Potential New Drug Option for Treatment-Naïve HIV-1 Patients

SEATTLE — The investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) with once-daily dosing doravirine appears to have similar efficacy and to be non-inferior to once-daily ritonavir-boosted darunavir (DRV+r) on a background of 2 NRTIs in HIV-1 treatment-naïve adults, according to an ongoing, phase 3, multicenter, double-blind, non-inferiority trial (DRIVE-FORWARD). The latest data in patients treated at 48 weeks were presented at CROI 2017 and the investigators found that efficacy was similar regardless of baseline HIV-1 RNA. In addition, doravirine was found to be generally safe and well-tolerated with a superior lipid profile for fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) compared with DRV+r.

“It has a low potential for drug-drug interaction,” said study investigator Kathleen Squires, MD, a professor and director of infectious diseases at Thomas Jefferson University, Philadelphia, Pennsylvania. “There was a low rate of discontinuation due to rash or neuro-psychiatric adverse events.”

Dr Squires, who presented the study findings at the CROI 2017 meeting, said these data provide solid evidence of the efficacy and safety profile of doravirine as a potential treatment option for treatment-naïve HIV-1 patients. The study met its primary efficacy end point of the percentage of participants achieving levels of HIV-1RNA less than 50 copies/mL after 48 weeks of treatment. It demonstrated the non-inferiority of once-daily doravirine to once-daily DRV+r, each administered with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC). In addition, a secondary end point showed that the DOR-treated group had statistically significant lower levels of fasting LDL-C than the DRV+r group.

Doravirine has been shown to have potent in vitro activity against the most common NNRTI resistant variants (K103N, Y181C, G190A), according to the researchers. A previously published phase 2b study showed that 100 mg once daily demonstrated similar efficacy to efavirenz, with favorable safety and tolerability through 48 weeks. 

The current study included 766 patients (383 in each group) and the mean age was 35.2 years. The cohort was 84% male and 73% white.  Out of 383 participants, 1 developed phenotypic and genotypic resistance in the doravirine arm (the patient came off the study at Week 24 because of non-adherence). None of the 383 participants receiving DRV+r developed phenotypic and genotypic resistance.

The rates of reported adverse drug reactions were 31% (117/383) in the doravirine arm and 32% (123/383) in the DRV+r arm. Discontinuations due to adverse events were 2% (6/383) in the doravirine arm and 3% (12/383) in the DRV+r arm. The most common adverse event occurring in ≥10% of participants were: diarrhea (14% in the doravirine group vs 22% in the DRV+r group); headache (14% in the doravirine group vs 11% in the DRV+r group); nausea (11% in the doravirine group vs 12% in the DRV+r group) and nasopharyngitis (8% in the doravirine group vss 10 % in the DRV+r group).

The study showed a mean change from baseline in the levels of LDL-C was -4.5 mg/dL vs +9.9 mg/dL and the mean change from baseline for non-HDL-C was -5.3 mg/dL vs +13.8 mg/dL. The mean change from baseline in total cholesterol was -1.4 mg/dL vs +3.9 mg/dL, for high-density lipoprotein cholesterol (HDL-C) it was -3.1 mg/dL vs +17.9 mg/dL, and for triglycerides it was +4.2 mg/dL, and +22 mg/dL.

Reference

Molina J-M, Squires K, Sax PE, et al. Doravirine is non-inferior to darunavir/r in phase 3 treatment-naive trial at week 48. Presented at: CROI 2017. Seattle, WA; February 13-16, 2017. Abstract 45LB.