Liver Safety Assessment in Clinical Trials of New Agents for Chronic Hepatitis B

Robert J. Fontana; Mark I. Avigan; Harry L. A. Janssen; Arie Regev; Poonam Mishra; Anuj Gaggar; Nathaniel Brown; Cynthia Wat; Patricia Mendez; Ryan T. Anderson; Bruce Given; Veronica Miller; Maria Beumont


J Viral Hepat. 2020;27(2):96-109. 

In This Article

Recommendations for Liver Safety Assessment in Hepatitis B Clinical Trials

Baseline and Reference ALT Values

The degree of serum ALT elevation along with the HBV replicative status of the patient is used to guide the decision to initiate conventional antiviral treatment in chronic HBV. To help standardize clinical management, the AASLD recommends an ULN for serum ALT of 35 U/L for males and 25 U/L for females.[3] Since many chronic HBV patients being considered for enrolment into clinical trials will have elevated serum ALT levels, it is necessary to compare treatment-emergent ALT elevations to a patient's baseline or nadir values. In addition to varying by patient age and sex, the ULN values for serum ALT and other liver safety biomarkers are known to vary among laboratories due to differences in reference populations and analytical variation among commercial assays.[41] Since serum ALT levels may fluctuate substantially over short periods of time, the serum ALT value at screening may not accurately represent the patient's true baseline value, defined as the last ALT taken before the first dose of study drug (Table 3). Registration trials of IFNs and NrtIs for chronic HBV studied immune active patients where the majority of patients had elevated ALT levels at baseline (Table 2).[42,43] In general, the majority of the screening and pretreatment baseline serum ALT values are anticipated to be lower or normal in NrtI-suppressed patients than in treatment naïve or experienced patients not receiving an antiviral drug. It is recommended that the serum ALT value obtained at the baseline visit, immediately prior to dosing be used as the reference value for further assessment of ALT changes on treatment rather than the ALT value obtained at the screening visit. If the baseline serum ALT level is significantly elevated compared with the screening ALT level (ie >2× screening level), an evaluation for possible alternative aetiologies of abnormal liver tests is advisable prior to initiation of study treatment.

Serum ALT levels usually decrease during effective antiviral therapy. The use of on treatment nadir serum ALT values as the post-baseline adjusted ALT values for 'flare' evaluations was employed in previous NrtI trials in chronic HBV patients as well as HCV drug development with direct-acting oral antiviral agents.[44,45] Therefore, we recommend that the on treatment nadir ALT value be used as a reference for identifying a serum ALT flare during treatment and follow-up.

Inclusion and Exclusion Criteria for Clinical Trials of Investigational Agents

Inclusion and exclusion criteria may need to be adjusted on a case-by-case basis according to the targeted patient population, and the mechanism(s) of action, PK/PD considerations and the preclinical safety profile of the investigational agent. In studies enrolling NrtI-suppressed patients, patients treated for a minimum of 6 months with a single NrtI should consistently have HBV DNA levels below the lower limit of quantitation (and ideally undetectable HBV DNA) on at least 2 separate tests using a quantitative PCR-based assay.[1]

Liver Disease Severity and Other Considerations

A thorough medical history, physical examination and serology tests for HCV, hepatitis D (HDV) and HIV infection at screening will help exclude patients with competing causes of liver disease. Patients who do not have a liver imaging study within 6 months of enrolment should have one at the time of screening to exclude HCC and concomitant pancreatobiliary disease. Investigational agents for CHB with new mechanisms of action should not be evaluated in patients with advanced fibrosis/cirrhosis until initial proof of efficacy and safety have been demonstrated in patients with less advanced liver disease (Table 3). Generally, this will not be available until phase 2b studies have been completed. Although a liver stiffness score of >9 kPa is frequently used to exclude chronic HBV patients with advanced fibrosis, the optimal cutoff value may be higher in those receiving oral antiviral therapy and lower in those with underlying hepatic steatosis.[46–48]

Clinical Trials in Hepatitis B Patients With HDV or HIV Co-infection

An estimated 10–20 million chronic HBV patients worldwide have HDV co-infection and are at increased risk for accelerated liver disease progression.[49] Investigational regimens aimed at functional cure for HDV co-infected patients may include agents targeting the HDV virus, the HBV virus or host immune response to infected hepatocytes.[50] Interpretation of liver safety biomarker data in these studies will require simultaneous assessment of both HBV and HDV efficacy biomarkers such as anti-HDV IgM, anti-HDV IgG and HDV-RNA levels. Similarly, clinical studies targeting the 30 million HIV co-infected CHB patients will also need to include assessment of HIV viral parameters such as HIV RNA levels and CD[4] counts.[51] Furthermore, interpretation of liver safety biomarker data will need to account for the potential of an immune reconstitution syndrome in HIV patients recently started on antiretroviral therapy, potential hepatic mitochondrial damage from the antiretroviral regimen and the higher incidence of pre-existing liver disease in HIV co-infected patients.[52]

Pretreatment Liver Safety Biomarker Exclusion Criteria

For treatment naïve or nonresponders to a previous treatment, chronic HBV patients with a screening serum ALT level > 7× ULN or > 300 U/L are recommended for exclusion. For NrtI-suppressed patients those with a serum ALT level > 3× ULN or >120 U/L should be considered for exclusion since the majority of NrtI-suppressed adult patients have a normal or near normal ALT.[53] Since most patients with chronic HBV have a normal or near normal ALK level, any patient with a serum ALK level >2× ULN is recommended for exclusion as this is suggestive of an additional cause of liver injury. For the purpose of a clinical trial, the ULN values provided by the central laboratory should be employed rather than ULN values suggested by various guidelines or consensus papers.