In a study assessing factors associated with a good or a poor response to interferon treatment in patients with chronic hepatitis type C, we analyzed serum samples taken from 26 interferon-treated patients and found further evidence that infection with genotype II is associated with a poor response. Whereas all seven patients with group III genotype tested showed a good response (normalization of alanine aminotransferase level for more than 6 months), only 10 of 19 (53%) patients infected with group II genotype showed a good response. We also observed that 16 of 17(94%) patients who exhibited a rapid virus titer decrease during the first 2 weeks of treatment later showed a good response. In contrast, only three of nine (33%) patients with an initially slow viral decrease eventually showed a good response (p<0.04). None of the 26 control patients exhibited a marked virus decrease or normalization of serum alanine aminotransferase level. Interestingly, high degrees of sequence variability were seen in three patients with group II hepatitis C virus who responded poorly to the therapy. All three showed slow decreases in virus titer during the first 2 weeks of treatment. In contrast, patients with genotype II who showed a good response to treatment were seen to have very few mutations. In three patients with genotype III who had responded well to interferon treatment, all showed very little amino acid sequence variability in the hypervariable region compared with patients with genotype II who had responded poorly to interferon treatment. These data suggest that a slow decrease in virus titer during the beginning of interferon treatment and a high degree of sequence variability, both of which are often seen in patients with group II genotype, are associated with poor response to interferon treatment.

Interferon has been shown to be an effective treatment for some patients with chronic hepatitis C. In this study, the value of retreatment of nonresponders to interferon was investigated. Thirty-eight patients with hepatitis C virus (HCV)-RNA-positive chronic hepatitis C who had been treated with beta-interferon but still showed an alanine aminotransferase (ALT) level > 50 KU upon completion of therapy were retreated with alpha-interferon. Eight patients (21.1%) had normalization of ALT levels for at least 6 months after the completion of retreatment. The factors related to normalization of ALT levels after interferon retreatment were studied. Of 16 patients with transient HCV-RNA negativity 1 month after the initial interferon therapy, 7 (43.8%) had a complete response, with normalization of ALT levels and undetectable HCV-RNA, more than 6 months after interferon retreatment. On the other hand, of the 22 patients with HCV-RNA activity 1 month after the initial interferon therapy, only 1 (4.5%) had a complete response. Multivariate analysis, using a multiple logistic model, indicated that a complete response to readministration of interferon was most strongly correlated to transient negative conversion for HCV-RNA after the initial course of treatment.

Five subtypes of hepatitis C virus (Pt[I], K1[II], K2a[III], K2b[IV] and Tr[V]) have been suggested based on the nucleotide sequence of the non-structural five region. To assess the susceptibility of each subtype to interferon therapy, we developed a one-step method which allows quick determination of subtype using polymerase chain reaction with a mixed primer set deduced from the sequence of each subtype. We were able to determine the subtype of 69 of 80 (86.3%) Japanese patients who received natural alfa-interferon treatment. The incidence of each subtype was K1: 53 (76.8%), K2a: 14 (20.3%), K2b: 3 (4.3%) and Tr: 1 (1.4%). Interferon was administered to these patients and found to be effective in 28 of 51 (54.9%) patients with K1 subtype and in 16 of 18 (88.9%) patients with other subtypes (P< 0.01). These data show that K1 is a major subtype in Japan and relatively resistant to interferon treatment.

Interferon(以下IFN)治療を施行したHCV-RNA陽性慢性肝炎でIFN終了後1年以上経過観察した185例につき,IFN有効性の予測解析を目的に多重ロジスティックモデルにより検討した.IFN著効を「IFN終了後6カ月以内にGPTが正常化し,その後6カ月以上正常値が持続し,かつIFN終了後6カ月の時点でのHCV-RNA陰性例」と定義し,年齢,性別,輸血歴の有無,肝の組織診断,IFNの種類,IFNの総投与量,IFNの投与法,IFN治療前のGPT値,GOR抗体の有無,HCV-subtypeの種類,HCV-RNA量の諸要因のいずれが著効達成に寄与しているかを検討した.IFN著効に寄与する有意な独立要因はHCV-subtype,IFN投与法,肝の組織診断,およびHCV-RNA量であり,subtypeではK2aないしK2b, IFN投与法では8週連日+間歇投与法,肝の組織診断ではCH2A, HCV-RNA量では105copy/ml未満の症例が治療効果が良好であった.

A method that allows the quantitation of hepatitis C virus (HCV) RNA is described. The RNA was extracted from serum samples and reverse transcribed. Target cDNA was then co‐amplified by nested polymerase chain reaction with a known amount of competitive template at various concentrations. Since this internal control DNA uses the same primers as those of the target and is distinguishable from the target cDNA after amplification by size, the initial concentration of the target could be estimated by comparing the intensity of the two bands of amplified DNA fragments. That is, if the starting amount of the cDNA and the competitive template are equal, the intensity of the two bands should also be equal. Using this method the amount of HCV RNA in serum samples obtained from 85 patients with chronic hepatitis type C was determined. There was as much as a 100 000‐fold difference in the levels of HCV RNA from patient to patient. A rapid decrease of HCV RNA in a patient treated with interferon is also described.

Four subtypes of hepatitis C virus (HCV), Pt(I), K1(II), K2a(III) and K2b(IV), have been suggested based on the nucleotide sequences of the non‐structural (NS) 5 region. A fifth subtype from Japanese patients, Tr(V), which shows a less than 68% homology in nucleotide sequence when compared with other subtypes has been identified. A one‐step method which enables a quick determination of subtype using polymerase chain reaction with a mixed primer set deduced from the sequence of each subtype has been developed. Using this technique, the subtypes of 418 out of 478 Japanese patients (87.4%) were determined. The incidence of each subtype in Japan was as follows: K1(II), 307 (73.4%); K2a(III), 74 (17.7%); K2b(IV), 28 (6.7%); and Tr(V), 3 (0.7%). This one‐step subtyping technique should be useful for studying the epidemiology or biology of the HCV.

To determine how various factors influence the response to interferon (IFN) therapy, we retrospectively studied 157 consecutive Japanese patients with chronic hepatitis C who received various treatment schedules of IFN. They were divided into two groups on the bases of outcome. One group was comprised of 65 patients who achieved a sustained normalization of serum alanine aminotransferase (ALT) levels for at least 6 months after treatment, while the other group was comprised of 84 patients with persistent elevation of serum ALT levels, despite treatment. Genotyping of hepatitis C virus (HCV) was done by polymerase chain reaction (PCR) with genotype specific primers, analysing the variations in nucleotide sequence within the NS 5 region of the HCV genome, namely genotypes PT, K1, K2a and K2b. We then used a multivariate analysis to determine the factors related to mode of treatment, patient characteristics and HCV genotype in relation to the response to IFN therapy. Of the 16 factors analysed, the HCV genotype (genotype K2a or K2b, P < 0.0008), treatment schedule (intermittent administration following a daily schedule, designated as combined schedule, P > 0.0014) and liver histology just before treatment (chronic persistent hepatitis or mild chronic aggressive hepatitis, P < 0.0324) were the most strongly correlated with a normalizing response to IFN therapy. These results suggest that not only are the IFN treatment schedule and patient profile significant, but the properties of the virus also influences the response. However, as the IFN treatment schedule is the only changeable factor, it should be designed to maximize the benefit of IFN therapy.

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As an aim toward developing new antiulcer agents, new N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas were synthesized and evaluated for histamine H2-receptor antagonistic, gastric antisecretory, and gastric mucosal protective activities. A QSAR study showed that the most favorable N-substituents were electron-donating straight-chain alkyl groups of short length such as ethyl group from the viewpoint of dual action, i.e., gastric antisecretory and mucosal protective actions. Among the ureas studied, compounds 4, 5, and 8-10 were selected as candidates for further study.

C型慢性肝炎症例71例にInterferon(以下IFN)を投与し,IFNの有効性について多重ロジスティックモデルを用いて検討した.IFN投与開始より6カ月後のGPT正常化率に及ぼす諸因子につき多変量解析を施行したところ,IFN総投与量,IFN開始時の年齢,IFN投与方法,IFN投与前の組織,性の違いによりGPT正常化率に差がみられ,年齢では35歳未満,IFN総投与量では400MU以上,IFN投与法では連日+間歇投与法,組織学的にはCH2A,性別では女性がGPT正常化は高率であった.またIFN開始より6カ月の時点でGPTが正常化した症例のうち15例でIFNを中止したところ,GPTの正常継続例は11例(73.3%)であり,HCV抗体価が陰性化した症例5例ではIFN中止後もGPTの正常化が続いた.

Among 612 patients with chronic hepatitis type B, 24 patients tested positive for anti-C-100 antibody. Clinical features and viral markers of these 24 patients were studied. Anti-C-100 antibody was detected more often in patients negative for HBe antigen than those positive for this antigen (22/385 vs. 2/227 [P less than 0.01]). HCV RNA, as detected by reverse transcription and nested polymerase chain reaction, was positive in 20 of 22 patients negative for HBe antigen whereas it was detected in only one of two patients positive for HBe antigen. In a patient who seroconverted from HBe antigen to anti-HBe HCV RNA was undetectable in the HBe antigen positive phase and had become detectable after seroconversion. These data indicate that both hepatitis virus (type B and type C) can co-infect in a patient and that type C becomes active after the seroconversion from HBe antigen to anti-HBe.

非A非B型慢性肝疾患1,619例をretrosepectiveにC-100抗体を測定し肝疾患の進行度別および性別にC-100抗体陽性率とC-100抗体の力価を検討した.男女間におけるC-100抗体陽性率は,男性73.8%,女性65.0%と男性に高率であり,さらに肝疾患進行度別のC-100抗体陽性率は,特に肝硬変症例で男性では,76.2%であったが,女性では56.0%と女性の方が男性よりC-100抗体陽性率が有意に低率(p<0.05)であった.また,C-100抗体力価でも25以上の高力価例は,女性の方が男性より低率であった.非A非B型慢性肝疾患1,619例のうち,初診時C-100抗体陽性かつ長期間経過観察しえた52例中C-100抗体が陰性化した症例は,14例で12例は初診時より肝硬変症例であり,うち11例は女性であった.この11例中4例(全例女性)は,HCV-RNAも陰性化し血清トランスアミナーゼ正常が持続し長期間経過観察中肝癌の発生は認められていない.

ステロイド離脱療法後e抗原が陰性化し5年以上経過観察した症例につきpolymerase chain reaction(以下PCR)法およびEthidium bromide法(以下EB法)ないしSouthern blot法(以下SB法)にて血清HBV DNAを測定し,HBV DNAの有無が肝炎の予後を反映するかどうかにつき検討した.PCR+EB法ではe抗原が陰性化し,GPTが正常化した10例で,最終的にHBV DNAの陰性化がみられ,e抗原は陰性化したがGPTが異常値を繰り返した5例ではPCR+EB法でHBV DNAは継続的に陽性を示した.一方PCR+SB法ではe抗原陰性化後GPTが正常化した10例中8例で最終観察時点でもHBV DNAが陽性であり,PCR+SB法では予後の推定は困難であった.すなわち,ステロイド離脱療法後e抗原陰性化がみられた症例でPCR+EB法によるHBV DNAの有無はその予後をよく反映すると考えられた.

Hepatitis C virus RNA as detected by reverse transcription and nested polymerase chain reaction was monitored in 16 patients with chronic hepatitis C treated with interferon. Hepatitis C virus RNA became undetectable after 4 to 8 wk of interferon administration in 13 of the 16 patients. During 6 mo of follow-up, 5 of the 13 patients who became negative for hepatitis C virus RNA after interferon administration remained negative, and all five continued to have normal ALT levels. Repeat liver biopsy in these five patients revealed histological improvement. Antibody to hepatitis C virus, which was initially positive in all treated patients, fell to undetectable levels in three of the five patients. In contrast, aminotransferase levels rose again in all eight patients who had become hepatitis C virus RNA negative but had again exhibited hepatitis C virus RNA after completion of therapy. In 16 untreated patients, hepatitis C virus RNA remained detectable. These results indicate that detection of hepatitis C virus RNA may be useful as a marker of viral replication in chronic hepatitis C; they also suggest that interferon should again be administered to patients who become hepatitis C virus RNA negative on treatment but again exhibit this marker of viral replication when treatment is stopped.