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Nonresponders to Previous Chronic Hepatitis C Treatment
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Current Treatment Options in Gastroenterology Dec 2004, 7:469-475
John B. Gross, MD
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
Opinion Statement
The main strategy governing treatment of chronic hepatitis C is the prevention of future liver complications. There is good evidence that curing hepatitis C infection prevents progression of liver disease and allows histologic regression to occur. Therefore, the primary goal of medical treatment is to cure the viral infection. Combination therapy with peginterferon alfa and ribavirin is the current standard of care; there are no other medical therapies currently available. Those who failed to respond to an earlier version of antiviral therapy should strongly consider treatment with peginterferon/ribavirin if possible. Nearly half of patients who start peginterferon/ribavirin are unable to achieve a sustained disappearance of infection. If there were problems related to dosing or adherence the first time around, it is reasonable to consider re-treating with more aggressive support. Nonresponders to the current therapy who have early-stage liver disease can afford to wait until new antiviral agents come along in the next 5 to 10 years. However, physicians should encourage nonresponding patients with advanced fibrosis to consider experimental alternatives in the meantime, provided there is a logical rationale for the treatment proposed. Some re-treatment strategies still aim to cure the hepatitis C virus infection whereas others focus on limiting liver damage. The best candidates for the first strategy are patients who had temporary clearance of the virus during previous treatment and those with hepatitis C virus genotype 2 or 3 infection. Logical candidates for the second strategy are those who already have advanced fibrosis. It is preferable to pursue further attempts at treatment within the framework of a controlled trial. Studies with strong rationales include those investigating high-dose peginterferon/ribavirin, long-term peginterferon suppression, potential immune modulators, and potential inhibitors of liver fibrosis. The rationales are weaker for re-treatment with a second brand of peginterferon/ribavirin, daily standard interferon plus ribavirin, and ribavirin monotherapy.
Introduction
In the past decade, we have seen stepwise improvements in the treatment of chronic hepatitis C virus (HCV) infection. Among patients starting peginterferon/ribavirin combination therapy, a sustained disappearance of HCV infection is now achieved in 40% to 45% of those infected with HCV genotype 1 and approximately 80% of those infected with genotype 2 or 3 [1, 2*]. Overall, this represents a five- to 10-fold improvement in response rates over the first interferon regimens used. However, nearly half of patients who start our best available treatment are still not cured, and many others have either contraindications to treatment or insufficient access to health care. Clearly, better treatments and methods of delivery are needed.
Most individuals with chronic HCV infection are asymptomatic, so the main rationale for treating HCV infection is the prevention of liver complications. There is good evidence that curing hepatitis C infection prevents progression of liver fibrosis [3**], and it may improve life expectancy [4]. Therefore, the first goal of treatment--"Plan A"--is to cure the infection. Several trials of experimental therapy for initial nonresponders have retained curing the infection as the main objective. Studies either use higher doses of peginterferon or ribavirin, or add a third agent. However, even patients who fail to achieve a permanent loss of HCV infection may experience a temporary reversal of liver inflammation and fibrosis while on an interferon-based regimen [5]. This observation has spurred trials of peginterferon long-term, suppressive therapy among virologic nonresponders, as well as pilot studies of potential inhibitors of fibrosis. This "Plan B" accepts the fact that HCV infection cannot be cured in a large number of patients and focuses on either suppressing the infection or limiting the liver damage. It remains to be seen whether or not the coming generation of HCV-specific antivirals will fit into Plan A or Plan B.
Not all nonresponders to antiviral treatment are the same. Some achieve clearance of detectable viremia during the period of treatment and then relapse with reappearance of HCV RNA in the blood after treatment is stopped. Technically, these individuals are not truly "nonresponders," but "relapsers." These patients would seem to be the best candidates for further efforts to cure HCV infection, perhaps with modifications of existing treatment. Some truly nonresponding patients may show a decrease in the level of HCV RNA during treatment, but a decrease that is insufficient to accomplish a sustained loss of infection. These patients do not have at least a 99% reduction in HCV RNA by the twelfth week of treatment [6]. Other nonresponders are those who have little or no reduction in the level of virus on treatment. Patients in this group have little chance of responding to further interferon-based treatments and are logical targets for new treatments.
One reason that some patients failed previous antiviral treatment is that they were under dosed. With regard to peginterferon/ribavirin treatment, retrospective analysis of data from a major trial showed that there was a direct relationship between the dose of ribavirin received per kg of body weight and the probability of a sustained virologic response [1]. Peginterferon/ribavirin nonresponders who received less than 10 to 11 mg/kg of ribavirin daily during the previous treatment might be re-treated using 12 to 15 mg/kg of ribavirin daily, with adjuvant epoetin alfa, if necessary, to mitigate the ribavirin-induced anemia.
Another reason for lack of sustained response during previous treatment is poor adherence to the intended therapy. Because of the adverse effects of interferons and ribavirin, many patients discontinue treatment prematurely. If patients with HCV genotype 1 infection--representing over 90% of nonresponders--are able to take at least 80% of their dose of medication for at least 80% of the intended treatment period, the chance of cure increases by 30% [7]. Thus, if there were problems related to dosing, adequate treatment of adverse effects, optimal support, or access to health staff, it is reasonable to consider treating again. This would be particularly true if other favorable treatment-response variables are present, such as infection with HCV genotype 2 or 3, disappearance of viremia during prior treatment, or low viral load, or if the patient is not African-American [8**].
Motivation to pursue experimental approaches should be proportional to the likelihood of progressive liver disease. Multiple studies of the natural history of HCV infection have shown that the factors that are independently associated with the risk of future liver fibrosis are heavy alcohol consumption, male gender, older age at the time of HCV infection, longer duration of infection, persistent elevation of serum aminotransferases, greater degrees of fibrosis and fat in the liver biopsy, and non-African-American ethnicity [9].
Treatment
Diet and lifestyle
- There is no evidence that a specific diet affects the liver in hepatitis C. However, insofar as hepatic steatosis may be fibrogenic, patients should maintain lean body weight and monitor blood sugar.
- Alcohol consumption should be minimized. It is reasonable to suggest no more than one drink per day for those with minimal fibrosis and complete abstinence for those with more advanced fibrosis (septal fibrosis or cirrhosis).
- Taking vitamin E (400 to 800 IU) daily may lower liver enzymes level among patients with hepatitis C, but there is no evidence of long-term benefit.
- Milk thistle may lower liver enzyme levels and is available over the counter in various supplements of uncertain potency. Controlled trials are pending, but no data are available.
Pharmacologic treatment
- Nonresponders to older antiviral therapies should consider treatment with peginterferon plus ribavirin, if possible.
- Nonresponders to peginterferon plus ribavirin may benefit from re-treatment with the same combination if there were problems of dosing, adherence, or monitoring during the previous treatment.
- Further attempts to cure HCV infection may be most appropriate for patients with temporary viral clearance or a good partial response (ie, decrease of two logs) during previous treatment.
- Patients with minimal fibrosis can be followed without treatment while waiting for new antiviral drugs to be developed, whereas those with more advanced fibrosis (ie, septal fibrosis or cirrhosis) should be encouraged to pursue experimental treatments that might have a chance of suppressing the virus or inhibiting fibrosis.
Note from Jules Levin: consider ongoing maintenance therapy if you have advanced stage hepatitis C disease. Infergen at high doses has been shown in several recently presented preliminary studies to be successful for a percentage of patients who did not respond to peginterferon+ribavirin. Some doctors initiate high-dose Infergen plus ribavirin at 12 weeks after starting peginterferon/ribavirin if there is inadequate response. Another approach by some doctors is to use the old version of interferon at higher doses for the first two days of therapy when beginning peginterferon. It takes a few days for peginterferon to reach good blood levels so administering high doses of standard interferon for 1-2 days may be effective. If nonresponsive to one brand of peginterferon you may want to consider trying the other brand (PegIntron, Pegasys). You may want to consider higher dosing of peginterferon or induction therapy.
Interferon alfa plus ribavirin
This combination would make sense only for those not responding to previous standard interferon monotherapy; it has now been superceded by the combination of peginterferon and ribavirin, but might be tried if cost is a major issue. The sustained virologic response (SVR), or long-term cure, among interferon nonresponders is 12% to 15% [8**, 10]. The rate of SVR is not improved by using higher doses of interferon or by using a 4- to 12-week "induction" period of daily interferon dosing. A recent pilot study suggested that the SVR rate with interferon/ribavirin might be improved if patients can tolerate daily interferon dosing for 48 weeks [11].
Standard dosage
Interferon alfa-2a or interferon alfa-2b, 3 million units subcutaneously (SC) three times weekly plus ribavirin 1000 to 1200 mg orally daily; interferon alfacon-1, 9 mg SC three times weekly plus ribavirin 1000 to 1200 mg orally daily. Ribavirin is administered in divided doses twice daily. If a response in the level of HCV RNA is observed, treatment is usually continued for 48 weeks.
Contraindications
Significant cardiac or pulmonary disease, hemoglobin less than 12 g/dL, absolute neutrophil count less than 1000, platelets less than 75,000, renal insufficiency, seizure disorder, severe depression, pregnancy, absence of contraceptive measures.
Main drug interactions
Ribavirin may possibly cause an increase in the chance of lactic acidosis from concomitant nucleoside analogs.
Main side effects
Interferon causes flu-like symptoms (fever, myalgias, arthralgias, headache, chills) that may last for 24 hours after each injection; these effects wane after the first 3 to 4 weeks. The subjective problems during treatment are persistent fatigue and mood disturbances, including hyperirritability and depression. Ribavirin may cause subjective dyspnea or cough, as well as itching and dry skin. Interferon causes varying degrees of reversible neutropenia and thrombocytopenia, whereas ribavirin induces a reversible hemolytic anemia that may become severe. Patients often experience hair thinning and decreased levels of concentration. There are occasional disturbances of thyroid function. Interferon may rarely cause retinopathy. Autoimmune diseases, diabetes, and psoriasis may worsen during interferon treatment.
Special points
With interferon alfa-2a, the dose of ribavirin is based on whether the patient weighs more or less than 75 kg. For both combination regimens, lack of curative response is demonstrated by a decrease of less than two logs in the level of HCV RNA after 12 weeks of treatment, or by the presence of detectable HCV RNA after 24 weeks of treatment. Virtually all adverse effects resolve after drug discontinuation. Ribavirin is excreted through the kidneys, so it cannot be used safely among patients with renal failure.
Cost effectiveness
There have been no formal cost-benefit analyses of retreatment. As noted, interferon and ribavirin is a less expensive combination than peginterferon and ribavirin.
Peginterferon alfa plus ribavirin
Trials of peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin among previously untreated patients demonstrated higher SVR rates than had been observed with interferon or interferon plus ribavirin. Peginterferon/ribavirin is an excellent choice for patients who relapsed after interferon plus ribavirin, achieving an SVR rate of about 60% in that group [8**]. The results among nonresponders to older therapy are less striking, with SVR rates of 28% among interferon nonresponders and around 10% among interferon/ribavirin nonresponders [12*, 13]. Re-treating interferon/ribavirin nonresponders with double the approved dose of peginterferon alfa-2b and a more aggressive (weight-based) ribavirin schedule achieves results in on-treatment viral clearance rates of 30% to 40% [14]. However, tolerability over a 48-week period has been an issue and preliminary estimates of SVR do not suggest significant improvement compared to standard dosing.
Standard dosage
Peginterferon alfa-2b 1.5 mg/kg SC weekly plus ribavirin 800 mg orally daily (in two divided doses). Peginterferon alfa-2a 180 mg SC weekly plus ribavirin 1000 to 1200 mg orally daily (in two divided doses).
Contraindications
Same as for interferon plus ribavirin.
Main drug interactions
Ribavirin may possibly cause an increase in the chance of lactic acidosis from concomitant nucleoside analogs.
Main side effects
Substantially the same as for interferon plus ribavirin. Because pegylated interferon is eliminated more slowly than standard interferon, post-injection systemic symptoms may last for close to 48 hours after the weekly dose. Neutropenia is slightly more frequent and more severe than with standard interferon but rarely requires discontinuation.
Special points
See points under interferon/ribavirin. Even though the approved dose of ribavirin in combination with peginterferon alfa-2b is 800 mg daily, the results of a large-scale controlled trial are due out soon and will likely support the widely held notion that weight-based dosing of ribavirin increases SVR rate. (The dosage range of ribavirin was 800 to 1400 mg daily.)
Cost effectiveness
No data among nonresponders. Peginterferon is more expensive than the standard interferon.
Long-term peginterferon
The only controlled trial of continued ("maintenance") interferon treatment for interferon nonresponders included only 53 patients that could be evaluated, but it showed that long-term interferon treatment might improve liver inflammation and fibrosis [5]. It should be noted that these virologic nonresponders were entered into the trial only if they had on-treatment biopsies showing histologic improvement to begin with. Patients were randomly assigned to stop or continue standard interferon for 2 years and were biopsied again. This study was the impetus for two large, ongoing multicenter trials of long-term peginterferon alfa treatment: the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial sponsored by the National Institutes of Health, and the Colchicine vs PegIntron Long-Term (COPILOT)study sponsored by Schering-Plough, Inc. Participants in both studies are limited to those with a liver biopsy showing septal fibrosis or cirrhosis. The endpoints are liver fibrosis, liver complications, death, or transplantion. Results are expected within the next 1 to 2 years.
Standard dosage
Dosage and efficacy is undetermined. One trial compares peginterferon alfa-2a, 90 mg sc weekly for 4 years with no treatment. The other trial compares peginterferon alfa-2b, 0.5 mg per kg SC weekly with daily oral colchicine. (These doses are one third to a half of the standard doses, to avoid long-term toxicity.)
Contraindications
Decompensated cirrhosis (ascites, variceal bleeding, or encephalopathy), minimal liver disease (mild inflammation and no or only portal fibrosis), discontinuation of previous therapy because of interferon toxicity, severe depression during previous therapy.
Main drug interactions
Negligible.
Main side effects
The same as those cited for interferons above, but milder in degree at these lower doses. Side effects due to ribavirin, such as hemolytic anemia, are eliminated.
Special points
For now, this approach should be targeted to patients with advanced liver fibrosis (septal fibrosis or cirrhosis). There is debate as to whether this strategy should be limited to those with a partial virologic response during previous treatment, or whether those who previously had no significant reduction in HCV RNA would benefit. If it turns out to be true that the antifibrosis effect of long-term peginterferon is related to reduction in viral load, then the best candidates would be those who relapsed after the previous treatment and those who had a significant reduction in viremia (eg, two logs) during previous treatment [15].
Cost effectiveness
Undetermined.
Long-term ribavirin
Previous trials of ribavirin alone among patients with chronic HCV showed no effect on virus levels but did show modest reductions in serum alanine aminotransferase during treatment. In a recent trial [16], 34 nonresponders to 24 weeks treatment with standard interferon alfa and ribavirin were randomly assigned to stop or continue ribavirin alone for another year. Those on ribavirin maintained lower alanine aminotransferase levels, and half of them met criteria for maintenance of liver biopsy improvement in inflammation scores.
Standard dosage
Dosage and efficacy are undetermined. In the study cited, patients received 1000 to 1200 mg orally daily in two divided doses based on a body weight breakpoint of 75 kg.
Contraindications
Severe toxicity to ribavirin during previous therapy.
Main drug interactions
Increase in chance of lactic acidosis from concomitant nucleoside analogs.
Main side effects
See previous. Mainly hemolytic anemia, birth defects, cough/dyspnea, itching, and upper gastrointestinal symptoms.
Special points
One fear of long-term ribavirin is the possible accumulation of tissue iron, as a result of drug-induced hemolytic anemia. The results in the pilot study could be interpreted as showing maintenance of already established on interferon improvement, so it is not clear whether ribavirin monotherapy actually initiated any improvement.
Cost effectiveness
Undetermined.
Other pharmacologic therapies
- Treating standard interferon nonresponders with interferon plus ribavirin plus amantadine poses no advantage over treating with interferon plus ribavirin [17].
- Among treatment-na•ve patients, agents that do not confer additional benefit in combination with interferon or interferon plus ribavirin include nonsteroidal anti-inflammatory drugs, histamine, ursodeoxycholic acid, and thymosin.
- A small pilot study among treatment-na•ve patients compared interferon plus ribavirin plus etanercept (tumor necrosis factor antagonist) with interferon plus ribavirin. The results suggested a possible antifibrosis effect on the triple treatment [18], but this has not been tried among previous nonresponders.
- A short-term pilot study of interleukin-10 among interferon nonresponders showed a possible antifibrosis effect [19], but a longer-term study showed negative results with regard to fibrosis, along with increased virus levels [20].
Emerging therapies
- A general approach that may apply to both untreated and previously nonresponding patients is enhancement of existing treatments [21*]. Current studies are examining extended treatment with daily dosing of standard interferon, continuous delivery of standard interferon via an implanted pump, new ribavirin analogs that avoid treatment-limiting hemolytic anemia, and new inhibitors of inosine monophosphate dehydrogenase (one of the targets of ribavirin).
- Experimental agents designed to degrade or inhibit HCV RNA have made slow experimental progress. These have included antisense oligonucleotides and ribozymes. Short interfering RNAs have recently appeared on the scene and perhaps hold the most promise in this area [21*].
- Specific anti-HCV antiviral drugs are finally making their way to early clinical testing. These are small molecules designed to inhibit HCV protease, helicase, or polymerase based on the known three-dimensional structure of these viral proteins. One of the first of these candidates looked very promising in early clinical testing but ran into problems with cardiac toxicity, so it is expected that these agents may not reach the clinical arena for another 4 to 6 years. Once they are available, it may turn out that multiple-drug regimens will have to be continued indefinitely, as for chronic HIV infection.
- experimental alternative for nonresponders who are at risk of progressive liver fibrosis. Existing drugs for which there are animal or human data supporting an antifibrosis effect include nitrates, alpha-adenergic blockers, angiotensin- converting enzyme inhibitors, and angiotensin-2 receptor antagonists [22, 23]. Other compounds showing an effect in animal models include glycyrrhizin (licorice extract), gliotoxin (a product of fungus), and camostat mesilate. Pilot human studies are either planned or in progress for several of these agents.
References and Recommended Reading
Recently published papers of particular interest have been highlighted as:
* Of importance
** Of major importance
1.Manns MP, 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, 358:958-965.
2.* Fried MW, et al.: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002, , 347:975-982.
Although carried out among previously untreated patients with hepatitis C, these two registration trials still hold major clues as to whether retreatment with a variant is likely to work.
3.** Poynard T, et al.: Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002, 122:1303-1313.
This study puts forward the strongest case yet that HCV antiviral treatment can retard or reverse liver fibrosis.
4.Yoshida H, et al.: Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology 2002, 123:483-491.
5.Shiffman ML, et al.: A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology 1999, 117:1164-1172.
6.Davis GL: Monitoring of viral levels during therapy of hepatitis C. Hepatology 2002, 36:S145-S151.
7.McHutchison JG, et al.: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002, 123:1061-1069.
8.** Shiffman ML: Retreatment of patients with chronic hepatitis C. Hepatology 2002, 36:S128-S134.
Excellent review of nonresponder retreatment data from the second NIH Consensus Conference.
9.Seeff LB: Natural history of chronic hepatitis C. Hepatology 2002, 36:S35-S46.
10.Fargion S, et al.: Sustained response to combination therapy in patients with chronic hepatitis C who failed to respond to interferon. J Hepatol 2003, 38:499-505.
11.Kaiser S: Retreatment of standard interferon/ribavirin nonresponder patients with chronic hepatitis C with daily consensus interferon and ribavirin yields high sustained response rates. Heptology 2003, 38:276A.
12.* Shiffman ML, et al.: Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004, 126:1015-1023.
Only published trial to date on peginterferon/ribavirin re-treatment for nonresponders to earlier antiviral therapy.
13.Jacobson I, et al.: 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 relapsers. Hepatology 2002, 36:358A.
14.Gross JB, et al.: The RENEW trial: a national, multicenter study of high-dose peginterferon alfa-2b + ribavirin for nonresponders with hepatitis C. Hepatology 2003, 38:312A.
15.Shiffman ML: Role of maintenance therapy in the management of patients with chronic hepatitis C virus infection. Hepatitis Index Rev 2004, 2:3-4,14.
16.Hoofnagle JH, et al.: Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin. Hepatology 2003, 38:66-74.
17.Teuber G, et al.: Randomized, controlled trial with IFN-a combined with ribavirin with and without amantadine sulphate in nonresponders with chronic hepatitis C. J Hepatol 2003, 39:606-613.
18.Zein NN: A phase II randomized, double-blind, placebo controlled study of tumor necrosis factor antagonist (etanercept, Enbrel") as an adjuvant to interferon and ribavirin in na•ve patients with chronic hepatitis C. Hepatology 2002, 36:304A.
19.Nelson DR: Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 2000, 118:655-660.
20.Nelson DR, et al.: Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 2003, 38:859-868.
21.* McHutchison JG: Future trends in managing hepatitis C. Gastroenterol Clin North Am 2004, 33:S51-S61.
Concise, readable review of where experimental treatment for hepatitis C is heading.
22.Kalmowitz BD: Maintenance therapies for hepatitis C. Curr Hepatitis Rep 2004, 3:23-29.
23.Bataller R: Hepatic stellate cells as a target for the treatment of liver fibrosis. Sem Liv Dis 2001, 21:437-451.
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