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HBV - State of the Art 2015 and
beyond: what will be the next
wave of treatments?
Prof. Dr. Robert G. Gish
Stanford University
Medical Director: Hepatitis B Foundatio
Chronic hepatitis B (CHB) is the world’s most common serious liver
infection1 and is a widespread global health issue that is under-diagnosed
and under-treated. CHB will progress in about a third of untreated patients,
causing liver damage, cirrhosis and hepatocellular carcinoma (HCC).
Although hepatitis B virus (HBV) infection is not currently curable, it can
be effectively controlled (defined by DNA undetectable) using pegylated
interferon-alpha (pegIFN-α) and/or one of the five nucleos(t)ide analog
(NUC) antivirals (lamivudine, adefovir, entecavir, telbivudine or tenofovir)
in sequence or combination or single therapy. Determination of which
therapy to use, and which combination includes careful consideration of
duration of treatment, stopping rules, drug efficacy, use of quant(s)Ag,
potential side effects, and potential for antiviral resistance with NUCs.
PegIFN-α has the advantage of a fixed duration of therapy with the option
of response-guided therapy based on HBsAg levels and can be an ideal
option for some patients with high ALT and medium to low DNA noting
that less than 20% of patients have a durable response defined by HBV DNA
being undetectable. While resistance can be a limiting factor for the long-
term use of early 2nd and 3rd level NUCs such as lamivudine, telbivudine
and adefovir, more recent agents (entecavir and tenofovir) have very high
barriers to resistance and the emergence of resistant variants in patients
treated with these agents has been extremely rare over a duration of up to
6 years yet treatment is now indefinite for most patients ( with treatment
termination defined by loss of sAg in patient with HBV DNA <LOQ). T
Importantly, entecavir and tenofovir are able to maintain extended virologic
control over several years, in compliant patients, resulting in histologic
improvement over time and leading
to a significantly reduced risk of cirrhosis, death, liver transplant and
HCC are supported by moderate quality grade criteria. There is also some
evidence that hepatic cccDNA levels can be decreased with NUC therapy.
The success of long-term NUC treatment prompts new questions for future
treatment strategies. Is it possible to permanently eliminate HBV infection
with therapies that specifically target the cccDNA pathway or should we
be aiming to achieve a “functional cure” using HBsAg elimination as an
endpoint as the ultimate maker that we are changing outcomes? Many
clinicians and scientist believe the answer is “yes”, but the use of new
technologies and anti-viral tools including iRNA, anti-sense, capsid
inhibitors, and immune modulators including PDL1 antagonists, TLR7
agonists, tarmogen based vaccines, vaccines with adjuvants and
extended preS1 epitopes as well as attacking the virus in the nucleus
by changing histones, and acylation patterns. Ultimately we need to
next clear sAg, then clear cccDNA, and finally clear all cells with
HBV DNA integration and prevent integration from starting in those
with early phases of disease. The therapies need to target multiple sites
in the HBV genome and /or the immune system. The major concept
moving forward with HBV therapeutics is the use of new combination
therapies, or new therapies in sequence. We need to further suppress
virus, stop the regeneration of cccDNA and awaken the sleeping giant: the
immune system that will ultimately have the final “word” in viral control
and clearance. One-shot, single drug therapy is the “pie-in the-sky”,
realistically this next phase in the search for the grail of HBV therapeutics
will require an integrated approach with pharma, clinicians and scientists.
We now have the attention of the investment community that see HBV as
the new “C”. Will orange (HBV) really be the new black (HCV) ?
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发表于 2015-3-15 21:06
