The Outcome of BNT162b2, ChAdOx1-Sand mRNA-1273 Vaccines and Two Boosters: A Prospective Longitudinal Real-World Study.

To date, the effectiveness of COVID-19 vaccines and booster doses has yet to be evaluated in longitudinal head-to-head studies. This single-center longitudinal study assessed the effectiveness of ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 vaccines and assessed two BNT162b2 boosters in 1550 participants, of whom 26% had comorbidities. In addition, the SARS-CoV-2 antibody dynamics was monitored. A group of 1500 unvaccinated subjects was included as the controls. The study's endpoint was the development of virologically-proven COVID-19 cases after vaccine completion, while the secondary endpoint was hospitalizations due to severe COVID-19. Overall, 23 (4.6%), 16 (3%), and 18 (3.8%) participants vaccinated with ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273, respectively, developed COVID-19 after vaccine completion, with an effectiveness of 89%, 92%, and 90%. Ten COVID-19 cases were reported in participants with comorbidities, three of whom were hospitalized. No hospitalizations occurred after boosters. SARS-CoV-2 antibody levels peaked 2-4 weeks after the second vaccine dose but declined after a mean of 28.50 ± 3.48 weeks. Booster doses significantly enhanced antibody responses. Antibody titers ≤ 154 U/mL were associated with a higher risk of COVID-19 emergence. Thus, COVID-19 vaccines effectively reduced COVID-19 and prevented severe disease. The vaccine-induced SARS-CoV-2 antibody responses declined after 28-32 weeks. Booster doses induced significant maintained responses. SARS-CoV-2 antibody levels may help determine the timing and need for vaccine booster doses.

Application of Mathematical Modeling in Prediction of COVID-19 Transmission Dynamics.

The entire world has been affected by the outbreak of COVID-19 since early 2020. Human carriers are largely the spreaders of this new disease, and it spreads much faster compared to previously identified coronaviruses and other flu viruses. Although vaccines have been invented and released, it will still be a challenge to overcome this disease. To save lives, it is important to better understand how the virus is transmitted from one host to another and how future areas of infection can be predicted. Recently, the second wave of infection has hit multiple countries, and governments have implemented necessary measures to tackle the spread of the virus. We investigated the three phases of COVID-19 research through a selected list of mathematical modeling articles. To take the necessary measures, it is important to understand the transmission dynamics of the disease, and mathematical modeling has been considered a proven technique in predicting such dynamics. To this end, this paper summarizes all the available mathematical models that have been used in predicting the transmission of COVID-19. A total of nine mathematical models have been thoroughly reviewed and characterized in this work, so as to understand the intrinsic properties of each model in predicting disease transmission dynamics. The application of these nine models in predicting COVID-19 transmission dynamics is presented with a case study, along with detailed comparisons of these models. Toward the end of the paper, key behavioral properties of each model, relevant challenges and future directions are discussed.

Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents.

Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world's population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.

Host and viral determinants of the outcome of exposure to HCV infection genotype 4: a large longitudinal study.

OBJECTIVES: The objective of this study was to characterize the factors that influence the outcome of exposure to hepatitis C virus (HCV) genotype 4 (HCV-G4) and the course of recent infection. METHODS: In this longitudinal study, we prospectively assessed the clinical, genetic, virological, and immunological parameters and retrospectively determined single-nucleotide polymorphisms at interleukin-28B (IL-28B) rs12979860 in a well-characterized large cohort recently exposed to HCV-G4. RESULTS: A total of 136 subjects with acute HCV (new viremia, seroconversion, and HCV-specific T-cell responses) were identified. Forty-eight subjects (35%) had spontaneous viral clearance and 88 subjects developed chronic HCV of which 42 subjects were treated with pegylated interferon monotherapy, with a sustained virologic response (SVR) rate of 88%. Twenty-six subjects developed HCV-specific T-cell immune responses without detectable viremia or seroconversion. IL-28B-CC (odds ratio (OR) 14.22; P<0.0001), multispecific T-cell responses (OR=11.66; P<0.0001), >300 IU/l alanine aminotransferase (ALT) decline within 4 weeks (OR=6.83; P<0.0001), jaundice (OR=3.54; P=0.001), female gender (OR=2.39; P=0.007), and >2.5 log10 HCV-RNA drop within 8 weeks (OR=2.48; P=0.016) were independently associated with spontaneous clearance. ALT normalization and undetectable HCV-RNA predicted SVR. Exposed apparently uninfected participants had a higher frequency of IL-28B-CC than patients with unresolved acute HCV (P<0.001). IL-28B-CC was associated with multispecific T-cell response (r(2)=0.0.835; P<0.001). CONCLUSIONS: IL-28B-CC genotype, multispecific HCV T-cell responses, rapid decline in ALT, and viral load predict spontaneous clearance and response to acute HCV-G 4 therapy. IL-28B-CC genotype correlates with developing early multispecific T-cell responses. These findings have important implications for predicting the outcome of HCV exposure and acute infection and identifying patients likely to benefit from therapy.

Enhanced efficacy of pegylated interferon alpha-2a over pegylated interferon and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of life analysis.

AIM: The therapy of chronic hepatitis C genotype 4 (HCV-4) has not been optimized yet. This randomized, prospective, parallel-group clinical trial compared the efficacy and safety of pegylated interferon α-2a (PEG-IFN α-2a) plus ribavirin and PEG-IFN α-2b plus ribavirin and assessed the health-related quality of life (HRQOL) in patients with chronic HCV-4. METHODS: Eligible patients with proven chronic HCV-4 were randomized to receive either a weekly dose of PEG-IFN α-2a (180 µg) or PEG-IFN α-2b (1.5 µg/kg) and a daily dose of ribavirin (1000-1200 mg) for 48 weeks with 24 weeks post-treatment follow-up. The primary end point was sustained virological response (SVR) defined by undetectable HCV RNA 24 weeks after treatment. The Short form-36 Health Survey version 2 (SF-36v2) and the Chronic Liver Disease questionnaires (CLDQ) were assessed before, during and after therapy. RESULTS: The overall SVR rate of the entire cohort was 59.9%. The SVR rates were significantly higher in patients treated with PEG-IFN α-2a and ribavirin (Group A; n=109) compared with those treated with PEG-IFN α-2b and ribavirin (Group B; n=108, 70.6 vs. 54.6%, respectively; P=0.017). The relapse rates were 5.1% for PEG-IFN α-2a and 15.7% for PEG-IFN α-2b (P=0.0019). The SF-36v2 and CLDQ were low during therapy and improved significantly after therapy successful therapy. CONCLUSION: Pegylated interferon α-2a plus ribavirin was significantly more effective than PEG-IFN α-2b and ribavirin therapy in the treatment of chronic HCV-4 patients. The tolerability and adverse events were comparable between the two regimens. The HRQOL improved significantly after successful PEG-IFN α-2a plus ribavirin therapy.

Hepatitis C virus genotype 4 therapy: progress and challenges.

The hepatitis C virus genotype 4 (HCV-4) is prevalent in Egypt, the Middle East and Africa. Recently, the epidemiology of HCV-4 has changed and this genotype has begun to cross borders and spread to several regions in Europe through immigration and injection drug use. HCV-4 has been considered a difficult-to-treat genotype based on the low sustained virological response (SVR) rates obtained with conventional interferon (IFN)-based regimens. Pegylated interferons (PEG-IFN) plus ribavirin therapy for chronic HCV-4 has been associated with increased SVR rates of more than 60%. Shorter treatment of chronic HCV-4 patients with rapid and early virological responses has been associated with high SVR rates, better compliance, fewer adverse events and lower costs. Despite this progress, the treatment of HCV-4 non-responders, injection drug users, patients coinfected with human immunodeficiency virus, thalassaemic patients, patients on haemodialysis and patients with HCV-4 recurrence after liver transplantation still represents a significant therapeutic challenge. Treatment of HCV-4 has markedly improved, with higher sustained response rates and the possibility of shorter regimens. Despite the recent progress in the treatment of HCV-4, more research is required to optimize current therapy and include genotype 4 patients in clinical trials on emerging therapies such as specifically targeted antiviral therapy for HCV with protease and/or polymerase inhibitors.

Viral hepatitis a to e in South mediterranean countries.

Viral hepatitis represents an important health problem in the South Mediterranean countries, Egypt, Libya, Tunisia, Algeria and Morocco. Emerging natural history and epidemiological information reveal differences in the overall epidemiology, risk factors and modes of transmission of viral hepatitis A, B, C, D, E infections in the South Mediterranean region. The differences in the in incidence and prevalence of viral hepatitis across North African countries is attributed to variations in health care and sanitation standards, risk factors and immunization strategies. The active continuous population movement through travel, tourism and migration from and to the South Mediterranean countries contribute to the spread of infections due to hepatitis viruses across borders leading to outbreaks and emergence of new patterns of infection or introduction of uncommon genotypes in other countries, particularly in Europe.

Hepatitis C genotype 4 therapy: increasing options and improving outcomes.

UNLABELLED: Hepatitis C virus genotype 4 (HCV-G4) is prevalent in the Middle East and Africa and has spread to several regions in Europe. HCV-G4 represents a major health problem in Egypt, with a prevalence rate of 13%. Recently, HCV-G4 has been spreading in Europe particularly among intravenous drug users (IDU) populations, who represent the main reservoir for HCV in Europe. This article reviews the current therapeutic strategies for HCV-G4 infections in different populations. HCV-G4 has been considered a difficult-to-treat genotype because of the poor sustained virological response (SVR) rates reported with a conventional interferon (IFN)-based regimen. Pegylated IFN and ribavirin combination therapy was associated with significant improvements in SVR rates that currently exceed 60%, particularly with individualized therapy. Lower response rates have been reported in specific situations, namely chronic HCV-G4 infection in IDUs and patients co-infected with human immunodeficiency virus (HIV). Rapid and early virological responses have been useful tools for determination of the duration of therapy. IN CONCLUSION: therapy of HCV-G4 has shown significant improvements, with higher sustained response rates and possibilities for a shorter duration. More research is required to optimize therapy in special populations such as IDUs and HIV-co-infected patients.

Acute hepatitis C: a systematic review.

INTRODUCTION: The annual incidence of acute hepatitis C virus (HCV) has fallen in recent years, primarily because of effective blood screening efforts and increased education on the dangers of needle sharing. However, hepatitis C infection is still relatively frequent in certain populations. Most patients infected with HCV are unaware of their exposure and remain asymptomatic during the initial stages of the infection, making early diagnosis during the acute phase (first 6 months after infection) unlikely. While some of those infections will have a spontaneous resolution, the majority will progress to chronic HCV. We scanned the literature for predictors of spontaneous resolution and treatment during the acute stage of HCV to identify factors that would assist in treatment decision making. METHODS: A medical literature search through MEDLINE was conducted using the keyword "acute hepatitis C" with a variety of keywords focused on (a) epidemiology, (b) natural history and outcome, (c) diagnosis, (d) mode of transmission, and (e) treatment. RESULTS: There are no reliable predictors for spontaneous resolution of HCV infection and a significant percentage of individuals exposed to HCV develop persistent infections that progress to chronic liver disease. An intriguing approach is to treat acute HCV and prevent the development of chronic hepatitis. Several clinical trials showed that treatment of hepatitis C infection during the acute phase is associated with high sustained virological response (SVR) rates ranging between 75% and 100%. Although there is a prevailing consensus that intervention during the acute phase is associated with improved viral eradication, relevant clinical questions have remained unanswered by clinical trials. Optimization of therapy for acute hepatitis C infection and identification of predictors of SVR represent a real challenge. CONCLUSION: With more than 170 million chronic hepatitis C patients worldwide and an increase in the related morbidity and mortality projected for the next decade, an improvement in our ability to diagnose and treat patients with acute hepatitis C would have a significant impact on the prevalence of chronic hepatitis and its associated complications particularly in countries with a high endemic background of the infection.

Hepatitis C genotype 4: What we know and what we don't yet know.

UNLABELLED: Hepatitis C virus genotype 4 (HCV-4) is the most common variant of the hepatitis C virus (HCV) in the Middle East and Africa, particularly Egypt. This region has the highest prevelance of HCV worldwide, with more than 90% of infections due to genotype 4. HCV-4 has recently spread in several Western countries, particularly in Europe, due to variations in population structure, immigration, and routes of transmission. The features of HCV-4 infection and the appropriate therapeutic regimen have not been well characterized. This review discusses the virology, epidemiology, natural history, histology, clinical data, and treatment options for patients with HCV-4 infections. Early reports on the treatment of patients with chronic HCV-4 with conventional interferon (IFN)-alpha monotherapy indicated poor rates of sustained viral response (SVR), which improved slightly when combined with ribavirin. Pegylated IFN and ribavirin combination therapy has dramatically improved the response rates, with recent clinical trials showing rates that exceed 60%. These data can now be used as a platform for further research to define optimal treatment duration and predictors of SVR in patients with HCV-4 infection. CONCLUSION: HCV-4 infection is spreading beyond its strongholds in Africa and the Middle East. Recent clinical trials show that HCV-4 is not difficult to treat, as the response to treatment may be at an intermediate level compared with genotype 1 and genotypes 2 or 3. Tailored treatment options that are comparable to the treatment approaches for genotype 1, 2, and 3 patients to optimize treatment for each patient are now being developed.

Acute hepatitis C: prospects and challenges.

More than 170 million people worldwide have chronic hepatitis C. Acute hepatitis C is rarely diagnosed because it is commonly asymptomatic. Most infected patients are unaware of their condition until the symptoms of chronic infection manifest. Treatment of acute hepatitis C is something of a paradox because spontaneous resolution is possible and many patients do not have symptoms. However, several factors provide a rationale for treating patients who have acute hepatitis C. Compared with acute hepatitis C, chronic hepatitis C is associated with a worse prognosis, the need for more intensive treatment, longer treatment duration, and a decrease in successful treatment outcomes. Conversely, early intervention is associated with improved viral eradication, using a regimen that is better tolerated, less expensive, more convenient, and of shorter duration than the currently approved combination therapies for chronic hepatitis C.

Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response.

UNLABELLED: In patients chronically infected with hepatitis C virus (HCV) genotype 4, the optimum duration of therapy and the predictors of sustained virologic response (SVR) have not been adequately determined. In this study, 358 patients with chronic hepatitis C genotype 4 were randomly assigned to pegylated interferon (PEG-IFN) alpha-2b (1.5 mug/kg/week) plus oral ribavirin (10.6 mg/kg/day) for a fixed duration of 48 weeks (control group, n = 50) or for a variable duration (n = 318). In the variable-duration group, patients with undetectable HCV RNA at week 4 were treated for 24 weeks (group A, n = 69), patients with undetectable HCV RNA at week 12 were treated for 36 weeks (group B, n = 79), and the rest of the patients were treated for 48 weeks (group C, n = 160). The primary endpoint was SVR (undetectable HCV RNA 24 weeks after treatment cessation). Groups A-C and the control group had SVR rates of 86%, 76%, 56%, and 58%, respectively. After the study was controlled for predictors, a low baseline histologic grade and stage were associated with SVR (P < 0.029) in all groups. In addition, among patients in group C, older age (P = 0.04), a higher baseline body mass index (P = 0.013), and low baseline HCV RNA (P < 0.001) were also associated with SVR attainment. The incidence of adverse events and the rate of discontinuation were higher in patients in the variable-duration and fixed-duration groups treated for 48 weeks. CONCLUSION: In patients with chronic hepatitis C genotype 4 and undetectable HCV RNA at weeks 4 and 12, treatment with PEG-IFN alpha-2b and ribavirin for 24 weeks and 36 weeks, respectively, is sufficient.

Improving outcome in patients with hepatitis C virus genotype 4.

Several factors influence treatment outcomes among patients with chronic hepatitis C. A trend is growing to adapt an individualized treatment approach to optimize treatment outcomes among chronic hepatitis C patients. Hepatitis C virus (HCV) genotype is an important factor that determines treatment outcomes among patients with chronic hepatitis C. HCV has six genotypes, and genotype 4 (G4) accounts for 20% of all global HCV infections. Patients with G4 are underrepresented in clinical trials involving patients with chronic hepatitis C because most patients infected with G4 are in Egypt, Africa, and Middle Eastern countries. Therefore, there is little information about the predictors of response to standard treatment among chronic hepatitis C patients with HCV G4. Initial evidence suggested that patients with G4 HCV are as difficult to treat as patients with G1; however, recent evidence suggests that the response rates to treatment among patients with G4 may be better than those with G1 but not those with G2 or G3. This review discusses the clinical data among patients with G4 and assesses the impact of an individualized approach on improved treatment outcomes in these patients.

Duration of peginterferon therapy in acute hepatitis C: a randomized trial.

Spontaneous resolution of acute hepatitis C virus infection cannot be predicted, and chronic evolution of the disease occurs in a majority of cases. To assess the efficacy and safety of peginterferon alpha-2b administered for 8, 12, or 24 weeks in patients with acute hepatitis C virus infection a total of 161 patients were identified with acute hepatitis C virus infection. Of these, 30 patients refused treatment but were retained in the study as a nonrandomized comparison group. Of the 131 patients who consented to treatment, 29 patients spontaneously resolved, leaving 102 patients randomly assigned to peginterferon alpha-2b (1.5 microg/kg) for 8 weeks (group A; n=34), 12 weeks (group B; n=34), and 24 weeks (group C; n=34). The primary end point was sustained virologic response. An intent-to-treat analysis was used for efficacy and safety end points. Sustained virologic response was achieved in 23/34 (67.6%), 28/34 (82.4%), and 31/34 (91.2%) of patients in groups A, B, and C, respectively; all had undetectable hepatitis C virus RNA 48 weeks after the end of therapy. Treatment for 8 or 12 weeks was effective in genotypes 2, 3, and 4, whereas genotype 1 required 24 weeks of therapy. The 8- and 12-week regimens were associated with fewer adverse events compared with the 24-week regimen. In conclusion, peginterferon alpha-2b effectively induces high sustained virologic response rates in patients with acute hepatitis C virus infection, thus preventing development of chronic hepatitis C. Duration of treatment should be further optimized based on genotype and rapid virologic response at week 4.

Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis.

Serial liver biopsies are the gold standard by which the progression of fibrosis is evaluated. This longitudinal cohort study assessed the different rates in the progression of fibrosis using serial liver biopsies and serum fibrosis markers YKL-40 and PIIINP and the cytokines, transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNuF-alpha). A 10-year cohort study was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis. Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two liver biopsies (at entry and end of follow-up), and true rates in the progression of fibrosis were calculated per year. Serum YKL-40, N-terminal propeptide of collagen III (PIIINP), TGF-beta, and TNF-alpha were measured, as well as the expression of TGF-beta, TNF-alpha, and YKL-40 mRNA in liver tissue. A significant increase in the progression rates of fibrosis occurred in the coinfected group (0.61 +/- 0.13) compared with the HCV monoinfection group (0.1 +/- 0.06; P < .001)). The progression of fibrosis rate/year had a direct linear correlation for YKL-40 (r = 0.892, P < .001) and for PIIINP (r = 0.577, P < .01). YKL-40 showed a linear correlation with TGF-beta (r = 0.897, P < .001). Hepatic mRNA levels of YKL-40 and TGF-beta correlated with the serum levels, confirming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and fibrosis markers can accurately determine the rate at which fibrosis is progressing, identifying both those with rapid fibrosis and those with stable disease.

Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response.

BACKGROUND & AIMS: Pegylated interferon therapy has not been adequately evaluated in acute hepatitis C virus (HCV) infection. This randomized trial assessed the efficacy, safety, and timing of pegylated interferon alfa-2b for treatment of acute hepatitis C. METHODS: One hundred seventy-five patients acutely infected with HCV were screened. Patients whose infection did not spontaneously resolve by week 8 were randomized to once weekly peginterferon alfa-2b monotherapy (1.5 microg/kg per week) started at weeks 8, 12, or 20 for a duration of 12 weeks. The primary endpoint was undetectable HCV RNA 24 weeks after the end of treatment (sustained virologic response [SVR]). All patients were followed for 48 weeks after cessation of therapy. RESULTS: One hundred twenty-nine subjects started treatment at week 8 (group A, n = 43), week 12 (group B, n = 43), or week 20 (group C, n = 43). By using an intent-to-treat analysis, the overall SVR rate was 87%. The SVR rates were 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. Overall, SVR rates were better for patients infected with genotypes 2, 3, and 4 than those infected with genotype 1. Earlier initiation of therapy improved SVR rates for patients infected with genotype 1 with high viral load. Peginterferon alfa-2b was well tolerated. Subjects with SVR maintained undetectable HCV RNA 48 weeks after therapy. CONCLUSIONS: Peginterferon alfa-2b monotherapy in acute hepatitis C induces high sustained virologic response rates, prevents chronic evolution, and is well tolerated. Initiation of treatment at week 8 or 12 results in higher sustained virologic rates than initiation at week 20.

Cellular immune responses in seronegative sexual contacts of acute hepatitis C patients.

Acute hepatitis C virus (HCV) is typically defined as new viremia and antibody seroconversion. Rates and immunologic correlates of hepatitis C clearance have therefore been based on clearance of viremia only in individuals who initially had an antibody response. We sought to characterize the immunological correlates of clearance in patients with acute hepatitis C and their sexual contacts. We prospectively determined CD4(+) and CD8(+) cytotoxic T-lymphocyte responses in index patients with acute HCV and their sexual contacts who developed acute infection, either with or without spontaneous clearance, as well as those contacts who never developed viremia. Responses were measured using proliferation and ELISpot assays for CD4(+) and CD8(+) responses. We demonstrate in this prospective study that cellular immune responses can develop in exposed but persistently aviremic and antibody-negative individuals as well as those individuals with spontaneous clearance of acute HCV. These findings lend further credence to the importance of cellular immune responses in recovery from HCV and suggest that low exposure to HCV may lead to development of HCV-specific immune responses without ongoing HCV replication. This finding has important implications for HCV vaccine and therapeutic development.

Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics.

Pegylated interferon alpha (PEG IFN-alpha) improves sustained virological response rates in chronic hepatitis C, but neither its role in acute hepatitis C nor the biologic basis for its action has been defined. This prospective study assessed the efficacy of PEG IFN-alpha treatment in acute hepatitis C in relation to the kinetics of hepatitis C virus (HCV)-specific CD4(+) T cell responses during therapy and follow-up. Forty subjects with proven acute hepatitis C who received either PEG IFN-alpha plus ribavirin (n = 20) or PEG IFN-alpha monotherapy (n = 20) for 24 weeks in addition to 14 untreated subjects with acute hepatitis C were prospectively followed. Serum HCV RNA, HCV-specific CD4(+) T cell responses, and cytokine production were measured before and during therapy and at follow-up and correlated to the outcome. The sustained virological response rate was 85% with PEG IFN-alpha/ribavirin combination and 80% with PEG IFN-alpha monotherapy. Five untreated subjects had spontaneous recovery. The frequency, magnitude, and breadth of HCV-specific CD4(+) T helper 1 responses were significantly higher in treated subjects compared with untreated subjects with self-limited disease or subjects with chronic evolution. The CD4(+) T cell responses were maintained in subjects with sustained virological responses and self-limited disease but fluctuated in those who developed chronic infection. In conclusion, PEG IFN-alpha therapy in acute hepatitis induces high rates of sustained virological response and prevents choronicity, probably through efficient early stimulation of multispecific HCV-specific CD4(+) T helper 1 responses.

Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis.

The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell responses and their role in progression of fibrosis have not previously been characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more rapid progression of HCV liver fibrosis than do those with HCV infection alone. The present prospective longitudinal study compared the liver histology, HCV-specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV infection with or without S. mansoni coinfection, at 6-10 months after acute infection and at the end of follow-up (96+/-8.7 months), and the findings were correlated to the rate of progression of fibrosis per year. Coinfected subjects had significant worsening of fibrosis, compared with subjects with HCV infection alone. At baseline, subjects with HCV infection alone had stronger multispecific intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver. The rate of progression of fibrosis and virus load inversely correlated with intrahepatic HCV-specific CD4(+) T cell response. The present prospective analysis indicates that enhancement of progression of liver fibrosis is associated with failure to develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that novel therapeutic approaches inducing strong cellular immune responses might limit subsequent liver damage in individuals with chronic hepatitis C.