Thank you Stephen for this very useful link.
Here is an example of an intestine abstract pointing to the possibility of blocking reinfection even after the virus has managed entry into the cytosol and preventing thus infection spreading and intracellular cccDNA replenisment.
Capsid assembly modulator JNJ-56136379 prevents
de novo infection of primary human hepatocytes with
hepatitis B virus.
Jan Martin Berke, Pascale Dehertogh, Karen Vergauwen, Ellen
van Damme, Pierre Raboisson, Frederik Pauwels, Koen Vandyck;
Janssen Research & Development, Beerse, Belgium
Background: The assembly of core proteins into viral capsids
containing HBV pgRNA is a critical step in the HBV life cycle.
Therefore, the core protein represents an attractive target
for new antiviral therapies due to its multiple functions. JNJ-
56136379 (JNJ-379) is a novel and potent HBV capsid assem-
bly modulator (CAM) currently being evaluated in a Phase
I clinical trial. Here, the effect of JNJ-379 on in vitro capsid
assembly and mechanism of action (MOA) studies in HBV
infected PHH are described. Methods: Size exclusion chro-
matography (SEC) with the recombinant assembly domain (aa
1-149) of HBV core and electron microscopy (EM) was used
to study the effect of JNJ-379 on capsid assembly. Primary
human hepatocytes (PHH) were either treated with CAMs or
nucleos(t)ide analogs (Entecavir, Tenofovir) during or after HBV
infection. HBV DNA in the cell culture supernatant and intracel-
lular HBV RNA were monitored by quantitative real time PCR.
HBsAg and HBeAg levels in the cell culture supernatant were
determined by AlphaLISA. Results: As determined by SEC and
EM, JNJ-379 induced the formation of empty, but morpholog-
ically intact viral capsids devoid of genomic material (class I
MOA), whereas BAY41-4109, a prototype CAM, induced the
formation of aberrant core containing structures (class II MOA).
JNJ-379 is a potent inhibitor of HBV replication in vitro with a
median EC90 of 226 nM in HepG2.117 cells. In PHH, when
compound was added after HBV infection, the median EC90 of
JNJ-379 on HBV DNA was 347 nM. In addition to its effect on
capsid assembly, JNJ-379 prevented the infection of primary
human hepatocytes with HBV in a dose-dependent fashion
when added together with the viral inoculum, whereas nucle-
os(t)ide analogues did not. This protective effect translated into
a dose-dependent reduction of intracellular HBV RNA levels
and reduced HBe- and HBsAg levels in the cell culture superna-
tant. Time of addition studies suggest that the compounds act at
a step beyond HBV entry. Conclusion: JNJ-379 is a novel CAM
with a class I MOA. JNJ-379 is a potent inhibitor of replication
on a stable HBV replicating cell line as well as on HBV infected
PHH. In addition, JNJ-379 has an impact on intracellular HBV
RNA and secreted antigens in PHH when added together with
the viral inoculum, suggesting that the compound inhibits the
establishment of the cccDNA pool. Taken together, our data
demonstrates for the first time that CAMs have a dual MOA on
early and late steps of the viral lifecycle in PHH. Those effects
clearly differentiate CAMs from nucleos(t)ide analogues, which
might translate into different treatment outcomes in the clinic.
I was told i can take part in this study, which is in phase 2a right now, it will be on 220 people only in 19 countries. Unfortunately there is little information about it, i have no idea if it's worth the risk or not