Hepatitis C Information Central

Controversial Issues in HCV

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 HCV.

HCV/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 (HCV). The overall incidence of HCV 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 HCV 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 HCV. ^[3,4] HCV treatment success rates are lower in these coinfected patients than in patients infected with HCV 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 HCV 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 HCV 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 HCV/HIV Coinfection

Other investigations in HCV/HIV coinfection included a report from Dr. Mika and associates on the viral pharmacokinetics of HCV in HIV-infected patients. It is now well established that during IFN treatment, two phases of HCV 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 HCV/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 HCV versus those with HIV infection alone. ^[12]

HCV in Renal Disease and Dialysis

Background: Estimates of the prevalence of HCV antibodies in patients on hemodialysis (HD) range from 15%-48% in North America. ^[12] The incidence of HCV 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-HCV antibodies have normal aminotransferases. ^[13] Although the natural history of HCV 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 HCV infection. Of 1251 HD patients, 7.8% were infected with HCV using enzyme immunoassay (EIA)-III with confirmatory RIBA-II. The incidence of HCV infection was found to be 260/100,000 patients. These data compare to current nationwide data on HCV prevalence and incidence of 1.8% and 3/100,000, respectively. ^[14]

Progression of chronic HCV after renal transplantation is suggested in a cohort study by Puoti and colleagues. Of 430 renal transplant recipients, 112 were HCV 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 HCV 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 HCV-infected patients who have received renal transplants are at substantial risk for fibrotic progression. ^[16]

Treatment of HCV in Patients With Renal Disease

Treatment of HCV 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 HCV. 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 HCV. 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."

HCV With Normal Transaminases

Background: It has been estimated that at least 20% of those individuals chronically infected with HCV 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 HCV antibodies and persistently normal ALT levels are common is confirmed by data from the UK HCV 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 HCV 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

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