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Doravrine - a relatively New ART [NNRTI]
  doravirine + an integrase inhibitor (raltegravir) dual therapy is being used by doctors in the clinic and new research studies using this dual combination are in progress is my understanding, here are recent studies
New Long Acting Potent Nuke MK-8591 + Doravirine Phase 2B Study Starts
New PrEP Long-Acting MK-8591, for HIV Treatment Too
IAS: First-in-Human Trial of MK-8591-Eluting Implants Demonstrates Concentrations Suitable for HIV Prophylaxis for at Least One Year - (07/25/19)
IAS: Tolerability, Safety, and Efficacy of Islatravir (MK-8591) at Doses of 0.25 to 2.25 mg QD, in Combination With Doravirine and Lamivudine Through 24 Weeks in Treatment-Naïve AdultsWith HIV-1 Infection - (07/25/19)
EACS2019: Islatravir Efficacy and Safety for Selected Demographic and Baseline Subgroups From a Phase 2 Trial In Treatment-naïve Adults With HIV-1 Infection
IAS2019: Tolerability, Safety, and Efficacy of Islatravir (MK-8591) at Doses of 0.25 to 2.25 mg QD, in Combination With Doravirine and Lamivudine Through 24 Weeks in Treatment-Naïve AdultsWith HIV-1 Infection
MK-8591 Potency and PK Provide High Inhibitory Quotients at Low Doses QD and QW
Understanding the Resistance Profile of the HIV-1 NNRTI Doravirine in Combination With the Novel NRTTI MK-8591
Merck Announces Presentation of Phase 2b Results for Investigational HIV-1 Therapy Islatravir (MK-8591) at IAS 2019
CROI2019: Once-Daily Doravirine in HIV-1-Infected, Antiretroviral-Naive Adults: An Integrated Efficacy Analysis
Rational Design of Doravirine (DOR): A Review of Development From Bench to Patients
EACS2019: Effect of doravirine on body weight and body mass index in treatment naive adults with HIV-1
Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial Clinical Infectious Diseases, Volume 68, Issue 4, 1 February 2019 supplementary material
Doravirine (DOR) Versus Ritonavir-Boosted Darunavir (DRV+r): 96-Week Results of the Randomized, Double-Blind, Phase 3 DRIVE-FORWARD Noninferiority Trial
Glasgow2018: Safety and Efficacy of Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in Treatment-Naïve HIV-1 Infected Adults With Transmitted Non-Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations
Doravirine Studies - efficacy, safety
IDWeek: Doravirine/Lamivudine/Tenofovir DF continues to be Non-Inferior to Efavirenz/Emtricitabine/Tenofovir DF in Treatment-naïve Adults with HIV-1 Infection: Week 96 Results of the DRIVE-AHEAD Trial - (10/06/18)
IDWeek: Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial - (10/06/18)
IDWeek: Merck Announces Week 96 Data from Pivotal Phase 3 DRIVE-AHEAD Study Evaluating DELSTRIGO™ (doravirine / lamivudine / tenofovir disoproxil fumarate) for the Treatment of HIV-1 in Treatment-Naïve Patients - (10/06/18)
Characterization of Doravirine-Selected Resistance Patterns From Participants in Treatment-Naïve Phase 3 Clinical Trials
IAC: Doravirine (DOR) Versus Ritonavir-Boosted Darunavir (DRV+r): 96-Week Results of the Randomized, Double-Blind, Phase 3 DRIVE-FORWARD Noninferiority Trial - (07/25/18)
FDA Accepts New Drug Applications for Merck's Doravirine, the Company's Investigational Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), for Treatment of HIV-1 Infection
September 9th, 2018
Doravirine Sets a New Standard for NNRTIs - But What Role in HIV Treatment Today?


"Hello, we are Pifeltro and Delstrigo."
The HIV drug class called "non-nucleoside reverse transcriptase inhibitors," or NNRTIs, must have something of an inferiority complex.
First, anything defined by what it is not is already in trouble. Believe me, hepatitis C was thrilled when it could shed the "non-A, non-B hepatitis" label.
Second, despite their high antiviral potency and good tolerability, the NNRTIs have always been an afterthought to the protease inhibitors (PIs) when discussing how combination therapy transformed the effectiveness of HIV therapy back in the 1990s. Take a look at this classic paper - over 5000 citations and counting - especially its famous figure.
However, from a global perspective, it has been NNRTI (not PI)-based regimens in that have had the greatest impact in years of life saved from antiretroviral therapy.
Let's add to the NNRTI list of accomplishments by citing that no study of initial therapy has ever demonstrated superiority over efavirenz from a purely virologic perspective (not even dolutegravir); that a meta-analysis did not show a difference in clinical outcomes between PI and NNRTI-based therapies; and that efavirenz-based regimens appear (ironically) to be quite safe for the fetus during conception and pregnancy.
So - now that I've defended the drug class, let's introduce the latest member, doravirine, which was approved by the FDA during their busy last week of August.
Approval of both doravirine individually and the coformulated doravirine/lamivudine/tenofovir DF tablet was based on the results of two clinical trials.
Given with TDF/FTC or ABC/3TC, doravirine was non-inferior to darunavir + ritonavir with a better lipid profile at 48 weeks, and superior at 96 weeks due to fewer adverse events. Similarly, the once-daily single tablet was compared to TDF/FTC/EFV in a double-blind trial, and also found to be non-inferior.
Dosed 100 mg once-daily, doravirine has several advantages over existing drugs in the NNRTI class:
• Few drug interactions, in particular none with acid-reducing agents.
• Can be taken with or without food.
• A more favorable lipid profile, lower incidence of rash, and fewer CNS side effects than efavirenz.
• A novel resistance pathway, with activity against viruses with K103N or Y181C mutations. By contrast, the V106I and F227C mutations selected by doravirine do not cause in vitro resistance to either rilpivirine or etravirine - and may induce hypersusceptibility to certain NRTIs.
These advantages notwithstanding, the role of doravirine or the coformulated tablet in HIV treatment today is uncertain. Major HIV treatment guidelines now list integrase inhibitor based regimens as preferred for initial therapy, and the drug has not been compared to an integrase inhibitor in any clinical trial. Furthermore, the single tablet option contains tenofovir disoproxil fumarate, which has more renal and bone toxicity than tenofovir alafenamide.
Still, since this appears to be a "best in class" drug, doravirine has enough advantages that it is a useful advance in HIV therapy, if not a transformational one. Think of the following patients, for example:
• Those who can't tolerate integrase inhibitors.
• Someone looking for efavirenz or rilpivirine alternatives within the same drug class, due to concerns over CNS side effects or use of acid-reducing agents, respectively.
• Off-label use as part of a switch strategy for patients with susceptible virus. (A switch study is ongoing.)
• As a cost-saving strategy, depending on listed and negotiated prices - in particular for the single tablet, since the non-doravirine components are generic.
Of note, doravirine is also under study with the potent and long-acting agent MK-8591 as part of a two-drug strategy. MK-8591 is an NRTTI, the second T standing for "translocation".
Two final points: The drug is abbreviated "DOR" - not "DRV," which was already taken by darunavir.
And the brand names are Pifeltro, for doravirine alone, and Delstrigo, for the coformulated single tablet - note that "STR" in there? One can assume that stands for "single tablet regimen."
Still, together they sound like the name of a famous Sicilian puppet duo, best known for their slapsti

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