Pifeltro and Delstrigo: New Options for HIV-1

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.
 


Stay up to date on the latest news in specialty pharmacy by getting Specialty Pharmacy Times in your mailbox or inbox for free!

Click here to sign up for free for the bi-monthly Specialty Pharmacy Times print journal delivered to your address.

Click here to sign up for our email newsletters delivered every Monday, Wednesday, and Friday, in addition to breaking news alerts.

Click here to follow us on Facebook. 

Click here to follow us on Twitter. 

Click here to join our LinkedIn group. 


Related Articles

The new indication would allow treatment-experienced patients with HIV to switch to Pifeltro in combination with other HIV medications or Delstrigo.
Clinical trial data show results from switching to Delstrigo from other antiretroviral treatments for HIV.
The approvals of Delstrigo and Pifeltro are based on findings from 2 phase 3 clinical trials.
Company Profile >
Industry Guide >
Market News >
Peer Exchange >
Conferences >
Subscribe >
Specialty Times Resources
About Us
Advertise
Careers
Contact Us
Terms & Conditions
Privacy
MJH Associates >
Pharmacy Times
OTCGuide
American Journal of Managed Care
Cure
MD Magazine
ONCLive
Targeted Oncology
Physicians' Education Resource
Pharmacy & Healthcare Communications, LLC
2 Clarke Drive
Suite 100
Cranbury, NJ 08512
P: 609-716-7777
F: 609-716-4747

Copyright Specialty Pharmacy Times 2006-2018
Pharmacy & Healthcare Communications, LLC. All Rights Reserved.
 

$vacMongoViewPlus$