ANRS HB07 IP-Cure-B Proof of Concept (PoC) Clinical Trial. Educating the Liver Immune Environment Through TLR8 Stimulation Followed by NUC Discontinuation

Epidemiology

Chronic hepatitis B (CHB) is a major public health care issue worldwide and one of the principal causes of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). Liver cancer is the third leading cause of cancer deaths globally, with the highest burden of disease found in regions where HBV is endemic.

WHO estimates that in 2015, 257 million people were living with CHB infection (defined as hepatitis B surface antigen [HBsAg]-positivity) representing a worldwide prevalence of 3.9%, with considerable geographic variability. In 2015, hepatitis B resulted in an estimated 887,000 deaths, mostly from cirrhosis and HCC, placing it among the top 20 causes of mortality worldwide.

As of 2016, 27 million people (10.5% of all people estimated to be living with hepatitis B) were aware of their infection, while 4.5 million (16.7%) of the people diagnosed were on treatment.

Standard-of-care for CHB treatment

Nucleos(t)ide (NUC) analogs, administered orally, are the standard of care treatment for CHB, providing durable suppression of viral replication, defined by the decline of serum HBV DNA below the lower limit of quantification of diagnostic assays. NUC induced viral suppression, which is observed in the vast majority of patients (> 95%), results in long-term clinical benefits with a reduced risk of liver complications, i.e. decreased risk of: i) liver fibrosis progression, ii) hepatic decompensation in patients with pre-existing cirrhosis, and iii) HCC development. However, treatment with NUC rarely results in clearance of HBsAg and seroconversion to HBsAb even after long-term administration. In highly selected patient populations, the rate of HBsAg loss can reach 10% after 5 years of Tenofovir disoproxil fumarate (TDF) administration.

New treatment options that enhance rates of HBsAg clearance with or without seroconversion are needed. Such treatments will allow patients to discontinue life-long oral antiviral therapy and provide an option for a functional cure with a finite duration of treatment. A therapy with a finite duration of treatment is expected to be applicable to a broader population of chronically infected patients with HBV, including those that are not currently considered eligible for treatment with available therapies by the current clinical practice guidelines. For example, immunotolerant patients and inactive carriers do not fall within the current treatment indications. Different treatment strategies aimed to increase the HBsAg loss rates, either different regimens of currently available medications or regimens including new direct acting antivirals or immune modulators, are being explored.

The host immune response to HBV infection plays a pivotal role in whether acute infection is resolved or becomes chronic. It is also pivotal for control of intrahepatic viral cccDNA, which acts as a viral minichromosome. Individuals who are able to clear HBV infection spontaneously following an acute infection display a vigorous, polyclonal, HBV-specific CD8+ and CD4+ T cell response and maintain trace amounts of intrahepatic cccDNA. In contrast, CHB is associated with a limited and dysfunctional CD8+ T cell response, impaired natural killer (NK) cell antiviral function, the persistence of transcriptionally active cccDNA, and active viral replication. Novel approaches under investigation to achieve functional cure include direct inhibition of the viral replication cycle, targeting of cccDNA, and the stimulation of antiviral immune responses.

Rationale for the trial

The ANRS HB07 IP-cure-B study is a proof of concept Phase II clinical trial in HBeAg negative virally suppressed non-cirrhotic CHB patients. It will explore whether stopping NUC or stopping NUC after SLGN administration can increase the rate of HBsAg decline compared to standard of care CHB treatment. Exploratory analyses will help elucidate whether modifications in the liver immune environment are responsible for HBsAg decline.

The ANRS HB07 IP-Cure-B PoC clinical trial will be conducted in virally-suppressed HBeAg-negative CHB subjects to minimize safety risks and maximize efficacy benefits associated with SLGN. Because they achieve long-term viral suppression under NUC therapy, these subjects have lower levels of HBV DNA in the serum as well as lower expression of HBV antigens, especially HBsAg. A virally suppressed population may have a higher chance of responding to SLGN, as suggested by the observation that immune responsiveness of CHB patients is improved in patients who are on chronic suppressive antiviral therapy with low HBsAg levels. Of note, only subjects with excellent hepatic reserve, i.e. non-cirrhotic patients with normal liver function tests, will be included in this study to further maximize safety. Moreover, in virally suppressed patients with normal liver function, any alteration of liver enzymes will be easier to interpret.

A similar line of reasoning applies for the stopping NUC strategy, since patients with lower HBsAg levels have a higher chance of losing HBsAg after NUC cessation. The enrolment of patients without extensive liver fibrosis, per EASL clinical practice guidelines, will also minimize the risk of severe ALT flares after NUC withdrawal.

Hypothesis of the trial

The hypothesis tested in this trial is built on previous clinical investigations of the stopping NUC strategy and of SLGN administration in patients with CHB.

Thus, the investigators expect that the modification of the liver immune environment induced by SLGN administration should amplify the modifications of the immune responses induced by NUC withdrawal and lead to a restoration of effective intrahepatic innate immunity and HBV-specific T cell responses. In this PoC clinical trial, the investigators will explore, in HBeAg negative virally suppressed HBV patients, whether a TLR8 agonist (SLGN) treatment followed by NUC discontinuation can increase the rate of HBsAg decline.