Vitamin D improves viral response in hepatitis C genotype 2-3 nave patients

AIM: To examine whether vitamin D improved viral response and predicted treatment outcome in patients with hepatitis C virus (HCV) genotype 2-3. METHODS: Fifty patients with chronic HCV genotype 2-3 were randomized consecutively into two groups: Treatment group [20 subjects, age 48 ± 14 years, body mass index (BMI) 30 ± 6, 65% male], who received 180 μg pegylated α-interferon-2a plus oral ribavirin 800 mg/d (Peg/RBV), together with oral vitamin D3 (Vitamidyne D drops; 2000 IU/d, 10 drops/d, normal serum level > 32 ng/mL) for 24 wk; and control group (30 subjects, age 45 ± 10 years, BMI 26 ± 3, 60% male), who received identical therapy without vitamin D. HCV RNA was assessed by reverse transcription polymerase chain reaction. Undetectable HCV RNA at 4, 12 and 24 wk after treatment was considered as rapid virological response, complete early virological response, and sustained virological response (SVR), respectively. Biomarkers of in? ammation were measured. RESULTS: The treatment group with vitamin D hadhigher BMI (30 ± 6 vs 26 ± 3, P < 0.02), and high viral load (> 400 000 IU/mL, 65% vs 40%, P < 0.01) than controls. Ninety-fi ve percent of treated patients were HCV RNA negative at week 4 and 12. At 24 wk after treatment (SVR), 19/20 (95%) treated patients and 23/30 (77%) controls were HCV RNA negative (P < 0.001). Baseline serum vitamin D levels were lower at baseline (20 ± 8 ng/mL) and increased after 12 wk vitamin D treatment, to a mean level of (34 ± 11 ng/ mL). Logistic regression analysis identifi ed vitamin D supplement [odds ratio (OR) 3.0, 95% CI 2.0-4.9, P < 0.001], serum vitamin D levels (< 15 or > 15 ng/mL, OR 2.2, P < 0.01), and BMI (< 30 or > 30, OR 2.6, P < 0.01) as independent predictors of viral response. Adverse events were mild and typical of Peg/RBV. CONCLUSION: Low vitamin D levels predicts negative treatment outcome, and adding vitamin D to conventional Peg/RBV therapy for patients with HCV genotype 2-3 signifi cantly improves viral response.

Interferon alpha plus ribavirin combination treatment of Japanese chronic hepatitis C patients with HCV genotype 2:A project of the Kyushu University Liver Disease Study Group

AIM： To determine the efficacy of an interferon alpha and ribavirin combination treatment for Japanese patients infected with hepatitis C virus （HCV） of genotype 2, a multi-center study was retrospectively analyzed. METHODS： In total, 173 patients with HCV genotype 2 started to receive interferon-alpha subcutaneously thrice a week and 600-800 mg of ribavirin daily for 24 wk. RESULTS： The overall sustained virological response （SVR）, defined as undetectable HCV RNA in serum, 24 wk after the end of treatment, was remarkably high by 84.4%, （146/173） by an intention-to-treat analysis. A significant difference in SVR was found between patients with and without the discontinuation of ribavirin （46.9% vs 92.9 %）, but no difference was found between those with and without a dose reduction of ribavirin. A significant difference in SVR was also found between patients with less than 16 wk and patients with 16 or more weeks of ribavirin treatment （34.8 % vs 92.0 %）. CONCLUSION： The 24-wk interferon and ribavirin treatment is highly effective for Japanese patients with HCV genotype 2. The significant predictor of SVR is continuation of the ribavirin treatment for up to 16

Four-week pegylated interferon a-2a monotherapy for chronic hepatitis C with genotype 2 and low viral load:A pilot,randomized study

AIM:To assess the efficacy and advantages of 4-wk pegylated interferon a-2a(peg-IFN-a2a) monotherapy for chronic hepatitis C patients with strong predictors of sustained virologic response(SVR).METHODS:Patients(n = 33) with genotype 2 and low viral load(< 100 KIU/mL),who became HCV RNA negative after 1 wk of IFN treatment,were randomly allocated to receive a 4-or 12-wk treatment course at a ratio of 2:1,respectively,with a subsequent 24-wk follow-up period.Peg-IFN-a2a was administered subcutaneously at a dose of 180 μg or 90 μg once weekly.SVR was defined as absence of serum HCV RNA at the end of the follow-up period.RESULTS:All patients completed the treatment schedule,and more than half were symptom-free during the treatment.In the 4-wk treatment group,20 of 22(91%) patients achieved SVR.Two patients relapsed,but achieved SVR following re-treatment with peg-IFN-a2a alone.In the 12-wk treatment group,11 of 11(100%) patients attained SVR.CONCLUSION:Our results show that a 4-wk course of peg-IFN-a2a monotherapy can achieve a high SVR rate in "IFN-sensitive" patients,without negatively affecting outcome.

Randomized controlled trial of consensus interferon with or without zinc for chronic hepatitis C patients with genotype 2

AIM： The beneficial effect of zinc supplementation on the efficacy of interferon as a treatment for chronic hepatitis C had been demonstrated in hepatitis virus genotype lb of high viral load. This study focused on patients with genotype 2, which is more sensitive to interferon than genotype lb, and used consensus interferon （CIFN） with or without zinc. METHODS： We randomized 83 patients with chronic hepatitis C to CIFN at 18 MIU six times/wk for 4 wk, followed by CIFN at 18 MIU six times/wk for another 20 wk, in combination with polaprezinc 300 mg （regimen A, n = 41） or as monotherapy （regimen B, n = 42）. Thirtyone patients in regimen A and 33 patients in regimen B completed the clinical trial; the remaining patients withdrew because of side effects or a transfer to another hospital. RESULTS： Sustained biochemical response, defined as a normal aminotransferase level at the end of the 6-too post-treatment observation, was 68% and 69%, and sustained virological response, defined as undetectable HCV-RNA at the end of the 6-too post-treatment observation, was 54% and 67% for regimens A and B, respectively. CONCLUSION： CIFN treatment combined with zinc did not enhance the effect of CIFN as shown by biochemical, virological criteria. No side effects related to polaprezinc were noted.

Treatment of genotype 2 and 3 chronic hepatitis C virus-infected patients

AIM： Before pegylated interferon alpha （IFN） was introduced for the therapy of chronic hepatitis C virus （HCV）-induced hepatitis, conventional thrice weekly IFN therapy was supplemented by ribavirin. Also, at that time, higher and more frequent doses of IFN were expected to be more effective than the standard regimen of 3 MU thrice weekly. As ribavirin significantly increases side effects and negatively influences the quality of life particularly in young patients, we started a prospective non-randomized study with a daily IFN-2a monotherapy as an initial treatment for chronic hepatitis C. METHODS： Forty-six consecutive chronic HCV-infected patients received 3 MU IFN-2a per day as an initial treatment. Patients with genotype 2 or 3 （n = 12） were treated for 24 wk, and patients with genotypes other than 2 or 3 （n = 34） for 48 wk. Treatment outcome was followed up for 48 wk after the end of treatment （EOT）. Virological response was defined as the absence of detectable serum HCV-RNA. Patients without virological response at 12 wk after the start of treatment received low-dose ribavirin （10 mg（kg·d）） additionally. RESULTS： During treatment, three genotype 3 patients were excluded from the study due to incompliance. The remaining patients （n = 9） infected with genotype 2 or 3 showed an initial virological response rate of 100%. Six patients （66.7%） were still found to be virus-free at the end of follow-up period. In these patients, initial virological response was evident already after 2 wk of treatment. In contrast, initial virological response occurred first after 4 wk of treatment in the three patients who relapsed （33.3%）. In comparison, patients infected with genotypes other than 2 or 3 （n = 34） showed an initial virological response rate of only 23.5% （n = 8）, and even in combination with ribavirin a sustained virological response （SVR） rate of only 11.8% （n = 4） could be achieved. CONCLUSION： In chronic HCV-infected patients with genotype 2 or 3, a SVR can be expected after 24 wk of daily dose IFN-2a treatment without ribavirin, if initial virological response develops early. This finding is worth to be confirmed in a prospective randomized study with pegylated IFN.

Locked nucleic acid real-time polymerase chain reaction method identifying two polymorphisms of hepatitis B virus genotype C2 infections,rt269L and rt269I

BACKGROUND The presence of two distinct hepatitis B virus(HBV)Pol RT polymorphisms,rt269L and rt269I,could contribute to the unique clinical or virological phenotype of HBV genotype C2.Therefore,a simple and sensitive method capable of identifying both types in chronic hepatitis B(CHB)patients infected with genotype C2 should be developed.AIM To develop a novel simple and sensitive locked nucleic acid(LNA)-real timepolymerase chain reaction(RT-PCR)method capable of identifying two rt269 types in CHB genotype C2 patients.METHODS We designed proper primer and probe sets for LNA-RT-PCR for the separation of rt269 types.Using synthesized DNAs of the wild type and variant forms,melting temperature analysis,detection sensitivity,and endpoint genotyping for LNA-RT-PCR were performed.The developed LNA-RT-PCR method was applied to a total of 94 CHB patients of genotype C2 for the identification of two rt269 polymorphisms,and these results were compared with those obtained by a direct sequencing protocol.RESULTS The LNA-RT-PCR method could identify two rt269L and rt269I polymorphisms of three genotypes,two rt269L types[‘L1’(WT)and‘L2’]and one rt269I type(‘I’)in single(63 samples,72.4%)or mixed forms(24 samples,27.6%)in 87(92.6%sensitivity)of 94 samples from Korean CHB patients.When the results were compared with those obtained by the direct sequencing protocol,the LNA-RT-PCR method showed the same results in all but one of 87 positive detected samples(98.9%specificity).CONCLUSION The newly developed LNA-RT-PCR method could identify two rt269 polymorphisms,rt269L and rt269I,in CHB patients with genotype C2 infections.This method could be effectively used for the understanding of disease progression in genotype C2 endemic areas.

Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome:A case report and review of the literature

BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiopathic jaundice as the main clinical manifestation.Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS;however,the causative ABCC2 point mutation in Chinese patients remains unknown.Research on ABCC2 mutations in Chinese DJS patients is extremely rare,and the diagnosis of DJS remains limited.The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS.Here,we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient.This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses.ABCC2 mutations were identified by next-generation sequencing(NGS).The patient showed intermittent jaundice and conjugated hyperbilirubinemia.Histopathological examinations were consistent with the typical phenotype of DJS.Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant,namely c.2443C>T(p.Arg815*),which has not been reported previously in the domestic or foreign literature.CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS,especially in patients with atypical presentations.Currently,NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.

Prediction of Crohn's disease aggression through NOD2/CARD15 gene sequencing in an Australian cohort

AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn&#x02019;s disease (CD) to identify patients who would benefit from early aggressive medical intervention.

Sofosbuvir plus ribavirin is tolerable and effective even in elderly patients 75-years-old and over

BACKGROUND Although clinical use of sofosbuvir plus ribavirin has been approved for patients infected with genotype 2 hepatitis C virus,patients≥75-years-old have not been included in previous clinical trials.AIM To evaluate the real-world safety and efficacy of sofosbuvir plus ribavirin for elderly patients(≥75-years-old)compared to nonelderly patients,we conducted a post-marketing prospective cohort study.METHODS We treated 265 patients with genotype 2 hepatitis C virus using standard approved doses of sofosbuvir(400 mg/d)plus ribavirin adjusted by body weight,administered orally for 12 wk.RESULTS Sustained virological response rates for the overall cohort,patients<65-years-old,≥65-years-old but<75-years-old,and≥75-years-old were 97%(258/265),98%(93/95),97%(84/87),and 98%(81/83),respectively(P=0.842).Logistic regression analyses identified history of hepatocellular carcinoma treatment and alpha-fetoprotein as factors significantly associated with sustained virological response.Alpha-fetoprotein was the only independent factor identified.Sustained virological response rate was significantly lower for patients with hepatocellular carcinoma treatment(91%)than for patients without history of hepatocellular carcinoma treatment(98%,P=0.004).One patient(0.4%)discontinued treatment due to drug-induced pneumonia.Dose reduction or interruption of ribavirin was required for 12.1%(32/265)of patients because of anemia,including 7.7%(14/182)of patients<75-years-old and 21.7%(18/83)of patients≥75-years-old(P=0.002).CONCLUSION Although ribavirin dose reduction or interruption was required with advanced age,sofosbuvir plus ribavirin appears tolerable and highly effective even in patients≥75-years-old.

Hepatitis B virus mutations related to liver disease progression of Korean patients

Hepatitis B virus(HBV)infection is a global health problem and more than 350 million people worldwide are chronic carriers of the virus.Despite the recent dramatic decline in HBV chronic patients through successful programs of hepatitis B surface antigen vaccination,South Korea is still recognized as an endemic area of HBV infection.HBV infections in South Korea exhibit several distinct features in epidemiologic and clinical aspects.In this review paper,we summarize the distinct HBV mutation patterns related to clinical severity and the molecular epidemiologic traits in Korean chronic patients based on previous reports.Generally,several lines of evidence,including our previous results,have led to the conclusion that a combination of the exclusive predominance of genotype C2,which is prone to mutations,the high prevalence of basal core promoter double mutations,and the presence of distinct immune responses against HBV proteins in the Korean population may generate the distinct HBV variants rarely or not encountered in other areas,which results in distinct clinical manifestations in Korean chronic patients.This may provide a novel insight into the relationships between clinical severity,HBV genotype distribution,and HBV naturally occurring variants.

Remission of hepatotoxicity in chronic pulmonary aspergillosis patients after lowering trough concentration of voriconazole

BACKGROUND Chronic pulmonary aspergillosis(CPA)is a rare syndrome that is often accompanied by gradual lung tissue destruction.Voriconazole is usually employed as the first-line agent for CPA treatment.However,some patients can develop hepatotoxicity and often were forced to stop voriconazole treatment.AIM To record the improving trend of liver function and the therapeutic effects in patients after lowering the trough concentration of voriconazole.METHODS This study retrospectively analyzed 12 adult CPA patients who developed hepatotoxicity during the voriconazole treatment.In these patients,the oral dose was reduced to 3/4 or 1/2 of the standard dose(4 mg/kg,twice daily),and the lower limit of voriconazole trough concentration was maintained more than 0.5μg/m L.The trend of remission of liver toxicity after drug reduction in 12 patients was recorded.During the same period,25 patients who received standard doses served as the control group.Data from the two groups were collected and analyzed for different parameters such as demographic characteristics,underlying pulmonary disorders,laboratory tests,and therapeutic effect.The differences between the two groups were statistically compared.RESULTS Hepatotoxicity occurred in 12 patients within 28-65 d after oral voriconazole treatment.Hepatotoxicity was mainly manifested by the significantly increased level of gamma-glutamyltransferase and a slight increase of alanine aminotransferase and aspartate aminotransferase.The oral dose of voriconazole was reduced to approximately 3 mg/kg in seven patients and approximately 2 mg/kg in five patients.The average trough concentrations for the 12 patients before and after voriconazole oral dose reduction were 3.17±1.47μg/m L(1.5-6.0μg/m L)and 1.70±0.78μg/m L(0.6-3.3μg/m L),respectively(P=0.02).After lowering the trough concentrations,the hepatotoxicity was alleviated in all the patients.However,gamma-glutamyltransferase levels declined slowly.After 4 mo of treatment,7 of the 12 patients were successfully treated in the low trough concentrations group(41.7%).Similarly,8 of the 25 patients in the standard treatment dose group(32.0%)were effectively treated.There was no statistical difference between the groups(P=0.72).CONCLUSION Reducing the lower limit of the voriconazole trough concentration to 0.5μg/m L can alleviate the hepatotoxicity and maintained certain clinical efficacy in CPA patients;however,patients should be closely monitored.

High-resolution linkage and quantitative trait locus mapping using an interspecific cross between Argopecten irradians irradians(♀) and A. purpuratus (♂)

The bay scallop and Peruvian scallop are economically important species.Interspecific hybrids of these two scallops outperformed both of their parent species in multiple growth traits but exhibited decreased fertility,which provides good models for the study of heterosis and species divergence.Genetic mapping serves as a chromosomal-level framework to investigate the molecular mechanisms of hybridization and introgression.In this study,high-resolution linkage maps were constructed for the bay and Peruvian scallops with an interspecific hybrid family.The linkage map of the bay scallop covered over 98.9% of the whole genome with 2994 mapped markers and the average marker interval of 0.32 cM.For the Peruvian scallop,1585 markers were mapped with the average maker interval of 0.51 cM,covering 97.7% of the genome.Both the two linkage maps have 16 linkage groups,corresponding to the haploid chromosome number of the two species.Approximately,54.5% of markers exhibited significant deviation from the expected Mendelian ratio of segregation,lending in sights into the intrinsic incompatibility between the two species.QTLs related to growth and shell coloration were detected,which could explain 13.1%and 74.9% of the phenotypic variance,respectively.This represents important information for further evaluation.These findings are an important addition to the genomic resources for scallop genetic studies,and are especially useful for investigations on genomic incompatibility for hybridization,genome evolution of closely related species,and genetic enhancement programs in aquaculture.

Analysis of the effect of HCV resistance-associated substitutions on the short-term efficacy of DAA after single administration in three phase Ib clinical trials

As crucial factors in hepatitis C virus(HCV)management,resistance-associated substitutions(RASs)are associated with the treatment outcome of some direct-acting antiviral(DAA)-based regimens.In this study,we mainly analyzed the impact of baseline Y93 H or Y93 Y/H on the short-term efficacy after single administration of NS5 A inhibitors in three phaseⅠb clinical trials(yimitasvir phosphate,KW-136 and fopitasvir),and analyzed the prevalence of baseline RASs and treatment-emergent RASs.A total of 94 treatment-naive HCV genotype(GT)-1 b(n=63)and GT-2 a(n=31)Chinese patients were enrolled in three phase lb clinical trials.We investigated RASs in 77 patients with next generation or Sanger sequencing.In the 7-day trial of yimitasvir phosphate,the mean maximum HCV RNA decrease of patients with baseline Y93 H or Y93 Y/H was lower than that of patients without the mutation in the 30 mg and 200 mg cohorts(0.83 vs.2.45 log10 IU/mL and 1.92 vs.2.63 log10 IU/mL).In the3-day trial of KW-136,the mean maximum HCV RNA decrease in patients with baseline Y93 H or Y93 Y/H was lower than that of patients without the mutation in the 30,60 and 120 mg cohorts(1.58 vs.2.89 log10 IU/mL,3.16 vs.4.09 log10 IU/mL and3.00 vs.5.04 log10 IU/mL,respectively).In the 3-day trial of fopitasvir,only 30 mg group had baseline Y93 H or Y93 Y/H,and the average maximum HCV RNA decrease of patients with baseline Y93 H or Y93 Y/H was lower than that of patients without the mutation(1.45 vs.3.59 log10 IU/mL).In the three trials,baseline RASs were observed in 54 patients(70.1%;54/77).The most prevalent baseline RASs were Y93 H and Y93 Y/H(18.2%;14/77),followed by L3 IM(16.9%;13/77).The most common RASs after single administration of DAA were Y93 H and Y93 Y/H.Our data could provide reference for future clinical treatment and clinical trial.