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.

Conclusion

The HCV prevalence is significantly elevated in detainees, patients with severe mental illness and PWID. Marginalized populations represent key clusters and reservoir with high dynamic interindividual BBV transmission. These populations further consume a wide range of medications and illicit drugs. Efficacy and safety are paramount during the prescription of DAA. Based on our literature review with PK and PD consideration, the interaction potential of DAA with most opioids and illicit drugs appears rather marginal. Taken together, most DAA mainly inhibit the transmembrane transporter P-gp and to a lesser extent the metabolizing enzyme subfamily CYP3A. Although, theoretically, interactions are plausible with opioids including methadone, these were not confirmed in PK studies. Large phase 3 and cohort studies did not show any clinically significant SVR decrease in PWID taking DAA.

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Abbreviations
4-MMC, 4-methyl-N-methylcathinone; 6-AM, 6-acetylmorphine; Ab, antibody; ADH, alcohol dehydrogenase; AE, adverse event; AUC, area under the curve; AZCERT, Arizona Education and Research on Therapeutics; BBV, blood-borne viral; BCRP, breast cancer resistance protein; CBD, cannabidiol; C_max, maximal concentrations; CYP450, cytochrome P450; DAA, direct-acting antiviral; DCV, daclatasvir; EBR, elbasvir; GZR, grazoprevir; HBV, hepatitis B virus; hCE, human carboxylesterase; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, injection drug use; M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronide; MDMA, 3,4-methylenedioxymethamphetamine; non-IV, non-intravenous; NS, non-structural; OATP, organic-anion-transporting polypeptide; OR, odds ratio; OST, opioid substitution therapy; OUD, opioid use disorder; PD, pharmacodynamics; P-gp, P-glycoprotein; PK, pharmacokinetic; PWID, people who inject drugs; PWSUD, people with substance use disorder; QALY, quality-adjusted life-year; SVR, sustained virologic response; TdP, torsades de pointes; UGT, uridine glucuronosyltransferase; Δ9-THC, delta-9-tetrahydrocannabinol.

Acknowledgements
None.

Table 1. Available drugs and fixed-dose combinations according to the EASL 2018 recommendations ⁶
Drug or fixed-dose combinations	Brand name	Recommended dose	Comment
Daclatasvir	Daklinza®	60 mg qd	In combination with other drugs
Elbasvir/grazoprevir	Zepatier®	50/100 mg qd
Glecaprevir/pibrentasvir	Maviret®	100/40 mg qd
Sofosbuvir	Sovaldi®	400 mg qd	In combination with other drugs
Sofosbuvir/ledipasvir	Harvoni®	400/90 mg qd
Sofosbuvir/velpatasvir	Epclusa®	400/100 mg qd
Sofosbuvir/velpatasvir/voxilaprevir	Vosevi®	400/100/100 mg qd

Note: bid: twice daily; qd: once daily.

Table 2. Main PK and PD characteristics of DAA
Drug	Metabolism and transport	Elimination	CYP/transporter inhibition or induction	Main adverse effects	References
NS5A inhibitors
Daclatasvir	CYP3A, P-gp	Faeces	P-gp, OATP1B1, BCRP inhibition	Headache, nausea, diarrhoea, arthralgia and cough	14
Elbasvir	CYP3A, P-gp	Faeces	P-gp, BCRP inhibition	Fatigue, headache, nausea	17,18
Ledipasvir	P-gp, BCRP	Faeces	P-gp, BCRP inhibition	Headache, fatigue, insomnia, nausea, diarrhoea	23,24
Pibrentasvir	No metabolism, P-gp (BCRP)	Faeces	CYP3A, UGT1A1, P-gp, BCRP, OATP1B1 and OATP1B3 inhibition	Headache, fatigue, nausea	19,20
Velpatasvir	Minor metabolism by CYP2B6, CYP2C8 and CYP3A4, P-gp, BCRP	Faeces	P-gp, BCRP, OATP1B1, OATP1B3, OATP2B1 inhibition	Headache, fatigue	29,30
NS5B inhibitors
Sofosbuvir	P-gp, BCRP	Urine (GS-331007)	—	Headache, fatigue, insomnia, nausea, diarrhoea	23,24
Protease inhibitors
Glecaprevir	CYP3A, P-gp, BCRP, OATP1B1 and OATP1B3	Faeces	CYP3A, UGT1A1, P-gp, BCRP, OATP1B1 and OATP1B3 inhibition	Headache, fatigue, nausea	19,20
Grazoprevir	CYP3A, P-gp, OATP1B1 and OATP1B3	Faeces	CYP3A, BCRP inhibition	Fatigue, headache, nausea	17,18
Voxilaprevir	CYP3A, P-gp, BCRP, OATP1B1 and OATP1B3	Faeces	P-gp, OATP1B1 and OATP1B3 inhibition	Headache, fatigue, diarrhoea, nausea	33,34

Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome; DAA, direct-acting antiviral; PD, pharmacodynamic; Pk, pharmacokinetic.

Table 3. Main PK and PD characteristics of substances of abuse
Drug	Metabolism and transport	Elimination	CYP/transporter inhibition or induction	Main adverse effects	References
Opioids
Buprenorphine	CYP3A, CYP2C8, UGT2B7, UGT1A1, UGT1A3	Faeces	—	Tolerance, dependence, cognitive effects, sedation, delirium, constipation, vertigo, nausea, respiratory depression	41,45 46,47
Fentanyl	CYP3A, P-gp	Urine	—	As for buprenorphine	41,43 46,47
Heroin	hCE then as morphine		—	As for buprenorphine	43 46,47
Methadone	CYP2B6, P-gp	Faeces and urine	CYP2D6, P-gp inhibition	As for buprenorphine, and QT prolongation, TdP	39,41,44,45 46,47
Morphine	UGT2B7, UGT1A1, UGT1A3, UGT1A9, CYP3A, CYP2C8, P-gp	Urine	—	As for buprenorphine	41,43,45,106 46,47
Oxycodone	CYP3A, CYP2D6	Urine	—	As for buprenorphine	41,45 46,47
Stimulants
Amphetamine and methamphetamine	CYP2D6, CYP2C	Urine	—	Anorexia, insomnia, nausea, vomiting, increases in blood pressure and heart rate	49,52,53
MDMA	CYP2D6 CYP1A2, CYP2B6, CYP3A	Urine	CYP2D6 inhibition	Perceptual disturbances, increases in blood pressure and heart rate, mydriasis, derealization, panic attacks, delirium	54
Cathinones	CYP2D6	Urine	CYP2D6 inhibition	Tachycardia, hypertension, agitation, hallucinations confusion, creatine kinase elevation	50,56,57
Cocaine	hCE	Urine	—		40,59
Various
Cannabinoids	CYP2C9, CYP3A4	Faeces (65%-80%) and urine (20%-35%)	CYP450, P-gp inhibition (probably minor)	Asthenia, balance problems, confusion, dizziness, dry mouth, fatigue, hallucinations, nausea, vomiting, drowsiness	40,64,66–68
Ethanol	ADH, CYP2E1, CYP2A1, CYP3A4	Urine, sweat, saliva, tears, expired air	CYP450, P-gp induction?	Depressive effect on the central nervous system: anxiolytic effect, disinhibition of behaviour, sedation, respiratory depression	73–75

Abbreviations: CYP, cytochrome; PD, pharmacodynamics; Pk, pharmacokinetic.

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

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