Kathleen Squires at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
Doravirine, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that reduced HIV viral load as well as boosted darunavir (a Protease Inhibitor) in a phase 3 clinical trial of people starting HIV treatment for the first time; but it had a better lipid (blood fat) profile, according to a late breaking presentation at CROI 2017.
Doravirine (formerly MK-1439) is active against HIV with common NNRTI-resistance mutations including K103N. It can be taken once daily with or without food and has low potential for drug-drug interactions.
At CROI Kathleen Squires (of Thomas Jefferson University, Philadelphia) presented results from DRIVE-FORWARD, a phase 3 trial comparing doravirine against ritonavir-boosted darunavir for first-line therapy.
At 48 weeks, 84% of participants in the doravirine arm and 80% of those assigned to boosted darunavir had undetectable HIV viral load below 50 copies/ml. The difference was not significant and doravirine was shown to be non-inferior to darunavir/ritonavir.
The major advantage of doravirine over darunavir/ritonavir was its favourable and superior effect on lipid levels (blood fats). Fasting lipid levels decreased slightly in the doravirine arm while increasing in the darunavir/ritonavir arm.
Darunavir is the only Protease Inhibitor (PI) currently recommended for commencing treatment, and all older NNRTIs are no longer recommended first-line. This study has potential to change the treatment guidelines to once again include an NNRTI, although further studies are needed yet.
Although doravirine is being developed as a single pill, Merck (the manufacturers) has also developed a fixed-dose co-formulation of doravirine, tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), which is being evaluated in ongoing studies. The phase 3 DRIVE-AHEAD trial is comparing doravirine (with TDF and 3TC) to efavirenz/TDF /FTC (Atripla) for initial treatment, while DRIVE-SHIFT is evaluating a switch from another treatment regimen (among people already taking effective treatment) to the doravirine co-formulation.
A new NNRTI (non-nuke) is highly welcomed as this research shows Doravirine overcomes the common resistance mutations of existing non-nukes and other limitations of existing drugs in this class (such as side effects or clinical limitations which restrict the use of some NNRTIs in some situations). Whether this proposed co-formulation combination single pill (DOR/TDF/3TC) containing the older higher dose tenofovir-DF (TDF) – as opposed to the newer lower dose tenofovir-AF (TAF) – will be a limitation for longer-term use and tolerability remains to be seen; given TDF is reported to be associated with kidney and bone related side effects. The decision to use 3TC – rather than the newer FTC (which are highly similar drugs in safety, tolerability and efficacy) – is likely less of a concern as 3TC is well tolerated.
Meantime, another NNRTI combination pill has recently been registered in Australia – ODEFSEY – containing rilpivirine (an existing NNRTI), TAF (lower dose tenofovir), and FTC (emtricitabine); although it is yet to become available on the Pharmaceutical Benefits Scheme (PBS) but is expected soon. Odefsey has been compared with Atripla (TDF/FTC/EFV) in study GS-1160, and results suggests its usefulness for initial and ongoing treatment.
Reference: Molina JM et al. (Squires K presenting) Doravirine is non-inferior to darunavir/r in phase 3 treatment-naive trial at week 48. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 45LB, 2017. Source: Adapted from article by Liz Highleyman, produced in collaboration with hivandhepatitis.com Published 19 February 2017 http://www.aidsmap.com/page/3119117/