Clearance Of Hepatitis C Virus RNA Research Articles

Brief Report: Reduced Cell-Associated HTLV-2 DNA in Antiretroviral Treated HIV-1-HCV-Coinfected Patients Who Either Received Interferon-α/Ribavirin-Based Hepatitis C Therapy or Had Spontaneous HCV RNA Clearance.

We analyzed the effect of interferon α (IFN-α) and ribavirin (RBV) therapy on cell-associated human T-lymphotropic virus type 2 (HTLV-2) DNA in HIV-1-coinfected patients receiving antiretroviral therapy. Sixty-one patients under suppressive antiretroviral therapy were included: 37 with hepatitis C virus (HCV) infection, 15 with sustained virologic response (N = 10), relapse (N = 2), or with nonresponse (N = 3) after IFN-α/RBV treatment, and 9 with spontaneous HCV RNA clearance. Patients who were treated with IFN-α/RBV or had spontaneous HCV clearance had lower level of cell-associated HTLV-2 DNA (P = 0.022 and P = 0.040, respectively). Both IFN-alpha treatment and the ability to spontaneously clear HCV infection seem to reduce cell-associated HTLV-2 DNA in HIV-1-coinfected patients.

Prevalence and characterization of hepatitis B and C virus infections in a needle-sharing population in Northern China.

BackgroundThe epidemiologies of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in specific populations in certain areas of China are poorly understood. A pilot survey of HCV/HBV infections was carried out in villages in Kuancheng County, Heben Province, where injection of sodium benzoate or amphetamines using shared needles has been a common practice. The aims of this study were to analyze the endemicity and characterize HCV/HBV infections in this population.MethodsData on demographic characteristics and drug abuse were collected from individuals who signed informed consent forms. Serum HCV antibody (anti-HCV), hepatitis B surface antigen (HBsAg), and hepatitis B core antibody (anti-HBc) were measured in all participants. HCV RNA was measured in samples positive for anti-HCV using real-time polymerase chain reaction.ResultsAmong 852 participants from 11 villages, 49.9% had used sodium benzoate or amphetamine at least once, by intravenous injection. The overall prevalence of anti-HCV, HCV RNA, anti-HBc, HBsAg, and HCV/HBV co-infection was 37.1%, 26.6%, 67.7%, 10.7%, and 30.0%, respectively. Two-hundred-twenty-three of 227 (98.2%) participants positive for HCV RNA were aged >40 years. Co-infection was related to sex, age, number of injections, and time from first injection. The rate of spontaneous HCV RNA clearance was 28.2% (89/316), and was related to the number of injections, time from first injection, and HBsAg positivity. However, HBsAg was related to the anti-HBc signal/cut-off ratio rather than to the above parameters. Trend tests demonstrated that the prevalence of anti-HCV, HCV RNA, and anti-HBc was related to the number of injections (P < 0.001), while HBsAg prevalence was not (P = 0.347).ConclusionsThe prevalence of HCV and HBV infection is likely to be high among individuals older than 40 years in areas of needle sharing, and one-time screening for HCV infection should be offered to these populations.

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

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

Modulation of host lipid metabolism by hepatitis C virus: Role of new therapies.

It is well established that hepatitis C virus (HCV) infection and replication relies on host lipid metabolism. HCV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides, circulating infective particles are associated with very low-density lipoprotein. On the other hand, higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HCV infection, suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy (> 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HCV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review, host genetic factors, viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism.

Spontaneous Clearance of Chronic HCV Infection: An Unusual Phenomenon

Introduction: In acute hepatitis C virus (HCV) infection, only about 25% of patients clear the infection through an immune response. Once chronic HCV infection is established in the remaining 75% of patients, spontaneous clearance of HCV infection is extremely uncommon. We present to you 5 such cases. We describe 5 consecutive patients at the Bronx VA Medical Center that spontaneously cleared chronic HCV infection within the last 10 years. The results are as follows: 3 out of 5 patients were chronically infected with HCV genotype 1. Spontaneous clearance occurred in 3 different scenarios: 1.) Two patients were HIV and HCV-co-infected (HIV infection was suppressed with antiretroviral therapy) and were never treated for hepatitis C. After many years of chronic HCV viremia, they spontaneously became HCV RNA undetectable and remained undetectable for up to 4 years. 2.) Two patients with chronic HCV mono-infection were each treated with antiviral therapy, which resulted in undetectable HCV RNA. After the end of therapy, they relapsed to high-level viremia and high ALT level, but spontaneously cleared HCV RNA to undetectable levels and a normal ALT. However, they relapsed again to high HCV RNA and high ALT. One patient subsequently cleared again and relapsed again. 3.) One HCV-mono-infected patient had received a liver transplant and was on immunosuppressive therapy. He never received HCV antiviral therapy. Two years after the liver transplant, his HCV RNA became undetectable, and it has remained undetectable since 3 years ago. Spontaneous clearance of chronic HCV infection is a very rare phenomenon, but we present 5 subjects in 1 medical center over a span of 10 years that exhibit this rare phenomenon, and in different scenarios: 1.) after relapse from antiviral therapy, 2.) post-liver transplantation, and 3.) in HIV/HCV co-infection.

Hepatitis C virus (HCV) antibody dynamics following acute HCV infection and reinfection among HIV-infected men who have sex with men.

A decline of hepatitis C virus (HCV) antibody titers (anti-HCV), ultimately resulting in seroreversion, has been reported following clearance of viremia in both acute and chronic HCV infection. However, frequency of seroreversion remains unknown in human immunodeficiency virus (HIV)/HCV-coinfected patients. We describe anti-HCV dynamics among HIV-infected men who have sex with men (MSM) following acute HCV infection and reinfection. Primary acute HCV infection was assumed when a subject was anti-HCV negative prior to the first positive HCV RNA test. Anti-HCV was measured at least annually in 63 HIV-infected MSM, with a median follow-up of 4.0 years (interquartile range [IQR], 2.5-5.7 years). Time from HCV infection to seroconversion, and from seroconversion to seroreversion, was estimated using the Kaplan-Meier method. Longitudinal anti-HCV patterns were studied using a random-effects model to adjust for repeated measures. Median time from HCV infection to seroconversion was 74 days (IQR, 47-125 days). Subjects who cleared HCV RNA (n = 36) showed a significant decrease in anti-HCV levels (P < .001). Among 31 subjects with sustained virologic response (SVR), anti-HCV became undetectable during follow-up in 8; cumulative incidence of seroreversion within 3 years after seroconversion was 37% (95% confidence interval, 18%-66%). Eighteen subjects became reinfected during follow-up; this coincided with a subsequent increase in anti-HCV reactivity. A decline of anti-HCV reactivity was associated with HCV RNA clearance. Seroreversion was very common following SVR. Upon reinfection, anti-HCV levels increased again. Monitoring anti-HCV levels might therefore be an effective alternative for diagnosis of HCV reinfection.

Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants with in vitro resistance to SR-BI-targeting agents.

Hepatitis C virus (HCV)-induced endstage liver disease is currently a major indication for liver transplantation. After transplantation the donor liver inevitably becomes infected with the circulating virus. Monoclonal antibodies (mAbs) against the HCV coreceptor scavenger receptor class B type I (SR-BI) inhibit HCV infection of different genotypes, both in cell culture and in humanized mice. Anti-SR-BI mAb therapy is successful even when initiated several days after HCV exposure, supporting its potential applicability to prevent HCV reinfection of liver allografts. However, HCV variants with reduced SR-BI dependency have been described in the literature, which could potentially limit the use of SR-BI targeting therapy. In this study we show, both in a preventative and postexposure setting, that humanized mice infected with HCV variants exhibiting increased in vitro resistance to SR-BI-targeting molecules remain responsive to anti-SR-BI mAb therapy in vivo. A 2-week antibody therapy readily cleared HCV RNA from the circulation of infected humanized mice. We found no evidence supporting increased SR-BI-receptor dependency of viral particles isolated from humanized mice compared to cell culture-produced virus. However, we observed that, unlike wild-type virus, the in vitro infectivity of the resistant variants was inhibited by both human high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The combination of mAb1671 with these lipoproteins further increased the antiviral effect. HCV variants that are less dependent on SR-BI in vitro can still be efficiently blocked by an anti-SR-BI mAb in humanized mice. Since these variants are also more susceptible to neutralization by anti-HCV envelope antibodies, their chance of emerging during anti-SR-BI therapy is severely reduced. Our data indicate that anti-SR-BI receptor therapy could be an effective way to prevent HCV infection in a liver transplant setting.

High rate of hepatitis C virus (HCV) recurrence in HIV-infected individuals with spontaneous HCV RNA clearance.

Following resolution of hepatitis C virus (HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV-1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA ≥ 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. Of 191 eligible patients, 35 [18.3%; 95% confidence interval (CI) 12.8-23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users (IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0-5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio (OR) 0.44; 95% CI 0.20-0.99; P = 0.046] and older persons (OR 0.51 per 10 years older; 95% CI 0.28-0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non-IDUs (OR 6.58; 95% CI 1.48-29.28; P = 0.013). Around 1 in 5 HIV-infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early.

Low prevalence of hepatitis C infection among HIV-infected individuals in Slovenia: a nationwide study, 1985–2013

After introduction of highly active antiretroviral therapy and consecutive successful control of HIV infection hepatitis C virus (HCV) has become an important pathogen in HIV infected patients. HIV infection in a person who is also HCV infected results in reduced rate of spontaneous HCV RNA clearance, faster liver disease progression and more aggressive course of liver disease. A total of 639 individuals were cumulatively reported as HIV-infected in Slovenia until the end of 2013. The majority of HIV-infected were men (553/639; 86.5%) and among them 68.2% were men who have sex with men. The predominant HIV-1 subtype in Slovenia is subtype B, which is present in 85.8% of the infected individuals. We tested 575 (90.0%) of 639 Slovenian individuals who were confirmed as HIV positive by the end of 2013 for HCV infection. All individuals included in a study were tested for both anti-HCV and HCV RNA. Out of 575 HIV-infected individuals 44 (7.6%) had anti-HCV specific antibodies, and 32 of them (72.7%) were also HCV RNA positive. We didn’t detect HCV RNA alone in any of the 531 anti-HCV-negative individuals. Anti-HCV positivity was significantly more frequent in HIV-infected individuals who acquired HIV by parenteral route (73.3%) comparing with those who acquired HIV by sexual route (2.6%). The most prevalent HCV genotype among HIV-infected individuals was genotype 1 (70.8%), followed by genotype 3 (16.7%), genotype 4 (8.3%) and genotype 2 (4.2%). HCV genotypes distribution didn’t significantly differ between HIV-positive and HIV-negative, HCV-positive Slovenian patients. Our study which was performed on the highest proportion per entire population of HIV-infected individuals from a certain country identified Slovenia as the country with the lowest prevalence of HCV infection among HIV-infected individuals. The predominance of sexual transmission of HIV (79.2%) in Slovenia and the fact that HIV has not yet entered the intravenous drug users’ community in Slovenia are the two most likely reasons for low prevalence of HIV-HCV co-infection. However, the present epidemiological situation in Slovenia needs to be monitored closely since it could quickly change in a case of an increase in the incidence of acute hepatitis C among HIV-infected men who have sex with men and/or increase of HIV infection among intravenous drug users in the country, as it happened recently in some neighboring countries.

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

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

A pilot study of triple therapy with telaprevir, peginterferon and ribavirin for elderly patients with genotype 1 chronic hepatitis C

The prevalence of hepatitis C virus (HCV) infection in elderly patients has been increasing in Japan. However, there are no reports on the safety and efficacy of the triple therapy of telaprevir, peginterferon, and ribavirin for elderly patients with chronic HCV infection. This study evaluated the safety and efficacy of triple therapy [12 weeks of telaprevir 1,500 mg/day, reduction dose, and 24 weeks of peginterferon and ribavirin] in 18 elderly Japanese patients aged >65 years, with chronic infection with HCV genotype 1b. Four patients received triple therapy with telaprevir 2,250 mg/day and the other 14 patients received telaprevir 1,500 mg/day. Sustained virological response-12 (HCV RNA negativity at 12 weeks after completion of therapy) was 50% (9 of 18 patients); while 4 of 18 (22%) patients discontinued triple therapy due to adverse events (skin rashes, anemia, poor appetite). The dose of telaprevir did not affect HCV RNA clearance rates. Regardless of the dose, 50% of the treated patients achieved sustained virological response-12, evaluated by intention-to-treat analysis. Furthermore, the fall in hemoglobin and the rise in serum creatinine were significantly milder in the telaprevir 1,500 mg group than the telaprevir 2,250 mg/day group. Further analysis showed that 67% (6 of 9 elderly patients) with IL28B gene (rs8099917) genotype TT, treated with telaprevir 1,500 mg, achieved sustained virological response-12. These results suggest that 24-week triple therapy with telaprevir 1,500 mg seems safe and efficacious for elderly Japanese patients infected with HCV genotype 1b.

Antiviral Therapy of Symptomatic HCV-mixed Cryoglobulinemia after Liver Transplant: Case Report and Literature Review

Hepatitis C virus (HCV) infection may be associated with extra-hepatic illness including mixed cryoglobulinemia (MC). Consistent evidence exists on HCV-MC in the non-transplantation setting but information on HCV-related cryoglobulinemia after solid organ transplantation is limited, particularly after liver transplantation (LT). We report on a 48-year-old man who developed HCV-associated cryoglobulinemic vasculitis with recurrent hepatitis after liver transplant. One year after transplant for HCV-positive cirrhosis, he presented severe cutaneous manifestations, and biopsy-proven cryoglobulinemic membrano-proliferative glomerulonephritis (MPGN). HCV RNA clearance occurred within a few weeks of antiviral therapy; sustained viral response (SVR) was obtained by one year of anti-HCV combination therapy (eight months of pegylated IFN/ribavirin and four months of standard IFN/ribavirin). SVR was linked to complete remission of skin, liver, and kidney abnormalities. Tolerance to the pegylated IFN/ribavirin regimen was not excellent due to the occurrence of lobar pneumonia with anemia; thus, peg-IFN was replaced by recombinant IFN, with a favorable outcome. Clinical and viral remission persisted over a 48-month follow-up. HCV-associated mixed cryoglobulinemia flareups following LT were successfully managed with combined antiviral therapy. HCV-related MC is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed at evaluating the efficacy and safety of anti-HCV therapy after solid organ transplantation or in the non-transplantation setting.

Impact of Soluble CD26 on Treatment Outcome and Hepatitis C Virus-Specific T Cells in Chronic Hepatitis C Virus Genotype 1 Infection

BackgroundInterferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50–80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells.MethodsBaseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8+ T cells.ResultsGenotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8+ T cells (P = 0.02).ConclusionsLow baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8+ T cells.

Role of GB Virus C in HIV-1–Infected and Hepatitis C Virus–Infected Hemophiliac Children and Adolescents

GB Virus C (GBV-C) has been associated with a better prognosis of HIV-1 disease in adults. Little is known about prevalence and interaction between GBV-C, HIV-1, and/or hepatitis C virus (HCV) in hemophiliac children and adolescents. A well-characterized cohort of HIV-1-infected and HIV-1-uninfected hemophiliac children and adolescents followed in the Hemophilia Growth and Development Study (HGDS) were evaluated using quantitative reverse transcription polymerase chain reaction to detect GBV-C RNA in samples from baseline and last follow-up visit. HIV-1-infected (n = 202) and HIV-1-uninfected (n = 119) patients had a low prevalence of GBV-C infection at baseline (0.9 and 0%), which increased at time of last follow-up visit to 25.2% and 26.3%, respectively. In addition, at the time of the follow-up GBV-C measurement, those GBV-C infected had been followed longer and had higher CD4(+) cell counts and lower HIV-1 viral loads than those GBV-C uninfected. These beneficial effects of GBV-C were no longer significant after controlling for CD4(+) cell count and HIV-1 RNA at baseline. HCV RNA clearance was more common amongst those who were not GBV-C infected than those who became GBV-C viremic. This study confirms a positive association of GBV-C with milder course of HIV-1 infection. GBV-C infection was associated with a higher likelihood of persistent HCV infection.

Therapy‐induced clearance of HCV core antigen from plasma predicts an end of treatment viral response

During viral assembly, viral proteins are released into plasma and can be used to infer viral load. The Architect hepatitis C virus (HCV) core antigen (Ag) assay is a potential alternative to HCV RNA quantification for measuring response to therapy and predicting an end of treatment viral response (EOTR). The HCVp22Ag assay was used to infer viral load in 68 window RNA-containing samples and in 284 samples from baseline to week 14 of ribavirin/interferon treatment in 23 patients with EOTR including three who relapsed, 20 not achieving EOTR and 11 controls. HCV Ag and RNA correlated well (r = 0.86) with linear dose responses on dilution. In patients on therapy and control patients, plasma HCV antigen was detected in 51 of 54 with an interpolated LOD cut off between 10(3) and 10(4) RNA IU/mL. Plasma HCV antigenaemia and plasma RNA levels were significantly different in EOTR from non-EOTR patients at 3 days after treatment start and all times thereafter. Positive and negative EOTR predictive values for HCV RNA >2 log drop and HCV Ag loss at 12 weeks were 70% and 74%, 85% and 93% respectively. HCV Ag reactivity has a linear dose response independent of genotype and correlates well with HCV RNA. The failure to clear HCV Ag is as accurate as the failure to clear HCV RNA at twelve weeks into therapy in predicting the likelihood of failure to achieve EOTR. HCV Ag potentially offers a convenient alternative to RNA measurement for defining a futility flag in HCV therapy.

Role of GB Virus C in Human Immunodeficiency Virus Type-1- and Hepatitis C Virus-infected Hemophiliac Children and Adolescents

GB Virus C (GBV-C) has been associated with a better prognosis of HIV-1 disease in adults. Little is known about prevalence and interaction between GBV-C, HIV-1, and/or hepatitis C virus (HCV) in hemophiliac children and adolescents.A well-characterized cohort of HIV-1-infected and HIV-1-uninfected hemophiliac children and adolescents followed in the Hemophilia Growth and Development Study (HGDS) were evaluated using quantitative reverse transcription polymerase chain reaction to detect GBV-C RNA in samples from baseline and last follow-up visit.HIV-1-infected (n = 202) and HIV-1-uninfected (n = 119) patients had a low prevalence of GBV-C infection at baseline (0.9 and 0%), which increased at time of last follow-up visit to 25.2% and 26.3%, respectively. In addition, at the time of the follow-up GBV-C measurement, those GBV-C infected had been followed longer and had higher CD4(+) cell counts and lower HIV-1 viral loads than those GBV-C uninfected. These beneficial effects of GBV-C were no longer significant after controlling for CD4(+) cell count and HIV-1 RNA at baseline. HCV RNA clearance was more common amongst those who were not GBV-C infected than those who became GBV-C viremic.This study confirms a positive association of GBV-C with milder course of HIV-1 infection. GBV-C infection was associated with a higher likelihood of persistent HCV infection.

An inadequate dose of ribavirin is related to virological relapse by chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin

The aim of this large-scale analysis was to assess the effect of 48-week pegylated interferon (PEG-IFN) α-2b and ribavirin (RBV) therapy on virological relapse by patients infected with hepatitis C virus (HCV) genotype 1. The relationship between virological relapse and the dose of PEG-IFNα-2b and RBV was investigated in 619 patients who had once cleared HCV RNA during PEG-IFNα-2b and RBV treatment for 48 weeks. The overall virological relapse rate was 34.1% (211 of 619). The relapse rate was 59.5% (22 of 37) for patients who received <6 mg/kg/day of RBV, even if a sufficient dose of PEG-IFNα-2b (≥1.5 μg/kg/day) was received. In contrast, the relapse rate was 28.1% (16 of 57) for patients who received ≥12 mg/kg/day of RBV, irrespective of the PEG-IFNα-2b dose. The relapse rates were significantly increased with the reduction of the RBV dose for both PEG-IFNα-2b doses of ≥1.2 and <1.2 μg/kg/week (P < 0.0001 and P = 0.0006, respectively). Moreover, the relapse rate was 41.2% (35 of 85) for patients with an early virological response (EVR) who received <6 mg/kg/day of RBV. The relapse rates were significantly increased with the reduction of the RBV dose in both those patients with an EVR and those with a late virological response (P = 0.0006 and P = 0.0088, respectively). To summarize, for HCV genotype 1 patients treated with PEG-IFNα-2b and RBV, the virological relapse of HCV was RBV dose-dependent, irrespective of the dose of PEG-IFNα or the effect of early viral kinetics.

Effect of interferon-alpha-based antiviral therapy on hepatitis C virus-associated glomerulonephritis: a meta-analysis

Hepatitis C virus (HCV) is associated with various glomerulopathies, in which HCV is responsible not only for the onset of glomerulopathy but also for its progressive loss of kidney function. The effect of antiviral treatment on the glomerular lesions and subsequent course of kidney disease remains controversial. Therefore, we performed a systematic analysis of the available evidence on the effect of interferon (IFN)-α-based therapy on HCV-associated chronic kidney disease. A meta-analysis was performed of controlled and uncontrolled clinical studies related to IFNα-based antiviral therapy and its impact on kidney function in HCV-associated glomerulonephritis. Improvement of proteinuria and serum creatinine levels after antiviral therapy was taken as the end points of interest. Data from eligible studies selected according to protocols were analysed using Review Manager 5.0. Eleven clinical trials involving 225 patients were included in our meta-analysis. At the end of antiviral therapy, the summary estimate of the mean decrease in proteinuria was 2.71 g/24 h [95% confidence interval (CI) 1.38-4.04, P < 0.0001], P-value for heterogeneity 0.05 (I(2) = 53%). The pooled decrease in mean serum creatinine levels was 0.23 mg/dL (95% CI 0.02-0.44, P = 0.03), P-value for heterogeneity 0.30 (I(2) = 17%). Comparison of non-sustained virological response (SVR) to SVR groups demonstrated a mean difference of proteinuria decrease in the SVR group of 1.04 g/24 h (95% CI 0.20-1.89, P = 0.02), P-value for heterogeneity 0.21 (I(2) = 36%) and of serum creatinine decrease of 0.05 mg/dL (95% CI -0.33 to 0.43, P = 0.80), P-value for heterogeneity 0.70 (I(2) = 0%). Antiviral therapy based on IFNα can significantly decrease proteinuria and stabilize serum creatitine, and therefore, should be undertaken in patients with HCV-associated glomerulonephritis. The improvement in protein excretion is greater in those who achieve HCV RNA clearance, a finding in line with a causal role for HCV in glomerulonephritis.

Retention of CD4 + CD25 + FoxP3 + Regulatory T Cells in the Liver after Therapy-Induced Hepatitis C Virus Eradication in Humans

Following infection with the hepatitis C virus (HCV), in most cases immunity fails to eradicate the virus, resulting in slowly progressing immunopathology in the HCV-infected liver. We are the first to examine intrahepatic T cells and CD4(+) CD25(+) FoxP3(+) regulatory T cells (Treg) in patients chronically infected with HCV (chronic HCV patients) during and after antiviral therapy by collecting multiple aspiration biopsy samples from the liver at different time points. We found that intrahepatic Treg frequencies were increased upon alpha interferon and ribavirin administration in about 50% of chronic HCV patients, suggesting stronger regulation of intrahepatic immunity by Treg during antiviral therapy. After cessation of antiviral therapy, the frequency of intrahepatic Treg remained above baseline in the large majority of livers of individuals who successfully cleared the virus. The phenotype of those Treg that were retained in the liver months after therapy-induced clearance of HCV RNA indicated a reduced contribution of effector memory cells. Our findings, gathered by multiple samplings of the liver, indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of the local immune response to a resting state comparable to that for healthy livers. The continuous presence of high numbers of Treg, with a phenotype reflecting a relatively weak suppressive activity, suggests ongoing residual regulation of immunopathology. These findings provide important insight into the dynamics of the immune response to HCV, as well as the effect of therapy on intrahepatic immunity.

Hepatocellular carcinoma xenograft supports HCV replication: A mouse model for evaluating antivirals

To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral treatment. We developed a stable S3-green fluorescence protein (GFP) cell line that replicated the GFP-tagged HCV sub-genomic RNA derived from a highly efficient JFH1 virus. S3-GFP replicon cell line was injected subcutaneously into γ-irradiated SCID mice. We showed that the S3-GFP replicon cell line formed human HCC xenografts in SCID mice. Cells were isolated from subcutaneous tumors and then serially passaged multiple times in SCID mice by culturing in growth medium supplemented with G-418. The mouse-adapted S3-GFP replicon cells were implanted subcutaneously and also into the liver of SCID mice via intrasplenic infusion to study the replication of HCV in the HCC xenografts. The tumor model was validated for antiviral testing after intraperitoneal injection of interferon-α (IFN-α). A highly tumorigenic S3-GFP replicon cell line was developed that formed subcutaneous tumors within 2 wk and diffuse liver metastasis within 4 wk in SCID mice. Replication of HCV in the subcutaneous and liver tumors was confirmed by cell colony assay, detection of the viral RNA by ribonuclease protection assay and real-time quantitative reverse transcription polymerase chain reaction. High-level replication of HCV sub-genomic RNA in the tumor could be visualized by GFP expression using fluorescence microscopy. IFN-α cleared HCV RNA replication in the subcutaneous tumors within 2 wk and 4 wk in the liver tumor model. A non-infectious mouse model allows us to study replication of HCV in subcutaneous and metastatic liver tumors. Clearance of HCV by IFN-α supports use of this model to test other anti-HCV drugs.