Glecaprevir/pibrentasvir for hepatitis C can be safely administered with common antiretrovirals

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 people with HIV/hepatitis C virus (HCV) co-infection, according to a study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last month in Seattle.

An estimated 25 to 30% of people living with HIV have HCV co-infection. 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, people with HIV/HCV co-infection respond to DAAs as well as people with HCV alone. Current hepatitis C guidelines recommend that people with HIV/HCV co-infection should be treated the same as people with HCV mono-infection, taking into account potential interactions with antiretroviral drugs.

Matthew Kosloski and colleagues of 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) and dolutegravir/abacavir/lamivudine (Triumeq), both of which are recommended first-line regimens in European and US HIV treatment guidelines.

Glossary

drug interaction

When a person is taking more than one drug, and drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

pharmacokinetics (PK)

How drugs are processed and used in the body, including how they are absorbed, metabolised, distributed and eliminated.

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

compensated cirrhosis

The earlier stage of cirrhosis, during which the liver is damaged but still able to perform most of its functions. 

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 people with co-infection – in the phase 3 ENDURANCE trials. AbbVie requested US Food and Drug Administration approval of glecaprevir/pibrentasvir in December, with a decision expected in June, and it is under accelerated assessment by the European Medicines Agency.

Glecaprevir and pibrentasvir are minimally metabolised or eliminated by the kidneys and were shown in earlier studies to not have clinically significant drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor (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 300mg glecaprevir plus 120mg pibrentasvir once-daily with elvitegravir/cobicistat/TAF/emtricitabine (150/150/10/200mg) or dolutegravir/abacavir/lamivudine (50/600/300mg), 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-characterised drugs, the changes in elvitegravir, cobicistat, emtricitabine and tenofovir levels when administered with glecaprevir and pibrentasvir were not considered clinically significant.

Based on analysis of phase 3 data, the higher glecaprevir levels when administered with elvitegravir/cobicistat/TAF/emtricitabine were not expected to significantly affect the safety profile of the glecaprevir/pibrentasvir combination. Conversely, lower levels of glecaprevir and pibrentasvir when administered with dolutegravir/abacavir/lamivudine were not expected to significantly reduce its efficacy.

"No dose adjustment is required when the glecaprevir/pibrentasvir combination 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 people with HIV/HCV co-infection treated with glecaprevir/pibrentasvir had a cure rate similar to that of people with HCV alone, with no notable safety issues. An ongoing study is evaluating glecaprevir/pibrentasvir in a larger co-infected population, including people with compensated cirrhosis.

References

Kosloski MP et al. Glecaprevir and pibrentasvir interactions with combination antiretroviral regimens. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 413, 2017.

View the abstract on the conference website.

Download this poster from the conference website.