Daily interferon monotherapy for chronic hepatitis C in patients with normal or nearnormal serum alanine transaminase levels: a comparison of two protocols.

Objectives: Up to 30% of the 5 million patients with chronic hepatitis C in the United States have normal serum alanine transaminase (ALT) levels. These individuals have not been treated aggressively, and reported response rates have been low. No study has targeted patients treated in a community practice setting.

Methods: Consecutive patients with chronic hepatitis C with normal or near-normal serum ALT levels seen over a 2-year period in a community gastroenterology-hepatology practice were randomly assigned to receive either 3 MU or 6 MU daily interferon (IFN)-[alpha]-2a monotherapy for 12 months.

Results: Sixteen patients (8 in each treatment arm) qualified for study. End-of-treatment response was 87.5% with 6 MU IFN daily and 75% with 3 MU IFN daily, whereas sustained virologic response was 62.5% and 50%, respectively. Genotype 1 patients had an improved outcome with the higher 6 MU dose.

Conclusions: Daily IFN monotherapy achieves high response rates in patients with chronic hepatitis C with normal or near-normal ALT. Present-day pegylated interferon regimes can be expected to be as effective.

Key Words: community practice, hepatitis C, interferon, normal alanine transaminase, randomized trial

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Chronic hepatitis C affects about 5 million people in the United States. Approximately 30% of these patients have normal serum alanine transaminase (ALT) levels and another 40% have ALT levels that are less than twice the upper limit of normal. (1) Treatment of patients with normal or near-normal ALT levels has been a contentious issue, and most trials of antiviral therapy for chronic hepatitis C have been limited to those with elevated ALT levels. The infectivity, symptoms, virologic characteristics, liver histology, and long-term outcome of chronic hepatitis C favors therapy. On the other hand, some investigators do not recommend antiviral therapy for individuals with normal ALT levels because of the side effects and cost of therapy, and the reported treatment efficacy in this subgroup of patients. (2) As a result, patients with normal or near-normal ALT currently are not recommended for antiviral therapy. However, despite normal serum ALT levels, the liver disease in these individuals may be advanced. Up to 10% of cases with near-normal ALT levels have histologically documented cirrhosis, (3) and most have some degree of inflammatory activity. Some of these patients may have a virologic response to interferon therapy. The relatively few studies of [alpha]-interferon (IFN-[alpha]) therapy in patients with normal ALT levels have been reported from large teaching hospitals and may not reflect the outcomes to be expected for the majority of patients, who are treated in a community practice setting. We have been treating patients with chronic hepatitis C with normal or near-normal ALT levels in a community gastroenterology/hepatology practice with interferon monotherapy on an a priori intention-to-treat basis to determine if patients with chronic hepatitis C with normal or near-normal serum ALT levels can be effectively treated and achieve viral clearance. Moreover, we have examined the efficacy of two different dose regimens of IFN-[alpha]-2a (Roferon) in their unique population.

Materials and Methods

Subjects

The principal aim of our study was to determine the efficacy of IFN treatment of previously untreated patients with hepatitis C, who had persistent normal to near-normal serum ALT levels. Patients were accrued sequentially over a 2-year period in a community gastroenterology/hepatology practice. Hepatitis C was diagnosed on the basis of the presence of anti-hepatitis c virus (HCV) antibodies (by enzymelinked immunosorbent assay) and confirmed by identifying HCV-RNA (by reverse transcriptase-polymerase chain reaction) in plasma. A normal or near-normal serum ALT level was defined as a level less than or equal to 1.5 times the upper limit of normal on at least two occasions at least 1 month apart. The inclusion and exclusion criteria utilized are outlined in Table 1 and represent the community standard. Informed consent was obtained from all patients, and the study was approved by the local institutional review board.

Overall study design

This was a pilot open-label, fixed-dose, parallel comparison of 3 million versus 6 million units of IFN-[alpha]-2a (Roferon) administered daily subcutaneously for 12 months in patients with chronic hepatitis C with normal or near-normal ALT levels. The assignment to either treatment arm was randomized, with each consecutively seen alternate patient being assigned to a treatment arm (ie, odd: 3 MU, even: 6 MU).

Baseline investigations

In addition to the investigations undertaken to exclude/include patients based on the above-defined entry and exclusion criteria, all subjects underwent the following baseline investigations: (1) viral loads in plasma by HCV-RNA quantitative reverse transcriptase-polymerase chain reaction; (2) complete blood counts; (3) assessment of hepatic function (bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, GGT, total proteins, A:G ratio, PT); (4) blood urea nitrogen, serum creatinine, and serum uric acid; (5) autoantibodies including ANA, AMA, ASMA; (6) serum ferritin, iron, and transferrin (patients with a high iron index or raised ferritin were phlebotomized, as decreasing the iron load has been shown to improve the efficacy of IFN); (7) serum ceruloplasmin; (8) [alpha]-fetoprotein; (9) TSH and T-4 levels; (10) glycated hemoglobin; (11) lipid profile; and (12) liver biopsy for histology and scoring of the histologic activity index, using the Metavir system.

Follow-up

All subjects enrolled in the study were followed weekly for the first 4 weeks and then monthly thereafter until completion of 12 months of treatment. Investigations performed at each follow-up visit included complete blood cell count, liver function tests (aspartate transaminase, alanine transaminase, alkaline phosphatase, GGT, and bilirubin), blood urea nitrogen and serum creatinine, TSH and T-4, cholesterol and triglycerides, calcium, phosphorus, and electrolytes. Viral loads were scheduled to be assessed at monthly intervals from 12 weeks after commencement of interferon therapy until three consecutive negative results were obtained. An HCV RNA qualitative assay in plasma and liver tissue obtained by percutaneous biopsy was performed at the end of the 12-month treatment period. All patients were followed for at least 6 months after completion of therapy and resubjected to an HCV RNA qualitative assay to distinguish sustained responders from end-of-treatment (ETR) responders.

Definitions of response

ETR was defined as achievement of three consecutive negatives on viral assays and a negative reverse transcriptase-polymerase chain reaction result both in plasma and the liver at the end of 12 months of treatment. If the virus reappeared in the plasma at this 12-month time point, the response was labeled as a breakthrough. Sustained virological response (SVR) was defined as a negative viral assay 6 months or more after completion of treatment. A positive result at this point was defined as a relapse.

Results

Sixteen patients with chronic hepatitis C seen in the period of October 1998 to December 2000 qualified for inclusion in the study. These patients were randomly assigned alternately at accrual into the 3 MU and 6 MU IFN-[alpha]-2a treatment arms. Patient characteristics are shown in Table 2. All the subjects accrued for study successfully completed the treatment protocol.

Viral genotypes were available in 10 of 16 patients. Two patients had HCV genotype-2, one had HCV genotype-3, and the others had HCV genotype-1. As a result of the randomization process, all three nongenotype-1 patients were randomly assigned to receive 3 MU IFN-[alpha]-2a by chance. Baseline biopsy specimens in the 16 subjects documented varying degrees of mild histologic inflammatory activity and minimal to mild fibrosis. The histologic activity indices did not correlate with any other parameter assessed. None of the 16 subjects had cirrhosis.

Seven of the eight subjects receiving 6 MU IFN-[alpha]-2a daily achieved ETR (87.5%). Six of these 7 had cleared the virus from their plasma at the first follow-up HCV RNA assay (ie, after 3 months of therapy). The seventh subject (no. 2), who had an initial viral load of 3.2 million copies/mL (genotype-1a), cleared the virus after 7 months of therapy. All 7 patients had 3 consecutive negative HCV assays. No break-through responses were observed. One patient (no. 6) with an initial viral load of 2.2 million copies/mL (genotype-1a) failed to clear the virus. Five of the 7 patients who achieved ETR remained virus free for 6 months after the end of therapy, yielding an SVR rate of 62.5%. Two patients (nos. 8 and 12) had a relapse while off therapy. The results are summarized in Table 3 and the Figure.

Of the eight subjects randomly assigned to receive 3 MU IFN-[alpha]-2a daily, six achieved ETR (75%). Five of these six had cleared the virus from their plasma at the first follow-up HCV RNA assay (12 weeks), whereas the sixth (no. 5) cleared the virus after 6 months of therapy. Again, all six of these patients had 3 consecutive negative HCV assays with no viral breakthrough responses. Two patients (nos. 1 and 7) failed therapy. Both were infected with HCV genotype-1a, and both had an initial viral load below 1 million copies/mL. Four of the six patients who achieved ETR also achieved SVR, yielding an overall SVR of 50%. One patient infected with HCV genotype-3a (no. 3) had a relapse. The sixth subject (no. 15) relocated and did not report back to be tested to document SVR, thus being lost to follow-up. The results are summarized in Table 3 and the Figure.

There were no serious adverse events necessitating discontinuation of therapy in this cohort. All patients had one or more adverse events but were able to continue their prescribed treatment until the end of the study. There were no significant differences between the two treatment arms with respect to decline in hemoglobin, hematocrit, leukocyte count, or neutropenia. The patients were given erythropoietin if the hemoglobin fell below 10 g/dL, and were given G-CSF if the white blood cell count fell below 2000/c[m.sup.3]. No patient had significant thrombocytopenia (platelet count <50,000/c[m.sup.3]). Two patients receiving 6 MU IFN had a transient increase in their serum ALT levels greater than 70 IU/L. Four patients on the 6 MU arm and 5 patients on the 3 MU arm had biochemical thyroid abnormalities, but all 11 remained clinically euthyroid. Twelve of 16 patients had hypertriglyceridemia, whereas seven had mild hyperglycemia (maximum plasma glucose levels in these seven subjects ranging from 118 to 169 mg/dL) during the course of the study. Three patients receiving 6 MU IFN and four receiving 3 MU Roferon had transient minimal elevations of serum chloride levels, with none above 110 mEq/L.

Discussion

Therapeutic regimes for individuals with chronic hepatitis C and having normal or near-normal ALT levels have been controversial. (4) However, 76% of these patients have evidence of histologic inflammation on liver biopsy. (5) Moreover, cirrhosis has been reported in up to 10% of patients with chronic hepatitis C with near-normal ALT levels. (3) Most studies have documented a lower incidence of cirrhosis, (5) thereby improving the chances of a response to therapy, in those with normal or near normal ALT levels. Unfortunately, trials to determine the response to IFN-[alpha] have usually excluded such patients. Tassopoulos et al (6) have reported that untreated individuals among those with normal ALT levels have a 13.5 times greater risk of being HCV RNA-positive as compared with treated patients. Several investigators have stated that patients with chronic hepatitis C should not be excluded from therapy solely on the basis of their ALT levels. (1,7)

The National Institutes of Health consensus conference notes that the SVR in monotherapy-treated patients with persistently normal ALT are similar to those of patients with higher ALT levels. (8) Large placebo-controlled trials of therapy for patients with chronic hepatitis C with elevated ALT have shown that only 15% to 20% of patients receiving IFN-[alpha] monotherapy alone and 40% of patients receiving interferon-ribavirin combination therapy can be expected to achieve a sustained virologic response. (2) We have earlier achieved even higher sustained virologic response rates in patients with elevated ALT with daily high-dose interferon continued for 1 year or more. (9) We undertook the present study to assess the outcomes of treatment in a cohort of patients with normal or near-normal ALT levels.

This study was envisaged and begun before combination therapy using IFN and ribavirin was established as the standard of care. Hence, the study was based on IFN monotherapy. Although 3 MU IFN was then considered adequate for therapy by most experts, we had achieved excellent response rates to higher doses in patients with elevated ALT levels. Therefore, this study was designed to compare the SVR with 3 MU versus 6 MU IFN. Ribavirin was introduced and recommended for standard use during the course of our study. Subsequent patients were given a choice before entry into the study to either enroll in the study or be treated on combination therapy. The major limitation of this study is the small number of cases, although it is representative of most community practices. Therefore, this is basically a clinical report of work done, and the conclusions drawn do not have statistical support.

In numerous trials of IFN-[alpha] for patients with chronic hepatitis C with persistent normal ALT levels, ETR has been reported to be less than 42%, whereas SVRs have been less than 33% at 6 to 12 months after therapy, leading to uncertainties about the value of treatment in this group of patients. (5,10-12) Analysis of the different studies, based on dose and duration of therapy, have shown that the previous standard schedule of 3 MU of IFN-[alpha] given for 6 months yielded an overall sustained virologic response of only 10%. (5) Low-dose therapy at 3 MU IFN 3 times per week, the standard of care in the past, has yielded SVRs as low as zero in some series. (13-16) Combination therapy with IFN-[alpha] and ribavirin have also yielded lower SVRs even when the IFN was given at a dose of 4.5 MU three times per week. (17)

In the present study, we achieved a much greater ETR (87.5% with 6 MU and 75% with 3 MU daily Roferon). The SVRs were 62.5% and 50%, respectively. One patient, who received 3 MU Roferon, achieved an ETR with a virologic response within 12 weeks of starting treatment. She completed her course of IFN treatment but did not return at 24 weeks after therapy for an assessment of her SVR. Had she tested negative (as occurred with most other subjects who tested negative at 12 weeks after onset of therapy), the SVR would have been 62.5% for both arms of this pilot study. These outcomes are better than those that have been reported to date with either IFN monotherapy or IFN-ribavirin combination therapy. In a MEDLINE search, we found only one other published study approaching similar high response rates. Sakugawa et al (18) reported an SVR of 57% in their cohort of patients with persistent normal ALT after therapy with either 6 MU or 10 MU IFN three times per week for 6 months. However, of their 19 patients, only the 14 who had favorable viral factors for a response to therapy (low viral loads and nongenotype 1 cases) were considered for analysis.

The patients in this series were treated with either a relatively low or a higher dose of IFN for 12 months. The high virologic response rates are likely to be related to both the dose and duration of therapy. Poynard (19) analyzed 17 trials of various IFN regimens in patients with elevated ALT and found a significant effect of dose (6 versus 3 MU 3 times per week) at 12 months of treatment and not at 6 months, with an increase in the SVR of 17%. Furthermore, there was also a duration effect (12 versus 6 months) at both the 3 MU (increase in SR of 16%) and the 6 MU dosages (increase in SR of 20%). Lee et al (20) reported a 47% SVR in patients with normal ALT levels when giving induction therapy with 5 MU daily for 4 weeks followed by 3 MU 3 times per week for 44 weeks. Thus, it appears important to treat patients aggressively with both a greater dose and for longer durations to achieve viral clearance.

Early loss of HCV RNA has been reported to be predictive of a sustained response in patients with elevated ALT levels. Orito et al (21) showed that 17 of 19 patients who achieved SVR after 6 months of treatment had cleared HCV RNA at 4 weeks. Of the 13 patients in the current series who achieved ETR, 11 had cleared the virus at 12 weeks after the onset of therapy. Two of these 11 patients (one each in each of the 3 MU and 6 MU arms) did not attain SVR. Furthermore, one patient in each arm had a late clearance of virus, and both achieved SVR. It is likely that sustained responses depend not only on early viral clearance, but also on the length of time that IFN therapy is continued after the HCV RNA becomes undetectable in plasma.

In several published studies of patients with chronic hepatitis C and elevated ALT levels, the strongest predictors of virologic response have been the pretreatment viral load, HCV genotype, and hepatic histology. These factors also held for patients with near-normal ALT levels. The overall virologic characteristics are similar in patients with and without elevated ALT levels. (3,22,23) Although mean serum/plasma HCV RNA titers are less in those with normal ALT levels, they are highly variable, (5) and the positive predictive value of a low HCV RNA level for a virologic SVR was only 71% in a meta-analysis of 11 trials. (2) In the present series, a wide range of pretreatment viral loads was found, ranging from 33,000 to 5 million copies/mL. Pretreatment viremia did not affect the outcome.

Liver histology has been reported to be normal in 24% of patients with normal or near-normal ALT levels, whereas cirrhosis has been reported in only 0.8% cases. (5) Some degree of fibrosis is, however, seen in 65% of such patients, although it is usually mild. (24) All of the patients in this study had varying degrees of inflammation and minimal to mild fibrosis on their pretreatment biopsy specimens. There was no evidence of severe fibrosis or cirrhosis in any of the biopsy specimens. Hepatic histology did not correlate with any other parameter or the type of response.

Some studies have found an older average age and a higher proportion of women in cohorts of patients with hepatitis C with normal ALT levels. (3,25) Of the 16 consecutive patients with normal or near-normal ALT levels in this study, 10 (62.5%) were female. Three patients were older than 50 years of age, and all three achieved SVR. Age and sex did not affect the outcome in this series.

Various investigators have suggested that IFN therapy may be harmful in patients with chronic hepatitis C with normal ALT levels and may induce worsening of their liver disease, based on serum ALT "flares" during therapy. Serum ALT levels have been documented to occur in up to half of these patients during treatment. (5,12) However, others have not encountered any ALT flares even when giving combination therapy with IFN-ribavirin, (17) or when treating with high-dose induction followed by maintenance therapy. (20) In another study, ALT flares occurred in 3 treated and 9 untreated patients, suggesting that a flare merely represents part of the natural course of chronic HCV infection rather than a response to the IFN. (6) Two patients in the present study, both of whom received 6 MU IFN daily, had a transient elevation in their serum ALT levels. There were no severe adverse events necessitating discontinuation of therapy.

Conclusion

Daily IFN-[alpha]-2a monotherapy achieves a high response rate (75% to 87.5% ETR and 50% to 62.5% SVR) in patients with chronic hepatitis C with normal or near-normal ALT levels. Outcomes appear to be better with 6 MU daily IFN, particularly among patients infected with HCV genotype-1. Present-day pegylated interferon regimes provide an equivalent daily dosage of approximately 5 MU IFN-[alpha]. Therefore, these preparations are expected to be at least as effective as those described in the present series.

Table 1. Inclusion and exclusion criteria (a)

Inclusion criteria               Exclusion criteria

Normal or near-normal serum      Serum ALT > 1.5 X upper limit
  ALT                              normal
Age over 18 years                Age under 18 years
Hemoglobin
  [greater than or equal to]
  13 g/dL (males)                Lower hemoglobin levels
  12 g/dL (females)
White blood cell count           Lower counts
  [greater than or equal to]
  4,000/[cm.sup.3]
Platelet count                   Lower counts
  [greater than or equal to]
  150,000/[cm.sup.3]
PT and APTT within normal        Abnormal PT or APTT
  limits
Serum bilirubin                  Higher levels
  [less than or equal to]
  1.2 mg/dL
Serum albumin                    Lower levels
  [greater than or equal to]
  3.5 g/dL
Normal TSH levels                Abnormal levels
No coinfection with HIV/HBV      HIV/HBV coinfection
Normal AFP levels                Abnormal levels
HbAlc [less than or equal to]7%  HbA1c > 7%
Acceptable contraception         Pregnancy or unwillingness to practice
  practice                         contraception
Absence of other liver disease   Other liver disease (including
                                   alcoholic liver disease, autoimmune
                                   hepatitis, drug, or obesity-related
                                   liver disease.
                                   Wilson disease, hemochromatosis,
                                   A-1AT deficiency, cirrhosis or
                                   history suggestive of liver failure)
No other preexisting medical     Preexisting illness that could
  illness                          interfere with participation in study

(a) ALT, alanine aminotransferase: PT, prothrombin time; APTT, activated
partial thromboplastin time; TSH, thyroid-stimulating hormone; HIV,
human immunodeficiency virus; HBV, hepatitis B virus; AFP, alfa-feto
protein: HbAlc, glycated hemoglobin; A-1AT, Alfa-1 antitrypsin.

Table 2. Patient characteristics (a)

                        6 MU IFN-[alpha]     3 MU IFN-[alpha]
Characteristics         2a qd                2a qd

Total number            8                    8
Age                     30-54 yr             34-66 yr
Sex (M:F)               3:5                  3:5
Serum ALT               27-69 IU/mL          22-68 IU/mL
Plasma viral loads      33,000 to 5 million  247,324 to 4 million
                          copies/mL            copies/mL
HCV genotype            Genotype 1, 5        Genotypes 1 and 2, 2
                                               each;
                        Not known, 3         Genotype 3, 1
                                             Not known, 3

(a) IFN, interferon: ALT, alanine aminotransferase.

Table 3. Patient-wise details of outcome (a)

                                      ALT-0       HCV-RNA
Patient         Age (yr)     Sex      (IU/L)      (c/mL)

 1              34           M        22          150,000
 2              45           F        57                3.2 mil
 3              42           F        30                1 mil
 4              40           M        65                5 mil
 5              60           F        16                2.1 mil
 6              30           F        56                2.2 mil
 7              39           M        47          731,285
 8              40           F        27                3.8 mil
 9              66           F        57          247,324
10              54           M        54          319,654
11              38           F        64                3.1 mil
12              37           M        37           46,000
13              43           M        68                4 mil
14              40           F        37                1 mil
15              37           F        48          940,000
16              30           F        69           33,000

Patient        Genotype      Rx       Relapse     ETR       SVR

 1             1a            3 MU     NA          N         NA
 2             1a            6 MU     No          Y         Y
 3             3a            3 MU     Y           Y         N
 4                           6 MU     No          Y         Y
 5             2a            3 MU     No          Y         Y
 6             1a            6 MU     NA          N         NA
 7             1a            3 MU     NA          N         NA
 8                           6 MU     Y           Y         N
 9             2             3 MU     No          Y         Y
10             1             6 MU     No          Y         Y
11                           3 MU     No          Y         Y
12                           6 MU     Y           Y         N
13             Fail          3 MU     No          Y         Y
14             lb            6 MU     No          Y         Y
15                           3 MU     ?           Y         LFU
16             1a            6 MU     No          Y         Y

(a) ALT, alanine aminotransferase; ETR, end-of-treatment response; SVR,
sustained virologic response.

3 MU IFN

No response                 25%
ETR & lost to follow-up     12.5%
Relapse                     12.5%
SVR                         50%

6 MU IFN

Relapse                     25%
No response                 12.5%
SVR                         62.5%

Treatment outcomes were better with 6 MU interferon daily, with 87.5%
end-of-treatment responders and 62.5% sustained virological response.

Note: Table made from pie chart.

Accepted August 13, 2004.

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RELATED ARTICLE: Key Points

* Six MU interferon-[alpha]-2a daily is more efficacious than 3 MU daily.

* Genotype 1 infections respond when higher doses of interferon are used.

* No differences in side effects were observed as a function of dose.

Dasarathy Srinivas, MD, Haresh Mani, MD, Charles C. Crumpler, MD, and David H. Van Thiel, MD

From Slidell Memorial Hospital, Slidell, LA.

This study was supported by a grant from Roche Pharmaceuticals Inc, Nutley, NJ.

This study was approved by the local Institutional Review Board, Slidell Memorial Hospital, Slidell, LA.

The authors have no commercial, proprietary, or financial interest in any drug mentioned in the submitted article.

Reprint requests to Dr. D. Srinivas, 1051 Gause Boulevard, Suite 290, Slidell, LA 70458.