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The widespread availability of sensitive and specific antibody testing has allowed the identification of chronic hepatitis C virus (HCV) infection in asymptomatic subjects with persistently normal alanine aminotransferase (ALT) levels.1 Currently, it is estimated that 30% of patients with chronic HCV infection have persistently normal ALT levels.1–3 Despite the presence of normal ALT levels, HCV-infected patients can have histological evidence of hepatic fibrosis and cirrhosis.4–7
To date, the management of chronic HCV-infected patients with persistently normal ALT levels remains controversial.1, 8 According to the 1997 guidelines proposed by National Institutes of Health Consensus Development panel, interferon monotherapy is not recommended for this group of patients because of the low sustained virological response (SVR) rates and the risk of treatment-induced hepatic enzyme abnormalities.9 In contrast, the 2002 National Institutes of Health Consensus Development Conference on Management of Hepatitis C and the recent American Association for the Study of Liver Diseases Practice Guidelines recommend that the decision to treat HCV-infected patients with persistently normal ALT levels should be made on an individual basis.1, 8
Recommended factors that should be considered when deciding to proceed with HCV treatment in patients with persistently normal ALT levels include the severity of liver disease, HCV genotype, age, presence of comorbid disease, patient motivation and the presence of symptoms.1 In addition, the severity of impairment in health-related quality of life (HRQOL) should be considered when deciding whether to treat these patients. To date, only a few studies have evaluated the efficacy of interferon and ribavirin combination therapy in HCV-infected patients with persistently normal ALT levels. Furthermore, it is unknown whether HCV treatment improves HRQOL in this population. Therefore, we undertook the present study to determine the efficacy and safety of interferon-α2b and ribavirin combination therapy in patients with chronic HCV infection and persistently normal ALT levels, and to evaluate the effects of treatment on HRQOL.
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In the present prospective controlled study, we demonstrated that the SVR rates in HCV-infected patients with persistently normal ALT levels who were treated with interferon-α2b and ribavirin was not different from the response rates seen in subjects with elevated ALT levels. Furthermore, therapy was well tolerated and was associated with significant improvements in HRQOL. These findings have important implications for the management of the estimated 30% of HCV-infected subjects who have persistently normal ALT levels.
Prior studies that have evaluated interferon-α monotherapy for the treatment of chronic HCV infection in patients with persistently normal ALT levels have enrolled a small number of subjects,15–28 and only two reports included a control group of patients with elevated ALT levels.16, 17 The SVR rates with interferon-α monotherapy in subjects with normal ALT levels are approximately 10–20%,29 which is similar to what has been reported in patients with elevated ALT levels.30, 31 However, some patients with persistently normal ALT levels developed ALT flares either during or shortly after therapy with interferon, and in some subjects these changes were persistent.16, 17, 22, 25–27 Based on the relatively low rates of SVR and the risk of ALT flare-ups, interferon-α monotherapy was not recommended in this population.9
The addition of ribavirin to interferon-α has resulted in SVR rates of approximately 40% in HCV-infected patients with elevated ALT levels.32 Despite the large amount of data available on interferon-α and ribavirin combination therapy for the treatment of chronic HCV infection in patients with elevated ALT levels, only a limited number of trials have been conducted in previously untreated subjects with persistently normal ALT levels.33–38 Although three of these six studies included a control group of patients with elevated ALT levels,34, 36, 37 only two enrolled more than 40 subjects with persistently normal ALT levels.36, 38 Overall, the SVR rates in patients with normal ALT levels were similar to the response seen in subjects with elevated ALT levels.
In contrast to the outcomes reported in the interferon-α2b and ribavirin registration trial conducted in the US,39 our SVR rates in genotype 1 as well as in those infected with genotype 2/3 were substantially lower. This discrepancy is likely due to differences in the patient populations studied. Nearly one-third of our patients were black, and it is well known that these individuals have lower sustained response rates to therapy than non-blacks.40, 41 In addition, our subjects were older, more likely to be male, had a higher mean body weight, and had a higher proportion of subjects with cirrhosis compared with the study by McHutchison et al.39
Nonetheless, our study confirms previous findings that the SVR rates in HCV-infected patients with normal ALT levels was not different from the response rates seen in those with elevated ALT levels. Furthermore, we found that ALT flares were uncommon, mild and transient. A recent study using pegylated interferon in combination with ribavirin also confirmed the safety and efficacy of treatment in patients with persistently normal ALT levels, with 52% of subjects having a SVR after 48 weeks of therapy.42 Therefore, interferon in combination with ribavirin appears to be a safe and effective treatment option for this population of HCV-infected subjects.
The decision to treat HCV-infected patients with persistently normal ALT levels should be based on a global evaluation of the patient. As part of the treatment evaluation process, it is important to consider patient HRQOL. It is well established that HRQOL is impaired in patients with chronic HCV infection and elevated ALT levels relative to healthy controls.43 Furthermore, treatment improves HRQOL in HCV-infected patients with elevated ALT levels, especially in those who achieve a SVR.43 However, the effect of treatment on HRQOL in HCV-infected patients with normal ALT levels is unknown. In the present study, we found that treatment was associated with significant and clinically meaningful improvements in HRQOL in subjects with persistently normal ALT levels. This important finding should be considered when deciding to treat these individuals.
The strengths of the present study include the prospective study design, inclusion of a control group of patients with elevated ALT levels, and measurement of HRQOL before and after therapy using a validated instrument. However, there are some limitations of this study that should be considered when interpreting our findings.
First, the study was conducted at a single VA medical centre and the majority of our patients were men. Secondly, we did not perform follow-up biopsies to determine whether treatment improves liver histology. Thirdly, we treated patients with standard interferon-α2b plus ribavirin instead of pegylated interferon and ribavirin because pegylated interferon was not available at the time the study was designed. However, given the higher SVR rates with pegylated interferon and ribavirin when compared with standard combination therapy, it is possible that the magnitude of improvement in HRQOL with pegylated interferon and ribavirin treatment would be even greater. Finally, patients were not blinded to their viral response and this could have influenced the HRQOL outcome data.
In conclusion, our study demonstrates that treatment of HCV infection with interferon-α2b and ribavirin combination therapy is efficacious, safe, and results in significant improvements in HRQOL in patients with persistently normal ALT levels. The present study adds to the growing body of evidence that suggests that patients with chronic HCV infection should not be excluded from treatment on the basis of normal ALT levels alone. In addition to the presence of fibrosis and other clinical criteria, reduced HRQOL should be considered as an indication for treatment in this population.