The Impact of Currently Licensed Therapies on Viral and Immune Responses in Chronic Hepatitis B

Considerations for Future Novel Therapeutics

Upkar S. Gill; Patrick T. F. Kennedy


J Viral Hepat. 2019;26(1):4-15. 

In This Article


The introduction of a preventative vaccine for hepatitis B virus (HBV) has led to the overall reduction in the incidence of chronic infection. This unfortunately is not the case for many middle and low income countries; thus, chronic hepatitis B (CHB) remains a major global healthcare challenge. In line with this, the viral hepatitides are the only communicable disease whereby there has been an increase in related morbidity and mortality over the last 20 years.[1] Both HBV and hepatitis C virus (HCV) contribute to end-stage liver disease and hepatocellular carcinoma (HCC). HCV remains prevalent in North America and Europe, although novel direct-acting antivirals (DAAs) now provide cure rates of >90% for chronic HCV.[2] CHB remains prevalent in Asia and sub-Saharan Africa,[1] but recent migration patterns have lead to an increase in the prevalence of CHB in the Western world.[3] An estimated 250 million people are chronically infected, and hepatitis B surface antigen (HBsAg) seroprevalence is approximately 4% globally, with much higher prevalence in Africa approaching 10% and 5% in the Western Pacific.[4,5] HBV is transmitted haematogenously and sexually; in high prevalence regions, the majority of HBV infections are transmitted vertically (or perinatally).[6]

Hepatitis B virus infection acquired at birth or in early childhood will result in chronicity in >95% of subjects. On the contrary, only 5%-10% of those who acquire the virus in adulthood will progress to chronic infection. Despite the use of passive-active immunoprophylaxis with HBV immunoglobulin and HBV vaccine, babies born to highly viraemic mothers are at risk of acquiring the infection. However, the risk of vertical or perinatal transmission can be significantly reduced by the administration of antiviral therapy to highly viraemic Hepatitis B envelope antigen (HBeAg)-positive mothers in the last trimester of pregnancy, which is in line with current national and international treatment guidelines.[7–9] Given the rise in UK prevalence of HBV, secondary to migration from endemic areas, hepatitis B has now been added to the infant vaccination schedule.[10] It is predicted that the incidence of HBV-related HCC will increase in the coming years,[11] and thus, it is vital for investment into new HBV therapeutics to prevent the complications of chronic infection and HCC.

Previous national and international guidelines suggested that HBeAg-positive patients in the immune active (HBeAg-positive chronic hepatitis; raised ALT with HBV DNA) or those in the HBeAg-negative immune escape phase (HBeAg-negative chronic hepatitis; raised ALT and/or HBV DNA) are deemed treatment candidates. More recent guidelines have lowered the threshold for treatment candidacy to HBV DNA levels >2000 IU/mL.[12–14] Despite evidence that high viral load, regardless of liver inflammation correlates with HCC,[15] those patients previously considered immune tolerant (HBeAg-positive chronic infection) are excluded from therapy.[16] Recent data have challenged the concept of immune tolerant disease,[17,18] providing weight to the argument for earlier treatment in young CHB patients,[19] where blocking viral replication and reducing oncogenic progression in earlier stages of CHB may be a more effective strategy. When treatment is withheld until there is elevation in serum ALT or until HBeAg seroconversion occurs, it is likely that patients will already experience significant cumulative hepatocyte turnover and be at increased risk of clonal hepatocyte expansion.[20] The recent European Association for The Study of the Liver international guidelines (EASL 2017) proposed new nomenclature for disease phase in CHB with potential implications for the early treatment of patients.[12] The timing of treatment initiation in patients is discussed in detail elsewhere.[16,21]

With novel CHB therapies in the developmental pipeline, the potential to increase the treatment candidacy pool also exists. Although existing therapies are limited in providing a functional cure, defined as HBsAg loss, they may still be employed in combination or sequential therapy strategies, while new drugs are in early phase clinical trials. Currently licensed therapies are discussed here along with their impact on the immune response in conjunction with modifications in viral response. In addition, we briefly outline novel pipeline therapies and how existing therapies may retain a role in combination approaches with new therapies in the future.