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A meta-analysis of the efficacy and safety of unboosted atazanavir compared with ritonavir-boosted protease inhibitor maintenance therapy in HIV-infected adults with established virological suppression after induction
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HIV Medicine 09 December 2013 - J Baril,1 B Conway,2 P Giguère,3 N Ferko,4 S Hollmann4 and JB Angel3 1Hospital of the University of Montreal, Montréal, QC, Canada, 2The University of British Columbia, Vancouver, BC, Canada, 3Ottawa Hospital Research Institute, Ottawa, ON, Canada and 4Cornerstone Research Group, Burlington, ON, Canada

Treatment simplification involving induction with a ritonavir (RTV)-boosted protease inhibitor (PI) replaced by a nonboosted PI (i.e. atazanavir) has been shown to be a viable option for long-term antiretroviral therapy. To evaluate the clinical evidence for this approach, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating efficacy and safety in patients with established virological suppression.
Several databases were searched without limits on time or language. Searches of conferences were also conducted. RCTs were included if they compared a PI/RTV regimen to unboosted atazanavir, after induction with PI/RTV. The meta-analysis was conducted using a random effects model for the proportion achieving virological suppression (i.e. HIV RNA < 50 and <400 HIV-1 RNA copies/mL), CD4 cell counts, lipid levels and liver function tests. Dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs).
Five studies (n = 1249) met the inclusion criteria. The meta-analysis demonstrated no statistically significant difference in efficacy (i.e. HIV RNA < 50 copies/mL) between PI/RTV and unboosted atazanavir [RR = 1.04; 95% confidence interval (CI) 0.99 to 1.10], with no heterogeneity. Findings were similar in a subanalysis of studies where atazanavir/RTV was the only PI/RTV used during induction. Additional efficacy results support these findings. A significant reduction in total cholesterol (P < 0.00001), triglycerides (P = 0.0002), low-density lipoprotein (LDL) cholesterol (P = 0.009) and hyperbilirubinaemia (P = 0.02) was observed with unboosted atazanavir vs. PI/RTV.
The meta-analysis demonstrated that switching patients with virological suppression from an RTV-boosted PI to unboosted atazanavir leads to improvements in safety (i.e. blood parameter abnormalities) without sacrificing virological efficacy.
HIV type 1 (HIV-1) infection can be successfully treated with a broad range of antiretroviral therapies. Current guidelines recommend that initial regimens consist of two nucleoside reverse transcriptase inhibitors (NRTIs), plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), an integrated strand transfer inhibitor (INSTI) or a ritonavir (RTV)-boosted protease inhibitor (PI) 1. RTV is an antiretroviral drug from the PI class that is co-administered at low doses with other agents (including other PIs) for its 'boosting' effect through inhibition of the cytochrome P450 34A (CYP34A) enzyme, thus increasing drug levels and allowing for less frequent administration of medications 1, 2. Some patients, however, experience high levels of adverse events (e.g. hyperbilirubinaemia, unfavourable lipid profiles and increased gastrointestinal toxicity) on a boosted PI-based triple combination regimen 3, 4. Studies have suggested that cardiovascular disease is associated with antiretroviral therapy, with recent data demonstrating an increased risk of myocardial infarction associated with a longer duration of PI use. This could be explained, in part, by alterations in lipid profiles associated with therapy 5-7. In particular, RTV has been shown to significantly increase plasma lipid levels (e.g. total cholesterol) 8-10, although recent data do not show any difference in myocardial infarction between RTV-boosted and unboosted PI regimens 11. Options to address this include switching to an NNRTI- or INSTI-based regimen, or removing the RTV boosting. Atazanavir (ATV) (ReyatazTM, Bristol-Myers Squibb, Princeton, NJ, USA) was the first once-daily PI approved for the treatment of HIV infection and is the only PI that can be currently given without RTV boosting with a relatively low daily dose and pill burden 12-15. ATV has been associated with a more favourable lipid profile when compared with other PI-based therapies 10. Recent trials have investigated whether patients can effectively continue on unboosted ATV regimens after an induction phase that included RTV. Results have suggested that such a regimen is noninferior to and potentially safer than an RTV-boosted PI regimen for patients with a suppressed HIV plasma viral load at the time of switching 3, 14. In contrast, when HIV plasma viral load is detectable, as in treatment-naïve patients or in those failing treatment, unboosted ATV is not recommended because its plasma drug concentrations are variable and may fall below the minimum threshold for maximal activity 15. In fact, Malan et al. showed that RTV-boosted ATV was associated with a lower virological failure rate than unboosted ATV in treatment-naïve patients 16.
To evaluate the clinical evidence, a systematic review and meta-analysis were conducted of randomized trials that evaluated the efficacy and safety of switching from an RTV-boosted PI to unboosted ATV compared with continuing on an RTV-boosted PI regimen in adult HIV-1-positive patients after patients showed established virological suppression through an induction phase of PI/RTV-based highly active antiretroviral therapy (HAART).
Although RTV-boosted PI regimens have long-term efficacy and a high barrier to resistance, an association has been found with metabolic abnormalities, including dyslipidaemia, related to RTV. As RTV is a potent inhibitor of CYP3A4 enzymes, patients are also more susceptible to drug-drug interactions 15. These concerns may be of particular importance in higher risk populations with a background cardiovascular risk, including those on certain non-ATV/RTV regimens, and elderly patients prone to drug-related toxicities 21. Therefore, given this unfavourable safety profile, a safer regimen that can maintain efficacy may be preferred.
The findings of the current report, being the most comprehensive meta-analysis to date, support a switch from an RTV-boosted PI (e.g. lopinavir, indinavir or ATV) to an unboosted ATV regimen in patients with established virological suppression after an induction period. Over 48 weeks (with one study reporting data to 24 weeks), virological efficacy was not significantly different between PI/RTV and unboosted ATV. Results remained consistent when other efficacy endpoints were evaluated and analyses were restricted to studies that only used ATV/RTV for induction. However, in sensitivity analyses, when two studies deemed to potentially have a higher risk of bias were excluded (i.e. leaving three studies in the meta-analysis), the results approached significance, indicating greater virological control in the PI/RTV arm. Furthermore, the meta-analysis demonstrated significant improvements in total cholesterol, triglycerides, LDL cholesterol, and hyperbilirubinaemia following a switch from an RTV-boosted PI to unboosted ATV. A recent meta-analysis by Carey et al. provided preliminary evidence that RTV co-administration resulted in higher total cholesterol and non-HDL cholesterol compared with unboosted ATV 10. The results of our meta-analysis confirm the findings of this published study, adding more recent and complete data on efficacy and safety. Data from several observational cohort studies also support our findings, often showing either a significantly or non-significantly improved lipid profile with an unboosted ATV regimen compared with an RTV-boosted PI 15, 22-24. However, recent data show no evidence of an association between cumulative exposure to RTV-boosted ATV and myocardial infarction risk 11. Several of these studies demonstrated favourable long-term efficacy of unboosted ATV with no evidence of increased virological breakthrough 24-26. For example, in the largest study to explore the long-term efficacy of unboosted ATV-based regimens (the NEAT Unboosted Atazanavir Study Group), 886 patients with sustained virological suppression were evaluated. The probability of virological failure (HIV RNA > 50 copies/mL) in this study over 1, 2 and 3 years was, respectively, 9.7, 16.1 and 20.1% 25. Three-year virological failure rates were reduced to 9.3% when the threshold was > 400 copies/mL. Caution must be exercised, however, when comparing the results of the NEAT study with those of the current meta-analysis, given the differences in study design (i.e. RCTs vs. a retrospective observational study) and time period.
Resistance testing and reporting were heterogeneous across the included studies, and therefore our meta-analysis did not evaluate mutation rates. The general conclusions from the studies suggested that there were no apparent differences in the rate of drug resistance mutations observed for the patients receiving ATV only compared with those patients receiving a PI in combination with RTV. However, given the limited data available (e.g. missing baseline data) and other confounding variables (e.g. medication adherence), these conclusions should be interpreted with caution.
The goals of simplification strategies in antiretroviral therapy are to reduce pill burden, minimize side effects, and improve treatment adherence to prevent virological failure and preserve future drug options. In this context, reducing toxicity appears to be most important, such that intolerance to RTV accounts for close to half of patient switches to unboosted ATV 22. Our results support use of an unboosted ATV regimen in that setting, and also for patients who may not be able to take or have access to RTV, as well as those at high risk of deleterious events that may be associated with RTV use. Discontinuation of RTV from the regimen may also remove the requirement for refrigeration of certain formulations. However, therapy with unboosted ATV may not be appropriate for patients with a history of suboptimal response to previous antiretroviral treatment, or for the majority of treatment-naïve patients 15, 27. In situations where lower adherence may be expected, or where concomitant medication use may reduce its bioavailability, unboosted ATV should only be prescribed with caution.
The choice of an NRTI backbone can be an important consideration in switching from boosted to unboosted ATV. The NEAT study showed that use of abacavir was associated with lower risk of virological failure vs. alternative NRTIs 25. This finding supports the conclusion that abacavir, usually with lamivudine as a fixed-dose combination backbone, is the ideal companion drug for unboosted ATV 15. In contrast, the co-administration of tenofovir with unboosted ATV may be problematic as a consequence of altered and less predictable ATV pharmacokinetic parameters 28, 29.
The current study has several limitations. First, not all data were available to inform variance inputs for the meta-analysis. To address this, we utilized imputation techniques recommended by Cochrane 17 whereby assumptions were minimized through having complete variance data for at least one study. Secondly, for some outcome measures (e.g. hyperbilirubinaemia), not all five studies had data available to be statistically combined, and so these results may not be as rigorous as for analyses with a larger sample size. Thirdly, renal function safety parameters could not be formally assessed because of inconsistencies in endpoints. Fourthly, in the SWAN study, a small proportion of those on 'unboosted ATV' (9%) remained on RTV because their regimens had a tenofovir-based NRTI backbone, with these patients considered as receiving 'ATV only', given the absence of disaggregated data. However, sensitivity analyses remained robust when this study was excluded. Finally, this study focused on trials of 48-week duration, which may not be predictive of the long-term efficacy of unboosted ATV regimens. On an individual study level, the ARIES 144-week extension study did demonstrate sustained and similar efficacy of unboosted and boosted ATV regimens in patients who completed the extended follow-up 30. At week 144, 77% vs. 73% of subjects in the unboosted and boosted ATV groups, respectively, maintained HIV RNA <50 copies/mL. This is reassuring, but additional studies involving longer follow-up are required to fully elucidate the long-term efficacy of unboosted ATV.
There is increasing clinical experience with unboosted ATV-based regimens in patients having achieved and maintained virological suppression on other combinations, particularly those including RTV-boosted PIs. Although longer term follow-up in larger numbers of subjects should be accumulated, the results of this meta-analysis suggest that this approach is evidence-based. It can be a legitimate option in patients who wish to change their medications to address issues of regimen complexity or safety.
Of the 1600 unique records identified, 1584 records were excluded (Fig. 1). The full-text publications of 16 studies were retrieved for detailed review, and 11 studies were subsequently excluded. Five studies involving a total of 1249 patients met the inclusion criteria 3, 14, 18-20. All studies evaluated antiretroviral treatment-experienced patients and measured the primary efficacy endpoint at the end of a maintenance phase. A summary of the study characteristics is presented in Table 1.
Of the five studies, two studies compared regimens including a PI/RTV combination (i.e. lopinavir/RTV 19, or lopinavir/RTV, indinavir/RTV or saquinavir/RTV 20) vs. unboosted ATV, and three studies compared regimens containing ATV/RTV vs. unboosted ATV 3, 14, 18. In one study 20, the ATV arm was composed mainly of patients receiving an unboosted ATV regimen; however, a small proportion of patients received ATV/RTV (9%) if tenofovir was co-administered. For this analysis, the proportion of patients on ATV/RTV was assumed to be small enough to be considered not clinically meaningful and therefore the ATV arm was analysed only as unboosted ATV. Overall, patient characteristics were comparable across studies, with some variations in NRTI backbones. Regarding the unboosted ATV groups, it is noted that a lamivudine and abacavir NRTI backbone regimen was commonly used. In contrast, a regimen containing tenofovir was used much less frequently (Table 1).
The results of the individual study quality assessments are summarized in Table 2. Study protocols were obtained, where available, to assess selective outcomes reporting. All studies described statistical analyses of outcomes and addressed any incomplete data such as loss to follow-up. Studies were open label; however, outcomes evaluated were objective measures and it was assumed that nonblinding represented a low risk of bias. Two studies did not sufficiently report methods of sequence generation and allocation concealment, and supplementary data from the authors were not available 18, 19. Only one study was presented at a conference 18 and lacked clarity on a majority of categories. Overall, the risk of bias within the included studies was assessed as adequate for three studies and acceptable for inclusion in our analysis for the other two.
Results from the meta-analysis demonstrated no statistically significant difference in virological efficacy (i.e. HIV RNA < 50 copies/mL) between PI/RTV and unboosted ATV regimens (RR = 1.04; 95% CI 0.99 to 1.10), with no heterogeneity observed (I2 = 0%) (Fig. 2). Findings for virological efficacy were similar in a subanalysis of studies where ATV was the only PI with RTV during induction (RR = 1.04; 95% CI 0.98 to 1.10; I2 = 0%). Results for the proportion of patients achieving HIV RNA < 400 copies/mL also indicated no statistically significant difference (RR = 1.05; 95% CI 0.99 to 1.11; I2 = 0%). The meta-analysis also showed no significant differences between the two groups for change in CD4 counts (MD = 14.10; 95% CI -13.27 to 41.48; I2 = 53%).
For lipid parameters, results showed that unboosted ATV was associated with significantly improved or comparable outcomes vs. an RTV-boosted PI regimen. Specifically, a significant reduction in total cholesterol (MD = -14.7 mg/dL; 95% CI -20.96 to -8.49; P < 0.00001), triglycerides (MD = -51.15 mg/dL; 95% CI -78.36 to -23.94; P = 0.0002) (Fig. 3) and LDL cholesterol (MD = -5.56 mg/dL; 95% CI -9.71 to -1.41; P = 0.009) (Fig. 3) was observed with unboosted ATV compared with PI/RTV. There were no significant differences in HDL cholesterol (Fig. 3). These results were supported in a subanalysis of only studies including ATV/RTV vs. unboosted ATV (data not shown).
The risk of grade 2-4 hyperbilirubinaemia was found to be significantly lower with unboosted ATV compared with ATV/RTV (RR = 0.43; 95% CI 0.21 to 0.89; P = 0.02; I2 = 0%) (Fig. 4). There were inadequate data to inform the meta-analysis for scleral icterus or jaundice. Renal function parameters could not be pooled because of inconsistent measures across studies; however, the results of individual trials are noteworthy. In particular, Ghosn et al. 3 reported 0% grade 3 to 4 renal function abnormalities (i.e. creatinine, blood urea nitrogen (BUN) and serum uric acid) for both treatment groups.
Results of a sensitivity analysis regarding study quality for the primary efficacy outcome (HIV RNA < 50 copies/mL) showed that findings did not change when each of the two studies deemed to have a potentially higher risk of bias was excluded individually 18, 19. However, when both studies were excluded together, leaving only three studies, the results reached statistical significance (i.e. RR = 1.07; 95% CI 1.0 to 1.15; P = 0.05), indicating greater virological control in the PI/RTV arm.

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