Doravirine Maintains Efficacy in Week 96 DRIVE-FORWARD Results

Long-term results from a phase 3 trial evaluating doravirine (DOR) indicate that, in combination with combination with the antiretroviral (ART) agents emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC), DOR produced higher rates of HIV suppression compared with ritonavir-boosted darunavir in combination. The results were presented at the 22nd International AIDS Conference (AIDS 2018) in Amsterdam, the Netherlands.

DOR is an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) formulated as a once-daily single-entity tablet in combination with other ART agents for the treatment of HIV in treatment-naïve adults. The safety and efficacy of DOR were studied in the phase 3 multicenter, double-blind, randomized, noninferiority trial DRIVE-FORWARD, which assessed 100mg of DOR versus 800 mg of darunavir plus 100 mg ritonavir (DRV+r), administered once daily, orally, in combination with FTC/TDF or ABC/3TC in 766 patients with HIV.

"Doravirine addresses many of the limitations associated with previous NNRTIs that have caused them to be removed as preferred agents in treatment guidelines." Carey Hwang, MD, PhD, director, clinical research and global clinical development, infectious diseases, Merck, told Contagion^®, "Doravirine has a resistance profile unique from other NNRTIs, minimal drug-drug interactions, high efficacy regardless of baseline CD4+ T-cell count or high viral load, and the ability to be taken with or without food."

Early results of the study, presented in 2017 at the annual Conference on Retroviruses and Opportunistic Infections, indicated that DOR, met the primary efficacy endpoint of non-inferiority compared to DRV+r, each in combination with FTC/TDF at week 48.

At week 96, 73.1% of the participants (277/379) in the group treated with once-daily DOR achieved viral suppression as measured by the proportion of patients who achieved HIV RNA of less than 50 c/mL, compared to 66% (248/376) of the group treated with once-daily ritonavir-boosted darunavir.

“These Week 96 data reinforce the efficacy and safety of DOR found at 48 weeks, and support the potential use of DOR in the clinic as an important new treatment option for people living with HIV-1,” said Chloe Orkin, lead for HIV and HIV/Hep C research, Ambrose King Centre, Royal London Hospital in a statement.

Results for participants with high baseline viral load (HIV-1 RNA greater than 100,000 c/mL) were 65.4% for DOR (95% CI: 17.6) and 65.2% for DRV+r (95% CI: 15.3) (treatment difference: -1.1%). The mean change from baseline in CD4+ T-cell count at 96 weeks was 224 cells/mm³ for DOR and 207 cells/mm³ for DRV+r (treatment difference: 17.4 cells/mm, 95% CI: -14.5,49.3)

According to the statement, “At Week 96 mean changes from baseline in fasting serum blood lipids for the DOR and DRV+r treated groups in levels of low density lipoprotein cholesterol (LDL-C) were DOR -0.4 mg/dL and DRV+r 14.0 mg/dL (treatment difference: -14.6, 95% CI: -18.2, -11.0); and in levels of non-high density lipoprotein cholesterol (non-HDL-C) were DOR -0.5 mg/dL and DRV+r 17.7 mg/dL (treatment difference: -18.4, 95% CI: -22.5, -14.3).

Mean changes from baseline in total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides for the DOR-treated group and the DRV+r treated group were 4.1 mg/dL and 21.9 mg/dL (treatment difference: -18.1, 95% CI: -22.5, -13.7), 4.5 mg/dL and 4.2 mg/dL (treatment difference: 0.4, 95% CI: -1.3, 2.1), and -1.1 mg/dL and 22.5 mg/dL (treatment difference: -25.7, 95% CI: -36.6, -14.7), respectively.”

Two participants in the DOR treatment group developed genotypic and phenotypic resistance to DOR through 96 weeks of treatment.

The most common adverse events occurring in >10% of participants in either treatment group were diarrhea, nausea, headache, upper respiratory tract infection, and viral upper respiratory tract infection. The rate of discontinuation due to adverse events was 1.6% in the DOR group and 3.4% in the DRV+r group.

"Doravirine is also being evaluated in several ongoing studies," Dr Hwang added, "A Phase 3 study (DRIVE-SHIFT) is evaluating a switch to DOR/3TC/TDF in adults who are currently virologically suppressed on another antiretroviral regimen. Phase 2 studies include an evaluation of DOR/3TC/TDF in treatment-naïve participants with transmitted resistance to NNRTIs and in adults switching from efavirenz due to intolerability."

The US Food and Drug Administration (FDA) has accepted a New Drug Application for DOR and DOR/3TC/TDF for the treatment of HIV in treatment-naïve adults. The target of action date for both applications is October 23, 2018.