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Doravirine (Pifeltro)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Potential Adverse Effects
Interactions with Other Drugs
Resistance
References
Related Resources
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decorative spacerDoravirine
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Class

Nonnucleoside reverse transcriptase inhibitor

Background
U.S. Manufacturer

Merck Sharp & Dohme Corporation

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Approval

Doravirine was granted approval by the U.S. Food and Drug Administration (FDA) in August 2018 for adults with HIV-1 infection. It is intended for use in initial therapy, in combination with other antiretroviral agents. Approval was based on 48-week results of 2 Phase III studies showing that previously untreated individuals who received doravirine + 2 nucleoside/nucleotide analogues (NRTIs) had rates of viral suppression that were similar to those of individuals who received either efavirenz + 2 NRTIs or darunavir + 2 NRTIs.(1,2)

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Formulation and Dosing

Doravirine is available in a tablet formulation. Doravirine also is available in a single-pill combination with tenofovir disoproxil fumarate and lamivudine (Delstrigo).

Dosing of Doravirine
Adult100 mg once daily
PediatricNot FDA approved
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decorative spacerdecorative itemDoravirine may be taken with or without food.
decorative spacerdecorative itemDoravirine interacts with a number of other medications; see "Database of Antiretroviral Drug Interactions" for information on recommendations for management of the interactions of doravirine with other medications.
decorative spacerdecorative itemNo dosage adjustment is necessary in renal insufficiency.
decorative spacerdecorative itemNo dosage adjustment is necessary in Child-Pugh Class A or B liver disease. Doravirine has not been studied in persons with Child-Pugh Class C hepatic impairment.
decorative spacerdecorative itemDoravirine has not been studied in pregnant or breastfeeding women.
decorative spacerdecorative itemPlease consult product labeling for detailed dosing information.

Clinical Use
Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate both doravirine/TDF/emtricitabine and doravirine + tenofovir alafenamide (TAF)/emtricitabine as "recommended initial regimens in certain clinical situations."

Doravirine has been studied in antiretroviral-naive adults in 2 Phase III randomized double-blind studies. In the first of these, called DRIVE-FORWARD, 769 patients (84% male) received either doravirine (100 mg once daily) or darunavir (800 mg once daily) + ritonavir (100 mg once daily), each in combination with 2 NRTIs (either abacavir/lamivudine [13%)] or tenofovir DF/emtricitabine [87%], as selected by investigators). After 48 weeks of treatment, by FDA snapshot analysis, HIV suppression to <50 copies/mL was seen in 84% of doravirine recipients and 80% of darunavir recipients; the difference was not statistically significant.(1) For patients whose baseline HIV RNA was ≥100,000 copies/mL or whose CD4 count was <200 cells/µL, rates of HIV RNA suppression to <50 copies/mL were lower but they were not significantly different in the two treatment groups: (for the HIV RNA ≥100,000 group, viral suppression was seen in 81% of doravirine recipients and 76% of darunavir recipients; for the CD4 <200 cells/µL group, viral suppression rates were 83% vs 72%). Mean CD4 cell count increases in the two treatment groups were 193 cells/µL and 186 cells/µL, respectively. At 96 weeks, by FDA snapshot analysis, 73% of the doravirine group and 66% of the darunavir group had HIV RNA <50 copies/mL.(3)

In the second Phase III study, called DRIVE-AHEAD, 728 patients were randomized to one of two single-pill coformulations, either doravirine/tenofovir DF/lamivudine or efavirenz/tenofovir DF/emtricitabine. At 48 weeks, by FDA snapshot approach, HIV RNA was <50 copies/mL in 84% of the doravirine group and 81% of the efavirenz group; the difference was not statistically significant. Mean CD4 count increases were 198 cells/µL in the doravirine group and 188 cells/µL in the efavirenz group.(2)

Doravirine has not been studied in treatment-experienced patients with a history of virologic failure.

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Potential Adverse Effects

Symptomatic side effects of doravirine include headache, nausea, diarrhea, and rash. In clinical studies to date, rash typically was not serious and usually resolved without discontinuation of doravirine.

Laboratory abnormalities include elevations in hepatic transaminases and total bilirubin. Modest declines in total cholesterol, LDL cholesterol, and triglycerides were seen in the Phase III studies.

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with doravirine is initiated.

Doravirine has not been studied in pregnant women.

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Interactions with Other Drugs

Doravirine is metabolized by hepatic cytochrome P450 3A, and drugs that induce or inhibit the action of this isoenzyme may alter serum doravirine levels. In some cases, these interactions may be therapeutically significant. For example, inducers of cytochrome P450 3A such as rifampin and rifapentine, certain anticonvulsants (eg, carbamazepine and phenytoin), and St. John's wort may substantially decrease doravirine concentrations and should not be given to persons who take doravirine. Rifabutin may be given concurrently if the doravirine dosage is increased (to 100 mg twice daily) to compensate for the drug-drug interaction.(4) Cytochrome P450 3A inhibitors such as ritonavir and ketoconazole may increase doravirine levels, but dosage adjustment is not recommended.(4)

Adequate pharmacokinetic data and clinical correlates are not yet available for many potential interactions. Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

For additional information, see "Database of Antiretroviral Drug Interactions."

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Resistance

Resistance to doravirine is associated with the selection of 1 or more resistance mutations, but the resistance profile of doravirine has not been characterized fully. In the Phase III clinical studies described above (see "Use in Initial and Subsequent Therapy"), a number of reverse transcriptase mutations emerged in the setting of doravirine failure. These include V106I, other V106 mutations (V106A/M/T), A98G, V108I, E138G/K, Y188L, H221Y, F227C/I/R, and Y318F. Phenotypic analysis showed high-level resistance to doravirine with various combinations of these mutations. In these studies of initial therapy, emergent resistance to doravirine often was accompanied by resistance mutations that affect nucleoside reverse transcriptase inhibitors.

Implications of resistance to doravirine for treatment with other antiretrovirals

Phenotypic analyses from the Phase III studies of doravirine showed that emergent resistance to doravirine (see "Resistance," above, for specific mutations) generally caused cross-resistance to efavirenz and rilpivirine; etravirine remained active against viruses with certain combinations of mutations.(5) To date, no clinical studies have evaluated the effects of doravirine resistance on virologic outcomes of second-line antiretroviral regimens.

Implications of resistance to other antiretrovirals for treatment with doravirine

Data on the effects of baseline resistance mutations on doravirine efficacy are limited. Resistance mutations selected by other NNRTIs, including any of the substitutions listed above, would be expected to contribute to doravirine resistance. In vitro studies have suggested that doravirine has activity against viruses with certain mutations selected by other NNRTIs, including the K103N and Y181C mutations, but not on viruses with Y188L or some combinations that include Y106A or E138K.(4,6) Clinical data will be needed to define the effect of resistance mutations on the activity of doravirine.

References
1.   Molina JM, Squires K, Sax PE, 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. Lancet HIV. 2018 May;5(5):e211-e220.
2.  Squires KE, Molina JM, Sax PE, 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. In: Program and abstracts of the 9th IAS Conference on HIV Science; July 23-26, 2017; Paris. Abstract TUAB0104LB.
3.  Molina JM, Squires K, P. Sax, et al. Doravirine (DOR) versus ritonavir-boosted darunavir (DRV+r): 96-week results of the randomized, double-blind, phase 3 DRIVE-FORWARD noninferiority trial. In: Program and abstracts of the 22nd International AIDS Conference; July 23-27, 2018; Amsterdam. Abstract LBPEB017.
4.  Pifeltro prescribing information. Merck Sharpe & Dhome: South San Francisco, CA.
5.  Lai MT, Xu M, Ngo W, et al. Characterization of doravirine-selected resistance patterns from participants in treatment-naive Phase 3 clinical trials. In: Program and abstracts of the 22nd International AIDS Conference; July 23-27, 2018; Amsterdam. Abstract THPDB0101.
6.   Feng M, Sachs NA, Xu M, et al. Doravirine suppresses common nonnucleoside reverse transcriptase inhibitor-associated mutants at clinically relevant concentrations. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2241-7.