Hepatitis D virus RNA in serum from patients with hepatitis B

To clarify the correlation of hepatitis D virus (HDV) infection and viral replication in liver diseases, the authors detected HDV RNA and serological HDV markers in serum from 285 patients with hepatitis B and 45 asymptomatic carriers of HBsAg. With dot blot hybridization, serum HDV RNA was detected in 8.8% (29/330) of the patients with HBV infection. The positive rate of HDV RNA in fulminant hepatitis was higher than that in benign hepatitis (15/74 vs 3/47, P less than 0.05). 10 of the 139 patients with chronic active hepatitis and 1 of the 6 cases with cirrhosis were positive for HDV RNA. However, all of the 19 cases with chronic persistent hepatitis and 45 asymptomatic carriers of HBsAg were negative fo, HDV RNA. Serological HDV markers, HDAgr anti-HD and IgM-anti-HD, were determined with ELISA. HDV RNA was detected in all of the serum samples with positive HDAg and/or IgM-anti-HD, in 15 of the 26 cases with positive-anti-HD and in 8 cases without HDV markers. Our results showed that 40 of the 330 patients with HBsAg were infected by HDV. This investigation suggests that HDV is one of the etiological factors for fulminant hepatitis and chronic active hepatitis.     

Determination of Hepatitis Delta Virus (HDV)-RNA in Asymptomatic Cases of HDV Infection

Objectives: To assess the frequency of hepatitis delta virus (HDV) viremia in asymptomatic cases of HDV infection and the clinical significance of the HDV viremia, we conducted a cross-sectional community-based study. Methods : Of 2207 examinees, 210 (9.5%) were found to be positive for hepatitis B surface antigen (HBsAg). Antibody to HDV was detected in 47 (22.4%) of the 210 examinees, and 43 of the 47 were further evaluated for serum HDV-RNA by polymerase chain reaction. Results : Twenty-one (48.8%) of the 43 had detectable levels of HDV-RNA in serum, and 22 (51.2%) were negative for serum HDV-RNA. The majority (61.9%) of the HDV-RNA-positive HBsAg carriers had high levels of serum ALT. In contrast, the frequency of an abnormally high level of serum ALT was only 9.1% in the HBsAg carriers positive for HDV antibody but negative for HDV-RNA and the frequency did not differ from that seen in the HBsAg-negative individuals. The semi-quantified HDV-RNA levels did not correlate with the serum ALT levels. Conclusion : Seropositivity of HDV-RNA was strongly associated with liver cell damage, even in asymptomatic cases. The absence of a detectable level of serum HDV-RNA might be related to previous HDV infection.     

Intrahepatic expression of hepatitis B core and surface antigens in chronic hepatitis delta-virus infection.

To evaluate the interference of hepatitis B virus (HBV) protein expression in the liver in chronic hepatitis delta-virus (HDV) infection, the intrahepatic expression of hepatitis B core and surface antigens (HBcAg and HBsAg) was studied in 36 HBsAg carriers who were seropositive for anti-HDV and in 36 anti-HDV negative controls [18 with serum hepatitis B e-antigen (HBeAg) and 18 with anti-HBe]. Of 18 HBeAg-positive patients with anti-HDV, 12 had HDV antigen (HDAg) in the liver. HBcAg was positive in 66.7% (8/12) of the HbeAg-positive patients with HDAg in the liver, and in 94.4% (17/18) of controls (p = 0.14). The distribution of HBcAg was exclusively cytoplasmic in 75% (6/8) of HDV-infected patients, but was mixed nuclear and cytoplasmic in 70.6% (12/17) of the controls. The prevalence and quantitative expression of HBcAg in the nucleus, but not in the cytoplasm, were significantly decreased in chronic HDV infection. HBsAg was positive in 91.6% (11/12) of HBeAg-positive patients with HDV infection and in all controls. Membranous expression of HBsAg was detected less frequently in HDV-infected patients than in controls (7/12 vs. 17/18, p = 0.05), while the prevalence and quantitative expression of HBsAg in the cytoplasm showed little or no difference. HDAg was detected in all of the anti-HBe-positive patients with anti-HDV. Of these, none had HBcAg detectable in the liver, nor did controls, while HBsAg was detected exclusively in the cytoplasm in 94.4% (17/18). The prevalence and quantitative expression of HBsAg in the cytoplasm was not different for HDV-infected patients or controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection of hepatitis delta virus (HDV) markers in HBV carriers]

To investigate the prevalence and clinical features of hepatitis delta virus (HDV) superinfection in hepatitis B virus (HBV) carriers, antibody to hepatitis delta antigen (anti-HD) was determined in the sera of 328 HBV carriers in Japan. 1) Of the 328 HBV carriers, six (1.8%) were seropositive for anti-HD by enzyme linked immunosorbent assay. IgM-antibody to hepatitis delta antigen was detected in 2/6 patients with a high anti-HDV titer. None of the patients was positive for hepatitis dealt antigen. 2) HBV carriers with chronic liver disease had a greater frequency of seropositivity of anti-HD than asymptomatic HBV carriers. These data indicate that HDV superinfection may be an etiologic agent of chronic liver disease in HBV carriers.     

Prevalence and clinical features of hepatitis delta virus infection in the Miyako Islands, Okinawa, Japan

The aims of this study were twofold: (1) to determine the prevalence and clinical features of hepatitis delta virus (HDV) infection among subjects positive for hepatitis B surface antigen (HBsAg) living in the Miyako Islands, Okinawa Prefecture, Japan, and (2) to clarify the relationship between HDV-RNA level and severity of HDV-related liver disease. One hundred and ninety-nine HBsAg-positive subjects (123 asymptomatic carriers [ASCs], 3 patients with acute hepatitis [AH], 50 patients with chronic hepatitis [CH], 15 patients with liver cirrhosis [LC], and 8 patients with hepatocellular carcinoma [HCC], were tested for antrbody to HDV (anti-HDV) by radioimmunoassay. Anti-HDV-positive individuals were examined to determine semi-quantified HDV-RNA level by polymerase chain reaction (PCR). The overall prevalence of anti-HDV among the 199 subjects was 21.1%. The positivity rate tended to increase with age or the severity of the underlying liver disease: anti-HDV-positive rates were 10.6% (13/123) in ASCs, 32.0% (16/50) in patients with CH, 40.0% (6/15) in patients with LC, and 87.5% (7/8) in patients with HCC. None of the patients with AH were positive for anti-HDV. There was no correlation between semi-quantified serum HDV-RNA levels and the severity of chronic liver disease in patients positive for anti-HDV. The present study showed the local spread of HDV infection in the Miyako Islands, Okinawa, Japan. Although the anti-HDV positivity rate tended to increase with the severity of the underlying liver disease, the severity of HDV-related liver disease did not correlate with the semi-quantified serum HDV-RNA level. (Received Oct. 13, 1997; accepted June 26, 1998)     

Why most patients with hepatitis delta virus infection are seronegative for hepatitis B e antigen. A prospective controlled study

A prospective age/sex matched control and follow-up study was conducted to explore the reason(s) for the association of hepatitis delta virus (HDV) infection with hepatitis B e antigen (HBeAg) negative hepatitis B surface antigen (HBsAg) carrier state. Over a 3-year period, a total of 110 patients (104 males and six females) with acute HDV superinfection were documented in our unit. Twenty-four (21.8%) of them were HBeAg positive at the onset of acute HDV infection. In the control study, 110 age- and sex-matched asymptomatic HBsAg carriers with normal serum transaminase, as well as 110 age- and sex-matched patients with chronic type B hepatitis were randomly selected from the computer files of the same 3-year period of entry. The prevalence of serum HBeAg in patients with HDV infection was similar to that of asymptomatic HBsAg carriers (20.9%), but significantly lower than that of the patients with chronic type B hepatitis (72.7%). In a follow-up study of 16 HBeAg-positive patients with HDV infection, eight (50%) cleared HBeAg and three (18.8%) seroconverted to anti-HBe within 3 months. The HBeAg clearance rate was significantly higher than for chronic type B hepatitis and asymptomatic carriers (p less than 0.01). The results suggest that the low prevalence of serum HBeAg in HDV infection simply reflects the HBeAg/anti-HBe status of the asymptomatic HBsAg carriers in the population under study. Also in some patients HDV superinfection may itself suppress HBV and thus clear HBeAg.     

Epidemiology of hepatitis δ virus infection in China

The prevalence of hepatitis δ virus (HDV) was evaluated in 1027 HBsAg positive people living in five provinces, two municipalities and four autonomous regions of China. Seventeen people had antibodies to HDV (anti-HD — 13 of 454 asymptomatic carriers of HBsAg, two of 151 patients with chronic persistent hepatitis and two of 59 patients with chronic active hepatitis). All of those who were anti-HD lived in the autonomous regions of Inner Mongolia, Tibet, and Xinjiang.     

Seroprevalence and epidemiological characteristics of HDV infection among HBV patients in the Nile Delta,Egypt

The epidemiology of HDV infection worldwide is obscure. Mapping the epidemiology of the infection is highly required, so, we aimed to estimate the prevalence of hepatitis D virus infection among chronic hepatitis B patients and the epidemiological characteristics in the Nile delta in Egypt. This was a prospective observational cross-sectional study including consecutive chronic hepatitis B patients in the out-patient clinics at the Egyptian Liver Research Institute and Hospital (ELRIAH) and its satellites in the Nile Delta from January 2016 until August 2018. They were recruited from patients enrolled in Educate, Test and Treat program, which was implemented in 73 Egyptian Villages. Subjects were tested by using HBsAg serological rapid diagnostic tests (RDTs), and then HBV DNA by PCR was done in HBsAg-positive cases. HDV IgG antibody testing and confirmatory HDV RNA PCR were done. Complete liver functions, abdominal ultrasonography and FibroScan were also performed. The prevalence of HDV was 3.4% using anti-delta antibody (22/631), and only 8 were positive for HDV RNA (8/22, 36.4%). Overall HDV prevalence using PCR was 8/631(1.27%). HDV-positive cases were mainly males (68.2%). Eight cases were cirrhotic (36.4%), 3 (13.6%) had HCC and 7 (31.8%) were HBeAg positive. HDV prevalence is low among chronic hepatitis B patients in the Nile delta, Egypt. Screening for HDV IgG is recommended in CHB patients who had cirrhosis, HCC or HBeAg positive.     

Rapidly progressive HBsAg-positive hepatitis in Italy: The role of hepatitis delta virus infection

Serum or liver markers of hepatitis delta virus (HDV) infection were found in 20 of 22 (90%) Italian patients presenting with an ostensible type B hepatitis that ran an accelerated course to cirrhosis. The features of the illness conformed to a syndrome of HDV infection in young males carrying the hepatitis B surface antigen (HBsAg); a latent HBsAg state was documented in many patients by a history of prior exposure to the hepatitis B virus (HBV) or by the absence of IgM antibodies to the HB core antigen. Characteristic of the disease were the clinical overture as a severe hepatitis, the lobular involvement by an extensive necroinflammatory reaction, the exuberant expression of intrahepatic hepatitis delta antigen and an atypical HBV profile of inactive infection or accelerated seroconversion from HBeAg to anti-HBe. Superimposed upon HBV infection, HDV may create a rapidly progressive course which resembles very aggressive hepatitis B but is infrequently observed in hepatitis B alone.     

Hepatitis delta virus infection in southern Taiwan

To determine the prevalence of hepatitis delta virus (HDV) infection in Southern Taiwan in comparison to that of Northern Taiwan, a consecutive series of 389 HBsAg-positive patients were tested for serum antibody to HDV (anti-HD) by radioimmunoassay. The anti-HD was positive in 2/122 (1.6%) asymptomatic "healthy" carriers, 1/61 (1.6%) blood donors, 1/24 (4.2%) patients with acute type B hepatitis, 4/25 (16%) carriers with superimposed acute hepatitis, 5/53 (9.4%) patients with chronic hepatitis, 3/42 (7.1%) patients with liver cirrhosis and 1/62 (1.6%) patients with hepatocellular carcinoma. Our findings confirm that the prevalence of HDV infection is low in asymptomatic carriers, acute type B hepatitis and hepatocellular carcinoma, but significantly higher in patients with chronic active liver disease. No significant difference in the prevalence of HDV infection between Southern and Northern Taiwan was observed.     

Prevalence of delta antibodies among urban HBsAg-positive chronic liver disease patients in Egypt

The prevalence of delta infection among urban Egyptians is reported for the first time. Sera of 44 HBsAg-positive chronic liver disease (CLD) patients and 48 asymptomatic HBsAg carriers were screened for antibodies to hepatitis delta antigen (anti-HD). Anti-HD was found in 21 (47.7%) of the patients compared with 4 (8.3%) of the asymptomatic carriers. The difference was statistically significant at the 0.001 level. Anti-HD was present in 14 out of 24 (58.3%) subjects with histological diagnosis of chronic active hepatitis, 4 of 9 (44.9%) with cirrhosis, and 3 out of 11 (27.2%) with chronic persistent hepatitis. This study points to a high prevalence of hepatitis delta virus in Egypt.     

Epidemiological studies on the prevalence of hepatitis Delta virus infections in the Federal Republic of Germany

This study evaluated the prevalence of hepatitis Delta virus (HDV) infections in various groups of HBsAg carriers including drug addicts and patients with hemophilia in the Federal Republic of Germany. HDV was found only occasionally (less than 1%) in individuals found HBsAg positive during an examination as potential blood donors or in hemodialysis patients, but in 3% in patients with chronic hepatitis and up to 50% in drug addicts and hemophilia patients. These findings are in agreement with data reported from other European countries. Presence of antibodies to HDV in two hemodialysis patients indicates the presence of HDV in this group and screening for HDV infections in hemodialysis units is indicated to prevent outbreaks of this disease in HBsAg-positive patients with possibly serious consequences.     

Contrasting prevalence of delta hepatitis markers in parenteral drug abusers with and without AIDS

Parenteral drug abusers are the second largest group at risk for developing AIDS (25% of US cases) and a major risk group for infection with both hepatitis B virus (HBV) and the HBV-dependent RNA hepatitis delta virus (HDV). This study was conducted to determine the prevalence in 1984-1985 and relationships of HDV and HBV infections in 372 unselected parenteral drug abusers without AIDS or symptoms related to human immunodeficiency virus type 1 (HIV-1) infection (but 49% of whom were positive for HIV-1 antibodies) and in 53 drug abusers hospitalized with AIDS. The prevalence of HDV markers in the combined study groups was 20%; 81% of study subjects with hepatitis B surface antigenemia (HBsAg) had one marker for HDV infection. Significant differences were found between patients with and without AIDS with respect to the prevalence of hepatitis delta antigen (5.7% vs. 0.8%, P less than .05) and antibody (0 vs. 21.4%, P less than .01) and HBsAg (15.1% vs. 5.1%, P less than .05). The significantly higher prevalence of hepatitis delta antigen and HBsAg in subjects with AIDS suggests that persistence or reactivation of these viruses is significantly greater among parenteral drug abusers with AIDS than among those without AIDS. These findings, along with the absence of hepatitis delta antibodies in the drug abusers with AIDS, are probably related to the profound general immunosuppression that occurs in AIDS.     

Magnitude and genotype of hepatitis delta virus among chronic hepatitis B carriers with a spectrum of liver diseases in Ethiopia

Introduction and ObjectivesChronic hepatitis D infection contributes substantially to the progression of chronic liver disease, especially in most low and middle-income countries, where hepatitis B virus-related chronic liver disease is endemic. Therefore, this study aimed to determine the magnitude and genotype of hepatitis delta virus (HDV) among patients with chronic hepatitis B (CHB)-related liver diseases in Ethiopia.Patients and MethodsIn this cross-sectional study, 323 known HBsAg positive individuals comprising 220 patients with CHB-related liver diseases [121 advanced liver diseases (hepatocellular carcinoma /HCC/ and non-HCC) and 99 chronic hepatitis (CH)], and 103 symptomless blood donors (BD) were enrolled. An ELISA kit was employed to determine HDV infection, and quantitative real-time PCR was used to detect HDV RNA. In addition, a non-coding genomic RNA region was sequenced for genotyping and phylogenetic analysis.ResultsIrrespective of the stage of liver disease, the overall magnitude of HDV was 7.7% (25/323). The frequency of anti-HDV increases with the severity of liver disease, 1.9%, 4%, 10%, and 21.3% among BD, CH, non-HCC, and HCC patients, respectively. HDV RNA has been detected in 1.54 %(5/323) cases with a mean viral load of 4,010,360 IU/ml. All isolates were found to be HDV genotype 1.ConclusionsThe magnitude of HDV infection increased with the severity of liver disease, indicating HDV infection is more common among patients with CHB-related liver diseases in Ethiopia.     

Prevalence of hepatitis C antibody in patients with chronic liver disease and hepatocellular carcinoma in Korea

Summary. To investigate the contribution of hepatitis C virus (HCV) to chronic liver disease and hepatocellular carcinoma (HCC) in Korea, antibodies to HCV (anti-HCV) were tested by enzyme immunoassay in 1759 patients with chronic liver disease and HCC, and in 808 healthy adults. The prevalence of anti-HCV was 1.6% in 808 controls. Anti-HCV was present in 32 (7.7%) of 418 hepatitis B surface antigen (HBsAg)-positive and 128 (53.1%) of 241 HBsAg-negative patients with chronic hepatitis, 16 (6.0%) of 265 HBsAg-positive and 90 (30.5%) of 295 HBsAg-negative patients with liver cirrhosis, and 16 (4.8%) of 330 HBsAg-positive and 61 (29.0%) of 210 HBsAg-negative patients with HCC. Antibodies to hepatitis B core antigen (anti-HBc) were present in 80–88% of patients who were seropositive for anti-HCV and seronegative for HBsAg. Among the sera from 114 patients with HBsAg-negative and anti-HCV-positive chronic liver diseases, HBV DNA and HCV RNA were detected by polymerase chain reaction (PCR) in 54 (47.4%) and 61 (53.3%), respectively. Both HBV DNA and HCV RNA were detected in 4 (4.4%) samples. The mean age of the patients with both HBsAg and anti-HCV was not different from that of patients who were seropositive for HBsAg alone. These findings indicate that current and/or past HBV infection is still the main cause of chronic liver disease in Korea. Although multivariate analysis showed that anti-HCV is a risk factor for chronic hepatitis, cirrhosis of the liver and HCC, PCR data for HBV DNA and HCV RNA indicate that HCV infection plays only a minor role in HBsAg-positive as well as in HBsAg-negative liver disease and does not accelerate the development of HCC in HBV carriers.     

Immunohistochemical research of HDV infection in Chinese patients with chronic liver disease

The prevalence of HDAg in the liver of Chinese patients with chronic hepatitis and hepatocellular carcinoma was determined using direct immunofluorescence and immunoperoxidase. Overall, 6 patients (6.31%) out of 95 HBsAg carriers with inflammatory liver disease and neoplasia were found to be HDAg positive. HDAg was detected in the livers of 6 (7.59%) out of 79 chronic hepatitis patients. The relative frequency of HDAg in cirrhosis-B, CAH-B and CPH-B was 14.3%, 7.1%, and 5.89%, respectively. These results suggest that a sizeable number of HBsAg carriers are also carriers of HDV. In view of the large number of HBV carriers in China, the relatively minor but distinct presence of HDV represents an important health problem.     

An outbreak of fulminant hepatitis delta in the Waorani, an indigenous people of the Amazon basin of Ecuador

An outbreak of delta hepatitis occurred during 1998 among the Waorani of the Amazon basin of Ecuador. Among 58 people identified with jaundice, 79% lived in four of 22 Waorani communities. Serum hepatitis B surface antigen (HBsAg) was found in the sera of 54% of the jaundiced persons, and 14% of asymptomatic persons. Ninety-five percent of 105 asymptomatic Waorani had hepatitis B core (HBc) IgG antibody, versus 98% of 51 with jaundice. These data confirm that hepatitis B virus (HBV) infection is highly endemic among the Waorani. Sixteen of 23 (70%) HBsAg carriers identified at the onset of the epidemic had serologic markers for hepatitis D virus (HDV) infection. All 16 were jaundiced, where as only two of seven (29%) with negative HDV serology were jaundiced (P = .0006). The delta cases clustered in families, 69% were children and most involved superinfection of people chronically infected with HBV. The data suggest that HDV spread rapidly by a horizontal mode of transmission other than by the sexual route.     

Identification of a natural intergenotypic recombinant hepatitis delta virus genotype 1 and 2 in Vietnamese HBsAg‐positive patients

Hepatitis D virus (HDV) infection is acquired as a co‐ /superinfection of Hepatitis B virus (HBV) and can modulate the pathophysiology of chronic hepatitis B and related liver diseases including hepatocellular carcinoma. Among the eight distinct HDV genotypes reported, relatively few studies have attempted to investigate the prevalence of HDV mixed genotypes and RNA recombination of HDV. With a recorded prevalence of 10–20% HBV infection in Vietnam, this study investigated the HDV variability, HDV genotypes and HDV recombination among twenty‐one HDV isolates in Vietnamese HBsAg‐positive patients. HDV subgenomic and full‐length genome sequences were obtained using newly established HDV‐specific RT‐PCR techniques. The nucleotide homology was observed from 74.6% to 99.4% among the investigated full‐length genome of the HDV isolates. We observed HDV genotype 1 and HDV genotype 2 in the investigated Vietnamese patients. Although no HDV genotype mixtures were observed, we report here a newly identified recombinant of HDV genotypes (HDV 1 and HDV 2). The identified recombinant HDV isolate C03 revealed sequence homology to both HDV genotype 1 (nt1 to nt907) and HDV genotype 2 (nt908 to nt1675; HDAg coding region) with a breakpoint at nt908. Our findings demonstrate the prevalence of intergenotypic recombination between HDV genotypes 1 and 2 in a Vietnamese HBsAg‐positive patient. Extended investigation on the distribution and prevalence of HDV, HDV mixed genotypes and recombinant HDV genotypes in a larger Vietnamese population offers vital insights into understanding of the micro‐epidemiology of HDV and subsequent pathophysiology in chronic HBV‐ /HDV‐related liver diseases.     

Prevalence of Hepatitis D in the Eastern Mediterranean Region: Systematic Review and Meta Analysis

Background

Hepatitis D Virus (HDV) causes the most threatening form of chronic viral hepatitis. To date, there is no overall estimation of HDV prevalence in the Eastern Mediterranean Region Office of WHO (EMRO) countries.

Objectives

To provide a clear estimation of HDV prevalence in the aforementioned region.

Patients and Methods

In the current systematic review, databases such as PubMed, Embase, Web of sciences and Google scholar were searched Until December 2010. The summary estimate of HDV prevalence in the EMRO region was calculated as an average of the pooled infection prevalence of each country weighted by the ratio of the country’s HBV population to the study’s sample size in the survey data analysis.

Results

We included 62 eligible studies. The weighted mean of HDV prevalence in the EMRO region was 14.74% (95% CI: 14.73 – 14.77), 27.8% (95% CI: 27.78 – 27.82), 36.57% (95% CI: 36.55 – 36.59) and 16.44%. (95% CI: 16.42 – 16.46) in asymptomatic HBsAg positive carriers, chronic hepatitis patients, cirrhosis/ hepatocellular carcinoma, and high risk group, respectively. Among the asymptomatic HBsAg positive group, HDV prevalence was increased by years in older patients in Saudi Arabia but its prevalence was decreased in Iran. No specific pattern was seen according to chronological analysis during years among the EMRO countries.

Conclusions

HDV infection is endemic in the EMRO countries and it is more common among patients with severe forms of hepatitis. Due to the high HDV infection rates in the EMRO countries, we recommend blood screening for HDV infection in this region.     

Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection.

To examine the role of hepatitis C virus (HCV) infection in spontaneous hepatitis B surface antigen (HBsAg) clearance during the course of chronic hepatitis B virus (HBV) infection, serum specimens from 32 asymptomatic HBsAg carriers and 22 patients with chronic hepatitis type B who underwent spontaneous HBsAg clearance were studied for antibody to HCV (anti-HCV) using commercial EIAs. The results were compared with those of control groups matched for age, sex, hepatitis B e antigen, antibody to hepatitis delta virus, and cirrhosis. Eight (25%) of the asymptomatic carriers and 9 (41%) of the patients with chronic hepatitis were seropositive for anti-HCV in contrast to 1.6% and 9.1% of their respective control groups (P less than .01). Serum alanine aminotransferase level was persistently abnormal after HBsAg clearance in one asymptomatic carrier and in four patients with chronic hepatitis. These patients were seropositive for anti-HCV and at least one of them was negative for HBV-DNA by polymerase chain reaction. The data suggest that HCV superinfection may not only suppress HBV or terminate the HBsAg carrier state but may also assume the role of HBV as the cause of persistent hepatitis or transaminase elevation.