Wen-Yung Sheng

Natural history of hepatitis D viral superinfection: Significance of viremia detected by polymerase chain reaction

BACKGROUND/AIMS Polymerase chain reaction (PCR) is very sensitive. The aim of the study was to reevaluate viral replication in hepatitis D virus (HDV) superinfection by PCR. METHODS HDV and hepatitis B virus (HBV) were detected by PCR in 185 patients. RESULTS The acute hepatitis group had the highest detection rate of HDV RNA compared with chronic hepatitis, cirrhosis, hepatocellular carcinoma, and remission groups (63 of 64 vs. 35 of 47, 17 of 23, 19 of 30, and 7 of 21) and the highest alanine aminotransferase (ALT) levels (mean, 1741 U/L vs. 266 to 27 U/L; P < 0.05). The detection rate of HBV DNA was the lowest in the acute group (41%) compared with 66%, 70%, 80%, and 57% in the remaining groups (P < 0.02). At the chronic stage, 13%-25% of cases had HDV RNA, and 30%-48% of cases had HBV DNA detected by PCR but not by traditional method. HDV RNA was associated with ALT levels in horizontal and longitudinal analyses. CONCLUSIONS HDV superinfection may be divided into the following three phases: acute phase, active HDV replication and suppression of HBV with high ALT levels; chronic phase, decreasing HDV and reactivating HBV with moderate ALT levels; and late phase, development of cirrhosis and hepatocellular carcinoma caused by replication of either virus or remission resulting from marked reduction of both viruses.

Decreasing hepatitis D virus infection in Taiwan: An analysis of contributory factors

Superinfection of hepatitis D virus (HDV) among hepatitis B virus (HBV) carriers is mainly through heterosexual contact in Taiwan. This study investigated the change of HDV endemicity and its associated contributory factors. Seventy‐seven patients with acute HDV superinfection among 527 consecutive exacerbating hepatitis B surface antigen (HBsAg) carriers were identified over the past 12 years. The prevalence decreased significantly by each 3‐year period from June 1983 to May 1995 (23.7, 15.5, 13.1 and 4.2%, respectively, P < 0.001). This trend was more significant in the hepatitis B e antigen (HBeAg)‐negative group (P < 0.001) than in the HBeAg‐positive group (P=0.073). Subjects with a history of paid sex and prostitutes were also recruited for analysis both in 1989 and 1996. Although not statistically significant, there was a trend showing a decrease in the prevalence of serum antibody against HDV (anti‐HDV) in each risk group: it was lower in 1996 among HBsAg‐positive brothel‐goers (10.3 vs 6.9%), licensed prostitutes (54.5 vs 50%) and unlicensed prostitutes (36.1 vs 30.8%). Accumulation of anti‐HDV‐positive subjects in risk groups may mask the actual decrease of new HDV‐infected cases. The prevalence of the HBsAg carrier rate among all prostitutes has significantly decreased (18.3 vs 12.2%, P=0.015). The efficacy of each preventive strategy was examined and mapped with the trend. It was concluded that active preventive measures directed against promiscuity and sexually transmitted disease and the promotion of disposable needles may have contributed to the decrease in HDV endemicity.

Supportive treatment, resection and transcatheter arterial chemoembolization in resectable hepatocellular carcinoma : an analysis of survival in 419 patients

OBJECTIVE AND DESIGN Both surgical resection and transcatheter arterial chemoembolization (TACE) are effective treatments for hepatocellular carcinoma (HCC). Few reports have compared the different treatment modalities for resectable HCC based on clinically matched groups. The aim of this study was to compare the survival rate after surgery, TACE or supportive treatment in resectable HCC patients, and also in elderly patients (> or = 70 y/o). METHODS From 1984 to 1993, 419 consecutive patients with resectable HCC were included in this study. Of these, 311 (74%) underwent resection of tumours and 46 (11%) refused operation, opting instead for TACE. The remaining 62 (15%) who refused both methods of treatment were given supportive care. Univariate and multivariate analyses for prognostic factors and the 5-year survival rate among the groups were studied. RESULTS Both surgical resection and TACE groups had a better 5-year survival rate than the supportive treatment group (43% and 34% vs. 7%). There was no difference in survival between the surgery and TACE groups. However, the 5-year survival rate was 11% in TACE and 41% in the surgical group when the patients were > or = 70. In multivariate analysis, female sex (P = 0.0466), tumour size < or = 3 cm (P = 0.0001), alpha-fetoprotein (AFP) < 400 U/l (P = 0.0036), single tumour (P = 0.0474), serum creatinine < or = 1.5 mg/dl (P = 0.0006) and alkaline phosphatase (AP) < or = 100 U/l (P = 0.0007) are associated with good prognosis for resectable HCC. CONCLUSION TACE is an alternative for resectable HCC. Tumour size, tumour number, AFP level, renal function, AP level and female sex are prognostic factors. In elderly people, TACE must be used prudently and has a worse prognosis.

Prevalence and risk factor analysis of GBV-C/HGV infection in prostitutes.

GB virus‐C (GBV‐C) and Hepatitis G virus (HGV) are variants of a recently cloned virus transmitted parenterally. It is unclear if sexual contact also transmits this virus. In this study, we detected serum GBV‐C/HGV RNA in 140 prostitutes by reverse transcription polymerase chain reaction (RT‐PCR) using different primers. Thirty (21%) were found with GBV‐C RNA by nested PCR although only 22 (73%) had HGV RNA by single round RT‐PCR. Both assays had a nearly perfect agreement (kappa value, 0.812). The prevalence of GBV‐C RNA in prostitutes was significantly higher than the control group (30/140 vs. 2/40, P < 0.02). Multivariate analysis revealed that a frequency of paid sex more than 120 times per month was the only factor significantly associated with positive GBV‐C RNA in prostitutes (P < 0.003). In summary, prostitutes are a high risk group and reservoir of GBV‐C/HGV infection due to high frequency of paid‐sex. J. Med. Virol. 52:83–85, 1997.

Comparison of clinico-pathological features in hepatitis B virus-associated hepatocellular carcinoma with or without hepatitis D virus superinfection

BACKGROUND/AIMS Hepatitis D virus superinfection in hepatitis B virus carriers produces additional damage in an already injured liver. Earlier reports noted that the development of hepatocellular carcinoma may be accelerated in hepatitis D virus-superinfected patients. This study aimed to investigate the impact of hepatitis D virus on the clinical course of hepatitis B virus-associated hepatocellular carcinoma. METHODS A total of 42 consecutive hepatocellular carcinoma cases seropositive for antibody against hepatitis D virus antigen (anti-HDV) were found from 1986 to 1994; the clinical manifestations, treatment and outcomes were compared with 255 consecutive hepatocellular carcinoma cases seropositive for hepatitis B virus surface antigen but seronegative for anti-HDV. RESULTS The mean age was 60 years in both groups of patients. Other features, including sex, duration of follow-up, presence of cirrhosis or ascites, serum biochemistry, status of HBV-e antigen, and gross and microscopic tumor appearance, were not significantly different between the two groups. Though more patients in the anti-HDV-positive group underwent active treatment (operation or transcatheter arterial chemoembolization) than those in the anti-HDV-negative group (54.8% in 42 versus 34.9% in 255 cases, p = 0.02), the cumulative 4-year survival rates (9.5% versus 9.8%) were similar. For the anti-HDV-positive hepatocellular carcinoma patients, tumor size < 5 cm and active treatment were favorable prognostic predictors associated with survival > 18 months. CONCLUSION Hepatitis D virus superinfection does not accelerate the development of hepatocellular carcinoma. The clinical manifestations were similar, and the outcome in anti-HDV-positive patients was not worse than in the general HBV-associated hepatocellular carcinoma patients, as long as they were diagnosed at an early stage and actively treated.

Diagnostic value of anti‐hepatitis D virus (HDV) antibodies revisited: A study of total and IgM anti‐HDV compared with detection of HDV‐RNA by polymerase chain reaction

A high serum titre (≥ 1000 or ≥ 5000) of total antibody to hepatitis D virus (anti‐HDV) and positive for immunoglobulin (Ig) M anti‐HDV have been used to represent HDV replication, while reverse transcription‐polymerase chain reaction (RT‐PCR) is currently the most sensitive assay for detecting HDV viraemia. The aim of the present study was to re‐evaluate the correlation of total anti‐HDV and IgM anti‐HDV with HDV viraemia based on RT‐PCR and to assess the clinical significance of these markers in acute and chronic HDV superinfection. Chronic HDV infection was defined as positive HDV‐RNA by RT‐PCR for more than 6 months, while total anti‐HDV titre was defined by serial dilution. Of 178 hepatitis B virus (HBV) carrier patients studied, 119 cases had been anti‐HDV positive for more than 6 months. Two‐thirds (79/119) were positive for HDV viraemia by RT‐PCR. Only half the chronic HDV viraemic patients had a high titre (≥ 1000) of total anti‐HDV, and there was only moderate agreement (K = 0.41) between total anti‐HDV titre/IgM anti‐HDV and HDV‐RNA and chronic HDV viraemia. Based on cross‐sectional and longitudinal follow‐up analyses, serum total anti‐HDV titres ≥ 100 appeared to be an excellent cut‐off titre (K = 0.91) in differentiating chronic from acute HDV infection among viraemic patients. In summary, IgM and a high titre total of anti‐HDV are not good markers of HDV viraemia, but an anti‐HDV titre of ≥ 100 appears to be an excellent marker for the differentiation of acute from chronic HDV superinfection.

Hepatitis D virus infection among prostitutes in Taiwan

Two hundred and sixty‐three adult licensed, 233 adult and 157 teenage unlicensed prostitutes from Taiwan were studied for prevalence and risk factors of hepatitis D virus (HDV) infection. The hepatitis B carrier rate among the three groups was 21, 15 and 20%, respectively, not significantly different from that of the general population in this area. However, the prevalence of HDV infection among carrier prostitutes was 55, 36 and 16%, respectively, much higher than that in general hepatitis B carriers. Univariate analysis revealed that the history of conducting paid sex for more than 12 months (P≤ 0.03), ear‐piercing (P≤ 0.02), tattooing (P≤ 0.02), and gonorrhoea or syphilis (P≤ 0.005) were significant factors associated with HDV infection among these subjects. Multivariate analysis revealed that the history of ear‐piercing and venereal diseases (P≤ 0.001) were still significant. In summary, genital ulcers caused by venereal diseases due to frequent sexual contact with multiple partners, and use of unsterilized needles in ear‐piercing or tattooing play important roles in the high prevalence of HDV infection in prostitutes.

Detection of serum hepatitis B, C, and D viral nucleic acids and its implications in hepatocellular carcinoma patients

Abstract: The association of viremia, elevated serum alanine aminotransferase (ALT) levels, and hepatocyte inflammatory activity in hepatocellular carcinoma (HCC) patients was studied. Serum samples from 114 HCC patients undergoing surgery were assayed for hepatitis B, C, and D viral nucleic acids by polymerase chain reaction (PCR) prior to surgery. Of these patients, 65 had HBV infection alone, 15 had HCV infection alone, 4 had HDV infection, 20 had HBV and HCV superinfection, 1 had triple viral infection, and 9 were negative for HBV and HCV infections. The prevalence of active viral replication was significantly higher in HCV than in HBV (92% versus 70%; P = 0.006) patients, and significantly higher mean serum ALT levels were also noted in the HCV group than in the HBV group (P = 0.02). The incidence of marked ALT elevation (>200 U/l) was highest in the HCV (27%) and the HDV (25%) groups. Patients in the HCV group were 10 years older than those in the HBV group. Viral superinfection did not accelerate the development of HCC. Viral replication persisted in a significant portion of HCC patients and a higher prevalence of hepatic inflammation was noted in patients with HCV- and, possibly, HDV-related HCC.

Prognostic factor analysis of fulminant and subfulminant hepatic failure in an area endemic for hepatitis B

In order to determine the criteria in selecting candidates for orthotopic liver transplantation (OLT), we assessed the aetiology and prognostic indicators in 61 patients with fulminant or subfulminant hepatitis during the past 13 years. Several previously reported models of high risk predictors were not suitable for a large portion of our patients with different aetiological and ethnic backgrounds. In the present study, serological markers of various hepatitis viruses were tested and clinical parameters were compared between survivors and non‐survivors. Multiple virus infection and multifactorial causes were important in the pathogenesis (48%) of acute liver failure. Among the 13 clinical parameters, six were considered significant on univariate analysis: prothrombin time prolongation (P< 0.001), total bilirubin, creatinine and α‐fetoprotein (P< 0.01), age and cholesterol (P< 0.05). With stepwise logistic regression using most discriminatory cut‐off values, an age of > 43 years (P= 0.0001), total bilirubin levels of > 23 mg/dL (P< 0.005) and prothrombin time prolongation > 19 s (P< 0.0001) were independent predictors of non‐survival. When applied to determine the index of poor prognosis, the sensitivity, specificity, positive predictive value, negative predictive value and predictive accuracy were 100, 67, 95, 100 and 95%, respectively, in the presence of any one of these prognostic factors. We conclude that these indicators may be useful for selecting patients with acute liver failure indicated for OLT.

Prevalence, implication, and viral nucleotide sequence analysis of GB virus-C/hepatitis G virus infection in acute fulminant and nonfulminant hepatitis.

The clinical impact of GB virus‐C (GBV‐C)/hepatitis G virus (HGV) infection on various causes of acute hepatitis and fulminant hepatitis is controversial. In this study, serum samples from 164 patients with acute hepatitis of various causes, 34 asymptomatic hepatitis B virus (HBV) carriers, and 34 healthy adults were tested for GBV‐C/HGV RNA by reverse transcription‐nested polymerase chain reaction using primers based on the 5′‐untranslated region. Nucleotide sequences of GBV‐C/HGV RNA from various groups were compared. The prevalence of GBV‐C/HGV RNA was significantly higher in patients with acute hepatitis D virus (HDV) superinfection than in HBV carriers or healthy controls (10/37 vs. 2/34, P < 0.02; 10/37 vs. 1/34, P < 0.005). GBV‐C/HGV RNA was detected in 11.1% of acute hepatitis A patients, 9.5% of acute hepatitis B patients, 15.8% of acute hepatitis C patients, 12.5% of acute hepatitis E patients, 11.8% of chronic hepatitis B patients with acute exacerbation, and 11.1% in patients with non‐A to ‐E hepatitis; each was not significantly higher than that in HBV carriers or healthy adults. There were no significant differences in gender, age, serum albumin, bilirubin, and alanine aminotransferase levels nor in the occurrence of fulminant hepatitis (6/28 vs. 36/136) between patients with or without GBV‐C/HGV RNA. All six patients with fulminant hepatitis who had GBV‐C/HGV RNA were complicated by infection with hepatitis B, C, or D. The GBV‐C/HGV clones from 21 patients with or without fulminant hepatitis belonged to group 3. No particular strain of GBV‐C/HGV was associated with fulminant hepatitis. J. Med. Virol. 56:118–122, 1998.