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

Disclosures

J Viral Hepat. 2019;26(1):4-15. 

In This Article

Treatment Paradigm in HBV

Therapy options with curative intent for CHB are unlikely to be available for several years; thus, patients with chronic infection remain at risk of developing liver cirrhosis and HCC. Current treatments for HBV include pegylated interferon-α (Peg-IFNα) and nucleos(t)ide analogues (NAs), but neither is efficient in delivering functional cure.[22]

Interferon

Conventional interferons (IFNs; Intron A) were first licensed in 1991 for use in the treatment of CHB. In 2005, a pegylated interferon-α (Pegasys) version, with the attachment of polyethylene glycol, replaced standard IFN due to improved pharmacokinetic properties, providing continuous drug exposure over the entire dosing interval, thus offering a less demanding injection schedule with comparable efficacy.[23] IFN provides a dual mode of action: antiviral via inhibition of viral replication and immunomodulatory via enhancement of the host immune response against the virus. Peg-IFNα's direct antiviral activity induces epigenetic modifications in the histones binding cccDNA causing an accelerated decay of replication-competent HBV nucleocapsids.[24] These direct antiviral effects, however, have limited potency in HBV infection. This is confirmed by the slow kinetic of HBV DNA inhibition observed in IFNα treated CHB patients, in comparison with the sharp decline of HCV RNA observed in patients with chronic HCV infection.[25] The ability of IFNα therapy to suppress HBV replication is more likely associated with its immunomodulatory effects.[26,27]

Pegylated interferon-α therapy offers a finite treatment course, is primarily more effective in those of younger age, with moderate viraemia and has the advantage of no antiviral resistance. Its overall success is limited to a small proportion of patients; approximately 10% of those treated achieve functional cure, defined as sustained serum aviraemia and loss of HBsAg. However, approximately 30% of HBeAg-positive patients have a favourable response to Peg-IFNα with sustained HBeAg seroconversion with a proportion of these patients going on to achieve HBsAg loss.[28] Importantly, Peg-IFNα also has a role in HBeAg-negative disease, where a sustained virologic response (HBV DNA <2000 IU/mL) is seen in up to 40% of patients and HBsAg loss reported in approximately 12% at 5 years post-treatment.[29] The use of "early stopping rules" based primarily on HBsAg decline at week 12 (or 24) of therapy can guide physicians in determining a suboptimal response, thus avoiding the potentially undesirable systemic effects associated with a full treatment course. This strategy would allow an early switch to NA therapy, providing an individualized approach to CHB treatment.[28–30]

Nucleos(t)ide Analogues

Nucleos(t)ide analogues sufficiently suppress the production of new virions, reducing HBV DNA to undetectable levels in the serum and normalizing transaminases, but HBsAg loss is rarely achieved.[31] Lamivudine (LAM) was the first nucleoside analogue approved for use in 1998 and although it has now been replaced by agents with higher genetic barriers to resistance, it played a major role in the transition of CHB management allowing dramatic reductions of HBV DNA with the potential to improve disease outcomes.[32] In 2002 adefovir (ADV), the first nucleotide analogue was licensed; however, although it had adequate viral potency, this was outweighed by problems associated with resistance and renal toxicity.[33] Entecavir (ETV) was introduced in 2005 as a potent inhibitor of HBV polymerase and still has a role in the HBV treatment arena today. Generally, it has a high genetic barrier to resistance, which is decreased in patients with previous LAM resistance. Another nucleoside analogue, telbivudine (LdT) was introduced in 2006 and although this agent was efficacious in reducing HBV DNA and having a role in the prevention of mother-to-child transmission, it is no longer recommended as first-line therapy, due to viral resistance and its side effect profile.[34] In 2008, tenofovir disoproxil fumarate (TDF) was approved for use in CHB. It is structurally similar to ADV, but has excellent durability of response. Thus, older agents such as LAM and ADV have now been superseded by TDF and ETV (3rd generation NAs; Figure 1), characterized by a high genetic barrier to resistance, these drugs now represent first-line therapy or are employed following suboptimal response to Peg-IFNα.[30]

Figure 1.

Timeline indicating the licensing and development of therapies for chronic hepatitis B as indicated by national and international guidelines

Recent studies have demonstrated histological improvement (reversal of fibrosis) and reduced development of cirrhosis with long-term NAs.[35] Importantly, there may also be a reduction in HCC development, but this needs to be substantiated in large clinical trials.[36] The REVEAL study demonstrated elevated HBV DNA to be strongly associated with cirrhosis and the development of HCC and thus NAs may have an impact on limiting disease progression.[37] NAs directly target HBV DNA synthesis and are ineffective in their ability to eradicate the cccDNA, the episomal form of HBV from infected cells.[31] Treatment with NAs is considered long-term with limited data on treatment discontinuation, which results in reactivation of HBV in the majority.[31] Recent data, however, demonstrate that certain patient cohorts may be able to stop NA therapy, with declines in HBsAg[38,39] and immune markers to identify such patients are emerging.[40] Although the side effect profile of 3rd generation NAs is favourable, potential drug toxicity with long-term use of TDF may occur, with a negative impact on bone mineral density.[41] For this reason, newer agents namely tenofovir alafenamide (TAF), although equally efficacious as 3rd generation TDF, have been shown to have a more favourable side effect profile.[42]

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