Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon‐alpha therapy via mathematical modeling

Abstract

There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy a median delay of 9 days (interquartile range IQR:[5;15]) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first-phase lasting for 25 days (IQR:[23;58]) was followed by a slower or plateau second-phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR:[93;99.8]). Median serum HDV half-life (t1/2) was estimated to 2.9 days (IQR:[1.5;5.3]) with pretreatment production and clearance of about 1010 (IQR:[109.8-1010.8]) virions/day. None of the patients with flat 2nd phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second-phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR:[20-460]. The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters. Conclusions Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients.

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…165 The likelihood of the long-term response to PegIFNa can be estimated to some extent by HDV RNA and HBsAg kinetics at weeks 12 and 24. 164,[166][167][168][169] However, stopping PegIFNa prematurely at this stage is not recommended, if treatment is well tolerated, as the negative predictive values of these markers are not very strong, and late responses may occur in patients with early non-response. Furthermore, long-term follow-up studies suggest that an IFNa based therapy per se can be taken as an independent factor associated with a lower likelihood of disease progression, and to develop clinical endpoints.…”

Reply to “does chronic hepatitis E virus infection exist in immunocompetent patients?”

“…We read with interest the study by Guedj et al 1 describing the dynamics of hepatitis D virus (HDV) and hepatitis B surface antigen (HBsAg) after the commencement of pegylated interferon (IFN)-alpha 2a therapy. This study provides valuable data on this virus, which results in increased morbidity and mortality over hepatitis B virus (HBV) monoinfection.…”

“…Kamar and Izopet for their interest in our case report on chronic hepatitis E in a patient with a distant history of systemic lupus erythematosus (SLE), and appreciate their comments on this patient's immune status. 1 While we acknowledge that our patient's history of SLE may have increased her susceptibility to developing chronic hepatitis E virus (HEV), it should be noted that the lupus has long been in remission (double-stranded DNA was negative in 2006, antinuclear antibody (ANA) was negative in 2007, and in 2008 C3 and C4 were both normal and Smith and RNP antibodies were negative), and we feel there is no strong temporal correlation between her medically induced immunosuppression for lupus and the development of her chronic viral hepatitis. While we feel that our patient was not immunocompromised during the period of infection with hepatitis E, we welcome Drs.…”

A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

“…There is no vaccine for HCV and for more than a decade the standard-of-care of pegylated interferon-alpha (IFN) and ribavirin was suboptima [3]. However the recent advent of direct-acting antivirals (DAAs) allows for interferon-free, all-oral treatment yielding cure rates exceeding 90% with pangenotypic activity and shorter durations of therapy (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) weeks) compared to IFN-based therapy (24-48 weeks [4]). While these highly effective DAAs are considered one of the greatest achievements in medicine, significant challenges remain for eliminating HCV infection such as finding an optimal approach to current DAA failures, preventing re-infection, identifying all those infected and the high cost of the new DAAs which represents a major barrier to treating the populations that are most affected by HCV [3].…”

“…Mathematical models are valuable tools for understanding the in vivo serum dynamics of viruses that trigger both persistent infection (e.g., HIV-1 [6][7][8][9], hepatitis B virus [10][11][12], hepatitis D virus [13][14][15], Theiler murine encephalomyelitis virus [16], herpes simplex virus [17] and HCV [18][19][20]) and acute infection (e.g., influenza A [21][22][23] and ebola [24]). Mathematical modeling is also improving our understanding of intracellular viral genome dynamics [25][26][27][28] and the quantitative events that underlie the immune response to pathogens [6,9].…”