Patients with Normal ALT Levels

Bruce R. Bacon, M.D.

At the 1997 NIH Consensus Development Conference on Management of Hepatitis C, it was concluded that “….treatment of patients with persistently normal ALT is not beneficial and may actually induce liver enzyme abnormalities.” (1) Since that time, this issue has been controversial with some investigators supportive of treatment and others suggesting that no work-up or therapy is necessary for these patients. Approximately 30 percent of patients with chronic hepatitis C have normal ALT levels, and another 40 percent have ALT levels that are less than two times the upper limit of normal. (2) Most patients with normal ALT levels have mild degrees of inflammation with mild or no fibrosis and their rate of disease progression is reduced compared to those with elevated ALT levels. (3,4) However, some patients with persistently normal ALT levels can progress to advanced fibrosis and cirrhosis. (3–6)

The issue regarding treatment of these patients has often focused on how to proceed in patients with mild disease, recognizing that ALT levels may actually be just a proxy for mild histology. The best treatment trials that have been performed are the registration trials for FDA approval, and those have all required that patients have elevated ALT levels to be included in the study. Therefore, there are no large treatment trials of normal ALT patients. When interferon monotherapy was used for HCV patients with normal ALT levels, sustained response (SR) rates generally ranged from 15 percent to 20 percent. These SR rates are similar to the results of studies obtained when interferon monotherapy was used to treat patients with elevated ALT levels.

Since the NIH Consensus Conference recommendations were issued in 1997, treatment of chronic hepatitis C has progressed from interferon monotherapy to combination therapy using interferon and ribavirin, and more recently to pegylated interferon and ribavirin. A few studies of interferon plus ribavirin in chronic hepatitis C patients with normal or near normal ALT levels have been reported. Gordon and colleagues studied patients from one of the large registration trials in which a total of 1,744 patients with hepatitis C received either interferon and placebo or interferon and ribavirin for 24 or 48 weeks. (7) Of these, 105 individuals (6 percent) had minimally elevated ALT levels, defined as ≤ 1.3 times the upper limit of normal (ULN), at their entry visit. Histologic activity index and fibrosis scores were lower amongst these patients with baseline ALT levels ≤ 1.3 times the ULN. There was no difference in SR between patients with ALT levels ≤ 1.3 times the ULN (24.8 percent) compared to those with ALT levels > 1.3 times the ULN (26.8 percent) for all treatment groups. Lee and Sherman studied 19 patients with ALT levels that were either normal or < 1.5 times the ULN. (8) Nine of the 19 patients (47 percent) had an SR. In studies from our group at Saint Louis University, Di Bisceglie, et al. reported on a group of interferon monotherapy nonresponders who were re-treated with the combination of interferon and ribavirin. (9) In total, of 124 patients were studied; 24 had normal ALT levels and 100 had elevated ALT levels. There was no difference in SR between the two groups (26 percent vs. 34 percent). Further, we have coordinated an investigator-initiated multicenter study evaluating the use of interferon and ribavirin in treatment of naïve patients with chronic hepatitis C who have persistently normal ALT levels. One hundred seventeen patients have been enrolled in this study and are currently in treatment or followup phases of the study. Thus, all reported studies have shown that SR rates for normal or near normal ALT patients are equivalent to those of elevated ALT patients when the combination of interferon and ribavirin is used.

Currently, the standard of care for most patients with chronic hepatitis C is to use the combination of pegylated interferon and ribavirin. Overall SR rates of about 55 percent can be achieved. There are no studies of normal ALT patients being treated with pegylated interferon and ribavirin, although a large investigator-initiated multicenter study is currently under way. When evaluating the effect of pegylated interferon and ribavirin, Manns and colleagues compared patients with minimal or no fibrosis to those with bridging fibrosis or cirrhosis. (10) When pegylated interferon and ribavirin were used as therapy, the SR rates for those with mild histologic changes were better (57 percent) than those with more advanced histology (44 percent).

In summary, approximately 30 percent of patients with chronic hepatitis C have normal ALT levels and another 40 percent have ALT levels < 2 times the ULN. The majority of these patients have disease that is histologically mild, but these patients can have progressive liver disease with the development of advanced fibrosis and cirrhosis. It no longer seems reasonable to conclude that SR rates for patients with normal ALT levels are any different than those for patients with elevated ALT levels. The issue at hand is whether or not patients with mild liver disease should be treated. There are numerous other factors which impact on this decision, including genotype, histology, patient motivation, symptoms, co-morbid illness, and the age of the patient. ALT levels may have less importance in deciding who should be treated.

References

1. Marcellin P, Levy S, Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997;26:133S–136S.
2. Conry-Cantilena C, VanRaden M, Gibble J, Melpolder J, Shakil AO, Viladomiu L, Cheung L, Di Bisceglie AM, Hoofnagle J, Shih JW, Kaslow R, Ness P, Alter HJ. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996;334:1691–6.
3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26:15S–20S.
4. Gholson CF, Morgan K, Catinis G, Favrot D, Taylor B, Gonzalez E, Balart L. Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study. American Journal of Gastroenterology 1997;92:1788–92.
5. Persico M, Persico E, Suozzo R, Conte S, De Seta M, Coppola L, Palmentieri B, Sasso FC, Torella R. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 2000;118:760–4.
6. Puoti C, Magrini A, Stati T, Rigato P, Montagnese F, Rossi P, Aldegheri L, Resta S. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. Hepatology 1997;26:1393–8.

7. Gordon SC, Fang JWS, Silverman AL, McHutchison JG, Albrecht JK. The significance of baseline serum alanine aminotransferase on pretreatment disease characteristics and response to antiviral therapy in chronic hepatitis C. Hepatology 2000;32:400–4.
8. Lee SS, Sherman M. Pilot study of interferon-á and ribavirin treatment in patients with chronic hepatitis C and normal transaminase values. J Virol Hepatitis 2001;8:202–5.
9. Di Bisceglie AM, Thompson J, Smith-Wilkaitis NS, Brunt EM, Bacon BR. Combination of interferon and ribavirin in chronic hepatitis C: Re-treatment of nonresponders to interferon. Hepatology 2001;33:704–7.
10. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M-H, Albrecht JK, and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–63.

Patients with Advanced Disease

Teresa L. Wright, M.D.

The majority of patients with HCV infection have mild liver disease, and concern about this virus would be vastly reduced if it were not for the minority that progress to cirrhosis. All of the potentially life-threatening complications of HCV infection such as hepatocellular carcinoma, bleeding esophageal varices, life-threatening infections, hepatic synthetic failure, and intractable ascites occur in patients with advanced liver disease. Unfortunately, it is not possible to reliably identify those patients who are risk for developing cirrhosis. The management of HCV disease is further complicated because, in general, therapeutic interventions are more successful in patients with early disease than in those with advanced liver disease.

With that background, how successful are existing interventions in patients with advanced liver disease? First and foremost, available therapies are currently limited. Many patients with advanced HCV disease are not candidates for interferon plus ribavirin. Contraindications in this population include cytopenias (platelet counts less than 75 k/mm 3 and white cell counts less than 1,500/mm 3 ) and/or co-morbid conditions such as uncontrolled psychiatric disease that preclude therapy.

Data on safety and efficacy of interferon (standard or pegylated) with or without ribavirin in patients with compensated cirrhosis or transition to cirrhosis have often been derived from subgroup analysis of larger trials, (1–3) although in some studies, this population has been the sole focus of the trial. (4) In patients with sufficient platelets and white blood cells to tolerate therapy, pegylated interferon alfa 2b in combination with ribavirin has been studied at two different dosing regimens and compared to standard interferon plus ribavirin (Table 1). Viral clearance in patients with advanced liver disease was the similar with all three regimens (41–44 percent), but was lower in patients with advanced liver disease than in patients with minimal or no fibrosis (Table 1). Similar analyses have been performed in patients receiving combination therapy, which includes pegylated interferon alfa 2a (Table 2). In patients with advanced liver disease, viral clearance ranged from 43 percent in patients receiving pegylated interferon alfa 2a in combination with ribavirin to 21 percent in patients receiving pegylated interferon alfa 2a as monotherapy. Response was 33 percent in patients receiving standard interferon alfa 2b plus ribavirin (Table 2). As for the results from other studies, (2) sustained virological response with all three regimens was lower in patients with advanced liver disease than in patients without cirrhosis (Table 2). Comparisons between trials should not be performed without information about distribution of other variables, such as infecting genotype, that could influence response in the different treatment arms.

In patients with advanced liver disease receiving pegylated interferon alfa 2a in combination with ribavirin, the optimal dose of ribavirin appears to be 1,000 mg/1,200 mg, rather than 800 mg, and the optimal duration of treatment appears to be 48 rather than 24 weeks. (5) Efficacy of different doses of ribavirin in combination with pegylated interferon alfa 2b is under study. Median reductions in white blood cell count and platelet count are greater in patients receiving pegylated interferon than in those receiving standard interferon. (2–4) Thus patients with significant cytopenias in the setting of advanced liver disease who receive antiviral therapy should be monitored closely.

Table 1. Comparison of Treatment With Standard Interferon Alfa 2b Plus Ribavirin vs. Pegylated Interferon Alfa 2b in Combination With Ribavirin for 48 Weeks (Manns et al., Reference 2)

Another end point of therapy that is pertinent to patients with advanced liver disease is delay in histological disease progression. The premise is that therapy, while not clearing virus, achieves a “clinically meaningful end point” usually defined as a reduction by two or more points in the histological activity index. The clinical relevance of achieving such an end point is currently under evaluation in an NIH-sponsored study (the HALT-C trial) of suppressive therapy with pegylated interferon alfa 2a in preventing the development of complications of advanced liver disease in patients who have previously failed pegylated interferon plus ribavirin. Prior to the availability of results from this trial, it will be necessary to rely on analysis of subsets of patients with advanced liver disease included in multicenter trials of ribavirin plus pegylated interferon alfa 2a or alfa 2b combination therapy. Improvement in liver histology (defined as a reduction of two or more points in the histological activity index) is observed in 68 percent of patients receiving pegylated interferon alfa 2b (1.5mcg/kg SQ q week) plus ribavirin 800mg/day for 48 weeks, compared with 69 percent of patients receiving standard interferon alfa 2b plus ribavirin. (2) Improvement in fibrosis score was seen less frequently (21 and 20 percent, respectively). (2)

During the lead-in phase of the HALT-C trial, on-treatment virological response has been observed in 30 percent of patients receiving pegylated interferon alfa 2a plus ribavirin who had previously failed standard interferon plus ribavirin. (6) Thirty-nine percent of patients required dose reduction of either interferon or ribavirin, but only 6 percent could not tolerate treatment. (6) Thus, pegylated interferon plus ribavirin, appears to be tolerated in the majority of patients with advanced HCV cirrhosis who have not yet developed clinical complications of their liver disease. Thus, it is likely that hepatitis C therapy can slow histological disease progression in patients with histologically advanced liver disease, and that sustained viral clearance can be achieved in a proportion of patients. Whether this “histological slowing” translates into reduction in development of life threatening complications remains to be determined.

A more problematic group of patients are those with decompensated cirrhosis. Patients with HCV-related cirrhosis who meet criteria for listing for liver transplantation have a five year survival rate of only 50 percent. (7) There are small case series of treating patients awaiting liver transplantation (8,9) that suggest that viral clearance is achievable in a proportion of patients with advanced liver disease although adverse events, including potentially life-threatening adverse events, have been observed. If viral clearance is achieved, these patients may be virus-free after liver transplantation. (8)

Until complete data are available on the safety and efficacy of pegylated interferon plus ribavirin in patients with advanced decompensated HCV-disease, such patients should, when possible, be enrolled in clinical trials. Pegylated interferon plus ribavirin is clearly indicated in patients with compensated HCV disease who have pre-treatment platelet and white blood cell counts that are sufficient to accommodate the cytopenias associated with therapy, but treatment is relatively contraindicated in patients with decompensated cirrhosis, particularly in patients with Childs-Pugh-Turcotte scores of greater than 10. (6)

What of interventions in patients with HCV disease following liver transplantation? Hepatitis C infection of the graft is the rule following liver transplantation, and disease progression is accelerated compared to immune competent patients with HCV disease. (10) Moreover, once histological cirrhosis of the allograft occurs, the risk of complications of liver disease is even higher than in the immune competent patients with cirrhosis. (11) Variables associated with post-transplantation disease progression include pre-transplantation antiviral therapy, HCV RNA level at the time of transplantation, and advanced age of the organ donor, as well as treatment of rejection in the post transplantation period. (10)

There has been interest in “pre-emptive” antiviral therapy early in the post transplantation period as well as treatment of established liver disease of the allograft. Responses to standard interferon plus ribavirin are generally lower following liver transplantation than in immune competent patients. Moreover, since many patients have renal insufficiency secondary to immunosuppressive agents, ribavirin is poorly tolerated, and if used, ribavirin dose should be reduced. Studies of pegylated interferon with or without ribavirin are under way.

References

1. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485–92.
2. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffmann M, Reindollar R, Goodman ZD, Koury K, Ling M-H, Albrecht JK and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–65.
3. Fried MW, Shiffman ML, Reddy RK, Marino G, Goncales F, Haeussinger D, Diago M, Garosi G, Zarski J-P, Hoffman J, Yu J. Pegylated (40 kDa) (PEGASYS R ) interferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively controlled multicenter study. Gastroenterology 2001;120:A55.
4. Heathcote J, Shiffmann M, Cooksley G et al. Peginterferon alfa 2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673–80.
5. Roche data on file.
6. Shiffman ML. Hepatitis C and co-morbid conditions. AASLD Single Topic Conference, Chicago April 2002.
7. Lucey MR, Brown KA, Everson GT, Fung JT, Gish R, Keeffe EB, Kneteman NM et al. Minimal listing criteria for placement of adults on the liver transplant waiting list: A report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transplantation and Surgery 1997;3:628–37.
8. Everson GT, Trouillot T, Trotter J, Skilbred J, Halprin A, McKinley C, Fey B, Epp J. Treatment of decompensated cirrhotics with a slow-accelerating dose regimen (LADR) of interferon-alfa-2b plus ribavirin: safety and efficacy. Hepatology 2000;32:308A.
9. Crippen JS, Sheiner P, Terrault NA, McCashland T, Charlkton M. A pilot study of the tolerability and efficacy of antiviral therapy in patients awaiting liver transplantation for hepatitis C. Hepatology 2000;32:308A.
10. Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatology 2001;35:666–78.
11. Berenguer M, Prieto M, Rayon JM et al. Natural history of clinically compensated HCV-related graft cirrhosis following liver transplantation. Hepatology 2000;32:852–8.

Therapy of Acute Hepatitis C

Alfredo Alberti, M.D.

Acute hepatitis C is uncommon and difficult to recognize and to diagnose. The main reasons are the following: a) the incidence of new infections with HCV has greatly decreased during the past decade in all civilized countries; b) acute hepatitis C is often mild and asymptomatic; c) there is no specific diagnostic test to identify acute infection with HCV and to distinguish it from reactivation phases that may occur in chronic infection. As a consequence, acute hepatitis C has been difficult to study and there is still limited information about its natural history and optimal management strategies. Early studies, which were conducted mainly in cases with acute post-transfusion NANB (Type C) hepatitis, indicated that this condition has an extremely high propensity to become chronic. On the basis of these observations, and of the data on the treatment of chronic hepatitis C with interferon, a number of studies have been conducted since the early 1990s to assess whether interferon therapy could prevent chronic outcome of acute hepatitis C.

Seventeen studies on the treatment of acute HCV infection with interferon have been published either as full papers (13) or as letters/abstracts (4), including 7 randomised controlled trials, 5 controlled but not randomised trials, and 5 studies without an untreated control group. Of these latter, 2 were randomised trials in which different treatment schedules were compared. In all these studies interferon (alfa or beta) monotherapy was used; there are no available reports on the treatment of acute hepatitis C with interferon plus ribavirin combination therapy or with the pegylated interferons. Overall, 295 treated patients and 162 untreated cases with acute hepatitis C have been included, with a sample size of 6–97 patients in each individual study. Analysis of the 17 published reports reveals great heterogeneity with respect to: (1) inclusion criteria and patients characteristics (for example, some studies included asymptomatic cases seen during prospective surveillance of transfused or otherwise exposed patients while others included only symptomatic cases identified clinically; 7 studies were conducted in PTH cases, 6 in patients with non-transfusion related hepatitis C, and 4 included a mixture of the two subgroups); (2) timing of treatment initiation (early or delayed treatment after infection or after clinical onset); (3) type of interferon used (interferon alfa: 12 studies, interferon beta: 5 studies); (4) dose and schedule of administration (total cumulative dose ranging from 8.4 MU to 780 MU, with daily administration in 4 studies, tiw administration in 10 studies, and daily induction followed by tiw administration in 3 studies); (5) duration of post-treatment followup (ranging from 6 to 36 months); (6) end points of biochemical (ALT) response only: 5 studies; biochemical (ALT) and virological (HCV-RNA) response: 12 studies.

Pooling all data from the 17 studies, an end-of-therapy biochemical (ETR-ALT) and virological (ETR-HCV-RNA) response was seen in 76 percent (range 15–100 percent) and in 82 percent (37–100 percent) of treated patients and in 24 percent (10–44 percent) and in 10 percent (0–20 percent) of untreated patients, respectively. A sustained biochemical (SR-ALT) and virological (SR-HCV-RNA) response was seen in 61 percent (25–100 percent) and 62 percent (37–100 percent) of treated patients and in 26 percent (16–50 percent) and 12 percent (0–20 percent) of untreated cases, respectively.

Results of RCTs

Among the 7 RCTs published, 4 were conducted in PTH cases with an identical schedule of 3 MU tiw of interferon alpha given for 12 weeks. These 4 studies were homogeneous and could be pooled together in a recent meta-analysis (Cochrane review). According to the results of this analysis, the ETR-HCV-RNA was 42 percent (95 percent CI 30–56 percent) with interferon vs. 4 percent (0–13 percent) with no treatment (p<0.00001), while SR-HCV-RNA was 32 percent (21–46 percent) with IFN vs. 4 percent (0–13 percent) without therapy (p= 0.00007). IFN therapy was associated with 45 percent (31–59 percent, p=0.00001) and 29 percent (14– 44 percent, p=0.0002) increase in ETR-HCV-RNA and SR-HCV-RNA, respectively, compared with no treatment. These results prove that interferon therapy is associated with a significant reduction of chronicity when given to patients with post-transfusion acute hepatitis C, even using a relatively low dose for a relatively short period. However, around 2/3 of the patients treated with this regimen still developed chronic infection.

Other Studies

Other studies have used more aggressive treatment schedules with higher IFN dosages and longer periods of administration, and these approaches have usually resulted in higher rates of sustained virological response. Unfortunately, most of these studies were conducted without a randomised untreated control group. Furthermore, many of them included patients with acutesymptomatic hepatitis C often acquired through a non transfusion source. In these cases, rates of spontaneous resolution of acute hepatitis C might be significantly higher than in asymptomatic cases with PTH. In studies where 5–10 MU of interferon were given daily for 4–12 weeks or up to ALT normalization, followed by the same or a lower IFN dose given tiw for 20–40 additional weeks, rates of sustained virological response reached 83 to nearly 100 percent. In other studies, conducted in similar patient cohorts treated with lower doses of IFN (3–6 MU tiw for 3–6 months), rates of sustained virological response were between 37 and 64 percent. In one study comparing different regimes of daily beta IFN, there was a clear dose dependent effect on sustained response rates. In those studies where an untreated control (although not randomised) group was included for comparison, rates of spontaneous resolution were usually lower (8–21 percent) although a statistically significant difference was rarely obtained due to the small number of patients included. These results indicate that high rates of sustained virological response (24 week SR) can be achieved in acute hepatitis C with IFN monotherapy, in a setting where the expected rate of spontaneous resolution can be estimated around 10–40 percent.

Predictors of Response

Pre-treatment HCV-RNA levels were reported in 5 studies. In 3 of them there was a statistically significant correlation with sustained virological response that was higher with lower viraemia. Interestingly, this association was lost when high dose IFN (5–10 MU daily) schedules were used. The HCV genotype was reported in 7 studies, but in only 2 of them was there a significant association between the HCV type and response (better with HCV2/3 and worse with HCV1).

Tolerability Profile

Detailed description of side/adverse effects seen during therapy has been reported only in 7 studies, with a total of 145 treated patients. The tolerability profile of IFN therapy was very similar to that usually observed when treating patients with chronic hepatitis C. Therapy was well tolerated also in patients with jaundice or very high ALT levels. No ALT flares or deterioration of liver function were observed during therapy, apart from one single patient treated with 10MU daily who developed “acute lobular hepatitis” after HCV-RNA clearance and required a short period of steroid treatment. Overall, the available data do not indicate higher rates of IFN associated side/adverse effects or unexpected adverse effects in patients with acute hepatitis C when compared with what is reported in patients treated for chronic hepatitis C.

Unsolved Issues and Conclusions

Whom to treat: Acute HCV infection may be seen in individuals with minimally elevated or completely normal ALT and serum HCV-RNA positivity following known exposure or needle-stick injury or in sick patients with symptomatic acute hepatitis C, exemplified by very high ALT levels and jaundice. Available data would indicate that the effect of IFN therapy is independent of the clinical phenotype, although more data is needed to better define outcomes with and without therapy in different patient subgroups and to determine safety of therapy in severely ill cases.

When to start therapy: Immediate treatment of all cases with acute HCV infection means giving unnecessary therapy to those who would have recovered spontaneously. A strategy of delaying therapy by 2–3 months after diagnosis should allow giving treatment only to patients with a high risk of chronic outcome. This approach might be particularly rational in those subgroups of patients in which a high rate of spontaneous recovery is expected, such as children, young adults (particularly women), and patients with jaundice. It remains to be defined whether delaying therapy could reduce its efficacy due to HCV quasispecies expansion towards a more heterogeneous and resistant virus population, as the infection evolves into chronicity. Available data, albeit limited, tends to suggest that delaying therapy by 2–3 months does not compromise the probability of a favorable response to interferon.

How to treat: The optimal schedule in terms of risk/benefit and cost/effectiveness ratio is far from having been defined. Available data would indicate that the minimum requirement for obtaining a significant benefit compared to untreated patients is to use 3 MU tiw for at least 12 weeks. With such a regimen, however, only between 30 and 40 percent of treated patients develop a sustained virological response. More aggressive regimens, based on induction with daily IFN (5 to 10 MU) followed by tiw therapy for 4–6 months, may allow the achievement of a sustained virological response (24 week SVR) in almost 100 percent of the cases. On the basis of these findings, studies with the PEG-IFNs are urgently needed. Combination therapy with addition of ribavirin might not be essential to treat most cases of acute hepatitis C, but this also needs to be explored in clinical trials.

Long-term benefit of treatment: More prolonged followup of patients with acute hepatitis C treated with interferon is needed. Most published studies refer to sustained virological response at 24 weeks after therapy. Studies on the natural history of acute hepatitis C have indicated the need for an accurate and prolonged virological followup to predict long-term outcomes as transient phases of HCV-RNA negativity occur after acute phase in patients with chronic evolution of hepatitis C. Furthermore, long-term clinical outcomes should be accurately modeled in treated and untreated patients considering the low rate of clinically relevant chronic sequelae seen during the first two decades of infection with HCV. Nevertheless, if a near 100 percent eradication of HCV can be achieved with IFN therapy in acute infection, it seems quite difficult not to believe that this result should transfer into significant clinical benefit in many of the patients.

References

1. Orland JR, Wright TL, Cooper S. Acute hepatitis C. Hepatology 2001;33:321–7.
2. Alberti A. Interferon therapy of acute hepatitis C. Viral Hepatitis Reviews; 1995;1:37–45.
3. Poynard T, Regime C, Myers RP, Thevenot T, Leroy V, Mathurin P, Opolon P, Zarski JP. Interferon for acute hepatitis C (Cochrane Review). In: The Cochrane Library, Issue 1, 2002. Oxford:Update Software.
4. Quin JW. Interferon therapy for acute hepatitis C viral infection. A review by meta-analysis. Aust N Z J Med 1997;27:611–17.
5. Jaekel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns MP, German Acute Hepatitis C Therapy Group. Treatment  C with interferon alfa 2b. NEJM 2001;345:1452–7.
6.  Hoofnagle JH. Therapy for acute hepatitis C. NEJM 2001;345:1495

Utility of Liver Biopsy in Management of Hepatitis C: A Systematic Review

Khalil G. Ghanem, Michael Torbenson, Mollie W. Jenckes, Kelly A.

Gebo, Geetanjali Chander, Mark S. Sulkowski, Kirk A. Harris, Samer

El-Kamary, Eric B. Bass, and H. Franklin Herlong

Introduction

Liver biopsies are frequently recommended in the management of patients with chronic hepatitis C. Histologic criteria have been established to assess the severity of both inflammation and fibrosis. However, it remains uncertain how this information assists in establishing prognosis or predicting efficacy of treatment.

Objective

We conducted a systematic review of the literature to determine: (1) how the results of initial liver biopsy relate to measures of disease progression and treatment outcome as assessed by histologic and virologic parameters and (2) the value of serum biochemistry tests and serologic measures of fibrosis in predicting histologic findings.

Methods

Literature Sources

Seven electronic databases were searched through DIALOG for the period from January 1996 to March 2002. Additional articles were identified by searching references in pertinent articles, hand searching relevant journals, and querying technical experts.

Eligibility Criteria

Exclusion criteria for review included: non-English language, articles limited to basic science or non-human data, previously reported data, and meeting abstracts. Inclusion criteria for review were: study designed to address our key question, information pertinent to management of hepatitis C, and 30 or more study subjects with hepatitis C. In addition, for those studies pertaining to how results of initial liver biopsy relate to measures of disease progression and treatment outcome, we required at least six months of followup after initial biopsy and outcomes measured by an appropriate objective standard such as virologic or histologic measures.

Assessment of Study Quality

Each eligible article was reviewed by a pair of reviewers, including at least one team member with relevant clinical training and/or one with training in epidemiology and research methods. Paired reviewers independently rated the quality of each study in terms of the following categories: representativeness of study subjects (5 items); bias and confounding (4 items); description of therapy (4 items); outcomes and follow-up (5 items); statistical quality and interpretation (4 items). Reviewers assigned each response level a score of 0 (criterion not met), 1 (criterion partially met), or 2 (criterion fully met) to each relevant item on the quality form. The score for each category of study quality was the percentage of the total points available in each category and therefore could range from 0–100 percent. The overall quality score was the average of the five categorical scores. We also documented source of funding.

Extraction of Data

The paired reviewers also abstracted data on type of study and geographical location; the study groups; specific aims; the inclusion and exclusion criteria; demographic, social, and clinical characteristics of subjects; and results. Differences between the two reviewers in either quality or content abstraction were resolved by consensus.

Synthesis

Results of Literature Search

We identified 3,104 potentially relevant citations and 1,731 of these were eligible for abstract review. Through the abstract review process we identified 254 articles that could contain data on one of our key questions regarding the utility of liver biopsy in patients with chronic hepatitis C. After reviewing these 254 articles, we found 147 studies that addressed the value of initial or follow-up biopsies predicting treatment outcomes and 107 articles that addressed the relationship between serological markers and histological findings. We subsequently reviewed the full articles to ensure they met our eligibility criteria. We have focused on randomized controlled trials of therapies for which assignment to a treatment was not determined by biopsy results. Data from these eligible studies will be presented in a series of evidence tables and figures highlighting their distinguishing characteristics, methodologic strengths and limitations, and key findings.

Hepatitis C and HIV

David L. Thomas, M.D.

An estimated 150–300 thousand person are infected with both hepatitis C virus (HCV) and HIV in the United States. Although the management of hepatitis C in HIV infected persons in 2002 is largely predicated on data from persons without HIV, it is important to appreciate the extent to which HIV infection may modify the transmission, natural history, diagnosis, and treatment of hepatitis C. (1)

Transmission

In more than 60 percent of published studies, the rate of HCV transmission from an HIV/HCV co-infected mother to her infant is greater than from HIV uninfected mothers. Increased heterosexual HCV transmission from HIV/HCV co-infected persons also has been reported, but in fewer than half of studies. Nonetheless, these data do not substantially modify existing United States Public Health Service recommendations for recognition and prevention of HIV and HCV transmission. (2,3)

Natural History

In the majority of published studies, progression of hepatitis C to cirrhosis and end-stage liver disease occurs more rapidly and in a greater proportion of HIV/HCV co-infected persons, and in several hemophilia cohorts and HIV treatment clinics, end-stage liver disease is a or the leading cause of death among HIV infected persons. Although the risk of cirrhosis associated with HIV infection varies substantially in different settings, in a meta-analysis, Graham and coworkers estimated that the average risk of progressive liver disease is 2.9-fold (95 percent CI, 1.7–5.0) higher in HIV/HCV co-infected persons. (4) Large prospective studies are needed in unbiased HIV/HCV co-infected populations to characterize the risk of cirrhosis more precisely. In the meantime, decisions regarding the timing of medical treatment and the frequency of monitoring HIV/HCV co-infected persons (e.g., by liver biopsy or with fibrosis markers, if available) should be commensurate with the observed increased risk and rate of progression to end-stage liver disease.

Diagnosis and Screening

Because the prevalence of hepatitis C is increased in HIV infected persons and HIV/HCV co-infected persons have an increased risk of cirrhosis and HAART-related liver toxicity, the United States Public Health Service and Infectious Diseases Society of America recommend that all HIV infected persons be screened for hepatitis C by using an enzyme immunoassay for detection of antibodies to HCV.(3)  HCV antibodies can be detected in the majority of HIV/HCV co-infected persons. However, in some studies HCV antibodies were not be detected in up to 10 percent of HIV/HCV co-infected persons, especially in those with advanced HIV-related immune suppression (CD4+ lymphocytes < 100/mm³ ). Thus, it is reasonable to test for HCV RNA in HCV antibody negative, HIV infected persons with unexplained liver enzyme elevations.

Treatment

No medications are approved by the United States Food and Drug Administration for the treatment of HCV infection in HIV infected persons, reflecting the absence of completed, randomized controlled trials investigating the treatment of more than 100 HIV/HCV co-infected persons. Therefore, the timing and choice of medical treatment for HIV/HCV co-infected persons are largely driven by their increased rate of progression of liver disease and the results of treatment of HIV uninfected persons. Nonetheless, a number of important issues in the treatment of hepatitis C in HIV infected persons can be addressed by accumulating published and formally presented data.

1. Sustained virologic responses can be achieved in HIV infected persons. Soriano et al. have demonstrated loss of HCV RNA from serum for >3 years after a course of interferon alpha in HIV infected persons. (5)
2. The addition of ribavirin to interferon alpha improves the likelihood of on-treatment (and presumably sustained) virologic responses in HIV/HCV co-infected persons. In an interim analysis of data from 110 HIV/HCV co-infected persons randomized to interferon alfa-2b with ribavirin or placebo, HCV RNA was undetectable after 12 weeks of therapy among 23 percent of persons receiving combination therapy compared to 5 percent of those receiving interferon alone. (6)
3. On-treatment virologic responses to pegylated interferon and ribavirin are better than responses to unpegylated interferon alpha and ribavirin. In ACTG a5071, in which 134 persons were randomized to pegylated interferon alpha plus ribavirin or unpegylated interferon alpha plus ribavirin, week 24 virologic responses were noted in 15 percent of those in the unpegylated arm vs. 44 percent of those randomized to pegylated interferon alpha, an effect that was also observed among persons with genotype 1 infection (7 percent vs. 33 percent, respectively). (7)
4. Although in vitro studies suggest ribavirin may diminish the efficacy of AZT, d4T, and 3TC, and increase levels of ddI, in several small published and presented case series, HIV RNA levels do not increase more in HIV/HCV co-infected persons taking ribavirin than in controls. Given apparent benefits and the burden of disease, many experts currently recommend its use in the treatment of hepatitis C in HIV/HCV co-infected persons, with careful monitoring.
5. As with HIV uninfected persons, the likelihood of a sustained virologic response in HIV/HCV co-infected persons varies by HCV genotype, pretreatment immune status, and other factors like HCV RNA level, stage of liver disease, gender, possibly race, and duration of treatment, which may need to be longer when virologic responses are delayed and in immunosuppressed persons.
6. Some HIV/HCV co-infected persons will not be able to take existing medical therapies, and liver transplant is rarely available for HIV/HCV co-infected persons.

Conclusion

Given the mounting morbidity and mortality associated with hepatitis C in HIV infected persons, the management tools (e.g., HCV RNA testing and liver biopsy) and therapies (e.g., pegylated interferon alpha and ribavirin) recommended for management of hepatitis C in persons without HIV should be made available for HIV/HCV co-infected persons while research is vigorously conducted to demonstrate their optimal use.

References

1. Sulkowski MS, Thomas DL. Hepatitis C in the HIV infected Patient. Ann Intern Med 2002 (in press).
2. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47 (No. RR-19):1–39.
3. CDC. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: disease-specific recommendations. MMWR 1999;48:1–82.
4. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis c virus infection: a meta-analysis. Clin Infect Dis 2001;33:562–9.
5. Soriano V, Bravo R, García-Samaniego J, Castilla J, González J, Castro A, Llibre JM. Relapses of chronic hepatitis C in HIV-infected patients who responded to interferon therapy. AIDS 1997;11:400–1.
6. Kostman JR et al. Results of a multicenter, randomized, double-blind, controlled trial of interferon alfa-2b/ribavirin combination therapy in HCV/HIV co-infected persons. Program and abstracts of The 1st IAS Conference on HIV Pathogenesis and Treatment; July 8–11, 2001; Buenos Aires, Argentina. Abstract 555.
7. Cheung R, Andersen J, Alston MV, Robbins G, Nevin T, Colquhoun D, Sherman K, Peters M, Harb G, volderding P, van der Horst, C. A randomized controlled trial of pegylated interferon alpha-2a with ribavirin versus interferon alpha-2a with ribavirin for the treatment of chronic HCV in HIV co-infection. ATG A5071. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, 2002. Abstract LB15.

Injection Drug Use and Hepatitis C

Brian R. Edlin, M.D.

Injection drug users (IDUs) constitute the largest group of persons infected with the hepatitis C virus (HCV) in the United States, and most new infections occur in IDUs. Controlling the HCV epidemic, therefore, will require developing, testing, and implementing prevention and treatment strategies that will be effective in persons who inject drugs. Preventing morbidity and mortality from HCV will require reducing exposure to HCV, reducing infection among those exposed, and reducing disease among those infected. Injection drug use could be greatly reduced if all those who needed substance abuse treatment could get it (prevention of exposure). HCV spread among drug users can be prevented if drug users have access to sterile syringes, HCV counseling and testing, and outreach programs that teach them how they can avoid acquiring and transmitting the virus (prevention of infection). Finally, barriers to medical treatment must be overcome so that drug users can benefit from advances in HCV treatment (prevention of disease). (1) HCV treatment may also reduce transmission (prevention of infection), because HCV-infected IDUs are the source for most HCV transmission in the United States. Efforts are particularly important to identify persons with new HCV infections, in whom treatment may be more effective during the acute phase than later, and those with advanced hepatic fibrosis, in whom treatment may improve survival.

Caring for drug user’s presents special challenges to the health care team that require patience, experience, and tolerance. Fortunately, substantial research and clinical experience in the prevention and management of chronic viral infections among IDUs, especially HIV infection, has led to the development of effective principles for engaging drug users in health care relationships (Table). (2–5) Learning from this experience will be critical for efforts to control HCV. Successful programs invariably adopt a respectful approach to substance users, understand the medical and behavioral sequelae of addiction, and refrain from moralistic judgments. These strategies reflect a harm reduction approach. (6,7) Harm reduction strategies help patients reduce high-risk behaviors without imposing unrealistic demands for global change. When ceasing all drug use is not likely in the immediate future, other measures must be taken to help patients reduce the harmful consequences of injection drug use. (8,9)

Decisions about the treatment of HCV infection in patients who use illicit drugs, as in other patients, should be made by the patients together with their physicians based on individualized risk-benefit assessments. (1) Adherence, psychological side effects, and the possibility of reinfection present challenges to effective treatment for some drug users. Fortunately, an array of effective strategies exists to overcome each of these challenges. Attention to ensuring optimal adherence is important for all patients, not just those who use drugs. (10) This is so because although certain risk factors for noncompliance have been identified, including depression, psychological stress, homelessness, lack of social support, and drug use, physicians are not able to predict accurately which patients will adhere to a treatment regimen. (11) Effective strategies for improving adherence range from basic clinical practices—such as establishing a consistent, trusting physician-patient relationship, providing clear information about intended effects and side effects of medication, and paying careful attention to perceived side effects—to specialized tools such as electronic reminder systems, directly observed therapy, and cash incentives. (12–17) Simplifying complex treatment regimens, treating depression, or helping a homeless patient find housing can help improve adherence. Patients may also benefit from counseling addressing individual barriers to and facilitators of adherence in the patient’s life.

1. Establish a climate of mutual respect.
2. Maintain a professional approach that reflects the aim of enhancing patients’ well-being; avoid creating an atmosphere of blame or judgment.
3. Educate patients about their medical status, proposed treatments, and their side effects.
4. Include patients in decision-making.
5. If possible, establish a multidisciplinary team consisting of primary care physicians, HIV specialists, psychiatrists, social workers, and nurses.
6. Have a single primary care provider coordinate the care delivered by such a team to maximize consistency and continuity.
7. Define and agree on the roles and responsibilities of both the health care team and the patient.
8. Set appropriate limits and respond consistently to behavior that violates those limits.
9. Minimize barriers to participation (penalties for missed visits, etc.).
10. Recognizing that patients must set their own goals for behavior change, work with patients to achieve commitment to realistic goals for healthier behaviors.
11. Acknowledge that abstinence is not always a realistic goal; emphasize risk reduction measures for patients who continue to use drugs.
12. Acknowledge that sustaining abstinence is difficult and that success may require several attempts
13. Be familiar with local resources for the treatment of drug users

    The psychological side effects of interferon-based regimens for the treatment of HCV infection is of concern in all patients. Interferon may have severe psychological side effects in patients with or without pre-existing psychiatric disorders. (18,19) To minimize psychological toxicity, all patients should be screened for depression and other mental health conditions before undergoing HCV treatment, treated for these conditions if necessary, and monitored for them during HCV treatment.

    Because those successfully completing HCV therapy may be at risk for reinfection, drug users need detailed counseling and support to avoid risky injection practices in case they continue or return to injecting drugs. Those who inject drugs after receiving effective treatment for HCV infection can avoid reinfection by using a new sterile syringe for each injection and by not sharing their injection equipment with other users. (20,21) There are 174 syringe exchange programs in 120 cities in 34 states in the United States, and the number is increasing yearly. For drug users without access to such programs, physicians in at least 46 states are allowed by law to prescribe syringes so that their patients can avoid acquiring and transmitting blood borne infections. (22–24) IDUs can master safe injection practices, and many do inject safely. When given access to sterile syringes, IDUs readily make use of them, reducing their high-risk behavior (25–27) and rates of disease transmission. (28,29) Physicians should refer patients who inject drugs to syringe exchange programs or, if necessary, prescribe syringes for them. HCV may be more readily transmitted than the human immunodeficiency virus (HIV) through the sharing of injection equipment other than syringes, such as “cookers” (bottle caps, spoons, and other containers used to dissolve drugs) and “cottons” (filters used to draw up the drug solution into a syringe). (30) Thus, it is particularly important for physicians to instruct their patients not to share these items. (20,21)

    All injection drug users should be offered treatment for substance abuse and such treatment should be provided to those wishing it. Medical services should be integrated with substance abuse treatment. (3) Alcohol treatment is particularly important because of the strong effect of heavy alcohol intake on the progression of hepatitis C. Finally, all patients with HCV infection should be instructed in how to avoid transmitting the infection to others. Patients should be warned that their blood may be infectious even in minute quantities. Those who inject drugs should be instructed not to share syringes or any other injection equipment with other persons and to avoid blood contact with others. They should be given biohazard sharps containers or instructed to safely dispose of injection equipment in puncture-resistant containers. (31)

Clinical Data

There is abundant evidence that when treatment strategies for drug users take into account the circumstances of their lives, very high rates of adherence can be achieved. (11,15–17,32–38) Several recent studies have demonstrated the safety and effectiveness of hepatitis C treatment in drug users, even when they are not completely abstinent from drug use. (39–41) Backmund et al. reported a 36 percent sustained virologic response rate in 50 injection drug users who were treated simultaneously for HCV infection and substance abuse, even though 80 percent of the patients relapsed to drug use. (39) Sustained response rates were not significantly different for patients who relapsed and those who did not. All patients were treated and supervised by physicians who specialized in both hepatology and addiction medicine. Patients who relapsed to drug use were offered opiate replacement therapy and were allowed to continue their HCV treatment even if they injected heroin again. The strongest predictor of virologic response was whether patients continued to keep their appointments; 45 percent of those who kept > 67 percent of their appointments but only 6 percent of those who did not had sustained virologic responses. This study demonstrates the importance of combining expertise in both hepatology and substance abuse and maintaining strong relationships with patients that can be sustained even through relapse to drug use.

Sylvestre et al. have treated 67 methadone maintenance patients with combination interferon/ribavirin, with an interim sustained virologic response rate in the first 59 patients of 29 percent, a rate identical to that in a comparison group of nonopioid-dependent patients. (40) No serious side effects occurred, although 61 percent of the patients had a prior psychiatric diagnosis. Response rates were not significantly different in patients who did or did not have 6 months of sobriety, or in patients who did or did not consume alcohol. They were not significantly worse in patients who continued using drugs unless they used every day. This study demonstrates that HCV can be effectively treated in patients receiving maintenance opiate replacement therapy despite substantial pre-existing psychiatric disease and despite ongoing, intermittent drug use.

Finally, Backmund et al. reported no reinfection during 24 weeks in 10 patients who continued to inject heroin. (39) They carefully instructed their patients how to avoid acquiring HCV when injecting drugs. Dalgard et al. reported one reinfection during 5 years in 9 patients who relapsed to injection drug use after sustained virologic responses to HCV treatment. (41)

Success in treating HCV infection in IDUs will require collaboration between experts in hepatitis and substance use to create programs specifically designed for drug users. Efforts to control HCV, including both prevention and treatment, can benefit from the expertise of those with experience working with drug users. Substance abuse treatment professionals have expertise working with drug users in treatment. Harm reduction workers and many substance abuse researchers have expertise working with out-of-treatment drug users. And many AIDS medical providers have expertise providing medical care to drug users both in and out of substance abuse treatment. Involvement of these professionals in HCV prevention and treatment efforts will greatly improve their effectiveness.

A sound policy for the control of the hepatitis C epidemic will require implementing prevention and treatment programs designed for IDUs, the group most severely affected by the epidemic. (42) Controlling the HCV epidemic, therefore, will require further research to develop and test prevention and treatment strategies that will be effective in persons who inject drugs. In the meantime, however, substantial progress can be made to control hepatitis C if existing knowledge and resources are brought to bear.

References

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2. O’Connor PG, Selwyn PA, Schottenfeld RS. Medical care for injection-drug users with human immunodeficiency virus infection. New Engl J Med 1994;331:450–9.
3. Weisner C, Mertens J, Parthasarathy S, Moore C, Lu Y. Integrating primary medical care with addiction treatment: a randomized controlled trial. JAMA 2001;286(14):1715–23.
4. Batki SL, Sorensen JL. Care of injection drug users with HIV. In: Cohen PT, Sande MS, Volberding PA, eds. The AIDS knowledge base: a textbook on HIV disease from the University of California, San Francisco and San Francisco General Hospital. 3rd ed. Philadelphia, PA: Lippincott, Williams and Wilkins, 1999. Available at URL: http://hivinsite.ucsf.edu/InSite.jsp?page=kb-03&doc=kb-03-03-06.
5. Wartenberg AA. HIV disease in the intravenous drug user: role of the primary care physician. J Gen Intern Med 1991;6(1 suppl):S35–40.
6. Des Jarlais DC, Friedman SR, Ward TP. Harm reduction: a public health response to the AIDS epidemic among injecting drug users. Annual Review of Public Health 1993;14:413–50.
7. Marlatt GA, ed. Harm reduction: Pragmatic strategies for managing high risk behaviors. New York: Guilford Press, 1998.
8. Robertson R, ed. Management of drug users in the community: a practical handbook. London: Arnold, 1998.
9. Gostin L. Waging a war on drug users: an alternative public health vision. Law Med Health Care 1990;18(4):385–94.
10. Sackett DL, Snow JC. The magnitude of compliance and noncompliance. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in health care. Baltimore: Johns Hopkins University Press, 1979, p. 11–22.
11. Bangsberg DR, Moss A. When should we delay highly active antiretroviral therapy? J Gen Intern Med 1999;14:446–8.
12. Friedland GH, Williams A. Attaining higher goals in HIV treatment: the central importance of adherence. AIDS 1999;13(Suppl 1):S61–72.
13. Panel on Clinical Practices for Treatment of HIV Infection. Adherence to potent antiretroviral therapy. In: Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Rockville, MD: U.S. Department of Health and Human Services, 2001. Available from URL: http://www.hivatis.org/guidelines/adult/text/adherence.html.
14. Reiter GS, Stewart KE, Wojtusik L, et al. Elements of success in HIV clinical care: multiple interventions that promote adherence. Topics in HIV Medicine 2000;8:21–30.
15. Bamberger J, Unick J, Klein P, Fraser M, Chesney M, Katz MH. Helping the urban poor stay with antiretroviral therapy. Am J Public Health 2000;90:699–701.
16. Lorvick J, Thompson S, Edlin BR, Kral AH, Lifson AR, Watters JK. Incentives and accessibility: a pilot study to promote adherence to TB prophylaxis in a high-risk community. Journal of Urban Health 1999;76:461–7.
17. Chaisson RE, Barnes GL, Hackman J, Watkinson L, Kimbrough L, Metha S, Cavalcante S, Moore RD. A randomized, controlled trial of interventions to improve adherence to isoniazid therapy to prevent tuberculosis in injection drug users. Am J Med. 2001;110(8):610–5.
18. Renault PF, Hoofnagle JH, Park Y, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147:1577–80.
19. Janssen HL, Brouwer JT, van der Mast RC, Schalm SW. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994;21:241–3.
20. U.S. Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Rockville, MD: Agency for Healthcare Research and Quality, 1996:591. Available at URL: http://www.ahcpr.gov/clinic/2ndcps/drugab.pdf.
21. HIV prevention bulletin: medical advice for persons who inject illicit drugs. Rockville, MD: Public Health Service, May 9, 1997. Available at URL: http://www.cdc.gov/hiv/pubs/hiv_prev.pdf.
22. Burris S, Lurie P, Abrahamson D, Rich JD. Physician prescribing of sterile injection equipment to prevent HIV infection: time for action. Ann Intern Med 2000;133:218–26.
23. Rich JD, Macalino GE, McKenzie M, Taylor LE, Burris S. Syringe prescription to prevent HIV infection in Rhode Island: a case study. Am J Public Health 2001;91(5):699–700.
24. Centers for Disease Control and Prevention. Fact sheet: physician prescription of sterile syringes to injection drug users. Atlanta, GA: Academy of Educational Development, 2002. Available at URL: http://www.cdc.gov/idu/facts/physician.htm.
25. Watters JK, Estilo MJ, Clark C, Lorvick JJ. Syringe and needle exchange as HIV/AIDS prevention for injection drug users. JAMA 1994;271:115–20.
26. Bluthenthal RN, Kral AH, Erringer EA, Edlin BR. Use of an illegal syringe exchange and injection-related risk behaviors among street-recruited injection drug users in Oakland, California, 1992–1995. J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:505–11.
27. Bluthenthal RN, Kral AH, Gee L, Erringer EA, Edlin BR. The effect of syringe exchange use on high-risk injection drug users: a cohort study. AIDS 2000;14:605–11.
28. Normand J, Vlahov D, Moses LE, eds. Preventing HIV transmission: the role of sterile needles and bleach. Washington, DC: National Academy Press, 1995.
29. National Institutes of Health. Interventions to prevent HIV risk behaviors. NIH Consensus Statement 11–13 February 1997;15(2):1–41. Available at URL: http://odp.od.nih.gov/consensus/cons/104/104_intro.htm.
30. Hagan H, Thiede H, Weiss NS, Hopkins SG, Duchin JS, Alexander ER. Sharing of drug preparation equipment as a risk factor for hepatitis C. Am J Public Health 2001;91:42–6.
31. Centers for Disease Control and Prevention. Fact sheet: physician prescription of sterile syringes to injection drug users. Atlanta, GA: Academy of Educational Development, 2002.   Available at URL: http://www.cdc.gov/idu/facts/aed_idu_dis.htm.

32. Broers B, Morabia A, Hirschel B. A cohort study of drug users’ compliance with zidovudine treatment. Arch Intern Med 1994;154:1121–7. 

33. Salomon N, Perlman DC, Rubenstein A, Mandelman D, McKinley FW, Yancovitz SR. Implementation of universal directly observed therapy at a New York City hospital and evaluation of an out-patient directly observed therapy program. Int J Tuberc Lung Dis 1997;1:397–404.
34. Moatti JP, Carrieri MP, Spire B, Gastaut JA, Cassuto JP, Moreau J. Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment. AIDS 2000;14:151–5.
35. Harrison K, Vlahov D, Jones K, Charron K, Clements ML. Medical eligibility, comprehension of the consent process, and retention of injection drug users recruited for an HIV vaccine trial. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10:386–90.
36. Gourevitch MN, Wasserman W, Panero MS, Selwyn PA. Successful adherence to observed prophylaxis and treatment of tuberculosis among drug users in a methadone program. J Addict Dis 1996;15:93–104.
37. Marco A, Cayla JA, Serra M, et al. Predictors of adherence to tuberculosis treatment in a supervised therapy programme for prisoners before and after release. Eur Respir J 1998;12:967–71.
38. Smirnoff M, Goldberg R, Indyk L, Adler JJ. Directly observed therapy in an inner city hospital. Int J Tuberc Lung Dis 1998;2:134–9.
39. Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of hepatitis C infection in injection drug users. Hepatology 2001;34:188–93.
40. Sylvestre DL, Aron R, Greene DR, Perkins P. Treating hepatitis C in recovering injection drug users (abstract #2886). Gastroenterology 2001;120:A-568.
41. Dalgard O, Bjoro K, Hellum K, et al. Treatment of chronic hepatitis C in injecting drug users: 5 years’ follow-up. Eur Addict Res 2002;8:45–9.
42. Edlin BR. Hepatitis C prevention and treatment for substance users in the United States: acknowledging the elephant in the living room. Int J Drug Policy (in press).

Alcohol and Hepatitis C

Marion G. Peters, M.D., M.B.B.S., and Norah Terrault, M.D.

Excess alcohol consumption can worsen the course and outcome of chronic hepatitis C. (1–3) However; adverse effects of moderate amounts of alcohol intake have not been clearly shown. (4) Alcohol use has been reported in some studies to be associated with higher HCV RNA levels and lower responses to therapy. (5) Despite a large number of publications on the topic of alcohol and hepatitis C, current evidence from the literature is not adequate to provide clear and definitive recommendations regarding alcohol use in patients with hepatitis C. In the absence of conclusive data, a conservative approach is taken and abstinence is usually recommended.

What Level of Alcohol Intake Is Harmful in Chronic Hepatitis C?

Poynard and coworkers compared liver histology of patients with hepatitis C drinking >50 g per day to that of non-drinkers and found a 34 percent increased rate of progression of fibrosis in heavy drinkers. (1) Associations between fibrosis progression and lesser amounts of alcohol intake were not significant, but the measurement of alcohol intake was assessed in a uniform, standardized manner. The HCV National Register Steering Group in the UK traced 924 patients who had received an anti-HCV-positive unit of blood for an average of >10 years after transfusion and assessed alcohol intake using validated questionnaires. (6) Liver-related deaths were increased among those who drank >20 units per week (approximately 30 g per day) in both patients with hepatitis C and controls. The Dionysos study analyzed hepatitis virus markers, alcohol intake (assessed by questionnaires of daily and lifetime intake), and clinical and biochemical evidence for liver disease among 6,917 unselected residents of two Northern Italian cities. (3,7) In all, 2.3 percent had HCV RNA and 62 percent drank alcohol, including 21 percent who drank more than 30 g per day. Both control subjects and persons with HCV who drank more than 30 g per day for >10 years had a threefold higher risk of cirrhosis (95 percent CI = 1.2 to 7.4, p<0.01). Intake below 30 g per day did not increase the risk of clinically apparent cirrhosis, but histology was not assessed in most patients. Harris and coworkers analyzed factors associated with cirrhosis among 206 patients who developed hepatitis C after transfusion and were followed for an average of 15 years in addition to a cohort of controls who were transfused but did not develop hepatitis C. (8) Among those with hepatitis C, 17 percent developed cirrhosis. The risk of cirrhosis increased fourfold among those who were also heavy drinkers (>80 g per day). Corrao and Arico analyzed results from two hospital-based, case-control studies of 285 patients with cirrhosis and 417 controls. (4) A lifetime daily alcohol intake of >50 g per day was associated with an increased risk of cirrhosis in both HCV-positive and negative subjects. The combination had an additive effect on the risk, and these risks were multiplied (synergism) at very high levels of alcohol intake (>125 g per day). Wiley and coworkers analyzed factors associated with more advanced liver disease in a cohort of 176 patients who underwent liver biopsy for chronic hepatitis C. (2) Alcohol intake of > 80 g daily was associated with a higher rate of cirrhosis (56 percent vs. 22 percent) and an increase in the estimated rate of progression of fibrosis. In a study from Japan, Khan and Yatsuhashi found higher degrees of fibrosis on liver biopsies from patients with chronic hepatitis C who drank alcohol compared to those who did not, and this increase was seen with both heavy (>80 g per day) and “moderate” (<80 g per day) alcohol intake. (9) Further delineation of effects of lower levels of alcohol intake was not given. Excess alcohol intake can also predispose to the development of liver cancer. (10) Thus, multiple studies have shown that heavy alcohol intake increases the risk of cirrhosis and liver cancer in hepatitis C, but the effects of moderate alcohol intake have not been adequately evaluated.

Are There Gender Differences in Effect of Alcohol on Progression of HCV Infection?

Chronic hepatitis C is often milder in women, but women may be more sensitive to the adverse effects of alcohol. The Dionysos cohort study found the risk of cirrhosis was twice as high in women as in men with the same alcohol intake. (3,7) Wiley et al. found a lower alcohol threshold for development of cirrhosis in women. (2) Thus, women may be at increased risk of alcohol effects on chronic hepatitis C.

What Are the Effects of Alcohol Consumption on Treatment of Hepatitis C?

Alcohol can affect the outcome of therapy in decreasing adherence or interfering with the antiviral actions of interferon or combination therapy. Virtually all large trials of therapy of hepatitis C have excluded persons who have a recent history of alcohol abuse, requiring a one- to two-year period of abstinence before therapy is initiated. However, the need for a period of abstinence has never been shown. Among patients treated for hepatitis C, a proportion continued drinking, and the ultimate response rate correlated inversely with the level of alcohol intake during therapy. The mechanism of the decreased response rate in patients drinking alcohol has not been defined. Some studies have shown that alcohol intake is associated with higher levels of HCV RNA (1,5) but other studies have not, (2,3,10) and the increase in HCV RNA levels with drinking alcohol has been modest. Thus, continued alcohol intake during therapy is likely to adversely affect the response to treatment, and both counseling and monitoring before and during therapy is recommended.

Does Alpha Interferon Therapy Cause Increase in Rate of Relapse Among Persons with a History of Alcohol Abuse or Dependence?

Relapse in alcohol intake during alpha interferon therapy has been reported, but the rate of relapse has not been compared in studies using untreated control patients. Nevertheless, the depression, irritability, and anxiety that occur in 20–30 percent of patients treated with alpha interferon are likely to be difficult for the patient with a recent history of alcohol dependence and predisposition to relapse.

Conclusions

While the effects of heavy daily alcohol intake on the course of chronic hepatitis C appear to be incontrovertible, lesser amounts of alcohol may not be harmful. On the other hand, abstinence appears to be prudent for the patient with chronic hepatitis C, particularly while receiving a course of alpha interferon or combination therapy. Patients with a history of alcohol abuse or dependence should be asked to be abstinent for a period before starting therapy and need to be supported by professional counseling and monitoring during therapy. Better studies using validated instruments to measure alcohol intakes in larger numbers of patients, followed for longer periods and with careful histological documentation, are needed to better define the effects of moderate alcohol intake on chronic hepatitis C and the need for abstinence before and during therapy. At the present time, there is no reason to withhold antiviral therapy of chronic hepatitis C from the patient with a history of alcoholism as long as adequate support can be provided during the period of therapy.

References

1. Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR, CLINVIR, and DOSVIRC groups. Lancet 1997;349:825–32.
2. Wiley TE, McCarthy M, Breidi L, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998;28:805–9.
3. Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Croce LS, Mazzoran L, et al. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut 1999;44:874–80.
4. Corrao G, Arico S. Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hepatology 1998;27:914–9.
5. Loguercio C, Di Pierro M, Di Marino MP, Federico A, Disalvo D, Crafa E, et al. Drinking habits of subjects with hepatitis C virus-related chronic liver disease: prevalence and effect on clinical, virological and pathological aspects. Alcohol Alcohol 2000;35:296–301.
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8. Harris DR, Gonin R, Alter HJ, Wright EC, Buskell ZJ, Hollinger FB, et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 2001;134:120–4.
9. Khan KN, Yatsuhashi H. Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol Alcohol 2000;35:286–95.
10. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155:323–31.