Review Article

Clinical Pharmacology of Current and Investigational Hepatitis B Virus Therapies

Elise J. Smolders; David M. Burger; Jordan J. Feld; Jennifer J. Kiser

Disclosures

Aliment Pharmacol Ther. 2020;51(2):231-243. 

In This Article

Abstract and Introduction

Abstract

Background: Treatment of hepatitis B virus (HBV) infection with current therapy suppresses HBV DNA, but loss of hepatitis B surface antigen (HBsAg; functional cure), is rare. Multiple compounds are under investigation.

Aims: To describe the pharmacology, including drug interactions, efficacy, safety and mechanisms of action of investigational compounds for HBV infection.

Methods: Descriptive review using PubMed and Google to identify literature/conference papers on investigational compounds (≥Phase 2) with data on efficacy and safety in HBV-infected patients.

Results: Bulevirtide, JNJ-56136379, ABI-H0731, REP-2139, and inarigivir decrease HBV DNA/RNA, with greater potency than current nucleos(t)ide analogues. REP-2139 (25%–75% of patients, 20–48 weeks treatment) and inarigivir (26% of patients, 12–24 weeks treatment) induce HBsAg loss. ARO-HBV reduced (>1.5 log10 UI/mL) HBsAg in 85% of patients (12 weeks treatment). There are some safety concerns with investigational agents (e.g., increased bile acids with bulevirtide, and liver enzyme flares with REP-2139) which will require a risk benefit assessment compared with current therapies. Single and multidose pharmacokinetic data are available for bulevirtide, JNJ-56136379, ABI-H0731; no such data are available for REP-2139, ARO-HBV, inarigivir. Initial drug interaction assessments have been performed with bulevirtide and inarigivir (only in vitro).

Conclusions: There are promising investigational therapies for HBV infection. Increasing the potential for HBsAg loss may result in more patients achieving functional cure. However, many knowledge gaps remain such as pharmacokinetics in those with HBV, cirrhosis and renal impairment but also the interaction potential between investigational therapies, risk-benefit profiles, and potential for drug interactions with medications used to treat comorbidities associated with aging.

Introduction

Worldwide, approximately 257 million people are chronically infected with the hepatitis B virus (HBV).[1] Chronic HBV infection is most endemic in the Western Pacific and Africa where 6.2% and 6.1% of the adult population is infected.[2] In contrast, the prevalence is low in Europe and the United States of America (US) (<2%).[1] In 2009, around 2.2 million people were living with HBV in the US[3] and 15 million people in Europe.[4] HBV prevalence in the US is highest in foreign-born individuals (1.0%-2.6% HBsAg+) and in individuals living in correctional institutions (2.0% HBsAg+).[5] Liu and colleagues found in a cohort of 2,734 persons newly diagnosed with HBV in California, that 86%-91% originated from Asia.[6] It is estimated that 53% of the HBV infections in western, northern, and central Europe are in persons born outside the European Union.[7]

HBV is a partially double stranded DNA virus which replicates in the liver. HBV is transmitted through blood contact, or other body fluids, of infected individuals. In high endemic countries, transmission is mostly vertical or early horizontal. Sexual transmission and intravenous drug use are other well-known routes of HBV transmission; however the probability of chronicity upon exposure is much lower in immunocompetent adults. Thus, the majority of chronic infections globally were acquired in infancy or early childhood. An effective HBV vaccine has been available since 1982. In 2017, global vaccine coverage was 84% for the full three dose course and only 37% for the birth dose.[2]

The course of HBV infection can be divided into an acute phase, in which persons may clear the virus naturally, and a chronic phase. Persons are considered to have chronic infection if hepatitis B surface antigen (HBsAg) persists for >6 months.

The most important complication of a chronic HBV infection is liver damage. Cirrhosis or hepatocellular carcinoma (HCC) occurs in 20%-30% of the patients that fail to clear the virus.[1] These complications take years to develop. A Taiwanese cohort showed that the mean age of liver complications was 57.2 years when patients were infected in early childhood.[8]

Worldwide, the HBV population is aging, and the frequency of co-morbidities in this population is rising. A study in 44,026 chronic HBV patients insured in the US showed that the median age in three different payer cohorts in 2006 was 47, 71, and 52 years and rose to 51, 73, and 52 years, respectively, in 2015. The proportion of Medicare (n = 2,938) insured HBV patients with diabetes (28%-41%), hypertension (43%-76%), and hyperlipidemia (8%-47%), non-alcoholic fatty liver disease (NAFLD) and hepatic steatosis (1.8%-4.5%) increased.[9] Liu and colleagues reported similar trends: the mean age increased from 43.3 years in the group that presented for the first time with HBV in 2000–2005 to 49.1 years in the 2005–2011 cohort (P < .001). Also, the following diseases increased significantly in those years (P < .001): cirrhosis (12.6%-24.6%), decompensated cirrhosis (1.1%-7.9%), HCC (4.9%-9.1%), diabetes (4.9%-22.9%), hypertension (12.3%-36.1%) and chronic kidney disease (4.4%-19.7%).[6] Comparable findings were observed in a large patient cohort in Hong Kong.[10] Given the increase in age-associated conditions in persons with HBV, providers must remain vigilant to the identification and management of potential drug-drug interactions (DDI) between HBV therapies and medications used to treat these comorbidities, as well as potential alterations in the pharmacokinetics of HBV therapies in the aging HBV population. There are few DDI with current therapies, pegylated-interferon alfa (peg-IFN-α) and nucleos(t)ide analogues (NA). However, many compounds are in development for HBV and the DDI potential of these compounds will need to be established.

The current treatment goal of HBV therapy, as stated by the AALSD guidelines, is to reduce the risk of progression to cirrhosis- and liver-related complications, including HCC.[11] Similarly, EASL guidelines state that the goal is to improve survival and quality of life by preventing disease progression, and HCC development.[12] The benefit of current therapy, primarily with NA, is that treatment is well-tolerated. Safety of NAs in children and pregnant women (for tenofovir disoproxil fumarate (TDF)) has also been established. NA also has favorable pharmacokinetics, with no food restrictions, limited DDI and low pill burden (one pill once daily).

Another advantage of NA therapy is that HBV DNA suppression is achieved in most patients (60%-93%).[11] Reduction of HBV DNA correlates with normalisation of liver enzymes (68%-88% ALT normalisation when treated with NA[11]), and reduced development of cirrhosis/HCC.[13,14] A disadvantage of NA therapy is that they are not curative because they act late in the viral lifecycle (Figure 1) and do not affect the pool of long-lasting covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes nor do they prevent HBV DNA integration into the host.[11] The other current therapy, peg-IFN-α, also has limited efficacy and many toxicities. At present, the best that can be achieved with current HBV therapies is a functional cure (HBsAg loss with anti-HBs seroconversion and undetectable HBV DNA), which is correlated with excellent long-term outcomes.[15,16] However, achieving HBsAg loss rarely occurs (0%-8%). The ultimate treatment goal would be eradication of cccDNA from the liver and integrated HBV DNA elimination from the host (sterilisation), which has not been achieved to date.

Figure 1.

Viral replication cycle of the hepatitis B virus and possible drug targets. The viral replication cycle of the HBV virus is shown in Figure 1. The HBV virion attaches to the hepatocyte via reversible and noncell-type specific binding to the hepatocyte. Next, entry is facilitated by the hepatic bile acid transporter, sodium taurocholate co-transporting polypeptide (NTCP). NTCP has high affinity for the preS1 domain of the large HBsAg (L) protein.1,58,62 After entry, the virion is uncoated and relaxed circular partially double stranded DNA (rcDNA) is released in the cytoplasm, which is then transported to the nucleus. rcDNA is repaired by the host enzymes into cccDNA. cccDNA is the template for HBV replication and exists as a mini-chromosome including histone and nonhistone proteins and topoisomerases. The cccDNA has 4 open reading frames which encode 7 proteins, hepatitis B e antigen (HBeAg), hepatitis B core antigen (HBcAg), HBV polymerase, HBsAg proteins (large (preS1), medium (preS1), and small (S)) and HBx protein.12 The mini-chromosome forms pregenomic (pgRNA) and subgenomic RNA using the cellular machinery (transcription) of the host. Precore mRNA is responsible for HBeAg formation (which is secreted) and subgenomic RNA is translated into HBsAg proteins and HBx protein. HBx is required for HBV transcriptional activity.58 pgRNA produces core protein and the viral polymerase. The core protein formation is important as it forms an immature nucleocapsid containing pgRNA and the viral polymerase (encapsidation). In the immature nucleocapsid, pgRNA is reversed-transcribed into HBV DNA (which is rcDNA). These mature HBV DNA containing nucleocapsids can either be imported back into the nucleus to form more cccDNA or can be enveloped by HBsAg for secretion.58,62 Due to a mispriming event, a minority (10%) of the viral DNA (linear double stranded) is integrated in the genome of the host.1 This integrated HBV DNA does not contribute to viral replication but can produce HBsAg or HBsAg sub viral particles and may also be important for hepatocyte transformation that may be a precursor to the development of HCC.12,58 In addition to mature HBV virions, HBeAg, and excessive numbers of HBsAg sub viral particles (SVP, spherical and filamentous) are secreted from the hepatocyte. These SVP are secreted in 103-106-fold excess compared to mature virions and they do not have a nucleocapsid.58 Therefore, SVPs are not infectious, but are thought to contribute to the impaired immune response during HBV infection.58,62 The stop sign indicates a possible drug target. Abbreviations: cccDNA, covalently closed circular DNA; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen subviral particles; HBcAg, hepatitis B core antigen; pgRNA, pregenomic RNA; rcDNA, relaxed circular partially double stranded DNA

To achieve higher rates of HBsAg loss or HBsAg seroconversion, many compounds are under investigation for the treatment of HBV (http://www.hepb.org/treatment-and-management/drug-watch/). In general, the current compounds can be divided in two main drug classes: (a) immune modulators (such as peg-IFN-α) and (b) direct-acting antivirals, containing the NA, and the new drug classes of the entry inhibitors, capsid assembly modulators, secretion inhibitors and RNA interference compounds.

In this descriptive review, the pharmacology of investigational HBV compounds is summarised. When data are not available, we speculate on the potential for DDI with other HBV therapies and common concomitant medications. In addition, available safety and efficacy data are presented. The mechanisms of actions are also described.

PubMed and Google were used to identify papers and conference abstracts/posters of compounds. Compounds selected for this review were based on the availability of efficacy and safety data in HBV-infected patients (Phase ≥ 2).

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