A Comprehensive Update on the Recent Advancements in the Treatment of Chronic Hepatitis B: Is it Feasible to Attain a Complete Cure-Practical Hurdles

Abstract

Background: Hepatitis B virus (HBV) discovery occurred over half a century ago; however, about 300 million patients with 
chronic hepatitis B (CHB) still live in the world, leading to approximately one million deaths every year. Despite the fact that presently recommended antivirals (for instance, nucleoside analogs) are efficacious at reducing HBV replication, they practically do 
not impact the present HBV covalently closed circular deoxyribonucleic acid (cccDNA) reservoir. HBV cccDNA is a key barrier 
to the total depletion of the virus via antiviral therapy. Having reviewed earlier HHBV and CHB cures, we have updated the latest 
advancements in this field.
Methods: A narrative review was performed with the search engines Pubmed, Google Scholar, and others, using the MeSH terms, 
for instance. “Plausible Therapies; antivirals”; “NAs”; “pegylated-interferon-alpha (PEG-IFNα)”; “direct-acting antivirals (DAA’s)”; “Core 
protein allosteric modulator (CpAM)”; “post-transcriptional regulation”; “Host targeted treatments (HTT)”; “agents hampering viral entry”; “targeting cccDNA directly; epigenetics”; “DNA methylation”; “Histone post-translational modifications”; “DNA methylation”; “Histone acetylation”;
“Histone deacetylase”; “zinc finger nucleases”; (TALEN)”; “CRISPR/Cas9”; “Designer nuclease(s)” from 2000 till date in 2024 February.
Results: We found a total of 900 articles, out of which we selected 142 for this review. No meta-analysis was done.
Conclusions: The true cure for HBV infection requires the elimination of viral cccDNA from HBV-infected cells; thus, the generation of new agents directly or indirectly targeting HBV cccDNA is the immediate requirement of restricting presently available 
drugs against HBV infection. Regarding this, it is the major focus of current anti-HBV research worldwide via separate modes 
to either inactivate or inhibit (functional cure) or eliminate (complete cure) BV cccDNA. Here we provide present advances and 
challenges for inactivating, silencing, or depleting viral cccDNA using anti-HBV agents from various sources, like small molecules 
(inclusive of epigenetic drugs), polypeptides, and proteins, small interfering ribonucleic acid (siRNA), or gene-editing strategies 
targeting or attenuating HBV cccDNA via several modes, and future directions that might be taken into account in efforts to 
truly cure chronic HBV infection. Till now, no breakthrough has been made in ameliorating HBV cccDNA, despite the fact that a 
plethora of candidates have advanced into the phase of clinical trials. Moreover, considerable substances work to indirectly target 
HBV cccDNA. No special substance possesses the capacity to directly target HBV cccDNA. Specifically, CCCC_R08, in addition 
to nitazoxanide, might be some of the most favorable compounds to clear HBV infection in small-molecule agents. Furthermore, 
CRISPR-Cas9 systems have the capacity to directly target HBV cccDNA for decay and illustrate significant anti-HBV activity. 
Consequently, gene-editing targeting HBV cccDNA might be one of the most attractive means for achieving the core goal of 
anti-HBV therapeutic approaches. Basic studies on HBV infection are required to get rid of these hurdles.