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Interferon Alpha-2b and Ribavirin for Patients with Chronic Hepatitis C and Normal ALT
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The American Journal of Gastroenterology
Volume 99 Issue 9 - September 2004
Ira M. Jacobson, Furqaan Ahmed, Mark W Russo, Edward Lebovics, Douglas T. Dieterich, Stephen P. Esposito, Nancy Bach, Franklin Klion, Hillel Tobias, Louis Antignano, Robert S. Brown Jr., David Gabbaizadeh, Jane Geders, and Hulya Levendoglu.
Weill Medical School of Cornell University, New York; New York Medical College, Valhalla; Cabrini Medical Center and New York University School of Medicine, New York; New York Hospital-Queens, Queens; Mount Sinai Medical Center, New York; New York University Medical Center; University of Rochester School of Medicine, Rochester; Columbia Presbyterian Medical Center, New York; Huntington Hospital, Long Island; Mount Kisco Medical Group, Mount Kisco; Brookdale Hospital Medical Center, Brooklyn, New York
EDITORIAL in Am J Gastr
Chronic Hepatitis C and Normal ALT: Considerations for Treatment
Bruce R. Bacon, M.D.
Saint Louis University Liver Center
St. Louis, Missouri
SUMMARY: Improvements in the treatment of patients with chronic hepatitis C have progressed over the past 14 yr. Initially, treatment of patients with persistently normal ALT levels was not considered necessary. As treatment response improved, more of these patients were treated. Jacobson and colleagues have shown that patients with normal ALT levels respond similarly to those with elevated ALT levels when treated with the combination of interferon and ribavirin. ALT levels are a poor marker of disease severity and/or indication for treatment in patients with chronic hepatitis C... it is recognized that the majority of patients with normal ALT levels have mild disease histologically, it is also understood that as many as 15-20% can have advanced fibrosis and/or cirrhosis... Importantly, patients with mild disease may have other indications for treatment independent of an effect on disease progression. These include the presence of symptoms of HCV viremia, extrahepatic manifestations of chronic hepatitis C, concerns about infectivity, and the wishes of patients to be free of the hepatitis C virus... The argument to limit therapy only to those patients with elevated ALT levels is no longer valid. Factors that should be considered relative to therapy include patient motivation, patient age, duration of infection, viral genotype, HCV RNA levels, and presence of symptoms. SEE FULL EDITORIAL AT END OF THIS ARTICLE. (note from Jules Levin: a liver biopsy should be helpful in making the decision of treatment in general and when ALT are normal)
"...There have been concerns about the safety of treating patients with baseline normal ALT, because some patients treated with interferon monotherapy developed ALT elevations. Cumulative data on interferon monotherapy have shown that nearly half (45.9%) of these patients developed ALT elevations during or after therapy. Others have speculated that the ALT elevations on treatment are a result of interferon-induced enhanced immunity against HCV-infected hepatocytes. However, the clinical significance of this finding and whether or not it reflects an exacerbation of liver injury is unclear. Five of our patients had ALT elevations while on therapy. However, the ALT elevations were transient in all the cases and did not rise more than two times the upper limit of normal. These elevations did not lead to changes in therapy for any patients..."
"...SVR is usually associated with normalization of ALT in patients with a baseline elevated ALT. In agreement with other studies, we found that SVR in normal ALT patients is associated with a significant decrease in serum ALT values, even within the normal range..."
"...Notably, 36% of the patients in our study cohort had Metavir stage 2 or greater on liver biopsy. Our less strict criteria for normal ALT may explain the slightly higher frequency of advanced fibrosis in our cohort compared with that reported in trials of standard interferon and RBV in patients with normal ALT (11-29%) and from studies describing the histologic findings of normal ALT patients (19-24%). In support of this, the number of ALT levels used to define patients with persistently normal ALT appears to be inversely correlated with the degree of liver fibrosis..."
SEE AUTHOR DISCUSSION below
ABSTRACT
OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alpha-2b (IFN) with ribavirin (RBV) in patients with normal ALT.
METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy.
RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted.
CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.
BACKGROUND
Approximately 30% of patients with chronic hepatitis C (CHC) have a persistently normal ALT. These patients are more commonly female and tend to have lesser degrees of inflammation and fibrosis on liver biopsy. Studies also have suggested that these patients have a more benign natural history with slower disease progression. Patients with normal ALT have traditionally been excluded from most of the major clinical trials that establish the role of antiviral therapy for CHC, because prior to the advent of molecular testing there was uncertainty regarding viremia in these patients. Indeed, early treatment studies used normalization of ALT as a surrogate marker for response. Later, these patients were thought to have a milder form of the disease and potentially different response rates.
It is now recognized that all normal ALT patients do not have mild liver disease and slower progression. In fact, in some series, up to 14-20% of these patients have advanced fibrosis or cirrhosis on liver biopsy and the degree of liver injury may not differ from the matched controls with elevated ALT. Moreover, patients with mild liver disease may want to eradicate their HCV infections and some, including health-care workers and young women contemplating pregnancy, may have a compelling reason to do so. The NIH Consensus Conference in 2002 also reflects this change in approach and has revised its 1997 statement recommending that patients with normal ALT should not be treated outside of clinical trials. The new guidelines favor a more individualized approach taking into account the degree of liver injury and fibrosis, HCV genotype, comorbid illnesses, and patient preferences among other considerations.
Correspondingly, there has been a continued interest in the treatment outcomes of patients with normal ALT. Studies done using interferon (IFN) monotherapy in these patients found SVR rates inferior or comparable to those in patients with an elevated ALT, with the aggregate data suggesting the comparability. However, there were concerns based on initial observations that treatment may lead to de novo ALT elevations and exacerbate liver injury. There are limited data on combination interferon and ribavirin (RBV) therapy in normal ALT patients. Lee and Sherman conducted an uncontrolled pilot study in which they treated 19 patients with normal or near-normal ALT levels and reported a sustained response rate of 47%. Other published studies on combination therapy in prior nonresponders to interferon monotherapy and in patients with minimally elevated ALT suggest similar rates of response to those seen in patients with elevated ALT. In this study, we sought to determine the efficacy of two doses of interferon alpha-2b in combination with ribavirin in CHC patients with normal ALT who were naïve to the treatment.
AUTHOR DISCUSSION
We conducted this study to determine the efficacy of treating patients with a persistently normal ALT with combination interferon alpha-2b and RBV therapy. The overall SVR rate in our patients was 32% (95% CI, 20%, 46%). This SVR rate is higher than the rate of 14.5% (32/221) obtained by combining 13 studies of interferon monotherapy published in patients with normal or near-normal ALT (<1.5 times the upper limit of normal). Other reviews of the interferon treatment in patients with a normal ALT have published similar SVR rates of 15-20%. Our SVR rate of 32% after 48 wk of treatment is similar to the rates of 38-43% described with the combination treatment in patients with elevated ALT. We also obtained similar response rates to those previously published for genotype 1 patients (24%vs 28-31%) and genotype 2 or 3 (80%vs 64-66%). Our data conform to the established superior efficacy of therapy in patients with genotype 2 and 3 versus genotype 1. The low response rate in a small number of patients with HCV genotype 4 in this trial is consistent with the prior studies suggesting response in this group to be closer to that seen in patients with genotype 1 than with 2 or 3; however, this is being reevaluated with peginterferon and RBV (34). The low rate of response in African-Americans in this study is consistent with previous observations in large trials.
Four other studies have evaluated combination interferon and RBV therapy in patients with normal or near-normal ALT. Lee and Sherman published a small uncontrolled pilot study of patients with normal or near-normal ALT who were treated with interferon alpha-2b and RBV and reported an overall SVR rate of 47% (9/19). SVR rates were 44% (7/16) in genotype 1 patients and 66% (2/3) in genotype non-1 patients. Sponseller et al. (36) recently presented a preliminary data from a multicenter trial of interferon alpha-2b and RBV for the treatment of naïve patients with CHC and normal ALT levels. Twenty-four patients had reached 24 wk of follow-up and 12 (50%) had SVR. Of these patients, 6/14 (43%) genotype 1 and 6/10 (60%) genotype 2 and 3 patients have SVR. The SVR rates reported by these small studies are not significantly higher than ours (p= 0.27, p= 0.14, respectively).
In a study on retreatment of nonresponders to interferon monotherapy with combination therapy, 24 patients with baseline normal ALT were included (28). Eleven of these patients were treated for 24 wk and the rest were treated for 48 wk, with an overall SVR rate of 25% (6/24). This result seems consistent with the incremental increase in response to treatment with interferon and RBV over interferon monotherapy. Of note, although all the patients in their study had a normal ALT in the 6 months preceding the study, almost half (11/24) were known to have elevated ALT in the past. This group may, therefore, not truly reflect a normal or even near-normal ALT population. Gordon et al. reviewed data from two prospective randomized-controlled trials comparing interferon monotherapy with combination interferon and RBV therapy and evaluated 105 (6% of total) patients with near-normal baseline ALT values (<=1.3 times the upper limit of normal). They found similar SVR rates in patients with minimally raised ALT and those with higher ALT levels who were treated with interferon alone (5/34, 15%vs 90/700, 13%). They reported results similar to ours in patients treated with combination therapy (21/71, 30%).
There was a trend toward a better response with higher doses of interferon in some of the interferon monotherapy studies. Lee and Sherman used a high dose induction phase of interferon in their study and this may have contributed to their high SVR rate of 47%, although a large study on induction therapy did not demonstrate an advantage. Our data show a trend toward higher SVR rates with the higher dose of interferon, although this difference did not reach statistical significance. Based on our small study size, however, we cannot exclude the possibility of added benefit from a dose of standard interferon alpha-2b greater than 3 MU three times a week. Like Di Bisceglie et al., we did not find SVR rates to be associated with the degree of fibrosis on biopsy or HCV titers (28) but our study may not have been adequately powered to do so. A larger study would have been preferable to address this and other issues, but extension of the present study was precluded by the advent of pegylated interferon.
Our data were similar to that of other studies using combination interferon and RBV therapy with respect to the number of patients who required dose reduction or discontinuation of therapy. There have been concerns about the safety of treating patients with baseline normal ALT, because some patients treated with interferon monotherapy developed ALT elevations. Cumulative data on interferon monotherapy have shown that nearly half (45.9%) of these patients developed ALT elevations during or after therapy. Others have speculated that the ALT elevations on treatment are a result of interferon-induced enhanced immunity against HCV-infected hepatocytes. However, the clinical significance of this finding and whether or not it reflects an exacerbation of liver injury is unclear. Five of our patients had ALT elevations while on therapy. However, the ALT elevations were transient in all the cases and did not rise more than two times the upper limit of normal. These elevations did not lead to changes in therapy for any patients. Among the other combination interferon and RBV treatment studies, Di Bisceglie et al. reported transient ALT changes during and after treatment in 50% (12/24) patients but they were all mild and self-limited. In their study of 19 patients, Lee and Sherman did not report any ALT flares. The other studies did not report data on ALT changes. In one study using interferon monotherapy, ALT elevations were similar in normal ALT patients undergoing treatment and in normal ALT controls who were not treated. The ALT elevations seen in some normal ALT patients while on interferon may reflect clinically insignificant enhancement of liver injury and does not appear to constitute a contraindication to treatment.
SVR is usually associated with normalization of ALT in patients with a baseline elevated ALT. In agreement with other studies, we found that SVR in normal ALT patients is associated with a significant decrease in serum ALT values, even within the normal range. In our study, patients who achieved a SVR had a significantly lower mean ALT at follow-up week 24 when compared to baseline, while nonresponders did not.
There is no standard definition of the number, frequency, and interval of ALT values required to classify a patient as having persistently normal ALT levels. Although most studies use a definition of at least three normal ALT levels over a 6-month period, our requirements were slightly less stringent. We enrolled patients with at least two normal ALT levels over three or more months because it is likely that these patients would, in most cases, have a persistently normal ALT if followed longer and, even more importantly, would have been excluded from most historical treatment protocols. Similarly, there has been much interest in the definition of normal ALT, but our goal was to address the efficacy and safety of treatment in patients with ALT levels within the normal range in widespread clinical use.
Notably, 36% of the patients in our study cohort had Metavir stage 2 or greater on liver biopsy. Our less strict criteria for normal ALT may explain the slightly higher frequency of advanced fibrosis in our cohort compared with that reported in trials of standard interferon and RBV in patients with normal ALT (11-29%) and from studies describing the histologic findings of normal ALT patients (19-24%). In support of this, the number of ALT levels used to define patients with persistently normal ALT appears to be inversely correlated with the degree of liver fibrosis (38). However, the high prevalence of significant fibrosis in our study is probably attributable to the likelihood that the investigators would have tended to select patients with significant fibrosis for therapy. Thus, the prevalence of fibrosis in this study cannot be interpreted as representative of the histologic findings in a random or consecutive population of HCV patients with normal ALT. Nevertheless, our data do underscore the well-documented capacity of patients with normal ALT to have moderate-to-advanced fibrosis in a significant number of cases.
In conclusion, we found that patients with normal ALT had a rate of SVR similar to or only slightly lower than published SVR rates in patients with high ALT. The SVR rate in patients with genotype 1 approached that reported in patients with genotype 1 and elevated ALT. The higher dose of interferon tended to have greater efficacy in patients with genotype 1 infection but no definite conclusions can be drawn. Side effects were similar to those seen in other populations and, in contrast to prior concerns about interferon monotherapy, de novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of normal ALT alone. In light of the demonstrated superiority of pegylated interferons with RBV in treatment naïve patients with CHC, combination therapy with pegylated interferon and RBV is currently being evaluated in this group of patients.
MATERIALS & METHODS
Eligible subjects were adult patients with liver biopsy-proven CHC who were EIA positive for HCV antibody, treatment naïve, and had detectable HCV RNA by polymerase chain reaction (PCR) assay. Patients were eligible if they were 18 yr of age or older and had an ALT within normal limits 12 wk or more prior to the entry visit and at the entry visit, which occurred within 4 wk of initiation of therapy. Patients were excluded from the participation if they had decompensated liver disease, substance abuse (alcohol or drugs) within the last year, neutropenia (ANC < 1,500/mm3), thrombocytopenia (platelets < 100,000/mm3), anemia (hemoglobin < 12 g/dl in females, hemoglobin < 13 g/dl in males), hepatocellular carcinoma, concomitant liver disease, HIV infection, poorly controlled psychiatric disease, serum creatinine more than 1.4 mg/dl, or significant co-existing medical conditions.
This randomized, controlled clinical trial was conducted at 11 centers in New York State from 1998 to 2001. Patients were randomized to: Group 1-3 MU of IFN alpha-2b thrice a week plus daily RBV for 48 wk or Group 2-5 MU of IFN alpha-2b thrice a week plus daily RBV for 48 wk. Patients weighing 75 kg or less received RBV 1,000 mg orally per day and those over 75 kg received 1,200 mg per day. All the patients were tested for HCV RNA by a reverse transcription polymerase chain reaction assay (PCR) (National Genetics Institute, Los Angeles, lower limit of detectability 100 copies/ml) at entry, week 12, week 24, week 48, and 24 wk after discontinuation of therapy. If HCV RNA was detectable at 24 wk therapy was discontinued, and if treatment was discontinued prior to 48 wk with undetectable HCV RNA a 24 wk-follow-up PCR was obtained. The primary efficacy endpoint was sustained virologic response (SVR) defined as the absence of detectable HCV RNA at 24 wk of follow up. Safety and tolerance were evaluated at weeks 1, 2, 4, 8, and then every 4 wk during treatment and at weeks 4, 8, 12, and 24 following the end of therapy.
RESULTS
Fifty-six patients were enrolled and received at least one dose of study medications; 29 were randomized to receive 3 million units of IFN and 27 were randomized to receive 5 million units of IFN. The pretreatment characteristics of the patients in the two treatment groups were similar. Forty-three (77%) patients received at least 24 wk of treatment. Twenty of the 56 patients (36%; 95% confidence interval [CI], 23%, 50%) had Metavir stage 2 fibrosis or more (stage 2-13 patients, stage 3-6 patients, or stage 4-1 patient).
Forty-five percent (95% CI, 31%, 59%) of patients (25/56) became PCR-negative while on therapy. Four patients had a breakthrough while on therapy and three patients had a relapse after cessation of therapy. Overall, 32% (18/56) had a sustained response to interferon therapy (95% CI, 20%, 46%). The sustained response rate was higher in patients with genotype 2 and 3 (80%) than in those with genotype 1 (24%, p= 0.002). None of the four patients with genotype 4 had a SVR. The SVR rate was higher in genotype 1 patients receiving the higher dose of interferon (36%vs 10%) but this difference did not reach statistical significance (p= 0.07). The SVR rate was similar among patients with mild (Metavir stage 0 and 1) and advanced (Metavir stage 2, 3, and 4) fibrosis (33%vs 30%, p= 0.89). The SVR rate also did not differ significantly between patients with low and high viral concentrations (40%vs 21%, p= 0.15), where low viral concentration was defined as less than or equal to 2 million copies/ml. Among 40 evaluable patients with genotype 1 infection, 5 of 19 (26%) with low viral load had an SVR compared with 3 of 21 (14%) with high viral load. Two patients with genotype 1 had viral levels reported as over 1 million copies on baseline PCR, and hence could not be classified as low or high; both had an SVR. The SVR rate was 9% (1/11) for the African-American patients and 38% (17/45) for the Caucasian patients. Within the latter group, 6 patients were Hispanic and none had an SVR. Compliance rates were similar across ethnic groups. Of the 18 sustained responders, PCR results were available for 14 patients at 12 wk, and all 14 were negative. Thus, no evaluable patient with sustained response had detectable HCV RNA at week 12.
The end of treatment ALT were significantly lower than baseline ALT values in both sustained responders and nonresponders. In patients with sustained response to therapy, the mean ALT levels at follow-up week 24 remained significantly lower than baseline levels. There was no difference between patients treated with higher and lower doses of interferon. In nonresponders, the mean ALT rose by follow-up week 24 so that they approached baseline.
While on interferon therapy, five patients had ALT elevations. All ALT elevations were transient despite continued therapy and none rose to more than two times the upper limit of normal. One patient had a concomitant transient elevation in bilirubin. Two patients had serious adverse effects; one developed confusion, and the other had suicidal ideation. Four patients developed thyroid dysfunction while on treatment. Adverse events led to discontinuation of therapy in nine (16%) patients. There were no unexpected adverse events. Of the patients who received 3 million units of interferon, 3 (10%) underwent interferon dose reduction and 7 (24%) underwent ribavirin dose reduction. In patients treated with 5 million units of interferon, 2 (7%) and 9 (33%) patients had dose reductions of interferon and RBV, respectively.
EDITORIAL
Bruce Bacon, MD
Treatment of patients with chronic hepatitis C has advanced considerably since 1990. Initial therapies with interferon monotherapy were only successful in about 10-15% of patients. More recently, with the use of pegylated interferon and ribavirin, sustained virologic response (SVR) rates occur in over 50% of patients. Approximately 30% of patients with chronic hepatitis C have normal alanine aminotransferase (ALT) levels and another 40% have ALT levels that are less than twice the upper limit of the normal range. Several studies have shown that hepatitis C patients with normal ALT levels usually have mild changes on biopsy and a slow progression of disease over time. Accordingly, in the past, when SVR rates were so low, the benefit of treatment in these patients with mild disease was limited. Further, it was thought by some that treatment might actually make matters worse since some patients who had normal ALT levels prior to treatment with interferon monotherapy developed ALT elevations during or after therapy, suggesting that treatment may in fact be harmful. Since treatment was considered by some to be harmful, and was not clearly beneficial, given the low SVR rates, it was recommended at the 1997 National Institutes of Health Consensus Development Conference on "Management of Hepatitis C," that patients with normal ALT levels should not be treated except in experimental protocols. With the advent of improved therapy, which came about when ribavirin was added, this concern was moderated in the 2002 NIH Consensus Conference statement. It was determined that SVR rates for patients with normal ALT levels were really no different than for those with elevated ALT levels. This was seen both for treatment with interferon monotherapy and then for patients treated with the combination of interferon and ribavirin. These studies were limited in that they included small numbers of patients.
In this issue of the Journal, Jacobson and colleagues present their results of a large multicenter trial with rigorously defined criteria of normal ALT and once again show that SVR rates are equivalent to those seen in studies done with patients with chronic hepatitis C who have elevated ALT levels. In their study, patients had to have at least two normal ALT levels three or more months apart and then they were randomized to receive either three or five million units of standard interferon three times per week plus ribavirin at 1,000-1,200 mg/day. Fifty-six patients were randomized to receive at least one dose of treatment and the overall SVR rate was 32%. As expected, SVR rates were higher in patients with genotype 2/3. Five patients had mild and transient ALT elevations and none of these was sustained. This study adds increased support to the notion that patients with normal ALT levels respond to the same degree as do patients with elevated ALT levels to the combination of interferon and ribavirin. Also, a recent preliminary study has shown that the use of pegylated interferon with ribavirin in patients with normal ALT levels also achieves response rates similar to studies done in patients with elevated liver enzymes (11).
(11) Zeuzum S, Diago M, Gane E, et al. International multicenter, randomized, controlled study for the treatment of patients with chronic hepatitis C and persistently normal ALT levels with peginterferon alfa-2a and ribavirin. Hepatology 2003: 38: 208A.
Thus, SVR rates seem equivalent in patients with normal ALT levels compared to those with elevated ALT levels and there is no evidence that there are any long-term adverse sequelae for patients who do not respond. These findings by Jacobson and colleagues add to the body of literature suggesting that ALT levels are a poor marker of disease severity and/or indication for treatment in patients with chronic hepatitis C. While it is recognized that the majority of patients with normal ALT levels have mild disease histologically, it is also understood that as many as 15-20% can have advanced fibrosis and/or cirrhosis. Importantly, patients with mild disease may have other indications for treatment independent of an effect on disease progression. These include the presence of symptoms of HCV viremia, extrahepatic manifestations of chronic hepatitis C, concerns about infectivity, and the wishes of patients to be free of the hepatitis C virus. Current SVR rates are much improved over what we had in the early 1990s. The argument to limit therapy only to those patients with elevated ALT levels is no longer valid. Factors that should be considered relative to therapy include patient motivation, patient age, duration of infection, viral genotype, HCV RNA levels, and presence of symptoms.
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