JANIS AND FRIENDS HEPATITIS C WEB SITE 

Special Populations

Doris B. Strader, M.D.

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 erythropoietin 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, provide 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 who no clear options are available. The latter is particularly important in order to allay fears and ensure that patients are not lost to follow-up. At present, many patients with HCV who are not on treatment have a physical examination, blood tested for aminotransferase 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 follow-up. 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 γ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

1. Cawthorne CH, Rudat KR, Bruton MS, et al. Limited success of HCV antiviral therapy in United States veterans. Am J Gastro 2002;97(1):149–55.
2. Falck-Ytter Y, Kale H, Mullen KD, et al. Surprisingly small effect of antiviral treatment in patients with hepatitis C. Ann Intern Med 2002;136:288–92.
3. Yawn BP, Wollan P, Gassuola L, et al. Diagnosis and 10-year followup of a community-based hepatitis C cohort. J Fam Pract 2002;51(2):135–40.
4. Muir AJ, Provenzale D. A descriptive evaluation of eligibility for therapy among veterans with chronic hepatitis C virus infection. J Clin Gastroenterol 2002;34(3):268–71.
5. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. New Engl J Med 1998;339:1485–92.
6. Manns MP, McHutchison JG, Gordon SC et al. 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.
7. Fried MW et al. Pegylated interferon alfa-2b in combination with ribavirin: efficacy and safety results from a Phase III randomized, actively-controlled multicenter study. (Unpublished.)
8. Lau J, Standring D. Development of novel therapies for hepatitis C. In: Hepatitis C, Academic Press 2000; p. 453–7.
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.
10. Zacks S, Fried M. Hepatitis C and renal disease. In: Hepatitis C, Academic Press 2000; p. 363–87.
11. Schiff ER, Tagle FM. Treatment of HCV: Approach to difficult cases. Clinics in Liver disease; Hepatitis C 1997;1:647–62.
12. Schramm TM, Lawford BR, Macdonald GA, et al. Sertraline treatment of interferon-induced depressive disorder. Med J Austr 2000;173(7):359–61.
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 (descarboxy 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 γ-glutamyltransferase. Am J Clin Pathol 1998;110:743–9.

Side Effects of Therapy and Management

Michael W. Fried, M.D.

Introduction

The side effect profile of combination therapy of standard interferon plus ribavirin is well known. In the registration trials of these agents, significant side effects were noted that resulted in discontinuation of treatment in approximately 20 percent of subjects. (1,2) The major types of side effects of combination therapy include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Pegylated interferons (pegylated interferon alfa-2a and pegylated interferon alfa-2b) have significantly improved pharmacokinetics, (3–5) resulting in improved antiviral efficacy, that also has the potential to alter the side effect profile. This review will focus on the prevalence and management of side effects reported with the use of pegylated interferon plus ribavirin for the treatment of chronic hepatitis C.

Peginterferon Alfa-2a Plus Ribavirin

The results of a large, phase III clinical trial of peginterferon alfa-2a plus ribavirin have recently been reported in preliminary form. (6) Over 1,100 subjects were randomized to therapy with peginterferon alfa-2a plus ribavirin, peginterferon alfa-2a plus placebo, or standard interferon alfa-2b plus ribavirin. Premature withdrawal from therapy due to laboratory abnormalities or adverse events in the combination arms with either pegylated interferon alfa-2a (10 percent) or standard interferon alfa-2b (11 percent) was comparable. The most common reason for withdrawal was depression, although the rate of depression in subjects treated with peginterferon alfa-2a was lower than those treated with standard combination therapy (22 percent vs. 30 percent). Influenza-like symptoms were also lower in the peginterferon treatment groups.

Dose reductions of peginterferon alfa-2a for any adverse event were required in 32 percent in the combination arm. Laboratory abnormalities such as anemia, neutropenia, and thrombocytopenia were the most frequent indications for dose reductions. Thus, approximately 25 percent of participants required at least one dose reduction (temporary or permanent) for laboratory abnormalities during therapy. The frequency of ribavirin dose reduction for anemia was similar in the combination arms of the study. The frequency of dose reduction for neutropenia was greater in the peginterferon combination arm compared to standard interferon (20 percent vs. 5 percent). Thrombocytopenia was also more common in the peginterferon arms. However, only a minority of patients discontinued therapy due to laboratory abnormalities in the two combination arms (peginterferon + ribavirin = 3 percent vs. standard interferon plus ribavirin = 1 percent).

Peginterferon Alfa-2b Plus Ribavirin

In a large, phase III study that compared the antiviral efficacy of two different regimens of peginterferon alfa-2b plus ribavirin to standard interferon alfa-2b plus ribavirin, (7) premature withdrawal from therapy due to an adverse event occurred in 14 percent of participants treated with the higher dose of peginterferon. Discontinuation of therapy due to neutropenia (~1 percent) or anemia was very uncommon. Dose reductions for any adverse event occurred in 42 percent of patients treated with the higher dose peginterferon alfa-2b plus ribavirin compared to 34 percent treated with standard interferon and ribavirin. Dose reduction due to neutropenia was also more common in the higher dose combination (18 percent) than in the low dose pegylated (10 percent) or the standard interferon combination arms (8 percent).

Few differences were noted in the side effect profile in the pegylated combination arms compared to those seen with standard interferon plus ribavirin. The incidence of depression was similar in all treatment arms (~30 percent). The increase of several flu-like symptoms over standard therapy was attributed to the higher dose of interferon provided by the pegylated preparation. Injection site reaction, generally mild, was also noted to be more common in those receiving peginterferon alfa-2b (58 percent) compared to the standard interferon alfa-2b (36 percent).

Management of Side Effects

General strategies for management of side effects of combination therapy have been previously reviewed and are applicable to the newer agents. (8) Before starting treatment, patient education about expectations and self-management techniques are most beneficial. Regular follow-up visits during therapy and a supportive environment will permit early detection and intervention for developing adverse events and will also encourage patient adherence to the medication regimen.

Depression is a frequent and often dose-limiting side effect of combination therapy with pegylated interferon and ribavirin. The mechanism of interferon-associated depression remains largely speculative. Directed questioning of the patient and significant others, when available, about the presence and severity of depression is warranted. Treatment should be discontinued immediately in patients with suicidal ideation and, for patients judged to be in potential danger; immediate referral should be made to a mental health professional. Antidepressants, particularly selective serotonin-reuptake inhibitors, are prescribed frequently for less severe depression associated with antiviral therapy. Prophylactic paroxetine, evaluated in patients treated with high-dose interferon alfa-2b for melanoma, was shown to minimize depressive symptoms and decrease the rate of interferon discontinuation compared to placebo. (9) However, prophylactic strategies could result in inappropriate use of these agents in the 70–80 percent of patients that do not develop significant depression while on combination therapy for hepatitis C. Thus, additional information is needed concerning the mechanisms of interferon-associated depression and the optimal treatment regimen that will minimize disruptions to antiviral therapy.

Anemia, thrombocytopenia, and especially, neutropenia occur regularly in patients treated with peginterferon and ribavirin. To date, management of hematologic abnormalities in all phase III clinical trials has relied upon dose reductions of study medications according to predetermined criteria. This has proven to be a safe and effective approach to management; hemoglobin, absolute neutrophil and platelet counts improve quickly so that discontinuation of therapy is rarely necessary. Nevertheless, the possibility that adherence to study medications may affect sustained virological response has encouraged evaluation of erythropoietin and granulocyte stimulating factors as adjunctive therapies to minimize dose reductions of interferon and ribavirin. Preliminary data suggest that the dose of ribavirin may be maintained with epoietin alfa. (10) However, no study thus far has demonstrated that the use of stimulating factors to maintain full doses of interferon and ribavirin will improve sustained virological response. Furthermore, the incidence of serious sequelae associated with hematologic abnormalities appears to be low. Thus, these adjunctive agents cannot be routinely recommended as treatment for the hematologic abnormalities induced by combination therapy for hepatitis C. Additional studies are required to better understand the consequences of neutropenia in the patient with chronic hepatitis C and to determine whether lower levels of neutropenia can be safely tolerated. Detailed investigations of the relationship between dose reduction on outcome and prospective trials of alternative methods for managing hematologic abnormalities with growth factors are necessary.

In summary, no unique or unexpected side effects have been noted with the administration of pegylated interferons plus ribavirin in two large phase III trials of these agents. Hematologic abnormalities requiring dose reductions may be more common with the newer agents. Additional emphasis on improving patient management strategies is warranted.

References

1. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426–32.
2. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis 1999;19 Suppl 1:57–65.
3. Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68:556–67.
4. Zeuzem S, Heathcote JE, Martin N, Nieforth K, Modi M. Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy. Expert Opin Investig Drugs 2001;10:2201–13.
5. Reddy KR, Wright TL, Pockros PJ, Shiffman M, Everson G, Reindollar R, Fried MW, et al. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 2001;33:433–8.
6. Fried MW, Shiffman ML, Reddy KR, Sulkowski M, Smith C, al. e. Pegylated (40kDa) interferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively controlled multicenter study. Gastroenterology 2001.
7. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65.
8. Afdhal NH, Geahigan T: Supporting the patient with chronic hepatitis during treatment. In: Koff RS, Wu GY, eds. Clinical Gastroeneterology: Diagnosis and Therapeutics. Totowa, NJ: Humana Press.
9. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344:961–6.
10. Talal AH, Weisz K, Hau T, Kreiswirth S, Dieterich DT. A preliminary study of erythropoietin for anemia associated with ribavirin and interferon-alpha. Am J Gastroenterol 2001;96:2802–4.

Future Therapy of Hepatitis C

John G. McHutchison, M.D.

Introduction

Although current therapies are effective in more than half of all treated patients, therapy is costly, associated with significant morbidity, requires substantial commitment from the patient and medical staff, and is not suitable for all patients. Thus, there is an important need for more effective therapies, and this remains a priority in terms of continued research endeavours. The lack of an effective cell culture system and small animal model for HCV infection has hampered the development and discovery of alternative effective small molecules or vaccines. Nevertheless, the ideal therapy for patients with chronic hepatitis C would be cost-effective, be orally bioavailable, have an acceptable side effect profile, and be effective in the majority of patients. Such therapies are probably unlikely to be developed in the near future. Therapies in current development and/or in human clinical trials will be discussed.

Adjuvant Agents That May Be Added to Current Regimens

Alternative Interferons or Interferon Inducing Agents

The development of alternative type 1 interferon compounds or methods of delivering longer acting preparations with theoretically different pharmacokinetic profiles may lead to the availability of alternate interferon preparations. Whether these will improve or enhance sustained response rates or side effect profiles in combination with ribavirin or other agents in larger clinical trials is unknown and is currently under early stage clinical investigation. Oral interferon inducing agents are also in pre-clinical trials, and probably phase I human development will occur in late 2002.

IMPDH Inhibitors.  The development of compounds which specifically inhibit inosine 5 monophosphate dehydrogenase (IMPDH) may provide an alternative for patients with chronic hepatitis C when combined with interferon. This enzyme, which is also inhibited by ribavirin and mycophenolate, is essential for modulation of host cellular pathways and has antiviral and immunomodulatory effects. Phase I and II clinical trials in patients with chronic hepatitis C have shown one such agent (VX-497) to be safe, but with no observable antiviral effect when given alone. As in the initial ribavirin monotherapy studies, ALT reductions were also noted in some patients. A subsequent phase II, randomized, double-blind study of VX-497 combined with interferon in treatment naïve patients for 4 weeks indicated safety in combination with interferon, but no enhancement of antiviral activity. Further development of more potent and specific IMPDH inhibitors will require randomized controlled clinical trials to determine their efficacy and future place in the management of patients with chronic hepatitis C.

Alternative Ribavirin-Like Drugs. Other agents similar to ribavirin that bias the immune response toward a type 1 profile are in development. These drugs will further test the hypothesis that a significant component of the benefit of ribavirin is by its action as a type 1 cytokine enhancer. Levovirin, the l-isomer of ribavirin, is associated with lesser degrees of hemolytic anemia, appears safe in animal studies, and has been well tolerated in phase I dose finding studies in healthy volunteers. Viramidine, a ribavirin prodrug, also produces less hemolysis, is converted rapidly to ribavirin in vivo, has a three- to sixfold longer residence time in the liver, and is less concentrated in peripheral blood red cells compared to ribavirin. The safety, utility and future development of these and other similar agents will need to be established in larger-scale clinical trials in combination with alpha interferons.

Other Immunomodulators

Histamine. Histamine dihydrochloride, through binding of H2 receptors on phagocytic cells, disrupts NADPH-oxidase responsible for the production of reactive oxygen species and is also an immunomodulator acting on NK and T cells. This compound has been tested in combination with interferon in certain malignancies and in initial pilot studies in patients with hepatitis C. In two phase II studies where histamine dihydrochloride was administered to patients along with interferon, or in combination with interferon and ribavirin, the data suggest there may be benefit in terms of end of treatment and sustained response rates. An ongoing European, multinational trial is currently evaluating the safety and efficacy of peginterferon plus ribavirin vs. peginterferon plus ribavirin plus histamine injections in hepatitis C patients.

Molecular Based Therapies

Hepatitis C Specific Viral Enzyme Inhibitors

Based upon current knowledge of the structural biology and actions of HCV specific enzymes during viral replication, many groups are pursuing the development of compounds that specifically inhibit enzymes critical to the HCV life cycle. There are three initial and important virus specific targets for antiviral drug development including the HCV protease, polymerase, and helicase enzymes. The efficacy of these compounds is now being evaluated using the HCV replicon model system, and promising compounds will undergo testing in animals for oral bioavailability and toxicity. The structure of many potential inhibitors has been described, and a number of early phase I trials are being undertaken with HCV specific protease and polymerase inhibitors in chronic hepatitis C patients.

Barriers to the development of these agents are numerous, and include the shallow protease binding cleft, viral drug resistance, and the fact that such agents will be required to have activity profiles against a broad range of HCV genotypes. Also, the importance of combination therapy to multiple enzyme targets has been demonstrated in the HIV clinical setting to avoid the selection of resistant viral strains. As such, multiple targets of this class will be required in order to reduce or eliminate drug resistant HCV quasispecies, and assays to detect viral resistance patterns must be established.

Antisense Oligonucleotides

HCV specific antisense oligonucleotides, short sequences of 15–40 nucleotides stabilized to protect these molecules against cellular nuclease degradation, can hybridize to and prevent translation of viral RNA and thus inhibit disease causing protein expression. A 20 nucleotide phosphorothioate oligonucleotide with a sequence complementary to the HCV translation initiation region (ISIS 14803) is currently undergoing phase I and II clinical trials in patients who have failed to respond to available antiviral therapies. Some patients have had viral load reductions of ≥ 1 log drop in HCV RNA after 28 days of therapy.  For unexplained reasons these viral load changes are sometimes, but not always, associated with asymptomatic but significant ALT elevations. The efficacy and safety of this compound is now being evaluated in phase II studies of 12 weeks’ duration in previous nonresponders to other antiviral therapies.

HCV Specific Ribozymes

Synthetic nuclease resistant ribozymes designed to cleave the hepatitis C virus IRES are currently in phase II clinical trials. These stabilized ribozymes contain modified nucleotides and phosphorothioate linkages and are efficiently taken up by the liver. In preliminary cell culture studies, these ribozymes inhibited viral replication in a dose dependent fashion, and this effect was potentiated by interferon. Phase II trials administering these HCV specific ribozymes, alone or in combination with interferon for 12 weeks’ duration, are currently in progress.

While these newer small molecule approaches provide hope and excitement for the treatment of HCV infected patients, many further studies will be necessary to determine the safety and efficacy of these approaches, their effect on liver histology, and the mechanisms of any antiviral effects, and to evaluate whether such agents will need to be administered in combination with our available antiviral therapies to prevent the development of resistance.

Strategies to Minimize Hepatic Fibrosis

Interferon Gamma. Interferon γ is an antifibrotic cytokine in murine and human hepatic stellate cells, is an immunomodulatory cytokine, and has HCV specific antiviral activiy. A phase II randomized, double-blind, multicenter trial to determine the antifibrotic efficacy of interferon gamma 1b is currently underway in patients with hepatic fibrosis due to hepatitis C and compensated cirrhosis, using a histologic primary end point.

Cellular immuno therapy. Cytotoxic T lymphocytes play an important role in viral clearance and immunological memory in chronic hepatitis B, and likewise it is thought that a strong, multispecific directed CTL response contributes to HCV clearance in those individuals who are fortunate enough to spontaneously resolve HCV infection. Various groups have created vaccines containing HCV specific viral epitopes that are recognized by cytotoxic T-cells. Whether these agents can be successfully used as potential vaccines in the primary prophylaxis setting, or in the setting of a therapeutic vaccine to modify the host immune response in patients with chronic hepatitis C infection is currently unknown. One such agent is currently in early phase human trials.

Conclusion

Although many of these future strategies are currently in development, it will require a number of years before the safety, short- and long-term efficacy, clinical value, and appropriate setting for each of these agents alone and in combination regimens is established. For these reasons, it is unlikely that many of these newer therapies, even if proven to be effective, will be available for routine clinical use within the next 3–5 years.

References

1. Mercer DF, Schiller DE, Elliot JF, Douglas DN, Hao C, Rinfret A, Addison WR, Fischer KP, Churchill TA, Lakey JRT, Tyrell DLJ, Kneteman NM. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 2001;7:927–33.
2. Lohmann V, Korner F, Koch J-O, et al. Replication of subgenomic hepatitis C virus RNA’s in a hepatoma cell line. Science 1999;285:110–3.
3. Lau JYN, Standring DN. Development of novel Therapies for Hepatitis C. In Hepatitis C, Biomedical Research Reports, Academic Press, 2000 (Eds TJ Liang and JH Hoofnagle) p. 453–67.
4. Di Bisceglie AM, McHutchison JG, Rice CM. New Therapeutic Strategies for Hepatitis C. Hepatology 2002;35:224–31.
5. Dymock BW. Emerging therapies for hepatitis C infection. Emerging Drugs 2001;6(1):13–42.
6. McHutchison JG, Cheung R, Shiffman ML, et al. A 4 week trial of VX 497 (an IMPDH inhibitor) combined with interferon in previously untreated patients with chronic hepatitis C. Hepatology 2001;34:329A (abstract).
7. Hong Z, Zhong W, Hamatake R, et al. Antiviral activities of a new generation of ribavirin analogs: Levovirin and Viramidine. Hepatology 2001;34:415A (abstract).
8. Tam R, Lim C, Bard J, et al. Immunomodulatory activities of viramidine, a liver-targeting ribavrin prodrug, in vitro and in vivo. Hepatology 2001;34:351A (abstract).
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Pegylated Interferon Alfa-2b plus Ribavirin in Patients with Chronic Hepatitis C: A Trial in Prior Nonresponders to Interferon Monotherapy or Combination Therapy and in Combination Therapy Relapsers

Ira M. Jacobson, Mark W. Russo, Robert S. Brown Jr, E. Lebovics, A. Min, S. Esposito, H. Tobias, F. Klion, D. Rovner, C. Brass, N. Y. Peg Intron Study Group, New York, NY; Westchester, NY; Flushing, NY; Kenilworth, NJ

Pegylated interferons have proven superior to standard interferons as monotherapy for chronic hepatitis C and, more recently, in combination with ribavirin (RBV) in treatment-naive patients. Currently 60% of the patients that were treated with standard interferon and ribavirin (Rebetron) are either non-responder or relapsers looking for additional options for treatment.

The aim of this study is to compare the efficacy of two dose regimens of pegylated interferon alfa-2b plus ribavirin in patients with prior non response to interferon (IFN) monotherapy or combination therapy, or with relapse after combination therapy. 

Patients in the three categories are randomized in this ongoing trial to receive pegylated interferon alfa-2b 1.0 ug/kg plus RBV 1000-1200 mg/d with patients >75kg receiving 1200mg/day of ribavirin and patients <75kg receiving 1000mg/day of ribavirin (Group 1), or pegylated interferon alfa-2b 1.5 ug/kg plus ribavirin 800 mg/d (Group 2) which is the currently approved dosing regimen by the FDA. 

Prior therapy must have been stopped at least three months prior to entry. Treatment is planned for 48 weeks, with cessation of therapy if PCR for HCV RNA (Roche Amplicor) remains positive at 24 weeks. The inclusion criteria had no ALT restriction. The average age of the patients was 49 with an average fibrosis score by Metavir of 2.2.  87% of the patients were genotype 1 in both groups compared to 7-9% genotype 2.  Approximately 75% of the patients were male and generally both groups well represented the general population with hepatitis C.  Approximately 70% in each group had a viral load > 1 million copies/ml and approximately 40% of patients had stage 3 or 4 fibrosis. 

In the genotype 1 non-responders to previous combination therapy there was an SVR of only 10% in Group 1 and 11% in Group 2.  The preliminary results of this study are based on only 49/160 in Group 1 being available for evaluation at week 72 and only 35/160 in Group 2.  The EOT response at 48 weeks for genotype 1 was 10% in Group 1 and 20% in group 2.  This was consistent with the 24 week data which showed 16%HCV RNA negative in Group 1 versus 29% in Group 2.  Despite this early separation in the groups there was considerably greater relapse in Group 2 since the SVR results were very similar that the author thought could be attributable to needing greater than 800mg of ribavirin.  The overall SVR in patients that had been relapsers (instead of non-responders) to previous therapy was 43% in group 1 and 60% in group 2 even though the numbers of patients being evaluated were too small to draw conclusions.  The overall SVR for patients that were non-responders to interferon monotherapy was 40% in group 1 and 25% in group 2.

In summary this study demonstrates a high percentage of breakthrough and relapsers as witnessed by the SVR’s being so much lower than the early 24 week PCR negative results.  The author said that about 35% of patients need a dose reduction and that a factor that increased likelihood of response was a low viral load at the end of a patient’s prior treatment.  Other factors that the author pointed out was that normal ALT’s did not impact response, higher doses of pegylated interferon alpha 2b were needed in patients with more advanced disease.  Additionally the author commented that greater than 12 months of therapy might be needed in these types of patients that are intrinsically resistant to therapy.  When asked how African Americans responded in the trial, the presenter stated that in genotype 1 African Americans the SVR was 1/12 (8%) versus 17/87 (20%) in Caucasians.