Chronic infection with the hepatitis C virus (HCV) is common throughout the world, and an estimated 170 million people are infected with HCV worldwide [1]. In some untreated HCV-infected individuals, end-stage liver disease develops [2]. To avoid the complications of chronic infection, therapy is recommended and involves a 24- or 48-week course of a long-acting pegylated interferon combined with the antiviral agent ribavirin [3,4]. That combination treatment leads to a sustained virologic response in up to 60% of those who are infected with HCV, although response rates vary according to the genotype of the infecting virus. In patients infected with genotype 1 HCV, response rates are typically less than 50%, and in those with genotype 2 or 3 HCV, therapy induces a sustained response in up to 80% of patients. A number of factors, such as the age at which treatment is initiated (early treatment is beneficial) or alcohol consumption (alcohol abuse reduces the response to therapy), influence the success of therapy [3].
In the Western world, most people who are infected with HCV have used illicit drugs and are believed to have acquired their infection by sharing needles and other drug paraphernalia. Although many of those who contracted HCV from drug use have now ceased to use illicit drugs, others who are infected persist in that practice. In this review, the risks and benefits of treating people who continue to inject illicit drugs are discussed. Issues pertaining to those who have ceased illicit drug use and are no longer in contact with drug abusers and to former injecting drug users who are stably enrolled in a methadone replacement program have been excluded. Such individuals are likely to differ from people who continue to abuse drugs and are best regarded as a separate group.
BENEFITS OF ANTIVIRAL THERAPY
In patients who do not inject illicit drugs, the primary reason for treating and eliminating HCV is to prevent the long-term consequences of chronic infection. Some people who are infected with HCV will experience end-stage liver disease and die from their infection. An ongoing debate about the magnitude of the final death toll from chronic HCV infection continues. Consensus estimates indicate that cirrhosis will develop in up to 16% of those who are infected within 20 years after infection [5] and that after cirrhosis has developed, about 3% to 5% of those individuals per year will experience a life-threatening complication such as liver cancer or decompensated cirrhosis [6]. These complications are fatal without effective intervention, which usually involves a liver transplant. The prognosis beyond 20 years of infection is unclear; some studies (which may be biased because they include only patients referred for a liver biopsy) have indicated that cirrhosis may develop in up to 70% of patients with HCV [7]. Cost-effective analysis has shown that treating chronic HCV infection before the onset of end-stage liver disease is highly beneficial and results in significant cost savings [8]. Numerous national and international guidelines concur that people with chronic HCV infection should receive antiviral therapy unless there are contraindications to such treatment. To our knowledge, there are no studies analyzing either the long-term healthcare benefits of therapy for patients who continue to inject illicit drugs or the cost-effectiveness of such therapy. It is well recognized that those who inject illicit drugs have a higher mortality rate than do noninjectors and that the increase in mortality from drug-related violence or accidental overdose may overshadow any increase in mortality from chronic HCV infection [9]. Clearly, the clinical and cost-effectiveness arguments for treating chronic HCV infection do not apply to individuals who are unlikely to live long enough to experience diseaserelated complications. In addition, those who inject drugs often have additional addictions, such as alcohol abuse, that may lead to more rapidly progressive infection and an increased likelihood of HCV-associated mortality. One study from the United Kingdom found that almost 30% of active injectors who were assessed for treatment with antiviral therapy had evidence of cirrhosis [10]. Bearing in mind the very significant economic costs of treating end-stage liver disease and progressive disease in those who continue to inject illegal drugs, it is probable that therapy for injecting users will remain cost-effective, although this has not been formally proven and the benefits in terms of life-years saved have not been established in that population. Many patients with mild chronic hepatitis C who do not inject drugs express a strong desire for treatment with antiviral therapy, because their quality of life is compromised by the many nonhepatic effects of chronic HCV infection [11]. In carefully controlled studies, the quality of life in patients with chronic HCV has been much improved by viral eradication, the hope of which is a major indication for such therapy in those without evidence of progressive liver disease [12].
No studies have been performed in injecting drug users to evaluate their quality of life before and after effective antiviral therapy, but it seems probable that they would experience the same benefi ts that noninjectors derive from successful therapy.
Numerous studies have examined the transmission of HCV in people who inject drugs. Although such studies are technically challenging, their authors agree that individuals who inject drugs transmit HCV to other drug users, and thus there is a constant reservoir of infected people who transmit that infection [13]. In the medium term, this undoubtedly leads to an increase in the number of people with chronic HCV infection.
Considerable efforts have been made to reduce blood-borne virus transmission in injecting drug users by promoting “safe-injecting” campaigns that provide clean injecting equipment. Although many believe that such programs reduce the transmission of HCV, the data to confirm that theory are insufficient. Most published studies on that topic, however, indicate that transmission is likely to be reduced by programs that provide clean needles and drug paraphernalia.
Given that therapy for chronic HCV may eliminate the virus in some of those who are infected and because those who are not infected cannot transmit HCV, it is reasonable to presume that therapy for injectors will reduce transmission. However, this may be very difficult to confirm. It has been remarkably difficult to substantiate anecdotal evidence that needle exchange reduces HCV transmission, and conducting studies to confirm that viral eradication reduces infection rates will be challenging. It seems reasonable to assume that successful therapy would reduce patient-to-patient spread, but it has also been suggested that active injectors who undergo the rigors of therapy are more likely to be relatively stable drug users who may be less likely to transmit HCV because they are engaged in needle-exchange programs and are well aware of the risks of transmission. The difficulties of conducting robust studies in that patient population may prevent a formal analysis of this issue and, in the absence of evidence to the contrary, it seems reasonable to presume that effective antiviral therapy in active drug users would ultimately reduce patient-to-patient transmission.
Treatment for chronic HCV infection involves a 6- to 12-month course of a long-acting pegylated interferon combined with the antiviral agent ribavirin. Therapy is arduous and is associated with a wide range of adverse effects ranging from mild flulike symptoms to severe psychiatric reactions such as depression. Ribavirin causes a significant reduction in the hemoglobin level that may precipitate cardiovascular problems, and interferon induces neutropenia and thrombocytopenia, both of which can lead to severe clinical problems [14,15]. The number and range of adverse effects associated with interferon-based antiviral therapy necessitates close monitoring during treatment. In many medical units in which such treatment is provided, patients are encouraged to develop a close relationship with their healthcare provider during therapy. That relationship facilitates the exchange of many beneficial healthcare messages between patient and clinician. In the context of injecting drug users, the close interaction between supportive staff members and those who administer therapy is likely to enable other healthcare interventions that may improve long-term outcome.
Evidence of the supplementary benefits of antiviral therapy is lacking, although 1 study of therapy for injecting drug users did show a reduction in illicit drug use [16]. Our studies of injecting drug users in East London suggest that there may be a reduction in illicit drug taking as a result of prolonged therapy. A number of patients so treated in our program have reduced their drug intake, and a handful have gained employment. Thus treating active drug users may result in important societal benefits, although again, evidence supporting that view is difficult to obtain.
RISKS OF ANTIVIRAL THERAPY
Evidence from a number of studies indicates that antiviral therapy for patients with chronic HCV infection reduces mortality and morbidity and that in injecting drug users, there may be small but significant improvements in drug taking and aberrant behavior. However, therapy for those who inject drugs is not without risk. The major concern in treating injecting drug users is that treatment will be futile because compliance and response rates will be poor and reinfection after viral eradication will mitigate any benefits of therapy. Clearly if the response to therapy is reduced in those who inject drugs or if reinfection rates are high, then the benefits of therapy may be much reduced. A number of studies have now evaluated the results of therapy for those who continue to inject drugs [10,17-20]. Those studies vary in quality and most of them were uncontrolled, but they reveal that response rates in very heterogenous groups of illicit drug users are similar to those documented in pivotal, randomized, controlled clinical trials. It should be noted, however, that the total number of patients studied remains relatively small and that the populations studied have often been carefully selected so that strict entry criteria precluded therapy in the more chaotic drug users. As a result, modest reductions in response rates may have been overlooked in those underpowered studies, and there may be cohorts of injecting drug users in whom therapy is less likely to be effective.
In our study of injecting drug users in East London, we treated a highly chaotic group of injectors, including those who were homeless or whose social circumstances were very poor. The results of that study, which was relatively small, indicated that no behavioral characteristics were associated with poor compliance (Figure 1). Some published studies [17-20] indicate that a substantial proportion of patients who continue to inject drugs can be successfully treated with current antiviral drug regimens.
 | Figure 1. Factors influencing the response to therapy in a cohort of injecting drugs users.
In 2007, 54 active injecting drug users were treated at an outreach center in East London, UK, where factors thought to be associated with noncompliance were assessed.
Note the percentage of patients with each of the specified risk factors for poor compliance and their compliance status. |
A major concern in treating patients who are actively using drugs is that they may reinfect themselves, even if viral eradication can be achieved. To date, very long-term follow-up studies of treated injecting drug users have not been completed, and reinfection rates over the long term have therefore not been evaluated. However, the studies that have been performed all show very low reinfection rates in those in whom the virus has been eliminated. A recent review [21] confirmed that reinfection rates in drug users are low, but whether that is due to improved compliance with harm-reduction protocols or to the development of protective immunity is unclear.
Therapy with pegylated interferon and ribavirin is not without risk, and there are significant treatment-related complications that can be mitigated but not completely prevented in those who continue to use illicit drugs. One of the greatest fears pertaining to injecting drug users is that the high prevalence of psychiatric disease in that population will ultimately result in significant harm to a substantial proportion of those individuals. Studies to date have not confirmed an increase in psychiatric morbidity in those who inject drugs, but as increasing numbers of illicit drug users are enrolled in treatment programs, it will be important to monitor the development of psychiatric disorders to enable appropriate modifications to entry criteria for therapy.
In addition to the risks associated with psychiatric illness, therapy for chronic HCV is associated with other significant complications. A reduction in circulating neutrophils is common in treated patients, but in general, that is not associated with an increase in bacterial infections. However in illicit drugs users, bacteremia associated with the use of infected drug paraphernalia can compound changes in the host immune response and may lead to increased rates of infection.
Thrombocytopenia is a feared complication of antiviral therapy, because in the context of impaired clotting due to a reduction in liver synthetic function, bleeding may be difficult to control. In injecting drug users who have an increased risk of personal assault, the risk of untreated thrombocytopenia may also be increased. Careful monitoring of platelet and white blood cell counts can prevent potentially dangerous changes in blood function, but such monitoring clearly requires close compliance with the clinic visit schedule as well as a willingness to undergo regular phlebotomy. Many of those who use or have used illicit drugs have difficult venous access. Concerns have been expressed about whether the necessary close monitoring can be maintained in that group of patients, who are at above-average risk for complications and pose difficulties in close monitoring. Thus there are real risks in treating people who inject drugs, but the data to date from clinical studies suggest that those difficulties can be overcome.
MODELS OF CARE
It is clear from the discussion above that there may be significant benefits to treating injecting drug users but that therapy has an increased risk of complications in injectors. As we have shown, a number of studies have demonstrated that cohorts of injecting drug users can be successfully treated, and it is therefore clear that in appropriate circumstances, individuals who actively inject drugs can benefit from treatment. The studies completed to date have involved a wide variety of different models of care and chronicle treatment that is administered in inpatient settings, outreach clinics, and multidisciplinary hospital clinics. A characteristic of all such successful studies presented to date is the involvement of a multidisciplinary team. Those teams invariably involve nursing support, psychiatric involvement, and clinical care provided by a clinician (either a hepatologist or an infectious disease physician) with an interest in treating viral hepatitis. A physician with an interest in managing the care of individuals with a substance abuse disorder is a key component of a successful treatment team. If all key elements are in place, then the risk-benefit ratio in injecting drug users can be manipulated in favor of therapy.
REFERENCES
1. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hep 1999;6:35-47. [Medline]
2. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-832. [Medline]
3. Foster GR, Fried MW, Hadziyannis SJ, Messinger D, Freivogel K, Weiland O. Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scand J Gastroenterol 2007;42(2):247-255. [Medline]
4. D’Souza R, Foster GR. Diagnosis and treatment of hepatitis C. J R Soc Med 2004;97(5):223-225. [Medline]
5. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fi brosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008;48(2):418-431. [Medline]
6. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients [see comments]. Gastroenterology 1997;112(2):463-472. [Medline]
7. D’Souza R, Glynn MJ, Ushiro-Lumb I, et al. Prevalence of hepatitis C-related cirrhosis in elderly Asian patients infected in childhood. Clin Gastroenterol Hepatol 2005;3(9):910-917. [Medline]
8. National Institute for Health and Clinical Excellence (NICE). Peginterferon Alfa and Ribavirin for the Treatment of Mild Chronic Hepatitis C. London, UK: National Institute for Health and Clinical Excellence (NICE); 2006.
9. Degenhardt L, Hall W, Warner-Smith M. Using cohort studies to estimate mortality among injecting drug users that is not attributable to AIDS. Sex Transm Infect 2006;82(suppl 3):iii56-iii63. [Medline]
10. Wilkinson M, Crawford V, Tippet A, et al. Community based treatment for chronic hepatitis C in drug users: high rates of compliance with therapy despite on-going drug use (HCV in drug users). Aliment Pharmacol Ther 2008 Aug 26. [Epub ahead of print]. [Medline]
11. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis [see comments]. Hepatology 1998;27(1):209-212. [Medline]
12. Bonkovsky HL, Woolley JM. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. Hepatology 1999;29(1):264-270. [Medline]
13. Crofts N, Caruana S, Bowden S, Kerger M. Minimising harm from hepatitis C virus needs better strategies. BMJ 2000;321(7265):899. [Medline]
14. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13):975-982. [Medline]
15. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958-965. [Medline]
16. Carden MR, et al. Unpublished data presented at AASLD, San Francisco, 2008.
17. Jeffrey GP, MacQuillan G, Chua F, et al. Hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants. Hepatology 2007;45(1):111-117. [Medline]
18. Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of hepatitis C infection in injection drug users. Hepatology 2001;34(1):188-193. [Medline]
19. Grebely J, Raffa JD, Meagher C, et al. Directly observed therapy for the treatment of hepatitis C virus infection in current and former injection drug users. J Gastroenterol Hepatol 2007;22(9):1519-1525. [Medline]
20. Jack K, Willott S, Manners J, Varnam MA, Thomson BJ. A primary care based model for the delivery of anti-viral treatment to injecting drug users infected with hepatitis C. Aliment Pharmacol Ther 2008 Oct 11. [Epub ahead of print]. [Medline]
21. Dalgard O. Follow-up studies of treatment for hepatitis C virus infection among injection drug users. Clin Infect Dis 2005;40(suppl 5):S336-S338. [Medline]