Hepatitis C treatment in patients with substance use disorder: the faster the better

Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma worldwide (1). HCV is a blood-borne infection and prevalence is particularly high in patients with a history of injective drug use or unsafe health care or sexual practices. Substance use disorder (SUD), and especially opioid misuse is a growing problem worldwide (2). This is particularly relevant in the United States (US) where opioid misuse has raised sharply in the last years (3,4), termed also opioid epidemic. SUD is associated with an increase incidence of HCV infections and reinfections and associated liver disease (2,4). Moreover, alcohol use disorder is frequent in patients with SUD (5), representing another major risk factor for chronic liver disease in this population. Patients with SUD often experience poor access to health care resulting in higher mortality (5,6). Finally, SUD is associated with psychiatric conditions and social problems such as housing instability, unemployment, and reduced access to medical care (7) which could result in a reduced access and compliance to HCV treatment.

HCV cure by treatment with direct antiviral agents (DAA) reduces liver disease progression and hepatocellular carcinoma (HCC) occurrence and overall liver-related deaths (8). DAA are all-oral regimens highly effective in obtaining viral cure (>95%) with only minor side effects (9). Little is known regarding the long-term outcomes of HCV treatment on liver disease in patients with SUD. Social vulnerability, concomitant alcohol and opioid abuse and HCV reinfection could, in theory, reduce the benefit of HCV treatment in terms of liver-related outcomes.

In the article by Park et al. recently published in Hepatology (10), the authors conducted a retrospective analysis on two large databases of patients from US to assess liver-related outcomes associated with DAA treatment in chronic HCV patients with and without SUD. Disease identification and patient selection were performed using the International Classification of Diseases (ICD) codes. Included patients had a newly diagnosed chronic HCV infection, untreated or treated with DAA, and had no recent history (1-year before the HCV diagnosis) of liver decompensation or HCC. The primary endpoint was the incidence of HCC and liver decompensation according to SUD and cirrhosis status.

Patients with SUD were younger at time of HCV diagnosis and more likely to have alcoholic liver disease (ALD). HCV treatment initiation rate was significantly lower in SUD patients (24% in SUD vs. 34% in non-SUD patients). Patients with SUD had also a more aggressive disease. Non-cirrhotic SUD patients had a 2-fold increased risk of liver decompensation while cirrhotic SUD patients had >1.5-fold increased risk of both HCC and liver decompensation.

Overall, DAA treatment markedly reduced HCC and liver decompensation incidence rates in patients with and without SUD. Among patients without cirrhosis, DAA reduced liver decompensation incidence by more than 85% in SUD and non-SUD patients, and HCC risk by almost 70% in non-SUD patients. Among patients with cirrhosis, DAA reduced liver decompensation and HCC incidence in patients without SUD by more than 60%. SUD patients treated with DAA also experienced a reduction of HCC incidence by more than 60% while the benefit on liver decompensation occurrence was more limited (36% of reduction, non-statically significant). These data, summarized in Table 1, highlight the importance of universal treatment of HCV. Both SUD and non-SUD patients, independently from liver cirrhosis, greatly benefit from DAA treatment in terms of reduction of liver disease complications.

The results from the stratified analysis according to the SUD and cirrhosis status have shown no benefit in HCC prevention in SUD patients without cirrhosis while non-SUD patients had a 69% reduction risk. This difference between SUD and non-SUD patients should not induce an underestimation of the HCV treatment benefit in non-cirrhotic SUD patients. The lack of effect on HCC incidence in non-cirrhotic SUD patients is probably due to the smaller cohort including more younger patients with an overall short follow-up (5 years). Indeed, the crude incidence of HCC in SUD HCV untreated patients was low, 3 per 1,000 person-years, and the impact of any preventive therapy would be difficult to evaluate on a short term and small population.

How can we explain the differences in liver decompensation incidence in cirrhotic patients with and without SUD? The SUD group had higher prevalence of patients with alcohol abuse which is a major risk factor for liver decompensation and therefore, may have reduced the benefit of HCV treatment (11).

Interestingly, chronic kidney disease (CKD) has been found to be an independent risk factor for HCC or liver decompensation in both SUD and non-SUD patients, together with other well-known risk factors such as cirrhosis and diabetes. CKD incidence is constantly increasing among patients with chronic liver disease and cirrhosis (12), in line with the increased incidence of metabolic diseases and risk factor for CKD such as diabetes and hypertension. CKD has been reported to be associated with negative kidney and liver outcomes and associated with worse liver function (13). Whether CKD is an independent risk factor for HCC is still unclear because CKD is strongly associated with major HCC risk factors such as diabetes, obesity, decompensated cirrhosis.

It is important to note that HCV treatment was offered to only a minority (around 30%) of patients in both SUD and non-SUD patients. There might be several social or economic reasons behind this limited treatment of eligible patients. This may be due to insurance restrictions, uncertainty regarding patient compliance or treatment outcomes. Collectively, these data should rise awareness for intensifying both medical, economic, and social initiatives and policies enabling offer HCV treatment to all infected patients.

The study was conducted using ICD codes and medical databases. This methodology probably underestimates the prevalence of SUD and overestimate the HCV treatment rates, making the overall results more alarming. Other limitations of the study are the short follow-up, the absence of data of HCV reinfections and of former SUD.

In conclusion, the study of Park et al. confirms that HCV treatment should be universally offered to all eligible patients. SUD is a risk factor for more aggressive liver disease and should not be a limiting factor for treatment, conversely, should result in intensified HCV management and care. Finally, HCV treatment rates are still too low, with only 1 patient out of 3 who received DAA. It is urgent then to implement social and medical policies to increase HCV screening, expand access to HCV drugs and improve treatment rates.

Acknowledgments

Funding: This work was supported by ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC1.0 and 2.0 IHUARC IHU201301187 and IHUARC2019 to TFB), the European Union (ERC-AdG-2014-671231-HEPCIR to TFB, EU H2020-667273-HEPCAR to TFB, and INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012 to TFB), ANRS, Paris (2013/108 and ECTZ103701 to TFB), NIH (CA233794, CA209940, R21CA209940, and R03AI131066 to TFB), US Department of Defense (W81XWH-16-1-0363 to TFB), and the Foundation of the University of Strasbourg (HEPKIN to TFB) and the Institut Universitaire de France (IUF; TFB). This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and Inserm Plan Cancer and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-507/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Asrani SK, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world. J Hepatol 2019;70:151-71. [Crossref] [PubMed]
2. Verna EC, Schluger A, Brown RS Jr. Opioid epidemic and liver disease. JHEP Rep 2019;1:240-55. [Crossref] [PubMed]
3. Rudd RA, Aleshire N, Zibbell JE, et al. Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014. MMWR Morb Mortal Wkly Rep 2016;64:1378-82. [Crossref] [PubMed]
4. Liang TJ, Ward JW. Hepatitis C in Injection-Drug Users - A Hidden Danger of the Opioid Epidemic. N Engl J Med 2018;378:1169-71. [Crossref] [PubMed]
5. Bahorik AL, Satre DD, Kline-Simon AH, et al. Alcohol, Cannabis, and Opioid Use Disorders, and Disease Burden in an Integrated Health Care System. J Addict Med 2017;11:3-9. [Crossref] [PubMed]
6. Aldridge RW, Story A, Hwang SW, et al. Morbidity and mortality in homeless individuals, prisoners, sex workers, and individuals with substance use disorders in high-income countries: a systematic review and meta-analysis. Lancet 2018;391:241-50. [Crossref] [PubMed]
7. Daley DC. Family and social aspects of substance use disorders and treatment. J Food Drug Anal 2013;21:S73-6. [Crossref] [PubMed]
8. D'Ambrosio R, Degasperi E, Anolli MP, et al. Incidence of liver- and non-liver-related outcomes in patients with HCV-cirrhosis after SVR. J Hepatol 2022;76:302-10. [Crossref] [PubMed]
9. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: Final update of the series☆. J Hepatol 2020;73:1170-218. [Crossref] [PubMed]
10. Park H, Jiang X, Song HJ, et al. The Impact of Direct-Acting Antiviral Therapy on End-Stage Liver Disease Among Individuals with Chronic Hepatitis C and Substance Use Disorders. Hepatology 2021;74:566-81. [Crossref] [PubMed]
11. Pearson MM, Kim NJ, Berry K, et al. Associations Between Alcohol Use and Liver-Related Outcomes in a Large National Cohort of Patients With Cirrhosis. Hepatol Commun 2021;5:2080-95. [Crossref] [PubMed]
12. Kumar R, Priyadarshi RN, Anand U. Chronic renal dysfunction in cirrhosis: A new frontier in hepatology. World J Gastroenterol 2021;27:990-1005. [Crossref] [PubMed]
13. Wong F, Reddy KR, O'Leary JG, et al. Impact of Chronic Kidney Disease on Outcomes in Cirrhosis. Liver Transpl 2019;25:870-80. [Crossref] [PubMed]