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1.  Effect of Retreatment with Interferon Alone or Interferon plus Ribavirin on Hepatitis C Virus Quasispecies Diversification in Nonresponder Patients with Chronic Hepatitis C 
Journal of Virology  1999;73(9):7241-7247.
Alpha interferon (IFN-α) treatment is effective on a long-term basis in only 15 to 25% of patients with chronic hepatitis C. The results of recent trials indicate that response rates can be significantly increased when IFN-α is given in combination with ribavirin. However, a large number of patients do not respond even to combination therapy. Nonresponsiveness to IFN is characterized by evolution of the hepatitis C virus (HCV) quasispecies. Little is known about the changes occurring within the HCV genomes when nonresponder patients are retreated with IFN or with IFN plus ribavirin. In the present study we have examined the genetic divergence of HCV quasispecies during unsuccessful retreatment with IFN or IFN plus ribavirin. Fifteen nonresponder patients with HCV-1 (4 patients with HCV-1a and 11 patients with HCV-1b) infection were studied while being retreated for 2 months (phase 1) with IFN-α (6 MU given three times a week), followed by IFN plus ribavirin or IFN alone for an additional 6 months (phase 2). HCV quasispecies diversification in the E2 hypervariable region-1 (HVR1) and in the putative NS5A IFN sensitivity determining region (ISDR) were analyzed for phase 1 and phase 2 by using the heteroduplex tracking assay and clonal frequency analysis techniques. A major finding of this study was the relatively rapid evolution of the HCV quasispecies observed in both treatment groups during the early phase 1 compared to the late phase 2 of treatment. The rate of quasispecies diversification in HVR1 was significantly higher during phase 1 versus phase 2 both in patients who received IFN plus ribavirin (P = 0.017) and in patients who received IFN alone (P = 0.05). A trend toward higher rates of quasispecies evolution in the ISDR was also observed during phase 1 in both groups, although the results did not reach statistical significance. However, the NS5A quasispecies appeared to be rather homogeneous and stable in most nonresponder patients, suggesting the presence of a single well-fit major variant, resistant to antiviral treatment, in agreement with published data which have identified an IFN sensitivity determinant region within the NS5A. During the entire 8 months of retreatment, there was no difference in the rate of fixation of mutation between patients who received combination therapy and patients who were treated with IFN alone, suggesting that ribavirin had no major effects on the evolution of the HCV quasispecies after the initial 2 months of IFN therapy.
PMCID: PMC104248  PMID: 10438811
2.  Higher clearance of hepatitis C virus infection in females compared with males 
Gut  2006;55(8):1183-1187.
Background and aims
According to the literature, 14–46% of subjects clear hepatitis C virus (HCV) from blood after infection. Controversy exists about sex differences in HCV clearance rates.
Patients and methods
We compared HCV clearance in males and females using data from a large population based study on HCV infection in Egypt. Definitions used in the paper were: cleared HCV infection (positive HCV antibody and negative HCV RNA test results) and chronic HCV infection (positive HCV antibody and positive HCV RNA test results). The study sample included 4720 village residents aged 18–65 years recruited through home based visits (n = 2425) or voluntary screening (n = 2295).
Overall, HCV antibody prevalence was 910/4720 (19.3% (95% confidence interval 18.2–20.4)). Of those with HCV antibodies (n = 910), 61.5% had chronic HCV infection. Compared with males, females were more likely to have cleared the virus (44.6% v 33.7%, respectively; p = 0.001). Control for age, schistosomiasis history, iatrogenic exposures, and sexual exposure to HCV did not alter the positive association between female sex and viral clearance.
This study provides strong evidence in favour of a higher HCV clearance rate in females compared with males.
PMCID: PMC1856273  PMID: 16434426
hepatitis C virus; natural history; epidemiology
3.  Prevalence of Occult Hepatitis B Virus in Plasma and Peripheral Blood Mononuclear Cell Compartments of Patients With Chronic Hepatitis C Infection in Tehran-Iran 
Hepatitis Monthly  2013;13(5):e10134.
Occult hepatitis B virus (HBV) infection (OBI) is frequently reported in patients with chronic hepatitis C virus (HCV) infection. An association between OBI and more liver damage, cirrhosis, hepatocellular carcinoma, and reduced response to interferon therapy in patients with HCV infection is suggested.
The aim of this study was to determine the prevalence of occult HBV, and evaluate its clinical influence on patients with chronic HCV.
Patients and Methods
A cohort study including50 patients with positive results for HCV, and negative results for HBsAg tests was performed. The patients were divided into two groups: one group had positive results for both HCV and occult HBV tests (n = 18), and the other had positive results for HCV, but negative findings for occult HBV (n = 32). All were treated with PEG-IFN alpha-2a and Ribavirin. Presence of HCV RNA was followed in these patients.
HBV-DNA was detected using nested-PCR in 20% of plasma and 32.6% of peripheral blood mononuclear cell (PBMC) compartments. No significant differences were observed between patients with and without occult HBV for sex, age, duration of HCV infection, histological markers, presence of anti-HBc, HCV viral load, and HCV genotype. The response rate was significantly higher in patients with positive results for HBV-DNA test compared to those with negative findings (100% vs. 71.9 %, P < 0.05).
In conclusion, occult HBV was found in 36% of patients with negative results for HBsAg, but positive results for HCV. Detection of HBV-DNA in both PBMCs and plasma together in comparison with plasma alone provided more true identification of OBI.The SVR rate was significantly higher in coinfected patients than mono-infected ones.
PMCID: PMC3741907  PMID: 23967017
Hepatitis B; Hepatitis C Virus; Peripheral Blood Mononuclear Cell
4.  Prevalence and Seroincidence of Hepatitis B and Hepatitis C Infection in High Risk People Who Inject Drugs in China and Thailand 
We determined the prevalence and incidence of HBV and HCV infection in people who inject drugs (PWIDs) at high risk for HIV in China and Thailand and determined the association of HBV and HCV incidence with urine opiate test results and with short-term versus long-term buprenorphine-naloxone (B-N) treatment use in a randomized clinical trial (HPTN 058). 13.8% of 1049 PWIDs in China and 13.9% of 201 PWIDs in Thailand were HBsAg positive at baseline. Among HBsAg negative participants, the HBsAg incidence rate was 2.7/100 person years in China and 0/100 person years in Thailand. 81.9% of 1049 PWIDs in China and 59.7% of 201 in Thailand were HCV antibody positive at baseline. The HCV confirmed seroincidence rate among HCV antibody negative PWIDs was 22/100 person years in China and 4.6/100 person years in Thailand. Incident HBsAg was not significantly different in the short-term versus long-term B-N arm in China or Thailand. Participants with positive opiate results in at least 75% of their urines during the time period were at increased risk of incident HBsAg (HR = 5.22; 95% CI, 1.08 to 25.22; P = 0.04) in China, but not incident HCV conversion in China or Thailand.
PMCID: PMC3985324  PMID: 24860664
5.  Factors Associated with Seronegative Chronic Hepatitis C Virus Infection in HIV Infection 
Chronic seronegative hepatitis C virus (HCV) infection is defined as being HCV antibody (anti-HCV) negative, but HCV RNA positivity occurs in individuals infected with human immunodeficiency virus (HIV). However, associated factors are not well established because of the small number of reported cases.
Multivariate logistic regression analysis of HIV-infected subjects from 4 cohorts (Tien et al., 2006; Bonacini et al., 2001; George et al., 2002; and Hall et al., 2004) determined factors associated with HCV RNA positivity in anti-HCV–negative subjects. HCV enzyme immunoassay 2.0 was used to determine anti-HCV status.
Among 1174 anti-HCV–negative, HIV-infected subjects, the prevalence of seronegative HCV infection was 3.2% (95% confidence interval [CI], 2.2%–4.3%). History of injection drug use (IDU; OR, 5.8; 95% CI, 2.7–12.8), higher alanine aminotransferase (ALT) level (OR, 2.0 per doubling; 95% CI, 1.3–3.2), and CD4 cell count <200 cells/μL (OR, 2.3; 95% CI, 1.1–4.8) were associated with HCV RNA positivity in anti-HCV–negative subjects. Among those with a history of IDU who had either a CD4 cell count <200 cells/μL or an ALT level greater than the upper limit of normal, the prevalence of seronegative HCV infection was 24% (95% CI, 13%–39%).
Detectable HCV RNA in the context of a negative HCV enzyme immunoassay 2.0 result in HIV-infected patients is low, but higher than the reported prevalence in HIV-uninfected patients. Our findings suggest that HCV RNA testing should be performed in anti-HCV–negative, HIV-infected patients, especially those with a history of IDU and either a CD4 cell count <200 cells/μL or an abnormal ALT level.
PMCID: PMC3170414  PMID: 17243063
6.  Sustained virological response: A milestone in the treatment of chronic hepatitis C 
AIM: To evaluate the long-term eradication of hepatitis C virus (HCV) infection and liver-related complications in chronically infected patients that have achieved sustained virological response.
METHODS: One hundred and fifty subjects with chronic hepatitis C (CHC) or cirrhosis and sustained virological response (SVR) between the years of 1989 and 2008 were enrolled in a long-term clinical follow-up study at the Gastrointestinal and Liver Unit of the University Hospital of Naples “Federico II”. At the beginning of the study, the diagnosis of HCV infection was made on the basis of serum positivity for antibodies to HCV and detection of HCV RNA transcripts, while a diagnosis of chronic hepatitis was formulated using imaging techniques and/or a liver biopsy. SVR was achieved by interferon-based therapy, both conventional and pegylated, with and without ribavirin treatment. The patients were evaluated for follow-up at a median length of 8.6 years, but ranged from 2-19.9 years. Among them, 137 patients had pre-treatment CHC and 13 had cirrhosis. The patients were followed with clinical, biochemical, virological, and ultrasound assessments on a given schedule. Finally, a group of 27 patients underwent a liver biopsy at the beginning of the study and transient elastography at their final visit to evaluate changes in liver fibrosis.
RESULTS: The median follow-up was 8.6 years (range 2-19.9 years). HCV RNA remained undetectable in all patients, even in patients who eventually developed liver-related complications, indicating no risk of HCV recurrence. Three liver-related complications were observed: two cases of hepatocellular carcinoma and one case of bleeding from esophageal varices resulting in an incidence rate of 0.23%/person per year. Further, all three complications took place in patients diagnosed with cirrhosis before treatment began. Only one death due to liver-related causes occurred, resulting in a mortality rate of 0.077% person per year. This amounts to a 99.33% survival rate in our cohort of patients after therapy for HCV infection. Finally, of the 27 patients who underwent a liver biopsy at the beginning of the study, a reduction in liver fibrosis was observed in 70.3% of the cases; only three cases registering values of liver stiffness indicative of significant fibrosis.
CONCLUSION: Patients with CHC and SVR show an excellent prognosis with no risk of recurrence and a very low rate of mortality. Our data indicate that virus-eradication following interferon treatment can last up to 20 years.
PMCID: PMC3653153  PMID: 23687416
Antiviral therapy; Cirrhosis; Hepatitis C virus; Sustained virological response; Fibrosis
7.  Epidemiology and long term prognosis of hepatitis C virus infection in Japan. 
Gut  1993;34(2 Suppl):S13-S16.
In Japanese blood donors, positivity for antibodies to hepatitis C virus (HCV) ranges from 0.2% in subjects under 20 to 3.9% in those over 50 years. It is estimated that at least 2.3 million Japanese have contracted HCV infection through contaminated blood. HCV carrier state was confirmed by polymerase chain reaction for HCV-RNA in subjects positive for antibodies to more than one viral protein (70% of cases). Subjects positive for core antibody alone, however, were found to be HCV-RNA negative with normal liver function, and are considered to have only a past history of HCV infection (30% of cases). Acute hepatitis C progresses to chronic infection in about 90% of cases. In comparison with hepatitis B, chronic hepatitis C leads more frequently to cirrhosis and liver cancer, and rarely remits spontaneously. In typical HCV infection, aminotransferase activities fluctuate markedly in the early stages, then become relatively stable for 10 years or more, with chronic persistent hepatitis shown by histological examination. Thereafter, aminotransferase activities may change dramatically, with progression to chronic active hepatitis and rapid development of cirrhosis and hepatocellular carcinoma. On average, it takes about 30 years for chronic hepatitis C to progress from initial infection to cirrhosis and cancer, but the disease progresses much more rapidly in elderly patients.
PMCID: PMC1373997  PMID: 7686112
8.  Coinfection with hepatitis C virus and schistosomiasis: Fibrosis and treatment response 
AIM: To assess whether schistosomiasis coinfection with chronic hepatitis C virus (HCV) influences hepatic fibrosis and pegylated-interferon/ribavirin (PEG-IFN/RIB) therapy response.
METHODS: This study was designed as a retrospective analysis of 3596 chronic HCV patients enrolled in the Egyptian National Program for HCV treatment with PEG-IFN/RIB. All patients underwent liver biopsy and anti-schistosomal antibodies testing prior to HCV treatment. The serology results were used to categorize the patients into group A (positive schistosomal serology) or group B (negative schistosomal serology). Patients in group A were given oral antischistosomal treatment (praziquantel, single dose) at four weeks prior to PEG-IFN/RIB. All patients received a 48-wk course of PEG-IFN (PEG-IFNα2a or PEG-IFNα2b)/RIB therapy. Clinical and laboratory follow-up examinations were carried out for 24 wk after cessation of therapy (to week 72). Correlations of positive schistosomal serology with fibrosis and treatment response were assessed by multiple regression analysis.
RESULTS: Schistosomal antibody was positive in 27.3% of patients (15.9% females and 84.1% males). The patients in group A were older (P = 0.008) and had a higher proportion of males (P = 0.002) than the patients in group B. There was no significant association between fibrosis stage and positive schistosomal serology (P = 0.703). Early virological response was achieved in significantly more patients in group B than in group A (89.4% vs 86.5%, P = 0.015). However, significantly more patients in group A experienced breakthrough at week 24 than patients in group B (36.3% vs 32.3%, P = 0.024). End of treatment response was achieved in more patients in group B than in group A (62.0% vs 59.1%) but the difference did not reach statistical significance (P = 0.108). Sustained virological response occurred in significantly more patients in group B than in group A (37.6% vs 27.7%, P = 0.000). Multivariate logistic regression analysis of patient data at treatment weeks 48 and 72 showed that positive schistosomal serology was associated with failure of response to treatment at week 48 (OR = 1.3, P = 0.02) and at week 72 (OR = 1.7, P < 0.01).
CONCLUSION: Positive schistosomal serology has no effect on fibrosis staging but is significantly associated with failure of response to HCV treatment despite antischistosomal therapy.
PMCID: PMC3645388  PMID: 23674877
Hepatitis C virus; Schistosomiasis; Coinfection; Fibrosis; Treatment response
9.  Hepatitis B and/or C co-infection in HIV infected patients: A study in a tertiary care centre from south India 
Background & objectives:
Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in human immunodeficiency virus (HIV) infected individuals results in increased hepatic complications. We undertook this study to evaluate the presence of HBV and HCV in HIV infected individuals attending a tertiary care centre in southern India.
A total of 120 cases with HIV infection and 120 healthy adult control subjects were included in the study. Samples were tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies by enzyme linked immunosorbent assay (ELISA) method. HBsAg and anti-HCV positive serum samples were further tested for the presence of hepatitis B e antigen (HBeAg), anti-HBe antibodies, HBV-DNA and HCV-RNA.
The most common mode of transmission was sexual promiscuity (79%), followed by spouse positivity (15%) and history of blood transfusion (6%). HBsAg and anti-HCV were positive in 18 (15%) and 10 (8.3%) HIV infected patients; the corresponding figures in healthy controls being 2 (1.6%) 0 (0%) (P<0.0001). Among HIV infected patients, presence of HBeAg and anti-HBe antibodies was seen in 33.3 and 55.5 per cent, respectively; both HBeAg and anti-HBe antibodies were negative in 11.1 per cent. HBV DNA and HCV RNA were positive in 10 of 18 and in all anti-HCV positive samples. Triple infection with HBV, HCV and HIV was seen in three patients. CD4+ T-lymphocyte count less than 200/μl was seen in 22 of 28 co-infected cases.
Interpretation & conclusions:
The findings of our study showed presence of HBV (15%) and HCV (8.3%) co-infections in HIV positive patients which was higher than that seen in HIV negative controls. Co-infection with HBV and HCV is a common problem in HIV infected patients in India. Hence, all HIV patients need to be routinely tested for markers of HBV and HCV infection.
PMCID: PMC3978987  PMID: 24521641
Co-infection; hepatitis B virus; hepatitis C virus; human immunodeficiency virus
10.  De Novo Superinfection of Hepatitis B Virus in an Anti-HBs Positive Patient with Recurrent Hepatitis C Following Liver Transplantation 
Gut and Liver  2011;5(2):248-252.
A 60-year-old woman with end stage liver cirrhosis caused by genotype 2 hepatitis C virus (HCV) infection received an orthotopic liver transplantation (OLT). The patient was negative for the hepatitis B surface antigen (HBsAg) and positive for the anti-hepatitis B surface antibody (anti-HBs) prior to and one and a half months following the OLT. Due to reactivation of hepatitis C, treatment with interferon-alpha and Ribavirin started two months following the OLT and resulted in a sustained virological response. We performed a liver biopsy because a biochemical response was not achieved. Surprisingly, liver pathology showed HBsAg-positive hepatocytes with a lobular hepatitis feature, which had been negative in the liver biopsy specimen obtained one and a half months post-OLT. High titers of both HBsAg and HBeAg were detected, while anti-HBs antibodies were not found. Tests for IgM anti-hepatitis B core antibody and anti-delta virus antibodies were negative. The serum HBV DNA titer was over 1×107 copies/mL. A sequencing analysis showed no mutation in the "a" determinant region, but revealed a mixture of wild and mutant strains at an overlapping region of the S and P genes (S codon 213 (Leu/Ile); P codons 221 (Phe/Tyr) and 222 (Ala/Thr)). These findings suggest that de novo hepatitis B can develop in patients with HCV infection during the post-OLT period despite the presence of protective anti-HBs.
PMCID: PMC3140676  PMID: 21814611
De novo hepatitis B virus infection; Occult hepatitis B virus infection; Post-orthotopic liver transplantation recurrent hepatitis C; Orthotopic liver transplantation
11.  Effect of hepatitis C and B virus infection on risk of hepatocellular carcinoma: a prospective study. 
British Journal of Cancer  1997;76(7):968-974.
To assess whether there is an additive effect between chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on the development of hepatocellular carcinoma (HCC), 400 consecutive cirrhotic patients were followed prospectively with periodic abdominal ultrasound examination and measurement of serum alpha-fetoprotein (AFP) level every 4 months. During a follow-up of 1185 person-years, 80 (20%) patients developed HCC, with an annual incidence of 6.8%. The annual incidence was 2.0% in patients negative for hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV), 6.6% in patients with HBsAg alone, 7.0% in patients with anti-HCV alone and 13.3% in patients co-infected with HBV and HCV. There was a positive linear trend in the annual incidence of HCC among patients without either marker, patients with single viral infection and patients with dual viral infection (P[for trend] < 0.0001). Cox's proportional hazard model indicated that HCV/HBV co-infection [hazard ratio (HR), 6.41; 95% confidence interval (CI), 1.80-22.80], anti-HCV alone (HR, 3.74; 95% CI, 1.07-13.07) and HBsAg alone (HR, 4.06; 95% CI, 1.23-13.34) were independently risk factors of HCC. In conclusion, there is an additive and independent effect modification of HCV and HBV infection on HCC development.
PMCID: PMC2228256  PMID: 9328161
12.  Effective treatment of injecting drug users with recently acquired Hepatitis C virus infection 
Gastroenterology  2009;138(1):123.
Background & Aims
Patients with acute hepatitis C virus (HCV) infection that receive treatment achieve high rates of sustained virological response (SVR), but few studies have examined outcomes among injecting drug users (IDUs). We evaluated the efficacy of treatment of recent HCV infection in IDUs with acute and early chronic HCV.
We analyzed data from the Australian Trial in Acute Hepatitis C (ATAHC)—a prospective study of the natural history and treatment outcomes of patients with recent HCV infection. Participants eligible for the study had their first anti-HCV antibody positive test result within the past 6 months and either acute clinical HCV within the past 12 months or documented anti-HCV seroconversion within 24 months. Participants with HCV received pegylated interferon (PEG-IFN)α-2a (180 μg/week, n=74); those with HCV/HIV co-infection received PEG-IFNα-2a (180 μg/week) with ribavirin (n=35) for 24 weeks.
From June 2004 to February 2008, 167 participants were enrolled in the ATAHC; 79% had injected drugs in the previous 6 months. Among 74 with only HCV, the SVRs were 55% and 72% by intention-to-treat and per protocol analysis, respectively. In multivariate analyses, baseline factors independently associated with lower SVR included decreased social functioning and current opiate pharmacotherapy. Adherent participants had higher SVR rates (63% vs 29%, P=0.025). Of the 35 participants with HCV/HIV co-infection, the SVRs were 74% and 75% by intention-to-treat and per protocol analysis, respectively.
Treatment of recent HCV infection among IDUs, including those with HIV co-infection, is effective. Strategies to engage socially marginalized individuals and increase adherence should improve treatment outcomes in this population.
PMCID: PMC2813391  PMID: 19782085
hepatitis C; HCV; acute hepatitis C; pegylated interferon; injection drug users
13.  Hepatitis C Virus (HCV)–Specific Immune Responses of Long-Term Injection Drug Users Frequently Exposed to HCV 
The Journal of infectious diseases  2008;198(2):203-212.
Injection drug users (IDUs) who successfully clear hepatitis C virus (HCV) have a reduced risk of developing chronic reinfection, despite their continuing exposure to the virus. To identify immunological correlates for this apparent protection, we studied HCV-specific immune responses in long-term IDUs (duration, >10 years).
HCV-specific T cell responses were assessed in proliferation, enzyme-linked immunospot (ELISPOT), interferon (IFN)–γ secretion, and cytotoxicity assays, whereas HCV-specific antibodies were assessed in enzyme immunoassays (EIAs), chemiluminescent assays, and in vitro neutralization assays.
HCV-specific T cell proliferation and IFN-γ production were more common in nonviremic EIA-positive IDUs (16 [94%] of 17 IDUs) than in viremic EIA-positive IDUs (9 [45%] of 20 IDUs) (P = .003). They were also noted in 16 (62%) of 26 nonviremic EIA-negative IDUs. In contrast, 19 (90%) of 21 viremic IDUs displayed neutralizing antibodies (nAbs), compared with 9 (56%) of 16 nonviremic EIA-positive IDUs (P = .04) and 0 of 24 nonviremic EIA-negative IDUs. Nonviremic IDUs with nAbs were older (P = .0115) than those without nAbs, but these groups did not differ in terms of either injection drug use duration or HCV-specific T cell responses.
The reduced risk of HCV persistence in IDUs previously recovered from HCV infection correlated with T cell responses, and prolonged antigenic stimulation appears to be required to maintain humoral responses.
PMCID: PMC2699613  PMID: 18505381
14.  Interpretation of Positive TMA Test Results from PCR-Negative Samples Obtained after Treatment of Chronic Hepatitis C 
Hepatology (Baltimore, Md.)  2008;48(5):1412-1419.
The Siemens VERSANT™ transcription mediated amplification (TMA) assay is extremely sensitive for the detection of hepatitis C virus (HCV) RNA in serum. Eleven of 180 subjects in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial who achieved polymerase chain reaction (PCR)-defined sustained virologic response (SVR) at week 72 also had TMA-positive results from the same blood draw; 6 were positive on repeat testing. We report the follow-up on these 11 patients, and the reproducibility of TMA test results from PCR-negative samples in relationship to antiviral treatment outcome.
Materials and Methods
1145 interferon nonresponders with advanced hepatic fibrosis were retreated with peginterferon and ribavirin for 48 weeks if HCV RNA was undetectable by PCR (Roche COBAS Amplicor HCV Test v. 2.0) at week 20. Frozen serum samples from weeks 12, 20, 24, 48 and 72 were subsequently tested by TMA.
Nine of the 11 patients returned for testing (mean 30 months after completing treatment) and all had undetectable HCV RNA by TMA and PCR. Among 759 PCR-negative samples obtained during treatment that were tested twice by TMA, 17% overall exhibited consistently positive results and 21% exhibited inconsistently positive results. SVR was more likely if TMA was consistently negative than if consistently or inconsistently positive. With continued treatment, patients with inconsistently positive TMA results were more likely to become TMA-negative than TMA-positive (p<0.0001).
In PCR-negative samples, positive TMA results may indicate the presence of low levels of HCV RNA. However, because patients with positive TMA results may achieve SVR, management decisions during therapy should not be based upon a single positive TMA test result.
PMCID: PMC2804270  PMID: 18816437
peginterferon alfa; ribavirin; Versant; Amplicor; SVR (sustained virological response); antiviral; therapy
15.  Clinical significance of occult hepatitis B virus infection in chronic hepatitis C patients 
The Korean Journal of Hepatology  2011;17(3):206-212.
We investigated the frequency of occult hepatitis B virus (HBV) infection in anti-hepatitis C virus (HCV)-positive individuals and the effects of occult HBV infection on the severity of liver disease.
Seventy-one hepatitis B virus surface-antigen (HBsAg)-negative patients were divided according to their HBV serological status into groups A (anti-HBc positive, anti-HBs negative; n=18), B (anti-HBc positive, anti-HBs positive; n=34), and C (anti-HBc negative, anti-HBs positive/negative; n=19), and by anti-HCV positivity (anti-HCV positive; n=32 vs. anti-HCV negative; n=39). Liver biopsy samples were taken, and HBV DNA was quantified by real-time PCR.
Intrahepatic HBV DNA was detected in 32.4% (23/71) of the entire cohort, and HBV DNA levels were invariably low in the different groups. Occult HBV infection was detected more frequently in the anti-HBc-positive patients. Intrahepatic HBV DNA was detected in 28.1% (9/32) of the anti-HCV-positive and 35.9% (14/39) of the anti-HCV-negative subjects. The HCV genotype did not affect the detection rate of intrahepatic HBV DNA. In anti-HCV-positive cases, occult HBV infection did not affect liver disease severity.
Low levels of intrahepatic HBV DNA were detected frequently in both HBsAg-negative and anti-HCV-positive cases. However, the frequency of occult HBV infection was not affected by the presence of hepatitis C, and occult HBV infection did not have a significant effect on the disease severity of hepatitis C.
PMCID: PMC3304657  PMID: 22102387
Occult infection; Hepatitis B virus; Hepatitis C virus; HBV DNA
16.  Microalbuminuria in hepatitis C-genotype 4: Effect of pegylated interferon and ribavirin 
AIM: To study the relation between hepatitis C virus (HCV) genotype 4 and microalbuminuria and renal impairment in relation to hepatic histology, and viremia in the absence of cryoglobulinemia, and to examine the effect of treatment on microalbuminuria.
METHODS: Three hundred subjects, including 233 HCV genotype-4 infected patients, were tested for cryoglobulinemia, microalbuminuria, albumin creatinine ratio (ACR), urea, creatinine, and estimated glomerular filtration rate (eGFR). The parameters were measured again in the HCV patients after 48 wk of treatment with pegylated interferon and ribavirin.
RESULTS: Significantly higher levels of microalbuminuria were detected in HCV-positive patients compared to HCV-negative controls (median 9.5 vs 5.9, respectively, Kruskal-Wallis P = 0.017). Log microalbuminuria was significantly correlated with hepatic inflammation (r = 0.13, P = 0.036) and fibrosis (r = 0.12, P = 0.061), but not with viral load (r = -0.03, P = 0.610), or alanine transaminase (r = -0.03, P = 0.617). Diabetes mellitus neither significantly moderated (χ2 = 0.13, P = 0.720), nor mediated (Sobel test P = 0.49) the HCV effect. HCV status was significantly associated with log microalbuminuria (χ2 = 4.97, P = 0.026), adjusting for age, gender, diabetes, cryoglobulinemia, urea and creatinine. A positive HCV status was not significantly associated with low eGFR (< 60 mL/min every 1.73 m2) [odds ratio (OR): 0.5, 95% confidence interval (CI): 0.2-1.4], nor with high ACR (OR: 1.7, 95% CI: 0.7-4.1). End-of-treatment response (ETR) was achieved in 51.9% of patients. Individuals with ETR had significantly lower microalbuminuria post-treatment (χ2 = 8.19, P = 0.004).
CONCLUSION: HCV affected the development of microalbuminuria independent of diabetes or cryoglobulinemia. Combination therapy of pegylated interferon-ribavirin had a positive effect in reducing microalbuminuria.
PMCID: PMC2839175  PMID: 20222166
Hepatitis C virus; Genotype; Kidney diseases; Albuminuria; Proteinuria; Peginterferon α-2a; Ribavirin
17.  Hepatitis C virus (HCV) genotypes and the influence of HCV subtype 1b on the progression of chronic hepatitis C in Korea: a single center experience 
Clinical and molecular hepatology  2012;18(2):219-224.
There is some controversy regarding whether or not hepatitis C virus (HCV) subtype 1b is more influential than non-1b subtypes on the progression of chronic hepatitis (CH) C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC).
We retrospectively analyzed 823 patients with chronic HCV infection, including 443 CH patients, 264 LC patients, and 116 HCC patients, who were HCV RNA positive and HBsAg negative. These patients had not received any prior treatment with either interferon alone or a combination of interferon and ribavirin.
HCV subtypes 1b (51.6%) and 2a/2c (39.5%) were the two most common genotypes. The proportions of genotypes 2 (2a/2c, 2b, and 2) and 3 were 45.8% and 1.1%, respectively. One case of genotype 4 was found. HCV subtype 1b (47.3%) was less common than the non-1b subtypes (52.7%) in non-LC patients, but its proportion (56.9%) was higher than that of non-1b subtypes (43.1%) in LC patients (P=0.006). The proportions of patients with HCV subtype 1b did not differ significantly between the LC (55.3%) and HCC (60.3%) groups. Older age, male gender, and the relative progression of liver damage (non-LC vs. compensated LC vs. decompensated LC) were significant risk factors for HCC, with odds ratios of 1.081 (95% confidence interval [CI], 1.056-1.106), 5.749 (95% CI, 3.329-9.930), and 2.895 (95% CI, 2.183-3.840), respectively. HCV subtype 1b was not a significant risk factor for HCC (odds ratio, 1.423; 95% CI, 0.895-2.262).
HCV subtypes 1b and 2a/2c were the two most common HCV genotypes. HCV subtype 1b seemed to be more influential than non-1b subtypes on the progression of CH to LC, but not on the development of HCC from LC.
PMCID: PMC3415883  PMID: 22893873
Genotype; Hepatitis C; Hepatocellular carcinoma; Liver cirrhosis
18.  Declining Incidence of Hepatitis C Virus Infection among People Who Inject Drugs in a Canadian Setting, 1996-2012 
PLoS ONE  2014;9(6):e97726.
People who inject drugs (PWID) are at high risk of hepatitis C virus (HCV) infection. Trends in HCV incidence and associated risk factors among PWID recruited between 1996 and 2012 in Vancouver, Canada were evaluated.
Data were derived from a long-term cohort of PWID in Vancouver. Trends in HCV incidence were evaluated. Factors associated with time to HCV infection were assessed using Cox proportional hazards regression.
Among 2,589, 82% (n = 2,121) were HCV antibody-positive at enrollment. Among 364 HCV antibody-negative participants with recent (last 30 days) injecting at enrollment, 126 HCV seroconversions were observed [Overall HCV incidence density: 8.6 cases/100 person-years (py); 95% confidence interval (95% CI): 7.2, 10.1; HCV incidence density among those with injecting during follow-up: 11.5 cases/100 py; 95% CI 9.7, 13.6]. The overall HCV incidence density declined significantly from 25.0/100 py (95% CI: 20.2, 30.3) in 1996–99, as compared to 6.0/100 py (95% CI: 4.1, 8.5) in 2000–2005, and 3.1/100 py (95% CI: 2.0, 4.8) in 2006–2012. Among those with injecting during follow-up, the overall HCV incidence density declined significantly from 27.9/100 py (95% CI: 22.6, 33.6) in 1996–99, as compared to 7.5/100 py (95% CI: 5.1, 10.6) in 2000–2005, and 4.9/100 py (95% CI: 3.1, 7.4) in 2006–2012. Unstable housing, HIV infection, and injecting of cocaine, heroin and methamphetamine were independently associated with HCV seroconversion.
HCV incidence has dramatically declined among PWID in this setting. However, improved public health strategies to prevent and treat HCV are urgently required to reduce HCV-associated morbidity and mortality.
PMCID: PMC4045728  PMID: 24897109
19.  Nanomedicines in the treatment of hepatitis C virus infection in Asian patients: optimizing use of peginterferon alfa 
Asia is endemic for hepatitis C virus (HCV) infection, which is the leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplantation worldwide. HCV has six major genotypes and each HCV genotype has its specific geographic distribution. HCV genotypes 1, 2, 3, and 6 are common in Asia. The aim of HCV treatment is to eradicate the virus by effective therapeutic agents; viral clearance is durable after long-term post-treatment follow-up. In most Asian countries, peginterferon alfa (PEG-IFN α) in combination with ribavirin remains the standard of care, and the overall sustained viral response (SVR) rate in Asian HCV patients is higher than that in Western patients. The differences are most significant in patients with HCV genotype 1 (HCV-1) infection, which is attributed to the higher frequency of IFN-responsive or favorable interleukin-28B (IL-28B) genotype in Asian populations than in other ethnic populations. In addition, the introduction of response-guided therapy, where the optimized treatment duration is based on the early viral kinetics during the first 12 weeks of treatment, increases the SVR rate. Recently, telaprevir or boceprevir-based triple therapy was found to further improve the SVR rate in treated and untreated HCV-1 patients and has become the new standard of care in Western and some Asian countries. Many novel direct-acting antiviral agents, either in combination with PEG-IFN α plus ribavirin or used as IFN-free regimens are under active investigation. At the time of this writing, simeprevir and sofosbuvir have been approved in the US. Because the SVR rates in Asian HCV patients receiving PEG-IFN α plus ribavirin therapy are high, health care providers should judiciously determine the clinical usefulness of these novel agents on the basis of treatment duration, anticipated viral responses, patient tolerance, financial burdens, and drug accessibility.
PMCID: PMC4008289  PMID: 24812506
20.  Simultaneous Detection of Hepatitis C Virus (HCV) Core Antigen and Anti-HCV Antibodies Improves the Early Detection of HCV Infection 
Journal of Clinical Microbiology  2005;43(8):3877-3883.
To evaluate whether a new enzyme immunoassay developed for the simultaneous detection of hepatitis C virus (HCV) core antigen (Ag) and anti-HCV antibodies (anti-HCV Ab) (Monolisa HCV Ag/Ab ULTRA; Bio-Rad) could improve the early detection of HCV infection, we compared its sensitivity to that of anti-HCV, HCV core Ag, and HCV RNA assays. The populations studied included 12 blood donor samples positive for HCV RNA and HCV core Ag but negative for anti-HCV antibodies and 23 hemodialysis patients who developed anti-HCV Ab (seroconversion) during the follow-up. From these 23 individuals, 83 samples sequentially collected prior to seroconversion and 108 samples collected after seroconversion were tested. Six of 12 blood donations were positive by the HCV Ag/Ab assay. In the hemodialysis cohort, the 24 HCV RNA-negative samples were negative by the HCV Ag/Ab assay and 23 of the 59 HCV RNA-positive samples (39%) were positive. The HCV Ag/Ab assay detected HCV infection on average 21.6 days before the most sensitive antibody assay. The HCV Ag/Ab assay did not detect HCV infection as early as the HCV RNA assay (mean delay, 30.3 days) or HCV Ag assay (mean delays, 27.9, and 16.3 days by the HCV core Ag quantification assay and the HCV Ag blood screening assay, respectively). This new assay provides a notable improvement for the early detection of HCV infection during the so-called window period compared with anti-HCV Ab assays and could be a useful alternative to HCV RNA detection or HCV core Ag assays for diagnosis or blood screening when nucleic acid technologies or HCV core Ag detection are not implemented.
PMCID: PMC1234013  PMID: 16081925
The Australian Trial in Acute Hepatitis C (ATAHC) is an NIH funded prospective cohort study of natural history and treatment efficacy in individuals with recently acquired hepatitis C. Enrolment is open to both HIV positive and HIV negative individuals. The aim of this paper was to evaluate characteristics and virological outcomes within HIV positive individuals enrolled in ATAHC
Eligibility criteria include first anti-HCV antibody positive within 6 months and either clinical hepatitis C within the past 12 months or documented anti-HCV seroconversion within the past 24 months.
Of the initial 103 subjects enrolled 27 (26%) were HIV positive. HIV positive subjects were more likely to be older, have genotype 1 infection and high HCV RNA at baseline than HCV monoinfected subjects. Sexual acquisition accounted for the majority (56%) of HCV infections in HIV positive subjects compared to only 8% of HCV monoinfected subjects. Median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of Pegylated interferon and ribavirin resulted in rates of HCV RNA undetectability of 95%, 90% and 80% at weeks 12, 24 and 48 respectively. Week 4 undetectability was achieved in 44% of subjects and gave positive and negative predictive values for SVR of 100% and 33% respectively.
Significant differences are demonstrated between HIV positive and HIV negative individuals enrolled into ATAHC. Treatment responses in HIV positive individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high risk individuals and early treatment for recently acquired HCV infection.
PMCID: PMC2895679  PMID: 19191653
22.  Laboratory Evaluation of a Fully Automated Chemiluminescence Immunoassay for Rapid Detection of HBsAg, Antibodies to HBsAg, and Antibodies to Hepatitis C Virus 
Journal of Clinical Microbiology  2004;42(2):610-617.
The performance of a fully automated, random access, enhanced chemiluminescence immunoassay (Ortho/ECi) for the detection of antibody to hepatitis C virus (HCV) (anti-HCV), HBsAg, and antibody to HBsAg (anti-HBsAg), in human serum was compared to a Abbott second-generation enzyme immunoassay (EIA 2.0). The Ortho/ECi assays employ an immunometric technique with enhanced chemiluminescence for optimal assay performance. With regard to the study of clinical laboratory performance, six groups of sera prescreened with Abbott EIAs were assayed: anti-HCV-negative samples (n = 318), anti-HCV-positive samples (n = 177), anti-HBsAg-negative samples (n = 241), anti-HBsAg-positive samples (n = 239), HBsAg-positive samples (n = 158), and HBsAg-negative samples (n = 312). Sera with discrepant results in the two serological assays were resolved by confirmatory tests. Sera with indeterminate results by one or more confirmatory tests were evaluated by reviewing medical records. The overall concordance between the Ortho/ECi assay and the Abbott EIA were 97.78, 93.54, and 97.66% for anti-HCV antibodies, anti-HBsAg antibodies, and HBsAg, respectively. After resolving the discrepancies, the specificities of the new assay for anti-HCV and anti-HBsAg antibodies and HBsAg were 98.1, 92.8, and 100%, respectively. The sensitivities of the new assay for anti-HCV, anti-HBsAg, and HBsAg were 100, 98.8, and 97.4%, respectively. In conclusion, The Ortho/ECi assays for diagnosis of HCV and hepatitis B virus (HBV) infections are highly specific and sensitive assays. The rapid turnaround time, random access, full automation, and high throughput make it an effective assay system for clinical laboratory diagnosis of HCV and HBV infections.
PMCID: PMC344481  PMID: 14766824
23.  PCBP2 Enhances the Antiviral Activity of IFN-α against HCV by Stabilizing the mRNA of STAT1 and STAT2 
PLoS ONE  2011;6(10):e25419.
Interferon-α (IFN-α) is a natural choice for the treatment of hepatitis C, but half of the chronically infected individuals do not achieve sustained clearance of hepatitis C virus (HCV) during treatment with IFN-α alone. The virus can impair IFN-α signaling and cellular factors that have an effect on the viral life cycles. We found that the protein PCBP2 is down-regulated in HCV-replicon containing cells (R1b). However, the effects and mechanisms of PCBP2 on HCV are unclear. To determine the effect of PCBP2 on HCV, overexpression and knockdown of PCBP2 were performed in R1b cells. Interestingly, we found that PCBP2 can facilitate the antiviral activity of IFN-α against HCV, although the RNA level of HCV was unaffected by either the overexpression or absence of PCBP2 in R1b cells. RIP-qRT-PCR and RNA half-life further revealed that PCBP2 stabilizes the mRNA of STAT1 and STAT2 through binding the 3′Untranslated Region (UTR) of these two molecules, which are pivotal for the IFN-α anti-HCV effect. RNA pull-down assay confirmed that there were binding sites located in the C-rich tracts in the 3′UTR of their mRNAs. Stabilization of mRNA by PCBP2 leads to the increased protein expression of STAT1 and STAT2 and a consistent increase of phosphorylated STAT1 and STAT2. These effects, in turn, enhance the antiviral effect of IFN-α. These findings indicate that PCBP2 may play an important role in the IFN-α response against HCV and may benefit the HCV clinical therapy.
PMCID: PMC3191149  PMID: 22022391
24.  Successful treatment of HCV/HBV/HDV-coinfection with pegylated interferon and ribavirin 
Clinics and Practice  2012;2(3):e64.
Dual and triple infections with hepatitis virus C (HCV), B (HBV) and D (HDV) frequently lead to severe liver damage. Hereby we describe a 38-year-old Caucasian male coinfected with HCV (genotype 3a), HBV [positive hepatitis B surface antigen (HbsAg) and antibody to hepatitis B core antigen; negative hepatitis B e antigen (HbeAg) and antibody to hepatitis B e antigen (anti-HBe)] and HDV. Laboratory diagnostics revealed increased liver enzymes and histological examination of the liver showed signs of fibrosis with moderate inflammation. On therapy with pegIFN-α2b and ribavirin HCV-RNA was undetectable at week 8. After week 24 the antiviral therapy was stopped because of a HBs-seroconversion, the loss of HbeAg and the detection of anti-HBe. Furthermore the HCV-RNA was negative. Six months after successful treatment of the triple-infection, HCV- and HDV-RNA and HbsAg remained negative and the liver enzymes had been completely normalized. In conclusion, pegylated-interferon plus ribavirin may be an effective therapy for HCV, HBV and HDV-coinfected patients.
PMCID: PMC3981316  PMID: 24765463
HCV; HBV; HDV; triple-hepatitis; pegylated interferon; ribavirin.
25.  Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening 
BMC Infectious Diseases  2013;13:181.
Treatment for chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is improving but not benefiting individuals unaware to be infected. To inform screening policies we assessed (1) the hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus antibody (anti-HCV-Ab) prevalence for 34 European countries; and (2) the cost-effectiveness of screening for chronic HBV and HCV infection.
We searched peer-reviewed literature for data on HBsAg and anti-HCV-Ab prevalence and cost-effectiveness of screening of the general population and five subgroups, and used data for people who inject drugs (PWID) and blood donors from two European organizations. Of 1759 and 468 papers found in the prevalence and cost-effectiveness searches respectively, we included 124 and 29 papers after assessing their quality. We used decision rules to calculate weighted prevalence estimates by country.
The HBsAg and anti-HCV-Ab prevalence in the general population ranged from 0.1%-5.6% and 0.4%-5.2% respectively, by country. For PWID, men who have sex with men and migrants, the prevalence of HBsAg and anti-HCV-Ab was higher than the prevalence in the general population in all but 3 countries. There is evidence that HCV screening of PWID and HBsAg screening of pregnant women and migrants is cost-effective.
The prevalence of chronic HBV and HCV infection varies widely between European countries. Anti-HCV-Ab screening of PWID and HBsAg screening of pregnant women and migrants have European public health priority. Cost-effectiveness analyses may need to take effect of antiviral treatment on preventing HBV and HCV transmission into account.
PMCID: PMC3716892  PMID: 23597411
Hepatitis B virus; Hepatitis C virus; Europe; Prevalence; HBsAg; Anti-HCV-Ab; Cost-effectiveness analyses

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