A 96‐Week Comparison of Lopinavir‐Ritonavir Combination Therapy Followed by Lopinavir‐Ritonavir Monotherapy versus Efavirenz Combination Therapy

Cameron, D. William; Silva, Barbara A. da; Arribas, José Ramón; Myers, Robert A.; Bellos, Nicholaos C.; Gilmore, Norbert; King, Martin; Bernstein, Barry; Brun, Scott; Hanna, George J.

doi:10.1086/589622

Cited by 102 publications

(86 citation statements)

References 9 publications

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“…Moreover, in contrast to previous studies, patients with a history of VF while on a PI-based regimen were enrolled, and there was no previous period in which tolerance to LPVr was determined before the start of monotherapy. Despite these facts, the virological efficacy was similar to that observed in clinical trials of mtLPVr (6,7,(9)(10)(11)(12)(13). It is noteworthy to mention that neither a history of VF on an unboosted or ritonavir-boosted PI-containing regimen nor the presence of minor resistance mutations to LPVr nor the once-daily administration of LPVr had negative influences on the virological outcome.…”

Section: Discussionsupporting

confidence: 62%

“…Notwithstanding, a considerable proportion of patients maintained an undetectable viremia on lopinavirritonavir maintenance monotherapy (mtLPVr) and could benefit from a simpler regimen without nucleoside analogues or other antiretroviral drugs. Moreover, lack of adherence has been indicated as the main reason for virological failure (VF) in different studies (6)(7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

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Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

López‐Cortés

Ruiz-Valderas

Sánchez-Rivas

et al. 2013

Antimicrob Agents Chemother

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There is significant intra-and intersubject variability in lopinavir (LPV) plasma concentrations after standard dosing; thus, this prospective study was conducted to determine whether low plasma LPV concentrations could be associated with virological outcome throughout lopinavir-ritonavir maintenance monotherapy (mtLPVr) in the clinical practice setting. If this hypothesis would be confirmed, LPV drug monitoring could improve the efficacy of mtLPVr regimens. Patients with previous virological failure (VF) on protease inhibitor-based regimens were also included if the genotypic resistance tests showed no major resistance mutation associated with reduced susceptibility to lopinavir-ritonavir. VF was defined as 2 consecutive determinations of HIV RNA levels of >200 copies/ml. Efficacy was analyzed by per-protocol analysis. Plasma LPV trough concentrations were measured by high-performance liquid chromatography using a UV detector. A total of 127 patients were included (22% with previous failure on protease inhibitors). After 96 weeks, the efficacy rate was 82.3% (95% confidence interval [CI 95 There is significant controversy regarding ritonavir-boosted protease inhibitor (PI) monotherapy as a maintenance therapeutic strategy (1-5). Notwithstanding, a considerable proportion of patients maintained an undetectable viremia on lopinavirritonavir maintenance monotherapy (mtLPVr) and could benefit from a simpler regimen without nucleoside analogues or other antiretroviral drugs. Moreover, lack of adherence has been indicated as the main reason for virological failure (VF) in different studies (6-13).Moreover, there is significant intra-and intersubject variability in LPV plasma concentrations after standard dosing, determined largely by variability in drug absorption, cytochrome P450 metabolism, plasma protein binding, and drug transporter activity, which may affect the disposition of the drug (14, 15). As LPV plasma concentrations and the genotype inhibitory quotient have been related to virological efficacy in experienced patients on LPVr-based regimens (16)(17)(18)(19), in this study, we tested whether low plasma LPV trough concentrations contribute to VF throughout the mtLPVr treatment period. The confirmation of this hypothesis would demonstrate that LPV therapeutic drug monitoring could be useful in improving the efficacy of LPV when prescribed as a monotherapy. MATERIALS AND METHODSStudy population and design. From April 2009 to April 2010, adult HIV-1-infected patients who started a regimen of mtLPVr at our outpatient clinic were consecutively included in this observational, prospective, open-label study. The LPVr dosing regimen (400 mg of LPV and 100 mg of ritonavir twice daily or 800 mg-200 mg once daily) was selected by the patients' physicians. All subjects had plasma HIV RNA levels of Ͻ50 copies/ml for at least 6 months. Patients with VF while on a PI-containing regimen were also included in the study when genotypic resistance tests showed no major or Յ3 minor resistance mutations associated with reduced...

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Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 99%

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

López‐Cortés

Ruiz-Valderas

Sánchez-Rivas

et al. 2013

Antimicrob Agents Chemother

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“…Indeed, combination therapy with LPV/r rarely selects for PI resistance in antiretroviral-naïve patients (13). The prevalences of PI resistance during single-drug maintenance therapy with LPV/r in the previously mentioned randomized studies were comparable to those observed during LPV/r-based triple therapy, with the selection of major PI resistance mutations such as M46I, V82A, and L90M (1,2,18). In the first 48 weeks of the MONARK study, resistance mutations in the HIV protease gene were detected in 3 (3.6%) of 83 patients receiving LPV/r monotherapy and resistance mutations in the HIV reverse transcriptase gene were detected in 1 of 53 patients receiving LPV/r triple therapy (3).…”

mentioning

confidence: 83%

“…Lopinavir-ritonavir (LPV/r) was evaluated for use in these simplification strategies on the basis of its virological potency and high barrier to the development of resistance. Previous analyses of induction/maintenance strategies showed that, after full viral suppression is obtained with HAART, the efficacy of maintenance with LPV/r monotherapy is comparable to that with triple therapy (1,2,18). Another approach is to use boosted-PI monotherapy initially as a first-line regimen, thereby avoiding nucleoside reverse transcriptase inhibitor (NRTI) exposure entirely.…”

mentioning

confidence: 99%

Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy

Delaugerre

Flandre

Chaix

et al. 2009

Antimicrob Agents Chemother

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The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society-USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75-to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.Highly active antiretroviral therapy (HAART) has dramatically improved the prognoses of patients infected with human immunodeficiency virus type 1 (HIV-1). However, because of the absence of HIV-1 eradication, patients require lifelong therapy, making long-term cumulative toxicity and cost critical issues in the treatment of HIV infection. Maintaining effective therapy is mandatory to avoid viral replication and subsequent drug resistance emergence.In the context of simplification, different strategies of boostedprotease-inhibitor (boosted-PI) monotherapy have been evaluated. Lopinavir-ritonavir (LPV/r) was evaluated for use in these simplification strategies on the basis of its virological potency and high barrier to the development of resistance. Previous analyses of induction/maintenance strategies showed that, after full viral suppression is obtained with HAART, the efficacy of maintenance with LPV/r monotherapy is comparable to that with triple therapy (1, 2, 18). Another approach i...

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“…It has been evaluated in a number of clinical trials including also HCV-coinfected individuals [1][2][3][4], but currently there are still no conclusive data on the efficacy and toxicity of such a regimen in daily clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Durability of Lopinavir/Ritonavir Monotherapy in Individuals with Viral Load ≦50 Copies/Ml in an Observational Setting

et al. 2013

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Background: The main objective is to evaluate the efficacy and durability of lopinavir-ritonavir monotherapy (LPV/r-MT) in virologically controlled HIV-positive individuals switching from combination antiretroviral therapy (cART). Methods: Criteria to be included in this observational study were to have initiated for the first time LPV/r-MT after ≥2 consecutive HIV RNA≤50 copies/ml achieved on a ≥3-drugincluding regimen. The main end points were time to virological rebound (VR; defined in two ways: time of first of two consecutive viral load [VL]>50 and >200 copies/ml), time to discontinuation/intensification and time to experience either a single VL>200 copies/ml or discontinuation/ intensification (treatment failure [TF]). Individuals' followup accrued from the date of starting LPV/r-MT to event or last available VL. Kaplan-Meier curves and Cox regression analyses were used.Results: A total of 228 individuals were included: median age 46 years (IQR 40-50), 36% females, 36% intravenous drug users and 25% HCV-coinfected. Median CD4 + T-cell count at nadir was 215 cell/mm 3 (IQR 116-336) and at baseline was 615 cell/mm 3 (IQR 436-768). By 36 months after switching to LPV/r-MT, the proportion of individuals with VR (confirmed VL>200 copies/ml) was 11% and with TF was 35%. In the multivariable Cox model the factors associated with a lower risk of TF was the duration of viral suppression <50 copies/ml prior to baseline (ARH=0.92; 95% CI 0.85, 0.99; P=0.024, per 6 months longer) and having LPV/r as part of last cART (ARH=0.45; 95% CI 0.21, 0.95; P=0.037). Conclusions: In daily clinical practice, we confirm a relatively safe approach of treatment simplification to LPV-MT in a selected population with long-lasting virological control.

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A 96‐Week Comparison of Lopinavir‐Ritonavir Combination Therapy Followed by Lopinavir‐Ritonavir Monotherapy versus Efavirenz Combination Therapy

Cited by 102 publications

References 9 publications

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy

Durability of Lopinavir/Ritonavir Monotherapy in Individuals with Viral Load ≦50 Copies/Ml in an Observational Setting

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