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Highlights from

The European Congress of Clinical Microbiology & Infectious Diseases

29th Annual Meeting

Amsterdam 13-16 April 2019

Finding a cure for hepatitis B is a ‘dream’, but novel therapies show considerable promise

Take-home messages
  • Over 250 million people are infected with HBV worldwide, and prevalence is increasing
  • A large number of novel therapeutic approaches are under investigation
  • The most advanced of these approaches at present are CAMs, nucleic acid-based antiviral strategies and immune therapies
“The number of drugs in preclinical or early clinical development is huge.”

Dr Jean-Michel Pawlotsky, Professor of Medicine, University of Paris-Est, Director, National Reference Center for Viral Hepatitis B, C and Delta

At the 2019 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), keynote speaker Jean-Michel Pawlotsky, Professor of Medicine, University of Paris-Est, and Director, National Reference Center for Viral Hepatitis B, C and Delta, summarised the exciting new developments in the treatment of HBV infection, and how goals of treatment are changing.

“Chronic HBV infection alone is responsible for nearly 700,000 deaths per year from the complications of cirrhosis or HCC [hepatocellular carcinoma],” Professor Pawlotsky began, “We have, here, a major public health problem.” Over 250 million people are infected worldwide, and, where incidence of other infectious diseases such as tuberculosis, HIV and malaria have shown a downward trend, HBV prevalence continues to rise.

Current therapies, including pegylated interferon-alpha and nucleos(t)ide analogues, have proven to be very effective in providing sustained suppression of HBV replication and in reducing liver-related events. Professor Pawlotsky argued, however, that we can do better.

“The question I had in the title of this presentation is ‘how far are we from HBV cure?’ and the answer… chronic HBV is incurable,” Professor Pawlotsky stated, explaining that this is due to the virus’ cccDNA reservoir, ability to integrate into DNA, and HBV-infected patients’ defective or inefficient immune responses.

Instead, he remained realistically positive. “The number of drugs in preclinical or early clinical development is huge,” he stated, listing the investigational groups in the pipeline, which includes direct-acting antivirals (such as entry inhibitors, capsid assembly modulators (CAMs), nucleic acids and ribonuclease H inhibitors) as well as immune- or host-based therapies (such as innate immunity inducers, therapeutic vaccines, CRISPR/Cas 9 gene editing, and many more).

“Obviously, they will not all reach the clinic, but I think it’s a good sign that the field is very energetic, and we have hope that some of these drugs will work.”

Professor Pawlotsky singled out what he considered to be the three most advanced approaches in 2019:

1) CAMs (class I and II)

“This is the most advanced group of drugs currently.” He explained that CAMs are thought to work via two different mechanisms: firstly, interfering with capsid assembly kinetics, preventing pgRNA encapsidation, and blocking viral replication. Secondly, they have the ability to inhibit de novo formation of cccDNA; this mechanism is reliant on a high drug concentration, however, and investigational doses must take into account the benefit:risk ratio.

28-day efficacy phase Ib data for various class I/II CAMs have showed promising reductions in HBV DNA from baseline. “The problem…” however, he pointed out “…the CAMs are very good antiviral drugs… but they don’t have a clear effect on HBsAg levels.” He also mused over the potential issue of CAM resistance.

2) Nucleic acid-based antiviral strategies

“There are three potential approaches: silencing [si]RNAs, for which we have clinical data, antisense oligonucleotides, which are moving forward, and the nucleic acid polymers.”

An siRNA in development, JNJ-3989, showed a sharp and sustained decline in HBsAg levels from baseline. “These data are the most striking in all HBV drug development,” he stated, explaining that nadir HBsAg ≤100 IU/mL was achieved in 88% of the patients (n=35).

There are potential disadvantages to weigh up. Manufacturing of siRNAs is costly and complex, and there could be safety issues, such as the potential for off-target effects.

3) Immune therapies

Professor Pawlotsky recounted three examples of therapies designed to restore the immune function: RIG-I agonist inarigivir, checkpoint inhibitor nivolumab, and therapeutic vaccine HepTCell, which is a fluoropeptide vaccine with a depot-forming TLR-9 adjuvant.

“Here, the results are much less convincing, in my opinion.” Despite being unmoved by the data so far, he did not think that they should be discounted.

There are other considerations to take into account. Ideal immune HBV targets are not necessarily well understood, immune therapies may have low specificity, or they may increase risk of immune stimulation, which is a concern for patients with advanced liver disease.

Overall, the abundance of drugs in development is certainly promising, and Professor Pawlotsky believes that some of these trials could yield positive results, providing they are designed in a way that relates to clinical practice. “I have seen in my career, on the HCV side, many drugs that could have been good drugs ‘die’ because of poor design of trials. I think it’s important to keep the drugs alive as long as there is some hope that they may have clinical utility. I think the medical community should be aware [of this], and insist on the drug industry not to give up if the trial is negative.”

Based on Pawlotsky J M. Hepatitis B therapy pipeline: how far are we from cure? (KN153). Presented on Monday 15 April 2019.

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The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.

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