1 Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710, USA; 2 Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA
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Abstract |
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Keywords: antiretroviral therapy , protease inhibitors , acquired immune deficiency syndrome , AIDS
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Introduction |
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The fifth protease inhibitor to receive U.S. Food and Drug Administration (FDA) approval, lopinavir/ritonavir (Kaletra) was specifically designed to overcome some of the limitations of its predecessors. The active part of the fixed-dose combination drug, lopinavir, is metabolized via the hepatic enzymes CYP3A4 and CYP3A5,4 and when given alone, does not achieve drug concentrations sufficient to suppress HIV-1 replication.5 The second component of the combination, ritonavir, potently inhibits these hepatic enzymes in a concentration-dependent manner.6 The combination of lopinavir and ritonavir thus achieves significantly increased plasma levels of lopinavir, well above the mean 50% inhibitory concentration (IC50) for wild-type HIV-1.5,7,8
Lopinavir was designed to avoid the resistance problems which had arisen in Abbott's first protease inhibitor, ritonavir. The development of resistance to ritonavir was often due to a mutation of the amino acid valine at position 82 in protease. Lopinavir was specifically designed to avoid interaction with the valine at this position, thus avoiding development of resistance by this mechanism.
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Antiviral activity and resistance profile of lopinavir/ritonavir-based therapy |
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A larger Phase III study in treatment-naive patients demonstrated the superiority of lopinavir/ritonavir over another protease inhibitor, nelfinavir. The M98-863 study randomized 653 adults to either lopinavir/ritonavir or nelfinavir, in combination with stavudine and lamivudine.12 By intention-to-treat analysis after 48 weeks, 75% of lopinavir/ritonavir-treated patients and 63% of nelfinavir-treated patients achieved HIV-1 RNA suppression to <400 copies/mL (P < 0.001). CD4 cell gains were similar between the two groups (207 cells/mm3 for lopinavir/ritonavir, 195 cells/mm3 for nelfinavir). Through 96 weeks of follow-up, 79% of lopinavir/ritonavir-treated patients remaining on the study medications and 56% of nelfinavir-treated patients maintained HIV-1 RNA <400 copies/mL.13
In treatment-experienced patients, lopinavir/ritonavir has also proven to be a valuable agent. The M97-765 study placed patients failing an initial protease inhibitor-based regimen (n = 70) on a regimen of lopinavir/ritonavir, nevirapine and nucleoside reverse transcriptase inhibitors.14 By intention-to-treat analysis after 48 weeks of therapy, 70% of patients had HIV-1 RNA <400 copies/mL, 60% <50 copies/mL.
Similar results were obtained in the M98-888 study which randomized single protease inhibitor-experienced patients (n = 288) to a new regimen of lopinavir/ritonavir or an investigator-selected alternative protease inhibitor, plus nevirapine and nucleoside reverse transcriptase inhibitors.15 Fifty-seven percent of patients receiving lopinavir/ritonavir had HIV-1 RNA <400 copies/mL after 48 weeks by intention-to-treat analysis, compared with 33% receiving investigator-selected alternative protease inhibitors (P < 0.001).
Finally, study M98-957 documented efficacy of lopinavir/ritonavir in patients who had previously received two or more different protease inhibitors.16 The 57 patients in this study received lopinavir/ritonavir as well as efavirenz and nucleoside reverse transcriptase inhibitors. After 48 weeks of therapy, 65% of patients maintained HIV-1 RNA <400 copies/mL, and 56% <50 copies/mL by intention-to-treat analysis. Thus, the value of lopinavir/ritonavir has been demonstrated in a broad spectrum of patient types, affirming its benefit in both antiretroviral-naive and -experienced patients.
In an effort to simplify treatment regimens for patients, once-daily dosing of antiretroviral agents including lopinavir/ritonavir has been the subject of increasing numbers of studies. The M02-418 study randomized 190 antiretroviral-naive patients to either once-daily or twice-daily lopinavir/ritonavir in combination with emtricitabine and tenofovir DF.17 By intention-to-treat analysis after 48 weeks, 70% of patients receiving once-daily therapy achieved HIV-1 RNA <50 copies/mL compared with 64% of patients receiving twice-daily dosing. Similar results were seen in an earlier pilot study by Eron et al.,18 which randomized antiretroviral-naive patients to once- or twice-daily lopinavir/ritonavir in combination with stavudine and lamivudine.
Lopinavir/ritonavir has also been studied in a paediatric population composed of antiretroviral-naive and -experienced patients. Excellent therapeutic efficacy similar to adult populations has been demonstrated, and the medication appears to be well tolerated in this patient population.19
As previously mentioned, lopinavir/ritonavir was specifically designed to overcome issues of resistance that have affected the efficacy of earlier protease inhibitors. In antiretroviral-naive patients, de novo development of lopinavir/ritonavir resistance has not been demonstrated in large clinical trials. Extensive resistance testing has been completed in patients remaining on therapy after 5 years in the M97-720 study, the cohort followed for the longest time period to date.20 All patients with HIV-1 RNA >500 copies/mL at any time after week 24 had samples submitted for genotypic testing. Thirty-four samples were tested from 27 patients, and resistance testing was successfully accomplished in 22 samples from 17 patients. (Testing failed for the other specimens due to low levels of HIV-1 RNA.) No specimen demonstrated mutations in the protease gene associated with resistance to lopinavir/ritonavir. Resistance to other components of the patient's regimen was also rare, with no patient developing mutations associated with stavudine resistance, and only 3/17 patients showing resistance to lamivudine.
A similar analysis was performed in the M98-863 study, which randomized antiretroviral-naive patients to either lopinavir/ritonavir or nelfinavir. Among patients with at least one HIV-1 RNA >400 copies/mL while receiving lopinavir/ritonavir (n = 51), no genotypic evidence of resistance in protease was demonstrated.21 This contrasted with patients receiving nelfinavir (n = 96), where 45% of samples demonstrated a primary resistance mutation to nelfinavir, D30N or L90M (P < 0.001). Resistance to other components of the treatment regimen was also more common among patients receiving nelfinavir. Eighty-two percent of the available isolates demonstrated resistance to lamivudine in nelfinavir-treated patients, compared with 37% of patients receiving lopinavir/ritonavir (P < 0.001). Resistance to stavudine was not observed in lopinavir/ritonavir-treated patients, and was found in 9% of nelfinavir-treated patients.
In the M02-418 study which compared once- and twice-daily dosing of lopinavir/ritonavir, similar results were obtained. Samples from 11 patients with HIV-1 RNA >500 copies/mL between weeks 12 and 48 were available for genotypic testing. Testing was unable to be performed in three specimens due to low viral load. Of the eight specimens with genotypic results available, no resistance mutations in protease were observed.22
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Safety of lopinavir/ritonavir-based therapy |
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In antiretroviral-naive patients, the most common adverse effects associated with lopinavir/ritonavir are diarrhoea, nausea and abnormal stools.9,10,12 Discontinuation rates as a result of adverse events were 2% or less in these two trials. In the longest study of lopinavir/ritonavir to date, 28% of patients reported diarrhoea of at least moderate severity at some time through week 312.11 In the study comparing once- and twice-daily dosing of lopinavir/ritonavir, the incidence of diarrhoea was increased among patients receiving once-daily dosing.17 Similar adverse event profiles have been seen in antiretroviral-experienced patients, with diarrhoea being the most frequently reported adverse event of moderate or greater severity.1416
As a class, protease inhibitors have been associated with the metabolic syndrome, due to the association of protease inhibitor therapy with the development of hyperlipidaemia, fat redistribution and insulin resistance.23 Frank diabetes mellitus is uncommon.24 Lopinavir/ritonavir has been shown to be independently associated with the development of the metabolic syndrome.25
Lipid elevations are the most common laboratory abnormalities associated with lopinavir/ritonavir treatment. In registrational trials, grade III/IV elevations in total cholesterol and triglycerides were reported in 10% of antiretroviral-naive patients during the first 48 weeks of therapy.9,12 Mean increases in total cholesterol were 4953 mg/dL and in triglycerides 111125 mg/dL. In antiretroviral-naive patients receiving lopinavir/ritonavir for over 6 years, 23% developed grade III/IV elevations in total cholesterol, and 26% in triglycerides.11 Similar results were seen in protease inhibitor-experienced patients.15 In both patient populations, subjects with elevations at baseline were more likely to experience grade III/IV elevations during the course of the study.
While the trials mentioned above involved samples that may not have been obtained in the fasting state, some studies have been specifically designed to assess lipids measured under fasting conditions. Martinez et al.26 examined the impact of 6 months of lopinavir/ritonavir therapy on metabolic parameters in 353 HIV-infected patients, the majority of whom had received therapy with other protease inhibitors previously. During the follow-up period, significant increases in triglyceride levels and total cholesterol were observed. Elevated total cholesterol and triglycerides before study entry as well as the use of lipid-lowering medications at baseline were independently associated with the results. Similar results were seen in a cohort of antiretroviral-naive patients.27 All available data indicate that increases in lipid profiles tend to occur within the initial months of therapy, and reach a plateau thereafter.
In one study of antiretroviral-naive patients, lipodystrophy was reported in 13% of patients through week 312.11 This side effect (which remains relatively poorly characterized) has not been rigorously studied in other clinical trials, mainly because this complication was not widely recognized at the time the studies were designed.
Although protease inhibitors have been associated with the development of insulin resistance, significant increases in fasting glucose levels have not been reported in patients treated with lopinavir/ritonavir.26
Asymptomatic elevations in hepatic transaminases have also been noted in persons treated with lopinavir/ritonavir. Grade III/IV elevations have been reported in 58% of antiretroviral-naive patients receiving lopinavir/ritonavir in the first year of therapy, and in 11% of patients over 6 years of therapy.9,11,12 Similar results were observed in antiretroviral-experienced patients.14 Over time, these elevations tended to normalize, and few patients discontinued therapy due to hepatic inflammation. Patients with transaminase elevations at baseline are more likely to experience elevations while receiving therapy with lopinavir/ritonavir. Concomitant infection with hepatitis B or C also appears to increase the risk of transaminase elevation, but does not increase the risk of hepatotoxicity.9,2830
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Conclusions |
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The dramatic success of antiretroviral therapy has forced HIV practitioners to focus on the longer-term consequences of HIV management strategies. In particular, evidence from studies of long-term antiretroviral therapy suggest that there may be an increased risk of cardiovascular disease among HIV-infected patients receiving antiretroviral therapy.34,35 This increased risk may be mediated in part by changes in lipids, and observed elevations in total cholesterol and triglycerides necessitating institution of lipid-lowering therapy remain a concern with lopinavir/ritonavir therapy. Further studies will be needed to document the causality of this association, and to determine the optimal management of HIV-infected patients with cardiovascular risk factors. The recent availability of protease inhibitors with diminished lipid effects over time36 may ultimately affect which drugs are preferred for initial therapy, but this remains to be determined. The observed efficacy of lopinavir/ritonavir-based therapy in a variety of settings has established the important role of this drug in the management of persons infected with HIV-1, and its continued use as a key protease inhibitor seems assured for the foreseeable future.
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References |
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