Pooled resistance analyses of darunavir once-daily regimens and formulations across 10 clinical studies of treatment-naïve and treatment-experienced patients with human immunodeficiency virus-1 infection

Lathouwers, Erkki; Seyedkazemi, Sareh; Luo, Donghan; Brown, Kimberley; Meyer, Sandra De; Wong, Eric

doi:10.1080/25787489.2020.1794439

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…These results are consistent with those from other darunavir-based studies, in which patients were able to achieve virologic response despite harboring baseline NNRTI and/or N(t)RTI resistance-associated mutations. 28 There are limited clinical trial data regarding the initiation of ART in acute or early HIV-1 infection. 1 However, in a retrospective case-note analysis of 113 patients in the United Kingdom diagnosed with acute HIV-1 infection, the time from diagnosis to ART initiation was 20 days (median), and high rates of virologic suppression were observed.…”

Section: Discussionmentioning

confidence: 99%

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis

Dunn

Rogers

Simonson

et al. 2021

HIV Research & Clinical Practice

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Background: Treatment during acute or early human immunodeficiency virus (HIV)-1 infection is associated with immunologic and virologic benefits. Objective: To evaluate darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) efficacy/safety among patients with acute or early HIV-1 infection who rapidly initiate treatment. Methods: DIAMOND (ClinicalTrials.gov Identifier: NCT03227861), a phase 3 study, evaluated the efficacy/ safety of D/C/F/TAF 800/150/200/10 mg in rapid initiation. Adults aged 18 years began D/C/F/TAF within 14 days of diagnosis, prior to the availability of screening/baseline laboratory results. In this subgroup analysis, virologic response (HIV-1 RNA <50 copies/mL) was assessed at Week 48 by intent-to-treat FDA snapshot (ITT-FDA snapshot) and observed (excluding patients with missing data) analyses in patients with acute (HIV-1 antibody negative and HIV-1 RNA positive/p24 positive) or early (HIV-1 antibody positive and suspected infection 6 months before screening/baseline) infection. Results: Among 109 patients, 13 had acute and 43 had early HIV-1 infection. High rates of virologic response were demonstrated at Week 48 by ITT-FDA snapshot (acute: 10/13 [76.9%]; early: 37/43 [86.0%]) and observed (acute: 10/11 [90.9%]; early: 37/38 [97.4%]) analyses. No patients discontinued or required regimen change due to baseline resistance or lack of efficacy, or developed protocol-defined virologic failure.

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Section: Discussionmentioning

confidence: 99%

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis

Dunn

Rogers

Simonson

et al. 2021

HIV Research & Clinical Practice

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“…64 There are only very rare cases of treatment-emergent resistance in clinical trials of boosted DRV-based regimens in treatmentnaive and virologically suppressed treatment-experienced PLWH, with slightly more cases in individuals who were treatment-experienced and had active viral replication at study entry. 12 Virologic failure while receiving DRV-based regimens usually requires multiple PI DRMs and DRV-specific DRMs, such as V32I, I84V, I54L/M, I50V and L76V. 64 Compared with INSTIs and PIs, treatment-emergent resistance is more common for NRTIs, which are frequently used as the backbone of contemporary treatment regimens.…”

Section: Patterns Of Drug Resistance To Contemporary Artmentioning

confidence: 99%

“…3,4 Despite this, drug resistance to contemporary antiretrovirals has been demonstrated in vitro and is evident, although in small numbers, in clinical trials and real-world settings. [5][6][7][8][9][10][11][12][13][14][15] Drug resistance is likely to reduce ART options and so reduce the likelihood of achieving virologic suppression. If virologic failure is not managed appropriately, HIV can become more resistant and lead to deterioration of the immune system and the development of clinical sequelae (AIDS and non-AIDS morbidities), with a continued risk of onward transmission.…”

Section: Introductionmentioning

confidence: 99%

HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective

Carr,

Mackie,

Paredes

et al. 2023

Antiviral Therapy

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Contemporary antiretroviral therapy (ART) regimens have high barriers to the development of drug resistance. However, resistance to earlier antiretrovirals and uncommon cases of resistance to contemporary ART illustrate the continued need for good clinical management of HIV drug resistance. Here, we describe HIV drug-resistance mechanisms, the interaction of HIV drug-resistant mutations and the patterns of drug resistance to contemporary ART. We then provide guidance on the management of HIV drug resistance, including how to limit the development of resistance and manage virologic failure that is complicated by resistance. To complement this, links to resources and treatment guidelines are provided that can assist with the interpretation of HIV drug resistance test results and optimal ART selection in the clinic.

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“…Advances in the potency and resistance barrier of antiretroviral drugs for HIV infection, as well as evidence from recent randomized clinical trials (RCTs) in people living with HIV (PLWH), support the use of dual therapy including a boosted protease inhibitor (PI) or a second-generation integrase strand transfer inhibitor (INSTI) in specific patient populations such as PLWH on suppressive antiretroviral therapy (ART) without a history of virologic failure or -at least for some combinations -treatment-naïve PLWH [1][2][3][4]. Both the 2 nd generation INSTI dolutegravir (DTG) and the PI darunavir (DRV, boosted with ritonavir or cobicistat) have been shown to be potent antiretroviral drugs with a high resistance barrier in treatment-naïve and treatmentexperienced PLWH [5][6][7][8]. The DUALIS study (Eudra-CT 2015-000360-34), a phase IIIb, open-label 48-week RCT in virologically suppressed PLWH, demonstrated that switching to a 2-drug regimen (2DR) consisting of boosted DRV (bDRV) plus DTG was non-inferior to continuing a 3-drug regimen (3DR) including bDRV plus two nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs).…”

Section: Introductionmentioning

confidence: 99%

Virologic outcomes of switching to boosted darunavir plus dolutegravir with respect to history of drug resistance

et al. 2021

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Objective The DUALIS study showed that switching to boosted darunavir (bDRV) plus dolutegravir (DTG; 2DR) was non-inferior to continuous bDRV plus 2 nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs; 3DR) in treatment-experienced virologically suppressed people living with HIV (PLWH). We analyzed virologic outcomes with respect to treatment history and HIV drug resistance. Design Post hoc analysis of a randomized trial. Methods Main inclusion criteria were an HIV RNA level < 50 copies/mL for ≥ 24 weeks and no resistance to integrase strand transfer inhibitors or bDRV. Resistance-associated mutations (RAMs) were interpreted using the Stanford HIVdb mutation list. Outcomes measures were 48-week virologic response (HIV RNA < 50 copies/mL, FDA snapshot) and HIV RNA ≥ 50 copies/mL (including discontinuation due to a lack of efficacy or reasons other than adverse events and HIV RNA ≥ 50 copies/mL, referred to as snapshot non-response). Results The analysis population included 263 patients (2DR: 131, 3DR: 132): 90.1% males; median age, 48 years; CD4 + T-cell nadir < 200/µl, 47.0%; ≥ 2 treatment changes, 27.4%; NRTI, non-NRTI (NNRTI), and major protease inhibitor (PI) RAMs in 9.5%, 14.4%, and 3.4%, respectively. In patients with RAMs in the 2DR and 3DR groups, virologic response rates were 87.8% and 96.0%, respectively; the corresponding rates in those without RAMs were 85.7% and 81.8%. RAMs were unrelated to virologic non-response in either group. No treatment-emergent RAMs were observed. Conclusions DTG + bDRV is an effective treatment option without the risk of treatment-emergent resistance for PLWH on suppressive first- or further-line treatment with or without evidence of pre-existing NRTI, NNRTI, or PI RAMs. Trial registration: EUDRA-CT Number 2015-000360-34; registered 07 April 2015; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000360-34/DE.

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Pooled resistance analyses of darunavir once-daily regimens and formulations across 10 clinical studies of treatment-naïve and treatment-experienced patients with human immunodeficiency virus-1 infection

Abstract: (2020) Pooled resistance analyses of darunavir once-daily regimens and formulations across 10 clinical studies of treatment-naïve and treatment-experienced patients with human immunodeficiency virus-1 infection,

Cited by 5 publications

References 24 publications

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis

HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective

Virologic outcomes of switching to boosted darunavir plus dolutegravir with respect to history of drug resistance

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