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Doravirine, a Promising New HIV-1 Novel Therapy

Friday, June 21, 2019  
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The DRIVE-FORWARD and DRIVE-AHEAD trials indicate doravirine as a new therapy for HIV-1 in treatment naive patients.

 

Deirdre Kaan, Doctor of Pharmacy Candidate 2020, Temple University School of Pharmacy

Preceptor: Amy Min, PharmD, BCACP, AAHIVP, Clinical Assistant Professor,

Department of Pharmacy Practice of Pharmacy at Temple University

 

In 2017, over 36.9 million people worldwide were living with HIV; only 75% were aware that they were living with HIV and 59% were able to access antiretroviral therapy (ART). Advancements in HIV drug therapies, such as the development of integrase strand transfer inhibitors (INSTIs) and single tablet regimens, have reduced polypharmacy associated with the management of this viral infection. Therapeutic advancements have also reduced medication side effects, potential drug interactions, and toxicities impacting patient care. New ARTs have been approved with new mechanisms of action and/or with higher genetic barriers to overcome drug resistance. Current initial therapies for most people living with HIV consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with certain INSTIs including dolutegravir, bictegravir, and raltegravir. The NNRTI drug class, which has recently fallen out of favor due to the approval of INSTIs, still remains as a recommended option for patients in certain clinical situations. Doravirine (DOR), a novel NNRTI, was approved by the FDA in August 2018 as an option for the treatment of HIV in patients with no prior ART history, based off of the results of 2 large phase III clinical trials.2

The DRIVE-FORWARD trial is a phase III, randomized, double-blind, multicenter, non-inferiority study assessing the efficacy of doravirine versus ritonavir-boosted darunavir (DRV/r) in patients living with HIV who had received no previous ART (treatment-naïve). Patients were randomized to receive either DOR or DRV/r with a backbone combination regimen of emtricitabine (FTC) with tenofovir disoproxil fumarate (TDF) or abacavir (ABC) with lamivudine (3TC).The primary endpoint evaluated was the proportion of patients with a HIV-1 RNA viral load ≤ 50 copies per mL by week 48. Of the 385 patients randomized to the DOR arm and the 384 patients randomized to the DRV/r arm, 383 patients from each arm were included in the primary efficacy analysis. Of these patients, 321 (84%) participants in the DOR arm and 306 (80%) participants in DRV/r arm achieved ≤ 50 HIV-1 RNA copies per mL, the optimal outcome of highly active ART, by week 48, indicating non-inferiority of DOR containing regimens. The most notable secondary outcome assessed was the development of virologic resistance. In the DOR arm, no genotypic mutations or phenotypic resistance associated with DOR were identified at week 48. In the DRV/r arm, 3 patients exhibited polymorphic mutations to darunavir that did not affect drug susceptibility at week 48. Commonly reported adverse events observed were diarrhea, nausea, and headache. In the DOR arm, of the 383 participants, 21 (5%) experienced diarrhea, 25 (7%) experienced nausea, and 23 (6%) experienced headache.  Comparatively in the 383 participants included in DRV/r arm, 49 (13%) experienced diarrhea, 29 (8%) experienced nausea, and 10 (3%) experienced headache.3

Similarly, the DRIVE-AHEAD trial was also a phase III, randomized, double-blind, multicenter, non-inferiority study. DRIVE-AHEAD evaluated the virologic efficacy of DOR versus efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, in treatment-naïve patients living with HIV-1. In this study, results were analyzed for doravirine combination therapy (DOR/3TC/TDF) versus efavirenz combination therapy (EFV/FTC/TDF) at 48 weeks. The primary efficacy endpoint was identical to the DRIVE-FORWARD trial.4 Of the 364 patients receiving a DOR-based regimen, 307 (84.3%) achieved ≤ 50 HIV-1 RNA copies per mL by week 48. Similarly, 294 (80.8%) of the 364 patients in the EFV arm achieved the primary efficacy endpoint. NNRTI genotypic resistance was detected in 7 (1.9%) of patients in the DOR arm and in 12 (3.3%) patients in the EFV arm at week 48. Additionally, patients in the DOR arm reported lower rates of dizziness (8.8% compared to 37.1%) than the EFV arm. Patients on efavirenz-based regimens exhibited more sleep disturbances (25.2% compared to 12.1%) and altered sensorium (8.2% versus 4.4%) compared to the patients on a DOR-based regimen.

The DRIVE-FORWARD and DRIVE-AHEAD are the clinical trials that drove the FDA approval of doravirine, a novel NNRTI for treatment-naive patients living with HIV. The study results showed that DOR was non-inferior compared to EFV and DRV/r based on HIV-1 RNA viral load reduction. Use in patients who are ART treatment-experienced has also been evaluated in switch studies. In DRIVE-SHIFT, an open-label, active-controlled, non-inferiority trial, patients switched from their baseline ART regimen of 2 NRTIs and either a boosted protease inhibitor, boosted elvitegravir, or an NNRTI, to a single tablet regimen of DOR/3TC/TDF or continued their baseline ART regimen for 24 weeks. DRIVE-SHIFT also demonstrated non-inferiority of DOR/3TC/TDF when compared to the patient’s baseline regimen.5

Although doravirine is a CYP3A4 substrate, it exhibits minimal pharmacokinetic drug-interactions compared to other members of the NNRTI class. Other benefits over other antiretrovirals in the NNRTI class are that there are no strict administration requirements; doravirine can be taken with or without food. Its high barrier to resistance and limited adverse effect profile, make this NNRTI an option for treatment-naive patients in certain clinical situations.2 Its coformulation with 3TC and TDF as the single tablet regimen, DelstrigoÔ, limits its widespread use as it is not recommended to be used in patients with a renal function of ≤ 50 mL/min.6 However, DelstrigoÔ, when compared with other single tablet regimens, may be a more affordable option for patients (Table 1).7 The approval of doravirine serves as another option for patients living with HIV.

 

Table 1: Monthly cost of select single tablet regimens7

 

 

Single tablet regimen

Approximate AWP* 30-day supply cost

DelstrigoÔ (Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate)

$2,520

CompleraÒ (Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate)

$3,375

OdefseyÒ(Emtricitabine/Rilpivirine/Tenofovir Alafenamide)

$3,375

AtriplaÒ(Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate)

$3,429

TriumeqÒ(Abacavir/Dolutegravir/Lamivudine)

 

$3,467

BiktarvyÒ(Bictegravir/Emtricitabine/Tenofovir Alafenamide)

$3,708

SymtuzaÒ(Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide)

$4,467

 

*AWP= average wholesale price

 

References

  1. UNAIDS. Global Statistics. HIV.gov. https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics. Published January 10, 2019. Accessed April 28, 2019.
  2. PIFELTRO [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018.
  3. Molina J-M, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5): 211-220.
  4. Orkin C, Squires KE, Molina J-M, et al. 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. Clin Infect Dis. 2018;68(4):535-544.
  5. Johnson M, Kumar P, Molina J-M, et al. Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintain HIV-1 Virologic Suppression Through 48 Weeks. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2019 Apr 11. doi: 10.1097/QAI.0000000000002056 .
  6. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615.
  7.  Lexi-Drugs Online, Lexicomp Online. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  http://online.lexi.com.  Accessed May 3, 2019.

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