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Review of Doravirine Resistance Patterns Identified in Participants During Clinical Development.

ABSTRACT: BACKGROUND:Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for the treatment of HIV-1 infection in patients with no known DOR resistance-associated mutations. DOR was rationally designed to address limitations associated with other approved NNRTIs, particularly resistance from common NNRTI resistance-associated mutants containing K103N, Y181C, or G190A reverse transcriptase substitutions. SETTING:Data to date from both in vitro studies and clinical trials have been compiled to summarize the resistance profile of DOR. METHODS:We analyzed data from in vitro studies and phase 2 and 3 trials to assess the emergence of resistance-associated mutations and their impact on efficacy among participants treated with DOR. RESULTS:DOR exhibited a distinct resistance profile compared with efavirenz and rilpivirine in vitro and in vivo; mutant viruses that were resistant to DOR showed limited cross-resistance to efavirenz and rilpivirine. In clinical trials, the development of DOR resistance-associated substitutions in reverse transcriptase was uncommon. CONCLUSION:Overall, minimal cross-resistance across NNRTIs was observed for DOR and limited development of DOR-related resistance. These data should assist clinicians in further understanding the resistance profile of DOR, so appropriate treatment decisions can be made for their patients.

SUBMITTER: Martin EA

PROVIDER: S-EPMC7655028 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Review of Doravirine Resistance Patterns Identified in Participants During Clinical Development.

Martin Elizabeth Anne EA Lai Ming-Tain MT Ngo Winnie W Feng Meizhen M Graham Donald D Hazuda Daria J DJ Kumar Sushma S Hwang Carey C Sklar Peter P Asante-Appiah Ernest E

Journal of acquired immune deficiency syndromes (1999) 20201201 5

<h4>Background</h4>Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for the treatment of HIV-1 infection in patients with no known DOR resistance-associated mutations. DOR was rationally designed to address limitations associated with other approved NNRTIs, particularly resistance from common NNRTI resistance-associated mutants containing K103N, Y181C, or G190A reverse transcriptase substitutions.<h4>Setting</h4>Data to date from both in vitro studies a ...[more]

PMID: 32925358

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Project description:BackgroundThe validity of ratings of perceived exertion (RPE) during aerobic training is well established; however, its validity during resistance exercise is less clear. This meta-analysis used the known relationships between RPE and exercise intensity (EI), heart rate (HR), blood lactate (BLa), blood pressure (BP) and electromyography (EMG) to determine the convergent validity of RPE as a measure of resistance exercise intensity and physiological exertion, during different forms of resistance exercise. Additionally, this study aims to assess the effect of several moderator variables on the strength of the validity coefficients, so that clearer guidance can be given on the use of RPE during resistance exercise.MethodsAn online search of 4 databases and websites (PubMed, Web of Science SPORTDiscus and ResearchGate) was conducted up to 28 February 2020. Additionally, the reference lists of the included articles were inspected manually for further unidentified studies. The inclusion criteria were healthy participants of any age, a rating scale used to measure RPE, resistance exercise of any type, one cohort receiving no other intervention, and must present data from one of the following outcome measures: EI, HR, BP, EMG or BLa. Weighted mean effect sizes (r) were calculated using a random-effects model. Heterogeneity was assessed using the τ2 and I2 statistics. Moderator analysis was conducted using random-effects meta-regression.ResultsOne-hundred and eighteen studies were included in the qualitative synthesis, with 75 studies (99 unique cohorts) included in the meta-analysis. The overall weighted mean validity coefficient was large (0.88; 95% CI 0.84-0.91) and between studies heterogeneity was very large (τ2 = 0.526, I2 = 96.1%). Studies using greater workload ranges, isometric muscle actions, and those that manipulated workload or repetition time, showed the highest validity coefficients. Conversely, sex, age, training status, RPE scale used, and outcome measure no significant effect.ConclusionsRPE provides a valid measure of exercise intensity and physiological exertion during resistance exercise, with effect sizes comparable to or greater than those shown during aerobic exercise. Therefore, RPE may provide an easily accessible means of prescribing and monitoring resistance exercise training. Trial Registration The systematic review protocol was registered on the PROSPERO database (CRD42018102640).

Project description:Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0-24), maximum observed plasma concentration (Cmax), and observed plasma concentration at 24 h postdosing (C24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0-24, Cmax, and C24, respectively, by day 14 after efavirenz cessation. The doravirine C24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.

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Review of Doravirine Resistance Patterns Identified in Participants During Clinical Development.

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Review of Doravirine Resistance Patterns Identified in Participants During Clinical Development.

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