JAC Advance Access originally published online on June 7, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):436-439; doi:10.1093/jac/dkm198
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Lopinavir/ritonavir monotherapy as a simplification strategy in routine clinical practice
1 ‘Lluita contra la SIDA’ Foundation, Germans Trias i Pujol Hospital, Badalona, Spain 2 Universidad Autónoma de Barcelona, Barcelona, Spain 3 ’IrsiCaixa’ Foundation, Germans Trias i Pujol Hospital, Badalona, Spain
* Correspondence address. Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet s/n, 08916 Badalona, Barcelona, Spain. Tel: +34-93-497-88-87; Fax: +34-93-465-76-02; E-mail: jmolto{at}flsida.org
Received 8 March 2007; returned 8 May 2007; accepted 8 May 2007
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Abstract |
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Objectives: The efficacy and safety of lopinavir/ritonavir monotherapy has been explored with promising results in well-controlled, randomized clinical trials. However, less information about its clinical usefulness in routine clinical practice is currently available. The objective of this study was to assess the effectiveness and safety of monotherapy with lopinavir/ritonavir as a treatment simplification strategy in HIV-infected patients with viral suppression outside a clinical trial setting.
Methods: Fifty-one subjects who were switched to lopinavir/ritonavir monotherapy and whose HIV-1 RNA was < 50 copies/mL were included in this retrospective study. Data were obtained from a prospectively compiled database. The primary endpoint was the percentage of subjects who maintained viral suppression after 48 weeks of follow-up. Secondary endpoints included the incidence of adverse events and changes in CD4+ T cell count and in lipid profile.
Results: Two patients lost viral suppression, seven patients interrupted lopinavir/ritonavir monotherapy because of adverse events and four patients were lost before completing 48 weeks of follow-up. Thus, 38/40 (95.0%) patients maintained viral suppression when only subjects whose outcomes were available up to week 48 were considered and 38/51 (74.5%) patients maintained viral suppression when subjects who discontinued therapy or who were lost to follow-up were considered as treatment failures. The mean CD4+ T cell count significantly increased, from 541 (280) cells/mm3 at baseline to 609 (212) cells/mm3 at week 48 of follow-up (P = 0.034). This increase was similar to that observed in the 48 weeks prior to lopinavir/ritonavir monotherapy (P = 0.792). Although total cholesterol remained unchanged, there was a significant decrease in triglyceride levels during follow-up (P = 0.029).
Conclusions: Monotherapy with lopinavir/ritonavir is safe and effective as a treatment simplification approach in HIV-1-infected patients with sustained viral suppression in routine clinical practice, particularly in those patients already receiving a lopinavir/ritonavir-based antiretroviral regimen.
Keywords: protease inhibitors , nucleoside-sparing therapy , HIV infection
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Introduction |
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The pillar of the current standard of care for highly active antiretroviral therapies (HAART) is the use of two nucleoside reverse transcriptase inhibitors (NRTIs).1 However, these agents can inhibit the mitochondrial DNA polymerase gamma, causing mitochondrial dysfunction, which, in turn, may cause NRTI-related adverse events such as peripheral neuropathy, pancreatitis, liver disturbances, lipid profile abnormalities or lipoatrophy.2 As a result, various strategies aimed to avoid these toxicities are currently under evaluation.
Monotherapy with protease inhibitors (PIs) as an antiretroviral therapy simplification approach after an induction period with conventional antiretroviral treatment appears to be of great utility for minimizing mitochondrial toxicity because of NRTI. This approach may also increase patient adherence, reduce costs and preserve future treatment options. Results coming from well-controlled, randomized clinical trials which have assessed the clinical usefulness of this strategy are encouraging.3–6 However, the question remains as to whether the results obtained in clinical trial settings can be extrapolated to routine clinical practice or not.
The objective of this retrospective study was to assess the effectiveness and safety of monotherapy with lopinavir/ritonavir as an NRTI-sparing treatment simplification strategy in HIV-infected patients with sustained viral suppression in routine clinical practice.
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Patients and methods |
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Between January 2004 and December 2006, from a prospectively compiled database (electronic medical files), we identified all consecutive patients who were switched to lopinavir/ritonavir (Kaletra®, Abbott Laboratories, Abbott Park, IL, USA) as single antiretroviral agent, and whose HIV-1 RNA load was <50 copies/mL. Those patients who had been followed for at least 48 weeks as well as those who had discontinued therapy or who had been lost before completing 48 weeks of follow-up were included in the analysis. Demographic and clinical characteristics, viral load, CD4+ T cell count and fasting lipid profile [total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides] were recorded when monotherapy was started (baseline) and every 12 weeks thereafter. In addition, changes in CD4+ T cell count were recorded during the year before lopinavir/ritonavir monotherapy was started. The study was performed according to the stipulations of the declaration of Helsinki, and all subjects had given their written informed consent for using their medical information in scientific research.
The primary endpoint of the study was the percentage of subjects who maintained HIV-1 RNA <50 copies/mL after 48 weeks of follow-up. Secondary endpoints included the incidence of adverse events or laboratory abnormalities leading to treatment discontinuation and changes in CD4+ T cell count and lipid profile. In addition, the financial impact of this strategy was assessed considering the cost of the drugs included in the previous regimen and the expenses derived from performing resistance tests in those patients who failed on lopinavir/ritonavir monotherapy.
Comparisons between baseline and week 48 of follow-up were performed using SPSS version 12.0 statistical software (Chicago, IL, USA). Variables with a normal distribution were described as mean (SD) and compared with the Student's t-test. Median and interquartile range were employed to describe variables that did not follow a normal distribution, which were compared by using the Mann–Whitney non-parametric test. Differences were considered statistically significant at P < 0.05.
Treatment failure was defined as either the presence of HIV-1 RNA >50 copies/mL in at least two consecutive determinations (virological failure) or the premature discontinuation of lopinavir/ritonavir therapy because of adverse events.
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Results |
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A total of 63 patients who maintained viral suppression and who switched from their conventional antiretroviral therapy to lopinavir/ritonavir monotherapy were identified. Twelve of the 63 patients had not reached 48 weeks of follow-up at the time of this analysis and were excluded.
Among the 51 patients included in the study, reasons for changing to lopinavir/ritonavir were to try to improve patient adherence in 10 (19.6%) patients, to ameliorate NRTI-related toxicities in 7 (13.7%) patients and to accede to the patient's request in the remaining 34 (66.7%). Patients had received a mean of 8.6 (4.3) antiretroviral regimens, and viral load had remained below 50 copies/mL for a median of 30 (15–56) months before lopinavir/ritonavir monotherapy was started. The antiretroviral regimen before monotherapy included lopinavir/ritonavir in 37 (72.5%) patients, another boosted PI in 3 (5.9%) and non-NRTIs in 11 (21.6%) patients. In addition, 31 (60.8%) patients were receiving lamivudine and 21 (41.2%) patients were receiving tenofovir prior to lopinavir/ritonavir monotherapy. Table 1 summarizes other characteristics of the patients.
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Genotype information prior to lopinavir/ritonavir monotherapy was available for 13 patients. Out of these, eight patients had viral strains showing mutations in the protease gene related to lopinavir resistance (median number of mutations was 2, range 1–5). Moreover, two patients harboured major mutations in the protease gene associated with resistance to lopinavir (82V in one patient and 32I plus 82V in the other).
Two patients had loss of viral suppression, seven patients discontinued lopinavir/ritonavir monotherapy because of adverse events and four were lost to follow-up before completing 48 weeks of follow-up. Thus, the proportion of patients who maintained viral suppression was 38/40 (95.0%) when only patients whose viral load was available up to week 48 were considered and 38/51 (74.5%) when those patients who discontinued lopinavir/ritonavir monotherapy or who were lost to follow-up were considered as treatment failures.
Regarding the two patients who experienced virological failure, HIV-1 RNA load remained <50 copies/mL for 66 months in the first patient, but it rose to 9900 copies/mL after 12 weeks on lopinavir/ritonavir monotherapy. The L63P mutation in the protease gene was evident in the genotype performed at that time, but had been absent in a previous assay. Tenofovir and emtricitabine were added to lopinavir/ritonavir and the viral load was successfully re-suppressed to <50 copies/mL after 12 weeks. The viral load of the second patient had been suppressed for 9 months before he switched to lopinavir/ritonavir monotherapy, but it increased to 710 copies/mL 12 weeks later. The patient admitted to suboptimal adherence to antiretroviral therapy and, due to the low-level viraemia, the viral genome was not amplified. As in the first case, this patient was also successfully re-suppressed when the same NRTI he was receiving before lopinavir/ritonavir monotherapy was re-introduced. Twelve weeks later, viral load was <50 copies/mL.
Adverse events leading to lopinavir/ritonavir discontinuation included gastrointestinal complaints in six subjects and impaired glucose tolerance in one patient. It is noteworthy that five out of these seven patients had being treated with non-NRTIs before they switched to lopinavir/ritonavir monotherapy.
Mean CD4+ T cell count significantly increased from 541 (280) cells/mm3 at baseline to 609 (212) cells/mm3 at week 48 of follow-up (P = 0.034). This increase in CD4+ T cell count was similar to that observed within the 48 weeks prior to lopinavir/ritonavir monotherapy (P = 0.792).
Regarding the lipid profile, the median total cholesterol level was 216.7 (179.4–239.0) mg/dL at baseline and 201.2 (176.6–232.2) mg/dL at week 48 of follow-up (P = 0.808). Similarly, there were no significant changes in HDL or LDL cholesterol during follow-up (P = 0.179 and P = 0.987, respectively). Nevertheless, triglyceride levels decreased significantly from 168.3 (97.5–261.4) mg/dL at baseline to 150.6 (97.4–186.1) mg/dL at week 48 of follow-up (P = 0.029).
Considering the cost of the drugs included in the previous regimen as well as those derived from performing resistance tests in the patients who experienced virological failure, simplification to lopinavir/ritonavir monotherapy resulted in a median (range) decrease in the annual cost of antiretroviral therapy of 
2630 (30–8218) per patient.
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Discussion |
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Our results confirm that monotherapy with lopinavir/ritonavir as an NRTI-sparing antiretroviral therapy simplification approach for HIV-infected patients with sustained viral suppression is efficacious and well tolerated in routine clinical practice, especially if patients are already receiving a lopinavir/ritonavir-based antiretroviral regimen.
Antiretroviral treatment simplification with PI monotherapy has raised interest for some time, even though initial studies with unboosted PI demonstrated high rates of virological failure and the development of drug resistance.7 Currently, lopinavir/ritonavir continues to be considered a good candidate for monotherapy on the basis of its favourable pharmacokinetic and resistance profiles.8,9 At the usual doses, lopinavir trough concentrations in plasma are at least 75 times the protein-binding-corrected concentration needed to inhibit the replication of wild-type strains of HIV-1 by 50% (IC50).10 In addition, the incidence of new mutations associated with PI resistance is much lower in patients failing antiretroviral therapy with lopinavir/ritonavir than in patients who failed with unboosted PI.9
The efficacy and safety of lopinavir/ritonavir monotherapy as a treatment simplification approach has been explored with quite promising results in well-controlled, randomized clinical trials conducted by Arribas et al.3,6 In both those studies, more than three quarters of patients maintained viral suppression after 48 weeks of follow-up, treatment was well tolerated and the incidence of new mutations related to PI resistance was low. Our results are consistent with those findings and suggest the usefulness of this strategy in routine clinical practice. The only mutation that appeared in the protease gene after lopinavir/ritonavir monotherapy failure in our study was L63P. This mutation is already present in a high proportion of HIV-infected patients with or without previous PI experience,11 and it does not significantly increase the lopinavir IC50 in the absence of other major mutations in the protease gene.8 Consistent with this and our interpretation that failure on lopinavir/ritonavir monotherapy does not imply loss of future therapeutic options, both patients who experienced viral rebound were successfully re-suppressed to <50 copies/mL after re-introducing baseline NRTI. Furthermore, discontinuation of NRTI had no negative impact on immunological recovery, and the rate of increase in CD4+ T cell count with lopinavir/ritonavir monotherapy was similar to that observed with conventional triple HAART.
Overall, lopinavir/ritonavir monotherapy was well tolerated in our study, probably because nearly three quarters of the patients were already receiving lopinavir/ritonavir. As expected, adverse events leading to treatment discontinuation were mostly gastrointestinal and they mainly appeared in patients who were switched to lopinavir/ritonavir from non-NRTI-based therapies. In this regard, the new melt extrusion technology applied to the new formulation of lopinavir/ritonavir may further improve gastrointestinal tolerance of therapy, it requires taking fewer pills and following fewer dietary restrictions and has a better pharmacokinetic profile than the previous soft-gel lopinavir/ritonavir formulation. In addition, it does not require freezer storage, which reduces the interference of antiretroviral therapy with daily life and promotes treatment adherence.
Regarding NRTI-related toxicity, there was a decrease in the triglyceride concentrations during follow-up, but such decline was only mild, probably because of the low percentage of our patients who were receiving stavudine at baseline, as that drug has been consistently related to the development of dyslipidaemia.12 In contrast, although it was not assessed in the present study, lopinavir/ritonavir monotherapy seems to have a promising role for the management of HAART-related lipodystrophy, and clinical trials specifically designed to explore this possibility are warranted in the near future.
Finally, treatment simplification to lopinavir/ritonavir monotherapy resulted in a substantial decrease in the annual cost of antiretroviral therapy, which may be of great relevance, especially in those countries with limited economic resources for the management of HIV-infected patients.
In conclusion, monotherapy with lopinavir/ritonavir seems to be safe and effective as an NRTI-sparing treatment simplification strategy in HIV-1-infected patients with sustained viral suppression in routine clinical practice, especially if patients are already receiving a lopinavir/ritonavir-based antiretroviral regimen. Clinical studies evaluating the usefulness of this strategy for the management of NRTI-related adverse events and the potential use of the new meltrex formulation are needed.
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Transparency declarations |
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E. N. has received honoraria for speaking and participating in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences and GlaxoSmithKline. S. V. has received honoraria for collaborating with Laboratorios Dr Esteve. B. C. has received honoraria for speaking and participating in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer and Roche.
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Acknowledgements |
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We wish to acknowledge the contribution of Mary Ellen Kerans who gave her assistance with English language expression. This study was funded by a grant from the Lluita Contra La SIDA Foundation. J. M. is supported by FIS trough grant CM030135 from the Fundació per a la Recerca Biomédica Germans Trias i Pujol, Badalona, in collaboration with the Spanish Health Department. J. R. S. is supported by the Fundació Lluita contra la SIDA from Hospital Germans Trias i Pujol, Badalona. S. V. is supported by the Fundació Lluita contra la SIDA from Hospital Germans Trias i Pujol, Badalona.
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References |
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