HCV Treatment in Substance Users: Background Paper
AIDS Institute, New York State Department of Health

Hepatitis C is believed to be the most common blood borne disease in the United States. Approximately 3 million people are chronically infected, at least 60% of them were infected through the injection of illicit substances. The current treatment of this infection is a 24-48 week course of Interferon (IFN) in combination with Ribavirin. The treatment leads to significant side effects in many patients and has a 30-40% chance of sustained viral clearance.

The National Institute of Health Consensus Panel on HCV in 1997 recommended that heavy alcohol users and users of illicit drugs maintain abstinence for at least 6 months prior to treatment for Hepatitis C. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has extended this recommendation to 2 years.

"Interferon therapy is also associated with relapse in people with a previous history of drug or alcohol abuse. Alpha interferon should not be given to a patient who has only recently stopped alcohol or substance abuse. Typically a 2-year abstinence is recommended before starting therapy. Strict abstinence from alcohol is recommended during therapy with interferon."

The consensus statement testifies that this is recommended because of issues of compliance with therapy among drug and alcohol users and because of purported toxicities. The NIDDK states that IFN is associated with relapse. Finally as reinfection with HCV is possible following treatment others have suggested that drug users are at high risk of reinfection. The validity of each of these concerns will be examined.

Adherence to therapy: There are no studies on adherence to HCV therapy among alcoholics and other drug users. However examination of drug users and adherence to HIV treatment may shed some light on the issue.

Some studies have found somewhat lower rates of adherence to AZT among drug users (Samet, Webster). However a number of other studies of drug users and AZT have found that drug users are able to comply with AZT treatment at levels which are comparable to nonusers (Samuels, Broers) though they may delay initiation of therapy (Broers). Highly active antiretroviral therapy is more complicated and there is as of yet little information in the published literature. There were 10 posters and abstracts on this subject at The 12th World AIDS Conference 6 of which found little or no impact of drug use on adherence and 4 found that fewer drug users were fully adherent to therapy. In addition to drug users other sociodemographic groups which have been inconsistently found to be associated with nonadherence include Medicaid patients, Latinos, women, youth (Wenger) African Americans, depressed patients and those with low educational (Paterson). In view of the inconsistencies in such studies it has been suggested that physicians should develop individual treatment plans rather than withhold medication from "disadvantaged patients with complicated social problems" (Lerner). This position was adopted by the New York State AIDS Advisory Council in the Report of the Ethical Issues in Access to HIV Treatment Workgroup.

Toxicity

Alcohol is known to be highly toxic to the liver. Furthermore, one study shows that the response to IFN among drinkers related to the alcohol dose- heavy drinkers are unlikely to clear the virus (Ohnishi). However some studies suggest that persons with cirrhosis who are also highly unlikely to clear the virus may be less likely to develop hepatocellular cancer even without a biochemical response to therapy (International Interferon-alpha Hepatocellular Carcinoma Study Group). As heavy drinkers are among those most likely to progress it is clear that more research is needed among these patients. There is no literature documenting the length of abstinence required to respond to therapy.

Heroin, like other opioids, is not toxic to the liver or other organs and is unlikely to interact with IFN or Ribavirin. Opioids for pain management are not contraindicated, nor is methadone maintenance. Cocaine has also not been found to be toxic to the human liver nor is it known to have adverse interactions with interferon (Lefkowitz).

Relapse to drug use

The concern about the likelihood of relapse has not been demonstrated and is based on anecdote. A side effect of IFN is a flu like syndrome which is similar to heroin withdrawal thus the concern about relapse is logical (though not documented). As many HCV patients acquired the infection through injection drug use and conversely the majority of injection drug users are infected it would seem that the issue of relapse in relation to IFN needs further research and remedying. While it might be assumed that someone abstinent for 2 years is less likely to relapse than someone abstinent for 6 months this is also not well documented in the literature, particularly in relationship to a medication which may provoke craving.

The role of interferon in relapse to cocaine or alcohol use is neither documented in the literature nor is it a logical possibility.

Reinfection

Viral clearance of HCV and the presence of HCV antibody do not confer immunity (Kao). A patient who has achieved full response to treatment could become reinfected upon reexposure to virus. Thus there is the hypothetical concern that an injection drug user would be likely to become reinfected- although no such cases have been documented. The incidence of HCV among IDUs in the United States appears to be decreasing, this has been attributed to education about safer injection and the provision of the tools to follow the recommendations (Alter). Thus it is equally possible that a successfully treated IDU who continued injecting or who relapsed would change behavior and not become reinfected in addition to not being infectious to others.

An issue analogous to the denial of Hepatitis C treatment to drug users is the history of liver transplantation among alcoholics. As the technology was being developed it was felt that the likelihood of return to drinking after transplantation would lead to poor compliance with immunosuppressive medications and high rates of transplant rejections. This was not borne out in most studies as recidivists appear to do as well as nondrinkers (Pageaux) and studies also suggest that transplantation may result in lower rates of drinking than most alcohol treatment programs (Beresford). Furthermore in a 1990 legal case a judge ruled that alcoholism was not sufficient justification to deny a liver transplant (Beresford). Six months has been the standard abstinence period required but this has not been found a factor strongly predictive of continued abstention, (Beresford, Knetchle). Pageaux et al aver that "alcoholism is not a vice but a disease" and discuss the implications of refusing medical care in these circumstances. The ethics of denying care to patients on the basis of drug and alcohol use has also been explored by Batey.

Treatment for Hepatitis C is not currently an easy therapy, nor is it highly efficacious, it is possible that few drug users and alcohol abusers that are otherwise eligible for treatment are currently sustaining morbidity from this illness. However this guideline sets a precedent ó a group of high-risk patients may be denied therapy without documentation that they cannot benefit from it. Furthermore it puts patients seeking or participating in drug treatment at a significant disadvantage as drug treatment requires admission of drug or alcohol use and frequent monitoring for relapse. The exclusion of these patients from therapy directly contradicts the NYS AIDS Advisory Councilís statement on HIV treatment: "It is unethical to deny access to HIV treatment based on the patientís membership in any category or group, past or current risk behaviors, or past behavior concerning medications;" (New York State AIDS Advisory Council).

References

Alter MJ Epidemiology of HepC Hepatology 1997 26(3 Supl 1):62S-65S

Batey RG Denying treatment to drug and alcohol-dependent patients. Addiction 1997 Sep;92(9):1189-93

Broers B, Morabia A, Hirschel B A cohort study of drug users' compliance with zidovudine treatment. Arch Intern Med 1994 May 23;154(10):1121-7

International Interferon-alpha Hepatocellular Carcinoma Study Group. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. Lancet 1998 May 23;351(9115):1535-9

Kao JH, Chen PJ Superinfection with homotypic virus in hep C virus carriers: studies on patients with post-transfusion hepatitis. J Med Virol 1996 Dec;50(4):303-308

Knechtle SJ, Fleming MF, Barry KL, Steen D, Pirsch JD, Hafez GR, D'Alessandro AM, Reed A, Sollinger HW, Kalayoglu M, et al Liver transplantation for alcoholic liver disease. Surgery 1992 Oct;112(4):694-701; discussion 701-3

Lefkowitz SS, Brown DJ, Grattendick K, Lefkowitz DL Cocaine inhibits production of murine hepatitis virus by peritoneal macrophages in vitro. Proc Soc Exp Biol Med 1997 May;215(1):87-93

Lerner BH, Gulick RM, Dubler NN Rethinking nonadherence: historical perspectives on triple-drug therapy for HIV disease. Ann Intern Med 1998 Oct 1;129(7):573-8

Management of Hepatitis C. NIH Consens Statement Online 1997Mar 24-26 15(3): 1-41. http://odp.od.nih.gov/consensus/cons/105/105_statement.htm

National Institute of Diabetes and Digestive and Kidney Diseases, Chronic Hepatitis C: Current Disease Management, 5/99 http://www.niddk.nih.gov/health/digest/pubs/chrnhepc/chrnhepc.htm

New York State AIDS Advisory Council. Report of the Ethical Issues in Access to HIV Treatment Workgroup September 1998

Ohnishi K Interferon therapy for chronic hepatitis C in habitual drinkers: comparison

with chronic hepatitis C in infrequent drinkers. Am J Gastroenterol 1996 Jul;91(7):1374-9

Pageaux GP, Michel J, Coste V, Perney P, Possoz P, Perrigault PF, Navarro F, Fabre JM, Domergue J, Blanc P, Larrey D Alcoholic cirrhosis is a good indication for liver transplantation, even for cases of recidivism. Gut 1999 Sep;45(3):421-6

Paterson D, Swindells S, Mohr J, Brester M, Vergis E, Squier C, Wagener M, Singh N. How Much Adherence is Enough? A Prospective Study of Adherence to Protease Inhibitor Therapy Using MEMSCaps. 6th Conference on Retroviruses and Opportunistic Infections 1999 (Abstract # 98)

Samet JH, Libman H, Steger KA, Dhawan RK, Chen J, Shevitz AH, Dewees-Dunk R, Levenson S, Kufe D, Craven DE Compliance with zidovudine therapy in patients infected with human immunodeficiency virus, type 1: a cross-sectional study in a municipal hospital clinic. Am J Med 1992 May;92(5):495-502

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Webster RD, Barr D Adherence to Highly Active Antiretroviral Therapy (HAART) Among Individuals with HIV/AIDS: A Compendium of HAART Adherence Research, November 1997- November 1999 Adherence to HIV Therapy: Building a Bridge to Success, Forum for Collaborative HIV Research, Center for Health Policy Research, George Washington University Medical Center November 1999, Washington, DC

Wenger N, Gifford A, Liu H, Chesney M, Golin C, Crystal S, Berry S, Coplan P, Bozzette P, Shapiro M. Patient Characteristics and Attitudes associated with Antiretroviral (AR) Adherence. 6th Conference on Retroviruses and Opportunistic Infections 1999 (Abstract # 98)

12th World AIDS Conference abstracts

Brigido LF, Veiga AP, d'Ambrosio AC, Bueno A, Casseb J, Galbitti FF.

Low adherence in antiRetroviral users at Sao Paulo, Brazil 12th World AIDS Conference. Geneva, June 1998 (Abstract # 32370)

Goetz MB, Rossman BL. Evaluation of predictors of adherence in HIV-infected patients receiving combination anti-Retroviral therapy 12th World AIDS Conference. Geneva, June 1998 Abstract #32351)

Jones AM, Thaker H, Foley B, Barry C, Prunty G, Sweeney B, Sheehan GJ. A qualitative study on Retroviral Therapy: Drug compliance in IVDU patients. 12th World AIDS Conference. Geneva, June 1998 (Abstract # 32361)

Mannheimer S, El-Sadr W, Flowers J, H. Safavi H, Curtis J. Virologic response to antiRetroviral therapy among HIV-infected injection drug users. 12th World AIDS Conference. Geneva, June 1998 (Abstract # 499/32407)

Ohmit S, Schuman P, Schoenbaum E, Rompalo A, Cohen M, Richardson J, Sacks H, Young M, Adherence to antiRetroviral therapy (ART) among women in the HIV Epidemiology Research Study (HERS) and Women's Inter-Agency HIV Study (WIHS). 12th World AIDS Conference. Geneva, June 1998 (Abstract # 32347)

Olgiati M, Wang J, Oppliger R, Basic A, Somaini B, Grob P, Flepp M.

Prior experience with HIV/AIDS therapy among HIV-positive clients in opiate substitution clinics: The Zurich Prometheus Study 12th World AIDS Conference. Geneva, June 1998 (Abstract #42290)

Patrizia M, Carrieri M, Reynaud-Maurupt C, Pradier C, Moatti JP. Compliance to multiple combination therapy with antiprotease inhibitors among HIV-infected IDUs in France (cohort MANIF 2000). 12th World AIDS Conference. Geneva, June 1998 (Abstract #32359)

Stone VE, Adelson-Mitty J, Duefield CA, Steger KA, Stein MD, Mayer KH. Adherence to protease inhibitor (PI) therapy in clinical practice: Usefulness of demographics, attitudes and knowledge as predictors. 12th World AIDS Conference. Geneva, June 1998 (Abstract # 32337)

Turner JG, Nokes KM, Corless IB, Holzemer WL, Inouye J, Brown MA, Powell-Cope GM. History of drug use and adherence in HIV+ persons. 12th World AIDS Conference. Geneva, June 1998 (Abstract #392/32366)

Weidle PJ, Ganea CE, Ernst J, McGowan J, Irwin KL, Holberg SD. Multiple reasons for nonadherence to antiRetroviral medications in an inner-city minority population: Need for a multifaceted approach to improve adherence 12th World AIDS Conference. Geneva, June 1998 (Abstract # 32360)