- Category: Experimental HCV Drugs
- Published on Saturday, 18 February 2017 00:00
- Written by Liz Highleyman
AbbVie's investigational glecaprevir/pibrentasvir treatment for hepatitis C is not expected to interact with or require dose adjustment when taken with commonly used antiretroviral regimens, offering a new option for HIV/HCV coinfected people, according to a study presented at the Conference on Retroviruses and Opportunistic Infections this month in Seattle.
An estimated 25% to 30% of people living with HIV are coinfected with hepatitis C virus (HCV). The advent of direct-acting antivirals (DAAs) used in interferon-free regimens has made hepatitis C treatment simpler, shorter, and much more effective. Although considered a "hard-to-treat" population in the interferon era, HIV/HCV coinfected people respond to DAAs as well as people with HCV alone. Current hepatitis C guidelines recommend that HCV/HIV coinfected patients should be treated the same as HCV monoinfected patients, taking into accountpotential interactions with antiretroviral drugs.
Matthew Kosloski and colleagues from AbbVie presented findings from a Phase 1 drug-drug interaction study assessing the pharmacokinetics, tolerability, and safety of co-administering glecaprevir and pibrentasvir with the widely used antiretroviral regimens elvitegravir/cobicistat/tenofovir alafenamide [TAF]/emtricitabine (Genvoya coformulation) and dolutegravir/abacavir/lamivudine (Triumeq coformulation), both of which are recommended first-line regimens in U.S. and European HIV treatment guidelines.
The HCV protease inhibitor glecaprevir (formerly ABT-493) and NS5A inhibitor pibrentasvir (formerly ABT-530) were shown to be a safe and highly effective treatment for all HCV genotypes. As reported at the recent AASLD Liver Meeting, glecaprevir/pibrentasvir cured 98%-99% of treatment-naive and treatment-experienced people without liver cirrhosis -- including coinfected patients -- in the Phase 3 ENDURANCE trials. AbbVie requested U.S. Food and Drug Administration approval of glecaprevir/pibrentasvir in December, with a decision expected in June.
Glecaprevir and pibrentasvirare minimally metabolized or eliminated by the kidneys and were shown in earlier studies to not have clinically significant drug-drug interactions with the NNRTI rilpivirine (Edurant) or the integrase inhibitor raltegravir (Isentress), the researchers noted as background.
This multiple-dose study enrolled 48 healthy adult volunteers with neither HIV nor HCV. About 95% were men (women of childbearing potential were excluded), around half were black and half white, and the average are was approximately 35 years.
Participants received 300 mg glecaprevir plus 120 mg pibrentasvir once-daily with elvitegravir/cobicistat/TAF/emtricitabine (150/150/10/200 mg) or dolutegravir/abacavir/lamivudine (50/600/300 mg), either alone or in combination.
The researchers performed pharmacokinetic assessments for all drugs on multiple days, and looked at the effects of glecaprevir and pibrentasvir on the pharmacokinetics of the antiretroviral drugs, and vice versa. Safety was evaluated based on adverse events, vital signs, physical exams, electrocardiograms, and laboratory tests.
- Glecaprevir and pibrentasvir increased elvitegravir and cobicistat peak (Cmax), total (AUC24), and 24-hour post-dose (C24) concentrations by 29% to 72%, but did not affect tenofovir or emtricitabine levels.
- When taken with elvitegravir/cobicistat/TAF/emtricitabine, glecaprevir peak, total, and 24-hour concentrations increased by 2.5-, 3.1-, and 4.6-fold, while pibrentasvir total and 24-hour concentrations rose by 57% and 89%.
- Glecaprevir and pibrentasvir increased the abacavir 24-hour concentration by 31%, but otherwise had no notable effect on dolutegravir, abacavir, or lamivudine exposures.
- When taken with dolutegravir/abacavir/lamivudine, glecaprevir and pibrentasvir peak and total concentrations were 25% to 28% lower.
- One person taking glecaprevir and pibrentasvir with elvitegravir/cobicistat/TAF/emtricitabine stopped the study early due to an adverse event (decreased neutrophil count).
- No other clinically significant adverse events and no clinically significant changes in vital signs or laboratory measurements were observed.
Based on label recommendations for interactions with other well-characterized drugs, the changes in elvitegravir, cobicistat, emtricitabine, and tenofovir levels when administered with glecaprevir and pibrentasvirwere not considered clinically significant.
Based on analysis of Phase 3 data, the higher glecaprevir levels when administered with elvitegravir/cobicistat/TAF/emtricitabinewere not expected to significantly affect the safety profile of the glecaprevir/pibrentasvircombination. Conversely, lower levels of glecaprevir and pibrentasvirwhen administered with dolutegravir/abacavir/lamivudinewere not expected to significantly reduce its efficacy.
"No dose adjustment is required when the glecaprevir/pibrentasvircombination is co-administered with elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide, abacavir, dolutegravir, or lamivudine," the researchers concluded.
In clinical trials to date, the small number of HIV/HCV coinfected patients treated with glecaprevir/pibrentasvirhad a cure rate similar to that of people with HCV alone, with no notable safety issues. An ongoing study is evaluating glecaprevir/pibrentasvirin a larger coinfected population, including people with compensated cirrhosis.
MP Kosloski, S Dutta, RM Viani, et al. Glecaprevir and pibrentasvir interactions with combination antiretroviral regimens. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 413.