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Persistent Hepatitis C Viremia Predicts Late Relapse after Sustained Response to Interferon-α in Chronic Hepatitis C
- Liliana Chemello, MD, PhD;
- Luisa Cavalletto, MD;
- Carla Casarin, MD;
- Paola Bonetti, MD;
- Elisabetta Bernardinello, MD;
- Patrizia Pontisso, MD;
- Carlo Donada, MD;
- Fabio Belussi, MD;
- Silio Martinelli, MD; and
- Alfredo Alberti, MD
- The TriVeneto Viral Hepatitis Group From the University of Padova, Padova, Italy; O.C. Pordenone, Pordenone, Italy; O. Le Grazie, Venezia, Italy; and O.C. Cittadella, Cittadella, Italy. Grant Support: In part by grant 407/01/94 from Ricerca Sanitaria Finalizzata-Regione Veneto. Requests for Reprints: Alfredo Alberti, MD, Clinica Medica 2, via Giustiniani 2, 35100 Padova, Italy. Current Author Addresses: Drs. Chemello, Cavalletto, Casarin, Bonetti, Bernadinello, Pontisso, and Alberti: Clinica Medica 2, University of Padova, via Giustiniani 2, 35100 Padova, Italy. Dr. Donada: III Divisione Medica, O.C. Pordenone, via Monteverde, 33170 Pordenone, Italy.
Abstract
Objective: To define long-term outcome in patients with chronic hepatitis C who remain viremic after sustained biochemical response to interferon-α therapy.
Design: Prospective evaluation of an outpatient cohort.
Setting: University hospital.
Patients: 107 patients with chronic hepatitis C who maintained normal aminotransferase levels as long as 12 months after interferon-α therapy. Patients were followed prospectively for an additional 6 to 36 months.
Measurements: Aminotransferase levels were monitored at 3-month intervals. Serum hepatitis C virus (HCV) RNA was tested by polymerase chain reaction before therapy, at the end of therapy, and 12 months after therapy. The HCV genotype was defined by spot hybridization using serum specimens obtained before treatment.
Results: Hepatitis C virus RNA was detected in 27 (25%) patients with sustained biochemical response; 80 (75%) patients were negative for HCV RNA. Patients positive for HCV RNA were older (P < 0.001), had received a smaller interferon-α dose (P = 0.02), and were more frequently infected with HCV genotype 2 (P < 0.01). Liver histologic findings were active in 57% of patients positive for HCV RNA, despite normal alanine aminotransferase levels, compared with only 12% of patients who were negative for HCV RNA (P = 0.01). The estimated probability of hepatitis relapse by 4 years after therapy was 53% in viremic patients and 0% in patients negative for HCV RNA (P < 0.001).
Conclusion: Patients with chronic hepatitis C should be tested for serum HCV RNA 1 year after a sustained biochemical response to interferon-α therapy to determine whether the response is complete and permanent.
Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. In many countries, interferon-α therapy is the only licensed method for treating this condition. It has been licensed on the basis of randomized, controlled trials that have shown its effectiveness in reducing disease activity and virus replication [1, 2]. However, few treated patients achieve a complete response that is maintained after therapy, and many others have a transient response or no response at all [3, 4]. Serum alanine aminotransferase activity is the conventional marker used to monitor response to therapy, and sustained biochemical response is defined as normalization that lasts for 6 to 12 months after cessation of interferon-α therapy. More recently, serum HCV RNA testing has been recognized as an important component of assessing response to treatment; patients who respond at the biochemical level and maintain normal alanine aminotransferase levels after therapy may remain viremic, indicating that interferon-α has suppressed liver disease activity but has not eradicated the virus [5]. There is increasing agreement that patients with biochemical response should be tested for serum HCV RNA to more accurately define the effect and efficacy of treatment. However, little is known of the clinical significance and long-term outcome of persistent viremia with normal alanine aminotransferase activity after interferon-α therapy. It is still unclear whether this profile reflects delayed virus clearance or persistence of a noncytopathic type or load of HCV or whether it should instead be regarded as a predictor of reactivation of liver damage and progression of disease. To clarify these issues, we investigated the long-term outcome of a large series of consecutive patients with chronic hepatitis C who had persistently maintained normal alanine aminotransferase activity for at least 1 year after cessation of interferon-α therapy.
Methods
Patients
Between January 1990 and November 1993, 440 consecutive patients with chronic hepatitis C were treated with interferon-α therapy in three consecutive randomized trials [6, 7] using different schedules of treatment. Inclusion and exclusion criteria were identical for the three studies, and the clinical characteristics of patient subgroups were similar [8]. Enrolled patients were between 18 and 65 years of age and had a persistent (lasting more than 6 months) elevation of alanine aminotransferase levels of more than twice the upper limit of normal positive result on testing for antibody to HCV, and histologic evidence of chronic hepatitis with or without Child grade A cirrhosis. Patients who were also infected with hepatitis B virus or human immunodeficiency virus who had autoimmunity or comorbid conditions were not included. The total interferon-α dose ranged from 234 MU to 740 MU, administered for 6 or 12 months. Alanine aminotransferase levels were tested monthly during therapy. Complete biochemical response was defined as normalization of liver enzyme levels during therapy, maintained until withdrawal of therapy. After cessation of interferon-α therapy, patients who had responded were monitored for serum alanine aminotransferase at 3-month intervals; sustained biochemical response was defined as enzyme levels that were normal for as long as 12 months after therapy.
Of 440 treated patients, 259 (59%) showed complete biochemical response during treatment, but 141 (54%) of the 259 had relapse within 12 months after therapy was discontinued. Of the 118 patients with alanine aminotransferase levels that were normal for as long as 12 months after therapy, 107 could be tested for serum HCV RNA and followed prospectively for an additional 6 to 36 months (mean follow-up after therapy, 35 ± 18 months). In the remaining 11 patients who had responded to interferon-α, serum samples were not available for HCV RNA testing 1 year after therapy.
Testing
Serum HCV RNA was tested using nested polymerase chain reaction [9]; the sensitivity limit of the assay was between 103 and 104 copies/mL. The virus genotype was identified using spot hybridization with genotype-specific oligonucleotide probes [9] and was classified according to the system of Simmonds and colleagues [10]. Liver biopsies were done during the 6 months before therapy. Sixty-three of the 107 patients with persistently normal alanine aminotransferase levels consented to have liver biopsy, done 8 to 12 months after cessation of interferon therapy. The histologic evaluation was made by a pathologist who was blinded to clinical data and to the sequence in which biopsy specimens had been obtained.
Continuous variables were compared by using the t-test, and proportions were compared by using the chi-square test. The probability of maintaining a sustained response to therapy in different groups was analyzed by using the Kaplan-Meier method and was compared by using the log-rank test.
Results
One year after therapy, serum HCV RNA was detectable in 27 (25%) of the 107 patients with sustained biochemical response; 80 patients were negative for HCV RNA. Retrospective analysis of stored serum samples showed that 13 of 27 (48%) patients positive for HCV RNA were viremic at completion of therapy. In the remaining 14 patients (52%), HCV RNA had reappeared either during the first 6 months (6 patients) or the second 6 months (8 patients) after therapy. Patients who were positive for HCV RNA differed substantially from those who were negative for HCV RNA; the former were older and were treated with a smaller total dose of interferon-α. Furthermore, a statistically significant difference was seen in the distribution of virus genotypes; HCV RNA-positive patients had a higher prevalence of HCV genotype 2 and a lower prevalence of HCV genotype 3 than did HCV RNA-negative patients. After treatment, a liver biopsy could be done while alanine aminotransferase levels were normal in 14 HCV RNA-positive patients and 49 nonviremic patients. Chronic hepatitis with piecemeal necrosis was seen in 8 of 14 (57%) HCV RNA-positive patients; the remaining patients had chronic hepatitis with portal inflammation but no periportal necrosis (4 patients) or minimal changes (2 patients). In contrast, active histologic findings were seen in only 6 of 49 (12%) HCV RNA-negative patients (P = 0.01); the remaining patients had chronic hepatitis with portal inflammation but no piecemeal necrosis (25 patients) or either normal liver histologic findings or minimal changes (18 patients). When the 107 patients were followed prospectively beyond the first year after therapy had been discontinued, the outcomes in viremic and nonviremic patients clearly differed. All HCV RNA-negative patients maintained normal alanine aminotransferase levels and remained negative for HCV RNA, whereas a biochemical relapse was seen in 8 of the 27 (30%) viremic patients. The estimated probability of a return of elevated alanine aminotransferase levels 4 years after cessation of treatment was 53% in viremic patients and 0% in the negative patients (P < 0.001) (Figure 1). No characteristics could be used to distinguish patients with early (within 12 months) or late (beyond 12 months) relapse after therapy. However, when all patients who had relapse were compared with all patients who had sustained biochemical and virologic long-term responses, the former were older (P < 0.01), had a longer duration of disease (P < 0.01), and had a different distribution of HCV genotype (P < 0.05) with increased prevalence of genotype 1 and decreased prevalences of genotypes 2 and 3.
Discussion
Our study shows that serum HCV RNA testing is clinically useful when done 1 year after interferon-α therapy in patients with chronic hepatitis C who have responded to therapy with persistently normal aminotransferase levels. If the test result is negative 1 year after therapy, the response is permanent; in patients who are still viremic 1 year after therapy, liver disease is often still histologically active and the risk for a late reactivation of hepatitis is substantial (53% of patients in our study had probability of reactivation by 4 years after therapy). Our results are consistent with previous reports on the discrepancy between biochemical and virologic responses to interferon-α in chronic hepatitis C and on the possibility of late relapse after a prolonged biochemical response [11, 12]. Only one HCV RNA test was done 1 year after therapy, and we cannot exclude the possibility of some false-negative results caused by intermittent viremia or HCV-RNA levels below the sensitivity of our assay. Furthermore, viremia may not accurately reflect the presence or absence of the virus in the liver. Despite these limitations and the fact that not all of our patients who responded to interferon could have a liver biopsy done after treatment, our results clearly indicate that serum HCV RNA should be tested in all patients who have developed a sustained biochemical response to interferon-α to establish whether the response is complete and permanent. Patients who are negative for HCV RNA may be considered cured. Viremic patients with normal alanine amino-transferase levels should be followed carefully well beyond the first year after cessation of therapy, because many will eventually relapse.
Studies must be done to determine whether treatment with larger interferon-α doses could reduce the prevalence of residual viremia after therapy and whether patients who remain positive for HCV RNA after interferon-α therapy could benefit from early retreatment.
Dr. Belussi: Divisione Malattie Infettive, O. Le Grazie, 5501 San Marco, 30124 Venezia, Italy.
Dr. Martinelli: Divisione Medica, O.C. Cittadella (PD), via Circonvallazione, 35013 Cittadella (PD), Italy.
- Copyright ©2004 by the American College of Physicians
