Phase 2 of new ARVs

Doravirine
(non nucleoside reverse transcriptase inhibitor)

Etude MK1439007 :
doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
Original article : Morales-Ramirez JO, CROI 2014, Abs. 92LB, Gatell JM. HIV Drug Therapy 2014, Abs. O434
Last update : 02/06/2015

Dr Anton Pozniak
Chelsea and Westminster Hospital
London, UK

  • In antiretroviral-naïve, HIV-1 infected subjects, DOR 100 mg qd + TDF/FTC had a lower rate of treatment-emergent CNS events by week 8 than EFV + TDF/FTC
  • DOR 25 to 200 mg qd for 48 weeks
    • had simialr virologic and immunologic efficacy to EFV
    • with low rate of resistance mutation development
    • and good safety and tolerability profile
  • DOR 100 mg qd dose was selected for further development

Design


* Randomisation stratified on HIV RNA (> or ≤ 100,000 c/mL)

Objective

  • Primary endpoints
    • % HIV-1 RNA < 40 c/mL at W24 (estimation comparisons for DOR dose selection), ITT, NC=F
    • Safety : general at W24, pre-specified CNS AEs by W8 and W24

Design

Objective

  • CNS adverse events analysis, W8
    • Parts 1 and 2 combined (DOR 100 mg vs EFV)
  • Efficacy and safety analyses, W48 : part 1 only, W96 : parts 1 and 2
    • % with HIV RNA < 40 c/ mL , < 200 c/ mL , NC=F approach for missing data
    • Change from baseline in CD4 cell count, observed failure approach
    • Safety endpoints : adverse events, laboratory parameters

Baseline characteristics and patient disposition (Part 1)


* DOR 25 mg : stupor (n = 1), DOR 50 mg: abdominal pain/nausea/insomnia (n = 1), sleep disorder (n = 1), DOR 100 mg : hallucinations (n = 1), EFV : right-sided dysesthesia (n = 1), hallucinations (n = 1)

Baseline characteristics (Parts 1 and 2)

CNS events at W8, all causality (Parts 1 and 2)

Response to treatment, HIV RNA < 40 c/ mL (ITT, NC = F)

Mean change in CD4/mm 3 at W48

  • DOR all doses : + 168
  • EFV : + 179

HIV RNA < 40 c/ mL (ITT, NC = F) at W48 by screening HIV RNA

Virologic failure definition

  • Non-response : HIV RNA never < 40 c/mL by Week 24, or
  • Rebound : after initial response of HIV RNA < 40 c/mL, 2 consecutive HIV RNA ≥ 40 c/mL at least 1 week apart, at or after Week 24

Criteria for resistance testing

  • HIV RNA > 500 c/mL

Resistance data at virologic failure, W48

Clinical adverse events at W48 (Part 1)

Laboratory abnormalities at W48 (Part 1 ), N

 

 

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