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

Review of Clinical Evidences

Interactions of DAA With Opioids

The DDI between DCV and methadone, and the association buprenorphine-naloxone was assessed in a PK study including 25 subjects on stable OST (14 on methadone, 11 on buprenorphine/naloxone). This study showed no clinically relevant effect of DCV on methadone PK, whereas a raise in buprenorphine and norbuprenorphine exposure was observed (buprenorphine: AUC and Cmax increased by 30%-40%). However, these increases were not considered to be clinically significant by the authors. None of the opioid had an impact on DCV PK as compared to historical data in healthy volunteers.[80]

The DDI between elbasvir/grazoprevir and buprenorphine/naloxone has been assessed in two PK studies, one in healthy volunteers (13 subjects), and one in patients on stable buprenorphine/naloxone OST (12 subjects). Elbasvir/grazoprevir did not significantly affect the PK of buprenorphine, norbuprenorphine or naloxone. Similarly, the OST had no impact on the PK profiles of EBR and GZR.[81]

The DDI between glecaprevir/pibrentasvir and methadone or buprenorphine/naloxone has been assessed in a PK study in 23 subjects on stable OST (11 on methadone, 12 on buprenorphine/naloxone). No significant impact of glecaprevir/pibrentasvir on methadone and buprenorphine/naloxone PK was observed. The exposures of glecaprevir and pibrentasvir when administered with methadone or with buprenorphine-naloxone were marginally lower than those observed in other studies of glecaprevir and pibrentasvir administered alone in healthy subjects, which could be explained by the reduced rate of gastric emptying induced by opioids, decreasing the absorption of glecaprevir and pibrentasvir. However, these changes in the PK of glecaprevir and pibrentasvir were not considered as clinically significant.[82]

The lack of clinically relevant DDI between glecaprevir/pibrentasvir and OST has been recently confirmed based on data from eight international phase 2 and 3 trials of glecaprevir/pibrentasvir. Among 2256 enrolled patients, 157 patients (7%) were on OST, with 76% receiving methadone. With similar adherence frequencies between OST and non-OST patients (98% and 99% respectively), the SVR 12 rates were high in both groups (96.2% in OST vs 97.9% in non-OST patients). The safety profile was comparable, with a modestly higher percentage of patients on OST experiencing AE considered as possibly related to the study drugs (48% vs 40%).[83]

We did not find published PK studies on DDI between opioids and sofosbuvir-based combination. The lack of effect of sofosbuvir on methadone PK was already reported in the EMA reports of Sovaldi®.[84] The risk of a clinically relevant DDI with the addition of voxilaprevir is low.[34] In a pooled analysis of phase 3 studies, 194 patients (4%) were on OST (113 on methadone, 75 on buprenorphine): the SVR 12 rates were high in both groups (94% in OST vs 97% in non-OST patients). The rates of AE were similar in both groups (78% vs 77%). These results suggest that sofosbuvir-based therapies are effective and safe in patients receiving OST.[85] A Canadian cohort study that enrolled 5283 eligible PWSUD treated by sofosbuvir/ledipasvir (n finally treated = 3413) or sofosbuvir/velpatasvir (n treated = 1574) showed that patients with injection drug use (IDU) were less likely to achieve SVR as compared to other groups without IDU (adjusted odds ratio: 1.91 in patients not on OST, and 1.50 in patients on OST). The lower observed SVR among PWID was related to higher loss to follow-up, with a part of this loss related to deaths from drug overdose, rather than detrimental interactions between DAA and OST and/or drugs of abuse.[86] Another cohort study compared the efficacy of DAA (sofosbuvir-based therapy as well as paritaprevir-ritonavir/ombitasvir ± dasabuvir and elbasvir/grazoprevir) in patients with or without a history of injecting drug use: among the 1752 patients enrolled, 47% reported no history of injecting drug use and 53% were PWID, with 42% not on OST and 11% on OST (mainly methadone). This study confirmed that the SVR rates were lower among PWID (92% in PWID not on OST, 89% in PWID on OST) compared to patients without a history of injecting drug use (95%). This observation was mainly attributable to higher rates of discontinuations after the occurence of AEs and, especially, loss to follow-up in PWID, and not to virologic failure.[87] The likelihood of potential interactions issues is not plausible.

Interactions of DAA With Stimulants

No detrimental outcome associated with potential interactions of DAA with stimulants was reported. Based on their respective metabolism and clearance, a clinically significant interaction is unlikely (see the website

Interactions of DAA With Ethanol

High-risk alcohol consumption was recognized as a factor associated with lower adherence to antiviral treatment and increased propensity of failure with former interferon and ribavirin treatment.[88] Few comparable data are available with the DAA.[89] Some authors suggested that alcohol consumption may be a risk factor in a lower response to DAA, through different mechanisms: decreased susceptibility of viruses to DAA and decreased immune response to eliminate remaining viruses.[90]

A study compared the SVR of 15 151 veterans treated with DAA according to alcohol consumption. The DAAs were as follows: sofosbuvir, ledipasvir/sofosbuvir or ombitasvir-paritaprevir-ritonavir and dasabuvir. Most patients were abstinent (10 387, 69%), while 3422 (23%) had low alcohol consumption, and 1342 (9%) had high-risk drinking. The proportion of patients with SVR was comparable between the three groups: 91.9% (95% CI: 91.3–92.5) vs 93.2 (95% CI: 92.2–94.1) vs 91.4% (95% CI: 89.5–92.9). These results suggested that the response to DAA remained regardless the level of alcohol use.[91]

A German registry study assessed the impact of alcohol and cannabis consumption on the efficacy of DAA (sofosbuvir-based therapy and paritaprevir-ritonavir/ombitasvir ± dasabuvir). Among the 7747 enrolled patients, 1015 reported alcohol consumption, and 631 of them were not on OST and did not use injected drugs. In these non-OST non-IDU patients with high alcohol consumption, the SVR rates were lower (85%) than in patients consuming no or less than 30 g/day (women) or 40 g/day (men) (91%-92%). Regarding cannabis consumption, SVR rates did not differ between the different patient groups.[92]