Doravirine (Pifeltro)

Doravirine (Pifeltro) is an anti-HIV drug that reduces the amount of virus in the body. It belongs to the class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Pifeltro contains 100mg of doravirine.

Doravirine is also available in a combination pill with lamivudine and tenofovir disoproxil, marketed as Delstrigo.

Doravirine was developed by Merck. It was approved in the European Union and United States in 2018 for treatment of HIV infection in combination with other antiretroviral drugs for people with no evidence of resistance to any drug in the NNRTI class.

Doravirine is taken once daily in combination with other drugs or as part of the fixed-dose combination Delstrigo. Doravirine can be taken with or without food.

Doravirine was approved based on findings from the phase 3 DRIVE-FORWARD and DRIVE-AHEAD clinical trials in previously untreated people.

The DRIVE-FORWARD study 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 (Truvada) or abacavir/lamivudine (Kivexa).

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. (Molina)

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).

After 48 weeks on treatment, 84% of people on the Delstrigo combo and 81% of those taking Atripla 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. (Squires)

Glossary

undetectable viral load

A level of viral load that is too low to be picked up by the particular viral load test being used or below an agreed threshold (such as 50 copies/ml or 200 copies/ml). An undetectable viral load is the first goal of antiretroviral therapy.

viral load

Measurement of the amount of virus in a blood sample, reported as number of HIV RNA copies per milliliter of blood plasma. Viral load is an important indicator of HIV progression and of how well treatment is working. 

 

non-nucleoside reverse transcriptase inhibitor (NNRTI)

Non-nucleoside reverse transcriptase inhibitor, the family of antiretrovirals which includes efavirenz, nevirapine, etravirine, doravirine and rilpivirine. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to and block HIV reverse transcriptase (an HIV enzyme), preventing HIV from replicating.

randomisation

A process by which interventions are allocated to patients in a clinical trial on the basis of chance alone. This means that the characteristics of the people receiving each intervention should be similar at the start of the trial, so if there are any differences in outcomes at the end of the trial, it can be assumed that these are due to the intervention itself. 

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

Doravirine is also being investigated as a switch option for people with undetectable viral load. In the DRIVE-SHIFT study, 90% of participants randomised to switch to the fixed-dose combination of Delstrigo maintained an undetectable viral load compared to 94% of participants who continued treatment with a three-drug combination containing two NRTIs. (Kumar)

Common side-effects of doravirine include abnormal dreams, difficulty in sleeping, nightmare, depression, headache, dizziness, drowsiness, nausea, diarrhoea, abdominal pain, vomiting, rash, tiredness.

You should not take doravirine if you are currently taking the following medicines:

  • carbamazepine, oxcarbazepine, phenobarbital, phenytoin (drugs used to treat epilepsy and seizures)
  • rifampicin, rifapentine (treatment for tuberculosis)
  • St John's wort (Hypericum perforatum) (a herbal remedy used for depression and anxiety)
  • mitotane (a cancer treatment)
  • enzalutamide (a treatment for prostate cancer)
  • lumacaftor (treatment for cystic fibrosis).

Doravirine is not recommended for use by pregnant women due to lack of evidence on its effects during pregnancy.

Doravirine retains its activity against viruses with the most common NNRTI-associated resistance mutations (K103N, Y181C). (Feng)

References

Molina JM et al. 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. The Lancet HIV, 5: e211-e220, 2018.

Squires KE et al. Fixed-dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naive adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study. 9th IAS Conference on HIV Science, Paris, abstract TUAB0104LB, July 23-26, 2017.

Kumar P et al. Switch to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains virologic suppression through 48 weeks: results of the DRIVE-SHIFT trial. ID Week 2018, San Francisco, abstract LB-2, 3-7 October 2018.

Feng M et al. Doravirine suppresses common nonnucleoside reverse transcriptase inhibitor-associated mutants at clinically relevant concentrations. Antimicrobial Agents and Chemotherapy, 60: 2241-7, 2016.