Table 4.

Future Needs in Investigational Trials of Chronic Hepatitis B

Area of Interest	Specific Need
Definitions	Uniform definitions of cure (functional or partial) and inactive state, as well as biochemical and virologic relapse, should be used across trials.
Predictors	Predictors of success should be systematically evaluated in all trials, including those with NrtI discontinuation and should include quantitative HBsAg and other markers, such as HBV RNA and HBcrAg.
Stopping criteria	Stopping criteria for low level of HBsAg need validation in clinical trials; different criteria may need to be developed for regimens depending on whether different MOAs (viral inhibitors and/or immune modulators) are incorporated in a treatment regimen.
Source of HBsAg	There is a major need for assays able to differentiate between iDNA and cccDNA in serum as the source of HBsAg [40].
Immunology	No immune biomarkers predict functional cure currently, and they should be tailored to reflect the MOAs of different agents and identify immune system targets (prioritizing the analysis of HBsAg-specific T and B cells for drugs targeting HBsAg and ensuring analysis of liver immunity if using a liver-targeted agent, such as LNA oligonucleotide targeting PD-L1); new methods are needed for measuring restoration of HBV-specific immune control.
Trial samples	All trials should include banked serum/plasma samples, and PBMCs, minimally at pretreatment and EOT to screen and evaluate potential immune and virolologic markers; pathogenesis-focused trials should also include fine-needle aspiration and liver biopsy.
Drug resistance	Assessment for resistance against all drugs in the regimen will be an important consideration for participants with lack of on-treatment response and/or relapse after stopping a finite treatment regimen.

Abbreviations: cccDNA, covalently closed circular DNA; EOT, end of treatment; HBcrAg, hepatitis B core-related antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; iDNA, integrated DNA; LNA, locked nucleic acid; MOAs, mechanisms of action; NrtI, nucleos(t)ide reverse-transcriptase inhibitor; PBMCs, peripheral blood mononuclear cells; PD-L1, programmed death ligand 1.