Will we need novel combinations to cure HBV infection?

Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Currently numerous investigational agents being developed to either interfere with specific steps in HBV replication or as host cellular targeting agents, that inhibit viral replication, and deplete or inactivate cccDNA, or as immune modulators. Synergistic mechanisms will be needed to incorporate a decrease in HBV transcription, impairment of transcription from HBV genomes, loss of cccDNA or altered epigenetic regulation of cccDNA transcription, and immune modulation or immunologically stimulated hepatocyte cell turnover. Nucleoside analogue suppressed patients are being included in many current trials. Trials are progressing to combination therapy as additive or synergistic effects are sought. These trials will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe. Withdrawal of therapy in short‐term trials is challenging because short‐term therapies may risk severe hepatitis flares, and hepatic decompensation. The limited clinical trial data to date suggest that combination therapy is inevitable.

titis B is a numerically important cause of cirrhosis and hepatocellular carcinoma.
Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Currently numerous investigational agents being developed to either interfere with specific steps in HBV replication or as host cellular targeting agents, that inhibit viral replication, and deplete or inactivate cccDNA, or as immune modulators. Synergistic mechanisms will be needed to incorporate a decrease in HBV transcription, impairment of transcription from HBV genomes, loss of cccDNA or altered epigenetic regulation of cccDNA transcription, and immune modulation or immunologically stimulated hepatocyte cell turnover. Nucleoside analogue suppressed patients are being included in many current trials. Trials are progressing to combination therapy as additive or synergistic effects are sought. These trials will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe. Withdrawal of therapy in short-term trials is challenging because short-term therapies may risk severe hepatitis flares, and hepatic decompensation. The limited clinical trial data to date suggest that combination therapy is inevitable.

K E Y W O R D S
antiviral therapy, Hepatitis B, nucleoside analogues, treatment of hepatitis B, viral eradication

| INTRODUC TI ON
Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. HBV can cause HCC in the absence of cirrhosis, but most cases worldwide occur in patients with cirrhosis (70%-90%). Indications for antiviral therapy using nucleoside analogues or pegylated interferon (PEG IFN) have been expanding to include earlier treatment to prevent progression to cirrhosis. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe.
Nucleoside analogue suppression of HBV replication modifies the risk of HCC amongst patients with chronic hepatitis B.
Nucleoside analogue therapy is associated with a considerable reduction in risk but not elimination of HCC in patients with chronic hepatitis B. In many cases long-term treatment is required, although treatment may be discontinued in a proportion. Finite, circumscribed courses of treatment with nucleoside analogues and functional cures (generally defined as loss of HBsAg off treatment) are an uncommon conclusion of antiviral treatment. Current HBV therapies suppress viral replication but do not generally cure the disease, as they do not eliminate cccDNA, or integrated viral genomes. Thus, most of patients with chronic hepatitis B require maintenance suppressive therapy. A complete sterilizing cure with viral eradication and elimination of all HBV gene products from the host is improbable at present.

| HBsA g CLE AR AN CE
Spontaneous clearance of HBsAg occurs infrequently at rates of 1% per year in treatment naïve adults with chronic hepatitis B. 1,2 Typically, HBsAg loss has been observed in those with inactive disease and lower degrees of replication encountered in HBeAgnegative infection, and low quantitative HBsAg concentrations.
However, HBsAg loss can occur after intense exacerbations of chronic disease in patients with high levels of HBV replication, (or during and after cessation of nucleoside analogue and PEG IFN therapy). 3 Lower concentrations of HBsAg (<1000 IU/mL or lower, and HBV DNA concentrations < 2000 IU/mL) favour HBsAg loss. 4 HBsAg loss in patients treated with nucleoside analogues is similarly unusual (<1%), but can modify the aftermath of disease. [5][6][7] The rates are ostensibly higher in patients treated with PEG IFN or combinations of nucleoside analogues and PEG IFN. 8,9 Baseline and on-treatment HBsAg levels that go some way to predicting loss of HBsAg and determine interferon therapy failure have been identified. 10,11 Incident cirrhosis after HBsAg seroclearance is rare, if it has not developed beforehand. The incidence of HCC is reduced but not prevented if HBsAg loss is achieved. 12

| FUN C TI ONAL CURE S: ACHIE VING THE G OAL OF HBsA g LOSS WITH IMPROVED TRE ATMENTS
A functional cure is defined as sustained loss of HBsAg, with or without acquisition of anti-HBs and undetectable HBV DNA 6 months after completing treatment. This definition recognizes that HBV genomes are not cleared from the liver. Although a functional cure cannot be considered a true cure, because of persistent integrated viral genomes, HBsAg loss is a recognizable endpoint for ongoing clinical trials of new HBV treatments. HBsAg loss, and thus an improved clinical outcome could be obtained in a higher proportion of patients than is now possible with nucleoside analogues or PEG IFN. A reduction in the HBsAg antigen load could improve immunomodulatory strategies.
Measurements of HBsAg are assays are standardized (if the sensitivity of detection and lower limits of quantification are defined). Once HBsAg loss is achieved, the rationale is that there will be no further need for therapy. Based on the observed effects of a reduction in HBV replication, it is hoped that a functional cure, achieved at a relatively young age, will prevent progression to cirrhosis and HCC. However, follow-up of patients with past chronic hepatitis B, especially those with cirrhosis, will be needed to confirm a long-term benefit.

| E XPERIMENTAL COMB INATIONS
The combination of a liver targeted HBV locked nucleic acid antisense oligonucleotide with RO7020531, a TLR7-agonist in the AAV HBV mouse model in mice treated for 8 weeks showed that the combination reduces HBsAg and HBV DNA concentrations compared to monotherapy. The combination also delayed rebound for several weeks after the end of treatment. 68 Treatment of HBV infected hepG 2-NTCP cells with HBV specific siRNA inhibited HBV replication and suppressed HBV antigen production. The reduced antigen production initially suppresses CD8 T cell recognition, but CD8 T cell recognition shows evidence of subsequent recovery after siRNA treatment. 69 A hypothesis has been proposed that a liver tar-

| CON CLUS IONS
New compounds are currently limited to clinical trials and proof of mechanism and safety studies. Strategies with a combination of agents and additive or synergistic effects being sought. These agents will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. New combination therapies for HBV will require individualization but broad eligibility is sought.
The safety of new therapies will be paramount given the safety of currently approved nucleos(t)ide analogues. Patients with cirrhosis are being excluded from early phase trials. Harm vs benefit in young adults will require careful consideration. Withdrawal of therapy in short-term trials is challenging because short-term therapies may have the risk of severe hepatitis flares, hepatic decompensation or death. Therapies in development that rely on altering CD8 T cell recognition will require a deeper understanding of the effects of new inhibitory compounds and interactions between hepatocyte antigen expression, inflammatory cytokines and adaptive immune responses. Combination treatments appear to be an unavoidable strategy for improving functional cure. The cost of combination curative treatments may become problematic in low-and middle-income countries, given the low cost of generic nucleoside analogues and the minimal monitoring required.

CO N FLI C T O F I NTE R E S T
None declared.