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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”



Controversial Issues in Hepatitis C Virus

 

American Association for the Study of Liver Diseases 50th Annual Meeting

Steven K. Herrine, MD

Introduction

Hepatitis C, its pathogenesis, natural history, and approaches to treatment were certainly a focal point of this year's meeting of the American Association for the Study of Liver Diseases in Dallas, Texas. Many of the seminal presentations concerning this virus and its clinical sequelae will be reviewed throughout the remainder of this meeting coverage. This summary will specifically review data presented on a variety of controversial areas in the world of clinical Hepatitis C Virus.

Hepatitis C Virus/HIV Coinfection

Background: Improved therapies and subsequent survival of patients infected with HIV have changed the approach to patients coinfected with HIV and hepatitis C virus (Hepatitis C Virus). The overall incidence of Hepatitis C Virus in patients infected with HIV is approximately 8%. [1] Progression to cirrhosis has been reported to be more common and more rapid in this patient population than in those infected with Hepatitis C Virus alone. [2] In addition to more rapid progression of liver disease, the clinical progression of HIV disease appears to be higher in those coinfected with Hepatitis C Virus. [3,4] Hepatitis C Virus treatment success rates are lower in these coinfected patients than in patients infected with Hepatitis C Virus alone, especially in those with lower CD4 counts. Furthermore, significant decreases in CD4 counts have been noted during interferon (IFN) therapy in coinfected patients. [5]

Treatment of Patients With Coinfection

Much of the research presented at this year's meeting concerned the treatment of patients coinfected with Hepatitis C Virus and HIV. Sauleda and colleagues from Barcelona reported a 50% virologic response at 6 months of combination IFN/ribavirin (RBV) therapy in 19 coinfected hemophiliacs. No worsening of CD4 count was seen in patients receiving highly active antiretroviral therapy (HAART). [6] Another group from Barcelona reported a virologic sustained response in 11.6% of 43 coinfected patients treated with IFN monotherapy. [7] Dr. Dieterich and colleagues reported that reduction in Hepatitis C Virus RNA was more profound in patients receiving IFN/RBV combination therapy than in those receiving IFN monotherapy. These 24 coinfected patients had significant fibrosis scores by biopsy. Further data on the virologic and histologic response of this cohort will prove very interesting. [8] A more novel approach to therapy was described by Dr. Schlaak and colleagues from Germany. A small cohort of coinfected patients was given interleukin (IL)-2, 2MU daily; a virologic response was observed in 2/7. More work with this compound seems indicated. [9]

Other Topics in Hepatitis C Virus/HIV Coinfection

Other investigations in Hepatitis C Virus/HIV coinfection included a report from Dr. Mika and associates on the viral pharmacokinetics of Hepatitis C Virus in HIV-infected patients. It is now well established that during IFN treatment, two phases of Hepatitis C Virus RNA decline are seen: there is a rapid decline shortly after IFN administration, corresponding to clearance of free virus, followed by a slower decline over the next several days, which corresponds to clearance of infected hepatocytes. In this study using IFN alphacon-1 given daily for a 2-week induction period, the first phase of kinetics was unchanged, but the second phase was slowed in those patients with Hepatitis C Virus/HIV coinfection. [10] This change in the second phase of pharmacokinetics may have implications in the design of further treatment strategies, particularly in the use of pegylated interferons. Finally, Zylberberg and associates reported that a higher than expected rate of antiretroviral hepatotoxicity was observed in those HIV patients coinfected with Hepatitis C Virus versus those with HIV infection alone. [12]

Hepatitis C Virus in Renal Disease and Dialysis

Background: Estimates of the prevalence of Hepatitis C Virus antibodies in patients on hemodialysis (HD) range from 15%-48% in North America. [12] The incidence of Hepatitis C Virus in HD patients is on the decline, probably due to blood product screening and tighter infection control measures in HD units. Unlike the non-HD population -- in part because baseline alanine aminotransferase (ALT) levels are depressed in patients on HD -- 50%-65% of patients with anti-Hepatitis C Virus antibodies have normal aminotransferases. [13] Although the natural history of Hepatitis C Virus infection in the HD population is largely unknown, liver failure is the cause of death in 8%-28% of long-term renal transplant survivors. [12] Viral load and genotype frequency in this setting are comparable to non-HD populations. End-of-treatment response rates (ETR) and sustained response rates (SR) are also similar to those found in non-HD patients when data are analyzed assuming intention to treat. The use of ribavirin in patients with endstage renal disease (ESRD) may be limited by hemolytic anemia.

 

Epidemiology

Saab and associates emphasized the fact that chronic hepatitis C infection continues to represent a significant problem in the chronic HD population. Seven dialysis centers participating in the UCLA Hepatitis Screening Program provided data regarding the incidence and prevalence of Hepatitis C Virus infection. Of 1251 HD patients, 7.8% were infected with Hepatitis C Virus using enzyme immunoassay (EIA)-III with confirmatory RIBA-II. The incidence of Hepatitis C Virus infection was found to be 260/100,000 patients. These data compare to current nationwide data on Hepatitis C Virus prevalence and incidence of 1.8% and 3/100,000, respectively. [14]

Progression of chronic Hepatitis C Virus after renal transplantation is suggested in a cohort study by Puoti and colleagues. Of 430 renal transplant recipients, 112 were Hepatitis C Virus RNA-positive (of which 49 had one or more liver biopsies after transplant). Fifty-five percent had mild to moderate inflammation, while 37% of these patients had at least some fibrosis on their baseline biopsies. Forty-eight percent of patients who had more than one biopsy showed progression in both grade and stage. Enrollment ALT, PCR, and immunosuppression were not correlated with histology or progression. [15] These findings are confirmed by Zylberberg, who observed 28 renal transplant patients with untreated Hepatitis C Virus who underwent at least two liver biopsies. Fibrosis progressed significantly more rapidly in these patients than in matched controls. Twenty-one percent of this cohort progressed to cirrhosis within 13 years of infection, with no correlation to level or type of immunosuppression. These data indicate that Hepatitis C Virus-infected patients who have received renal transplants are at substantial risk for fibrotic progression. [16]

Treatment of Hepatitis C Virus in Patients With Renal Disease

Treatment of Hepatitis C Virus in patients following renal transplant has led to a rather high incidence of graft malfunction and even graft loss. Degos and colleagues from France confirmed this experience in a report of a planned study of 120 patients terminated due to side effects, including "acute graft necrosis," myocardial disorders, pancreatitis, neurologic/psychiatric disorders, lymphoma, and infection. [17] Accordingly, treatment efforts have focused on this patient population prior to transplantation. Angelico's group took a novel approach by treating 10 patients on chronic HD with intravenous beta-interferon (3MU tiw). Although neither histologic or genotype data are provided, the 70% virologic SR at 6 months should provide the impetus for further study. [18]

Ribavirin in Renal Disease

Some of the most important data arising from this meeting concerned the safety profile of ribavirin in patients with abnormal renal function. Dr. Glue and his colleagues presented elegant data regarding the pharmacokinetics of ribavirin in patients with varying levels of renal insufficiency. Ribavirin levels were significantly increased in those patients with renal insufficiency due to the combined effects of higher oral bioavailability, decreased volumes of distribution, and decreased clearance. Furthermore, very little (<4%) of the ribavirin was removed by hemodialysis. In a follow-up tolerability study, most patients required dose reduction from a starting dose of 200 mg/d of ribavirin. Based on these data, the researchers recommended against the use of ribavirin in patients with creatinine clearance of < 50 mL/min. [19] A similar experience was reported by Tan and colleagues from The Netherlands. In a pilot study of 5 patients on chronic HD given IFN alpha-2b (3MU tiw) and ribavirin (200 mg/day), 2 patients had to stop ribavirin therapy at 7 weeks due to unacceptable hemoglobin concentrations. Dose reduction to 200 mg tiw was not tolerated in these patients. In 2 other patients, 200 mg tiw was tolerated, while the remaining patient tolerated 200 mg/d. The study's authors advised against ribavirin in HD patients. [20]

Alternative/Complementary Therapies

Background: Many practitioners have noted frequent use of complementary and alternative medicine (CAM) in their patients with chronic liver disease. Anecdotal evidence suggests widespread use of silymarin compounds among patients diagnosed with Hepatitis C Virus. The effects of silymarin are assumed to be due to antioxidant and hepatoprotective properties. Animal and in vitro studies with silymarin have demonstrated its protective effect against a variety of known hepatic insults, including bile duct occlusion, hepatic ischemia, alcohol, iron, acetaminophen, and carbon tetrachloride and phalloidin toxin extracted from Amanita phalloides . There are no published reports of silymarin toxicity. [21]

CAM

Leonard Seeff, MD, of the National Institutes of Health, gave a probing review of the status of CAM in chronic liver disease during the annual postgraduate course. His well-attended lecture provided a number of proposed definitions of CAM and also addressed a recent NIH conference designed to foster communication and understanding between allopaths and naturopathic practitioners. The formation of the National Center for Complementary and Alternative Medicine (NCCAM) of the NIH, with an operating budget of $50 million, should promote research into these types of therapies. A lively Meet-the-Professor Lunch with Dr. Seeff and Dr. Karen Lindsay of the University of Southern California was characterized by general acceptance of the further investigation of CAM in chronic liver disease.

Prevalence of CAM

Dr. Peyton and colleagues from Arkansas reported on 117 patients with chronic Hepatitis C Virus. Interview data revealed 36% of these patients were currently taking herbal preparations. One third of these users were doing so without the knowledge of their physicians. The most commonly used herbs were milk thistle, St. John's Wort, ginkgo biloba, ginseng, and echinacea. [22] Remarkably similar results were provided by Jensen and coworkers from Chicago who interviewed 60 patients, all on IFN -- 87% reported taking vitamins or supplements and 40% reported taking herbs, most commonly milk thistle, St. John's Wort, ginseng, and garlic extract. [23] Dr. Berk and colleagues from Oregon reported follow-up data on their 1996 findings, noting an increase in herbal usage from 31% to 42%. Milk thistle remains the most popular botanical used in this population. Average monthly expenditure was unchanged at $10-$30. [24]

Increasing acceptance and use of CAM seems inevitable in the practice of hepatology. The establishment of the NCCAM should provide the impetus and funding to allow further investigation of these approaches, which are not limited to botanicals, but include use of other such "healing systems."

 

Hepatitis C Virus With Normal Transaminases

Background: It has been estimated that at least 20% of those individuals chronically infected with Hepatitis C Virus have persistently normal serum aminotransferases. This group of patients has been reported to have milder histological activity and lower progression of fibrosis. [25] Treatment in this population has led to disappointing response rates and ALT flares during IFN administration. [26] More recent reports provide different data: no difference in histology was observed between patients with elevated ALT and those with persistently normal ALT, according to Puoti and colleagues, although 43% of these patients were infected with genotype 2a. [27]

Natural History of Patients With Normal ALT

The fact that patients with Hepatitis C Virus antibodies and persistently normal ALT levels are common is confirmed by data from the UK Hepatitis C Virus National Register, which noted that 42.7% of patients match this profile. [28] Martinot-Peignoux and associates provided valuable information on a cohort of 137 untreated patients with Hepatitis C Virus antibodies and persistently normal ALT. Thirty-one percent of these patients had undetectable virus. In those patients with viremia, liver biopsy was classified as mild in 80%. Follow-up biopsy in a group of 18 patients (3.5 ± 1 years later) showed moderate hepatitis in 66%, without a change in fibrosis score. Although the number of follow-up biopsies is insufficient to make a clear conclusion, the observed progression in inflammation lends credence to the theory that patients with persistently normal ALT levels are at risk for significant liver disease. [29]

Treatment of Patients With Normal ALT

Dr. Jacobson and colleagues from New York provided a preliminary report of IFN/ribavirin combination therapy in 18 patients with persistently normal ALT levels. In those patients for whom data were available, 11 (61%) had a virologic response at 24 weeks. No ALT elevations were observed during treatment. No data were provided on histology. [30] The question of the natural history and appropriateness of treatment of this group of patients remains controversial. Only large controlled trials will provide the required answers.

References

1.      Quan C, Krajden M, Grigoriew G, et al. Hepatitis C virus infection in patients infected with the human immunodeficiency virus. Clin Infect Dis 1993;17:117-119.

2.      Soto B, Sanchez-Quijano A, Rodrigo, et al. Human immunodeficiency virus infection modifies the natural history of chronic parenterally acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 1997;26:1-5.

3.      Piroth L, Duong M, Quantin C, et al. Does hepatitis C virus co-infection accelerate clinical and immunological evolution of HIV infected patients? AIDS 1998;12:381-388.

4.      Benhamou Y, Bochet M, DiMartino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus co-infected patients. Hepatology 1999;30:1054-1058.

5.      Soriano V, Garcia-Samaniego J, Bravo R, et al. Interferon-alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;23:585-591.

6.      Sauleda S, Esteban JI, Altisent C, et al. Impact of interferon plus ribavirin combination treatment on HIV infection in hemophiliacs with chronic hepatitis c and under HAART. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 134.

7.      Coll S, Sola R, Vila MC, Seoane A. Treatment of hepatitis C HIV-co-infected patients with interferon: controlled study. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 153.

8.      Dieterich DT, Weisz KB, Goldman DJ, Malicdem ML. Combination treatment with interferon (IFN) and ribavirin (RBV) for hepatitis C (Hepatitis C Virus) in HIV co-infection. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 422.

9.      Schlaak JF, Bueschenfelde KH, Gerken G, Galle PR. Sustained Hepatitis C Virus eradication after interleukin-2 therapy in patients with HIV/Hepatitis C Virus co-infection. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 431.

10.  Mika BP, McCarthy ME, Layden TJ, Wiley TE. HIV/Hepatitis C Virus co-infected patients experience Hepatitis C Virus viral rebound after the second day of IFN. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 140.

11.  Zylberberg H, Adda C, Nalpas B, et al. Incidence and predictors of acute hepatitis occurring under antiretroviral therapy including a protease inhibitor. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 698.

12.  Pereira BJG, Levey AS. Hepatitis C virus infection in dialysis and renal transplantation. Kidney International 1997;51:981-999.

13.  Rostaing L, Izopet J, Cisterne JM, et al. Prevalence of antibodies to hepatitis C virus and correlation with liver disease in renal transplant patients. American Journal of Nephrology 1997;17:46-52.

14.  Saab S, Langfield D, Gitnick G. Hepatitis C prevalence and incidence in dialysis patients. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 1288.

15.  Puoti M, Sandrini S, Chiappini R, et al. Liver histology in renal allograft recipients with chronic hepatitis C and without pre-transplant evidence of liver disease. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 1184.

16.  Zylberberg H, Nalpas B, Carnot F, et al. Renal transplantation is associated with severe evolution of chronic hepatitis C. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 1178.

17.  Degos F, Stanislas Pol S, Valerie Laffite V, et al. Multicentric prospective assessment of the tolerance and efficacy of alpha-2b interferon in hemodialysis patients. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 819.

18.  Angelico M, Morosetti M, Stefano P, et al. Safety and effectiveness of intravenous recombinant beta-interferon in Hepatitis C Virus-infected patients under maintenance hemodialysis: a pilot study. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 160.

19.  Glue P, Tan Y, Sack M, et al. Use of ribavirin in patients with renal and hepatic dysfunction - pharmacokinetic data and recommendations. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 596.

20.  Tan AC, Brouwer JT, Leusen RV, et al. Safety of interferon and ribavirin therapy in dialysis patient with chronic hepatitis C: results of a pilot study. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 813.

21.  Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113 .

22.  Peyton BG, Spears TL, Lindsey A, et al. A survey of the use of herbal medicine in patients with hepatitis C. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 123.

23.  Jensen DM, Ganger DR, Cotler SJ, et al. Herbal and vitamin/mineral supplement use during antiviral therapy for hepatitis C. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 130.

24.  Berk BS, Chaya C, Benner KG, et al. Comparison of herbal therapy for liver disease: 1996 versus 1999. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 1271.

25.  Mathurin P, Moussalli J, Cadranel JF, et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology 1998;27:868-872.

26.  Sangiovanni A, Morales R, Spinzi G, et al. Interferon alfa treatment of Hepatitis C Virus RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study. Hepatology 1998;27:853-856.

27.  Puoti C, Magrini A, Stati T, et al. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. Hepatology 1997;26:1393-1398.

28.  Harris HE, Ramsay MEB. The clinical course of Hepatitis C Virus-related disease in the first decade of infection: a preliminary analysis of data from the UK Hepatitis C Virus national register. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 1173.

29.  Martinot-Peignoux M, Boyer N, Le Breton V, et al. Anti-Hepatitis C Virus positive patients with persistently normal ALT characteristics and long term outcome. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 185.

30.  Jacobson I, Lebovics E, Tobias H, et al. Interferon alfa-2b and ribavirin in treatment-naive patients with chronic hepatitis C and normal ALT levels. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; Dallas, Texas; November 5-9, 1999. Abstract 1193.