Q J Med 2001; 94: 153-158
© 2001 Association of Physicians
Managing chronic hepatitis C acquired through intravenous drug use
From the Centre for Liver Research, University of Newcastle, Freeman Hospital 1 Specialist Drug and Alcohol Unit, Plummer Court, Newcastle upon Tyne, UK
Received 24 July 2000 and in revised form 1 December 2000
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Summary |
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We retrospectively reviewed the provision and uptake of hospital services for 253 current and ex-intravenous drug users with hepatitis C virus (HCV). Overall, 237 attended at least one clinic (mean age 32 years, 70% male, 43% on maintenance methadone); 81% had evidence of active viral replication and 137 agreed to a liver biopsy to assess disease severity. Of these 137, 24% had mild chronic hepatitis with a low risk of progression to cirrhosis, but 9% had cirrhosis (mean age 40 years, mean time since initial intravenous drug use 15.8 years). Only 50 of the 100 patients in whom antiviral therapy was indicated, commenced treatment; 18 (36%) have had a sustained virological response. The natural history or response to treatment of chronic HCV in those who acquire it through intravenous drug use is not different to that previously reported for post-transfusion HCV. However, a substantial proportion default from follow-up or decline further intervention. As intravenous drug use is now the main risk factor for acquisition of HCV, these data have implications for future delivery of care aimed at limiting the morbidity of chronic HCV, and limiting the spread of hepatitis C virus infection amongst intravenous drug users.
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Introduction |
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Hepatitis C virus (HCV) is a positive-strand RNA virus that is a major cause of chronic liver disease worldwide. Chronic hepatitis C can be a benign liver disorder with an indolent course1 associated with impaired quality of life2 or it may cause progressive liver disease with cirrhosis and hepatocellular cancer,3,4 the incidence of which is increasing in developed countries.5 Progression appears to be accelerated in men, in those who acquired the infection when aged >40 years, and in patients who drink heavily.6
Detection of antibodies to HCV (anti-HCV) has become the most practical means of diagnosing past and present infection.7 In the US, 1.8% of the general population are anti-HCV-positive and illegal drug use is one of the strongest factors independently associated with infection.8 The prevalence of anti-HCV amongst intravenous drug users has consistently been high, and is 67% in our local population in the North-East of England.9 The prevalence in Scottish prisons is 49% in injector-inmates and 20.3% overall.10 Since the introduction of screening of blood donors, intravenous drug use (IVDU) remains the major mode of transmission, but users' perception of their viral status is often inaccurate.11
Because 20–30% of individuals with chronic HCV are at risk of developing cirrhosis, with its attendant risks of liver cancer, transplantation and death, antiviral therapy should ideally be offered to all patients with moderate to severe chronic hepatitis on liver biopsy.12 Until recently alpha interferon (
IFN) monotherapy was the only available treatment for chronic HCV;13 approximately 40–50% of patients achieved normalization of ALT levels and viral disappearance at the end of therapy, but at least half of these ‘responders’ relapsed after treatment cessation.13 The combination of IFN with the nucleoside analogue ribavirin has recently been shown to be superior to monotherapy, with enhanced sustained response rates,14–16 and the current European consensus is that it should be offered to those without contraindications.17 This has recently been ratified by guidance from the National Institute for Clinical Excellence.18
Anti-viral therapy for chronic HCV is controversial in current injecting drug users; in view of frequent problems with compliance, and the risk of re-infection, IFN is not normally offered to actively injecting drug users. However many clinical drug misuse services are advocating screening for HCV infection in intravenous drug users in order to discourage high-risk behaviour and prevent the spread of HCV.9,11 Thus current or past users may be referred to a liver clinic for further treatment.
This study reviewed the medical management of a large cohort of anti-HCV-positive patients whose main risk factor was IVDU, referred to a regional liver unit, and particularly, studied their attendance, outcome, compliance and response to treatment.
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Methods |
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Identification of subjects
All patients seen at a regional Liver Unit, between September 1991 and August 1998 who were anti-HCV-positive were identified from a database. Those who had IVDU as their main risk factor were included in the study. Demographic details, attendance and progression through the stages of investigation and management (as outlined by the liver biopsy based algorithm, Figure 1
) were documented from case notes.
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Determining HCV viraemia
The liver-biopsy-based algorithm dictates investigation in a stepwise fashion and determines whether antiviral treatment is indicated. The first step is to determine whether the patient is viraemic. Since the start of this study, tests for hepatitis C viraemia have been developed and refined.7 Initially, the recombinant immunoblot assay (RIBA) for anti-HCV combined with abnormal liver function tests (LFTs) was used, but since 1993 this has been replaced by the reverse transcriptase polymerase chain reaction (PCR) for detection of HCV RNA.
Classification of liver biopsies
Since 1995, liver biopsies have been assessed histologically according to the method described by Ishak et al.19 which grades liver histology according to the intensity of necroinflammatory activity (maximum score 18), and stages the degree of fibrosis and architectural damage (maximum score 6=cirrhosis). Biopsies reported prior to 1995 were retrospectively scored.
Treatment regimens
Before funding of IFN therapy was agreed in 1996, patients who met the clinical criteria for treatment without contraindications were entered into a trial of ribavarin monotherapy,20 received IFN on compassionate grounds or were advised to await funding. In 1998 an investigator-initiated study of combination therapy with IFN with ribavarin was started, and many patients received this combination. After 3 months of treatment, if the alanine transaminase (ALT) remained abnormal and/or the HCV-RNA remained detectable, treatment was stopped, as these patients were thought unlikely to achieve a sustained response to treatment.21 Treatment was continued for 12 months in the remainder. Three patients were included in multicentre studies; two received pegylated-interferon22 and one a combination of IFN and amantidine.23
Statistical methods
In the patients who met the criteria for anti-viral therapy, the necro-inflammatory grades and fibrosis stages in the treated and untreated groups were compared using Student's two-sample t-test. In the patients who received anti-viral therapy, Fisher's exact test was used to compare outcome between IFN monotherapy and combination treatment with IFN and Ribavirin. The SPSS version 9.0 statistical package was used.
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Results |
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Demographics
The mean age at referral of the 253 anti-HCV-positive patients was 32 years (18–56), and 70% were male. At presentation, 43% of the patients were on maintenance methadone therapy. Of the 210 patients whose employment status was known, 60% were unemployed, and 38 patients (15%) volunteered a history of imprisonment.
By definition, all patients had IVDU as their main risk factor, but 43% also had tattoos, 8% had body piercing, 7% had previously had blood transfusions, and 5% had a sexual contact known to be HCV-positive.
Referral agency and attendance
Most patients (n=116, 46%) were referred by General Practitioners; 38% were referred directly from drug rehabilitation services. Other sources of referral were the local Genito-Urinary Medicine clinic (7%), HM Prison services (2%) and other consultant gastroenterologists in the region (6%).
Sixteen patients never attended any clinic (6% of new referrals). The mean number of missed appointments was 2.95. In total, 747 clinic slots were wasted due to non-attendance (30% of all appointments).
HCV-RNA testing and liver histology
Of the 237 patients who attended at least one clinic, 187 patients were tested for HCV RNA by PCR, and 151 (81%) were HCV-RNA-positive. HCV genotyping was performed on a minority (n=48) of patients; 50% were 1a, 8.3% 1b, 37.5% 3a and 4.2% genotype 2. From the group of 50 patients who were investigated before routine PCR testing was available in 1993, 28 were anti-HCV-positive by RIBA with persistently abnormal LFTs. Hence a liver biopsy was indicated to confirm the diagnosis and assess the severity of the disease in 179 patients, of whom 137 agreed. However five patients, who had liver biopsies because of persistently abnormal LFTs, were subsequently shown to be HCV-RNA-negative and have been excluded from further analysis.
Criteria for interferon
Overall, 32 (24%) of the biopsies showed mild chronic hepatitis with a low risk of progression to cirrhosis and did not meet the local criteria for antiviral therapy (fibrosis stage 
2/6, necroinflammatory grade 3/18). Twelve patients (9%), with an average age of 40 years, had established cirrhosis on biopsy; the mean time since initial IVDU in this group was 15.8 years.
Of the 100 patients who met the criteria for interferon, 50 commenced treatment. The reasons the other 50 did not start therapy are varied; 33 declined or defaulted, 13 had contraindications (seven relapsed intravenous drug misuse, four alcohol abuse and two psychiatric illness), and four for miscellaneous reasons. There was no significant difference in necro-inflammatory grade between those that did and did not proceed to treatment (Figure 2): the mean difference between the treated and untreated groups was 0.6, 95%CI 0.3–1.5, p=0.19. There was however a significantly higher fibrosis stage in the patients who proceeded to treatment (Figure 3), the mean difference being 0.8, 95%CI 0.02–1.5, p=0.04.
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Response to antiviral therapy
Fifteen (30%) patients were non-responders who remained HCV-RNA-positive after 3 months of treatment. Of those who initially responded at 3 months, 18 patients (36% of those treated) have had a sustained response and are HCV-RNA-negative by PCR 6 months after completing antiviral therapy. Although this represents a 36% response rate, it is only 18% of those patients who are potentially eligible for treatment on histological grounds, because of poor uptake of treatment.
Included in the above are the results of 22 patients who received combination therapy of IFN plus ribavirin. In this small cohort there was no significant difference in the response rates (8/25 vs. 8/22, p=0.77) or withdrawals from treatment (6/25 vs. 3/22, p=0.47) when IFN monotherapy was compared to combination treatment (Table 1). This may reflect small numbers in the analysis, or uneven distribution of HCV genotype which is now known to affect response.15,16
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Side-effects
Side-effects were very common: 41 patients complained of minor side-effects such as lethargy, myalgia, headache and weight loss, and nine patients (18%) who initially responded at 3 months stopped treatment prematurely because of side-effects including profound neutropenia and depression.
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Discussion |
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Hepatitis C virus infection is a significant problem among both ex- and continuing intravenous drug users,9,24,25 but the natural history in this group has been poorly documented. In this retrospective study, 81% of anti-HCV-positive patients were viraemic, suggesting a spontaneous resolution rate of 19%, similar to other studies.26,27 Some 76% of patients had moderate or severe disease requiring anti-viral therapy18,21 and 9% of this young group had already progressed to cirrhosis. Similarly, in those compliant with treatment, side-effects28 and sustained response rates were comparable to rates reported for treatment of post-transfusion HCV.13–15
Since this study was completed, it has been reported that a virological response at the sixth month after discontinuation of combination of IFN and ribavirin is predictive of a 97.8% rate of long-term complete (virological and biochemical) response. Sustained response was associated with a disappearance of liver HCV RNA in these patients.29 Thus there is accumulating evidence that sustained response rates are maintained long-term and that patients with chronic HCV can be cured by anti-viral therapy.
This retrospective study demonstrates that as a group, patients who have acquired HCV through IVDU do not receive the maximum potential benefit of this effective treatment, because they demonstrate a high rate of non-compliance with investigation and treatment. Poor attendance also has implications for the logistics of running an out-patient clinic and for a hospital's financial planning.
The reasons for the high rate of default are uncertain, but may include resumed substance misuse,29 low socioeconomic status with attendant poor uptake of hospital services, comorbid psychiatric conditions, lack of family or social support and entry into prison for drug-related crime. Non-attendance may also be explained by a lack of understanding of the implications of a positive result and negative preconceived ideas acquired from the drug subculture regarding liver biopsies and interferon.
As many ex- or current drug misusers interact poorly with hospital treatment services, good clinical practice demands that we adjust provision of care to take into account the sub-culture of IVDU. The rising use of heroin among young people in England and Wales30 emphasizes the need for an effective management strategy for HCV acquired through IVDU. As imprisonment can follow drug-related crime, and inmates may compound the high rate of HCV transmission through shared equipment,10 the situation of IVDU with chronic HCV in prisons in particular needs to be reviewed. Ideally, as outlined in the recent joint report from the NHS and the prison service there should be seamless health care between prisons and the outside community.31
Provision of services to this young population with chronic HCV acquired through drug misuse provides a challenge, as it requires integration of drug and prison services, specialist medical care and psychiatric services. In the absence of a vaccine, combination therapy with IFN and ribavirin must form part of a strategy for controlling hepatitis C.18 Effective delivery of such treatment to those acquiring HCV through IVDU should not only limit the morbidity and public health costs of the increasing burden of HCV-related disease, but also limit spread.
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Notes |
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Address correspondence to Professor M.F. Bassendine, Centre for Liver Research, 4th Floor, William Leech Building, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH. e-mail: M.Bassendine{at}ncl.ac.uk
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