Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study

Valantin, M.A.; Lambert-Niclot, Sidonie; Flandre, Philippe; Morand‐Joubert, Laurence; Cabie, André; Meynard, Jean-Luc; Ponscarme, Diane; Ajana, F.; Slama, Laurence; Curjol, Angélique; Cuzin, Lise; Schneider, Luminita; Taburet, Anne‐Marie; Marcelin, Anne–Geneviève; Katlama, Christine; Duvivier, Claudine; Cálvez, Vincent; Peytavin, Gilles; Kolta, Sami; Costagliola, Dominique; Génin, Michèle; Commoy, M.- J.; L'henaff, M.; Chéret, Arnaud; Raffi, François; Garaffo, Rodolphe; Descamps, Diane; Chêne, Geneviève

doi:10.1093/jac/dkr504

Cited by 61 publications

(36 citation statements)

References 11 publications

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“…Furthermore, we hypothesized that removing NRTIs entirely (using a protease inhibitor alone) would be noninferior to the standard regimen (as has been shown in some first-line studies), [6][7][8] with the advantage of reduced toxicity, regimen complexity, and cost.…”

Section: Methodsmentioning

confidence: 99%

Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa

Paton

Kityo

Hoppé³

et al. 2014

N Engl J Med

179

182

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Section: Methodsmentioning

confidence: 99%

Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa

Paton

Kityo

Hoppé³

et al. 2014

N Engl J Med

179

182

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“…The ability to make tight binding transition state analogs that require multiple mutations to confer resistance suggests that it may be possible eventually to treat HIV-1 with a single PI if it were sufficiently potent. Efforts along these lines have been explored with some success (47)(48)(49).…”

Section: Protease Inhibitors Resistance and Viral Fitnessmentioning

confidence: 99%

The Choreography of HIV-1 Proteolytic Processing and Virion Assembly

Lee

Potempa

Swanstrom

2012

Journal of Biological Chemistry

113

128

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HIV-1 has been the target of intensive research at the molecular and biochemical levels for >25 years. Collectively, this work has led to a detailed understanding of viral replication and the development of 24 approved drugs that have five different targets on various viral proteins and one cellular target (CCR5). Although most drugs target viral enzymatic activities, our detailed knowledge of so much of the viral life cycle is leading us into other types of inhibitors that can block or disrupt proteinprotein interactions. Viruses have compact genomes and employ a strategy of using a small number of proteins that can form repeating structures to enclose space (i.e. condensing the viral genome inside of a protein shell), thus minimizing the need for a large protein coding capacity. This creates a relatively small number of critical protein-protein interactions that are essential for viral replication. For HIV-1, the Gag protein has the role of a polyprotein precursor that contains all of the structural proteins of the virion: matrix, capsid, spacer peptide 1, nucleocapsid, spacer peptide 2, and p6 (which contains protein-binding domains that interact with host proteins during budding). Similarly, the Gag-Pro-Pol precursor encodes most of the Gag protein but now includes the viral enzymes: protease, reverse transcriptase (with its associated RNase H activity), and integrase. Gag and Gag-Pro-Pol are the substrates of the viral protease, which is responsible for cleaving these precursors into their mature and fully active forms (see Fig. 1A).The Gag and Gag-Pro-Pol precursors assemble at the plasma membrane of the cell, with the membrane ultimately being pinched off from the cell surface to create a membrane-bound virion with a diameter of ϳ120 nm, representing a volume of ϳ0.9 attoliters (Fig. 1). The host ESCRT (endosomal sorting complex required for transport) pathway that is subverted to drive the membrane fission event needed for virion budding has been reviewed in detail (1-3). The virion assembly process that takes place at the cell membrane results in a finite number of each viral protein within the particle. The budded particle has ϳ2400 Gag molecules embedded in the membrane via the N-terminal matrix (MA) 3 protein domain, which, in a 120-nm sphere, gives Gag a concentration of ϳ4.4 mM, with a crude estimate that the Gag molecules occupy 50 -60% of the volume of the sphere (4). There are also ϳ120 Gag-Pro-Pol molecules (5). The embedded protease (PR) must dimerize, release itself from the Gag-Pro-Pol precursor, and then cleave the other PR cleavage sites in Gag and Gag-Pro-Pol (6). From these cleaved products, the nucleocapsid (NC) condenses and stabilizes the viral dimeric RNA, and ϳ1500 copies of the processed capsid (CA) protein reform to make the mature conical capsid structure around viral RNA to create an infectious particle (7). In this minireview, we examine outstanding issues surrounding the HIV-1 PR, the role of protein processing and rearrangement in the assembly pathway, the impact of PR inhibi...

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“…The aim of this analysis was to review the evidence and update a meta-analysis evaluating the efficacy and safety results from randomized controlled trials (RCTs) of ritonavirboosted PI/r monotherapy. There were 2,303 patients from 13 different randomized clinical trials of DRV/r monotherapy (n=784: MONET [8], MONOI [9,19], Monarch [10] and PROTEA [11]), LPV/r monotherapy (n=829: OK pilot, OK-04, KalMo, KALESOLO, KRETA, MOST and DREAM), atazanavir/r monotherapy (n=103: MODAT), or all three (n=587: PIVOT). HIV-1 RNA plasma suppression was lower in the PI/r monotherapy arm compared with the triple therapy arm in the switchequals-failure analysis, but not when intensification was included.…”

Section: Discussionmentioning

confidence: 99%

“…Although IP have a high genetic barrier and a good tolerability and safety profile, RTV is associated with gastrointestinal adverse effects, numerous interactions with other drugs, insulin resistance, lipoatrophy and hyperlipidemia [4,5]. Different studies have evaluated the efficacy of DRV/r once daily in combination with other ART (ARTEMIS [6] study in naive patients and ODIN [7] study in pretreated patients) or monotherapy in pretreated patients (MONET, MONOI, Monarch and PROTEA studies) [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

One Year Follow-Up of Darunavir/Cobicistat Monotherapy in Pretreated HIV Patients

Yunquera-Romero¹,

Diez²,

Rio-Valencia³

et al. 2017

J AIDS Clin Res

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IntroductionThe availability of antiretroviral treatment (ART) has made it possible to consider HIV-1 infection as a chronic disease. This has led to a change in the objectives of ART with a greater importance in improving the patient's quality of life and more efficient use of the resources, without compromising the effectiveness of treatments. In ART naive patients, on the first and successive lines after ART failure, preferred regimens remain the combination of three active drugs against HIV: Two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), a protease inhibitor (PI) with a pharmacokinetic (PK) enhancer (booster) (cobicistat or ritonavir), integrase strand transfer inhibitor (INSTI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) [1][2][3].Currently, boosted protease inhibitor monotherapy (PI/r): Darunavir/ritonavir (DRV/r) or Lopinavir/ritonavir (LPV/r) is only contemplated in the main treatment guidelines in pretreated patients to avoid toxicity associated with NRTIs, reduce costs and simplify ART. PI/r monotherapy with Atazanavir/ritonavir (ATV/r) is not recommended because of the worst results obtained in clinical trials. To initiate monotherapy based on PI/r, the patient must meet the following criteria: absence of chronic hepatitis B, plasma HIV-RNA viral load <50 copies/mL for at least 6 months and absence of mutations in the protease gene or virological failures (VF) prior to PI/r. PI/r are drugs that have a high genetic barrier and are used in monotherapy to maintain virological suppression in most patients, but with lower rates than triple therapy. The use of monotherapy with Lopinavir/ritonavir (LPV/r) and Darunavir/ritonavir (DRV/r) is associated with a higher frequency of "blips", defined as isolated and transient viral load values between 50 and <200 copies/mL. The "blips", although in most studies are not related to the increased risk of virological failure, do recommend re-evaluation of ART (degree of adhesion and genetic barrier) and in some patients may select resistant mutants [1]. Virological failure occurs when, in a patient with strict adherence and optimal tolerability to ART, there are any of the following two situations: a) Viral load detectable after 24 weeks of initiation of ART; B) if after reaching undetectability, th e viral load returns to >50 copies/mL in two consecutive determinations (separated by 2-4 weeks), excluding intercurrent vaccinations or infections (they may produce transient elevations of viral load). Virologic a l failure is AbstractIntroduction: Boosted protease inhibitor monotherapy (PI/r ) : Darunavir/ritonavir (DRV/r) or Lopinavir/ritonavir (LPV/r) monotherapy is only provided in the major treatment guidelines in pre-treated HIV patients to prevent toxicity associated with nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs), reduce costs and simplify antiretroviral treatment. To start PI/r monotherapy, according to GESIDA g uidelines 2016, patients need to meet the following criteria: absence of chronic hepatitis B, pla...

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Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study

Cited by 61 publications

References 11 publications

Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa

Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa

The Choreography of HIV-1 Proteolytic Processing and Virion Assembly

One Year Follow-Up of Darunavir/Cobicistat Monotherapy in Pretreated HIV Patients

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