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NVR 3-778 Plus Pegylated Interferon-α Treatment for Chronic Hepatitis B Viral Infections: Could 1 + 1 = 3?
John E. Tavis'Correspondence information about the author John E. TavisEmail the author John E. Tavis
, Elena Lomonosova
Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri
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DOI: https://doi.org/10.1053/j.gastro.2018.01.011 |
See “Efficacy of NVR 3-778, alone and in combination with pegylated interferon, vs entecavir in uPA/SCID mice with humanized livers and HBV infection,” by Klumpp K, Shimada T, Allweiss L, et al, on page 652.
Treatment for chronic hepatitis B virus (HBV) infection primarily uses monotherapy with nucleos(t)ide analogues or (pegylated)interferon-α (peg-IFN).1 These therapies can effectively suppress viral replication and significantly improve liver function. However, loss of hepatitis B surface antigen (HBsAg) is rare with either type of therapy, and treatment does not completely stop disease progression in all patients.2 Furthermore, interferon can cause substantial side effects, and nucleos(t)ide analogue therapy often needs to be continued indefinitely, leading in some cases to resistance to the nucleos(t)ide analogues and potential long-term side effects.3 The failure of these monotherapies to cure HBV infection implies that improving hepatitis B therapy or curing HBV infection will require combinations of new drugs that work by different mechanisms.4 Unfortunately, combining nucleos(t)ide analogs with each other or with interferon has been disappointing.4
The best animal models for HBV infection use immunodeficient mice with defects in liver metabolism that permit engraftment with human hepatocytes. The most widely used model uses uPA/SCID mice with humanized livers.5 These animals support high-titer chronic HBV infections, but they are very expensive and fragile, and their immunodeficiency precludes evaluating immune modulators.
Core protein assembly modifiers such as NVR 3-778 are experimental HBV replication inhibitors that disrupt capsid formation.6 Compounds in the NVR 3-778 series block encapsidation of viral RNA, preventing production of infectious virus in vitro.7 NVR 3-778 is currently well-tolerated in phase 1 human trials; preliminary data imply that NVR 3-778 suppresses HBV DNA and hepatitis B e antigen (HBeAg), and that reductions are larger when NVR 3-778 is combined with peg-IFN.8
Klumpp et al9 used humanized uPA/SCID mice to ask whether NVR 3-778 could suppress HBV viremia, how efficacy of NVR 3-778 alone compared with the efficacy of peg-IFN and entecavir, and whether combining NVR 3-778 with peg-IFN or entecavir improved suppression of viremia compared to the monotherapies. Secondary endpoints included the effects on serum HBeAg and HBsAg levels and on the critical nuclear form of the viral genome, the covalently closed circular DNA (cccDNA). NVR 3-778’s antiviral efficacy was similar to that of entecavir and superior to that of peg-IFN. Combining NVR 3-778 with entecavir did not improve suppression of HBV, but the efficacy of NVR 3-778 plus peg-IFN was better than either compound alone. Serum levels of HBV DNA in the NVR 3-778 plus peg-IFN group declined by >2.2 log by day 14, and all 16 animals had DNA titers below the limit of quantification by day 41 of treatment. The NVR 3-778 plus peg-INF group also demonstrated reduced levels of HBeAg by 0.8 log(S/CO) and HBsAg by 0.5 log(IU/mL), but none of the treatments altered intrahepatic cccDNA levels. The complementarity between NVR 3-778 and peg-IFN is convincing and the results are consistent with the known mechanisms of both drugs.
This study is exciting because, to the best of our knowledge, NVR 3-778 plus peg-IFN is the first experimental combination therapy shown to exceed the efficacy of entecavir monotherapy in a relevant animal model of HBV infection. Therefore, it provides proof-of-principle support for the assumption that combination therapy can be superior to monotherapy that is driving anti-HBV drug discovery.
The Klumpp et al study9 has a number of implications for the development of NVR 3-778 plus peg-IFN as a potential therapy for hepatitis B. First, the failure of the drug combination to reduce hepatic cccDNA is not surprising, given the drugs’ mechanisms and the short treatment duration. This implies that NVR 3-778 plus peg-IFN will be unlikely to completely eradicate HBV, at least not without long-term administration. Unfortunately, the maximum dosing period for the combination is likely to be about 1 year owing to side effects from peg-IFN, and this duration may not be long enough to clear HBV. A more promising implication stems from the possibility that a cure (or functional cure, generally defined as HBsAg loss with undetectable serum HBV DNA, but persistence of cccDNA10) for hepatitis B will be promoted by immune stimulation or reconstitution of anti-HBV immune responses. Reactivation of properly regulated anti-HBV immune responses will probably depend on major reductions in viremia and antigenemia, and NVR 3-778 plus peg-IFN reduced viral DNA, HBeAg, and HBsAg. This finding implies that some immune reconstitution might occur, but the immunodeficiency of the mice used in this study precluded assessing anti-HBV immunity.
Off-therapy durability of responses to NVR 3-778 plus peg-IFN is likely to be dominated by interferon’s innate immune stimulation because NVR 3-778 is a direct-acting drug whose primary effect is to reduce viral replication. If NVR 3-778 plus peg-IFN does improve immune function, the rate of HBeAg seroconversion could be increased compared with peg-IFN monotherapy. This improvement would increase the off-therapy durability of viral control, and would presumably improve attenuation of hepatitis B progression. This would be a major advance.
These results indicate that follow-up study of this drug is warranted in uPA/SCID mice. Dosing of both NVR 3-778 and peg-IFN in the combination should be optimized to determine if responses can be improved and if peg-IFN can be reduced to minimize side effects. Dose optimization is particularly important for NVR 3-778 owing to the high concentration at which it was used in the Klumpp study (405 mg/kg twice per day, or 48 g/d for a 60-kg patient). Extended dosing periods should be explored to determine whether antigenemia can be further suppressed, and particularly whether cccDNA levels begin to decrease. Finally, treatment cessation studies with and without NVR 3-778 and peg-IFN monotherapy after suppression of viremia below the limit of detection by combination treatment should be done to explore response durability. Expanded testing of NVR 3-778 plus peg-IFN in people is likely to be warranted once the safety profile of NVR 3-778 is fully defined. Overall, if these animal data hold up in human studies and posttreatment durability can be demonstrated, neither of which is assured, the Klumpp study9 would point the way toward significant improvements in outcomes for patients with chronic hepatitis B. |
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发表于 2018-2-14 08:48
