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Study summaries of darunavir 800 mg QD-containing treatment arms Notes: QD, once daily; DRV, darunavir; HIV-1, human immunodeficiency virus-1; TN, treatment-naïve; rtv, ritonavir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; cobi, cobicistat; TAF, tenofovir alafenamide; TE, treatment-experienced; N(t)RTI, nucleos(t)ide reverse transcriptase inhibitor; ETR, etravirine; ARV, antiretroviral. a For each ARV regimen, agents combined in the same tablet are separated by a '/' and those in different tablets are separated by a '+'
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Background: Darunavir 800 mg once daily (QD) is indicated for HIV-1–infected treatment-naïve and treatment-experienced (without darunavir resistance-associated mutations [RAMs]) individuals, and has been evaluated in phase 2/3 studies with durations between 48 and 192 weeks.
Objective: To summarize the development (or identification) of post-baseli...
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Background
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Methods
Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir i...
Citations
... Darunavir shows strong anti-HIV activity with lower cytotoxic effect [31]. In T-cells, the effectiveness of Darunavir is greater compared to other such drugs [32],due to formation of a highly stable complex between Darunavir and the protease enzyme for its flexibility and backbone interactions [33]. Numerous studies provide evidence of the substantial restriction to HIV resistance to darunavir [34]. ...
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... The absence of resistance is a further advantage for darunavir and is consistent across multiple studies of once-daily darunavir, including a second-line trial in Africa that found no darunavir resistance among patients with treatment failure, 15,23 and across other studies challenging darunavir in dual or monotherapy regimens. [24][25][26] Both darunavir and dolutegravir are second-generation drugs considered to have the highest genetic barrier to resistance within their respective drug classes. 7,20 However, based on the head-tohead comparison in this trial, the genetic barrier appears to be more robust with darunavir when protection from NRTIs in the regimen is more limited. ...
Background
WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.
Methods
In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.
Findings
Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI −3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3–4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.
Interpretation
Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.
Funding
Janssen.
... 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). ...
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 .
... [1][2][3] The oral, once-daily, STR darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg, currently approved in Europe, the US, and Canada 4,5 is based on the protease inhibitor (PI) darunavir (DRV), which has demonstrated a high, durable virologic response (VL <50 copies/ mL), high barrier to resistance, and long-term safety in a broad range of patients. [6][7][8][9] International HIV-1 treatment guidelines include D/C/F/TAF or DRV boosted with ritonavir (RTV) or cobicistat (COBI) combined with two nucleoside or nucleotide analogs reverse transcriptase inhibitors (N(t)RTIs). [10][11][12] DRV is also recommended for rapid initiation of treatment, when resistance test results are not available, 11 and when treatment adherence may be unpredictable. ...
... 22 These results are consistent with previous DRV and D/C/F/TAF studies and the established high genetic barrier to resistance of DRV. 9,43,44 The lack of emergence of significant resistance mutations over time for virologically suppressed, treatment-experienced patients is important, particularly given concerns for re-emergence of archived RAMs in patients with prior VF. D/C/F/TAF demonstrated a high genetic barrier to resistance in ART-experienced adults in EMERALD through 96 weeks, even in patients with HIV-1 virus harboring archived study drug RAMs at baseline. ...
Background Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917). Objective To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent). Methods Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL
... HIV drug-resistance mutations can occur both before and during HIV treatment [118]. Numerous studies have demonstrated a high barrier to resistance of HIV against darunavir [119][120][121]. An analysis of multiple clinical studies confirmed that the development of darunavir resistance-associated mutations was very rare [122]. ...
Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.
... 4,5 Darunavir, an HIV-1 protease inhibitor (PI), has demonstrated potent antiviral activity against wild-type and multidrug-resistant HIV-1, and has a high barrier to the development of resistance. [6][7][8][9] Darunavir QD has been studied extensively across diverse populations in clinical trials, demonstrating excellent efficacy and safety. [10][11][12][13][14][15][16] Guidelines from the European AIDS Clinical Society recommend boosted darunavir as an initial ARV regimen, 17 and the high barrier to resistance of boosted darunavir is cited in guidelines from both the US Department of Health and Human Services (DHHS) and International Antiviral Society-USA (IAS-USA). ...
... 3,18 Reported here is an extension of a previous evaluation of post-baseline HIV-1 resistance data from seven phase 2 or 3 clinical studies (1686 patients) of darunavir 800 mg QD-based ARV regimens. 6 The current analysis incorporates post-baseline findings from three recent studies of the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/ 200/10 mg QD STR [19][20][21][22][23] to evaluate resistance across a total of 10 clinical studies of darunavir 800 mg QDbased regimens. ...
... Methodological details for the seven clinical studies included in the previous analysis have been described. 6,[10][11][12][13][14][15][16] Detailed methods for the three recent studies of the D/C/F/TAF STR have also been reported [19][20][21][22][23] and are briefly summarized here. Key study design information for all 10 studies is shown in Supplemental Figure S1. ...
Background
The efficacy and high barrier to resistance of darunavir have been demonstrated across diverse populations with HIV-1 infection.
Objective
To evaluate post-baseline resistance among patients in studies of once-daily (QD) darunavir-based regimens and formulations.
Methods
The analysis included treatment-naïve and virologically failing or suppressed patients from 10 phase 2/3 studies (48–192 weeks in duration) of boosted darunavir 800 mg QD-based regimens. Three were phase 3 studies of the QD darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen. Post-baseline resistance was evaluated upon protocol-defined virologic failure (PDVF). Resistance-associated mutations (RAMs) were identified using International Antiviral Society-USA mutation lists. Phenotypic analyses varied across studies.
Results
Overall, 250 of 3635 patients in the analysis met PDVF criteria; 205 had post-baseline genotypes/phenotypes. In total, four (0.1%) patients developed (or had identified) ≥1 darunavir and/or primary protease inhibitor (PI) RAM; only one (<0.1%) patient (with prior lopinavir virologic failure) lost darunavir phenotypic susceptibility. Among 3317 patients using nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs; mostly emtricitabine and tenofovir), 13 (0.4%) had ≥1 N(t)RTI RAM (10 with M184I/V). Among patients receiving D/C/F/TAF (n = 1949), none had post-baseline darunavir, primary PI, or tenofovir RAMs; only two (0.1%) patients developed an emtricitabine RAM, M184V/I.
Conclusions
Across a large, diverse population using darunavir 800 mg QD-based regimens and formulations, resistance development remains rare. After clinical trials that span >10 years, loss of phenotypic susceptibility to darunavir was only observed once in a PI-experienced patient and has never been observed in treatment-naïve patients, treatment-experienced PI-naïve patients, or treatment-experienced virologically suppressed patients.
... Patient-reported outcomes (PROs) were measured by validated, standardized questionnaires. These included the Hospital Anxiety and Depression Scale (HADS) with categorical scoring: normal (0-7), borderline abnormal (8)(9)(10) and abnormal (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), the ACTG symptom distress module (ASDM), and the SF-12, a short version of the SF-36 Health Survey. PRO questionnaires were provided according to the patient's preference in either electronic form on mobile devices or in paper-and-pencil format at baseline, 12 and 24 months after treatment initiation. ...
... ART modification rates were highest in the PI arm, which is not unexpected considering that this drug class was more frequently administered to patients with advanced immune deficiency. PIs may be the drug of choice in late presentation due to their presumed high genetic barrier and well documented long-term effectiveness in patients with advanced disease [9][10][11]. Many patients in the PI arm switched to other regimens for simplification reasons only. ...
PurposeCurrent German/Austrian antiretroviral treatment guidelines recommend more than 20 combination regimens for first-line therapy, without a preference. Regimens include two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an integrase strand transfer inhibitor (INSTI), a non-NRTI (NNRTI) or a boosted protease inhibitor (PI). The objective was to examine the outcomes of recommended first-line ART in Germany.Methods
This nationwide observational study included treatment-naïve chronically HIV-1 infected patients receiving one of the recommended first-line regimens. Patients were allocated to three arms (INSTI, NNRTI, PI) and were prospectively followed for 24 months. Delayed treatment initiation was defined by a baseline CD4 T-cell count of < 350/µl or CDC clinical stage C.ResultsAmong a total of 434 patients enrolled, virologic failure was rare and occurred in 4.3% (6/141) in the PI arm, in 3.3% (4/122) in the NNRTI arm and in 0.6% (1/171) in the INSTI arm (p = 0.10). De novo drug resistance mutations developed in only two patients in the NNRTI arm. Nonetheless, treatment modifications were frequent (51%) and mostly performed for strategic reasons. Retention on all initial compounds at month 24 was 64%, 49%, and 22% in the INSTI, NNRTI and PI arms respectively. Delayed treatment initiation was common (47%) and more frequently observed in patients in the PI arm. It was not associated with virological failure.Conclusion
High efficacy and low virological failure rates were observed with recommended first-line regimens independent of delayed treatment initiation, chosen regimen and subsequent treatment modifications, demonstrating the validity of the current treatment guidelines.
... 57 An analysis of seven adult studies of once-daily DRV reported treatment-emergent DRV resistance of <0.1%. 58 For adolescents struggling with adherence, even with the potential risk of further DR developing, the risks associated with stopping ART completely far outweigh the benefits of retention on some ART due to poorer immunological outcomes and should be avoided. 59 The pill size -and for those with access only to lopinavir, pill number and frequency -and gastrointestinal toxicity associated with bPIs has been a challenge for many adolescents who have failed first-line NNRTI-based therapy. ...
Poorer adherence to medication is normal in adolescence and is one of a range of risk-taking behaviours common during a developmental stage that encompasses enormous cognitive, physical, sexual, social and emotional change. For adolescents living with human immunodeficiency virus (HIV) infection, poor adherence to antiretroviral therapy (ART) confers two significant challenges: poor health, but also the specific additional burden of onward transmission to partners. Late adolescence (15–19 years) is the only age group where HIV-associated mortality is rising, driven by poor adherence to ART and lack of access to second-line therapy, particularly amongst surviving perinatally infected young people. A previous lack of well-powered randomised multimodal behavioural ART adherence interventions specifically targeting adolescents is now being addressed and ongoing studies registered to ClinicalTrials.gov are described in the context of previous data. Accepting that despite enhanced support, some adolescents will continue to struggle with adherence, we must address how best to use existing ART agents to reduce mortality and allow adolescents the time to mature into adult life. Single-tablet regimens with a high genetic barrier to resistance based on integrase inhibitors and boosted protease inhibitors exist, but global access, in resource limited settings of young people living with HIV reside, is limited. Pragmatically, such regimens tolerate the intermittent adherence so characteristic of adolescence, preserving immune function, without the rapid evolution of resistance. The potential role of long-acting injectable ART, specifically cabotegravir and rilpivirine, is discussed and future strategies including ultra-long-acting drug-delivery systems and broadly neutralising monoclonal antibodies explored.
... -Used for the treatment of MERS-CoV in experimental animals -Used for the treatment of HIV-1 patients [116] ...
... -Used for the treatment of MERS-CoV in experimental animals -Used for the treatment of HIV-1 patients [116] ...
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