HEPATITIS C: THERAPY
Gary L. Davis, MD
University of Florida
Gainesville, Florida

1. Chronic hepatitis C is a heterogeneous disease whose natural history and  response to treatment is probably influenced by multiple factors including but  not limited to viral genotype, level of viral replication, and histology.
    
2. Interferon is the only agent of proven efficacy in the treatment of  hepatitis C. Standard treatment is interferon alfa-2b at a dose of three million  units three times a week. The initial course of treatment is 6 months, but  nearly all patients relapse and require retreatment. The goal of interferon  treatment is suppression of active disease; this usually requires long term  therapy. Eradication of virus does not appear to be a realistic goal in most  patients
    
3. Higher doses and longer duration of initial therapy have limited benefit  over standard therapy. However, higher initial doses may increase the interval  before relapse and escalation of the dose may achieve response in some  non-responders.
    
4. Treatment trials have tended to study relatively homogenous patient groups  and the possibility of extrapolating these results to different patient  populations is extremely limited. This is especially true of studies from  geographic areas. Thus, future studies should: (1) consider genotype, viral  load, and histology in stratification; and (2) include a control group of  standard treatment for comparison.
    
5. Selection of patients for this chronic treatment remains controversial.  Treatment of patients with active disease is most cost- effective, but other  factors such as the degree of symptoms must be considered.
    
6. The definition of response to treatment is evolving as a technology of  measurement of HCV improves. It is likely that future treatment strategies will  be dependent upon virologic endpoints in addition to, or instead of, serum ALT.
    
7. Different agents and adjuncts have been incompletely studied to date.  Ribavirin reduces serum ALT levels to normal and improves fatigue in nearly half  of patients. Histology and virus levels do not appear to be significantly  altered. The mechanism of its action of this interesting agent is not clear.
   

INTRODUCTION

The first trial of interferon as therapy for chronic non-A, non-B hepatitis  was reported in 1986. This pilot study demonstrated that alpha interferon  therapy: (1) was effective at low doses (in comparison to doses previously shown  to be required for hepatitis B and D); (2) decreased serum ALT levels promptly  upon initiation of therapy, a pattern suggestive of an antiviral effect of  interferon; and (3) was usually associated with relapse when treatment was  stopped, indicating a failure to eradicate the virus. Many subsequent controlled  studies have now confirmed all of these original observations. A dose of 3  million units of recombinant interferon alfa-2b thrice weekly for 6 months is  the currently approved standard for initial therapy in the United States. With  the discovery of the hepatitis C virus responsible for non-A, non-B hepatitis  and the availability of moderately sensitive techniques for detaching the virus,  it is now apparent that the biochemical response to interferon (normalization of  ALT) is associated with loss of detectable viremia; thus, the primary response  it interferon is indeed due to the antiviral effects of the drug. However, the  high relapse rate confirms the earlier suspicion that interferon is usually  unable to eradicate the virus, which persists at levels below the current limits  of detection in serum, liver, or peripheral blood mononuclear cells.

It is apparent that the usual effect of interferon in patients with chronic  hepatitis C who respond to this therapy is one of viral suppression, not  eradication or cure. Sustained or prolonged response to treatment (persistently  normal ALT levels) occurs in only 15-20% of patients and is often associated  with detectable viremia despite the biochemical absence of apparent hepatic  injury. The observations from these early studies are important and must be  considered in establishing appropriate justification and goals for interferon  therapy in clinical practice. Several crucial points must be made:

1. Interferon therapy appears to eradicate or cure infection in only a small  proportion of patients. Thus, cure is an unrealistic goal of current interferon  regimens.
2. Interferon is suppressive to the hepatitis C virus. The goal of therapy  should be to suppress infection to a degree that liver disease is minimized.
3. The currently approved regimen of therapy (3 million units 3x per week for 6  months) is suboptimal. It should be considered as initial therapy, not as  definitive therapy. The goal of chronic viral suppression will require prolonged  therapy, retreatment of relapse, or maintenance regimens
    

Currently, clinical and basic research in hepatitis C is just beginning to shed  light on the issues important to therapeutics in this confusing disease. It is  now apparent that the disease course is only slowly progressive in most  patients; thus, histology may be important in assessing the timing of  therapeutic investigation. It is evident that the natural history is different  between genotypes. The initial and long-term response to therapy is also  effected by both genotype and the level of viremia.

The differences in response to interferon therapy which occur as a result of  viral differences are critical to clinical research in therapeutics. Literally  dozens of studies of various interferon dose regimens have appeared to  demonstrate superiority of every conceivable permutation of dosing to the  currently accepted regimens. However, few have compared these novel and  potentially useful regimens to standard dosing. Since genotypes are  geographically diverse and have significant influence on response to interferon,  trials conducted on one continent or even in different countries of regions  within a continent are not comparable. Changes in therapeutic regimens from the  current standard must be based on careful comparisons of different regimens  among genotypically similar patients with similar viral loads. It is likely that  a single dosing strategy is not appropriate for all patients. Differences in the  hepatitis C virus from country to country may warrant local modifications in  interferon dosing. Unfortunately, this implies that the considerable effort and  expense of clinical trials may have little applicability outside of the area  where they are conducted. At a bare minimum, genotype and the degree of viremia  need to be considered as stratification levels in designing future clinical  trials.
 

Finally, the traditional marker for assessing treatment response is  normalization of the serum ALT level. Although this endpoint was established  before identification of the hepatitis C virus, it appears to be as appropriate  as measuring HCV-RNA for determining the initial response to interferon, i.e.  normalization of ALT is usually associated with loss of detectable virus from  the serum. However, after discontinuation of interferon, HCV-RNA usually becomes  detectable well before re-evaluation of ALT (the traditional definition of  relapse) occurs. In fact, viremia may be present for months to years after  interferon is stopped despite persistently normal ALT levels ("sustained  remission"). Other markers include aGST, procollagen III, and cholate clearance  are under study and may serve as adjunctive markers of response. Clearly, future  studies should consider alternative markers of response and relapse which might  prove to be more clinically useful than those currently employed.
 
 
TREATMENT OF CHRONIC HEPATITIS C
Standard Therapy
Standard initial therapy for chronic hepatitis C infection is recombinant  interferon alfa-2b at a dose of 3 x 106 units administered subcutaneously 3  times per week for 6 months. This regimen is based on the results of 3  randomized controlled trials, which employed an identical protocol and were  conducted in France and the United States. These trials demonstrated that 41% of  patients normalized the serum ALT level during treatment and 70% of responders  had histological improvement. Response to treatment is greatest in those  patients without advanced inflammation or cirrhosis, high HCV-RNA levels, or  genotypes 1a and 1b (Simmonds). Almost all responders (normal ALT) lose  detectable HCV-RNA by reverse transcription polymerase chain reaction (RT-PCR)  by the end of therapy. However, relapse occurs in 50-70% of patients after the  end of the initial course and is associated with return of detectable HCV-RNA.  Relapse usually responds to retreatment with interferon.

Alternative regimens: Higher dose, Longer duration
The best way to improve the efficacy of interferon treatment is to improve  the initial response and its durability. Controlled trials of alternative  regimens including higher doses, daily dosing or longer durations of therapy  have not shown that these schedules improve the response rate. However, higher  doses of interferon may increase the durability of the initial response, i.e.  reduce early relapse. The effect of tapering the dose after the initial 6 months  on subsequent relapse is unclear, having been reported to both reduce or have no  effect on relapse. These findings need to be confirmed.

Adjuncts to Interferon Therapy & Combination Therapy
Several compounds have been suggested to improve the response to interferon  in patients with chronic hepatitis C. Ursodeoxycholic acid has been proposed as  either a single agent or adjunct to interferon, but its effects on viral  replication and inflammation have been incompletely examined. NSAIDS have a  potential role in augmenting the antiviral effects of interferon through their  ability to block prostaglandin synthesis, increase the epoxygenase pathway, and  increase 2', 5' oligoadenylate synthetase, one of the effectors of interferon  activity. These effects have not been proven in vivo. N-acetyl cysteine (NAC),  an antioxidant and glutathione source, has been shown in one pilot study to  induce response to interferon when patients had previously failed to respond.  However, most patients with chronic hepatitis C are not glutathione deficient  and the therapy is expensive and distasteful. Controlled trials need to  determine if NAC has any effects in chronic hepatitis C.

Ribavirin has not proven to significantly increase response to interferon in  a single published study. However, several pilots studies published in abstract  form suggest a possible effect. This agent's role has only begun to be explored.  No scientific rationale exists for prednisone pretreatment in chronic hepatitis  C. Corticosteroids increase HCV replication. Nonetheless, prednisone  pretreatment has been shown in one study in the Orient to increase the  durability of response. These findings need to be reexamined in a controlled  fashion in genotyped patients.
 

Alternatives to Interferon
There are few alternatives to interferon on the horizon for patients with HCV  infection. Thymosin is not effective. Ribavirin shows some promise as a single  agent in the treatment of chronic hepatitis C, but its effects are difficult to  interpret. Although ribavirin is a nucleoside analogue and know antiviral agent,  its ability to normalize serum ALT levels and improve symptoms in patients with  chronic HCV infection does not appear to result from inhibition of HCV (viral  levels remain unchanged). It is possible that the agent acts through inhibition  of some effector of tissue damage. Certainly, clarification of the mechanism of  action of this agent will help define the pathogenesis of hepatic injury in HCV  infection.

PROBLEMS WITH TREATMENT OF CHRONIC HEPATITIS C:
Interferon therapy of chronic HCV infection is not straight-forward. Therapy  is initially effective in only a portion of patients and it appears that  eradication of infection is unusual in patient infected with the genotypes most  common in the United States and most areas of Europe. Thus, several issues are  important in understanding the appropriateness and limitations of interferon  treatment.

Selection of Patients
Treatment of patients should be directed at those who will benefit from the  intervention. Several issues are important to defining this benefit: cost,  durability for response, and natural history of disease. In the case of HCV  infection, interferon treatment is effective in only about 40%. Since response  is usually not permanent, retreatment and perhaps long-term maintenance therapy  is required to maintain control of the disease. Natural history studies have  shown that HCV is a slowly progressive disease and that patients at greatest  risk of progression are those with moderate to severe periportal inflammation,  with or without fibrosis, on their liver biopsy. Therapy is easy to justify in  ill patients and those at greatest risk of disease progression. It is also most  likely to cost-effective in such patients. On the other hand, therapy which is  likely to be long-term is difficult to justify in patients with mild histologic  disease who would have a low risk of disease progression without treatment. This  area is controversial. The observation of higher early response to treatment in  patients with minimal disease fuels the argument to initial treatment early, but  does not address the high cost of treatment in patients who do not usually  require any intervention.

Non-response
Approximately half of all patients will not respond to interferon using a  standard regimen. Few alternative exist for these patients. If the patient has  not responded after the first 12 weeks of treatment, escalation of the dose to  10 million units will result in response in about 20% of patients. However, this  strategy is associated with the high cost and side effects, and should therefore  be reserved for those who have aggressive liver disease or incapacitation  symptoms. The emerging role of treatment adjuncts is discussed above.

Relapse
Most patients who respond to treatment will relapse. Although initial reports  suggest that as many as only half of responders maintained the initial response  to interferon, it is now clear that only 20-30% will maintain normal ALT levels  for 6-12 months. Additionally, recent data has suggested that virologic relapse  occurs even more commonly and many patient who continue to maintain normal ALT  levels may actually be viremic and have active liver disease. These disturbing  observations reinforce the need for effective identification of relapse with  virologic tools and retreatment to maintain control of infection and active live  disease. Unfortunately, the best way to treat relapse is not clear. Although  almost all patients will again normalize their ALT levels when retreated, it is  not clear whether repeated 6 month courses, a titrated long-term maintenance  regimen, or some other schedule will best serve the patient. Long-term  retreatment with a fixed dose is clearly not well tolerated and is associated  with frequent breakthrough (see below). An international multicenter study (US,  Canada, France, Spain, Australia) is currently underway to determine the best  way to retreat and maintain remission in interferon-responsive patients.

 

Breakthrough
In reported trials of interferon, between 0-50% of patients have demonstrated  a phenomenon known as breakthrough. Breakthrough occurs in patients who  normalized their serum ALT levels in the first weeks of treatment but  demonstrate re-evaluation of ALT despite ongoing therapy. It is essentially a  relapse during treatment. These episodes are usually associated with  reappearance of detectable HCV RNA and appear to be emergence of resistance to  the effects of interferon. The cause of this phenomenon is unclear. Naturalizing  anti-interferon antibodies are responsible for a few cases, particularly with  some recombinant interferon not approved for hepatitis treatment in this  country. These cases might also be due to loss of host response to the virus.  However, it is likely that most cases result from changes in the virus itself  which render it resistant to the effects of interferon. This remains to be  confirmed.

Definition of Response
The currently accepted definition of response to interferon is normalization  of the serum ALT levels at the end of treatment. This definition was arbitrarily  defined by investigators in the interferon studies initiated before the  identification of the HCV agent. Obviously, documentation of viremia was  lacking. The availability of serologic markers of HCV replication (HCV RNA by  RT-PCR) confirmed that biochemical response (Normal ALT) was usually associated  with a virologic response (negative serum HCV RNA). However, it has recently  become apparent that exceptions occur and are associated with early relapse.  Additionally, virologic relapse always precedes biochemical relapse, sometimes  by months or years. It is clear that the definition of response and relapse  needs to be revised to include HCV RNA. Trials are currently underway which will  test the appropriateness of various combinations of serologic, biochemical and  virologic markers of response, remission, and relapse.

SPECIAL PATIENT GROUPS
Decompensated Cirrhosis
Interferon treatment of decompensated cirrhosis due to hepatitis B is a risky  proposition because of the possibility of further decompensation or infection  with the flare in ALT which occurs shortly after beginning treatment. Early  experiences with treatment of decompensated cirrhosis due to hepatitis C  indicate that interferon can be administered to most of these patients with good  results and no risk of further decompensation (Balart, personal communication).  Synthetic function improves in responding patients. Cytopenia and infection may  limit therapy in some.

HIV infected patients
HIV coinfected patients have an increased risk of liver failure from chronic  hepatitis C. HCV RNA levels increase over time after HIV seroconversion,  particularly once immunodeficiency ensues. HIV and HCV coinfected patients  appear to respond no differently to interferon than do patients not infected  with HIV, although no study has compared response to HCV RNA levels yet. Thus,  interferon treatment should be considered in HIV coinfected patients before  onset of manifestations of immunodeficiency.

Hemophiliacs
Between 60-90% of factor-dependent hemophiliacs have serologic evidence of  HCV infection. This occurs because factor concentrates are prepared from plasma  pooled from hundreds of individuals who, in many cases, are commercially paid  donors. HCV infection is most prevalent in those who have received greater  volumes of concentrate, especially of unpasteurized products, and is virtually  nonexistent in patients who either have not required factor transfusion of have  received exclusively vapor-treated plasma concentrates of recombinant clotting  factors. About half of infected patients have abnormal serum ALT levels.  Interferon treatment is as effective in this patient population as it is in  others and does not appear to be associated with any unique problems. The  question of whether or not such patients should be biopsied before considering  treatment is controversial because of the cost and risks of the procedure in  these individuals.

Transplant Recipients
HCV infection is common in organ transplant recipients. The true prevalence  of infection is considerably underestimated by the tendency for aminotransferase  levels to be low to normal and the insensitivity of antibody-based diagnostic  tests in immunosuppressed patients. The natural history of HCV infection in  transplant recipients is unknown. However, there is a unique syndrome of  fibrosing, cholestatic hepatocellular injury similar to that observed in  hepatitis B which occurs in a subset of patients. The role of interferon in  treating HCV infection in transplant recipients is not known. Complete response  appears to be unusual and there is a small but real risk of acute graft  rejection.

Asymptomatic Carriers
Chronic portal or periportal inflammation (CPH or CAH) occurs in 70-100% of  anti-HCV and HCV-RNA positive patients with normal ALT levels. In most, the  degree of inflammation is mild. Interferon is currently not indicated for these  patients for the following reasons: (1) the natural history of the HCV carrier  is not known, but is probably comparable to CPH or mild CAH; (2) markers of  response to treatment are not available; and (3) most patients are not  symptomatic. The possible availability of affordable markers of HCV replication  may make treatment based on monitoring the viral response feasible in the  future.
 

Extrahepatic Disease
Mixed cryoglobulinemia, membranous glomerulonephritis, and porphyria cutanea  tarda may all be associated with HCV infection. In the case of cryoglobulinemia,  the cryoglobulins and the associated disease improve or disappear in about half  of treated patients. Patients who do not respond to interferon require treatment  with immunosuppressive agents including prednisone, cytoxan, and/or pheresis.  HCV-associated porphyria responds to phlebotomy. The effects of interferon are  not yet described.

TREATMENT OF ACUTE HEPATITIS C
There is a growing consensus that interferon treatment of acute hepatitis C  reduces the risk of chronicity. Four randomized controlled trials have all  demonstrated a reduction in the proportion of patients with either abnormal ALT  levels or detectable HCV RNA following a 4-12 week course of interferon.  Although most "responders" maintain their response, some early responders have  evidence of infection at a later follow-up. Unfortunately, such patients are  rarely identified since acute infection is usually inapparent and it is  impractical to serially screen patients with identifiable risk factors.

FUTURE TREATMENT STRATEGIES
Considerable progress has been made in the therapy of chronic hepatitis C in  the few years since the identification of this virus. While interferon treatment  is quite effective by antiviral standards, there is no doubt that the currently  approved regimen is far from optimal. A great deal of work remains in order to  better define the clinical guidelines for the use of interferon in patients with  chronic hepatitis C. It is likely that strategies will develop that  individualize treatment regimens according to patient characteristics (body  size, histology, ect.) and the predominant viral isolate (genotype and level).  Better markers of treatment response will allow fine tuning of the treatment  duration and dose. Ongoing trials will hopefully identify the utility of viral  markers of response and determine the optimal way to manage the treatment of the  infection over the long- term. Finally, new classes of therapeutic agents such  as proteinase inhibitors, antisense compounds, and therapeutic vaccines will  eventually find their way to clinical trials.
 

Continued
 

More About Interferon
 

REFERENCES
 

TREATMENT OF CHRONIC HEPATITIS C
Standard Therapy 
Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B  hepatitis with recombinant human alpha interferon: A preliminary report. New  Engl J Med 1986; 315:1575-1578.
Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with  recombinant interferon alpha: A multicenter randomized, controlled trial. New  Engl J Med 1989; 321:1501-1506.
Marcellin P, Boyer N, Giostra, et al. Recombinant human alpha- interferon in  patients with chronic non A non B hepatitis: a multicenter randomized controlled  trial from France. Hepatology 1991; 13:393-397.
Causse x, Godinot H, Ouzan D, et al. Comparison of 1 or 3 MU of interferon  alfa-2b and placebo in patients with chronic non-A non-B hepatitis.  Gastroenterology 1991; 101:497-502.
TinŽ F, Margin S, Craxi A, Pagliaro L. Interferon for non-A, non- B chronic  Hepatitis: a meta-analysis of randomized clinical trials. J Hepatol 1991;  13:192-199.
 
Alternative regimens: Higher dose, Longer duration
Beloqui O, Prieto J, Suarez M, Gil B, Qian CH, Garcia N, Civeira MP.  N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis  C: a pilot study. J Interferon Res 1993; 13:279-282.
Kakumu S, Yoshioka K, Wakita T, Ishikawa T, Takayanagi M, Higashi Y. A pilot  study of ribavirin and interferon beta for the treatment of chronic hepatitis C.  Gastroenterology 1993; 105:507- 512.
Liaw YF, Sheen IS, Lin SM, Chen TJ, Chu CM. Effects of prednisolone  pretreatment in interferon alfa therapy for patients with chronic non-A, non-B  (C) hepatitis. Liver 1993; 13:46-50.
 
Alternatives to Interferon
Camps J, Garcia N, Riezu-Boj JI, Civiera MP, Prieto J. Ribavirin in the  treatment of chronic hepatitis C unresponsive to alfa interferon. J Hepatol  1993; 19:408-412.
Bodenheimer HC, Lindsay K, Davis GL, et al. Ribavirin treatment of chronic  hepatitis C. Hepatology 1994; 20:(abstract in press).
 
SPECIAL PATIENT GROUPS
Decompensated Cirrhosis
Dimopoulou M, Fafoutis K, Basiliou K, Ketikoglou J, Karvountzis G.  Interferon alfa-2a for decompensated liver disease caused by wither chronic  hepatitis B or C: preliminary results of a pilot study. Gut 1993; 34 (suppl  2):S104-105.
 
HIV infected patients
Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ. The  natural history of hepatitis C virus infection in multitransfused hemophiliacs:  Effects of coinfection with human immunodeficiency virus. Acquir Immune Defic  Syndr 1993; 6:602.
Eyster ME, Fried MW, DiBisceglie AM, Goedert JJ. Increasing HCV RNA levels  in hemophiliacs: Relationship to HIV infection and liver disease. Blood 1994;  (in press).
Boyer N, Marcellin P. Degott C, Degos F, Saimot AG, Erlinger S, Benhamou JP.  Recombinant interferon-alpha for chronic hepatitis C in patients positive for  antibody to human immunodeficiency virus. J Infect Dis 1992; 165:723-726.
 
Hemophiliacs
Makis M, Preston FR, Triger DR, Underwood JC, Westlake L, Adelman MI. A  randomized controlled trial of recombinant interferon-alpha in chronic hepatitis  C in hemophiliacs. Blood 1991; 78:1672-1677.
 
Transplant Recipients
Lim HL, Lau GK, Davis GL, Dolson DJ, Lau JYN. Cholestatic hepatitis leading  to hepatic failure in a patients with organ- transmitted hepatitis C virus  infection. Gastroenterology 1994; 106:248-251.
Ferrel LD, Wright TL, Roberts J, Ascher N, Lake J. Hepatitis C viral  infection in liver transplant recipients. Hepatology 1992; 16:865-876.
Wright HI, Gavaler JS, Van Thiel DH. Preliminary experience with alpha-2b  interferon therapy of viral hepatitis in liver allograft recipients.  Transplantation 1992; 53:121-124.
 
Asymptomatic Carriers
Naito M, Hayashi N, Hagiwara H, Hiram N, Kasahara A, Fusamato H, Kamada T. Serum  hepatitis C virus RNA quantity and histological features of hepatitis C virus  carriers with persistently normal ALT levels. Hepatology 1994; 19:871-875.
 
Extrahepatic Disease
Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases:  role of hepatitis C virus and liver damage. Gastroenterology 1994;  106:1291-1300.
 
TREATMENT OF ACUTE HEPATITIS C
Viladomiu L, Genesca J, Estaban JI, et al. Interferon alpha in acute  posttransfusion hepatitis C: a randomized controlled trial. Hepatology 1992;  15:767-769.
Omata M, Yokosuka O, Takano S et al. Resolution of acute hepatitis C after  therapy with natural beta interferon. Lancet 1991; 338:914-915.
Lampertico P, Rumi M, Romeo R, Craxi A, Soffrededini R, Biassoni D, Colombo  M. A multicenter randomized controlled trial of recombinant interferon alpha-2b  in patients with acute transfusion- associated hepatitis C. Hepatology 1994;  19:19-22.
Tassopoulos NC, Koutelou MG, Papatheodoridis G, et al. Recombinant human  interferon alfa-2b treatment for acute non-A, non-B hepatitis. Gut 1993;  34:S130-132.
 

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