Before study entry, a genotypic resistance analysis of HIV was available in 53 of 121 patients (44%) in the ATV/r group. At least 1 PI resistance mutation was detected in 43 of 53 patients screened (ie, at least 36% of patients in this arm) and at least 1 major PI resistance mutation in 17 of 53 (at least 14%) patients in this treatment arm (14 with 1 and 3 with 2 major PI resistance mutation). Genotypic analysis was available in 63 of 127 patients (50%) in the LPV/r group, revealing that 41 of 63 (minimum 32% of LPV/r patients) patients had at least 1 PI resistance mutation and 13 of 63 (minimum 10%) had at least 1 major mutation (6 with 1, 6 with 2, and 1 with 3 major PI resistance mutation) (Table 1). Fifty patients (25 per arm) had previous PI failures: 8 cases while receiving indinavir alone, 8 nelfinavir alone, 3 saquinavir alone, and 6 PI combinations in the ATV/r arm and 3 while receiving indinavir alone, 12 nelfinavir alone, 4 saquinavir alone, and 6 PI combinations in the LPV/r arm (Table 1).
A total of 265 patients were randomized in the study. Eleven patients in the ATV/r arm and 6 in the LPV/r arm were excluded. Reasons were violation entry criteria (8 and 6 patients in the ATV/r and LPV/r arms, respectively) and randomization error (3 patients in the ATV/r arm). Two hundred fourty-eight of 265 randomized patients were eligible and received at least 1 dose of study medication (121 patients switched to ATV/r and 127 patients remained on LPV/r). Overall, 105 patients (87%) who switched to ATV/r and 109 (86%) of those who continued on LPV/r completed the study to week 48. The trial flow chart is shown in Figure 1.
Primary and Secondary Efficacy Analyses
At week 48, the number of patients who experienced treatment failure was 21 (17%) in the ATV/r group and 25 (20%) in the LPV/r group in the ITT analysis (difference analysis −2.3%; 95% CI −12.0% to 8.0%; P = 0.0018; Fig. 2), demonstrating noninferiority for the primary end point.
Virological failure developed in 6 ATV/r patients (5%) and nine LPV/r patients (7%) in the on-treatment analysis (difference analysis -2.1%; 95% CI: −8.7% to 4.2%, P < 0.0001; Fig. 2, again demonstrating noninferiority of ATV/r versus LPV/r). Six patients (5%) experienced virological rebound in the ATV/r arm versus 8 (6%) in the LPV/r arm (P = 0.597). The characteristics of patients experiencing virological rebound are shown in Table 3. Potentially confounding unbalanced baseline characteristics (diagnosis of AIDS at baseline and age) did not show any association with outcomes either in estimating the difference in treatment effects or in virological failure.
There were no significant differences between treatment arms in survivor functions (P = 0.652). Time to treatment failure and time to virological failure did not differ between groups. CD4+ T-cell counts during the study are shown in Figure 3. The median changes at 48 weeks were +27 cells per cubic millimeter (IQR: −42 to 119) with ATV/r and +48 cells per cubic millimeter (IQR: −5 to 112) with LPV/r (P = 0.315). Inclusion of those patients who had entry criteria violations or who never took the study medication in the analysis did not significantly affect the overall results (data not shown). We have also performed an exploratory subanalysis including only those patients with a high baseline risk, defined as those who previously had ≥1 PI failure, ≥3 PI resistance mutations, or ≥1 major PI resistance mutation. Treatment failure developed in 8 of 45 (18%) in the ATV/r arm and in 7 of 39 (18%) in the LPV/r arm. Virological failure rate was higher in this subgroup of patients for both treatment arms: 11% for ATV/r and 13% for LPV/r. Moreover, virological failure was developed in 6 of 43 and in 1 of 41 patients in the ATV/r and LPV/r, respectively, for those patients with a previous ≥1 PI mutations. In those patients with a previous ≥1 major PI mutation, virological failure was developed in 2 of 17 and in 1 of 13 in the ATV/r and LPV/r arm, respectively. One of 49 and 3 of 73 patients with prior AIDS diagnosis developed virological failure in the ATV/r and LPV/r arm, respectively.
Overall, 12 patients discontinued therapy due to AEs (6 patients in each arm), and there was only 1 death (hepatic encephalopathy, LPV/r group). No new cases of CDC class C events were recorded (Table 4).
The proportions of patients with abnormal levels of hepatic transaminases and bilirubin are shown in Table 5. There was a similarly low incidence of abnormal levels of hepatic enzymes in each treatment group, although patients with elevated ALT or AST at baseline were at an increased risk of experiencing abnormal ALT or AST levels after 48 weeks' treatment, in both arms. Hyperbilirubinemia (bilirubin >2.5 mg/dL and >5 mg/dL) was present in 66 patients (55%) and 21 patients (17%), respectively in the ATV/r arm and in 6 patients (5%) and 2 (2%) patients, respectively, in the LPV/r arm. However, only 2 patients (2%) in the ATV/r arm discontinued study medication due to jaundice.
The median changes in fasting plasma lipids from baseline to 48 weeks are shown in Figures 4A and B. There were significant reductions in TG (P < 0.001), TC (P < 0.001), and TC/HDL-C ratio (P = 0.043) for patients who switched to ATV/r compared with those who continued on LPV/r, with no significant differences between groups regarding changes in LDL-C or HDL-C.
At week 96, there were no major changes in terms of efficacy and safety when compared with week 48. Treatment failure occurred in 30% (40 of 127) in the LPV/r arm and in 25% (33 of 121) in the ATV/r arm (difference −4.2%; 95% CI −15.6% to 7.1%) and virological failure occurred in 9% (12 of 127) in the LPV/r arm and in 8% (11 of 121) in the ATV/r arm (difference −0.36%; 95% CI −7.6% to 6.9%). Median CD4 changes from baseline were 100.5 and 40 cells per cubic millimeter in the LPV/r and ATV/r arm, respectively. Median fasting TG and TC decreased significantly in the ATV/r arm, −53 and −24 mg/dL, respectively.
This study demonstrated that, overall, in patients with virological suppression who received a stable LPV/r-based antiretroviral regimen and with no more than 2 previous virological failures of PI therapy or fewer than 5 PI resistance-associated mutations, a switch from LPV/r to ATV/r provided comparable efficacy, safety and tolerability, and improvements in lipid parameters, particularly TGs, at 48 weeks. However, the study has not enough statistical power to test for noninferiority among subgroups.
This study was adequately powered, and the ATV/r group met the predefined noninferiority criteria versus the LPV/r group. The proportions of patients experiencing virologic (HIV RNA load ≥200 copies/mL) or treatment failure over 48 weeks were similar in the 2 arms. These results were confirmed with additional analyses involving a subset of patients with a high baseline risk of treatment failure.
In the ATV/r, 11 patients were excluded after randomization due to protocol violation in 8 cases and due to randomization error in 3 cases, and 6 additional patients were excluded in the LPV/r arm due to protocol violation. Consequently, this 17 excluded cases after randomization must be considered as a study limitation.
Approximately, 30% of patients in each group had elevated levels of liver transaminases (ALT and AST) at baseline; and approximately, one-third were coinfected with hepatitis C virus. In each case, the proportion was marginally higher in the ATV/r group than in the LPV/r group. Similarly, at week 48, the proportion of patients with abnormal levels of transaminases remained marginally higher among those who switched to ATV/r. One concern when using ATV/r could be the occurrence of hyperbilirubinemia/jaundice, and although in our study we observed a high incidence of hyperbilirubinemia, it was considered mild in terms of clinical management and only 2 patients discontinued study medication due to jaundice. Another concern when using ATV/r is some drug-drug interaction, specially the contraindicated use of proton pump inhibitors. This combination decreases the bioavailability of ATV by approximately 50% and consequently will be not recommended. Overall, both arms were associated with similar rates of AE-related discontinuation. One major difference between treatment groups was that ATV/r arm was associated with a significant reduction in levels of TGs and TC at week 48. Overall, a switch to ATV/r demonstrated comparable efficacy, safety, and tolerability and was associated with an improvement in lipid profiles in a clinical trial that did not require lipid-related abnormalities as study entry criteria. The improved lipid parameters observed in this study are also consistent with findings from earlier trials that evaluated both boosted and unboosted atazanavir therapy in a variety of treatment populations.6,13-18
The results of this study should be interpreted in view of study design limitations, in particular, that this was an open-label, stable-switch study. Although the intention was to enroll patients to simplify their antiretroviral dosing, it is possible that some patients may have been somewhat disenchanted if allocated to their current PI regimen. On the other hand, one factor that may influence outcomes within switch arms in studies of this type is that possible short-term tolerability issues with the new drug initiated could penalize the switch group.
Currently, ATV/r-containing regimens have been extensively evaluated in both naive and experienced HIV-infected subjects. Consistently, efficacy outcomes in treatment-naive patients, simplification strategies, and rescue therapy were comparable to LPV/r-containing regimens with improved lipid profile and in some cases improved gastrointestinal tolerability.9,14,19
In summary, switching to a simplified PI-based regimen containing ATV/r provided comparable virological suppression, as demonstrated by rates of virological rebound, and treatment failure similar to those observed with continued unmodified therapy with LPV/r. No unexpected drug-related AE was observed, and the ATV/r group was associated with similar safety and tolerability profile to the comparator, LPV/r. Improved lipid parameters were observed in the ATV/r arm of the study, and changes were sustained up to 48 weeks. However, the long-term clinical significance of these changes in lipid parameters in HIV-1-infected patients has not been determined.
Based on the results of this study, the treatment simplification strategy of switching patients to once-daily ATV/r can provide an effective and well-tolerated treatment option.
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Members, ATAZIP Study Team:
Trial chair: J.M.G.; Trial coordinators and monitors: Helena Agell, Juan A. Arnaiz, Ana Cruceta, and Judit Pich, Trial statisticians: Elisa de Lazzari.
Participating Centers and Investigators (in alphabetical order):
1. Hospital de Bellvitge, L'Hospitalet (E.F., Gabriela Leibenger, and D.P.)
2. Hospital Clínic, Barcelona (J.L.B., J.M.G., J.M., E.M., A.M., José M. Miró)
3. Hospital Clínico de San Carlos, Madrid (Maria Jesús Téllez, V.R.*, and Javier Vergas)
4. Hospital General Universitario de Elche, Elche (Enrique Bernal, F.G., Mar Masiá, and Sergio Padilla)
5. Hospital Germans Trías i Pujol, IrsiCaixa Foundation, Badalona (Carmen Alcalde, B.C., and Patricia Echeverría)
6. Hospital de Granollers (Elissabet Deig and E.P.)
7. Hospital Gregorio Marañón, Madrid (Juan Berenguer, Jaime Cosín, Isabel Gutiérrez, Margarita Ramírez, and Matilde Sánchez)
8. Hospital de l'Hospitalet, Hospitalet de Llobregat (I.G.)
9. Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona (Joaquim Peraire, Sergio Veloso, F.V., and Consuelo Viladés)
10. Hospital del Mar, Barcelona (Alicia González, H.K., Gabriel Mestre, and Gabriel Vallecillo)
11. Hospital de Mútua de Terrassa, Terrassa (Mireia Cairó, D.D., and Carol García)
12. Hospital Príncipe de Asturias, Alcalá de Henares (J.A.A., Esperanza Casas, and José Sanz)
13. Hospital Sant Jaume, Calella (J.M.L. and Silvia Valero)
14. Hospital Sant Pau (P.D., Mar Gutiérrez, and Gracia Mateo)
15. Hospital Son Dureta, Palma de Mallorca (J.M. and Maria Peñaranda)
16. Hospital Consorci Sanitari de Terrassa, Terrassa (M.A.)
17. Hospital Vall d'Hebron, Barcelona (Esteban Ribera and Sara Villar)
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
atazanavir; HIV; HAART; lopinavir; protease inhibitor