Great and rapid HBsAg decline in patients with on‐treatment hepatitis flare in early phase of potent antiviral therapy

Abstract

HBsAg decline during nucleos(t)ide analogue therapy in chronic hepatitis B with lower pretherapy ALT is usually small and slow. This study aimed to investigate why ~10% of such patients showed "rapid HBsAg decline" ≥0.5 log IU/mL by month 6 of therapy. Patients with persistent pretherapy ALT <5X ULN who had qHBsAg at baseline, months 6 and 12 of entecavir or tenofovir therapy were studied. "On-treatment ALT elevation" was defined as >10% increase above baseline to >2X ULN during first 6 months of therapy. Of the 256 patients treated, 51 experienced transient "on-treatment ALT elevation" [group A], including 30 (11.7%) with ALT elevation to 2-5X ULN [group A-1] and 21 (8.2%) flared to >5X ULN [group A-2]. The magnitude of qHBsAg decline and rate of "rapid HBsAg decline" by month 6 was significantly greater and more frequent in group A (-0.446 vs -0.042 log IU/mL; 45.1 vs 8.8%, respectively, P = 0.000) than in the remaining 205 patients without on-treatment ALT elevation (group B), being greatest in patients with hepatitis flare (group A-2: -0.559 log IU/mL and 57.1%, respectively). In patients with therapy ≥2 years, patients with "on-treatment ALT elevation" also showed significantly greater annual HBsAg decline, more frequent to <100 IU/mL and 4 times higher HBsAg seroclearance rate. "On-treatment ALT elevation," especially flare >5X ULN, during entecavir therapy or tenofovir therapy may enhance/accelerate HBsAg decline, suggesting the effect of immune restoration upon potent viral suppression.

The impact of hepatitis flare on HBeAg loss was effective mainly in the first year of Nucleot(s)ide therapy in chronic hepatitis B

“…‘HBeAg seroconversion’ was defined as sustained HBeAg loss with seroconversion to its antibody (anti‐HBe) by the end of follow‐up. ‘Rapid HBsAg decline’ was defined as qHBsAg reduction ≥0.5 log 10 IU/mL by week 24 or ≥1.0 log 10 IU/mL by week 48 of Nuc therapy 17 . Follow‐up duration was counted from the start of Nuc therapy till end of Nuc therapy (EOT) or last visit date for those who remained HBeAg positive and received Nuc treatment.…”

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

“…The development of drug resistance to ETV and TDF/TAF is rare [ 115 , 116 , 117 ], and as a result, transaminase flares are less frequent with these NUCs but also not accompanied by biochemical flare or hepatic decompensation [ 79 , 114 , 118 , 119 ]. Flares during therapy with these later-generation NUCs are frequently associated with declines in HBV DNA, HBeAg seroconversion [ 79 , 119 ] and, in rarer instances, HBsAg loss [ 80 , 120 ], indicating an immunological basis for these flares. In these cases of transaminase flares during NUC-mediated HBV suppression, liver regeneration can match or outpace hepatocyte injury/infected hepatocyte loss ( Figure 4 C), preventing progression of fibrosis and hepatic decompensation.…”

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

“…During the natural history or treatment of chronic HBV infection, transient elevations in transaminases (flares) are observed in a minority of subjects, even those with advanced cirrhosis, and are rarely associated with hepatic decompensation, except during acute infection or when HBV DNA titres exceed 10 9 copies/mL. [2][3][4][5][6][7][8][9][10][11] In the absence of hepatic decompensation and viral rebound, transaminase flares are considered to be immune-mediated and may reflect clearance of infected hepatocytes from the liver via T-cell mediated cytolytic mechanisms. 12,13 This is consistent with the well-established correlation of transaminase flares in HBV mono-infection with reduction of viraemia and or HBeAg seroconversion in the absence of treatment 2 or during NUC therapy 7,8 or with HBsAg loss 14 and the establishment of partial cure (HBV DNA ≤2000 IU/mL, normal ALT) or functional cure of HBV (HBV DNA TND, HBsAg <LLOQ, normal ALT) during interferon therapy.…”

“…At least 292 million people worldwide are chronically infected with HBV, 1 and this hepatotropic infection is associated with fibrosis, cirrhosis and hepatocellular carcinoma. During the natural history or treatment of chronic HBV infection, transient elevations in transaminases (flares) are observed in a minority of subjects, even those with advanced cirrhosis, and are rarely associated with hepatic decompensation, except during acute infection or when HBV DNA titres exceed 10 9 copies/mL 2‐11 . In the absence of hepatic decompensation and viral rebound, transaminase flares are considered to be immune‐mediated and may reflect clearance of infected hepatocytes from the liver via T‐cell mediated cytolytic mechanisms 12,13 .…”