Benefit of transaminase elevations in establishing functional cure of HBV infection during nap‐based combination therapy

Abstract

Treatment of HBV infection with nucleic acid polymers and pegIFN is accompanied by transaminase elevations in 95% of participants. HBV viral rebound, partial cure (HBV DNA < 2000 IU/mL, normal ALT) or functional cure (HBV DNA target not detected, HBsAg <LLOQ, normal ALT) occurred in 27%, 38% and 35% of participants. Correlations between ALT, AST and GGT elevations, virologic baseline, response during therapy and HBV therapeutic outcome were investigated. A retrospective analysis of all 40 participants in the REP 401 study (NCT02565719) included maxima and area under the curve for ALT, AST and GGT, baseline virology, HBsAg and anti-HBs response and HBV therapeutic outcomes. ALT, AST and GGT elevations were asymptomatic, independent of baseline virologic status and anti-HBs response but correlated with HBsAg reduction ≥3 log 10 from baseline. Functional cure was associated with significantly lower HBsAg during the nadir of ALT flares versus viral rebound or partial cure. ALT elevations >3X ULN while HBsAg was <1 IU/mL occurred in 3/11 (27%), 11/15 (74%) and 14/14 (100%) of participants experiencing viral rebound, partial or functional cure. ALT elevation >3X ULN during HBsAg <1 IU/mL and <10 IU/mL were the best predictors of partial and functional cure. In conclusion, elevations in ALT, AST or GGT while HBsAg <10 IU/ml during therapy with REP 2139 + pegIFN are associated with partial and functional cure. More potent HBsAg reduction during flare nadir is associated with the establishment of functional cure, suggesting a critical role for HBsAg-specific immunity to achieve this outcome. These on-therapy milestones may have similar positive prognostic value with other combination therapies.

HBsAg isoform dynamics during NAP‐based therapy of HBeAg‐negative chronic HBV and HBV/HDV infection

“…[ 36 , 37 ] In HBeAg‐positive chronic infection, rapid clearance and seroconversion of HBeAg are also observed, [ 36 ] and in HBV/HDV co‐infection, additional rapid clearance of HDV RNA occurs. [ 33 ] When combined with pegylated interferon (pegIFN) or tenofovir disoproxil fumarate (TDF) and pegIFN, NAP‐based combination therapy leads to high rates of HBsAg loss (<0.005 IU/ml) and seroconversion, host‐mediated transaminase flares, high rates of cccDNA silencing, and high rates of functional cure of HBV with persistent HBsAg seroconversion [ 38 , 39 , 40 ] and persistent undetectable HDV RNA (in co‐infected individuals). [ 41 ] A retrospective analysis of changes in HBsAg isoform composition during therapy and follow‐up from NAP‐based combination therapy was performed to establish the pattern of response in each HBsAg isoform during therapy and treatment‐free follow‐up.…”

Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP‐Based Therapy

“…Notwithstanding the limitations in the sensitivity of the HBV‐RNA and HBcrAg assays, the excellent suppression of HBV DNA and HBsAg in the absence of evidence of active HBsAg clearance by anti‐HBs strongly argues that not only is cccDNA suppressed (not eliminated) but the removal of hepatocytes with integrated HBV DNA (also a source of HBsAg) must also have occurred. This control of liver infection may also be due in part to the high incidence of strong host‐derived transaminase flares ( 21 ) and appears to persist in all participants achieving functional cure.…”

“…(18)(19)(20) These clinical benefits were recently shown to be linked to the high prevalence of therapeutic transaminase flares in the REP 401 study. (21) DOI 10.1002/hep4.1767 Potential conflict of interest: Dr. Anderson owns stock in and is employed by Abbott Laboratories. Dr. Bazinet is an employee and shareholder in Replicor Inc. Dr. Cloherty owns stock in and is employed by Abbott Laboratories.…”

“…( 18 , 19 , 20 ) These clinical benefits were recently shown to be linked to the high prevalence of therapeutic transaminase flares in the REP 401 study. ( 21 )…”

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure

“…In the latest study of TDF, pegIFN and REP 2139 or REP 2165, 95% of participants experienced transaminase flares (ALT and AST) as well as GGT flares, all of which were host-mediated [ 153 ]. Recent analysis of the effects of these high rates of flares on therapeutic outcomes in this latest study indicated that transaminase flares occurring during HBsAg clearance were associated with partial or functional cure, while transaminase flares occurring in the presence of HBsAg were associated with viral rebound after removal of therapy [ 154 ]. In cases of transaminase flares with HBsAg loss, HBsAg-specific exhaustion is absent, suggesting that these transaminase flares are associated with removal of all HBsAg reactive hepatocytes, those with active cccDNA or with integrated HBV DNA ( Figure 4 D).…”