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

Summary

Background

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection.

Methods

In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than −10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780.

Findings

Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI −1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one (<1%) participant of each group.

Interpretation

In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection.

Funding

Merck & Co.

Introduction

Although non-nucleoside reverse transcriptase inhibitors (NNRTIs) are important components of combination antiretroviral therapy for previously untreated HIV-1 infection, all available drugs in this class have disadvantages. Efavirenz is the preferred third drug for use in combination with tenofovir and emtricitabine in WHO guidelines, but in other guidelines (US Department of Health and Human Services, European AIDS Clinical Society [EACS], and British HIV Association [BHIVA] guidelines) it is included only as an alternative regimen because of CNS intolerance¹ and possible association with suicidality.² Rash is another common side-effect of efavirenz,³ and lipid abnormalities seem to be more common with efavirenz than with other NNRTIs.⁴ Rilpivirine has low antiviral efficacy in patients with high viral load5, 6 and therefore is not recommended for individuals with baseline HIV-1 RNA of more than 100 000 copies per mL or CD4 counts of less than 200 cells per μL because of the increased risk of virological failure.⁷ Additionally, rilpivirine requires dosing with food and should not be given with proton-pump inhibitors, which results in substantial lowering of rilpivirine plasma concentrations.⁷ Nevirapine is associated with serious dermatological and hepatic toxicity and should not be prescribed in men with CD4 counts of more than 400 cells per μL or in women with counts greater than 250 cells per μL.⁸ Etravirine is not approved for first-line treatment and requires twice-daily dosing.⁹ New NNRTI drugs without these limitations are needed.

Research in context

Evidence before this study

We searched PubMed from inception to March 31, 2017, for clinical trials that mentioned doravirine or MK-1439 and found two previous clinical trials in adults with HIV-1. In a short-term monotherapy study in treatment-naive men with HIV-1 infection, doravirine 25 mg or 200 mg once daily for 7 days had robust antiviral activity, without evidence of viral resistance, and was generally well tolerated. In a phase 2, dose-ranging study in treatment-naive adults, doravirine 100 mg once daily administered with tenofovir disoproxil fumarate and emtricitabine was efficacious and well tolerated, with significantly fewer neuropsychiatric adverse events than efavirenz. To date, no studies have compared doravirine with a protease inhibitor for the treatment of HIV-1 infection.

Added value of this study

To the best of our knowledge, this is the first randomised, controlled, phase 3 trial of the safety and efficacy of doravirine 100 mg for HIV-1 infection. We found that in treatment-naive adults with HIV-1 infection, the antiretroviral efficacy of doravirine was non-inferior to that of ritonavir-boosted darunavir when given with two nucleoside reverse transcriptase inhibitors (NRTIs), as assessed by the proportion of participants who had plasma HIV-1 RNA of less than 50 copies per mL at week 48. Antiretroviral responses were similar in the doravirine and ritonavir-boosted darunavir groups regardless of baseline factors (eg, HIV-1 RNA >100 000 copies per mL and CD4 counts of <200 cells per μL). One participant developed resistance to doravirine and was discontinued by the investigator for non-compliance. Doravirine was generally well tolerated up to 48 weeks of treatment.

Implications of all the available evidence

The safety and efficacy profiles of doravirine observed in this study support and supplement the findings of previous studies and suggest that doravirine 100 mg once daily, given in combination with two NRTIs, might offer a valuable treatment option for adults with previously untreated HIV-1 infection.

Doravirine is a novel NNRTI with potent antiviral activity against wild-type HIV-1 (half maximal inhibitory concentration [IC₅₀] 12 nM in the presence of 100% normal human serum) and variants with the most frequently transmitted NNRTI-resistance mutations (ie, Lys103Asn, Tyr181Cys, and Gly190Ala).10, 11 The in-vitro resistance profile of doravirine is distinct from other NNRTIs,¹² and mutant viruses selected by efavirenz or rilpivirine, including those with reverse transcriptase Glu138Lys or Lys101Glu mutations, remain susceptible to doravirine.10, 12 Doravirine is a substrate for cytochrome P450 3A-mediated metabolism but is not thought to have drug interactions via major drug-metabolising enzymes or transporters.¹³ No clinically meaningful interactions were observed in healthy volunteers when doravirine was given with tenofovir disoproxil fumarate, atorvastatin, oral contraceptives, or pantoprazole.14, 15, 16, 17 In other phase 1 studies,18, 19, 20 the bioavailability of doravirine was not affected by food intake, age, sex, or moderate hepatic impairment.

In a short-term monotherapy study,²¹ doravirine 25 mg or 200 mg once daily for 7 days had antiviral activity and was generally well tolerated in treatment-naive men with HIV. In a phase 2 study22, 23 of treatment-naive adults, doravirine 100 mg once daily given with tenofovir disoproxil fumarate and emtricitabine was efficacious and well tolerated, with significantly fewer neuropsychiatric adverse events than efavirenz. On the basis of these promising results, we did a randomised, controlled, double-blind, phase 3, non-inferiority trial comparing doravirine with ritonavir-boosted darunavir, both given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection.