Peginterferon Alfa-2b Therapy in Acute Hepatitis C: Impact of Onset of Therapy on Sustained Virologic Response

Kamal, Sanaa M.; Fouly, Amr El; Kamel, Rabab; Hockenjos, Bridgette; Tawil, Ahmed Al; Khalifa, Khalifa E.; He, Qi; Koziel, Margaret James; Naggar, Khairy M. El; Rasenack, J.; Afdhal, Nezam H.

doi:10.1053/j.gastro.2006.01.034

Cited by 189 publications

(144 citation statements)

References 23 publications

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“…Interferon is argued to have a pleiotropic influence on CTLs, enhancing their proliferation and activation in the early stages of infection and rendering them more exhausted during the late stages of infection 47. Indeed, early initiation of PR treatment has been suggested to improve treatment outcomes 48. Furthermore, blockade of interferon signaling during chronic LCMV infection of mice has been shown recently to clear the infection 49, 50.…”

Section: Discussionmentioning

confidence: 99%

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

2018

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A fraction of chronic hepatitis C patients treated with direct‐acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT +/SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT +/SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment. Whether the hypothesis is consistent with data of viral load changes in patients who experienced EOT +/SVR is unknown. Here, we constructed a mathematical model of viral kinetics incorporating the immunologic hypothesis and compared its predictions with patient data. We found the predictions to be in quantitative agreement with patient data. Using the model, we unraveled an underlying bistability that gives rise to EOT +/SVR and presents a new avenue to optimize treatment durations. Infected cells trigger both activation and exhaustion of CTLs. CTLs in turn kill infected cells. Due to these competing interactions, two stable steady states, chronic infection and viral clearance, emerge, separated by an unstable steady state with intermediate viremia. When treatment during chronic infection drives viremia sufficiently below the unstable state, spontaneous viral clearance results post‐treatment, marking EOT +/SVR. The duration to achieve this desired reduction in viremia defines the minimum treatment duration required for ensuring SVR, which our model can quantify. Estimating parameters defining the CTL response of individuals to HCV infection would enable the application of our model to personalize treatment durations.

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Section: Discussionmentioning

confidence: 99%

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

2018

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“…Genotype 4 was nearly as common as genotype 1 and had the highest response (100% SVR) in the 24-week treatment group. 128 In a second study, Kamal et al 129 followed patients for 8 weeks after the identification of acute HCV. Subjects were then randomized to receive pegylated interferon alpha 2b, beginning at 8, 12, or 20 weeks, and they underwent a 12-week treatment regimen.…”

Section: Treatment Of Acute Hcv Infectionmentioning

confidence: 99%

Acute hepatitis C virus infection: A chronic problem

et al. 2008

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S ince the discovery of the hepatitis C virus (HCV) in the late 1980s, there has been an explosion of information regarding its natural history, treatment, and replication cycle. Nonetheless, there are still relatively few data regarding acute HCV infection. By convention, the term acute hepatitis refers to the presence of clinical signs or symptoms of hepatitis for a period of 6 months or fewer after the presumed time of HCV exposure. Early studies of posttransfusion patients who developed non-A, non-B hepatitis provide a clinical picture of early infection. 1 Following the availability of specific serologic and virologic tests, most such patients were shown to have acute HCV infection. After acute infection, HCV RNA may become detectable in the serum/plasma in as little as 2 weeks ( Fig. 1). Several weeks later, a high percentage of patients experience an increase in serum aminotransferase levels consistent with the development of acute hepatocellular injury. In the majority of cases, patients develop mild constitutional symptoms, including abdominal pain, nausea, vomiting, anorexia, and fatigue. During this acute infection, serum aminotransferases often peak below 1000 IU/mL and may return to normal levels. A minority develops sufficient elevations in bilirubin to lead to overt jaundice or the development of dark urine. Unless the clinical suspicion is high, few patients will be tested for HCV RNA or HCV antibody seroconversion. However, in the majority-but not all-of infected patients, HCV RNA persists, and a chronic disease state develops.The reasons for the general lack of data regarding acute HCV infection are multifactorial and include (1) the relatively high percentage of asymptomatic or unrecognized early infections, (2) the lack of large-scale identification of chronic carriers in the general population who serve as a reservoir for infection, and (3) the decreased number of acute infections that occur in controlled clinical settings such as that of blood transfusions. These factors and the lack of nonprimate animal models necessitate reliance on retrospective studies in chronic carriers, the use of limited historical collections of banked sera, and the extrapolation of outcomes based on small disease outbreaks in unique settings (for example, transmission from a physician to a patient in the operating room setting or following parenteral exposure in healthcare workers). Moreover, there exist only a limited number of population cohorts that continue to experience high rates of HCV transmission (for example, Egypt); nonetheless, there is a growing body of information regarding the clinical presentation, natural history, and treatment outcomes of acute HCV infection.In this article, we review the current information regarding our understanding of the epidemiology, virology, and immunology of HCV with a particular emphasis on acute HCV infection. In addition, we review recent data related to interferon-based treatment intervention and propose an algorithm for the diagnosis and management of acute HCV inf...

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“…Monotherapy with pegylated interferon (peg-IFN) is recommended, either with peg-IFN a-2a (40 kDa) 180 mg/week or with peg-IFN a-2b (12 kDa) 1.5 mg/kg body weight per week during 24 weeks [13]. A shorter treatment duration may be considered for patients infected with HCV genotypes 2 and 3 with a rapid viral response (RVR), i.e.…”

Section: Treatment Recommendations For Adult Patientsmentioning

confidence: 99%

Treatment of hepatitis C virus infection: Updated Swedish Consensus recommendations

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et al. 2009

Scandinavian Journal of Infectious Diseases

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Peginterferon Alfa-2b Therapy in Acute Hepatitis C: Impact of Onset of Therapy on Sustained Virologic Response

Cited by 189 publications

References 23 publications

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Acute hepatitis C virus infection: A chronic problem

Treatment of hepatitis C virus infection: Updated Swedish Consensus recommendations

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