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Efficacy & Tolerability of NRTI-Sparing Combination of Kaletra and Efavirenz
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JAIDS Journal of Acquired Immune Deficiency Syndromes
1 July 2005
....Although numerous published clinical trials involving 1 or more NRTIs clearly demonstrate the utility of NRTI-based treatments, several NRTIs have been associated with mitochondrial toxicity during long-term exposure.....This study assessed the efficacy and tolerability of an NRTI-sparing regimen of lopinavir/ritonavir and efavirenz in NNRTI-naive patients. Most (76%) of patients were antiretroviral naive, and among the 9 PI-experienced patients, protease resistance mutations at baseline genotypic testing were evidenced in 5, with a major resistance mutation in only 1 case. It should also be noted that among these 9 PI-experienced patients enrolled in the study, 4 had discontinued PI-based therapy before resistance testing at screening, with the possibility that archived resistant variants might thus not have been detected. Still, there was no indication of impaired virologic response in those patients. Overall, patients in this study had moderately advanced HIV infection, with a mean CD4 count just greater than 300 cells/mm3. Approximately three quarters of the patients remained in the study by 48 weeks. Counting all noncompleters as failures, 78% and 73% of patients achieved a plasma viral load less than 400 copies/mL at weeks 24 and 48, respectively; the corresponding numbers for patients achieving a plasma viral load less than 50 copies/mL were 69% at both visits. Of note, plasma viral load was suppressed to less than 400 copies/mL in 93% of the patients who completed 24 weeks on the study medication and to less than 50 copies/mL in 82% of the patients who remained in the study at week 48. These data are within the expected ranges typically seen with most active conventional triple antiretroviral-based combinations.1,22,23 Despite many limitations, NRTIs are still considered an essential part of any recommended first-line antiretroviral combination.5,6 This is most likely attributable to limited experience and data with NRTI-sparing regimens for first-line therapy.....
Authors: Allavena, Clotilde MD*; Ferre, Virginie PharmD, PhD; Brunet-Francois, Cecile MD*; Delfraissy, Jean-Francois MD, PhD; Lafeuillade, Alain MD; Valantin, Marc-Antoine MD; Bentata, Michelle MD; Michelet, Christian MD, PhD#; Poizot-Martin, Isabelle MD**; Dailly, Eric MD; Launay, Odile MD; Raffi, Francois MD, PhD*; the Bitherapy Kaletra-Sustiva Study Group
From the *Service des Maladies Infectieuses et Tropicales/IFR26, Hotel-Dieu, Nantes, France; Laboratoire de Virologie/IFR26, Hotel-Dieu, Nantes, France; Service de Medecine Interne, Hopital Bicetre, Paris, France; Service de Medecine Interne Hopital Avicenne, Bobigny, France; Service de Maladies Infectieuses, Hopital Chalucet, Toulon, France; Service de Maladies Infectieuses, Hopital Pitie-Salpetriere, Paris, France; #Service de Maladies Infectieuses, Hopital Pontchaillou, Rennes, France; **Service d'Hematologie, Hopital Sainte Marguerite, Marseille, France; and Laboratoire de Pharmacologie, Hotel-Dieu, Nantes, France.
Received for publication November 29, 2004; accepted March 31, 2005.
Supported by the Association de Recherche sur le SIDA et les Infections des Immunodeprimes (ARSIID), Abbott Laboratories, and Bristol-Myers Squibb.
Choosing an initial antiretroviral regimen is one of the most important decisions faced by clinicians managing HIV disease. Numerous antiretroviral combination regimens have shown potency sufficient to achieve viral suppression in most treated patients.1,2 Other criteria to take into account are durability of antiviral suppression, tolerability, risk of long-term toxicity, and patient convenience.3,4 Based on these considerations and on results of comparative trials, most international treatment guidelines recommend 2 first-line regimens consisting of a backbone of 2 nucleoside reverse transcriptase inhibitors (NRTIs), with 1 of them being lamivudine or emtricitabine, and lopinavir/ritonavir or efavirenz.5,6
Lopinavir/ritonavir is considered the preferred protease inhibitor (PI) because of its high antiviral potency and durability as well as acceptable patient tolerance, and efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI).5,7 Although the advantages associated with all classes of antiviral drugs are numerous, several disadvantages do exist. PIs are associated with an increased risk of lipodystrophy, hyperlipidemia, and insulin resistance.5 The principal limitation of NNRTIs is the high risk of cross-class resistance that occurs in the setting of suboptimal adherence or potency. Although numerous published clinical trials involving 1 or more NRTIs clearly demonstrate the utility of NRTI-based treatments, several NRTIs have been associated with mitochondrial toxicity during long-term exposure.8,9 The emergence of resistance mutations to NRTIs in a multiple antiretroviral combination has also been shown to confer variable cross-resistance within the NRTI class.10,11 In the absence of substantial data supporting the potential for alternative approaches, NRTIs have been accepted as an essential component of standard regimens since the beginning of the era of antiretroviral therapy and still are in most recent guidelines.5,6 It could be argued that the third agent, an NNRTI or a PI, mainly drives the potency of modern regimens, however. Indeed, among the 2 preferred regimens, most of the potency and durability are likely attributable to efavirenz or lopinavir/ritonavir.12,13 Therefore, an innovative approach would be to construct and evaluate an NRTI-free antiretroviral regimen as part of a broader therapeutic strategy. We designed an open-label proof-of-concept study to assess the immunologic and virologic efficacy and tolerability of an NRTI-free combination of efavirenz and lopinavir/ritonavir in NNRTI-naive HIV-1-infected adults for 48 weeks.
Abstract
Background: Recommended antiretroviral regimens include a nucleoside reverse transcriptase inhibitor (NRTI) component. Class cross-resistance and mitochondrial toxicity are recognized as problems with this class of antiretrovirals.
Methods: In a pilot open-label study, 65 antiretroviral-naive and 21 experienced but nonnucleoside reverse transcriptase inhibitor-naive HIV-1-infected adults were given a combination of lopinavir/ritonavir (533.3/133.3 mg twice daily) and efavirenz (600 mg once daily) for 48 weeks.
Results: At baseline, the mean viral load was 4.84 log10 copies/mL and the mean CD4 count was 311 cells/mm3.
At week 24, the proportions of patients with a viral load <400 copies/mL were 78% and 93% using an intent-to-treat and on-treatment analysis, respectively. At week 48, proportions were 73% and 97%, respectively.
Treatment discontinuation occurred in 21 patients during the 48-week period, with 33% of those attributable to drug-related adverse effects. A viral load >400 copies/mL at week 24 or 48 was associated with nonadherence in 3 patients and virologic failure in 1 patient. After an increase during the first 8 weeks, fasting lipid levels remained stable up to 48 weeks.
Conclusion: The lopinavir/ritonavir-efavirenz combination is associated with a high rate of virologic response and should be compared with more classic NRTI-containing regimens in randomized and controlled clinical trials.
Virologic and Immunologic Response
The proportions of patients achieving a plasma viral load <400 copies/mL and <50 copies/mL at weeks 24 and 48 are shown in Table 3. The mean HIV-RNA change from baseline was -2.90 log10 copies/mL at week 24 and -3.00 log10 copies/mL at week 48. The mean (±SD) CD4 count change was 95 (±100) cells/mm3 at week 4, 163 (±149) cells/mm3 at week 24, and 238 (±198) cells/mm3 at week 48. At week 24, 5 patients had a viral load greater than 400 copies/mL, of whom 3 were not considered to be protocol-defined virologic failures: 1 patient had a viral load of 424 copies/mL at week 24 (3.2 log10-copies/mL reduction from baseline) and reached an undetectable viral load at all subsequent visits, and 2 patients had transient virologic rebound to <2000 copies/mL with a viral load <400 copies/mL at immediate subsequent evaluation. The 2 remaining patients were confirmed as experiencing virologic failure: the first had stopped therapy after week 16 for personal reasons, and the second had no reported adherence problems and had a viral load <400 copies/mL at week 16. Genotype testing of a plasma sample from this patient at week 24 demonstrated emergence of the signature resistance mutation for NNRTI (K103N in reverse transcriptase) but no protease mutations. Genotype testing of samples from the remaining 4 patients with a viral load >400 copies/mL only revealed the presence of wild-type virus. At week 48, 2 of the 65 patients who continued the study beyond week 24 had a viral load >400 copies/mL; both patients were nonadherent. Genotype testing showed wild-type virus in the first patient and the K103N mutation in reverse transcriptase in the second patient. At week 48, the ITT analysis of virologic response rate was not different between the 2 subgroups of antiretroviral-naive and pretreated patients (71% and 81%, respectively, of patients with a plasma viral load less than 400 copies/mL; P = 0.359). Patients with a baseline viral load greater than 100,000 copies/mL had a similar rate of virologic success (78%) at week 48 compared with patients with a lower baseline viral load (69%) at week 48 (P = 0.351).
Safety Assessment
Eight patients (9%) experienced 11 serious clinical adverse events. Four of these events were considered to be drug related by the investigator, including hospitalization for a central nervous system (CNS) disorder in 2 patients and a cutaneous rash in 2 patients. Grade 3 and 4 clinical and laboratory adverse events, regardless of causality, are shown in Table 4. Seven (8%) patients discontinued the study because of drug-related adverse events. This included intolerance to efavirenz with early CNS symptoms in 3 cases and a cutaneous event in 3 cases; 1 patient discontinued the study because of grade 4 dyslipidemia. Fasting lipid levels increased in most patients on treatment at 48 weeks. After an initial, although not significant, increase between baseline and week 8, the median change in fasting total cholesterol and triglycerides remained stable (0.60 and 1.19 g/L at week 48, respectively; Fig. 2). There were no differences in changes from baseline between antiretroviral-naive and pretreated patients. Mean high-density lipoprotein (HDL) cholesterol significantly increased between baseline and week 48 (0.42 g/L vs. 0.49 g/L, respectively; mean variation = 0.11 g/L; P = 0.019). The percentage of patients with HDL cholesterol >0.4 g/L was 44% at baseline and 80% after 48 weeks of therapy for the antiretroviral-naive group and 41% and 54%, respectively, for antiretroviral-experienced patients. The mean and median total cholesterol/HDL cholesterol ratios did not significantly change between baseline and week 48. A LDL cholesterol level >1.60 g/L was seen in 2% of the antiretroviral-naive patients and 12% of the experienced patients at baseline and in 35% of the antiretroviral-naive patients and 20% of the experienced patients at week 48. At baseline, none of the patients were receiving a lipid-lowering agent. During the course of the study, 3 patients were prescribed a lipid-lowering agent: 1 patient after 8 weeks of therapy for grade 2 hypercholesterolemia, 1 patient after 8 weeks of therapy for grade 3 hypertriglyceridemia, and 1 patient at week 36 for grade 3 hypercholesterolemia. Based on clinical assessment, lipodystrophy was reported in 6 patients, of whom 5 were pretreated: 3 had a prior history of lipodystrophy and experienced subjective self-reported worsening of body changes, whereas 2 developed lipodystrophy after 4 and 16 weeks of therapy, respectively. A mild cheek lipoatrophy occurred after 36 weeks of treatment in 1 treatment-naive patient. No modification in the waist/hip ratio of the total study population was observed at week 24 or 48 compared with baseline.
AUTHOR DISCUSSION
This study assessed the efficacy and tolerability of an NRTI-sparing regimen of lopinavir/ritonavir and efavirenz in NNRTI-naive patients. Most (76%) of patients were antiretroviral naive, and among the 9 PI-experienced patients, protease resistance mutations at baseline genotypic testing were evidenced in 5, with a major resistance mutation in only 1 case. It should also be noted that among these 9 PI-experienced patients enrolled in the study, 4 had discontinued PI-based therapy before resistance testing at screening, with the possibility that archived resistant variants might thus not have been detected. Still, there was no indication of impaired virologic response in those patients. Overall, patients in this study had moderately advanced HIV infection, with a mean CD4 count just greater than 300 cells/mm3. Approximately three quarters of the patients remained in the study by 48 weeks. Counting all noncompleters as failures, 78% and 73% of patients achieved a plasma viral load less than 400 copies/mL at weeks 24 and 48, respectively; the corresponding numbers for patients achieving a plasma viral load less than 50 copies/mL were 69% at both visits. Of note, plasma viral load was suppressed to less than 400 copies/mL in 93% of the patients who completed 24 weeks on the study medication and to less than 50 copies/mL in 82% of the patients who remained in the study at week 48. These data are within the expected ranges typically seen with most active conventional triple antiretroviral-based combinations.1,22,23 Despite many limitations, NRTIs are still considered an essential part of any recommended first-line antiretroviral combination.5,6 This is most likely attributable to limited experience and data with NRTI-sparing regimens for first-line therapy. Indeed, initial results of other NRTI-sparing regimens, such as those using a combination of indinavir and efavirenz, demonstrated the inferiority of this dual combination when compared with lamivudine/zidovudine (fixed-dose combination; Combivir) with efavirenz but not when compared with lamivudine/zidovudine (fixed-dose combination) with indinavir.12 This outcome may be related to the use of a regimen with a high pill burden, (ie, 200-mg pills of unboosted indinavir taken 3 times daily) as well as to the negative pharmacokinetic interaction between efavirenz and indinavir.24 In a study of 57 multiple NRTI- and PI-experienced patients who were NNRTI naive, the combination of lopinavir/ritonavir-efavirenz plus NRTIs was able to obtain a viral load less than 400 copies/mL at week 72 in 67% of the patients with the ITT analysis and in 88% with the OT analysis.25 Of note, based on prestudy extensive NRTI exposure, it can be assumed that the backbone NRTIs in the latter study did not make a major contribution to the observed efficacy. Dual-PI combination therapy using ritonavir and saquinavir has been associated with a good immunovirologic response; however, this combination has demonstrated disadvantages associated with safety and pill burden issues.26 The combination of lopinavir/ritonavir and efavirenz was shown to have a good rate of immunologic and virologic efficacy in our pilot study. This is the first clinical trial demonstrating efficacy of a lopinavir/ritonavir plus efavirenz NRTI-free regimen. Within 48 weeks of follow-up, we observed only 1 true documented virologic failure on therapy, and failure attributable to nonadherence was also infrequent. We chose to optimize the lopinavir/ritonavir dosage by increasing the daily dose by one third (ie, 4 pills taken twice daily) to counterbalance the negative pharmacokinetic interaction induced by efavirenz.14,15,25,27,28 Previously reported pharmacokinetic studies have demonstrated that dose adjustment of lopinavir/ritonavir provides lopinavir levels in the presence of efavirenz similar to those obtained with a standard dose of lopinavir/ritonavir and NRTIs.20,21 Regarding safety, only 1 patient stopped the study medication because of a lopinavir/ritonavir-related side effect (ie, grade 4 hypertriglyceridemia). Most discontinuations occurred early, during the first month of treatment, and the main reasons for discontinuation were efavirenz-related adverse events. Because of the pilot nature of the study and to assess the chosen regimen better, we did not allow an efavirenz-nevirapine switch. Such a switch in clinical settings, especially in case of CNS side effects, would allow maintenance of the initial strategy of an NRTI-sparing regimen.29 In addition, the relatively high pill burden of the tested combination (ie, 11 pills taken daily) represents a limitation in the practicability of the regimen explored and could account for some of the discontinuations. Nevertheless, our study has proven the potential of an innovative approach of an NNRTI-PI NRTI-sparing regimen. Because of the documented high potency of lopinavir/ritonavir, the relative contribution of efavirenz to the efficacy of the combination could be questioned. Even if limited and mostly uncontrolled data on lopinavir/ritonavir as single-agent therapy have shown the potential of this monotherapy, failures have been reported, with the need for intensification of lopinavir/ritonavir with NRTIs.30,31 Few cases of the emergence of protease gene resistance mutations have been reported in patients failing therapy with lopinavir-ritonavir only.32,33 We therefore believe that until controlled comparative clinical studies have proven that a boosted PI as a single agent is as effective as combination therapy, the concept of combining antiretrovirals should remain the rule for any given antiretroviral regimen. In patients receiving a PI-containing antiretroviral regimen, the prevalence of hyperlipidemia ranges from 28% to 80%, including hypertriglyceridemia in most cases (40%-80%) as well as hypercholesterolemia (10%-50%).34-36 Hypertriglyceridemia seems to be more frequent in patients receiving ritonavir-containing therapy.36-38 The NNRTIs cause alterations in the lipid profile, although generally to a lesser degree than what is observed with some PIs.39-42 As expected, in our study, the combination of lopinavir/ritonavir and efavirenz led to a rapid, although not significant, increase of fasting triglycerides and total cholesterol, with the maximum increase being achieved by week 4 or 8, followed by stabilization up to week 48. These results suggest a combined effect of both drugs in increased lipids. Interestingly, the HDL cholesterol level significantly improved over 48 weeks, whereas the total cholesterol/HDL cholesterol ratio did not change over time.41
Another important finding of our study is the data on emergence of resistance. NNRTI resistance was only documented in 2 patients by week 48 and in none of the slow responders, whereas none of the patients with a detectable viral load during follow-up had protease-resistant viruses selected. These results confirm previous data with lopinavir/ritonavir-based triple regimens in antiretroviral-naive patients.43
In conclusion, this pilot study has proven that an NRTI-sparing regimen combining a potent boosted PI, lopinavir/ritonavir, and a potent NNRTI, efavirenz, is associated with a high rate of virologic success for up to 48 weeks as well as a sustained immunologic response. Most discontinuations were not related to adverse event emergence or virologic failure and could have been related to the pill burden of the formulations used in this study. The availability of a more convenient formulation of efavirenz should lessen the risk of dropouts unrelated to tolerability problems. In addition, the relative lack of drug resistance or virologic failure among subjects who remained on the medication holds promise for this regimen. Larger randomized and controlled trials are needed to assess the immunologic and virologic response further, to evaluate the safety of a PI-NNRTI combination compared with standard NRTI-inclusive regimens, and to determine the best components, in terms of efficacy and safety as well as convenience, within the NNRTI and the boosted PI drug classes.
RESULTS
Patient Characteristics and Disposition
Eighty-six patients were enrolled in the study between May 2001 and April 2002. Patient characteristics and dispositions are shown in Tables 1 and 2. Among the 86 patients, 65 were antiretroviral naive and 21 were pretreated, of whom 12 had only NRTI experience. Among 9 patients with prior PI exposure, genotype testing performed at screening showed no lopinavir-associated mutation in 3 cases, 1 mutation in 4 cases (L63P [n = 3], V82I [n = 1]), 2 mutations in 1 case (L63P + A71T/A), and 3 mutations in 1 case (L10V + L63P + A71T). Of note, among these 9 patients, 5 were still on PI therapy at the time of screening and 4 had interrupted their prior PI therapy for a mean of 15.5 months (range: 8-22 months). Within the 48 weeks of follow-up, treatment discontinuation occurred in 21 (24%) patients. These discontinuations were primarily attributed to emerging adverse events (n = 7) or loss to follow-up (n = 6); only 1 patient discontinued meeting criteria for virologic failure. Adverse event-related discontinuations occurred more frequently during the first 4 weeks of therapy (n = 6, weeks 0-4; n = 1, weeks 4-24; n = 0, weeks 24-48). Among 43 patients who had at least 1 episode of adherence <80% during follow-up, 5 did not complete the initial 24-week period (lost to follow-up or nonadherence) and 2 discontinued the study between weeks 24 and 48 for reasons unrelated to study drugs (pregnancy in the first case and tuberculosis in the second case).
Lopinavir and Efavirenz Plasma Concentrations
Trough plasma concentrations of lopinavir and efavirenz were measured in 37 patients who received their last intake of study medication 12 ± 2 hours before the week 4 visit. Mean lopinavir and efavirenz concentrations were within ranges typically observed in patients receiving these agents in combination with NRTIs: 6.22 ± 3.25 mg/L and 2.36 ± 2.58 mg/L, respectively.19-21 No correlation was found between plasma concentrations of lopinavir and efavirenz and initial viral load decrease, CD4 cell response, or increase in fasting lipid levels at week 4. Based on lopinavir plasma concentration results, a decrease in lopinavir/ritonavir dosage to 400/100 mg twice daily was made in 6 cases because of associated digestive intolerance, and an increase in dosage to 667/167 mg twice daily was made in 1 case.
Genotypic Resistance Testing in Slow Responders
Among the 65 treatment-naive patients, the subgroup of slow virologic responders (ie, 19 patients who had a plasma viral load still greater than 400 copies/mL at week 8 or 16 and achieved a viral load less than 400 copies/mL at week 24) was further tested to detect the possible selection and emergence of resistance mutations. Genotypic testing performed on stored samples from baseline and week 8 or 16 revealed the absence of emergence of new resistance mutations in the reverse transcriptase and protease genes.
PATIENTS AND METHODS
Study Design
The Bitherapy Kaletra-Sustiva (BIKS) trial was a pilot, single-arm, open-label, prospective study designed to evaluate the immunologic and virologic efficacy and safety of lopinavir/ritonavir and efavirenz combination therapy in antiretroviral-naive or, if antiretroviral-experienced, NNRTI-naive HIV-1-infected adults. This multicenter study was conducted at 16 HIV reference centers in France and was approved by the Institutional Review Board of Nantes University Hospital. All patients gave their written informed consent.
Population
To be eligible for enrollment, patients had to meet the following criteria: age ≥18 years, documented HIV-1 seropositivity, CD4 count ≥100 cells/mm3, and plasma HIV-1 RNA level ≥5000 copies/mL. Patients had to be NNRTI naive and, if PI experienced, to have had no more than 1 documented virologic failure on a PI-containing regimen, with less than 5 lopinavir/ritonavir-associated mutations among L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M (2001 French algorithm) on screening genotype ( http://www.frenchresistance.org ). Patients were not eligible if any of the following abnormal laboratory results were documented at screening: hemoglobin <8 g/dL, absolute neutrophil count <750 × 106 cells/L, platelet count <50 × 109 cells/L, aspartate transaminase (AST) or alanine transaminase (ALT) >3 times the upper limit of normal, or creatinine >1.5 times the upper limit of normal.
Treatment Regimen
Lopinavir/ritonavir (Kaletra; Abbott Laboratories, Abbott Park, IL) was prescribed at a dose of 533.3/133.3 mg (4 capsules) twice daily with food. Although standard dosing of lopinavir/ritonavir is 400/100 mg twice daily, a higher dose is recommended to compensate for the decrease in lopinavir plasma exposure when coadministered with efavirenz.14,15 Efavirenz (Sustiva; Bristol-Myers Squibb, New York, NY) was given at a dose of 600 mg (3 capsules) once daily with no food restriction and instructions to take it at bedtime.
The protocol allowed for a dose reduction of lopinavir/ritonavir to 3 capsules (400/100 mg) twice daily in cases of poor gastrointestinal tolerance in the first weeks after treatment initiation and a lopinavir trough plasma concentration level greater than 8 mg/L.
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