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Introduction and Objectives: Sustained virologic response (SVR) is achieved in most cases of C-type liver disease after direct-acting antiviral (DAA) therapy. Although liver fibrosis improves, the degree of improvement is different. This study aimed to analyze the factors involved in improving liver fibrosis using the fibrosis 4 (FIB-4) index., Material and Methods: Patients were monitored for >3 years after SVR. At the start of therapy (SOT), liver fibrosis was categorized as either mild (<1.45 n = 28), moderate (1.45-3.25 n = 139), or advanced (>3.25 n = 236) based on the FIB-4 index. The FIB-4 index in the advanced group decreased significantly compared to that of the other two, so we selected the advanced group as the analysis target. SOT and end of therapy (EOT) factors that contributed to the FIB-4 index ≤3.25 at 3 years after therapy were examined using a multivariate analysis., Results: Among the SOT factors, age (<72 years old), absence of liver cirrhosis (LC), alanine transferase (ALT) (≥50 U/L), platelet (PLT) (≥10.2 × 10 4 /mm 3 ), and total bilirubin (T.Bil) (<0.8 mg/dl) were the significant factors contributing to the improvement of the FIB-4 index. Among the EOT factors, age (<72 years), PLT (≥12.0 × 10 4 /mm3), and hemoglobin (Hb) (≥12.1 g/dl) were the significant factors contributing to the improvement of FIB-4 index., Conclusions: Factors involved in the improvement of liver fibrosis after SVR were young age, absence of LC, low T.Bil., high ALT, high PLT, and high Hb levels. The levels of T.Bil, PLT, and Hb were considered to be related to portal hypertension. Aging strongly impaired the improvement in liver fibrosis., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.

Background: We aimed to investigate the effects of ribavirin on hepatitis C virus (HCV). Immunological and virological effects were analysed in patients undergoing treatment with ribavirin monotherapy prior to the initiation of combination therapy with interferon-alpha., Methods: A total of 25 patients with chronic HCV infection were enrolled in this study. All patients received ribavirin for 4 weeks during monotherapy; subsequently, interferon-alpha2b was additionally given as combined therapy. Patients were divided into two groups according to virological response. A rapid viral responder (RVR) was defined as a patient in whom HCV RNA became undetectable within 4 weeks after combination therapy. The changes of the T-helper (Th)1/Th2 subset of peripheral blood CD4(+) T-cells, serum cytokine levels and the alignment of the interferon sensitivity-determining region (ISDR) during ribavirin monotherapy were analysed by flow cytometry, ELISAs and sequencing methods., Results: A total of 17 patients were classed as RVR. In the RVR group, the mean +/-sd serum alanine aminotransferase levels significantly decreased (before treatment 103 +/-92 IU/l and after treatment 57 +/-46 IU/l; P<0.05) during ribavirin monotherapy. The mean +/-sd Th1/Th2 ratio significantly increased (before treatment 13.9 +/-5.1 and after treatment 16.7 +/-6.2; P<0.05), but did not change in the non-RVR group. The levels of Th2 cytokines (interleukin-10 and soluble CD30) significantly decreased, especially in the RVR group. The mean +/-sd mutation rates of ISDR at the nucleotide level increased in the RVR group (before treatment 2.6 +/-0.9 sites/clone and after treatment 3.9 +/-1.6 sites/clone; P<0.05), but did not change in the non-RVR group., Conclusions: Ribavirin administration might increase the efficacy of interferon therapy for patients with chronic hepatitis C by stimulating the host immune system and promoting HCV gene mutation.

Hepatitis C virus (HCV) appears to circulate in various forms such as native virion, immune complexes, and nucleocapsids during chronic infections. To determine the association of the physicochemical properties of HCV and its response to interferon therapy in patients with chronic hepatitis C, we examined pretreatment serum samples from 43 patients with HCV RNA who had received interferon therapy, using differential flotation centrifugation in a NaCl solution with a density of 1.063 g/ml. After centrifugation, the ratio of HCV RNA in the top and bottom fractions was determined by the polymerase chain reaction and expressed as T/B. Patients with a sustained response to IFN therapy were found to have higher T/B ratios than transient responders who relapsed after treatment (P < 0.01) and nonresponders (P < 0.01). With regards to HCV genotypes, patients with genotype 1b had higher T/B ratios in the sustained response group than in the nonsustained response groups (P = 0.001), but patients with genotype 2 had a similar distribution of T/B among the 3 response groups (not significant). These findings indicate that the physicochemical properties of HCV affect the effectiveness of interferon therapy, particularly in patients with genotype 1b.

Some chronic hepatitis C patients show sustained response to interferon (IFN) therapy despite viremia. This condition seems to be related to the density populations of hepatitis C virus (HCV) [Kanto et al. (1995): J Med Virol 46:230-237]. To investigate further the relationship between alanine aminotransferase (ALT) levels after IFN therapy and the HCV density populations, we undertook differential flotation centrifugation of HCV and single strand conformation polymorphism targeted the hypervariable region (HVR) of E2 glycoprotein, which seems to be related to the density populations. Sera were obtained serially from 12 patients who had undergone IFN therapy (six sustained responders with viremia, six nonresponders). During the follow-up after interferon therapy, the HVR heterogeneities changed in 9 of the 12 patients. The remaining three patients whose heterogeneities did not changed persistently showed normal ALT. The changes in HVR heterogeneities were less pronounced in the sustained responders with viremia than in nonresponders; however, their density populations were prominently high in both responders. In two cases, changes in HVR heterogeneities and increase in low-density virion were observed before the hepatitis flare-up. These data indicate that HVR quasispecies show more relation to ALT levels after IFN therapy than HCV density populations and that the changes in the HVR sequences and HCV density populations may be associated with ALT elevation in some patients.

Second-generation assays for detection of hepatitis C virus (HCV) infection that include reactivity of antibodies to core, NS3, NS4 are used because of their high sensitivity. Among these antibodies, anti-core antibody seems to be the most sensitive. However, there are some patients without anti-core antibodies, although HCV RNA is detectable by reverse transcription-polymerase chain reaction and branched DNA assay. The mechanism for the absence of anti-core antibody on its own is unclear. We therefore determined the nucleotide and deduced amino acid sequences of the core region obtained from two anti-core antibody-negative patients with HCV RNA (genotype 1b) and compared them with those of four anti-core antibody-positive patients and a previously reported sequence. Amino acids spanning 1-47, which seemed to exist in major B cell epitopes, were found to be completely conserved among these patients. Furthermore, the predictive binding motif to HLA DR4 (a.a 81-90) was completely conserved in both of the anti-core antibody-negative patients. There were various mutations in the residual amino acids spanning 49-108, but specific mutations could not be found in anti-core antibody-negative patients. These data indicate that the absence of anti-core antibody in two patients is not due to the presence of some formerly unknown viral variants, but due to a possible defect in the host's immune system.

Although the mechanisms of elimination of HCV by IFN have not been fully elucidated, the 2-5A system was reported to be one of the mechanisms of the anti-viral effect of IFN. Therefore, the relationship between HCV genotype, induction of 2-5AS and clinical effect was investigated. As for the anti-viral effect during IFN therapy, in type III or IV, most patients lost HCV-RNA regardless of serum 2-5AS induction even in high HCV-RNA concentration cases. In contrast, in type II, the negativity rate of HCV-RNA became high along with an increase of serum 2-5AS activity, but in patients with high HCV-RNA concentration, HCV-RNA was persistently positive. As for the long term clinical effect of IFN therapy judged 6 months after completion of IFN therapy, HCV genotypes were closely related to the effect; that is, the patients with type III or type IV HCV genotype showed a higher complete response rate compared with the patients with type II HCV genotype. However, the relationship between the long term clinical effects and induction of serum 2-5AS during IFN therapy was obscure. These results suggest that induction of 2-5AS is closely related to the anti-viral effect during IFN administration, but the viral factors appeared to be related to long term clinical effects after cessation of IFN therapy.

Hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis worldwide. Since the HCV viral genome was molecularly cloned and antibody detection systems were established, a considerable amount of information on HCV has been accumulated. In the present study, I have examined the sera and liver tissues of the patients of type C chronic liver disease using molecular biological methods and tried to correlate the data obtained with the clinical, pathological and therapeutic outcomes. A reverse transcription-polymerase chain reaction (RT-PCR) method using radiolabeled nucleotides provided constant results in genome amplification, and could be shown to be a reliable method for quantifying the levels of HCV genome. The amount of HCV RNA in the serum tended to increase as a function of the duration of the disease and the progression of histopathologic changes of the liver. In addition, the serum HCV RNA titers correlated well with those of liver tissues, which showed that the amount of circulating HCV genome reflected the intrahepatic amount of HCV. HCV, a positive-stranded RNA virus, is likely to make a negative strand during viral replication. In studies to detect the positive and negative strands of HCV RNA separately using strand specific primers, the existence of both strands in the liver was demonstrated, confirming viral replication in the liver. The ratio of negative to positive strands ranged from 0.03% to 30%, being 3.7% in chronic persistent hepatitis, 4.8-6.0% in chronic aggressive hepatitis and 6.7% in liver cirrhosis. The viral factors influencing the interferon (IFN) response were also examined. Individuals who had low titers of HCV genome tended to respond well to IFN. Moreover, IFN was more effective for patients with HCV type III than for those with HCV type II. Thus, IFN response was shown to depend both on virus titers and genotypes. However, mean levels of HCV RNA were almost the same between the patients with HCV type II and those with HCV type III before the treatment, there were significant differences in the disappearance of HCV and the effects of IFN therapy. It is suggested that the susceptibility to IFN is different for each genotype. Hokkaido J Med Sci 69 (6), 1382-1398, 1994.

Genotypes of HCV have been reported to be one of the predictors of response to IFN therapy in patients with chronic hepatitis C. HCV genotypes were determined enzyme-linked immunoblot assay based on group I and II specific recombinant peptides of the NS-4 region (amino acid No. 1676-1670). We examined the correlation between HCV groups and response to IFN in patients with chronic hepatitis C. Among the 84 patients with chronic hepatitis C who underwent IFN treatment, 16 of 51 (31.4%) patients with group I and 12 of 23 (52.2%) patients with group II showed complete sustained response. These results suggest that HCV group assay may improve the ability to predict IFN treatment outcomes.