Direct-acting Antiviral Interactions With Opioids, Alcohol or Illicit Drugs of Abuse in HCV-infected Patients

Kuntheavy Ing Lorenzini; François Girardin


Liver International. 2020;40(1):32-44. 

In This Article

Abstract and Introduction


The hepatitis C virus (HCV) prevalence is extremely high in patients who consume and inject illicit drugs. Concerns about poor adherence and fear of interaction with drugs of abuse could constitute further disincentive for treatment initiation in these patients. We discussed the pharmacokinetics (PKs) and pharmacodynamics (PD) of currently prescribed direct antiviral agents (NSA5 inhibitors: daclatasvir, elbasvir, ledipasvir, pibrentasvir, velpatasvir; NS5B inhibitor: sofosbuvir; NS3/4A protease inhibitors: glecaprevir, grazoprevir, voxilaprevir) and most common substances of abuse (opioids: buprenorphine, fentanyl, heroin, methadone, morphine, oxycodone; stimulants: amphetamines, cathinones, cocaine; cannabinoids; ethanol). Overall, most direct-acting antivirals (DAAs) are substrates and inhibitors of the transmembrane transporter P-glycoprotein (P-gp), and several of them are metabolized by cytochrome P450 enzymes. Clinically relevant interactions are associated with P-gp and CYP3A modulators. Most substances of abuse are eliminated by Phase I and Phase II metabolizing enzymes, but none of them are either major inhibitors or inducers. PK studies did not show any relevant interactions between DAA and methadone or buprenorphine. Based on pharmacological considerations, neither efficacy loss nor adverse drug event associated with detrimental interaction are expected with opioids, stimulants, cannabinoids and ethanol. In summary, our literature review shows that the interaction potential of DAA with most opioids and illicit drugs is limited and should not be a hurdle to the initiate DAA.


Chronic viral hepatitis C infections are a major health problem, with approximately 1.75 million new cases worldwide (2015 estimation).[1,2] The hepatitis C virus (HCV) prevalence is variable across the world: around 0.1%-1.0% in European countries, 2.0%-6.5% in Central Asia and up to 7.0% in African countries.[3] In western countries, the major source of new HCV infections remains intravenous drug use, which caused 390 000 new cases in 2015.[2] People with substance use disorders (PWSUDs) constitute the majority of incident (75%) and prevalent (80%) HCV cases in high-income regions.[4] Thus, people who inject drugs (PWID) were more frequently HCV antibody (Ab)-positive than non-intravenous (non-IV) drug users.[5]

Since 2014, the development of direct-acting antivirals (DAAs) revolutionized the management of chronic HCV infections, with higher rates of sustained virologic response (SVR) (>90%) and shortened treatment duration (8 to 12 weeks). Current available regimens consist of pangenotypic fixed-drug combinations (sofosbuvir/velpatasvir or glecaprevir/pibrentasvir), or of alternative genotype-specific regimen that includes sofosbuvir, ledipasvir, daclatasvir, grazoprevir/elbasvir and tritherapy with the fixed-dose association of sofosbuvir/velpatasvir/voxilaprevir.[6,7]

In PWSUD, the eradication of HCV could decrease the virus circulation community, reducing the infection rate.[8] However, several barriers to HCV therapy have been identified, such as high rate of psychiatric disorders (psychosis and depression),[9] poor adherence, ongoing substance use including alcohol use, lower responses to therapy, medication price and the risk of reinfection.[10] The risk of interactions of DAAs with drugs used in substance disorders, such as opioid substitution therapy (OST), as well as with illicit or recreational substances (cocaine, alcohol), can constitute a barrier to DAA access in PWSUD.

DAAs could be subject to drug-drug interactions (DDI), as they are transformed by metabolic enzymes and substrates of efflux transporters. They can also act as perpetrator of DDI if they modulate enzyme or transporter activity.[7] The evidence regarding relevant DDI with most of the potential concomitantly prescribed drugs has been recently reviewed.[7,11]