Clearance Of Serum Hepatitis C Virus RNA Research Articles

Treatment of Chronic Hepatitis C with Viral-Suppression linked to Restoration of Innate-Immune Responses with Induction-Therapy with n-IFN-beta followed by Simeprevir

Complications associated with hepatitis C virus (HCV) infection may be prevented by viral eradication. Response rates with direct-acting antivirals regimens are generally lower in chronic hepatitis C (CHC) patients who have failed to respond to previous interferon (IFN) treatments. HCV persistence in the host results from in efficient innate and adaptive immune responses. The resolution of a HCV infection may restore impairments in innate and adaptive immunities. Our previous study suggested that induction treatment with natural (n)-IFN-beta followed by maintenance treatment with n-IFN-alpha restored innate immune responses, as indicated by the significant increase of IL-12, and IL-15 and significant decrease of CXCL-8. Persistent virologic clearance and the restoration of innate immune responses with Simeprevir plus Pegylated (Peg) - IFN-alpha/ribavirin (RBV) were more likely to result in a sustained virologic response (SVR). On the basis of these findings, we conducted to treat a CHC patient with genotype 1b, a high viral load, a prior null response to IFN treatments and chronic active hepatitis with advanced fibrosis using induction therapy with n-IFN-beta followed by Simeprevir plus Peg- IFN-alpha-2b/RBV. This is the first case of difficult-to-treat CHC with genotype 1b, a high viral load, null response to previous IFN treatment and advanced hepatic fibrosis that was successfully treated with induction therapy using n-IFN-beta, which induced the viral clearance of serum HCV RNA, followed by Simeprevir plus Peg-IFN-alpha-2b/RBV. Persistent viral clearance linked to restoration of innate immune responses and SVR were achieved 12 weeks after cessation of the treatment without virologic breakthrough or relapse and sustained biochemical response. Anemia and thrombocytopenia were managed without discontinuation of the treatment. Induction therapy with n-IFN-beta followed by Simeprevir plus Peg-IFN-alpha-2b/RBV was tolerated well and only mild adverse effects were noted. It also effectively eradicated HCV infection in a difficult-to-treat CHC patient with advanced fibrosis.

Spontaneous clearance of serum hepatitis C virus RNA during the clinical course of hepatocellular carcinoma in patients with chronic hepatitis C

Spontaneous clearance of serum hepatitis C virus (HCV) RNA in chronic HCV carriers is assumed to be rare especially after development of hepatocellular carcinoma (HCC). We analyzed patients with chronic hepatitis C who spontaneously resolved serum HCV RNA after the treatment for HCC. A database search was performed to identify patients with HCC in whom serum HCV RNA was positive before the treatment for HCC and became negative during the clinical course. Those who received interferon therapy were excluded. A total of 1145 patients with HCC who had not received interferon therapy were positive for HCV RNA before the treatment. Among them, five patients (M/F = 4/1) spontaneously resolved viremia during the clinical course, with the incidence rate of at least 0.11%/person-year (95% confidence interval: 0.05%-0.26%). The mean age at the time of negative test for HCV RNA was 77 (range: 52-84). Three and two were infected with HCV genotype 1 and 2, respectively. The mean initial viral load was 9.0 K IU/mL (range: 1.6-31.6). The alanine aminotransferase level decreased to within the normal range in all patients after the clearance of serum HCV RNA. Fibrosis grade of background liver, evaluated according to METAVIR classification, was F1 in 1, F2 in 1, F4 in 2, and unknown in 1. All patients survived more than 7 years after the initial treatment for HCC. Spontaneous clearance of serum HCV RNA after HCC development possibly occurs even in elderly patients. The prognosis was good probably due to improved inflammation in the liver.

Detection of HCV RNA in the Peripheral Blood Mononuclear Cells of Serum HCV RNA-Negative Egyptian Patients Under Interferon Treatment

IntroductionDespite recent success after the introduction of combination therapy with interferon (IFN)-α and ribavirin, approximately 60% of patients with hepatitis C virus (HCV) genotype 4 fail to respond. Resistance to antiviral therapy remains a serious problem in the management of chronic hepatitis C. In most patients, HCV RNA could be detected in peripheral blood mononuclear cell (PBMC). ObjectiveThe authors aimed to investigate the predictive value of HCV RNA in PBMC of patients with chronic hepatitis C after IFN treatment, which may act as the source of HCV reinfection of hepatic cells. MethodsSeventy patients with chronic hepatitis C were treated with IFN plus ribavirin for 48 weeks; they all achieved clearance of HCV RNA from serum. At the end of treatment, PBMC and serum were examined by real-time polymerase chain reaction for detection of HCV RNA. Six months later, HCV RNA in serum was monitored to detect sustained virologic response. ResultsAnalysis revealed the presence of detectable HCV RNA in the PBMC of 27% of patients despite clearance of serum HCV RNA. During follow-up, 80% of the patients who became serum HCV positive 6months after the end of treatment had detectable level of HCV RNA in PBMC at the end of treatment. ConclusionsThe absence of HCV in the serum of patients by the end of treatment does not exclude future viremia. The patient might still be a source of infection to others. It is strongly encouraged to test for HCV in PBMC to detect lack of response to treatment and persisting infection.

Telaprevir: A Promising Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Chronic hepatitis C affects 130,000,000 people worldwide. Hepatitis C virus (HCV) is a single-strand RNA virus responsible for most cases of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) in the Western world. The gold standard for the treatment of chronic hepatitis C (combination of pegylated-interferon alpha and ribavirin) results in a sustained virological response (namely, clearance of serum HCV RNA 6 months after therapy withdrawal) in only about half treated patients. Therefore, there is a race to develop new drugs for the treatment of HCV infection. One of the most promising approaches is to use protease inhibitors, i.e. drugs inhibiting NS3/NS4A HCV protease, which plays a crucial role in the viral life cycle. Telaprevir (VX-950) is the protease inhibitor in the most advanced phase of clinical testing. Telaprevir is orally available and when used in monotherapy it induced a median decline of 4 logs of HCV RNA after two weeks of therapy. However, mutants with a lower sensitivity to telaprevir have been demonstrated in a high proportion of patients within 14 days of monotherapy. The drug has been used in clinical trials in combination with pegylated-interferon and ribavirin. This triple combination resulted in a higher rate of SVR but also in a higher rate of side effects (rash, gastrointestinal disorders, and anemia) than standard treatment. This review focuses on the mechanism of action, pharmacokinetics, clinical efficacy, and tolerability of telaprevir, and on possible use of this drug in combination with other drugs for the treatment of HCV infection.

Risk factors for the development of hepatocellular carcinoma among patients with chronic hepatitis C who achieved a sustained virological response to interferon therapy

Hepatitis C virus (HCV)-infected patients who responded to interferon (IFN) treatment with clearance of serum HCV RNA may rarely develop hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the risk factors for liver carcinogenesis among such patients. In total, 126 patients with chronic hepatitis C (CHC) who achieved a sustained virological response (SVR) to IFN monotherapy, which was defined as the absence of detectable HCV RNA in the serum at 6 months after completion of treatment, were enrolled and possible risk factors for HCC were analyzed. During the observation period of 66 +/- 36 months after cessation of IFN treatment, five (4.0%) of the 126 patients developed HCC. The cumulative incidence of HCC at 3, 5 and 10 years was estimated to be 0.9, 4.7 and 7.5%, respectively. The cumulative incidence of HCC was significantly higher among patients with severe fibrosis (F3 or F4) than among patients with no or mild fibrosis (F0 to F2) in the liver before treatment (P = 0.007); among patients with alcohol intake of > or = 27 g/day than among patients with that of < 27 g/day (P = 0.015); and among patients who were > or = 65 years old than among patients who were < 65 years old at the start of treatment (P = 0.026). Patients with CHC who had severe fibrosis, who had regularly taken moderate amounts of alcohol, or who were > or = 65 years at the start of IFN treatment should be carefully followed to detect small and controllable HCC, even after eradication of HCV.

Long-Term Follow-Up of HIV-Infected Patients with Chronic Hepatitis C Virus Infection Treated with Interferon-Based Therapies

Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.

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.

Medicinal herbs for hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a serious health problem world-wide. Medicinal herbs are increasingly being used for hepatitis C. To assess the efficacy and safety of medicinal herbs for hepatitis C virus infection. Searches were applied to The Controlled Trial Registers of The Cochrane Hepato-Biliary Group, The Cochrane Complementary Medicine Field, and The Cochrane Library as well as MEDLINE, EMBASE, BIOSIS, Chinese and Japanese databases. Five Chinese journals and one Japanese journal were handsearched. No language restriction was used. Randomised clinical trials comparing medicinal herbs (single herb or compound of herbs) versus placebo, no intervention, general non-specific treatment, other herbal medicine, or interferon and/or ribavirin treatment. Trials of medicinal herbs plus interferon and/or ribavirin versus interferon and/or ribavirin alone were also included. Trials could be double-blind, single-blind, or unblinded. Data were extracted independently by two reviewers. The methodological quality of the trials was evaluated using the generation of allocation sequence, allocation concealment, double blinding, and the Jadad-scale. The outcomes were presented as relative risk or weighted mean difference, both with 95% confidence interval. Ten randomised trials, including 517 patients with mainly chronic hepatitis C, evaluated ten different medicinal herbs versus various control interventions (four placebo, four interferon, two other herbs). The methodological quality was considered adequate in four trials and inadequate in six trials. Compared with placebo in four trials, none of the medicinal herbs showed positive effects on clearance of serum HCV RNA or anti-HCV antibody or on serum liver enzymes, except one short-term trial in which a silybin preparation showed a significant effect on reducing serum aspartate aminotransferase and gamma-glutamyltranspeptidase activities. The herbal compound Bing Gan Tang combined with interferon-alpha showed significantly better effects on clearance of serum HCV RNA (relative risk 2.54; 95% confidence interval 1.43 to 4.49) and on normalisation of serum alanine aminotransferase activity (relative risk 2.54; 95% confidence interval 1.43 to 4.49) than interferon-alpha monotherapy. The herbal compound Yi Zhu decoction showed a significant effect on clearance of serum HCV RNA and normalisation of ALT levels compared to glycyrrhizin plus ribavirin. Yi Er Gan Tang showed a significant effect on normalising serum alanine aminotransferase compared to silymarin plus glucurolactone. There was no significant efficacy of the other examined herbs. The herbs were associated with adverse events. There is no firm evidence of efficacy of any medicinal herbs for HCV infection. Medicinal herbs for HCV infection should not be used outside randomised clinical trials.

An open-label trial of consensus interferon 15 μg in the treatment of Chinese patients with chronic hepatitis C

Consensus interferon (CIFN), a novel recombinant type 1 interferon (IFN), has been used recently to treat patients with chronic hepatitis C virus (HCV) infection. CIFN 9 μg, given subcutaneously 3 times a week for 24 weeks, offers sustained biochemical and virological responses in 32% of Chinese patients studied in Taiwan. Whether a higher dosage of CIFN will have greater efficacy is of clinical interest. This open-label trial was conducted to determine the efficacy and safety of CIFN 15 μg, given subcutaneously 3 times a week for 24 weeks, in 35 Chinese patients with chronic hepatitis C who in a previous randomized, controlled CIFN trial received placebo ( n=16) or showed no sustained response to CIFN 3 μg ( n=14) or 9 μg ( n=5), 3 times a week for 24 weeks. Efficacy was assessed by normalization of serum alanine transaminase (ALT) levels and clearance of serum HCV RNA to undetectable levels as measured by reverse-transcription polymerase chain reaction (RT-PCR). Results showed 14 of 35 patients (40%) achieved normalized serum ALT and cleared serum HCV RNA at the end of treatment, and 11 patients (31%) maintained a sustained response 24 weeks after treatment was discontinued. The sustained response rate was 31% in patients who had received a placebo injection in the previous trial, 36% in patients who had relapsed or not responded to previous CIFN 3 μg treatment, and 20% in patients who had relapsed or not responded to previous CIFN 9 μg treatment ( P>0.05). Upon re-treatment with CIFN 15 μg, sustained response was achieved in two of three patients who had relapsed from previous CIFN 3 μg treatment and in one of three patients who had relapsed from previous CIFN 9 μg treatment. CIFN 15 μg re-treatment achieved a sustained response in three of eleven patients and in none of two patients who were non-responders from previous CIFN 3 μg or CIFN 9 μg treatments respectively. Patients tolerated the treatment well, but two patients withdrew from the study due to intolerable side effects. In conclusion, subcutaneous injection of CIFN 15 μg, 3 times a week for 24 weeks, showed a similar efficacy as CIFN 9 μg 3 times a week treatment in Chinese patients with chronic hepatitis C. The treatment may benefit patients who have relapsed from a previous 3 μg or 9 μg treatment.

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon

Background/Aims: This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-in-fected patients who respond to interferon treatment with clearance of serum HCV RNA. Methods: We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994. Results: At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5–8.8 years (mean±SD, 5.4±1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1–8.7 years (mean±SD, 5.0±1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients. Conclusion: In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

Serum Hyaluronan as a Marker of Liver Fibrosis in Hemophiliacs with Hepatitis C Virus-Associated Chronic Liver Disease

We measured serum type III procollagen peptide, type IV collagen (IV-C), and hyaluronan (HA) in 36 hemophiliacs with hepatitis C virus (HCV)-related chronic liver disease. We also measured these markers in 19 interferon (IFN)-treated patients before and after a 6-month course of IFN-α. The serum concentrations of IV-C and HA were correlated with the stage of fibrosis (IV-C r = 0.38; HA r = 0.78). These markers fell only in complete responders showing sustained clearance of serum HCV RNA by IFN. These results suggest that, in hemophiliacs with chronic liver disease, serum HA measurement might be an alternative to liver biopsy and reflect the response to IFN.