Doris B. Strader, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

The current recommendations for the management of patients with chronic hepatitis C are derived from a number of excellent multicenter trials. However, these trials primarily involve the treatment of a select group of patients with a single therapy, interferon plus ribavirin in combination. The selection of appropriate candidates for therapy involves an informal assessment of the patient’s eligibility for treatment, followed by screening of all eligible candidates. It is unclear how many patients are not initially assessed as eligible, yet among those who are considered eligible and subsequently screened for therapy, reports from recent clinical trials indicate that 30–50 percent do not satisfy inclusion criteria. ^(1–4) The most common reasons for exclusion include severe psychiatric illness; active alcohol and substance abuse, comorbid illnesses such as autoimmune disease, hemophilia, and renal disease; decompensated liver disease; normal ALT; and refusal to participate. In addition, recent data on the response rate of those who receive treatment with combination therapy (standard or pegylated interferon plus ribavirin) suggest that at best, 50 percent achieve a sustained viral response (SVR). ^(5–7) These data indicate that at least 60 percent of anti-HCV-positive patients are either ineligible for therapy or do not respond to the available therapy. This suggests that the bulk of data obtained regarding hepatitis C and the management recommendations that followed were gathered from a small minority of pristine patients. While extrapolations regarding the management of the larger population of patients with HCV and confounding medical problems were made, the body of emerging data indicates that this may not have been appropriate. It is evident from previous discussions during this Conference that some exclusion criteria may have been too rigid, and that the reported response and adverse event rates may not be widely applicable. As a result, it appears that a large proportion of patients with HCV do not benefit from current antiviral therapy. What is missing from the literature is management guidance with respect to this large group of patients.

Before management decisions can be made, it is necessary to ask several important questions. First, “Is current anti-HCV therapy optimal?” Clearly, if therapy is optimal, all available resources should be channeled into treating as many patients as is safely possible. However, if available therapy is not optimal, research into alternative therapies should be pursued. Optimal therapy should be considered both safe and efficacious among the broadest cohort of affected patients. Current accessible data from anti-HCV treatment trials with pegylated interferon plus ribavirin report SVRs of approximately 50 percent among the relatively small group who qualify for treatment. This compares favorably with previously reported overall SVRs of 38 percent among those treated with standard interferon plus ribavirin. While few published data exist regarding the response rates of standard IFN plus ribavirin post-marketing, review of a few studies, as well as unpublished data obtained from several investigators indicates that the actual observed SVR is closer to 15–25 percent. ^(1,2) Although the SVRs with pegylated IFN plus ribavirin are expected to be higher, using the above data it is likely that less than 50 percent of treated patients will achieve an SVR. Therefore, it seems prudent to encourage research into novel forms of therapy.

Preliminary work on a number of potential candidates is already under way. It appears that as with therapy for HIV, therapy for HCV may require a multi-drug approach that exploits the replicative process at various stages, thereby containing, or at best eliminating, infection. Possible therapies include protease inhibitors, helicase inhibitors, NS5B RNA-dependent RNA polymerase blockers, modified ribavirins, and HCV immunotherapy. (8) These and other novel therapies will be discussed in detail in a subsequent discussion and may be the best hope for successful treatment of hepatitis C.

Second, “In lieu of other therapies, what can be done to increase the eligibility of HCV-infected patients currently considered ineligible for treatment?” A great deal of effort has recently been expended in attempts to enlarge the pool of eligible candidates, therapy either by liberalizing the inclusion criteria or by prophylaxing against or aggressively treating common side effects. Crude estimations from available data suggest that among those excluded from treatment trials, 20 percent have ongoing alcohol abuse, 19 percent have severe psychiatric illness, 12 percent use illicit intravenous drugs, 10 percent have comorbid disease, 10 percent have decompensated liver disease, 5 percent have normal ALT, and the remainder refuse therapy, are of advanced age, are undergoing evaluation for treatment, or are homeless.

Treatment strategies for those with alcohol or drug abuse, normal ALT, co-infection with HIV,and those with organ transplants have been extensively discussed during the course of this Conference. While not discussed herein, there are some helpful data regarding the management of patients with HCV and hemophilia, renal disease, autoimmune hepatitis, severe psychiatric disease, and anemia. For example, recent studies in hemophiliac children with HCV suggest that therapy with IFN plus ribavirin is safe and well-tolerated in carefully monitored patients. ⁽⁹⁾

Conversely, data show that hepatitis C is common among hemodialysis patients and may adversely affect long-term graft survival in renal transplant recipients. Unfortunately, ribavirin is not dialyzed during standard dialysis and is associated with a dose-dependent hemolytic anemia, thereby limiting its use. Likewise, therapy of hepatitis C after renal transplantation has been disappointing. While one study showed an encouraging 16 percent sustained viral response rate and a 3 percent rejection rate, several others have shown a 50 percent incidence of graft rejection in renal transplant recipients. ⁽¹⁰⁾ As a result, an upcoming NIH workshop is planned to define the impact of HCV on the morbidity and mortality of those with end-stage renal disease as well as identify appropriate HCV treatment strategies in such patients. Trials in patients with HCV and autoimmune disease (hepatitis, sarcoidosis, SLE, etc.) advocate primary treatment of the autoimmunity as it appears that the risk of augmenting HCV with steroids is less than the risk of exacerbating autoimmune disease with interferon. ⁽¹¹⁾ However, it is unclear whether this

recommendation is absolute or whether there are “degrees” of autoimmunity (low ANA, mild disease) for which treatment with interferon is not contraindicated. Finally, attempts to increase the number of patients completing the full course of HCV antiviral therapy have been relatively successful using prophylactic antidepressants, aggressively treating interferon-induced depression, and advocating the use of erythropoetin or GMCSF for hematopoetic side effects. ^(12,13)

It is clear that the approach of liberalizing inclusion criteria and aggressively treating side effects may be laudable and reasonable among some patients, particularly those with genotypes 2 or 3 in whom the likelihood of achieving a SVR is approximately 80 percent. However, this approach may be more difficult to defend when considering those with less favorable genotypes and severe coronary or cerebrovascular disease, severe diabetes, mental retardation, seizures or  neurologic disorders, or cytopenias. In addition, there are groups of patients for whom the safety and efficacy of IFN plus ribavirin are less clear, specifically the elderly and African-Americans.

It is reasonable to assume that patients with severe CAD or cerebrovascular disease are at increased risk for the potential adverse effects of hemolytic anemia. Similarly, interferon has been suggested to increase insulin resistance and it is possible that severe diabetes may complicate response to HCV antiviral therapy by its affects on hepatic steatosis. However, to my knowledge, no data exist regarding the treatment of HCV-infected patients with mental retardation, seizures or neurologic disorders, and the elderly. By contrast, a great deal of data is

beginning to surface with respect to the disparity in response to antiviral therapy among patients of different racial groups. Although the numbers of patients are small, the data suggest that African-American patients with HCV are less likely to respond to IFN plus ribavirin than whites, Hispanics, or Asians. In addition, some trials indicate that African-American patients are more likely to suffer treatment side effects. At present, the NIH is conducting a trial evaluating the efficacy of IFN plus ribavirin therapy among African-American patients infected with HCV.

In this author’s view, the potential risk of adverse events does not appear to be balanced by the small potential benefit of a sustained viral response in the patient groups described above. Even if the goal is halting the progression of fibrosis, an appropriately designed prospective trial is necessary to definitely demonstrate the histologic benefit of interferon therapy in the absence of loss of virus before it can be routinely recommended to push interferon in those currently considered ineligible or who suffer severe side effects. Recommendations for the management of HCV among these groups should be individualized until further study, such as with pegylated interferons, provides guidance.

Finally, and importantly, “What is the appropriate management of patients who cannot be treated or fail to respond to treatment?” It is incumbent upon us to remember that “management” does not necessarily mean “treatment.” Management involves providing education and counseling, initiating treatment when indicated, and supplying supportive care to those for whom no clear options are available. The latter is particularly important in order to allay fears and ensure that patients are not lost to followup. At present, many patients with HCV who are not on treatment have a physical examination, blood tested for aminotransferas  and AFP levels, and an abdominal US (if indicated) every 6–12 months. While these practices are conventional, few data can provide an absolute timetable for followup. It is well-known that ALT level fluctuates during the course of HCV infection and is not an adequate marker of progression of disease. (14) Although abnormalities in albumin and prothrombin time may provide more information regarding the degree of liver disease, they are not specific for liver injury, are only prognostic markers, and decline at a rate that varies from patient to patient. In addition, somewhat contradictory information exists in the literature. On the one hand, the Japanese literature recommends AFP plus ultrasound screening every 3–4 months to detect early hepatic tumors, while on the other, several studies suggest that AFP is not a sensitive surveillance test for the presence of HCC and a number of other tests including descarboxyprothrombin time,   isoforms of AFP, and an isoenzyme of ã GT have been advocated as alternatives. (15–17)

Similarly,  the pros and cons of the usefulness and timing of liver biopsy have been much debated, and intensive research in identifying surrogate serum markers of inflammation and fibrosis is ongoing. These data underscore the controversies and challenges regarding the type and schedule of tests and visits needed to appropriately follow patients with HCV.

In the meantime, it is important that physicians provide HCV-infected patients with up-to- date information about the expected course of their infection, methods of preventing transmission of HCV, and avoidance of practices (such as alcohol abuse) which may contribute to worsening liver function. In addition, we must provide balanced advice regarding the risks and benefits of current therapy and any new therapies as they become available. Until further data are known, it is reasonable to perform a physical exam, perform a liver panel (include PT and platelet count), and check an AFP every 6–12 months. Finally, in lieu of a serum marker of hepatic fibrosis, it may also be prudent to consider a liver biopsy every 3–5 years, particularly in those whose liver function appears to be deteriorating. While it is clear that abnormalities in these tests will be apparent before clinical symptoms appear, data to assist in determining the frequency with which they should be obtained are necessary.

Hepatitis C research has come a long way in the past 10 years. We are able to identify and quantify the virus, and in recent years, extensive investigation has identified ways to successfully treat some infected patients. Treatment of the approximately 30 percent of eligible patients with HCV has taken center stage, and a great deal of data has been generated regarding this population. However, it is clear that our obligation is to the universe of patients with HCV, not merely those who are candidates for current therapy. As physicians we must remember to provide “care,” not merely “treatment.” It is quintessential that we not marginalize our patients in our zeal to eradicate their disease. Solutions to the above problems are essential if we are to adequately follow and advise patients for whom therapy is not an option or has failed. [Note: Beyond the scope of this discussion is the management of institutionalized patients infected with HCV, particularly those in correctional facilities. In many such institutions the mechanisms necessary to provide appropriate management are not available, and the cost of treatment is prohibitive. In fact, the focus on treatment of HCV rather than treatment of substance abuse or other comorbid illnesses may be counterproductive. Further study into the medical and social implications of HCV infection in institutions is needed.]

References

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9. Ko JS, Choe YH, Kim EJ et al. Interferon alpha treatment of chronic hepatitis C in children with hemophilia. J Pediatr Gastroenterol and Nutr 2001;32:41–4.

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13. Talal AH, Weisz K, Hau T et al. A preliminary study of erythropoeitin for anemia associated with ribavirin and interferon-alpha. Am J Gastroenterol 2001;96(9):2802–4.

14. DuFour DR. Alanine aminotransferase variation in chronic hepatitis C infection: an analysis of 357 cases. Clin Chem 47:2001:A26–7.

15. Fujiyama S, Morishita T, Hashiguchi O, et al. Plasma abnormal prothrombin (des-ã -carboxy prothrombin) as a marker of hepatocellular carcinoma. Cancer 1988;61:1621–8.

16. Shiraki K, Takase K, Tameda Y, et al. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 1995;22:802–7.

17. Yao DF, Huang ZW, Chen SZ, et al. Diagnosis of hepatocellular carcinoma by quantitative detection of hepatoma-specific bands of serum ã -glutamyltransferase. Am J Clin Pathol 1998;110:743–9.