On August 30, 2018, the FDA approved Merck’s doravirine (Pifeltro) a non-nucleoside reverse transcriptase inhibitor and doravirine/lamivudine/tenofovir (Delstrigo) a once-daily single tablet regimen for the treatment of HIV-1 infection in appropriate patients.
 
“As part of Merck’s 30-year commitment to the care of people with HIV, we are pleased to now bring forward these two new antiretroviral treatment options, Delstrigo and Pifeltro, which we believe offer a compelling clinical profile for clinicians and people living with HIV,” Dr. George Hanna, vice president and therapeutic area head of infectious diseases, Global Clinical Development, said in a press release.
 
Mechanisms of Action
Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 that inhibits viral replication by non-competitive inhibition of HIV-1 reverse transcriptase. Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ.
 
Delstrigo is a single tablet regimen that contains lamivudine and tenofovir disoproxil fumarate (TDF), in addition to doravirine. Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP).
 
The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Lamivudine triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
 
TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate.
 
Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
 
Dosage and Administration
The recommended dosage regimen of doravirine in adults in a 100 mg tablet taken orally once daily with or without food in combination with other antiretroviral agents.
 
Doravirine/lamivudine/tenofovir is a fixed-dose combination product containing 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of TDF. The recommended dosage in adults is a single tablet taken orally once daily with or without food.

Clinical Studies
In the DRIVE-FORWARD clinical trial, 766 treatment naïve patients were randomized tp receive at least 1 dose of either doravirine once daily or darunavir 800 mg plus ritonavir 100 mg once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine selected by the investigator.
 
Doravirine demonstrated sustained vital suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared with darunavir plus ritonavir, each in combination with emtricitabine/tenofovir disoproxil or abacavir/lamivudine (84% in the doravirine group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 80% in the darunavir plus ritonavir group).
 
Additionally, at week 48, doravirine-treated patients demonstrated statistically significant superior lipid profile as measured by changes from baseline in low-density lipoprotein (LDL)-cholesterol and non-high-density lipoprotein (HDL) cholesterol (LDL-C: -4.6 mg/dL in the doravirine group versus 9.5 mg/dL in the darunavir plus ritonavir group, treatment different: -14.4 mg/mL; non-HDL-C: -5.4 mg/d: in the doravirine group versus 13.7 mg/dL in the darunavir plus ritonavir group, treatment difference: -19.4 mg/dL). However, the clinical benefit of these findings has not been demonstrated.
 
In the DRIVE-AHEAD clinical trial, 728 treatment naïve patients were randomized and received at least 1 dose of either doravirine/lamivudine/tenofovir or efavirenz/emtricitabine/TDF once daily. Doravirine/lamivudine/tenofovir demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared with efavirenz/emtricitabine/TDF (84% in the doravirine/lamivudine/tenofovir group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 81% in the efavirenz/emtricitabine/TDF group).
 
At week 48, doravirine/lamivudine/tenofovir-treated patients demonstrated statistically significant superior lipid profiles as measured by changes from baseline in LDL-cholesterol and non-HDL cholesterol (LDL-C: -2.1 mg/dL in the doravirine/lamivudine/tenofovir group vs. 8.3 mg/dL in the EFV/FTC/TDF group; treatment difference: -10.2 mg/dL, non-HDL-C: -4.1 mg/dL in the doravirine/lamivudine/tenofovir group vs. 12.7 mg/dL in EFV/FTC/TDF; treatment difference: -16.9 mg/dL).
 
However, the clinical benefit of these findings has not been demonstrated. Additionally, a statistically significant lower proportion of doravirine/lamivudine/tenofovir-treated patients compared with efavirenz/emtricitabine/TDF-treated participants reported neuropsychiatric adverse events in the 3 prespecified categories of dizziness, sleep disorders and disturbances, and altered sensorium.
 
Warnings and Precautions
Doravirine/lamivudine/tenofovir carries a black box warning for posttreatment acute exacerbation of hepatitis B virus (HBV). Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and have discontinued lamivudine or TDF, which are components of doravirine/lamivudine/tenofovir.
 
Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and who discontinued doravirine/lamivudine/tenofovir. If appropriate, initiation of anti-HBV therapy may be warranted.
 
Prior to initiating doravirine/lamivudine/tenofovir, and during treatment with it, serum creatinine, estimated creatinine clearance, urine glucose, and urine protein should be assessed on a clinically appropriate schedule. Avoid administering doravirine/lamivudine/tenofovir with concurrent or recent use of nephrotoxic drugs.
 
Bone mineral density in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss should be monitored.
 
Regarding doravirine/lamivudine/tenofovir and doravirine, immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (ART). During the initial phase of combination ART, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment.
 
Autoimmune disorders have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
 
Contraindications
Doravirine and doravirine/lamivudine/tenofovir are contraindicated when co-administered with drugs that are strong cytochrome P450 CYP 3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the efficacy of doravirine and doravirine/lamivudine/tenofovir.
 
Doravirine/lamivudine/tenofovir is contraindicated in patients with a previous hypersensitivity to lamivudine.
 
Drug Interaction Studies
Co-administration of doravirine or doravirine/lamivudine/tenofovir with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce the efficacy of doravirine. Co-administration of doravirine or doravirine/lamivudine/tenofovir and drugs that are inhibitors of CYP3A may result in increased plasma concentrations.
 
No clinically significant changes in concentrations of doravirine or doravirine/lamivudine/tenofovir were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam.
 
Because doravirine/lamivudine/tenofovir is a complete regimen, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended.
 
Use in Specific Populations
Pregnancy
No adequate human data are available to establish whether doravirine or doravirine/lamivudine/tenofovir poses a risk to pregnancy outcome. There is a pregnancy exposure registry that monitors outcomes in individuals exposed to doravirine or doravirine/lamivudine/tenofovir during pregnancy. Health care providers are encouraged to register their patients by calling the Antiretroviral Pregnancy Registry.
 
Lactation
The CDC recommends that HIV-1 infected mothers in the United States not breastfeed their infants to avoid the risk of potential transmission of HIV-1 infection.
 
Pediatric Use
The safety and efficacy of doravirine and doravirine/lamivudine/tenofovir have not been established in pediatric patients less than 18 years of age.
 
Geriatric Use
Clinical trials of doravirine or doravirine/lamivudine/tenofovir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
 
Renal Impairment
No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine/lamivudine/tenofovir has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients.
 
Doravirine/lamivudine/tenofovir is not recommended in patients with estimated creatinine clearance less than 50 mL/min.
 
Hepatic Impairment
No dosage adjustments of doravirine or doravirine/lamivudine/tenofovir is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Neither doravirine nor doravirine/lamivudine/tenofovir have been studied in patients with severe hepatic impairment (Child-Pugh Class C).
 
Adverse Events
In the DRIVE-AHEAD clinical trial, the rate of discontinuation of treatment due to adverse events was lower in the doravirine/lamivudine/tenofovir treatment group than in the efavirenz/emtricitabine/TDF treatment group (3% and 6%, respectively). Clinical adverse reactions of all grades occurring in greater than or equal to 5% of participants in the doravirine/lamivudine/tenofovir treatment group included dizziness (7%), nausea (5%) and abnormal dreams (5%).
 
In the DRIVE-FORWARD clinical trial, the rate of discontinuation of therapy due to adverse events in either treatment group was low (2% in the doravirine group and 3% in the darunavir plus ritonavir group). Clinical adverse reactions of all grades occurring in greater than or equal to 5% of participants in the doravirine treatment group included nausea (7%), headache (6%), fatigue (6%), diarrhea (5%) and abdominal pain (5%).
 
Storage and Handling
Store doravirine and doravirine/lamivudine/tenofovir in their original bottles. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant.
 
Store doravirine and doravirine/lamivudine/tenofovir at 20OC to 25OC (68OF to 77 OF); excursions permitted to 15OC to 30OC (59OF to 86 OF).
 
About the Author
Christa Eans earned her Bachelor of Science in Pharmaceutical Sciences and Doctor of Pharmacy degrees from the University of Pittsburgh. She most recently earned her Master of Science in Pharmacy Business Administration (MSPBA) at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines. Christa has spent the last 5 years working in Specialty Pharmacy, initially as a clinical pharmacist and most recently as the Manager of Clinical Programs. Christa is credentialed as a HIV Pharmacist (AAHIVP) through the American Academy of HIV Medicine and a Certified Specialty Pharmacist through the Specialty Pharmacy Certification Board.