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Available options for treatment of interferon nonresponders
Available Options for Treatment of Interferon Nonresponders Bruce R. Bacon, MD
In the great majority of patients, hepatitis C virus (HCV) infection is not self-limiting. Approximately 70% to 85% of patients exposed to HCV will go on to develop chronic hepatitis. Among those who undergo treatment with interferon ␣, only 15% to 20% can be expected to respond to a 12- to 18-month course of therapy. With the addition of ribavirin to interferon monotherapy, the likelihood of sustained response (defined as normal alanine aminotransferase levels and negative HCV RNA persisting 6 months after the end of therapy) increases to approximately 40%. The fact remains, however, that there is still a substantial proportion of patients who will fail to respond to treatment. Without viral eradication, cirrhosis and hepatocellular carcinoma persist as long-term risks. Several options are available for the treatment of patients who fail to respond to interferon monotherapy. These include interferon dose escalation, whether by administering higher doses or administering them more frequently; changing to a different form of interferon; retreatment with a combination of interferon and ribavirin; adjunctive therapies, of which the best studied is phlebotomy to decrease hepatic iron stores; use of long-term, low-dose “maintenance”-type therapy; and watchful waiting with frequent follow-up. In the absence of long-term, large-scale clinical trials to support these modalities, physicians must exercise their best clinical judgment and individualize treatment to suit the patient’s condition, needs, and preferences. Am J Med. 1999; 107(6B):67S–70S. © 1999 by Excerpta Medica, Inc.
From the Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA. Requests for reprints should be addressed to Bruce R. Bacon, MD, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Boulevard, St. Louis, Missouri 63110-0250. © 1999 by Excerpta Medica, Inc. All rights reserved.
D
espite the tremendous advances that have been made in the treatment of hepatitis C over the past few years, the majority of patients do not achieve a sustained response to currently available therapies. Therefore, attempts have been made to identify those who are most likely to respond, and, conversely, those factors that predict a poor response.1 Predictors of nonresponse include genotype 1 virus, high viral load (⬎12 million viral copies/mL), presence of stage 3 or stage 4 fibrosis/cirrhosis, and high hepatic iron concentration. Unfortunately, beyond the suggestion that nonresponders should be encouraged to participate in clinical trials, current recommendations for the management of hepatitis C offer clinicians little guidance by way of treatment of this large group of patients. Therefore, physicians must exercise their best clinical judgment in choosing from among the available options. Those options, which include dose escalation, changing drugs, retreating with combination therapy, use of adjunctive therapy, use of long-term therapy, and watchful waiting, are reviewed here.
DOSE ESCALATION Dose escalation is one option in the treatment of monotherapy nonresponders and can be carried out by increasing the dose of interferon at each administration, increasing the frequency of administration, or both. A regimen of interferon 5 million units administered subcutaneously either three times a week or daily has been suggested as a possibility for this purpose. There is little evidence of improved sustained response rates. Van Thiel et al2 have reported on a small series of interferon nonresponders (N ⫽ 30) who were randomized to receive a second 6-month course of either 5 million units of interferon daily (n ⫽ 15) or 5 million units of interferon plus regular phlebotomies at weekly intervals to achieve a hemoglobin level of 10 to 11 g/dL (n ⫽ 15). (The rationale for the use of phlebotomy is discussed later in this review.) Although these investigators found that patients treated with high-dose interferon plus phlebotomy were more likely to respond than were patients treated with high-dose interferon alone, the number of sustained responses was relatively small in both groups. Lindsay et al3 have also reported a transient initial benefit with dose escalation, but once again, the response was not sustained. 0002-9343/99/$20.00 67S PII S0002-9343(99)00386-1
A Symposium: Available Options for Treatment of Interferon Nonresponders /Bacon
Induction therapy, that is, the use of high doses of interferon administered on a daily rather than thriceweekly basis at the beginning of therapy, is being investigated, with some preliminary evidence of improved SR rates. (See Layden, “Principles of Interferon Induction Therapy” in this supplement.) However, many patients may not be able to tolerate these high-dose regimens.
CHANGING DRUGS Most of the clinical trials in chronic hepatitis C have evaluated interferon ␣-2b, although some trials have used interferon ␣-2a, interferon ␣-n1, consensus interferon, interferon , and interferon ␣-n3. In general, all forms of interferon appear to have similar efficacy in eradicating the virus.1 In the early 1990s, cases in which breakthrough developed as a result of interferon antibody production may have been an exception. The option of changing to a different form of interferon has not been widely evaluated. In one recently published trial, nonresponders to or relapsers after treatment with either consensus interferon (9 mcg) or interferon ␣-2b (3 million units) were randomized to receive a higher dose of consensus interferon (15 mcg) three times a week for 24 or 48 weeks.4 Patients were then followed for an additional 24 weeks. On this regimen, prior nonresponders achieved a sustained virologic (HCV RNA) response rate of 5% when treated for 24 weeks, and 13% when treated for 48 weeks. Biochemical (alanine aminotransferase [ALT]) response rates were higher, at 12% after 24 weeks of treatment and 17% after 48 weeks of treatment.4 The suggestion from these data is that retreatment with high-dose consensus interferon at 15 mcg as monotherapy may yield a small improvement in response rate in previous monotherapy nonresponders, but the percentage of patients who will be converted to sustained response remains small.
RETREATMENT WITH THE COMBINATION OF INTERFERON PLUS RIBAVIRIN Combination therapy with interferon plus ribavirin is now the therapy of choice for patients with hepatitis C who relapse after initial treatment with interferon monotherapy and is being increasingly used as initial therapy for naı¨ve patients. Our group is currently conducting a randomized, prospective, controlled trial in which 124 nonresponders to at least 3 months of interferon monotherapy have been randomized to either 24 weeks or 48 weeks of treatment with interferon ␣ 3 million units three times weekly plus ribavirin at a weight-dependent dose of 1,000 or 1,200 mg/day in divided doses.5 All 124 patients were HCV-RNA positive, 64% are male, and their mean age is 44.6 years. Of the 124 patients, 100 (81%) had elevated ALT levels, 101 (81%) had HCV genotype 1, and 27 (22%) had cirrhosis. 68S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
Although this study is still ongoing, interim data for 118 of the 124 nonresponders who have completed a course of treatment, and 24 weeks of follow-up demonstrate that 38 patients in this group (32%) have achieved a sustained response. Although the sample size is small, such variables as genotype, presence of cirrhosis, or baseline ALT do not appear to exert a significant effect on whether a response will be achieved. To date, hemolytic anemia, a known side effect of ribavirin therapy, has required dose reduction in 10 patients, but treatment discontinuation has been necessary in only one individual. Thus, although these results are only preliminary, it does appear that retreatment with interferon plus ribavirin may offer promise in nonresponders to previous interferon monotherapy.
ADJUNCTIVE THERAPIES Several adjunctive agents and procedures have been tried in an effort to induce a response in previous monotherapy nonresponders. Such adjuncts include, but are not limited to, milk thistle (silymarin), ozone therapy, thymus extract, ursodeoxycholic acid, and iron reduction via phlebotomy. Of these, only the latter has been relatively well investigated and found to have the potential for efficacy. The use of phlebotomy to produce iron deficiency is based on the observation from several studies that nonresponders have higher iron concentration than responders.6 It has been suggested that viral replication rates within infected liver cells are at least partially determined by the iron content of the liver, because iron is a required cofactor for the synthesis of RNA.3 This theory is consistent with the observation, made more than two decades ago, that hepatitis B–infected individuals with increased hepatic iron stores are more likely to become chronic carriers of hepatitis B and to have abnormal liver histology than are those with lesser iron stores.7 It is also consistent with more recent reports suggesting that individuals with high-normal levels of hepatic iron may have a reduced response to interferon therapy.6,8 The first study in which phlebotomy was used as a means of reducing iron stores was published in 1994.9 This small nonrandomized trial included 10 patients with chronic hepatitis C, 2 of whom had failed interferon therapy. Phlebotomy was performed weekly or monthly to reduce their ferritin levels to 10 ng/mL or their hemoglobin concentrations to 10 g/dL. ALT levels decreased from an overall mean of 152 IU/L to 55 IU/L and normalized in 5 of the 10 patients, but histologic abnormalities remained unchanged except for the disappearance of iron deposits from 7 patients.9 In 1996, Van Thiel et al2 published the results of a study enrolling 30 interferon nonresponders who were reVolume 107 (6B)
A Symposium: Available Options for Treatment of Interferon Nonresponders /Bacon
Table 1. Effects of Phlebotomy in 96 Patients With Hepatitis C PrePhlebotomy
PostPhlebotomy
35.1 335 44.3 138 9.7
7.4* 15* 36.1* 93* 7.5
Transferrin saturation (%) Ferritin (ng/mL) Hematocrit (%) ALT (U/L) HCV RNA (mEq/mL)
ALT ⫽ alanine aminotransferase; HCV ⫽ hepatitis C virus. * P ⬍0.01.
treated with interferon ␣ 5 million units daily for 6 months, with or without weekly phlebotomy.3 Both groups experienced a significant (P ⬍0.01) reduction in serum ALT levels and improvement in liver histology (Knodell scores). More biological and virologic sustained responses were achieved in the phlebotomy-plus-interferon group compared with the interferon-alone group, but the difference did not attain statistical significance.3 The results of these studies led us to initiate a 10-site trial comparing phlebotomy plus interferon with phlebotomy alone in 96 patients who had failed to respond to interferon monotherapy given at standard doses for at least 3 months. Phlebotomy was initiated in all patients during the first 3 months of the study, then interferon was administered from month 3 through month 9, with follow-up through month 16. Iron deficiency was achieved after removing a mean of 7.8 units of blood (range, 3 to 21 units). Serum ALT levels decreased with phlebotomy in 85 of the 96 patients (89%). ALT levels decreased by 50% in 15 patients (16%) and returned to normal in 15 patients (16%). HCV-RNA levels decreased from baseline but were not reduced significantly (Table 1).10 Histologic results will be available shortly.
LONG-TERM THERAPY
group 3. Among the 176 patients who underwent liver biopsy at 18 months, more patients in group 1 than in groups 2 or 3 had improved histology scores (70% vs 48% and 39%, respectively).11 These data suggest that longerterm therapy may improve histology even in the absence of a virologic response. Issues of cost effectiveness and long-term tolerability remain unresolved.
WATCHFUL WAITING Another option is “watchful waiting,” in the hope that better therapies will become available. Although this may be anxiety producing for some physicians and patients, it may be the best course of action for patients with mild, nonprogressive disease as demonstrated on liver biopsies. This approach is best undertaken with the understanding that frequent and regular follow-up will be needed.
SUMMARY For the many patients with chronic hepatitis C who fail to respond to initial treatment, effective regimens for retreatment are still being developed. Some degree of success has been obtained with use of another form of interferon in high doses, retreatment with interferon plus ribavirin, adjunctive phlebotomy, and long-term therapy. Nonetheless, evidence remains insufficient for most of these approaches, and the evidence that does exist only demonstrates a partial incremental improvement. It is likely that the next significant improvement after combination interferon-plus-ribavirin therapy in nonresponders will be the use of helicase or protease inhibitors. It is not clear whether pegylated interferon products with ribavirin will significantly impact successful retreatment of the nonresponder population. Clinical developments involving these new forms of therapy are eagerly awaited.
REFERENCES
Rather than eradicating the virus, the goal of long-term therapy would be to prevent or retard the longer-term complications of HCV, including cirrhosis, decompensation, and hepatocellular carcinoma. Poynard et al11 have studied long-term treatment in 303 HCV-infected patients, all of whom were treated for 6 months with interferon ␣ 3 million units administered three times a week. The patients were then randomly assigned to one of three regimens: the same treatment for an additional 12 months (group 1, n ⫽ 103), 1 million units three times a week for 12 months (group 2, n ⫽ 101), or no further treatment (group 3, n ⫽ 99). Follow-up was continued for 2 years after discontinuation of treatment. Patients in group 1 achieved the greatest reduction in serum ALT levels, with 45% of the group registering normal levels at 18 months, as compared with 27% in group 2 and 30% in
1. National Institutes of Health Consensus Development Conference Panel Statement: Management of Hepatitis C. March 24 –26, 1997;15(3) 2. Van Thiel DH, Friedlander L, Molloy PJ, et al. Retreatment of hepatitis C interferon non-responders with larger dose of interferon with and without phlebotomy. Hepato-Gastroenterology. 1996;43:1557–1561. 3. Lindsay KL, Davis GL, Schiff ER, et al. Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis interventional therapy group. Hepatology. 1996;25:1034 –1040. . 4. Heathcote EJ, Keefe EB, Lee SS, et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998;27:1136 –1143. 5. Bacon BR, Rauscher JA, Smith-Wilkaitis NL, et al. Interferon-ribavirin combination: sustained response in previous monotherapy non-responders. Hepatology. 1999;30:372A. Abstract. 6. Olynyk JK, Reddy KR, Di Bisceglie AM, et al. Hepatic iron
December 27, 1999
THE AMERICAN JOURNAL OF MEDICINE威
Volume 107 (6B)
69S
A Symposium: Available Options for Treatment of Interferon Nonresponders /Bacon concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology. 1995;108: 1104 –1109. 7. Sutnic AI, Blumberg BS, Lustbader ED. Elevated serum iron levels and persistent Australia antigen (HBsAg). Ann Intern Med. 1974;81:855– 856. 8. Van Thiel DH, Friedlander L, Fagivoli S, et al. Response to interferon ␣ therapy is influenced by the iron content of the liver. J Hepatology. 1994;20:410 – 415. 9. Hayashi H, Takikawa T, Nishimura N, et al. Improvement of
70S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol. 1994;89:986 –988. 10. Di Bisceglie AM, Bonkovsky HL, Krawitt EL, et al. Iron reduction therapy in chronic hepatitis C. Hepatology 1997; 26:214A. Abstract. 11. Poynard T, Bedossa P, Chevallier M, et al. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A; non-B hepatitis. N Engl J Med. 1995;332:1457–1462.
Volume 107 (6B)
In the great majority of patients, hepatitis C virus (HCV) infection is not self-limiting. Approximately 70% to 85% of patients exposed to HCV will go on to develop chronic hepatitis. Among those who undergo treatment with interferon ␣, only 15% to 20% can be expected to respond to a 12- to 18-month course of therapy. With the addition of ribavirin to interferon monotherapy, the likelihood of sustained response (defined as normal alanine aminotransferase levels and negative HCV RNA persisting 6 months after the end of therapy) increases to approximately 40%. The fact remains, however, that there is still a substantial proportion of patients who will fail to respond to treatment. Without viral eradication, cirrhosis and hepatocellular carcinoma persist as long-term risks. Several options are available for the treatment of patients who fail to respond to interferon monotherapy. These include interferon dose escalation, whether by administering higher doses or administering them more frequently; changing to a different form of interferon; retreatment with a combination of interferon and ribavirin; adjunctive therapies, of which the best studied is phlebotomy to decrease hepatic iron stores; use of long-term, low-dose “maintenance”-type therapy; and watchful waiting with frequent follow-up. In the absence of long-term, large-scale clinical trials to support these modalities, physicians must exercise their best clinical judgment and individualize treatment to suit the patient’s condition, needs, and preferences. Am J Med. 1999; 107(6B):67S–70S. © 1999 by Excerpta Medica, Inc.
From the Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA. Requests for reprints should be addressed to Bruce R. Bacon, MD, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Boulevard, St. Louis, Missouri 63110-0250. © 1999 by Excerpta Medica, Inc. All rights reserved.
D
espite the tremendous advances that have been made in the treatment of hepatitis C over the past few years, the majority of patients do not achieve a sustained response to currently available therapies. Therefore, attempts have been made to identify those who are most likely to respond, and, conversely, those factors that predict a poor response.1 Predictors of nonresponse include genotype 1 virus, high viral load (⬎12 million viral copies/mL), presence of stage 3 or stage 4 fibrosis/cirrhosis, and high hepatic iron concentration. Unfortunately, beyond the suggestion that nonresponders should be encouraged to participate in clinical trials, current recommendations for the management of hepatitis C offer clinicians little guidance by way of treatment of this large group of patients. Therefore, physicians must exercise their best clinical judgment in choosing from among the available options. Those options, which include dose escalation, changing drugs, retreating with combination therapy, use of adjunctive therapy, use of long-term therapy, and watchful waiting, are reviewed here.
DOSE ESCALATION Dose escalation is one option in the treatment of monotherapy nonresponders and can be carried out by increasing the dose of interferon at each administration, increasing the frequency of administration, or both. A regimen of interferon 5 million units administered subcutaneously either three times a week or daily has been suggested as a possibility for this purpose. There is little evidence of improved sustained response rates. Van Thiel et al2 have reported on a small series of interferon nonresponders (N ⫽ 30) who were randomized to receive a second 6-month course of either 5 million units of interferon daily (n ⫽ 15) or 5 million units of interferon plus regular phlebotomies at weekly intervals to achieve a hemoglobin level of 10 to 11 g/dL (n ⫽ 15). (The rationale for the use of phlebotomy is discussed later in this review.) Although these investigators found that patients treated with high-dose interferon plus phlebotomy were more likely to respond than were patients treated with high-dose interferon alone, the number of sustained responses was relatively small in both groups. Lindsay et al3 have also reported a transient initial benefit with dose escalation, but once again, the response was not sustained. 0002-9343/99/$20.00 67S PII S0002-9343(99)00386-1
A Symposium: Available Options for Treatment of Interferon Nonresponders /Bacon
Induction therapy, that is, the use of high doses of interferon administered on a daily rather than thriceweekly basis at the beginning of therapy, is being investigated, with some preliminary evidence of improved SR rates. (See Layden, “Principles of Interferon Induction Therapy” in this supplement.) However, many patients may not be able to tolerate these high-dose regimens.
CHANGING DRUGS Most of the clinical trials in chronic hepatitis C have evaluated interferon ␣-2b, although some trials have used interferon ␣-2a, interferon ␣-n1, consensus interferon, interferon , and interferon ␣-n3. In general, all forms of interferon appear to have similar efficacy in eradicating the virus.1 In the early 1990s, cases in which breakthrough developed as a result of interferon antibody production may have been an exception. The option of changing to a different form of interferon has not been widely evaluated. In one recently published trial, nonresponders to or relapsers after treatment with either consensus interferon (9 mcg) or interferon ␣-2b (3 million units) were randomized to receive a higher dose of consensus interferon (15 mcg) three times a week for 24 or 48 weeks.4 Patients were then followed for an additional 24 weeks. On this regimen, prior nonresponders achieved a sustained virologic (HCV RNA) response rate of 5% when treated for 24 weeks, and 13% when treated for 48 weeks. Biochemical (alanine aminotransferase [ALT]) response rates were higher, at 12% after 24 weeks of treatment and 17% after 48 weeks of treatment.4 The suggestion from these data is that retreatment with high-dose consensus interferon at 15 mcg as monotherapy may yield a small improvement in response rate in previous monotherapy nonresponders, but the percentage of patients who will be converted to sustained response remains small.
RETREATMENT WITH THE COMBINATION OF INTERFERON PLUS RIBAVIRIN Combination therapy with interferon plus ribavirin is now the therapy of choice for patients with hepatitis C who relapse after initial treatment with interferon monotherapy and is being increasingly used as initial therapy for naı¨ve patients. Our group is currently conducting a randomized, prospective, controlled trial in which 124 nonresponders to at least 3 months of interferon monotherapy have been randomized to either 24 weeks or 48 weeks of treatment with interferon ␣ 3 million units three times weekly plus ribavirin at a weight-dependent dose of 1,000 or 1,200 mg/day in divided doses.5 All 124 patients were HCV-RNA positive, 64% are male, and their mean age is 44.6 years. Of the 124 patients, 100 (81%) had elevated ALT levels, 101 (81%) had HCV genotype 1, and 27 (22%) had cirrhosis. 68S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
Although this study is still ongoing, interim data for 118 of the 124 nonresponders who have completed a course of treatment, and 24 weeks of follow-up demonstrate that 38 patients in this group (32%) have achieved a sustained response. Although the sample size is small, such variables as genotype, presence of cirrhosis, or baseline ALT do not appear to exert a significant effect on whether a response will be achieved. To date, hemolytic anemia, a known side effect of ribavirin therapy, has required dose reduction in 10 patients, but treatment discontinuation has been necessary in only one individual. Thus, although these results are only preliminary, it does appear that retreatment with interferon plus ribavirin may offer promise in nonresponders to previous interferon monotherapy.
ADJUNCTIVE THERAPIES Several adjunctive agents and procedures have been tried in an effort to induce a response in previous monotherapy nonresponders. Such adjuncts include, but are not limited to, milk thistle (silymarin), ozone therapy, thymus extract, ursodeoxycholic acid, and iron reduction via phlebotomy. Of these, only the latter has been relatively well investigated and found to have the potential for efficacy. The use of phlebotomy to produce iron deficiency is based on the observation from several studies that nonresponders have higher iron concentration than responders.6 It has been suggested that viral replication rates within infected liver cells are at least partially determined by the iron content of the liver, because iron is a required cofactor for the synthesis of RNA.3 This theory is consistent with the observation, made more than two decades ago, that hepatitis B–infected individuals with increased hepatic iron stores are more likely to become chronic carriers of hepatitis B and to have abnormal liver histology than are those with lesser iron stores.7 It is also consistent with more recent reports suggesting that individuals with high-normal levels of hepatic iron may have a reduced response to interferon therapy.6,8 The first study in which phlebotomy was used as a means of reducing iron stores was published in 1994.9 This small nonrandomized trial included 10 patients with chronic hepatitis C, 2 of whom had failed interferon therapy. Phlebotomy was performed weekly or monthly to reduce their ferritin levels to 10 ng/mL or their hemoglobin concentrations to 10 g/dL. ALT levels decreased from an overall mean of 152 IU/L to 55 IU/L and normalized in 5 of the 10 patients, but histologic abnormalities remained unchanged except for the disappearance of iron deposits from 7 patients.9 In 1996, Van Thiel et al2 published the results of a study enrolling 30 interferon nonresponders who were reVolume 107 (6B)
A Symposium: Available Options for Treatment of Interferon Nonresponders /Bacon
Table 1. Effects of Phlebotomy in 96 Patients With Hepatitis C PrePhlebotomy
PostPhlebotomy
35.1 335 44.3 138 9.7
7.4* 15* 36.1* 93* 7.5
Transferrin saturation (%) Ferritin (ng/mL) Hematocrit (%) ALT (U/L) HCV RNA (mEq/mL)
ALT ⫽ alanine aminotransferase; HCV ⫽ hepatitis C virus. * P ⬍0.01.
treated with interferon ␣ 5 million units daily for 6 months, with or without weekly phlebotomy.3 Both groups experienced a significant (P ⬍0.01) reduction in serum ALT levels and improvement in liver histology (Knodell scores). More biological and virologic sustained responses were achieved in the phlebotomy-plus-interferon group compared with the interferon-alone group, but the difference did not attain statistical significance.3 The results of these studies led us to initiate a 10-site trial comparing phlebotomy plus interferon with phlebotomy alone in 96 patients who had failed to respond to interferon monotherapy given at standard doses for at least 3 months. Phlebotomy was initiated in all patients during the first 3 months of the study, then interferon was administered from month 3 through month 9, with follow-up through month 16. Iron deficiency was achieved after removing a mean of 7.8 units of blood (range, 3 to 21 units). Serum ALT levels decreased with phlebotomy in 85 of the 96 patients (89%). ALT levels decreased by 50% in 15 patients (16%) and returned to normal in 15 patients (16%). HCV-RNA levels decreased from baseline but were not reduced significantly (Table 1).10 Histologic results will be available shortly.
LONG-TERM THERAPY
group 3. Among the 176 patients who underwent liver biopsy at 18 months, more patients in group 1 than in groups 2 or 3 had improved histology scores (70% vs 48% and 39%, respectively).11 These data suggest that longerterm therapy may improve histology even in the absence of a virologic response. Issues of cost effectiveness and long-term tolerability remain unresolved.
WATCHFUL WAITING Another option is “watchful waiting,” in the hope that better therapies will become available. Although this may be anxiety producing for some physicians and patients, it may be the best course of action for patients with mild, nonprogressive disease as demonstrated on liver biopsies. This approach is best undertaken with the understanding that frequent and regular follow-up will be needed.
SUMMARY For the many patients with chronic hepatitis C who fail to respond to initial treatment, effective regimens for retreatment are still being developed. Some degree of success has been obtained with use of another form of interferon in high doses, retreatment with interferon plus ribavirin, adjunctive phlebotomy, and long-term therapy. Nonetheless, evidence remains insufficient for most of these approaches, and the evidence that does exist only demonstrates a partial incremental improvement. It is likely that the next significant improvement after combination interferon-plus-ribavirin therapy in nonresponders will be the use of helicase or protease inhibitors. It is not clear whether pegylated interferon products with ribavirin will significantly impact successful retreatment of the nonresponder population. Clinical developments involving these new forms of therapy are eagerly awaited.
REFERENCES
Rather than eradicating the virus, the goal of long-term therapy would be to prevent or retard the longer-term complications of HCV, including cirrhosis, decompensation, and hepatocellular carcinoma. Poynard et al11 have studied long-term treatment in 303 HCV-infected patients, all of whom were treated for 6 months with interferon ␣ 3 million units administered three times a week. The patients were then randomly assigned to one of three regimens: the same treatment for an additional 12 months (group 1, n ⫽ 103), 1 million units three times a week for 12 months (group 2, n ⫽ 101), or no further treatment (group 3, n ⫽ 99). Follow-up was continued for 2 years after discontinuation of treatment. Patients in group 1 achieved the greatest reduction in serum ALT levels, with 45% of the group registering normal levels at 18 months, as compared with 27% in group 2 and 30% in
1. National Institutes of Health Consensus Development Conference Panel Statement: Management of Hepatitis C. March 24 –26, 1997;15(3) 2. Van Thiel DH, Friedlander L, Molloy PJ, et al. Retreatment of hepatitis C interferon non-responders with larger dose of interferon with and without phlebotomy. Hepato-Gastroenterology. 1996;43:1557–1561. 3. Lindsay KL, Davis GL, Schiff ER, et al. Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis interventional therapy group. Hepatology. 1996;25:1034 –1040. . 4. Heathcote EJ, Keefe EB, Lee SS, et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998;27:1136 –1143. 5. Bacon BR, Rauscher JA, Smith-Wilkaitis NL, et al. Interferon-ribavirin combination: sustained response in previous monotherapy non-responders. Hepatology. 1999;30:372A. Abstract. 6. Olynyk JK, Reddy KR, Di Bisceglie AM, et al. Hepatic iron
December 27, 1999
THE AMERICAN JOURNAL OF MEDICINE威
Volume 107 (6B)
69S
A Symposium: Available Options for Treatment of Interferon Nonresponders /Bacon concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology. 1995;108: 1104 –1109. 7. Sutnic AI, Blumberg BS, Lustbader ED. Elevated serum iron levels and persistent Australia antigen (HBsAg). Ann Intern Med. 1974;81:855– 856. 8. Van Thiel DH, Friedlander L, Fagivoli S, et al. Response to interferon ␣ therapy is influenced by the iron content of the liver. J Hepatology. 1994;20:410 – 415. 9. Hayashi H, Takikawa T, Nishimura N, et al. Improvement of
70S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol. 1994;89:986 –988. 10. Di Bisceglie AM, Bonkovsky HL, Krawitt EL, et al. Iron reduction therapy in chronic hepatitis C. Hepatology 1997; 26:214A. Abstract. 11. Poynard T, Bedossa P, Chevallier M, et al. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A; non-B hepatitis. N Engl J Med. 1995;332:1457–1462.
Volume 107 (6B)