The US Food and Drug Administration (FDA) has approved two new products containing the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine. These products are also under review by the European Medicines Agency.
Produced by Merck/MSD, Pifeltro is a stand-alone doravirine tablet that must be taken with other antiretrovirals. Delstrigo is a fixed-dose pill (single-tablet regimen) containing doravirine plus the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (sold separately as Viread) and lamivudine (also known as Epivir or 3TC).
Both Pifeltro and Delstrigo were approved for adults with HIV who are starting antiretroviral treatment for the first time. Both are taken once daily with or without food. Doravirine (formerly known as MK-1439) has a unique resistance profile and is active against HIV with common NNRTI-resistance mutations including K103N.
Approval of the new medications was based on findings from the phase 3 DRIVE-FORWARD and DRIVE-AHEAD clinical trials.
DRIVE-FORWARD included 766 HIV-positive participants with no prior treatment experience. They were randomly assigned to receive once-daily doravirine or boosted darunavir (Prezista), each in combination with tenofovir DF/emtricitabine (the drugs in Truvada) or abacavir/lamivudine (the drugs in Kivexa or Epzicom).
Kathleen Squires of Thomas Jefferson University presented the results at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI). After 48 weeks on treatment, 84% of people taking doravirine and 80% of those taking boosted darunavir had undetectable viral load (< 50 copies/ml), showing that doravirine was non-inferior.
DRIVE-AHEAD included 728 previously untreated participants. They were randomised to receive a fixed-dose co-formulation of doravirine, tenofovir DF and lamivudine – the same as the approved Delstrigo pill – or a single-tablet regimen containing efavirenz, tenofovir DF and emtricitabine (the drugs in Atripla).
As Squires reported last summer at the 2017 International AIDS Society Conference on HIV Science, 84% of people on the Delstrigo combo and 81% of those on the Atripla combo had undetectable viral load at 48 weeks, again showing that doravirine was non-inferior. Viral suppression rates were similar in the two treatment arms for people who started with either low or high (> 100,000 copies/ml) viral load at baseline.
Treatment with doravirine was safe and well tolerated. In DRIVE-FORWARD, 2% of doravirine recipients stopped treatment early due to adverse events compared with 3% of those taking boosted darunavir. In DRIVE-AHEAD, Delstrigo recipients were about half as likely as Atripla recipients to discontinue treatment because of adverse events (3% vs 7%).
The most common doravirine side-effects in both studies were headache, nausea, diarrhoea and nasopharyngitis (nose and throat inflammation). In DRIVE-FORWARD, side-effects associated with other NNRTIs, such as rash and neuropsychiatric symptoms, were similar in both treatment arms. In DRIVE-AHEAD, Delstrigo was associated with significantly fewer neuropsychiatric side effects – such as dizziness, sleep problems, abnormal dreams and altered cognition – than Atripla.
In both studies, participants taking doravirine saw small declines in LDL and non-HDL cholesterol, while those taking boosted darunavir or the Atripla combination experienced small increases. Although the differences were statistically significant, the clinical significance of these small changes is unclear.
The tenofovir DF component in Delstrigo has been associated with kidney problems and bone loss in susceptible individuals. For this reason, kidney function should be checked before starting this combination and monitored regularly thereafter. Of note, Gilead Sciences' newer tenofovir alafenamide (TAF) formulation, which causes less kidney and bone toxicity, remains under patent while a generic version of tenofovir DF is available for Merck to use in its co-formulation.
Because tenofovir is also active against hepatitis B virus (HBV), the Delstrigo label includes a warning about the possibility of worsening of HBV-related liver inflammation if the medication is stopped.
Pifeltro and Delstrigo should not be taken with drugs that are strong inducers of cytochrome P450 enzymes, as this can lead to lower doravirine levels in the blood that could reduce treatment effectiveness.
The ongoing DRIVE-SHIFT study is evaluating doravirine as a switch option for people with viral suppression on their current antiretroviral regimen. Doravirine and the Delstrigo combo are currently being tested in children and adolescents. At this year's CROI Randolph Matthews of Merck said that doravirine is also being tested in combination with the company's experimental nucleoside reverse transcriptase translocation inhibitor known as MK-8591 in a phase 2b called DRIVE2SIMPLIFY.
Merck. FDA approves Merck’s Delstrigo (doravirine / lamivudine / tenofovir disoproxil fumarate), a once-daily fixed-dose combination tablet as a complete regimen and Pifeltro (doravirine), an NNRTI, both for the treatment of HIV-1 in appropriate patients. Press release. 30 August, 2018.