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Anna S. Lok, MD, FAASLD
Director, Clinical Hepatology
University of Michigan
1500 East Medical Center Drive
3110G Taubman Center, SPC 5362
Ann Arbor, MI 48109
Email: [email protected]
Hepatitis B: Early Phase Clinical Studies of Novel Antiviral Therapies
Currently approved treatments for hepatitis B are effective in suppressing but not in eliminating HBV; thus, most patients require long durations and often lifelong treatment. There are many barriers to eliminating HBV: (1) existence of covalent
ly closed circular HBV DNA(cccDNA) with long half-life serving as template for transcription of pregenomic RNA and translation of HBV proteins, (2) presence of integrated HBV DNA, and (3) impaired innate and adaptive host immune response to HBV. Thus, even in persons with serological recovery from transient HBV
infection, HBV persists in the liver and reactivation can occur with potent immunosuppression. With improved understanding of the biology of HBV and better in vitro and animal models, many new antiviral targets have been identified and novel antiviral therapies directed at these targets are being tested in preclinical and early phase clinical trials. Novel antiviral therapies in development include compounds that inhibit or modulate entry receptors; capsid assembly; RNA transcription and translation; cccDNA formation, replenishment, transcription and persistence; HBx protein, RNAseH, and HBV assembly and secretion. While the primary role of
these agents is to suppress HBV DNA replication and HBV protein expression, they may also facilitate recovery of immune response.
Among these novel antiviral approaches, several are being evaluated in early phase clinical trials and have shown promise. These include entry inhibitors such as Myrcludex, capsid assembly inhibitors such as NVR-3778, RNAi such as ARC
-520, and nucleic acid polymers targeting HBsAg secretion such as REP-2139.
These agents have been shown not only to reduce serum HBV DNA levels but also serum HBV RNA and HBsAg levels. Most of these agents have only been tested for short durations and some were evaluated in combination with interferon or nucleos/tide analogues, and the long term safety and durability of antiviral efficacy
of these agents remain unclear. Regardless, it is envisioned that a combination of antiviral agents targeting multiple steps in HBV lifecyle will be necessary to achieve sustained control of HBV replication, and additional immune modulatory therapy will likely be needed to restore immune control to allow safe withdrawal of antiviral therapy. As new therapies are developed and tested in clinical trials, a key question is whether HBV cure is possible. While sterilizing cure is unlikely to be feasible, functional cure defined as clearance of HBsAg in a higher proportion of patients
that can be achieved with currently available therapies, after a finite duration of treatment may be possible. Accomplishment of this goal will require
the collaboration of multiple stake holders: regulatory agencies, diagnostic and
therapeutic companies, scientists and clinical investigators. In addition to new antiviral drugs, new assays for novel biomarkers will also be necessary.
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发表于 2018-3-21 21:37
