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1.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
2.  Serum Immunoglobulin G Antibodies to the GOR Autoepitope Are Present in Patients with Occult Hepatitis C Virus (HCV) Infection despite Lack of HCV-Specific Antibodies▿  
Clinical and Vaccine Immunology : CVI  2007;14(10):1302-1306.
Antibody responses to the GOR autoepitope are frequently detected among anti-hepatitis C virus (anti-HCV)-positive patients with chronic hepatitis. Sera from 110 anti-HCV-negative patients with occult HCV infection, as diagnosed by detection of HCV RNA in hepatic tissue, were investigated for GOR antibody reactivity. A positive test for anti-GOR immunoglobulin G (IgG) was found for 22 (20%) of them. The frequency and titers of anti-GOR IgG were significantly lower than those in chronic hepatitis C patients (70/110, 63.6%; P < 0.001). Anti-GOR IgG was not detected in any of the 120 patients with HCV-unrelated liver disease. The anti-GOR IgG assay showed specificity and sensitivity values of 100% and 20%, respectively, among the sera from patients with occult HCV infection; the positive and negative predictive values were 100% and 44.3%, respectively. None of the clinical, laboratory, or histological characteristics of the patients with occult HCV infection were different according to GOR antibody status, except that the percentage of HCV RNA-positive hepatocytes was significantly greater (P = 0.042) in patients with occult HCV infection who tested positive for anti-GOR IgG. In conclusion, serum anti-GOR IgG is present in patients with occult HCV infection, despite a lack of detectable HCV-specific antibodies as determined by commercial tests. Testing for anti-GOR IgG in patients in whom HCV RNA is not detected in their sera may help with the identification of a subset of patients with occult HCV infection without the need to perform a liver biopsy.
doi:10.1128/CVI.00128-07
PMCID: PMC2168120  PMID: 17699833
3.  New perspectives in occult hepatitis C virus infection 
Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases.
doi:10.3748/wjg.v18.i23.2887
PMCID: PMC3380315  PMID: 22736911
Occult hepatitis C virus; Hepatitis C virus RNA; Liver; Peripheral blood mononuclear cells; T-cell response
4.  Increased α-Fetoprotein Predicts Steatosis among Patients with Chronic Hepatitis C Genotype 4 
Background. The prognostic importance of α-fetoprotein (AFP) level elevation in patients with chronic hepatitis C and its clinical significance in steatosis associated with HCV infection remain to be determined. The present paper assessed clinical significance of elevated AFP in patients with CHC with and without steatosis. Methods. One hundred patients with CHC were divided into 50 patients with CHC and steatosis and 50 patients with CHC and no steatosis based on liver biopsy. Results. AFP was significantly increased in CHC with steatosis than patients without steatosis (P < 0.001). Highly significant positive correlation was found between serum AFP and necroinflammation as well as the severity of fibrosis/cirrhosis and negative significant correlation with albumin level in chronic HCV with steatosis (P < 0.001) but negative nonsignificant correlation with ALT and AST level (P ≤ 0.778 and 0.398), respectively. Highly significant increase was found in chronic hepatitis patients with steatosis than CHC without steatosis regarding necroinflammation as well as the severity of fibrosis/cirrhosis and AFP (P < 0.001). Conclusion. Patients with chronic HCV and steatosis have a higher AFP levels than those without steatosis. In chronic HCV with steatosis, elevated AFP levels correlated positively with HAI and negative significant correlation with albumin level.
doi:10.1155/2012/636392
PMCID: PMC3364564  PMID: 22675639
5.  Ultracentrifugation of Serum Samples Allows Detection of Hepatitis C Virus RNA in Patients with Occult Hepatitis C▿  
Journal of Virology  2007;81(14):7710-7715.
Occult hepatitis C virus (HCV) infection of patients with abnormal liver function tests of unknown origin who are anti-HCV and serum HCV RNA negative but who have HCV RNA in the liver has been described. As HCV replicates in the liver cells of these patients, it could be that the amount of circulating viral particles is under the detection limit of the most sensitive techniques. To prove this hypothesis, serum samples from 106 patients with occult HCV infection were analyzed. Two milliliters of serum was ultracentrifuged over a 10% sucrose cushion for 17 h at 100,000 × gav, where av means average, and HCV RNA detection was performed by strand-specific real-time PCR. Out of the 106 patients, 62 (58.5%) had detectable serum HCV RNA levels after ultracentrifugation, with a median load of 70.5 copies/ml (range, 18 to 192). Iodixanol density gradient studies revealed that HCV RNA was positive at densities of 1.03 to 1.04 and from 1.08 to 1.19 g/ml, which were very similar to those found in the sera of patients with classical chronic HCV infection. Antigenomic HCV RNA was found in the livers of 56 of 62 (90.3%) patients with detectable serum HCV RNA levels after ultracentrifugation, compared to 27 of 44 (61.4%) negative patients (P < 0.001). No differences in the median loads of antigenomic HCV RNA between patients with an those without serum HCV RNA (4.5 × 104 [range, 7.9 × 102 to 1.0 × 106] versus 2.3 × 104 [range, 4.0 × 102 to 2.2 × 105]) were found. Alanine aminotransferase and gamma-glutamyl transpeptidase levels, liver necroinflammatory activity, and fibrosis did not differ between both groups. In conclusion, HCV RNA can be detected in the sera of patients with occult HCV infection after circulating viral particles are concentrated by ultracentrifugation.
doi:10.1128/JVI.02750-06
PMCID: PMC1933375  PMID: 17475654
6.  Circulating Th1 and Th2 cytokines in patients with hepatitis C virus infection. 
Mediators of Inflammation  1998;7(4):295-297.
The imbalance of T-helper (Th) lymphocyte cytokine production may play an important role in immunopathogenesis of persistent hepatitis C virus (HCV) infection. To know whether an imbalance between Th1 and Th2 cytokines is present in chronic HCV infection, serum levels of Th1 cytokines, interferon gamma (IFN-gamma) and interleukin (IL)-2, and Th2 cytokines, IL-4 and IL-10, were measured using enzyme-linked immunosorbent assay in this study. Eighteen individuals with chronic HCV infection, 11 healthy subjects as normal controls and 10 chronic HBV infected patients as disease controls were observed. The results showed that the levels of Th2 cytokines (IL-4 and IL-10) were significantly increased in chronic HCV infected patients compared with normal controls (IL-4: 30.49+/-17.55 vs. 14.94+/-13.73, pg/ml, P<0.025; IL-10: 50.30+/-19.59 vs. 17.87+/-9.49, pg/ml, P<0.001). Similarly, the levels of Th1 cytokine, IL-2, was also elevated in individuals with chronic HCV infection when compared with normal controls (IL-2: 118.53+/-95.23 vs. 61.57+/-28.70, pg/ml, P<0.05). However, Th1 cytokine IFN-gamma level was not significantly changed during HCV infection (IFN-gamma: 28.09+/-15.65 vs. 24.10+/-15.61, pg/ml, P>0.05). Furthermore, the elevated levels of Th2 cytokines are greater than Th1 cytokines in HCV infection. Thus, the study indicates that an enhanced Th2 responses are present during chronic HCV infection, which may partly be responsible for the persistence of HCV infection.
PMCID: PMC1781851  PMID: 9792341
7.  Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology 
Gut  2000;47(3):429-435.
BACKGROUND—The histopathological spectrum and role of hepatitis viruses in cases of hypertransaminasaemia of unknown aetiology have not been correctly analysed in a sufficiently large number of patients.
METHODS—We studied 1075 consecutive patients referred for liver biopsy because of elevation of alanine aminotransferase (ALT) levels for more than six months. From this population we selected those cases in whom the aetiology could not be defined from clinical, biochemical, and serological data obtained before biopsy. In these patients liver biopsies were reviewed, and hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA were assayed in serum by polymerase chain reaction (PCR). Serum hepatitis G virus (HGV)-RNA was determined by PCR in 74 patients.
RESULTS—Of 1075 patients studied, the cause of the increased serum ALT levels remained elusive after appropriate testing in 109 patients (10.1%). Liver biopsies from these patients showed non-specific changes in 32.7% of cases, non-alcoholic steatohepatitis (NASH) in 15.8%, and chronic hepatitis or cirrhosis in 51.5%. HBV-DNA and/or HCV-RNA was detected more frequently in cryptogenic liver disease than in healthy blood donors (26.7% v 3.4%; p<0.001). HGV-RNA was found in only one patient. The proportion of cases with detectable HBV-DNA or HCV-RNA was 14.3% in patients with non-specific changes or NASH, 30.7% in patients with chronic hepatitis, and 61.5% in patients with cirrhosis. Cirrhosis was found more frequently in patients with positive HBV-DNA and/or HCV-RNA in serum than in those who tested negatively (p=0.005).
CONCLUSIONS—In our series, patients in whom biochemical and serological data did not determine the aetiology of the disease represented 10% of all cases referred for liver biopsy for persistent elevation of serum transaminases. Approximately 50% of patients had chronic hepatitis or cirrhosis and the remainder had NASH or non-specific changes. Occult viral infections were found in a high proportion of cases in the first group and in a low percentage of patients in the second.


Keywords: cryptogenic liver disease; cryptogenic hepatitis; hepatitis B virus; hepatitis C virus; hepatitis G virus; non-alcoholic steatohepatitis
doi:10.1136/gut.47.3.429
PMCID: PMC1728051  PMID: 10940283
8.  High prevalence of hepatitis C virus-ribonucleic acid positivity in anti-hepatitis C virus negative renal transplant patients 
Background
Hepatitis C virus (HCV) infection is common in renal transplant (RT) patients. Some of these patients remain anti-HCV negative despite presence of infection and these are identified by a positive HCV-ribonucleic acid (RNA) test.
Methods
We studied 404 RT patients for prevalence of HCV-RNA positivity in anti-HCV negative patients. Serum was tested for presence of anti-HCV antibodies using a third generation HCV micro-ELISA (enzyme-linked immunosorbent assay) test, which utilises a combination of HCV structural and nonstructural antigens. The RNA was extracted from patient serum for HCV viral quantification using Quiagen Ql Amp Viral RNA mini extraction kit. The HCV-RNA viral load was performed on Corbet Rotor Gene 3000 thermocycler using Taqman principle.
Results
About 308 patients were anti-HCV negative and 96 were anti-HCV positive, resulting in prevalence of overt HCV infection of 23.7%. A total of 130 anti-HCV negative patients tested positive for HCV-RNA making a prevalence of occult HCV infection of 42.2%. There was no significant difference in the rate of overt or occult HCV infection between males and females. Patients with HCV infection (whether overt or occult) had received more number of dialysis sessions (62.5 vs 32.2) and blood transfusions (2.78 vs 1.99) when compared to those without HCV infection (P=0.001). The mean duration on dialysis was also longer (8.15 months vs 4.53 months) in patients with HCV infection (P= 0.0001).
Conclusion
A direct test for HCV viraemia is important to accurately determine the epidemiology of HCV infection in RT patients who remain anti-HCV negative despite harbouring active HCV infection.
doi:10.1016/S0377-1237(12)60023-9
PMCID: PMC3862742  PMID: 24669050
hepatitis C; real time PCR; renal replacement therapy
9.  Hepatitis C virus replicates in peripheral blood mononuclear cells of patients with occult hepatitis C virus infection 
Gut  2005;54(5):682-685.
Background: Occult hepatitis C virus (HCV) infection is characterised by the presence of HCV-RNA in the liver in the absence of anti-HCV, and serum viral RNA. Up to 70% of these patients also have HCV-RNA in peripheral blood mononuclear cells (PBMC) but it is not known if HCV is replicating in these cells.
Aim: We studied possible HCV replication in PBMC of 18 patients with an occult HCV infection who were selected on the basis of HCV-RNA positivity in PBMC.
Methods: Detection of HCV-RNA positive and negative strands in PBMC was done by strand specific reverse transcriptase-polymerase chain reaction (RT-PCR) and by in situ hybridisation.
Results: The presence of HCV-RNA positive strand in PBMC was confirmed in all patients by strand specific RT-PCR and by in situ hybridisation. Mean percentage of PBMC which had the HCV-RNA positive strand was 3.3% (95% confidence interval (CI) 2.1–4.4) The HCV-RNA negative strand was found in the PBMC of 11/18 (61%) patients by strand specific RT-PCR and confirmed by in situ hybridisation, and the percentage of PBMC harbouring the HCV-RNA negative strand was 3.1% (95% CI 0.8–5.5). There was a significant correlation (p = 0.001, r = 0.84) between the percentage of PBMC with the HCV-RNA positive strand and that of PBMC with the HCV-RNA negative strand.
Conclusion: HCV replicates in the PBMC of patients with occult HCV infection and thus, although these patients do not have serum HCV-RNA, they could be potentially infectious.
doi:10.1136/gut.2004.057281
PMCID: PMC1774478  PMID: 15831916
hepatitis C virus; peripheral blood mononuclear cells; fluorescent in situ hybridisation
10.  Coinfection with HIV-1 Alleviates Iron Accumulation in Patients with Chronic Hepatitis C Virus Infection 
PLoS ONE  2014;9(6):e98039.
Most chronically-infected hepatitis C virus (HCV) patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n = 129) or coinfected with HCV/HIV-1 (n = 98). Healthy controls (n = 84) were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC), transferrin saturation (Tfs), and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p = 0.001) and ferritin (p = 0.009) and the Tfs (p = 0.002) were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001) than those in health controls, the levels in coinfected patients were higher (p = 0.025) than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ≥500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the status of serum iron and other iron-associated parameters will be helpful to understand the complexity of alternations in iron distribution in HCV/HIV-1-coinfected patients.
doi:10.1371/journal.pone.0098039
PMCID: PMC4057081  PMID: 24927015
11.  Hepatitis C virus in sickle cell disease. 
PURPOSE: To determine the prevalence of hepatitis C virus antibodies (anti-HCV) in patients with sickle cell disease. PATIENTS AND METHODS: Between 1983 and 2001, 150 patients from the Howard University Hospital Center for Sickle Cell Disease were screened for HCV antibody (52% women, 48% men, mean age 34 years). Frozen serum samples from 56 adult sickle cell patients who had participated in previous surveys (1983-92) of HIV and HTLV-1 serology and who were tested in 1992 for anti-HCV antibody--when commercial ELISA test (Ortho) became available--were included in this paper. Of the 150 patients in the study, 132 had sickle cell anemia genotype (SS), 15 had sickle cell hemoglobin-C disease (SC) and three had sickle beta thalassemia. Clinical charts were reviewed for history of blood transfusion, IV drug abuse, homosexuality, tattooing, iron overload, and alcohol abuse. RESULTS: Antibodies to HCV were detected in 53 patients (35.3%). Of the 55 patients who had frozen serum samples tested in 1992, 32 (58%) were reactive for anti-HCV, while only 21 of the 95 patients (22%) tested after 1992 were positive for HCV antibodies (P<0.001). Thirty-nine of 77 patients (51%) who received more than 10 units of packed red blood cells were positive for HCV antibody, and only 14 of 61 patients (23%) who received less than 10 units of packed red blood cells transfusion were positive for HCV antibodies (P<0.001). None of the 12 patients who never received transfusion were positive for HCV antibody. In the 53 anti-HCV positive patients, the mean alanine amino-transferase (ALT) value was 98- and 81 U/L, respectively, for males and females. These values were normal for the HCV-antibody negative patients. The aspartate amino-transferase (AST) and the total bilirubin were also higher in the anti-HCV positive patients compared to patients in the anti-HCV negative group. Forty-four patients (57.1%) who were transfused more than 10 units developed iron overload defined by a serum ferritin level higher than 1,000 ng/ml. A total of 20 of the patients with iron overload underwent liver biopsies. Seven of these 20 patients (35%) were HCV positive. These patients often had more severe liver disease and higher degree of iron deposition. CONCLUSION: The prevalence of HCV antibody and iron overload is directly related to the number of blood transfusions in patients with sickle cell disease. The prevalence of HCV infection has decreased significantly, since blood donor screening for HCV became available. Chronic HCV infection and iron overload place sickle cell patients at risk for significant liver disease.
PMCID: PMC2594496  PMID: 14620705
12.  Anti-hepatitis C virus core IgM antibodies correlate with hepatitis C recurrence and its severity in liver transplant patients 
Gut  2000;47(5):698-702.
BACKGROUND—The significance of immunoglobulin (Ig) M antibody to hepatitis C virus (HCV) core antigen was studied in 60 patients with HCV infection after orthotopic liver transplantation (OLT) diagnosed by polymerase chain reaction.
METHODS—Patients were followed up for a mean of 28 months after transplantation. Sera collected three months before transplantation, and one and 12 months after transplantation were analysed for anti-HCV core IgM (HCV-IgM EIA 2.0 assay). After OLT protocol biopsies, procedures were performed routinely every six months. Semiquantitative histopathological assessment of allograft hepatitis was performed using Knodell's score. The results were correlated with clinical features, liver histology findings, and virological features, such as genotype and viraemic levels assessed by a branched DNA assay.
RESULTS—One year after liver transplantation, 29/60 (48%) patients had chronic hepatitis on graft biopsy. The presence of anti-HCV core IgM one month (p=0.004) and 12 months (p=0.003) after OLT was positively correlated with recurrence of chronic hepatitis. The positive predictive value of anti-HCV core IgM detected one month after transplantation was 0.88. A significant relationship was observed between severity of graft disease and presence of anti-HCV core IgM 12 months after transplantation. The mean Knodell score was 8.9 in anti-HCV core IgM positive patients compared with 3.6 in those who were anti-HCV core IgM negative (p=0.001). The presence of IgM anti-HCV did not correlate with serum HCV RNA level or HCV genotype.
CONCLUSION—We confirm that the presence of anti-HCV core IgM after OLT is a marker of HCV induced graft damage. The recurrence and severity of HCV hepatitis in patients undergoing OLT for HCV cirrhosis is related to the presence of anti-HCV core IgM after liver transplantation. These findings have diagnostic relevance and confirm that measurement of IgM anti-HCV core may help to better monitor the treatment of HCV recurrence after transplantation.


Keywords: hepatitis C; orthotopic liver transplantation; anti-HCV core IgM; immunopathogenesis
doi:10.1136/gut.47.5.698
PMCID: PMC1728104  PMID: 11034588
13.  Significance of hepatitis B virus surface antigen, hepatitis C virus expression in hepatocellular carcinoma and pericarcinomatous tissues 
AIM: To investigate the correlation between hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) expression in hepatocellular carcinoma (HCC), the HAI score of the noncancerous region of the liver and the serum Alpha fetoprotein (AFP) level.
METHODS: The patterns of HBsAg and HCV in 100 cases of HCC and their surrounding liver tissues were studied on paraffin-embedded sections with immuno-histochemistry, the histological status was determined by one pathologist and one surgeon simultaneously using the hepatitis activity index (HAI) score, and AFP was detected by radioimmunity. The study included 100 consecutive patients who underwent curative resection for HCC. Based on HBsAg and HCV expression, the patients were classified into 4 groups: patients positive for HBsAg (HBsAg group), patients positive for HCV (HCV group), patients negative for both HCV and HBsAg (NBNC group) and patients positive for both HBsAg and HCV (BC group).
RESULTS: The BC group had significantly higher HAI scores than the other three groups. (BC > HCV > HBsAg > NBNC). HBV and HCV virus infection was positively correlated with HAI (rs = 0.39, P = 0.0001). The positive rate of AFP (85.7%) and the value of AFP (541.2 ng/mL) in the group with HBV and HCV co-infection were the highest among the four groups. The positive rate (53.3%) of AFP and the value of AFP ( 53.3 ng/mL) in the group with none-infection of HBV and HCV were the lowest. HBV and HCV virus infection was positively correlated with AFP(rs = 0.38, P = 0.0001).
CONCLUSION: The AFP increase in patients with liver cancer was positively correlated with the infection of HBV and HCV. The serum AFP elevation by the infection of HBV and HCV is one of mechanisms which lead to hepatocarcinogenesis, and the antivirus intervening treatment of hepatitis is significant for the prognosis of liver cancer. From our Spearman’s rank correlation analysis, we can conclude that the severity of virally induced inflammation is correlated with HBsAg and HCV expression in HCC tissues and noncancerous tissues. Prior co-infection of HBV in HCV patients may be an adverse risk factor for intrahepatic inflammation.
doi:10.3748/wjg.v13.i12.1870
PMCID: PMC4149970  PMID: 17465484
Hepatitis B virus surface antigen; Hepatitis C virus antigen; Histological activity index; Immunohisto-chemistry; Hepatocellular carcinoma; Alpha-fetoprotein.
14.  The Global Spread of Hepatitis C Virus 1a and 1b: A Phylodynamic and Phylogeographic Analysis 
PLoS Medicine  2009;6(12):e1000198.
Using phylodynamic and phylogeographic methods, Angelos Hatzakis and colleagues find that the global spread of Hepatitis C virus coincided with widespread use of transfused blood and with the expansion of intravenous drug use.
Background
Hepatitis C virus (HCV) is estimated to affect 130–180 million people worldwide. Although its origin is unknown, patterns of viral diversity suggest that HCV genotype 1 probably originated from West Africa. Previous attempts to estimate the spatiotemporal parameters of the virus, both globally and regionally, have suggested that epidemic HCV transmission began in 1900 and grew steadily until the late 1980s. However, epidemiological data suggest that the expansion of HCV may have occurred after the Second World War. The aim of our study was to elucidate the timescale and route of the global spread of HCV.
Methods and Findings
We show that the rarely sequenced HCV region (E2P7NS2) is more informative for molecular epidemiology studies than the more commonly used NS5B region. We applied phylodynamic methods to a substantial set of new E2P7NS2 and NS5B sequences, together with all available global HCV sequences with information in both of these genomic regions, in order to estimate the timescale and nature of the global expansion of the most prevalent HCV subtypes, 1a and 1b. We showed that transmission of subtypes 1a and 1b “exploded” between 1940 and 1980, with the spread of 1b preceding that of 1a by at least 16 y (95% confidence interval 15–17). Phylogeographic analysis of all available NS5B sequences suggests that HCV subtypes 1a and 1b disseminated from the developed world to the developing countries.
Conclusions
The evolutionary rate of HCV appears faster than previously suggested. The global spread of HCV coincided with the widespread use of transfused blood and blood products and with the expansion of intravenous drug use but slowed prior to the wide implementation of anti-HCV screening. Differences in the transmission routes associated with subtypes 1a and 1b provide an explanation of the relatively earlier expansion of 1b. Our data show that the most plausible route of the HCV dispersal was from developed countries to the developing world.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 150 million people (3% of the world's population) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people become infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with infected blood. Transmission routes include medical procedures (for example, transfusions with unscreened blood) and needle-sharing among intravenous drug users. This second transmission route is the most common one in developed countries where blood is now routinely screened before being used in transfusions. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes), but most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two expensive drugs called interferon and ribavirin, but these drugs are ineffective in many patients.
Why Was This Study Done?
Noone knows for sure where HCV originated although there is some evidence that it appeared first in West Africa or Southeast Asia. It is also unclear when the current HCV epidemic began. In this study, the researchers try to elucidate both the timescale and route of the global spread of the HCV epidemic by analyzing the genome sequence of HCV samples collected at different times and places. HCV is a ribonucleic acid (RNA) virus. That is, it stores the information it needs to replicate itself—its genome—as a series of “ribonucleotides.” Like other RNA viruses, the HCV genome continually accumulates small changes (mutations) and, over time, HCV has evolved into several different “genotypes,” each of which has several distinct subtypes. Furthermore, the viruses within a single subtype have subtly different genomes. By analyzing this viral diversity using complex “phylodynamic” and “phylogeographic” methods, scientists can build up a picture of how HCV has evolved in populations and how it has spread to reach its current geographical distribution.
What Did the Researchers Do and Find?
By examining the genomes of HCV samples collected between 1994 and 2006 at the Athens University Medical School (Greece), the researchers first defined a variable region of HCV called E2P7NS2 that is more informative for phylodynamic studies than the NS5B region that has been used in previous studies. They then retrieved the sequences of both regions for subtype 1a and 1b samples collected over the past 20–30 years in the Los Alamos HCV sequence database; HCV subtypes 1a and 1b cause 60% of global HCV infections. The researchers' phylodynamic analyses of these globally representative sequences (collected in the USA, Germany, Switzerland, and Greece) indicate that the transmission of HCV subtype 1a occurred at a low rate from 1906 until the 1960s, at which time there was an explosive increase in its transmission rate. Similarly, subtype 1b transmission occurred at a low rate from 1922 until the late 1940s but then increased exponentially. From 1980 onwards, the prevalence of both subtypes stabilized at a high level. The researchers' phylogeographic analyses (which considered 1a and1b NS5B sequences collected in 21 and 29 countries, respectively) suggest that HCV subtypes 1a and 1b may have spread from the developed to the developing world.
What Do These Findings Mean?
These findings indicate that the epidemic of HCV subtype 1b began in the 1940s when the use of transfused blood and blood products became widespread whereas the start of the subtype 1a epidemic coincided with the expansion of injected drug use that occurred in the 1960s. The findings also suggest that the transmission rates of both subtypes may have slowed before the widespread implementation of HCV screening in the early 1990s, possibly because the medical community was aware by then of the general risks associated with blood contamination. Finally, these findings provide new insights into how the HCV epidemic spread around the world and suggest that HCV may be evolving faster than previously thought. However, because this study relied on a small number of samples collected over a short time period, its findings need to be confirmed in larger studies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000198.
The World Health Organization provides detailed information about hepatitis C and HCV
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
MedlinePlus provides links to further resources on hepatitis C
The Los Alamos HCV database is available
The US National Center for Biotechnology Information provides a science primer on how scientists reconstruct evolutionary pathways from sequence information
doi:10.1371/journal.pmed.1000198
PMCID: PMC2795363  PMID: 20041120
15.  Assessment of human cytomegalovirus co-infection in Egyptian chronic HCV patients 
Virology Journal  2011;8:343.
Human cytomegalovirus (HCMV) is the most common cause of severe morbidity and mortality in immune- compromised individuals. This study was conducted to determine the incidence of HCMV infection in HCV patients who either spontaneously cleared the virus or progressed to chronic HCV infection. The study included a total of eighty four cases (48 females and 36 males) that were referred to blood banks for blood donation with an age range of 18-64 years (mean age 37.62 ± 10.03 years). Hepatitis C virus RNA and HCMV DNA were detected in sera by RT-nested PCR and nested PCR respectively in all subjects. Immunoglobulin G levels for HCV and HCMV were determined. Besides, IgM antibodies for HCMV infection were also determined in subjects' sera. Fifty three out of 84 cases (63%) were positive for HCV-RNA while 31 (37%) cases had negative HCV RNA. Forty six (87%) and 13 (25%) cases out of 53 HCV RNA positive patients were positive for HCMV IgG and IgM antibodies respectively. While 20 of 53 cases (38%) had detectable HCMV DNA. To examine the role of HCMV infection in HCV spontaneous resolution, two groups of HCV patients, group 1) chronic HCV infection (positive HCV RNA and positive IgG antibodies) vs group 2) spontaneous resolution (negative HCV RNA and positive IgG antibodies) were compared. The percentages of positive CMV IgG and IgM results is higher in chronic HCV patient than those in spontaneously cleared HCV patients and the difference is highly statistically significant (P value < 0.001). Also, there is a general trend towards elevated levels of CMV IgG antibodies in HCV chronic patients than those in spontaneously cleared HCV patients (P value < 0.02). HCMV DNA detection in group 1 was more than twice the value observed in group 2 (38% vs 14.3%, P value < 0.001). Moreover, levels of liver enzymes were significantly higher in HCV RNA positive cases co-infected with HCMV DNA than HCMV negative cases (P value < 0.001). The results indicate the role of HCMV in the liver pathogenesis. We conclude that chronic HCV patients co-infected with HCMV infection can be regarded as high risk groups for liver disease progression where they should be monitored for the long term outcome of the disease.
doi:10.1186/1743-422X-8-343
PMCID: PMC3145597  PMID: 21740595
Hepatitis C virus; Human Cytomegalovirus DNA; Co-infection
16.  Occult hepatitis B infection in egyptian chronic hepatitis C patients: prevalence, impact on pegylated interferon/ribavirin therapy 
Virology Journal  2010;7:324.
Background
Chronic HCV infection combined with occult hepatitis B infection has been associated with liver enzymes flare, advanced hepatic fibrosis and cirrhosis, poor response to standard interferon-α, and increased risk of HCC. This study aimed to elucidate the prevalence of occult hepatitis B infection in Egyptian chronic HCV patients, and to clarify its role in non-response of those patients to pegylated interferon/ribavirin therapy. This study enrolled 155 consecutive chronic HCV patients under pegylated interferon/ribavirin therapy. All patients were exposed to clinical assessment, biochemical, histological and virological examinations. HBV parameters (HBV DNA, anti-HBc, anti-HBs) and patients' response status to the combination therapy were determined.
Results
In this study, occult hepatitis B infection occurs in 3.9% of Egyptian chronic HCV patients; tends to affect younger age patients, associated with higher base line HCV viral load, less hepatic fibrosis than monoinfected patients. This occult hepatitis B infection is not a statistically significant cause of non-response to pegylated interferon/ribavirin therapy. Anti-HBs was not associated with any biochemical, histological or virological abnormalities in those patients, contrary to low response rate to therapy and higher HCV viral load that was observed with anti-HBc.
Conclusions
Detection of HBV DNA in HBsAg negative chronic HCV patients plays a non significant role in non-response of Egyptian patients to pegylated interferon/ribavirin therapy.
doi:10.1186/1743-422X-7-324
PMCID: PMC2998483  PMID: 21083926
17.  Cellular Immune Responses Associated with Occult Hepatitis C Virus Infection of the Liver 
Journal of Virology  2006;80(22):10972-10979.
Occult hepatitis C virus (HCV) infection is a type of recently identified chronic infection that is evidenced only by detection of HCV RNA in liver; patients consistently test negative for antibodies to HCV and HCV RNA in serum. Using ex vivo and in vitro measures of T-cell responses, we have identified functional virus-specific memory CD4+ and CD8+ T cells in the peripheral blood of patients with occult HCV infection. The features of the virus-specific T cells were consistent with immune surveillance functions, supporting previous exposure to HCV. In addition, the magnitudes of CD4+ and CD8+ T-cell responses were in parallel and correlated inversely with the extent of liver HCV infection. The detection of HCV-specific T cells in individuals in whom HCV RNA can persist in the liver despite the absence of viremia and antibodies indicates that HCV replication is prolonged in the face of virus-specific CD4+ and CD8+ T-cell responses. These findings demonstrate that HCV-specific cellular immune responses are markers not only of previous exposure to and recovery from HCV but also of ongoing occult HCV infection.
doi:10.1128/JVI.00852-06
PMCID: PMC1642164  PMID: 17071928
18.  Diagnostic Value of Serum Level of Soluble Tumor Necrosis Factor Receptor IIα in Egyptian Patients With Chronic Hepatitis C Virus Infection and Hepatocellular Carcinoma 
Hepatitis Monthly  2014;14(9):e19346.
Background:
The prognosis of hepatocellular carcinoma (HCC) is unfavorable and needs serum markers that could detect it early to start therapy at a potentially curable phase.
Objectives:
The aim of this study was to determine the value of serum soluble tumor necrosis factor (TNF) receptor-IIα (sTNFR-IIα) in diagnosis of HCC in patients with chronic hepatitis C virus (HCV) infection.
Patients and Methods:
The study was performed on 110 subjects who were classified into five groups. Group I included 20 patients with chronic noncirrhotic HCV infection and persistently normal transaminases for ≥6 months. Group II included 20 patients with chronic noncirrhotic HCV infection and elevated transaminases. Group III included 20 patients with Chronic HCV infection and liver cirrhosis. Group IV included 20 patients with chronic HCV infection with liver cirrhosis and HCC. Group V included 30 healthy age and sex-matched controls. Medical history was taken from all participants and they underwent clinical examination and abdominal ultrasonography. in addition, the following laboratory tests were requested: liver function tests, complete blood count, HBsAg, anti-HCVAb, HCV-RNA by qualitative PCR, and serum levels of α-fetoprotein (AFP) and sTNFR-IIα.
Results:
The serum level of sTNFR-IIα was significantly higher in patients with HCC in comparison to the other groups. A positive correlation was found between the serum levels of sTNFR-IIα and AST and ALT in patients of group-II. Diagnosis of HCC among patients with HCV infection and cirrhosis could be ascertained when sTNFR-IIα is assessed at a cutoff value of ≥ 250 pg/mL.
Conclusions:
Serum sTNFR-IIα could be used as a potential serum marker in diagnosing HCC among patients with HCV infection.
doi:10.5812/hepatmon.19346
PMCID: PMC4221961  PMID: 25386197
Liver Cirrhosis; Hepatocellular Carcinoma; Hepatitis C Virus; s TNF-RII
19.  Evaluating Liver Fibrosis by Transient Elastometry in Patients With HIV-HCV Coinfection and Monoinfection 
Hepatitis Monthly  2014;14(8):e15426.
Background:
Due to the high efficacy of combination antiretroviral therapy (cART), the number of patients living with HIV is increasing. Chronic HCV infection has become a leading cause of non-AIDS related morbidity and mortality in patients with HIV infection.
Objectives:
The aim of this cross-sectional study was to identify factors associated with liver fibrosis (LF) in patients with HIV monoinfection and HIV-HCV coinfection.
Patients and Methods:
We analyzed LF by transient elastometry ([TE], Fibroscan) in three groups of patients (HIV, HIV-HCV and HCV) followed at the Infectious Diseases Department of University of Ancona, Italy, between October 2009 and November 2012.
Results:
In total, 354 adults including 98 HIV, 70 HIV-HCV and 186 HCV patients were studied. HIV-HCV patients had a longer duration of HIV (P < 0.006) and HCV (P < 0.001) infections. Additionally, they were receiving cART therapy for a longer period (P < 0.001); they had higher prevalence of lipodystrophy (P < 0.001) and higher HCV load (P = 0.004). LF was significantly more pronounced in HCV and HIV-HCV compared to HIV patients (P < 0.001). A total of 13.3%, 39.2% and 51.4% of HIV, HCV and HIV-HCV, respectively, showed a LF ≥ F2. Additionally, a severe LF (F = 4) was significantly more frequent among HIV-HCV compared to other groups. A longer exposure to didanosine, stavudine, lopinavir/ritonavir and fosamprenavir resulted in increased LF by univariate analysis (P ranging from < 0.001 to 0.007). By logistic regression analysis, the only variables significantly associated with increased LF were HCV coinfection, older age, and high AST values (P ranging from < 0.001 to 0.036).
Conclusions:
HCV coinfection, older age and AST were associated with LF in patients with HIV infection.
doi:10.5812/hepatmon.15426
PMCID: PMC4199183  PMID: 25337140
Coinfection; Liver Fibrosis; Transient Elastometry
20.  A Novel Diagnostic Target in the Hepatitis C Virus Genome 
PLoS Medicine  2009;6(2):e1000031.
Background
Detection and quantification of hepatitis C virus (HCV) RNA is integral to diagnostic and therapeutic regimens. All molecular assays target the viral 5′-noncoding region (5′-NCR), and all show genotype-dependent variation of sensitivities and viral load results. Non-western HCV genotypes have been under-represented in evaluation studies. An alternative diagnostic target region within the HCV genome could facilitate a new generation of assays.
Methods and Findings
In this study we determined by de novo sequencing that the 3′-X-tail element, characterized significantly later than the rest of the genome, is highly conserved across genotypes. To prove its clinical utility as a molecular diagnostic target, a prototype qualitative and quantitative test was developed and evaluated multicentrically on a large and complete panel of 725 clinical plasma samples, covering HCV genotypes 1–6, from four continents (Germany, UK, Brazil, South Africa, Singapore). To our knowledge, this is the most diversified and comprehensive panel of clinical and genotype specimens used in HCV nucleic acid testing (NAT) validation to date. The lower limit of detection (LOD) was 18.4 IU/ml (95% confidence interval, 15.3–24.1 IU/ml), suggesting applicability in donor blood screening. The upper LOD exceeded 10−9 IU/ml, facilitating viral load monitoring within a wide dynamic range. In 598 genotyped samples, quantified by Bayer VERSANT 3.0 branched DNA (bDNA), X-tail-based viral loads were highly concordant with bDNA for all genotypes. Correlation coefficients between bDNA and X-tail NAT, for genotypes 1–6, were: 0.92, 0.85, 0.95, 0.91, 0.95, and 0.96, respectively; X-tail-based viral loads deviated by more than 0.5 log10 from 5′-NCR-based viral loads in only 12% of samples (maximum deviation, 0.85 log10). The successful introduction of X-tail NAT in a Brazilian laboratory confirmed the practical stability and robustness of the X-tail-based protocol. The assay was implemented at low reaction costs (US$8.70 per sample), short turnover times (2.5 h for up to 96 samples), and without technical difficulties.
Conclusion
This study indicates a way to fundamentally improve HCV viral load monitoring and infection screening. Our prototype assay can serve as a template for a new generation of viral load assays. Additionally, to our knowledge this study provides the first open protocol to permit industry-grade HCV detection and quantification in resource-limited settings.
Christian Drosten and colleagues develop, validate, and make openly available a prototype hepatitis C virus assay based on the conserved 3' X-tail element, with potential for clinical use in developing countries.
Editors' Summary
Background.
About 3% of the world's population (170 million people) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people are newly infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with the blood of an infected person. Globally, the main routes of transmission are the use of unscreened blood for transfusions and the reuse of inadequately sterilized medical instruments, including needles. In affluent countries, where donated blood is routinely screened for the presence of HCV, most transmission is through needle sharing among drug users. The risk of sexual and mother-to-child transmission of HCV is low. Although HCV infection occasionally causes an acute (short-lived) illness characterized by tiredness and jaundice (yellow eyes and skin), most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs called interferon and ribavirin, but these drugs are expensive and are ineffective in many patients.
Why Was This Study Done?
An effective way to limit the global spread of HCV might be to introduce routine screening of the blood that is used for transfusions in developing countries. In developed countries, HCV screening of blood donors use expensive, commercial “RT-PCR” assays to detect small amounts of HCV ribonucleic acid (RNA; HCV stores the information it needs to replicate itself—its genome—as a sequence of “ribonucleotides”). All the current HCV assays, which can also quantify the amount of viral RNA in the blood (the viral load) during treatment, detect a target sequence in the viral genome called the 5′-noncoding region (5′-NCR). However, there are several different HCV “genotypes” (strains). These genotypes vary in their geographical distribution and, even though the 5′-NCR sequence is very similar (highly conserved) in the common genotypes (HCV genotypes 1–6), the existing assays do not detect all the variants equally well. This shortcoming, together with their high cost, means that 5′-NCR RT-PCR assays are not ideal for use in many developing countries. In this study, the researchers identify an alternative diagnostic target sequence in the HCV genome—the 3′-X-tail element—and ask whether this sequence can be used to develop a new generation of tests for HCV infection that might be more appropriate for use in developing countries.
What Did the Researchers Do and Find?
The researchers determined the RNA sequence of the 3′-X-tail element in reference samples of the major HCV genotypes and showed that this region of the HCV genome is as highly conserved as the 5′-NCR. They then developed a prototype X-tail RT-PCR assay and tested its ability to detect small amounts of HCV and to measure viral load in genotype reference samples and in a large panel of HCV-infected blood samples collected in Germany, the UK, Brazil, South Africa, and Singapore. The new assay detected low levels of HCV RNA in all of the genotype reference samples and was also able to quantify high RNA concentrations. The viral load estimates it provided for the clinical samples agreed well with those obtained using a commercial assay irrespective of the sample's HCV genotype. Finally, the X-tail RT-PCR assay gave similar results to a standard assay at a fraction of the cost when used to measure viral loads in a Brazilian laboratory in an independent group of 127 patient samples collected in Brazil.
What Do These Findings Mean?
These findings suggest that the HCV 3′-X-tail element could provide an alternative target for screening blood samples for HCV infection and for monitoring viral loads during treatment, irrespective of HCV genotype. In addition, they suggest that X-tail RT-PCR assays may be stable and robust enough for use in laboratories in emerging countries. Overall, these findings should stimulate the development of a new generation of clinical HCV assays that, because the protocol used in the X-tail assay is freely available, could improve blood safety in developing countries by providing a cheap and effective alternative to existing proprietary HCV assays.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000031.
The World Health Organization has a fact sheet about hepatitis C (in English and French)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The MedlinePlus Encyclopedia has a page on hepatitis C; MedlinePlus also provides links to further information on hepatitis C (in English and Spanish)
doi:10.1371/journal.pmed.1000031
PMCID: PMC2637920  PMID: 19209955
21.  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.
Background
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.
Objectives
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.
Results
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).
Conclusions
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.
doi:10.5812/hepatmon.10134
PMCID: PMC3741907  PMID: 23967017
Hepatitis B; Hepatitis C Virus; Peripheral Blood Mononuclear Cell
22.  Relationship between vitamin D and IL-23, IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians 
World Journal of Hepatology  2012;4(8):242-247.
AIM: To assess vitamin D in hepatitis C patients and its relationship to interleukin (IL)-23, IL-17, and macrophage chemoattractant protein-1 (MCP-1).
METHODS: The study was conducted on 50 Egyptian hepatitis C virus (HCV) genotype number IV-infected patients and 25 age- and gender-matched healthy subjects. Venous blood samples were obtained. Samples were allowed to clot and sera were separated by centrifugation and stored at -20 °C. A 25 hydroxy vitamin D assay was carried out using solid phase RIA. A 1,25 dihydroxy vitamin D assay was carried out using a commercial kit purchased from Incstar Corporation. IL-17 and -23 and MCP-1 were assayed by an enzyme immunoassay. Quantitative and qualitative polymerase chain reaction for HCV virus were done by TaqMan technology. Only HCV genotype IV-infected subjects were included in the study. The mean ± SD were determined, a t-test for comparison of means of different parameters was used. Correlation analysis was done using Pearson’s correlation. Differences among different groups were determined using the Kruskal-Wallis test.
RESULTS: The mean vitamin D level in HCV patients (group I) was 15 ± 5.2 ng/mL while in control (group II) was 39.7 ± 10.8. For active vitamin D in group I as 16.6 ± 4.8 ng/mL while in group II was 41.9 ± 7.9. IL-23 was 154 ± 97.8 in group I and 6.7 ± 2.17 in group II. IL-17 was 70.7 ± 72.5 in cases and 1.2 ± 0.4 in control. MCP-1 was 1582 ± 794.4 in group I and 216.1 ± 5.38 in group II. Vitamin D deficiency affected 72% of HCV-infected patients and 0% of the control group. Vitamin D insufficiency existed in 28% of HCV-infected patients and 12% of the control group. One hundred percent of the cirrhotic patients and 40% of non cirrhotic HCV-infected patients had vitamin D deficiency. IL-23, IL-17, and MCP-1 were markedly increased in HCV-infected patients in comparison to controls.A significant negative correlation between vitamin D and IL-17 and -23 and MCP-1 was detected. HCV-infected males and females showed no differences with respect to viral load, vitamin D levels, IL-17, IL-23 and MCP-1. The viral load was negatively correlated with vitamin D and active vitamin D (P = 0.0001 and P = 0.001, respectively), while positively correlated with IL-23, IL-17, and MCP-1. We classified the patients according to sonar findings into four groups. Group Ia with bright hepatomegaly and included 14 patients. Group Ib with perihepatic fibrosis and included 11 patients. Group Ic with liver cirrhosis and included 11 patients. Group Id with hepatocellular carcinoma (HCC) and included 14 patients. Vitamin D and active vitamin D were shown to be lower in cirrhotic patients and much lower in patients with HCC, and this difference was highly significant (P = 0.0001). IL-17 and -23 and MCP-1 were higher in advanced liver disease) and the differences were highly significant (P = 0.0001).
CONCLUSION: Whether the deficiency of vitamin D is related to HCV-induced chronic liver disease or predisposing factor for higher viral load is a matter of debate.
doi:10.4254/wjh.v4.i8.242
PMCID: PMC3443706  PMID: 22993666
Vitamin D; Macrophage chemoattractant protin-1; Liver cirrhosis; Interleukin-23; Interleukin-17; Liver cirrhosis
23.  The influence of hepatitis B virus on antiviral treatment with interferon and ribavirin in Asian patients with hepatitis C virus/hepatitis B virus coinfection: a meta-analysis 
Virology Journal  2012;9:186.
Background
Clinical and laboratory studies have indicated that coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) can suppress one another, eliciting a dominant disease phenotype. To assess whether HBV can influence the antiviral effect of treatment on HCV, we performed a meta-analysis to comparatively analyze the response to interferon plus ribavirin treatment in patients with HBV/HCV coinfection and HCV mono-infection.
Methods
Published studies in the English-language medical literature that involved cohorts of HBV/HCV coinfection and HCV mono-infection were obtained by searching Medline, Cochrane and Embase databases. Studies that compared the efficacy of treatment with interferon plus ribavirin in HBV/HCV coinfection and HCV mono-infection were assessed. End-of-treatment virological response (ETVR), sustained virological response (SVR), HCV relapse rate, and alanine aminotransferase (ALT) normalization rate were compared between HBV/HCV coinfection and HCV mono-infection patients.
Results
Five trials involving 705 patients were analyzed. At the end of follow-up serum ALT normalization rates in patients with HCV mono-infection were significantly higher than in patients with HBV/HCV coinfection (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.40–0.80, P = 0.001). The ETVR and SVR achieved in HBV/HCV coinfection patients were comparable to those in HCV mono-infection patients (OR = 1.03, 95% CI: 0.37–2.82, P = 0.96 and OR = 0.87, 95% CI: 0.62–1.21, P = 0.38, respectively). The rate of relapse for HCV or HCV genotype 1 was not significantly different between HBV/HCV coinfection patients and HCV mono-infection patients (OR = 1.55, 95% CI: 0.98–2.47, P = 0.06; HCV genotype 1: OR = 2.4, 95% CI: 1.17–4.91, P = 0.19).
Conclusions
Treatment with interferon and ribavirin achieves similar ETVR and SVR in HBV/HCV coinfection and HCV mono-infection. HBV/HCV coinfection patients had distinctively lower end of follow-up serum ALT normalization.
doi:10.1186/1743-422X-9-186
PMCID: PMC3511228  PMID: 22950520
Coinfection; Hepatitis B; Hepatitis C; Interferon; Ribavirin
24.  Vitamin D deficiency: Correlation to interleukin-17, interleukin-23 and PIIINP in hepatitis C virus genotype 4 
AIM: To assess vitamin D (Vit D) abnormalities in hepatitis C infected patients and their relationship with interleukin (IL)-17, IL-23 and N-terminal propeptide of type III pro-collagen (PIIINP) as immune response mediators.
METHODS: The study was conducted on 50 Egyptian patients (36 male, 14 female) with hepatitis C virus (HCV) infection, who visited the Hepatology Outpatient Clinic in the Endemic Disease Hospital at Cairo University. Patients were compared with 25 age- and sex-matched healthy individuals. Inclusion criteria were based on a history of liver disease with HCV genotype 4 (HCV-4) infection (as new patients or under follow-up). Based on ultrasonography, patients were classified into four subgroups; 14 with bright hepatomegaly; 11 with perihepatic fibrosis; 11 with hepatic cirrhosis; and 14 with cirrhosis and hepatocellular carcinoma (HCC). Total Vit D (i.e., 25-OH-Vit D) and active Vit D [i.e., 1,25-(OH)2-Vit D] assays were carried out using commercial kits. IL-17, IL-23 and PIIINP levels were assayed using enzyme linked immunosorbent assay kits, while HCV virus was measured by quantitative and qualitative polymerase chain reaction.
RESULTS: Levels of Vit D and its active form were significantly lower in advanced liver disease (hepatic cirrhosis and/or carcinoma) patients, compared to those with bright hepatomegaly and perihepatic fibrosis. IL-17, IL-23 and PIIINP levels were markedly increased in HCV patients and correlated with the progression of hepatic damage. The decrease in Vit D and active Vit D was concomitant with an increase in viral load, as well as levels of IL-17, IL-23 and PIIINP among all subgroups of HCV-infected patients, compared to normal healthy controls. A significant negative correlation was evident between active Vit D and each of IL-17, IL-23 and PIIINP (r = -0.679, -0.801 and -0.920 at P < 0.001, respectively). HCV-infected men and women showed no differences with respect to Vit D levels. The viral load was negatively correlated with Vit D and active Vit D (r = -0.084 and -0.846 at P < 0.001, respectively), and positively correlated with IL-17, IL-23 and PIIINP (r = 0.951, 0.922 and 0.94 at P < 0.001, respectively). Whether the deficiency in Vit D was related to HCV-induced chronic liver disease or was a predisposing factor for a higher viral load remains to be elucidated.
CONCLUSION: The negative correlations between Vit D and IL-17, IL-23 and PIIINP highlight their involvement in the immune response in patients with HCV-4-related liver diseases in Egypt.
doi:10.3748/wjg.v18.i28.3738
PMCID: PMC3406428  PMID: 22851868
Vitamin D; Interleukin-17; Interleukin-23; N-terminal propeptide of type III pro-collagen; Hepatitis genotype 4
25.  Chronic Kidney Disease (CKD) after Liver Transplantation in HIV/ HCV Coinfected versus HIV/non-HCV Infected Recipients: Results from the NIH Multi-Site Study 
Hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV) are both associated with chronic kidney disease (CKD), a major complication after orthotopic liver transplantation (OLT). The aim of this study was to assess predictors of post-OLT CKD in HIV/HCV coinfected versus HIV/non-HCV infected recipients.
METHODS
Data from the NIH Solid Organ Transplantation in HIV: Multi-Site Study of 116 OLT recipients (35 HIV/non-HCV and 81 HIV/HCV co-infected) from 2003 to 2010 were analyzed for pre-transplant CKD prevalence (estimated glomerular filtration rate (eGFR) < 60 ml/min for ≥ 3 months) and incidence of CKD up to 3 years post-transplant. Proportional hazards models were performed to assess predictors of post-transplant CKD. A contemporaneous cohort of HCV monoinfected transplant recipients from the SRTR database was also analyzed.
RESULTS
Median age at transplant was 48 years, serum creatinine was 1.1 mg/dl, and median eGFR was 77 ml/min. Thirty-four patients had suspected pre-transplant CKD; 20 of these (59%) had post-transplant CKD. Among the 82 patients without pre-transplant CKD (26 HIV/non-HCV and 56 HIV/HCV coinfected), the cumulative incidence of stage 3 CKD at 3 years post-OLT was 62% (55% HIV/non-HCV versus 65% HIV/HCV coinfected) and stage 4/5 CKD was 8% (0% HIV/non-HCV versus 12% HIV/HCV coinfected). In multivariate proportional hazards analysis, older age (HR 1.05 per year; p 0.03) and CD4 count (HR 0.90 per 50 cells/µL; p 0.01) were significant predictors of CKD. HCV coinfection was significantly associated with stage 4/5 CKD (HR 10.8; p 0.03) after adjustment for age on multivariate analysis. The cumulative incidence of stage 4/5 CKD was significantly higher in HIV/HCV coinfected patients compared to HIV/non-HCV and HCV monoinfected transplant recipients (p=0.001).
CONCLUSIONS
CKD occurs frequently in HIV infected transplant recipients. Predictors of post-transplant CKD include older age, and lower post-transplant CD4 count. HCV co-infection is associated with a higher incidence of stage 4/5 CKD.
doi:10.1002/lt.23648
PMCID: PMC3667971  PMID: 23512786

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