A randomized, controlled trial comparing traditional herbal medicine and neuraminidase inhibitors in the treatment of seasonal influenza.

The herbal medicine, maoto, has been traditionally prescribed to patients with influenza in Japan. To better understand the efficacy of maoto for the treatment of influenza, a randomized trial was conducted for comparison with oseltamivir or zanamivir. Adult patients with influenza symptoms, including fever, positive for quick diagnostic kit for influenza within 48 h of fever onset were assessed for enrollment. The data of 28 patients randomly assigned to maoto (n = 10), oseltamivir (n = 8), or zanamivir (n = 10) were analyzed for the duration of fever (>37.5°C) and total symptom score from symptom cards recorded by the patient. Viral isolation and serum cytokine measurements were also done on days 1, 3, and 5. Maoto granules, a commercial medical dosage form, are made from four plants: Ephedra Herb, Apricot Kernel, Cinnamon Bark, and Glycyrrhiza Root. Median durations of fever of patients assigned maoto, oseltamivir, or zanamivir were 29, 46, or 27 h, respectively, significantly different for maoto and oseltamivir. No significant between-group differences were found in total symptom score among three groups. Viral persistent rates and serum cytokine levels (IFN-α, IL-6, IL-8, IL-10, and TNF-α) during the study period showed no differences among three groups. The administration of oral maoto granules to healthy adults with seasonal influenza was well tolerated and associated with equivalent clinical and virological efficacy to neuraminidase inhibitors.

Antibody response to influenza vaccine in adults vaccinated with identical vaccine strains in consecutive years.

Fifty seven hospital workers received influenza vaccine in November 2003, and the serum HI antibody titer was determined before, 2 and 4 weeks after the vaccination. Thirty seven were vaccinated in November, 2002 consecutively (the repeated vaccination group), and the remaining 20 had not been vaccinated in the previous year (the single vaccination group). Six of the repeated vaccination group received both influenza and hepatitis B vaccination in September, 2004 and the antibody responses were examined 2 weeks later. Two and four weeks after the 2003-vaccination, the HI antibody titers to A/H1N1, A/H3N2, and B in the repeated vaccination group were significantly lower than in the single vaccination group (P < 0.05). This phenomenon had no relation to the pre-vaccination HI antibody titer. The antibody response was low to repeated influenza vaccination, but normal to hepatitis B vaccine in six subjects who had a second vaccination in 2004, showing that this depressed response was influenza-specific. These results suggest that the decreased HI antibody response to repeated influenza vaccination was affected mainly by the previous vaccination per se rather than by the pre-existing antibody titer.

Serum antibody response to tuberculosis-associated glycolipid antigen after BCG vaccination in adults.

Tuberculous glycolipid antigens (TBGLs) are derived from the cell walls of Mycobacterium tuberculosis. Detection of anti-TBGL antibody in serum has recently become possible for the serodiagnosis of active tuberculosis. TBGL is not indigenous to M. tuberculosis, but it is widely found in Mycobacterium species. To elucidate the influence of M. bovis bacille Calinette-Guérin (BCG) vaccination, we assayed serum anti-TBGL antibody after BCG vaccination in adults. BCG vaccination was done for 20 Japanese healthcare workers with a negative tuberculin skin test reaction, and serum was collected 0, 2, 4, and 8 weeks and 1 year after vaccination. The tuberculin skin test became positive in 85% of the subjects. The mean anti-TBGL antibody titer remained negative throughout the observation period, but was elevated significantly compared with the pre-vaccination level, peaking at week 4 and showing a reduced level 1 year post-vaccination. These results showed that serological diagnosis using anti-TBGL antibody was not influenced by prior BCG vaccination.

Strenuous physical labor is important as a cause of elevated alanine aminotransferase levels in Japanese patients with chronic hepatitis C viremia.

To clarify the influence of lifestyle habits on the elevated alanine aminotransferase (ALT) levels deterioration of Japanese patients with chronic hepatitis C virus (HCV) viremia, we investigated the effects of smoking, drinking, and physical labor on the disease course of the residents living in a rural area of Kyushu, Japan. The data of patients with chronic HCV viremia and control subjects without HCV infection were analyzed retrospectively from 1986 to 1992 and prospectively from 1993 to 2000. In 2000, a questionnaire was given to 268 HCV-infected patients and 275 control subjects to survey for the lifestyle habits. The data of serial ALT level testing during the observation period was used as a measure of liver damage: 183 HCV patients (68.3%) and 10 control subjects (3.6%) had abnormal ALT levels greater than 35 IU/1 for more than half of their observation period. The percentage of HCV patients with elevated ALT levels significantly increased with the daily consumption of alcohol (p < 0.0001), the length of time spent in strenuous physical labor per day (p = 0.0056), and the number of cigarettes smoked per day (p = 0.0003). A stepwise logistic regression analysis showed male sex (p = 0.003), platelet counts (p < 0.001), strenuous physical labor (p = 0.002), and drinking history (p = 0.007) to be significantly associated with the elevated ALT levels of HCV patients. When strenuous physical labor was done for over 2 h, the probability of elevated ALT levels was increased compared with patients engaging in strenuous physical labor under 2 h (estimated odds ratio = 1.82 [under 2 h], 20.60 [over 2 h]). Interestingly, strenuous physical labor was extracted before alcohol consumption as a significant factor in the elevated ALT levels. Among the control subjects, only the amount of alcohol consumed per day (p = 0.0001) was significantly associated with the elevated levels. These data suggests that strenuous physical labor over a long period of time might be related to elevated ALT levels in patients with chronic HCV viremia as well as drinking.

Confirmation of nosocomial hepatitis C virus infection in a hemodialysis unit.

OBJECTIVES: To investigate a hepatitis C virus (HCV) outbreak in a hemodialysis unit and determine the source of transmission. METHODS: We have prospectively investigated the epidemiology of hemodialysis-related HCV infection in a single unit since 1989. In September 2000, acute hepatitis C (AH-C) was diagnosed in 5 patients by alanine aminotransferase elevation and HCV genotype 1b viremia without antibody to HCV. We surveyed the epidemiologic situation and performed polymerase chain reaction sequence analysis of the HCV 5'-noncoding (5'NC) region in the patients for comparison with 9 patients with chronic HCV genotype 1b viremia. RESULTS: Sequence analysis of the 5'NC region showed the consistency in the 5 independent clones from each AH-C patient and those from each chronic HCV viremia patient and no quasispecies over time in the clones of any of 14 analyzed patients. All AH-C patients had the same sequencing of the 6 variations in the region with the only other patient. A saline ampoule, used for heparin solution during hemodialysis, had a recap function. It was difficult to determine whether the ampoule was new or had already been used. The source-patient often underwent hemodialysis before the AH-C patients and most of their hemodialysis-related medicine was prepared during the source-patient's treatment. These findings suggested a high possibility that the AH-C patients shared a single heparin-saline solution ampoule contaminated by HCV from the source-patient. CONCLUSION: Nosocomial HCV infection occurred as a result of poor infection control practice when a patient with chronic HCV viremia received treatment prior to other hemodialysis patients.

Relationship of genotype rather than race to hepatitis B virus pathogenicity: a study of Japanese and Solomon Islanders.

The aim of this study was to determine the predominant hepatitis B virus (HBV) genotype in the Solomon Islands and determine if there is any racial correlation between genotype and hepatitis B e antigen (HBeAg) production in Japanese and Melanesian individuals. A total of 403 serum samples from 206 Melanesian HBV carriers in the Solomon Islands and 197 Japanese carriers from Fukuoka (n = 106) and Okinawa (n = 91) living in Japan in 2001 were tested. The HBV genotypes of 206 Melanesian subjects were 114 with genotype C (55.3%) and 92 with genotype D (44.7%). The HBV genotypes of 197 Japanese subjects were 74 with genotype B (37.6%) and 123 with genotype C (62.4%). The total HBeAg prevalence of subjects in Fukuoka (36.8%) was significantly higher than that of subjects in Okinawa (14.3%) (P < 0.0001) and subjects in the Solomon Islands (35.0%; P = 0.0014, by the Mantel-Haenszel test). The genotype C prevalences were significantly different, ranging from 24.2% in Okinawa, to 54.4% in the Solomon Islands, to 95.3% in Fukuoka (all P < 0.0001, by chi-square test). The prevalence of HBeAg positivity was significantly higher in Melanesian genotype C subjects (42.0%) than Melanesian genotype D subjects (26.6%) (P = 0.0310). Similarly, the prevalence of HBeAg positivity was significantly higher in Japanese genotype C subjects (36.6%) than Japanese genotype B subjects (9.5%) (P < 0.0001). These findings indicate that that HBV was of genotypes C and D in the Solomon Islands, and that the pathogenesis of HBV-infected patients is related to HBV genotype rather than race.

Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection.

BACKGROUND AND AIM: Hepatitis B virus (HBV) genotype C has a more severe pathogenesis than genotype B in Japan. We retrospectively investigated the relationship between HBV genotype and the core promoter (CP) (nt 1762 and 1764) and precore (PreC) (nt 1896) mutations of the HBV genome. METHODS: A total of 129 Japanese patients (42 genotype B and 87 genotype C) with chronic HBV infection, living in two different geographical areas in Japan, were evaluated (mean follow-up period 10.1 +/- 3.8 years). In 2000, CP and PreC HBV mutations were analyzed by direct sequencing from sera. Hepatitis B e antigen (HBeAg), HBV DNA and serial alanine aminotransferase (ALT) changes were followed and determined using serological methods. RESULTS: Genotype C patients had significantly higher rates of HBeAg (40.2%vs 2.4%), HBV DNA positivity (75.9%vs 7.1%) and ALT abnormality (71.3%vs 11.9%) than genotype B patients (all P < 0.05). Among genotype B patients, CP wild type (92.9%) was predominant and PreC mutation (88.1%) was predominant. However, among genotype C patients, CP mutation (75.9%) was predominant and PreC mutation (66.7%) was predominant. The CP mutation was found significantly more in genotype C than in genotype B (P < 0.05). Of the 67 patients with ALT abnormality, five (7.5%) genotype B and 62 (92.5%) genotype C patients (31 HBeAg positive and 31 negative) were found. Among the 31 genotype C patients who were HBeAg positive, the combination of CP mutation and PreC wild (54.8%) was predominant, while among the remaining 31 genotype C patients who were HBeAg negative, the combination of CP mutation and PreC mutant (71.0%) was predominant. CONCLUSION: Genotype C might be one of the worse prognostic markers in patients with chronic HBV infection, possibly because of mutation in the CP region.

A decrease in mother-to-child transmission of human T lymphotropic virus type I (HTLV-I) in Okinawa, Japan.

To investigate the chronologic change of mother-to-child transmission of human T lymphotropic virus type I (HTLV-I) in Okinawa, Japan, the presence of antibody to HTLV-I was tested in 4,187 healthy residents between, 4,528 nursery school children, and 3,837 pregnant women between 1968 and 2000. The chronologic change of the feeding method and the length of the breast-feeding period among 1,117 healthy mothers from 1937 to 1995 were also obtained by interview. Age-adjusted prevalence of HTLV-I among healthy residents decreased from 9.1% in 1968-1970 to 7.8% in 1981-1984 and to 6.3% in 1996-1998. The crude prevalence of antibody to HTLV-I among healthy residents less than 20 years old decreased significantly from 4.6% in 1968-1970 to 0.1% in 1996-1998 (P < 0.0001). The prevalence of antibody to HTLV-I among nursery school children decreased significantly over the study period, from a high of 1.8% in 1984 to a low of 0.2% in 1998 (P = 0.03). The prevalence among pregnant women decreased significantly from 5.6% in 1989-1992 to 3.7% in 1997-2000 (P = 0.0275). Prior to 1967, all healthy mothers breast-fed their children. After 1968, the use of bottled and mixed milk (breast milk and bottled milk) increased, with bottled milk becoming predominant after 1990 (89%). The percentage of healthy mothers breast-feeding for more than one year significantly decreased from 68.3% in 1937-1947 to 0.4% in 1990-1995 (P < 0.0001). Infection with HTLV-I in Okinawa has decreased mainly due to a reduction in the number of mothers breast-feeding and a shortening of the breast-feeding period. However, because the mother-to-child transmission rate among non-breast-feeders decreased from 12.8% in 1986-1991 to 3.2% in 1995-1999, there may be other factors involved in the decrease in mother-to-child transmission.

A prospective comparison of the effect of interferon-alpha and interferon-beta treatment in patients with chronic hepatitis C on the incidence of hepatocellular carcinoma development.

To investigate differences in the effect of interferon (IFN) -alpha and IFN-beta treatment for hepatitis C on hepatocellular carcinoma (HCC) development, we prospectively followed 351 consecutive patients (median age, 56.6 years; mean follow-up, 5.7 +/- 2.6 years) with chronic hepatitis C virus (HCV) viremia. Of 260 IFN-alpha and 91 IFN-beta treated patients, 17 (6.5%) and 4 (4.4%), respectively, developed HCC. Virological response (VR) was defined as persistent HCV RNA disappearance from serum, and biochemical response (BR) as persistent alanine aminotransferase (ALT) normalization after treatment. No significant between-group differences in HCC development were found between those with and without VR. Although the HCC development rate in patients without BR was significantly higher than that in patients with BR in the IFN-alpha group (11.4% and 0.8%; P << 0.05), no significant difference was found in the IFN-beta group (6.3% and 2.3%). Similar rates of HCC development were found in patients with chronic HCV viremia treated with either IFN-alpha or IFN-beta.

Clinical outcomes of hepatitis B virus (HBV) genotypes B and C in Japanese patients with chronic HBV infection.

The aims of this retrospective survey were to determine the epidemiologic distribution of hepatitis B virus (HBV) genotypes and analyze the genotype-related clinical differences among Japanese patients with chronic HBV infection. The 158 surveyed patients with chronic HBV infection lived in Fukuoka and Okinawa were serially tested for serum alanine aminotransferase (ALT) and hepatitis B e antigen (HBeAg). Follow-up was for a period of 10.8 +/- 6.4 years (mean +/- SD). The HBV genotypes were determined in sera by an enzyme-linked immunosorbent assay and detection of HBV DNA in serum was done by the transcription-mediated amplification-hybridization protection assay. Genotypes B and C were found in 58 (36.7%) and 100 (63.3%) of the patients, respectively. Genotype B was predominant in Okinawa (B = 86.9%, C = 13.1%), whereas genotype C was predominant in Fukuoka (B = 5.2%, C = 94.8%). The HBeAg positivity and ALT abnormality rates at the start of the observation period were significantly higher in patients with genotype C (66.0% and 84.0%) than in patients with genotype B (34.5% and 22.4%) (P < 0.05, respectively). The annual rate of spontaneous HBeAg disappearance in patients with genotype B was much higher than in patients with genotype C (8.38% versus 2.34%, respectively). Patients with genotype C who were continuously HBeAg negative from entry had a significantly higher ALT abnormality (58.8%) than those with genotype B (19.2%) (P < 0.05). Interestingly, patients with genotype C who became HBeAg negative after treatment with interferon had a high ALT abnormality (58.8%). All patients with an ALT abnormality were positive for HBV DNA in their serum. These findings indicate that patients with HBV genotype C have more severe liver deterioration because of the delay of HBeAg disappearance and continued HBV replication after HBeAg disappearance.

Hepatitis C virus (HCV) RNA level determined by second-generation branched-DNA probe assay as predictor of response to interferon treatment in patients with chronic HCV viremia.

Using first- and second-generation branched-DNA probe assays (1st- and 2nd-bDNA), we investigated the predictors of favorable clinical response to interferon (IFN) treatment in patients with chronic HCV viremia. A total of 122 patients (85 genotype lb and 37 genotype 2a) with chronic HCV viremia received 24-week IFN-alpha treatment. Patients with sustained clearance of serum HCV RNA by polymerase chain reaction at six months after IFN treatment were defined as having a sustained response (SR). HCV RNA level was determined by 1st- and 2nd-bDNA assays prior to treatment. Mean HCV RNA level by 1st-bDNA was significantly higher in genotype lb patients [5.4 x 10(6) HCV genome equivalent (Meq)/ ml] than in genotype 2a patients (0.9 Meq/ml) (P < 0.05). There was no significant difference between patients with these genotypes in the level by 2nd-bDNA (1b: 5.2 Meq/ml and 2a: 3.1 Meq/ml). SR was achieved by 43 (35.2%) of 122 patients. Mean HCV RNA levels by both the 1st- and 2nd-bDNA of SR patients (1.0 and 1.9 Meq/ml) were significantly lower than those of non-SR patients (5.3 and 6.0 Meq/ml) (both P < 0.05). The SR rate in genotype 2a patients (59.5%) was significant higher than in genotype lb patients (24.7%) (P < 0.05). Stepwise logistic regression analysis showed that HCV RNA level < or = 1.0 Meq/ml by 2nd-bDNA (odds ratio = 7.6, compared to level > 1.0 Meq/ml, P < 0.05) was a significant predictive cutoff for SR. Using 2nd-bDNA, a significantly higher rate of SR was found in genotype lb patients with level < or = 1.0 Meq/ml (57.6%) than in those with level > 1.0 Meq/ml (3.8%) (P < 0.05). The SR rate of genotype 2a patients with level >1.0 Meq/ml (68.6%) was somewhat higher than for those with level < or = 1.0 Meq/ml (52.4%). These findings suggested that, using 2nd-bDNA, a low HCV RNA level of < or = 1.0 Meq/ml was the most favorable marker of successful IFN treatment and that patients with genotype 2a, even those with level >1.0 Meq/ml, had a high rate of SR to IFN treatment.