Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

Santos, JR; Cozzi‐Lepri, Alessandro; Phillips, Andrew; Wit, Stéphane De; Pedersen, Court; Reiss, Peter; Blaxhult, Anders; Lazzarin, Adriano; Sluzhynska, M.; Orkin, Chloe; Duvivier, Claudine; Bogner, J. R.; Gargalianos‐Kakolyris, Panagiotis; Schmid, Patrick; Hassoun, Gamal; Khromova, Irina; Beniowski, Marek; Hadžiosmanović, Vesna; Sedláček, Dalibor; Paredes, Roger; Lundgren, JD

doi:10.1111/hiv.12581

Cited by 5 publications

(5 citation statements)

References 37 publications

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“…The Nucleosides and Darunavir/Dolutegravir In Africa (NADIA) trial is designed to address two questions. First, whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, 6,7 in a population of patients with high levels of background NRTI resistance switching to second-line therapy. Second, whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

et al. 2022

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Section: Implications Of All the Available Evidencementioning

confidence: 99%

Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

et al. 2022

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“…TT has been firmly established as an efficacious and effective treatment option over the last 20 years, both in clinical trials [14] and the real-world setting [15,16]. However, real-world evidence supporting the effectiveness of bPI+3TC, DTG+3TC or DTG+RPV 2DC is limited [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…Average adherence in the clinical trial setting is often at least 95% [10,11] while in the real-world it is often below 80% [12] with a significant proportion of patients experiencing treatment gaps [13]. While older TT regimens required 95% adherence for optimal effectiveness [14][15][16], there is currently evidence to support that more contemporary TT regimens are more "forgiving" of suboptimal adherence; indeed, >80% adherence may be enough to maintain suppression [15][16][17].…”

Section: Competing Interestsmentioning

confidence: 99%

Real world effectiveness of standard of care triple therapy versus two-drug combinations for treatment of people living with HIV

et al. 2021

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Background Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. Methods A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA<50 copies/mL at baseline, irrespective of the regimen used. The following endpoints were assessed: time to discontinuation for any reason, time to switch due to virologic failure, and time to switch due to toxicity (reasons for discontinuation according to clinician report in the database). Time-to-event analyses were conducted using Kaplan–Meier survival curves and Cox regression models. Results Overall 7,481 patients were included in the analysis, contributing to 9,243 patient-regimens. Patient characteristics at baseline differed among groups, with the 2DC group being significantly older and having a higher proportion of women, a longer time on ART and a higher number of previous virologic failures. Median (95% Confidence Interval [C.I.]) time to switch was 2.5 years (2.3, 2.7) in 2DC group versus 2.9 years (2.7, 3.0) in TT. Adjusted hazard ratios (95% C.I.) for discontinuation due to any reason, virologic failure and toxicity in the 2DC vs TT group were 1.29 (1.15; 1.44), 2.06 (1.54; 2.77) and 1.18 (0.94; 1.48), respectively. Results were consistent in the two sub-analyses. Conclusion In this analysis, time to discontinuation and probability of remaining free of virologic failure were significantly higher in patients on INSTI-based TT compared to DTG- and/or bPI-containing 2DC, with no differences in toxicity.

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“…In a clinical trial that evaluated the long-term effectiveness of ART, the results showed that a DRV-based regimen was superior to an LPV-based regimen in both ART-naive and treatment-experienced patients. The chances of virological failure were lower for DRV compared to LPV when HIV-1 PI therapy was initiated either as a salvage regimen or a switching strategy in treatment-experienced patients [68]. Another study also showed that the use of low dose DRV boosted with ritonavir (RTV) is an efficient switch option to suppress virological failure in patients failing LPV based treatment [69].…”

Section: Discussionmentioning

confidence: 99%

Acquired HIV-1 Protease Conformational Flexibility Associated with Lopinavir Failure May Shape the Outcome of Darunavir Therapy after Antiretroviral Therapy Switch

et al. 2021

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Understanding the underlying molecular interaction during a therapy switch from lopinavir (LPV) to darunavir (DRV) is essential to achieve long-term virological suppression. We investigated the kinetic and structural characteristics of multidrug-resistant South African HIV-1 subtype C protease (HIV-1 PR) during therapy switch from LPV to DRV using enzyme activity and inhibition assay, fluorescence spectroscopy, and molecular dynamic simulation. The HIV-1 protease variants were from clinical isolates with a combination of drug resistance mutations; MUT-1 (M46I, I54V, V82A, and L10F), MUT-2 (M46I, I54V, L76V, V82A, L10F, and L33F), and MUT-3 (M46I, I54V, L76V, V82A, L90M, and F53L). Enzyme kinetics analysis shows an association between increased relative resistance to LPV and DRV with the progressive decrease in the mutant HIV-1 PR variants’ catalytic efficiency. A direct relationship between high-level resistance to LPV and intermediate resistance to DRV with intrinsic changes in the three-dimensional structure of the mutant HIV-1 PR as a function of the multidrug-resistance mutation was observed. In silico analysis attributed these structural adjustments to the multidrug-resistance mutations affecting the LPV and DRV binding landscape. Though DRV showed superiority to LPV, as a lower concentration was needed to inhibit the HIV-1 PR variants, the inherent structural changes resulting from mutations selected during LPV therapy may dynamically shape the DRV treatment outcome after the therapy switch.

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Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

Abstract: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

Cited by 5 publications

References 37 publications

Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

Real world effectiveness of standard of care triple therapy versus two-drug combinations for treatment of people living with HIV

Acquired HIV-1 Protease Conformational Flexibility Associated with Lopinavir Failure May Shape the Outcome of Darunavir Therapy after Antiretroviral Therapy Switch

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