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Superinfection with HCV in HBV+ Patients Worsens Hepatitis
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"Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection"
Gastroenterology
April 2004, Volume 126, Number 4
Yun-fan Liaw*, Yi-Cheng Chen, I-shyan Sheen*, Rong-nan Chien*, Chau-ting Yeh*, Chia-ming Chu*
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan. Supported in part by grants from National Health Research Institute, Department of Health (DOH87-HR-522), Chang Gung Research Fund (CMRP800), and the Prosperous Foundation, Taipei, Taiwan.
Authors said: "...The results of the present study showed that acute HCV superinfection typically occurred as acute icteric hepatitis in male HBeAg negative patients with chronic HBV infection, of whom 34% succumbed to hepatic decompensation, 11% to hepatic failure, and 10% to death during acute phase of superinfection. The clinical presentations of the patients with acute HCV and HDV superinfection are very similar, including the rate of HBeAg seropositivity, which represents the HBV replication status. However, HDV superinfection involved younger male patients, possibly because the main route of HDV transmission in Taiwan was through heterosexual exposure in young adults. These results suggested that the severity of acute HCV superinfection is equivalent to that of acute HDV superinfection in patients with chronic HBV infection..."
"...acute HCV superinfection in patients with chronic HBV infection is a severe clinical situation during its acute phase, which is very similar to acute HDV superinfection. However, the long-term prognosis of acute HCV superinfection in patients with chronic HBV infection is much worse than that of acute HDV superinfection or active chronic hepatitis B in terms of the continuing hepatitis activity after HBsAg loss and the development of cirrhosis or HCC..."
ABSTRACT
Superinfection in patients with chronic hepatitis B virus (HBV) infection is not uncommon. Acute hepatitis delta virus (HDV) superinfection is associated with severe and/or progressive liver disease. The natural course following acute hepatitis C virus (HCV) superinfection has not been well studied. The aim of this study was to investigate the impact of acute HCV superinfection.
The clinical features during acute phase and long-term outcomes of acute HCV superinfection were studied and compared with a cohort of acute HDV superinfection and a matched control group of active chronic hepatitis B.
Acute HCV superinfection typically occurs as acute icteric hepatitis. The severity is similar to acute HDV superinfection in that hepatic decompensation developed in 34% of patients, hepatitis failure occurred in 11%, and 10% died. During a follow-up period of 1--21 years, patients with acute HCV superinfection had a significantly higher cumulated incidence of cirrhosis (48% at 10 years) and hepatocellular carcinoma (14% at 10 years, 21% at 15 years, and 32% at 20 years) than acute HDV superinfection or active chronic hepatitis B. Hepatitis B surface antigen (HBsAg) seroclearance occurred earlier in HCV superinfected patients. Continuing hepatitis after HBsAg seroclearance was observed only in HCV superinfected patients.
Acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase. The long-term prognosis following acute HCV superinfection is much worse than that following HDV superinfection or active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or hepatocellular carcinoma.
"...The HCV group had higher incidence of both cirrhosis and HCC development when compared with the HBV and HDV groups. By the end of the 10th year following the onset of acute superinfection, the cumulative probability of cirrhosis development was 48% in the HCV group as compared with 21% in the HDV group (P = 0.041) and 9% in the HBV group (P = 0.0001). At the same time point, the cumulative probability of HCC development was 14% in HCV group as compared with 3% in HDV group (P = 0.075) and 2% in the HBV group (P = 0.039). The significant differences maintained for 20 years. Except for the patients who died during the acute phase, none of the patients in the HDV group died during the follow-up period, in contrast to an annual mortality incidence of 0.64% in the HCV group (P = 0.009)..."
INTRODUCTION
Chronic hepatitis B virus (HBV) infection is a global problem in that there are more than 350 million chronically infected people worldwide. Concurrent hepatitis C virus (HCV) infection in this large pool of patients with chronic HBV infection is not uncommon. Studies have shown that concurrent HCV and HBV infections may be associated with a fulminant course of acute hepatitis, with more severe forms of chronic liver disease or with more rapid progression, and that HCV may exert an inhibitory effect on HBV. However, most of these earlier studies involved patients with unknown onset and/or sequence of the respective viral infections. Only a few studies have examined the natural history following the onset of acute HCV superinfection in a small number of patients and on a short-term basis. Therefore, little is known about the impact and the long-term consequences after the onset of acute HCV superinfection. In contrast, many studies have shown that acute hepatitis delta virus (HDV) superinfection in patients with chronic HBV infection is frequently associated with severe and/or progressive liver diseases. Our earlier study, however, evidently showed that acute HDV superinfection was more severe in acute phase, but its 3-year prognosis was not particularly different from that of active chronic hepatitis B unrelated to HDV. The purpose of this study is to compare the impact of acute HCV superinfection with that of acute HDV superinfection. The long-term outcomes were also compared with a well-matched control group of active chronic hepatitis B patients.
Patients
Chang Gung Memorial Hospital is a major teaching hospital providing primary to tertiary medical care to the residents of northern Taiwan, an area of 10 million inhabitants. About 90% of our patients are from this area, and 10% of our patients are from the remaining parts of the island of Taiwan. The majority of patients, who voluntarily visited our outpatient clinic, visited because of HBsAg seropositivity/abnormal alanine aminotransferase (ALT) detected on checkup or persistent ALT abnormality documented at local clinics. Patients with hepatitis flare or icteric hepatitis, however, visited our clinic usually because of referrals from the local clinic or hospital.
Because assays for HDV and HCV have been available as routine laboratory tests at our hospital in 1986 and 1991, respectively, all patients with HBV infection were assayed for serum antibodies against HDV (anti-HDV) or HCV (anti-HCV) as soon as the diagnosis of HBV infection had been confirmed. These included patients who were seropositive for hepatitis B surface antigen (HBsAg) for a minimum of 6 months, patients with acute hepatitis who were seropositive for HBsAg but negative for IgM class antibody to hepatitis B core antigen (IgM anti-HBc), or previously unrecognized chronic HBsAg carrier with acute hepatitis. Serum samples of the latter were also tested for serum HCV-RNA. Retrospective HDV and HCV assays were performed on patients who were lost to follow-up before the assays became available, if stored serum specimens were available. If a patient was found to be seropositive for anti-HDV, anti-HCV, or both, stored serum specimens of that particular patient were traced in an attempt to determine the earliest date of seropositivity, which is the onset of acute superinfection.
Patients who had evidence of other liver diseases, such as hepatitis A or E virus infection, alcoholic disease, or those who had both HCV and HDV infections were excluded from this study. For patients who received antiviral therapy during chronic phase, the follow-up period was considered up to the date of starting therapy. Patients with other significant systemic disease(s), such as uremia, cancer, or hematologic disorders were also excluded. Sixty-seven patients with acute HCV superinfection were followed for a period of over 1 year. Excluding 3 patients with underlying cirrhosis, a control group (HBV group; 1:1 matched according to age (±2 years), sex, and HBeAg status) of 64 patients with histologic proof of active chronic hepatitis B (chronic active hepatitis, chronic lobular hepatitis, or bridging hepatic necrosis) were identified from our computer file for comparison. This study was approved by Chang Gung Memorial Hospital and the National Health Research Institute and conducted according to general ethical guidelines.
Serologic and virologic tests
HBsAg, HBs antibody (anti-HBs), IgM anti-HBc, hepatitis B e antigen (HBeAg) HBe antibody (anti-HBe), and anti-HDV were assayed using commercially available radioimmunoassay kits (Ausria II, Ausab, Corab M, HBeAg-RIA and anti-delta; Abbott Laboratories, Chicago, IL). Serum anti-HCV was assayed using a third-generation enzyme immunoassay (Ax SYM HCV III; Abbott Laboratories). Serum IgM anti-HDV was assayed using an enzyme immunoassay (Deltassay IgM; Cambridge Biotech Ltd., Dublin, Ireland). Serum HBV DNA was assayed using hybrid-capture amplification assay (Digene HBV test, Hybrid Capture II; Digene Corp.). The detection sensitivity of this assay is 0.5 pg/mL. Serum HCV RNA was assayed by a combined RT-PCR assay (Amplicor HCV test; Roche Diagnostic System Inc., Branchburg, NJ). The detection sensitivity of this assay is 10--100 copies/mL. HCV genotypes were analyzed using a genotype-specific probe-based assay in the 5´ untranslated region (LiPA; Innogenetics, Ghent, Belgium), which is able to identify the 5 major genotypes and other subtypes (1a, 1b, 2a/2c, 2b, 3a, 3b, 4, and 5a). Serum HDV RNA was assayed by slot-blot hybridization as described elsewhere.
Definitions of clinical events
The diagnosis of acute HCV infection was based on de novo seroconversion of anti-HCV and on the presence of serum HCV-RNA in the first serum sample. Therefore, with clinical acute hepatitis, de novo seroconversion of anti-HCV indicates an acute HCV superinfection in HBsAg-positive but IgM anti-HBc negative patients or in patients with well-documented chronic HBV infection. Patients seropositive for HCV-RNA but negative for anti-HCV or seropositive for anti-HCV with low optical density (OD) ratio and increasing OD ratio in the follow-up assays also indicate acute HCV superinfection. Similarly, de novo seroconversion of anti-HDV or increasing titer of anti-HDV in serial serum samples or serum IgM anti-HDV or HDV-RNA positive but anti- HDV negative in acute phase indicates acute HDV superinfection.
Severe hepatitis with "hepatic decompensation" was defined as a clinical syndrome comprising both of the following features: (1) obvious constitutional symptoms with jaundice and (2) blood coagulation disorders, such as prolonged prothrombin time (>3 seconds) with or without ascites. Severe hepatitis associated with hepatic encephalopathy was defined as "hepatic failure." "HBsAg seroclearance" was defined as loss of serum HBsAg documented in 2 consecutive occasions at least 6 months apart and up to the last visit. HBsAg seroclearance associated with persistent hepatitis activity because of other virus was defined as "HBV displacement." The diagnosis of cirrhosis was made histologically or clinically, based on repeated ultrasonographic findings suggestive of cirrhosis, at least twice 6 months apart, supplemented with signs suggestive of cirrhosis, such as the presence of esophageal varices or ascites. Diagnosis of hepatocellular carcinoma (HCC) was made histologically or clinically, based on imaging findings plus an -fetoprotein level over 400 ng/mL.
RESULTS
Acute phase
A total of 93 patients with acute HCV superinfection (HCV group) was identified (71 patients showed de novo anti-HCV seroconversion; 22 patients were HCV-RNA positive but anti-HCV negative in acute phase). Twenty-six (28%) of them were seropositive for HBeAg and 43 (46%) were seropositive for HBV DNA in the early acute phase. Risk factors for HCV infection could be identified in 23 patients, including blood transfusion in 9 patients, IV drug abuse in 4 patients, instrumentation (operation, tattoo, acupuncture and dental procedures, and others) in 5 patients, and household or community contact in 5 patients. The clinical features of acute HCV superinfection are compared with that of acute HDV superinfection (HDV group). Patients with acute HDV superinfection were younger in age and more male dominant than patients with acute HCV superinfection.
Chronic phase
Excluding the patients who died, 76 patients of the HCV group were followed-up for longer than 6 months, and 51 (67%) of them remained HCV RNA positive or eventually have chronic HCV infection. In addition, 67 patients of the HCV group were followed-up for a duration greater than 1 year (1--21 years). Sixty of these patients had serum samples available for genotyping, and 45 (75%) showed genotype 1b HCV superinfection. The prognosis was not significantly different among patients superinfected with different HCV genotypes, although the number of patients with other non-1b genotypes was small. Because chronic HBV infection in Taiwan is usually acquired perinatally or by the age of 2 years, the age of our patients is almost equivalent to the duration of HBV infection. Considering that patients in the HDV group were significantly younger and more male dominant (Table 1), an age (±2 years), sex, and HBeAg status-matched (1:1) control group of acute HDV superinfection were selected and compared with the HCV group and the matched HBV control group. The cumulative probability of HBsAg seroclearance, cirrhosis, and HCC development of the HCV group, matched HDV, and HBV groups are compared. HBsAg seroclearance occurred earliest in the HCV group, but the difference was significant only when compared with the HBV group within 10 years.
In addition, the cumulative incidence of HBsAg clearance in the HCV group was exceeded by other groups after 16-year follow-up. HBV displacement only occurred in the HCV group (7%). The HCV group had higher incidence of both cirrhosis and HCC development when compared with the HBV and HDV groups. By the end of the 10th year following the onset of acute superinfection, the cumulative probability of cirrhosis development was 48% in the HCV group as compared with 21% in the HDV group (P = 0.041) and 9% in the HBV group (P = 0.0001). At the same time point, the cumulative probability of HCC development was 14% in HCV group as compared with 3% in HDV group (P = 0.075) and 2% in the HBV group (P = 0.039). The significant differences maintained for 20 years. Except for the patients who died during the acute phase, none of the patients in the HDV group died during the follow-up period, in contrast to an annual mortality incidence of 0.64% in the HCV group (P = 0.009).
AUTHOR'S DISCUSSION
In our earlier study of nearly 1500 patients with chronic hepatitis B, 12% were seropositive for anti-HCV. We now have demonstrated that, for many of them, the onset of HCV superinfection could be identified by de novo seroconversion of anti-HCV (71 of the 93 patients), by sensitive assay for HCV RNA in the absence of anti-HCV or HCV RNA positive and anti-HCV positive with low OD ratio. Also, we have recently demonstrated that the presence of active HBV replication can inhibit the antibody response to HCV.
The results of the present study showed that acute HCV superinfection typically occurred as acute icteric hepatitis in male HBeAg negative patients with chronic HBV infection, of whom 34% succumbed to hepatic decompensation, 11% to hepatic failure, and 10% to death during acute phase of superinfection. The clinical presentations of the patients with acute HCV and HDV superinfection are very similar, including the rate of HBeAg seropositivity, which represents the HBV replication status. However, HDV superinfection involved younger male patients (Table 1), possibly because the main route of HDV transmission in Taiwan was through heterosexual exposure in young adults. These results suggested that the severity of acute HCV superinfection is equivalent to that of acute HDV superinfection in patients with chronic HBV infection. Earlier studies, which were done mostly on white patients, showed that HDV infection was frequently associated with progressive liver diseases. Our earlier study involving 26 patients also showed that the annual incidence of cirrhosis within 3 years following acute HDV superinfection was 9.4%, which was not significantly different from a rate of 5.4%/yr in a matched control group with non-HDV acute exacerbation in patients with chronic hepatitis B. The results of this study involving 64 patients followed-up for 8 years showed an even lower incidence of cirrhosis development following acute HDV superinfection. The incidence cumulated to 21% in 5 years, and no more increase thereafter. Although cirrhosis developed earlier in the HDV group than in the matched HBV group, the difference in cumulative incidence became nonsignificant after the 10-year follow-up period. These relatively low incidences of cirrhosis development are consistent with our earlier observation that HDV infection was not a factor for cirrhosis development in patients with chronic hepatitis B. In contrast, the long-term prognosis following acute HCV superinfection is much worse in terms of cirrhosis or HCC development and associated mortality than that following acute HDV superinfection or active hepatitis B in age/sex/HBeAg status-matched patients. These parallel comparisons suggest that the long-term outcomes after the onset of acute HCV superinfection was more progressive than those of acute HDV superinfection or active hepatitis B alone.
Most of the previous studies, in which the onset of HCV or HDV superinfection was unclear, suggested that HCV was stronger than HDV in terms of HBV suppression leading to HBsAg loss. The results of this study, however, indicate that HBsAg seroclearance occurred earlier and more frequently in HCV superinfected patients than in matched HDV superinfected or HBV infected patients, but the difference was significant only when compared with the HBV group within 10 years. In addition, the cumulative probability of HBsAg clearance in the HDV group and the HBV group even exceeded that of the HCV group after 16-year follow-up (Figure 1). One aspect of note is that the present study compared the influence of HCV and HDV from the same starting point and for the same time span following the onset of acute superinfection. One possible explanation for the higher HBsAg seroclearance rate in HCV superinfected patients documented in earlier studies may be that the follow-up duration in HDV superinfected patients was insufficient. Another probable reason may be that HCV superinfected patients were older or had acquired HBV infection for longer periods of time, which were factors for HBsAg seroclearance. Because HDV is a defective viridae requiring the help of HBsAg, it is therefore conceivable that HBV displacement occurs only in patients with HCV superinfection, whereas hepatitis activity ceases after the loss of HBsAg in patients with HDV superinfection or HBV alone.
In conclusion, acute HCV superinfection in patients with chronic HBV infection is a severe clinical situation during its acute phase, which is very similar to acute HDV superinfection. However, the long-term prognosis of acute HCV superinfection in patients with chronic HBV infection is much worse than that of acute HDV superinfection or active chronic hepatitis B in terms of the continuing hepatitis activity after HBsAg loss and the development of cirrhosis or HCC.
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