD; William C. Woodward, DO; Kristine Patterson, MD; Hector Bolivar, MD; Constance A. Benson, MD; Ann C. Collier, MD; and for the AIDS Clinical Trials Group Study A5202 Team*
Abstract
Background: Limited data compare once-daily options for initial therapy for HIV type 1 (HIV-1).
Objective: To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1.
The primary efficacy end point was time from randomization to virologic failure (confirmed HIV-1 RNA ≥1000 copies/mL or greater at or after 16 weeks and before 24 weeks or ≥200 copies/mL at or after 24 weeks). The primary safety end point was time from treatment dispensation to first grade-3 or -4 sign, symptom, or laboratory abnormality (graded according to a toxicity rating scale developed by the Division of AIDS [version 1.0, December 2004]) at least 1 grade higher than at baseline, excluding unconjugated hyperbilirubinemia and creatine kinase. The primary tolerability end point was originally defined as time to change in assigned antiretroviral drugs.
Secondary outcomes included HIV-1 RNA less than 50 copies/mL, change in CD4 cell count, calculated creatinine clearance, and fasting lipid levels. Emergence of a resistant virus was assessed by genotypic testing at Stanford University for all who met protocol-specified criteria for virologic failure and on their baseline samples. Major mutations were defined by the International AIDS Society-United States of America (9), as well as T69D, L74I, G190C/E/Q/T/V for reverse transcriptase, and L24I, F53L, I54V/A/T/S, G73C/S/T/A and N88D for protease. An adherence questionnaire (10) was administered at weeks 8 and 24 and every 24 weeks thereafter.
Design: A randomized equivalence trial conducted from September 2005 to November 2007, with a median 138 weeks follow-up. Regimens assigned by central computer, stratified by screening HIV-1 RNA less than 100 000 copies/mL or 100 000 copies/mL or more, with blinding only known to the site pharmacist (ClinicalTrials.gov registration number: NCT00118898).
Setting: 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico.
Patients: Antiretroviral-naïve patients.
Intervention: Open-label atazanavir plus ritonavir or efavirenz with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine.
Measurements: Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion with HIV-1 RNA less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels.
Results: Eligible patients randomly assigned to atazanavir plus ritonavir versus efavirenz with abacavir-lamivudine were 463 and 465, with 322 (70%) and 324 (70%) completing follow-up, respectively. Total participants who received tenofovir DF-emtricitabine were 465 and 464, with 342 (74%) and 343 (74%) completing follow-up, respectively. Primary efficacy was similar between the groups who received atazanavir plus ritonavir and efavirenz with abacavir-lamivudine or tenofovir DF-emtricitabine. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively; although CIs did not meet prespecified criteria for equivalence. There was a longer time to safety (P = 0.048) and tolerability (P < 0.001) events in persons given atazanavir plus ritonavir than efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine.
Limitations: Neither HLA-B*5701 or resistance testing were the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz were open-label, the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum, and 32% of patients modified or discontinued their third drug.
Conclusion: Atazanavir plus ritonavir and efavirenz provide similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine.
Primary Funding Source: The National Institutes of Health.
Results
Study Patients and Follow-up Disposition
A5202 enrolled 1857 eligible patients (7 others were ineligible and excluded from the analysis) from September 2005 to November 2007 (Table 1). Follow-up was 0 to 208 weeks, a median (25th to 75th percentile) of 138 (106 to 169) weeks, with no significant difference in time to premature discontinuation between study groups and censoring persons who died, completed the study, or stopped because their study site closed due to loss of funding (P = 0.48). Details of patient disposition are summarized in Figure 1. Nine patients who never started the study drug regimen were included in the primary efficacy analyses. A total of 83 patients switched from the assigned efavirenz to atazanavir plus ritonavir; 6 before and 40 at or after virologic failure, and 37 without virologic failure. Forty-five switched from atazanavir plus ritonavir to efavirenz, 2 before and 16 at or after virologic failure, and 27 without having virologic failure.
Primary Virologic Outcome
Among persons randomly assigned to atazanavir plus ritonavir or efavirenz with abacavir-lamivudine, the HR (efavirenz being the reference) for time to virologic failure was 1.13 (CI, 0.82 to 1.56), with no difference in treatment effect by viral load stratum (P = 0.147) (Figure 2, Table 2, Appendix Table 1). For atazanavir plus ritonavir or efavirenz with tenofovir DF-emtricitabine, the HR was 1.01 (CI, 0.70 to 1.46), with no difference by viral load strata (P = 0.37). Although both CIs include a HR of no difference (1.0), neither met prespecified equivalence boundaries. The probability of remaining free of virologic failure at visit week 96 for atazanavir plus ritonavir or efavirenz with abacavir-lamivudine was 83.4% and 85.3%, respectively (difference, -1.9 [CI, -6.8 to 2.9]). Values for atazanavir plus ritonavir or efavirenz with tenofovir DF-emtricitabine were 89.0% and 89.8% (difference, -0.8 [CI, -4.9 to 3.3]). Table 2 and Appendix Table 1 summarize results and corresponding probability of virologic failure.
A prespecified sensitivity analysis included potential virologic failures without confirmation (n = 34) and suggested that third-drug treatment effect differed by screening viral load stratum (P for interaction = 0.096). In the high viral load stratum, persons assigned to abacavir-lamivudine with atazanavir plus ritonavir had a higher rate of virologic failure compared with persons assigned efavirenz (HR, 1.68 [CI, 1.08 to 2.60]; P = 0.019), a difference not seen in low viral load stratum (HR, 0.99 [CI, 0.64 to 1.54]; P = 0.97). For comparison of the third drugs with tenofovir DF-emtricitabine, this sensitivity analysis was similar to primary results. In another prespecified sensitivity analysis that classified unconfirmed virologic failure, death, and discontinued follow-up as failures, results were similar to the primary efficacy analysis. Additional prespecified sensitivity analyses included censoring at first modification of the third drug, censoring at first modification of any assigned drugs, and censoring persons in the high viral load stratum at the time of the data safety monitoring board action; all had similar results as the primary analyses (Appendix Table 2)
Secondary Virologic End Point Analyses
A prespecified comparison of atazanavir plus ritonavir and efavirenz with NRTIs combined (factorial analysis) was done because there was no evidence that the treatment effect differed by NRTIs (P = 0.65). For atazanavir plus ritonavir versus efavirenz, the HR for time to virologic failure was 1.08 (CI, 0.85 to 1.38), with CIs within the prespecified equivalence boundaries. However, for this comparison, there was a significant interaction with screening viral load (P = 0.080), in which the HR was 1.35 (CI, 0.96 to 1.92) and 0.88 (CI, 0.62 to 1.23) for the high and low viral load stratum, respectively.
A cross-sectional analysis that assessed the proportion of patients with HIV-1 RNA less than 50 copies/mL (regardless of previous virologic failure or regimen change) was done in 1642 (88%) and 1498 (81%) of patients with HIV-1 RNA results available at weeks 48 and 96, respectively. Data were missing primarily because of premature discontinuation of the study (such as the patient moved, was incarcerated, or was deported) or the patient was lost to follow-up. Patients with missing data were more likely to be younger, to be non-Hispanic black persons, to report previous intravenous drug use, and to have hepatitis B or C infection than were persons with results. The percentages of patients with available HIV-1 RNA data assigned to atazanavir plus ritonavir versus efavirenz combined with abacavir-lamivudine with HIV-1 RNA less than 50 copies/mL at week 48 (week 96) were 78% versus 87% (85% vs. 91%), with a difference of -8% (CI, -13 to -3); P = 0.003 (-6% [-11 to -1]; P = 0.012). Values at week 48 (week 96) for atazanavir plus ritonavir versus efavirenz with tenofovir DF-emtricitabine were 84% versus 90% (90% vs. 91%), with a difference of -6% (-11 to -1); P = 0.012 (-1% [-5 to 3]; P = 0.58). In a prespecified, worst-case sensitivity analysis, in which patients with missing data were assigned to the group of HIV-1 RNA of 50 copies/mL or more, 48-week results were similar to primary analyses, and at 96 weeks, abacavir-lamivudine no longer favored efavirenz. Finally, in the time-to-regimen failure analysis, with the end point defined as time to first confirmed virologic failure or discontinuation of assigned protease inhibitor or NNRTI, no significant treatment differences were found between atazanavir plus ritonavir and efavirenz with abacavir-lamivudine (HR, 0.87 [CI, 0.71 to 1.08]) or tenofovir DF-emtricitabine (HR, 0.93 [CI, 0.74 to 1.17]) (Appendix Figure).
Safety End Point
Time to safety event was longer among persons who received atazanavir plus ritonavir than efavirenz combined with abacavir-lamivudine (HR, 0.81 [CI, 0.66 to 1.00]; P = 0.048), with no significant difference in treatment effect by viral load stratum (P = 0.71) (Figure 2, Table 2, Appendix Table 1). Table 3 summarizes the main differences in triggering safety events. No significant difference in rate of safety events in persons given atazanavir plus ritonavir versus efavirenz combined with tenofovir DF-emtricitabine was found (HR, 0.91 [CI, 0.72 to 1.15]; P = 0.44), and no significant difference in treatment effect by screening viral load stratum was found (P = 0.85). Sensitivity analyses included censoring at the time of the first modification of any part of the original assigned regimen and time to first safety end point, regardless of whether the original regimen had been modified. The results did not differ from those of the primary analyses (Appendix Table 2).
Tolerability End Point
The third drug in the regimen was modified in 596 patients who initiated treatment (Figure 1). Time-to-regimen change was longer with atazanavir plus ritonavir than efavirenz with abacavir-lamivudine, HR 0.69 (CI, 0.55 to 0.86); P < 0.001), without significant evidence that results differed by viral load stratum (P = 0.63) (Figure 2, Table 2, Appendix Table 1). No significant difference in the time to tolerability end point was found in persons who received drugs with tenofovir DF-emtricitabine (HR, 0.84 [CI, 0.66 to 1.07]; P = 0.166), and no significant evidence was found that rates differed by viral load stratum (P = 0.90). Figure 1 shows reasons for modification. When analyzed as originally specified by the protocol, in which the end point was time to first change in any part of the assigned regimen, there was a longer time-to-regimen change among persons who received atazanavir plus ritonavir than efavirenz with abacavir-lamivudine (P = 0.06), a difference not seen when given with tenofovir DF-emtricitabine (P = 0.22) (Appendix Table 2).
Immunologic Outcome
Change in CD4 cells from baseline to weeks 48 and 96 were examined in 1645 (89%) and 1493 (80%) of patients with results available, respectively. Reasons for missing CD4 values were similar to reasons noted for HIV-1 RNA. Change in CD4 cells did not differ between persons given atazanavir plus ritonavir or efavirenz with abacavir-lamivudine, with a median change of 0.178 versus 0.188 x 109 cells/L (P = 0.94) and 0.250 versus 0.251 x 109 cells/L (P = 0.89), respectively. Change in CD4 cells was greater in persons given atazanavir plus ritonavir compared with efavirenz with tenofovir DF-emtricitabine at weeks 48 and 96, with a median change of 175 versus 0.163 x 109 cells/L (P = 0.040) and 0.252 versus 0.221 x 109 cells/L (P = 0.002), respectively.
Clinical Events and Laboratory Measures
Prespecified clinical and laboratory events were events of interest in persons with HIV-1 and events related to known toxicities of study drugs. These included deaths (n = 31) (Figure 1), and AIDS-defining events (95 events in 82 patients). No significant difference was found in time to AIDS or death in persons assigned to atazanavir plus ritonavir versus efavirenz with abacavir-lamivudine (HR, 0.93 [CI, 0.56 to 1.54]; P = 0.77) or tenofovir DF-emtricitabine (HR, 1.23 [CI, 0.70 to 2.39]; P = 0.42). Other events of interest for persons assigned to atazanavir plus ritonavir and efavirenz with abacavir-lamivudine were vascular events (coronary artery disease, infarction, ischemia, angina, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease) being present in 2 (<1%) in each treatment group; renal diagnoses of Fanconi syndrome, toxic nephropathy, proteinuria, or renal failure in 4 (1%) and 5 (1%); bone fractures in 16 (3%) and 22 (5%); and suspected hypersensitivity reaction in 34 (7%) and 53 (11%), respectively. Respective numbers for patients assigned to atazanavir plus ritonavir and efavirenz with tenofovir DF-emtricitabine were vascular events in 1 (<1%) and 6 (1%); renal diagnoses in 6 (1%) and 3 (1%); bone fractures in 21 (5%) and 21 (5%); and suspected hypersensitivity reaction in 27 (6%) and 25 (5%).
Analyses of change in lipid levels included persons with available fasting measurements at baseline and while receiving the originally assigned protease inhibitor or NNRTI at weeks 48 and 96. Data were available in 82% and 80% of these patients at weeks 48 and 96, respectively. Most patients with missing lipid values provided nonfasting samples. Patients with fasting lipid values did not seem to differ systematically from persons with missing or nonfasting lipid values. Table 3 summarizes changes in fasting values from baseline. Persons who received efavirenz compared with atazanavir plus ritonavir with abacavir-lamivudine or tenofovir DF-emtricitabine had significantly greater increases in all cholesterol levels but not in total to high-density lipoprotein cholesterol ratios.
Table 3 summarizes changes from baseline in calculated creatinine clearance (among persons receiving an assigned protease inhibitor or NNRTI) at weeks 48 and 96. An increase from baseline in calculated creatinine clearance occurred in patients who received atazanavir plus ritonavir or efavirenz with abacavir-lamivudine (P < 0.001 for both), with no significant difference in the distribution of change at weeks 48 and 96. Persons who received tenofovir DF-emtricitabine with efavirenz had an increase in calculated creatinine clearance at weeks 48 and 96 (P < 0.001 for both) but not with atazanavir plus ritonavir at week 48 (P = 0.53) and 96 (P = 0.38). The distribution of change in calculated creatinine clearance was significantly different at both weeks 48 and 96 between atazanavir plus ritonavir and efavirenz when given with tenofovir DF-emtricitabine. Tenofovir DF-emtricitabine was discontinued or the dose was reduced because of changes in renal function in 6 patients receiving atazanavir plus ritonavir and 3 receiving efavirenz.
HIV-1 Drug Resistance
Of the 269 patients with protocol-defined virologic failure, 265 had resistance data available at failure and baseline; 25 of whom had major mutations present at baseline. Of the persons with virologic failure, emergent resistance mutations were less frequent in persons who were assigned atazanavir plus ritonavir versus efavirenz when combined with either NRTI (P < 0.001 for both) (Appendix Table 3). There was also a lower frequency of NRTI-associated mutations among persons randomly assigned to atazanavir plus ritonavir than efavirenz with abacavir-lamivudine (P < 0.001) or tenofovir DF-emtricitabine (P = 0.046).
Adherence
Among persons with adherence data assigned to abacavir-lamivudine plus atazanavir plus ritonavir, no missed doses in the previous week were self-reported by 87% to 92% at weeks 8, 48, and 96, and 89% to 90% at weeks 8, 48 and 96 for persons assigned the same NRTIs with efavirenz (P ≥ 0.26 for all comparisons). For persons with data assigned tenofovir DF-emtricitabine with atazanavir plus ritonavir, no missed doses in the previous week were self-reported by 91% to 93% at weeks 8, 48, and 96, and 92% at weeks 8, 48 and 96 for persons assigned the same NRTIs with efavirenz (P ≥ 0.60 for all comparisons).
Discussion
Our analyses showed, for the first time in a large, randomized study, that a ritonavir-boosted protease inhibitor had similar virologic efficacy as an efavirenz-based regimen with either abacavir-lamivudine or tenofovir DF-emtricitabine. Rates of safety and tolerability end points were lower among persons assigned to atazanavir plus ritonavir than efavirenz with abacavir-lamivudine, with no differences when combined with tenofovir DF-emtricitabine.
Review of MEDLINE through August 2010 and meeting abstracts from the past 3 years showed that, before our study, the largest to compare a ritonavir-boosted protease inhibitor with efavirenz was A5142, which compared lopinavir plus ritonavir with efavirenz with nonrandomized NRTIs and showed that protocol-defined efficacy favored efavirenz (15). Our study differs from A5142 by randomizing and blinding the NRTIs as well as using atazanavir plus ritonavir (6). There are several recent studies reporting similar efficacy of ritonavir-boosted protease inhibitors to nevirapine-containing regimens (16, 17). Another study (n = 219) compared atazanavir plus ritonavir with efavirenz, both combined with tenofovir DF-emtricitabine showing virologic noninferiority of atazanavir at 48 weeks for a mean change from baseline in HIV-1 RNA (18).
In A5202 there were greater increases in CD4 cells, albeit of unknown clinical relevance, among persons assigned to atazanavir plus ritonavir compared with efavirenz when combined with tenofovir DF-emtricitabine. This is consistent with the lower immunologic responses in persons who were assigned efavirenz compared with lopinavir plus ritonavir in A5142 (15). In addition, the frequency of emergent resistance to protease inhibitors was very rare (Appendix Table 3), which is consistent with other studies (5, 6, 15). We also showed that NRTI resistance emerged more often among patients with virologic failure assigned to efavirenz than atazanavir plus ritonavir (Appendix Table 3). Mutations included those associated with NNRTI resistance in the efavirenz groups and the M184V/I mutations associated with lamivudine and emtricitabine resistance in all groups. Other NRTI mutations were only seen in persons who were assigned efavirenz. The L74I/V mutation that is associated with abacavir resistance (19, 20) emerged in 6 and 1 persons randomly assigned to abacavir-lamivudine and tenofovir DF-emtricitabine, respectively. Seven had emergent K65R: 3 had received abacavir-lamivudine (1 had switched to alternative NRTIs before the time of virologic failure) and 4 had received tenofovir DF-emtricitabine. This mutation is seen in patients who have virologic failure while taking tenofovir DF plus lamivudine and efavirenz (4) and rarely seen after in patients with virologic failure who take tenofovir DF-emtricitabine (5, 6) and abacavir- or lamivudine-based regimens (20).
Renal toxicity has been reported with tenofovir DF (21), with conflicting data about whether ritonavir-based regimens increase nephrotoxicity induced by tenofovir DF (22-24). We observed no significant change from baseline in calculated creatinine clearance in persons who received atazanavir plus ritonavir with tenofovir DF-emtricitabine compared with small but statistically significant increases in this measure within the other 3 study groups (Table 3). There was a difference in change from baseline in calculated creatinine clearance at 48 and 96 weeks between persons who received tenofovir DF- emtricitabine with efavirenz than atazanavir plus ritonavir. Nevertheless, few assigned tenofovir DF-emtricitabine had a decrease of 25% or more in renal function from baseline (data not shown) or had NRTIs discontinued or dose reduced because of changes in renal function. Moreover, targeted renal events were not demonstrably different from the other study groups and were rare, as seen in other studies (7, 25).
Despite efficacy results in A5202 being similar, we were unable to declare equivalence on the basis of prespecified HR boundaries, likely resulting from the low rate of virologic failure at week 96 (11% to 17%), rather than that projected (32%). Nevertheless, in a post hoc assessment, the difference in probability of remaining free of virologic failure at 96 weeks did not exceed the 10% to 12% threshold typically used for defining equivalence or noninferiority (5, 6, 26). Other limitations of this study included that atazanavir plus ritonavir and efavirenz were given open-label, the tenofovir DF-emtricitabine with efavirenz was not provided as the single fixed-dose combination pill, the NRTIs were prematurely unblinded in the high-screening viral load stratum, and approximately 32% of participants modified or discontinued their third drug. In addition, resistance testing before treatment initiation was done in only 40% to 50% of patients, and when A5202 enrolled it was not routine to do HLA-B*5701 testing before use of abacavir; the latter would probably have influenced rates of select safety and tolerability end points.
Results from A5202 provide useful information for clinicians and patients making decisions about the initial treatment of HIV-1 infection. Atazanavir plus ritonavir and efavirenz provide similar antiviral activity when used with either of the NRTI pairs. There were, however, differences between regimens in CD4 cell increases, frequency of emergent resistance, rates of safety and tolerability events, and changes in fasting lipid and in renal parameters. These factors should be considered when selecting initial treatment of patients with HIV-1 infection.
Methods
Design
A5202 was a phase 3b, randomized, equivalence study of 4 regimens for initial treatment of HIV-1. The study enrolled from September 2005 to November 2007. Median (25th to 75th percentile) follow-up was at 138 weeks (106 weeks to 169 weeks), with the last patients followed until November 2009. The protocol was amended in July 2006 to exclude persons with chronic hepatitis B infection because of new treatment guidelines. In February 2008, the National Institute of Allergy and Infectious Diseases Division of AIDS data safety monitoring board recommended that persons with screening HIV-1 RNA of 100 000 copies/mL or more be unblinded (8). Human subjects committees of all sites approved the protocol, and informed consent was obtained from all participants.
Setting and Participants
Fifty nine ACTG sites in the United States and Puerto Rico enrolled patients 16 years or older with HIV-1 who had, at most, 7 days of previous antiretroviral therapy. Patients were recruited from local clinics and excluded if they were pregnant or breast-feeding; using immunomodulators; had any known allergies to the study drugs; abused substances that would interfere with the study; had a serious illness; had an important cardiac conduction disorder; required prohibited medications; showed evidence of major resistance mutations; were incarcerated, and, as of July 2006, had Hepatitis B. Resistance testing was required for recently infected patients.
Randomization and Interventions
Patients were randomly assigned to open-label 300-mg atazanavir (Bristol-Myers Squibb, Plainsboro, New Jersey) plus 100-mg ritonavir (Abbott Laboratories, Abbott Park, Illinois) or 600-mg efavirenz (Bristol-Myers Squibb) with placebo-controlled 600-mg abacavir-300-mg lamivudine (GlaxoSmithKline, Research Triangle Park, North Carolina) or 300-mg tenofovir DF-200-mg emtricitabine (Gilead Sciences, Gilead Sciences, Foster City, California). Randomization was stratified by HIV-1 RNA (< or ≥100 000 copies/mL) at screening and intent to participate in a metabolic substudy. Participants were randomly assigned through permuted blocks in a 1:1:1:1 ratio. Allocation used a centralized-computer system, with assignment dynamically balanced by site. Balance was achieved by monitoring the total number of patients assigned to each study group by site and overriding assignments when imbalance would exceed a preset maximum. The NRTI treatment assignment was blinded to all except for the site pharmacist. Unblinding occurred in patients with high-screening viral load stratum (as a result of the data safety monitoring board recommendations) as well as in persons with NRTI-related toxicity (suspected by the investigator) that had protocol-defined virologic failure or enrolled with hepatitis B.
Outcomes and Follow-up
The primary efficacy end point was time from randomization to virologic failure (confirmed HIV-1 RNA ≥1000 copies/mL or greater at or after 16 weeks and before 24 weeks or ≥200 copies/mL at or after 24 weeks). The primary safety end point was time from treatment dispensation to first grade-3 or -4 sign, symptom, or laboratory abnormality (graded according to a toxicity rating scale developed by the Division of AIDS [version 1.0, December 2004]) at least 1 grade higher than at baseline, excluding unconjugated hyperbilirubinemia and creatine kinase. The primary tolerability end point was originally defined as time to change in assigned antiretroviral drugs. Study evaluations were pre-entry; at entry; at weeks 4, 8, 16, and 24; and every 12 weeks thereafter regardless of treatment modifications. Adverse event reporting was done by local investigators in an open-ended manner, including study drug causality, at each visit. After screening, HIV-1 RNA (Cobas Amplicor HIV-1 Monitor Test, version 1.5, Roche, Basel, Switzerland) was done at Johns Hopkins University. Planned and actual study duration was 96 weeks after enrollment of the last patient.
The ACTG Data Management Center oversaw the quality of completion of case report forms and computerized data. Monitors contracted by the National Institutes of Health visited all sites to review data. The data safety monitoring board reviewed study conduct and safety data at 2 planned annual reviews. Efficacy data were reviewed at the second review, and an additional safety and efficacy review was requested for 4 months later. Early stopping guidelines stated that a regimen would be considered inferior if the 99.95% 2-sided CI for the hazard ratio (HR) for virologic failure did not include 1.0.
Secondary outcomes included HIV-1 RNA less than 50 copies/mL, change in CD4 cell count, calculated creatinine clearance, and fasting lipid levels. Emergence of a resistant virus was assessed by genotypic testing at Stanford University for all who met protocol-specified criteria for virologic failure and on their baseline samples. Major mutations were defined by the International AIDS Society-United States of America (9), as well as T69D, L74I, G190C/E/Q/T/V for reverse transcriptase, and L24I, F53L, I54V/A/T/S, G73C/S/T/A and N88D for protease. An adherence questionnaire (10) was administered at weeks 8 and 24 and every 24 weeks thereafter.
Statistical Analysis
The primary efficacy hypothesis was that within each of the NRTI groups, atazanavir plus ritonavir was equivalent to efavirenz. Regimens were prespecified to be equivalent if the 2-sided 95% CI for the HR from a Cox proportional hazards model was between 0.71 and 1.40. Assessment of the proportional hazards assumption provided mixed results. Graphical methods (11, 12) did not indicate that the proportionality assumption was violated, whereas addition of a time-by-treatment interaction term to the model indicated for each third-drug comparison a significant decline in the HR over time, with effect changing direction at about 2 years of follow-up. The HR we report may be viewed as an average of the treatment effect over the range of observed times (13).
A sample size of 1800 patients (450 per group) provided 89.8% probability of declaring equivalence if 2 regimens were the same, assuming uniform accrual, exponential virologic failure, and time distributions, with assumed virologic failure probability of 31.9% by 96 weeks. This virologic failure rate assumption was based on available data at the time of protocol development from another ACTG trial using zidovudine-lamivudine plus efavirenz (8, 14). Based on this event rate, a HR of 1.40 would represent a 96-week difference in probability of virologic failure of approximately 10%.
Primary efficacy data were analyzed on the basis of each patient's randomly assigned regimen. The protocol originally defined safety events as events that occurred while receiving the assigned regimen and the tolerability end point as any change in the randomized regimen. After unblinding the high-screening viral load strata, the safety end point was modified to include events that occurred while receiving the assigned third drug (censoring at the time of the modification), and the tolerability end point was based on the first modification of the third drug (ignoring NRTI switches). Time-to-event survival distributions were estimated by the Kaplan-Meier method, compared with log-rank tests stratified by a screening viral load less than 100 000 copies/mL or of 100 000 copies/mL or more. The HRs were estimated with Cox proportional hazards models stratified by screening viral load. For patients without virologic failure, the time was censored at the scheduled visit week of measured HIV-1 RNA. Similarly, for patients without safety or tolerability events, the time was censored at the date of the last sign or symptom evaluation or laboratory measure (safety) or at the date of the last reported antiretroviral treatment evaluation (tolerability).
Binary end points were compared with a Cochran-Mantel-Haenszel (stratified) or Fisher exact test (unstratified), as appropriate. Changes in continuous measures (for example, CD4 count, fasting lipid levels, and calculated creatinine clearance) from baseline were compared with a stratified Mann-Whitney test. Calculated creatinine clearance change within the regimen was assessed by signed rank test.
Data analyses are based on all follow-up, including follow-up after unblinding to NRTIs. P values and CIs are reported 2-sided and nominal, with no adjustment for interim analyses. The significance level for assessing modification of treatment effect was prespecified at 0.10. Analyses were done by using SAS, version 9 (SAS Institute, Cary, North Carolina) and Splus, version 6 (Insightful, Seattle, Washington).
Role of the Funding Source
A5202 was funded by the National Institutes of Health. The funding source had no role in the design, data collection, analysis, manuscript preparation, interpretation, or decision to submit the manuscript for publication.
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