Monotherapy with boosted PIs as an ART simplification strategy in clinical practice

Santos, José Ramón; Llibre, Josep M; Berrio-Galan, Daniel; Bravo, Isabel; Miranda, Cristina; Pérez-Álvarez, Susana; Pérez-Álvarez, Núria; Paredes, Roger; Clotet, Bonaventura; Moltó, José

doi:10.1093/jac/dku509

Cited by 13 publications

(20 citation statements)

References 27 publications

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“…Most clinicians / patients selected darunavir although a sizeable minority (14%) used lopinavir. We did not see a difference between darunavir and lopinavir in virological rebound which is consistent with observational studies of PI monotherapy [6,8,25]. Two small trials have randomised patients to either lopinavir or darunavir monotherapy and reported no difference in virological failure [26,27].…”

Section: Discussionsupporting

confidence: 84%

Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy

Stöhr

Dunn

Arenas‐Pinto

et al. 2016

Aids

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Objective: The PIVOT trial found that protease inhibitor (PI) monotherapy as a simplification strategy is safe in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load (VL). We sought to identify factors associated with the risk of VL rebound in this trial.Methods: PIVOT was a randomized controlled trial in HIV-positive adults with suppressed VL for ≥24 weeks on combination therapy comparing a strategy of physician-selected ritonavir-boosted PI monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed VL rebound and its predictors using flexible parametric survival models.Results: Of 290 participants initiating PI monotherapy (80% darunavir, 14% lopinavir, 6% other), 93 developed VL rebound on monotherapy. The risk of VL rebound peaked at 9 months after starting monotherapy, and then declined to approximately 5 per 100 personyears from 18 months onwards. Independent predictors of VL rebound were duration of VL suppression prior to starting monotherapy (hazard ratio [HR] 0.81 per additional year <50 copies/mL; p<0.001), CD4 cell count (HR 0.73 per additional 100 cells/mm 3 for CD4 nadir; p=0.008); ethnicity (HR 1.87 for non-white versus white, p=0.025) but not the PI agent used (p=0.27). Patients whose VL was analysed with the Roche Taqman-2 assay had a 1.87-fold risk for VL rebound compared with Abbott RealTime assay (p=0.012). Conclusions:A number of factors can identify patients at low risk of rebound with PI monotherapy and this may help to better target those who may benefit from this management strategy.

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Section: Discussionsupporting

confidence: 84%

Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy

Stöhr

Dunn

Arenas‐Pinto

et al. 2016

Aids

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“…Our cohort had a median baseline CD4 count of 455 cells/mm, 3 lower than the averages reported in the other clinical studies, which were between 541 and 608. 18,19,21–23 The median nadir CD4 count of 180 was within the range found in the clinical studies (medians were between 155 and 238). 18–21,23 We did not find an independent association between CD4 count and failure, as did four of the observational studies.…”

Section: Discussionsupporting

confidence: 78%

“…18,19,21–23 The median nadir CD4 count of 180 was within the range found in the clinical studies (medians were between 155 and 238). 18–21,23 We did not find an independent association between CD4 count and failure, as did four of the observational studies. 18,20,21,23 One study found an association between a nadir CD4 of <200 cells/mm 3 and virological failure.…”

Section: Discussionsupporting

confidence: 78%

“…There have been other observational studies in Spain and France, where PI-containing cART is more frequently used as first-line treatment, and our cohort otherwise had comparable baseline characteristics to those studies, with a preponderance of male patients, white ethnicity, MSM mode of transmission and subtype B infection, all typical of a European setting. 18–22 Another similarity was that over three-quarters of patients were PI experienced prior to receiving monotherapy. Our cohort had a median baseline CD4 count of 455 cells/mm, 3 lower than the averages reported in the other clinical studies, which were between 541 and 608.…”

Section: Discussionmentioning

confidence: 99%

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Virological efficacy of PI monotherapy for HIV-1 in clinical practice

Bouzidi

Collier

Nastouli

et al. 2016

J. Antimicrob. Chemother.

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BackgroundClinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied.MethodsAn observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports. Survival analysis techniques were used to examine the times to virological failure and treatment discontinuation.ResultsNinety-five patients had PI monotherapy treatment for a median duration of 126 weeks. Virological failure occurred during 64% of episodes and 8% of patients developed emergent protease mutations. We estimate failure occurs in half of episodes within 2 years following initiation. Where PI monotherapy was continued following virological failure, 68% of patients achieved viral re-suppression. Despite a high incidence of virological failure, many patients continued PI monotherapy and 79% of episodes were ongoing at the end of the study. The type of PI used, the presence of baseline protease mutations and the plasma HIV RNA at initiation did not have a significant impact on treatment outcomes.ConclusionsThere was a higher incidence of virological failure and emerging resistance in our UK clinical setting than described in PI monotherapy clinical trials and other European observational studies. Despite this, many patients continued PI monotherapy and regained viral suppression, indicating this strategy remains a viable option in certain individuals following careful clinical evaluation.

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“…5A). In fact, DRV/RTV (DRV/r) monotherapy has been examined in HIV-1-infected patients (57)(58)(59)(60), and the monotherapy regimen proved to be a potential long-term strategy to avoid nucleoside/nucleotide analogue toxicities and to reduce costs. Even though the protease dimerization inhibition activity of GRL-015, -085, and -097 was moderate compared to that of DRV (Fig.…”

Section: Discussionmentioning

confidence: 99%

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

Aoki

Hayashi

Yedidi

et al. 2016

J Virol

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We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1 WT ), with 50% effective concentrations (EC 50 s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC 50 ) for GRL-015, -085, and -097 of 80, >100, and >100 M,

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Monotherapy with boosted PIs as an ART simplification strategy in clinical practice

Abstract: The virological efficacy of darunavir/ritonavir and lopinavir/ritonavir monotherapy is high in clinical practice. Treatment discontinuation due to safety issues is more frequent with lopinavir/ritonavir.

Cited by 13 publications

References 27 publications

Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy

Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy

Virological efficacy of PI monotherapy for HIV-1 in clinical practice

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

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