JAC Advance Access published online on November 13, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm413
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Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viraemia: final results of the SLOAT trial
1 Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain 2 Pharmacokinetic Unit, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain 3 Laboratory of Virology, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain
* Corresponding author. Tel: +34-91-4532500; Fax: +34-91-7336614; E-mail: vsoriano{at}dragonet.es
Received 23 June 2007; returned 27 August 2007; revised 13 September 2007; accepted 8 October 2007
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Abstract |
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Background: Atazanavir seems to be a protease inhibitor (PI) with a more favourable metabolic profile. Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected patients with prolonged viral suppression is scarce. If proved, this strategy could be particularly attractive for the subset of patients with greater cardiovascular risk.
Methods: SLOAT was a prospective, open, comparative trial in which patients receiving lopinavir/ritonavir-based regimens and having undetectable plasma HIV-RNA for longer than 24 weeks were randomized to continue on the same therapy or switch to atazanavir. Outcomes in viral rebound, CD4 counts, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose were compared in both groups of patients at 48 weeks of follow-up.
Results: A total of 189 patients were recruited and took at least the first dose of the assigned treatment arm. Overall, 102 switched to atazanavir (49 on 400 mg once daily, and 53 on 300 mg plus 100 mg of ritonavir once daily due to concomitant tenofovir use) and 87 continued on lopinavir/ritonavir. All patients received the PI along with two nucleoside analogues. Virological failure occurred in 12 patients switched to atazanavir and 9 continuing on lopinavir/ritonavir. A reduction (P < 0.001) in median total cholesterol (–19 mg/dL) and triglycerides (–80 mg/dL) was observed after 48 weeks of atazanavir switching, whereas no significant changes occurred in the lopinavir/ritonavir arm. Greater reductions in total cholesterol and triglycerides were seen in patients switched to atazanavir without ritonavir boosting.
Conclusions: The replacement of lopinavir/ritonavir by atazanavir provides an overall significant reduction in total cholesterol and triglycerides, without increased risk of virological failure.
Key Words: antiretroviral therapy , simplification strategies , drug resistance , metabolic syndrome , dyslipidaemia
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Introduction |
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Lopinavir/ritonavir has been the preferred and most widely used protease inhibitor (PI) until recent times.1 Its efficacy has been well established for up to 8 years, although metabolic abnormalities, including hyperlipidaemia and insulin resistance, are frequent side effects of this medication.2 Since cardiovascular risk has emerged as a leading cause of morbidity and mortality in HIV-infected individuals in developed countries3,4 and it has been significantly associated with PI exposure,5 the use of PI-sparing regimens has been eagerly explored and advised,6 particularly for individuals with high cardiovascular risk. For patients with no more options than PI, the use of atazanavir could be a good alternative, since it seems to have a more favourable metabolic profile.7,8 Moreover, the drug can be provided once daily as only two pills making for easier treatment adherence, which is one of the main challenges of therapy with other PIs, which often have to be provided twice a day and/or taking more pills daily.9
Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected patients with prolonged virus suppression is scarce and mainly derived from the SWAN trial,10 in which several PIs besides lopinavir/ritonavir were replaced by atazanavir and the main end-point of the study was virological failure. If substitution of atazanavir for lopinavir/ritonavir proves to improve the metabolic profile without compromising the antiviral activity, this strategy could be particularly attractive for the subset of patients with greater cardiovascular risk who have failed and/or did not tolerate non-nucleoside reverse transcriptase inhibitors.
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Patients and methods |
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The Simplification LOpinavir to ATazanavir (SLOAT) trial was a prospective, randomized, open, comparative trial in which patients receiving lopinavir/ritonavir-containing regimens and having plasma HIV-RNA <50 copies/mL for longer than 24 weeks were allocated to continue on the same therapy or switch to atazanavir. The study began to recruit patients in March 2005. All patients assigned to the atazanavir arm received 400 mg once daily; however, when tenofovir was taken concomitantly, ritonavir-boosted atazanavir (300/100 mg once daily) was prescribed. The study was conducted at a single HIV reference institution located in Madrid and was approved by the corresponding Ethics Committee.
Recruitment started in March 2004 and all patients included in the study were followed for at least 1 year. Outcomes in viral rebound, CD4 counts, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and glucose were compared in both groups of patients at 48 weeks of follow-up. All metabolic parameters were examined in blood samples taken on a fasting stomach.
Drug resistance testing was examined in samples obtained at the time of viral rebound in patients experiencing virological failure. Plasma trough concentrations of lopinavir or atazanavir were measured using a modified ultraviolet HPLC method described elsewhere.11 Effective minimal concentrations were considered as 4 mg/L for lopinavir and 0.15 mg/L for atazanvir, following the latest recommendations.12 Drug adherence was measured using a modified validated questionnaire,13 in which pills missed during the last week and over the past 3 months were recorded. Poor adherence was considered when three or more pills were missed during the last week or when 3 or more days of therapy were missed during the last trimester. The accuracy of these specific questions to recognize poor treatment adherent patients is the highest reported so far in several studies.13
The calculation of the size of the study population was of 105 patients per arm, based on the need to obtain a 90% power to demonstrate non-inferiority of the atazanavir regimen compared with the lopinavir/ritonavir arm. This calculation assumed a two-sided 95% confidence interval with an upper confidence limit of 90% and a rate of virological rebound of 5% in the lopinavir/ritonavir arm.
The virological response was defined as the proportion of patients with plasma HIV-RNA <50 copies/mL at 48 weeks. The virological data are reported on an intention-to-treat basis. With respect to changes in lipids, the results are provided only for subjects who were receiving the assigned study medication. The virological response was compared among treatment arms using the 
2 test. Treatment failure was defined on the basis of virological failure (plasma HIV-RNA >50 copies/mL) or discontinuation due to side effects. All efficacy analyses were made on an intent-to-treat basis, whereas metabolic comparisons were made in patients on-treatment at the end of the 48 week follow-up study period. Qualitative and quantitative baseline characteristics were compared using the 2 test (with Yates and Fisher's corrections when necessary) and the Mann–Whitney U-test, respectively. Changes in continuous variables between both treatment arms were compared using non-parametric tests. All statistical analyses were performed using the SPSS software (version 13.0).
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Results |
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A total of 224 patients were identified at our institution as fulfilling the study entry criteria. However, 9 declined to participate in the study before randomization and 26 did not accept the treatment allocation arm (the latter were mainly subjects assigned to continue on lopinavir/ritonavir). Of the 189 patients recruited in the study who received at least one dose of the assigned medication, 87 continued on lopinavir/ritonavir and 102 were switched to atazanavir (49 on 400 mg once daily and 53 on atazanavir/ritonavir 300/100 mg once daily, since they were taking tenofovir concomitantly). Another three patients did not complete the planned 48 week study period. One in the lopinavir/ritonavir arm was lost to follow-up and two in the atazanavir arm developed severe jaundice and withdrew from the study. Both were receiving ritonavir-boosted atazanavir along with tenofovir. In both cases, atazanavir was replaced by fosamprenavir/ritonavir and patients continued with undetectable viraemia. Figure 1 summarizes the allocation of patients during the study period.
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All patients received the PI along with two nucleos(t)ide analogues. The most common was tenofovir, which was prescribed along with emtricitabine in most cases, as it is co-formulated as Truvada®. Other nucleoside analogues used in order of frequency were lamivudine, zidovudine, didanosine and abacavir. Stavudine was only used by two patients in the whole study population. All these drugs were used at standard doses. There were no significant differences in the use of these drugs when comparing the two treatment arms. Moreover, all patients had been on their regimen for longer than 3 months and none had changed the nucleoside backbone at the time of study entry. Finally, it should be noted that most individuals (177/186; 95.1%) in the SLOAT trial had received other antiretroviral regimens before their current lopinavir/ritonavir-based combination. Nearly half had been exposed to other PIs, mainly indinavir and to a lower extent nelfinavir; and failures on prior PIs had occurred in two-thirds of PI-experienced patients.
Table 1 shows the main characteristics of the study population. There were no significant differences in median age, risk category nor in hepatitis B or C serostatus between groups. It should be highlighted that 
40% of patients in each arm had chronic hepatitis B and/or C. All but five patients (two in the lopinavir/ritonavir arm and three in the atazanavir arm) were Caucasians. There were more males in the atazanavir arm than in the lopinavir/ritonavir arm (84% versus 59%; P < 0.001). The median CD4 count was higher in the subset of patients who switched to atazanavir in comparison to those who continued on lopinavir/ritonavir (548 versus 403 cells/mm3; P < 0.001). Finally, total cholesterol and fasting triglycerides were significantly more elevated at baseline in patients who switched to atazanavir than in those who continued on lopinavir/ritonavir. The reasons for these differences in gender, CD4 counts and lipids at baseline between treatment arms might have been determined by the fact that 26 patients did not accept to stay on lopinavir/ritonavir upon randomization. Although patients with lower CD4 counts having been on prior antiretroviral therapy for a shorter time might have not been prone to change a successful antiviral therapy, those experiencing lipid abnormalities that were difficult to be controlled under longer antiretroviral therapy could have been more in favour of being recruited into a trial in which a potentially safer metabolic PI was evaluated. They expected to receive atazanavir and did not agree to stay on lopinavir/ritonavir for a longer period of time.
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Virological failure occurred in 12 patients switched to atazanavir and 9 on lopinavir/ritonavir (Table 2). Interestingly, eight out of nine patients who failed on lopinavir/ritonavir had no relevant protease resistance mutations. The only patient who failed with resistance changes at the protease gene had previously failed to nelfinavir. Among the 12 patients who failed on atazanavir, 5 were on atazanavir 400 mg once daily and 7 on atazanavir/ritonavir 300/100 mg once daily. Five of these patients harboured primary resistance mutations. All of them had previously failed other PIs, generally indinavir and/or nelfinavir. A retrospective review of the clinical charts revealed that poor drug compliance was the most likely reason for virological failure in this subset of patients, either on lopinavir/ritonavir or atazanavir. However, three out of the five individuals who failed on atazanavir with PI-resistant viruses were compliant with their medication and had atazanavir plasma trough concentrations above the Cmin.
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The median atazanavir plasma trough concentrations were 0.822 (0.042–1.278) µg/mL in patients taking atazanavir/ritonavir 300/100 mg/day and 0.234 (0.034–0.456) µg/mL in subjects taking atazanavir 400 mg/day. The minimum efficacious plasma concentration for the drug has been established in 0.150 µg/mL.12,14
Changes in CD4 cell counts from baseline were comparable between treatment arms at week 48, with median increases of 42 cells/mm3 for patients continuing on lopinavir/ritonavir and 46 cells/mm3 for patients switched to atazanavir.
A significant reduction in median fasting total cholesterol (–19 mg/dL) and triglycerides (–80 mg/dL) (P < 0.001) was observed after 48 weeks of atazanavir switching, although lipids remained relatively stable in the lopinavir/ritonavir arm (Table 3). Greater reductions in fasting total cholesterol and triglycerides were seen in patients on ritonavir-unboosted atazanavir in comparison with those switched to atazanavir/ritonavir 300/100 mg once daily. The benefits in the lipid profile did not differ significantly comparing patients with or without underlying chronic viral hepatitis (data not shown). The proportion of patients who achieved lipid levels below the threshold for therapeutic interventions with either life style, exercise and/or lipid-lowering drugs was greater in the atazanavir arm in comparison with the lopinavir/ritonavir arm. At week 48, the proportion of patients with LDL-cholesterol levels above the distinct cardiovascular risk categories was significantly lower in the atazanavir arm compared with the lopinavir/ritonavir arm (Figure 2). This difference could be appreciated despite a more frequent use of lipid-lowering drugs in the lopinavir/ritonavir arm compared with the atazanavir arm (17% versus 5%; P = 0.006).
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No significant changes in fasting serum glucose were seen in any of the treatment arms during the 48 week follow-up. Likewise, changes in HDL- and LDL-cholesterol did not differ significantly when comparing treatment arms, although a trend towards reduced LDL-cholesterol was seen in the subset of patients on ritonavir-unboosted atazanavir.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionFundingTransparency declarationsReferences |
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This study demonstrates that the replacement of lopinavir/ritonavir by atazanavir may provide an overall significant reduction in fasting total cholesterol and triglycerides, without an increased risk of virological failure throughout 48 weeks in patients with undetectable plasma viraemia under a stable lopinavir/ritonavir-based regimen. These data confirm what has recently been suggested in the SWAN trial for patients with virological control using different PI-based regimens.10 In contrast to the SWAN trial, in which patients switched to atazanavir experienced fewer viral rebound episodes than patients continuing on their prior PIs (7% versus 16%, respectively), in our study the rate of virological failure was 10% on average and similar between patients continuing on lopinavir/ritonavir and those switched to atazanavir. It should be noted, however, that patients who had experienced previous virological failure under other PIs were excluded from the SWAN trial but not from our study. Thus, the lower genetic barrier for resistance to atazanavir compared with lopinavir/ritonavir could explain at least in part the differences between virological outcomes in the two studies. In any case, it should be highlighted that poor drug compliance was the most likely reason for virological failure in our study population, regardless of treatment arm allocation, as demonstrated by looking at plasma drug trough concentrations. Measurement of plasma PI concentrations confirmed pharmacy records and a modified validated self-reported questionnaire for low drug adherence.13 As expected and not surprisingly, PI-associated resistance mutations were not seen in the majority of our patients experiencing viral rebound, although this was particularly true for lopinavir/ritonavir failures and less common for atazanavir failures.
At week 48, patients in the atazanavir arm experienced significant improvements in fasting total cholesterol and triglycerides compared with patients who continued on lopinavir/ritonavir. More patients who switched to atazanavir than patients who received lopinavir/ritonavir achieved lipid levels below the National Cholesterol Education Programme threshold for pharmacologic intervention,15 even when lipid-lowering agents had been more frequently used in the lopinavir/ritonavir arm than in the atazanavir arm during the study period. These results are in agreement with those obtained in the SWAN trial10 and other studies that have assessed the metabolic profile of atazanavir.16–19 It should be noted, however, that our findings extend the improvement in the lipid profile to patients with fewer severe lipid abnormalities at baseline in whom theoretically it might have been more difficult to recognize any further benefit in the lipid profile.
Around 40% of patients in the SLOAT trial suffered from chronic hepatitis C. While insulin resistance and hyperglycaemia have been reported to be more frequent among HIV/HCV-coinfected individuals, particularly following exposure to antiretroviral therapy,20 a paradoxical lower incidence of lipid abnormalities, especially hypercholesterolaemia, has been reported in HCV/HIV-coinfected versus HIV-monoinfected patients.21 In our study, the benefit in the lipid profile after switching from lopinavir/ritonavir to atazanavir was equally noticed regardless of the presence of underlying chronic hepatitis C.
The implications of our results are clear in an era in which more than 20 antiretrovirals exist and achievement of complete virus suppression is the rule for most patients in need of antiretroviral therapy. Undesirable metabolic consequences have become a relevant aspect of HIV care6–8 and for the already relatively large number of individuals who have failed non-nucleoside reverse transcriptase inhibitors and/or do not tolerate them, it is very welcome that active antiviral drugs with a clean lipid profile such as atazanavir have become available.
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Funding |
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This work was supported in part by grants from Fundación Investigación y Educación en SIDA (IES), the European NEAT project, and the Spanish Red de Investigación en SIDA (RIS, ISCIII-RETIC RD06).
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Transparency declarations |
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V. S. has received research grants and has been member of advisory boards and speaker's bureau from BMS, Gilead, GSK and MSD during the past 2 years. All other authors have none to declare.
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Acknowledgements |
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We would like to thank German Ramirez-Olivencia for his excellent assistance in the collection and analysis of data.
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References |
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