Antonio Gonçalves (1), Annabelle Lemenuel-Diot (2), Valerie Cosson (2), Yuyan Jin (3), Sheng Feng (3), Bo Qingyan(3), Jérémie Guedj (1)
(1) Université de Paris, IAME, INSERM, F-75018 Paris, France; (2) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Switzerland (3); Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, China
Objectives: Hepatitis B (HBV) is a complex virus responsible for 260 million chronic infections worldwide [1]. Current treatments (such as nucleosidic analogs, NA) are largely effective in suppressing viral load (HBV DNA) but they cannot cure the infection and need to be taken lifelong. One of the difficulty in targeting HBV cure is the variety of viral products produced by infected cells [2]. Among those particles, Hepatitis B RNA-containing particle (HBV RNA) are encapsidated pre genomic RNA (pgRNA) exported before the action of the reverse transcriptase. As HBV RNA is not affected by NA, it has recently been suggested as a marker of drug efficacy in virologically suppressed patients [3,4]. However, little is known about the kinetics of HBV RNA, and particularly how it may or not differ from the kinetics of HBV DNA. Further a novel therapeutic class has entered clinical trials, known as capsid assembly modulators (CAM), that directly disrupts the nucleocapsid assembly and hence affects both HBV DNA and HBV RNA [5,6]. The objective of this study was to tease out the determinants of HBV RNA dynamics during NA or CAM-based therapy.
Methods: We developed a model to describe the kinetics of HBV DNA and HBV RNA that extends the standard viral dynamic models by taking into account the intracellular processes of pgRNA production, encapsidation and secretion into circulation. Parameters were estimated using HBV DNA and HBV RNA data observed in a 4-week study where 35 patients received either RO7049389, a class I CAM [7] or placebo. Then the model was used to predict HBV RNA decay during NA-therapy, and these predictions were confronted to historical data of 51 patients treated with tenofovir alafenamide (TAF) [8]. Lastly, we predicted the kinetics of HBV DNA and HBV RNA in patients treated by the combination of CAM and NA during 28 days.
Results: CAM strongly inhibits the production of intracellular RNA, with an efficacy of 99.3% (range: 92.1% – 99.9%). This led to a biphasic decline of HBV DNA – comparable to the declines observed during 4-week NA therapy – but also a biphasic decline of HBV RNA. However, the first phase of viral decline differs between the two markers. With CAM blocking the production of encapsidated pgRNA, HBV RNA immediately declines at a rate close the viral clearance, c (t1/2 = 50 mins). However, since they do not directly inhibit already formed virions, the model attributes the slower initial decline of HBV DNA to the continued secretion of already formed capsids, with a rate ρ (t1/2 = 17±6 hours). Subsequently, both HBV RNA and HBV DNA decline in parallel, at the same rate attributed to the loss of infected cells (t1/2 ≅ 6±0.8 days). Further, the model also allows to describe the data of NA treated patients. The model predicts that NA, by blocking the reverse transcription of HBV RNA, leads to a transient intracellular accumulation of HBV RNA, and an increase of HBV RNA in the circulation. Finally, the model can also be used to predict the effect of ongoing drug combinations of CAM and NA. The model predicts drug combination could lead to a rapid suppression of both HBV DNA and HBV RNA, with reductions of 5.6±1.3 and 1.6±1.1 log10 after 1 month of treatment, respectively, as compared to 3.5±1.3 and 3.4±1.1 log10 in CAM-treated patients.
Conclusions: HBV DNA and HBV RNA represent different stages of viral lifecycle. Hence their dynamics are different and depend on the type of treatment used. By providing a framework integrating the two marker dynamics, our model could be used to better estimate the efficacy of drugs in blocking the different stages of viral replication.
References:
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[6] Lahlali T, Berke JM, Vergauwen K, Foca A, Vandyck K, Pauwels F, et al. Novel Potent Capsid Assembly Modulators Regulate Multiple Steps of the Hepatitis B Virus Life Cycle. Antimicrob Agents Chemother. 2018;62:e00835-18, /aac/62/10/e00835-18.atom.
[7] Gane E, Liu A, Yuen M-F, Schwabe C, Bo Q, Das S, et al. RO7049389, a core protein allosteric modulator, demonstrates robust anti-HBV activity in chronic hepatitis B patients and is safe and well tolerated. Journal of Hepatology. 2018;68:S101.
[8] Agarwal K, Fung SK, Nguyen TT, Cheng W, Sicard E, Ryder SD, et al. Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. Journal of Hepatology. 2015;62:533–40.
Reference: PAGE () Abstr 9394 [www.page-meeting.org/?abstract=9394]
Poster: Oral: Drug/Disease Modelling