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

Kuntheavy Ing Lorenzini; François Girardin

Disclosures

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

In This Article

Discussion

The interactions between DAA and substances of abuse have been assessed in four PK phase 1 studies, all involving opioids.[80–82] Even though a wide range of phase 3 studies including DAA were performed and taken into account in the review, we did not identify any adverse outcome associated with PK/PD interactions. PK studies with opioids were performed in a limited number of healthy volunteers or patients on OST, whereas no specific PK data on ethanol and stimulants were found. Hence, our hypothesis on the lack of interaction with alcohol and amphetamine derivatives is derived from in vitro PK considerations. Clinical data involving higher numbers of patients were mainly based on post hoc and pooled analysis of phase 2 or 3 studies, whose primary endpoint was SVR.

In PWID (ie 0.34% of the total population in Western Europe), the prevalence of HCV is significantly higher (up to 50%).[93] PWID are a key cluster and reservoir because of the interindividual dynamics of HCV transmission. However, only approximately 50% of PWID in Switzerland and in other European countries were adequately screened in the past with at least one antibody test, followed by the HCV RNA quantification if tested positive for antibodies.[94]

An increased access screening program using rapid antibody saliva test and dried blood spot testing to the PWID population is likely to be highly cost-effective, since the increased uptake of DAA could achieve significant reduction in this vulnerable population. (Incremental Cost-Effectiveness Ratio per Quality-Adjusted Life-Year (QALY): USD 8337 – net monetary benefit USD 99 192 per person).[95] At a willingness-to-pay threshold approaching USD 100 000 per QALY, an increased access screening program linked to treatment scale-up with DAA is expected to have a 97.0% probability of being cost-effective compared to standard screening methods.

Treatment scale-up with DAA was identified as a requirement to achieve a significant reduction in HCV prevalence in European countries, including custodial setting as a virus reservoir.[96] Similarly to the PWID population, comprehensive screening strategies in detention centres are likely to be very worthwhile, with 82.3% probability of cost-effectiveness. Extended screening strategies in the largest custodial setting of Switzerland are expected to achieve positive HCV-RNA identification in 63% instead of 35% of detainees and 117 instead of 65 cures per year compared with current practice.[97]

Associations between blood-borne viral (BBV) diseases and severe mental illnesses were identified and more precisely documented. Before HIV (odds ratio – OR = 2.57) and HBV (OR = 2.29), HCV (OR = 6.18) appears to have the highest risk in people having severe mental illness in Sweden.[98] A systematic review and meta-analysis indicated that pooled prevalence of HCV in people with mental illness was as high as 17.4% in North America (HIV 6%; HBV 2.2%) and 5% in Europe (HIV 1.9%; HBV 2.7%).[99]

In psychiatric patients, the potential for interaction with DAA is particularly critical because of dose-dependent and life-treating AEs, such as torsades de pointes associated with long QT.[100] In psychiatric setting, drug-induced long QT patients had more prevalent HCV infection (41.9% vs 9.8%, P < .001) associated with additional T-wave abnormality frequencies (35.5% vs 15.4%, P = .003).[101] Independent predictors for long QT tend to cluster and correlate indirectly with chronic HCV infection, such as drug abuse (or uncontrolled intravenous administration), and opiate maintenance program.

This finding is likely explained by the higher number of prescribed drugs in patients with severe mental illness and HCV infection. Altered liver function is further an independent risk factor to develop repolarization abnormalities, including drug-induced long QT. Since the 1970s, patients under a methadone maintenance treatment appeared to have a lower heroin overdose mortality, lower probability of relapse, blood-borne infections (including chronic HCV infection) and criminal activities compared to those who did not receive treatment.[102] Methadone is largely prescribed as maintenance treatment in patients suffering from dependence since it is considered as the most effective opiate substitution.[103] In psychiatric patients and PWID receiving methadone in addition to psychotropic medications (antidepressants, antipsychotics), an impaired liver function (with consecutive reduced cytochromes P450 enzymatic activity) increases the likelihood of DDI and long QT interval to occur.

Moreover, methadone appears to be more effective than other opiate maintenance treatments in retaining patients in cares.

In a cohort study of 1648 patients over a 3-year period, HCV co-infection nearly doubled the propensity of QTc of 470 ms or greater in patients with HIV infection (29.6% vs 15.8%, P < .001).[104] In contrast to HIV infection, it is not known whether the HCV viral load is associated with QT interval lengthening. Further, there are associated immunological mechanisms, such as liver kidney microsomal type 1 antibodies triggered by the HCV with reduction in the CYP2D6 activity, the most significant metabolic pathway that metabolizes a wide range of antipsychotics and antidepressants.[105]

A still ongoing case-control study in the largest custodial setting in Switzerland shows a linear correlation between QT interval and methadone dose (personal communication). Initial analyses of the preliminary results suggest that methadone dose, HCV infection and patient age may have an influence that could provide further insight to envision indirect benefit of DAA, to optimize screening and medical management of vulnerable population. There is neither increased propensity of adverse drug reaction nor reported repolarization disorder (eg long QT) in detainees taking DAA.

Overall, it is reasonable to assume that treating chronic hepatitis infection with DAA does not significantly increase the risk of both PK and PD interactions. In high-risk patients such as PWIDs or patient with severe mental illness, the risk of serious drug AEs by adding DAA appears limited. It is expected that screening and treatment of chronic hepatitis C infection as early as possible before hepatic dysfunction are not only cost-effective (limited transmission and complication) but also safe even in the presence of QT interval lengthening drugs.

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