Clinical impact of the early alanine amininotransferase flare during tenofovir monotherapy in treatment-naïve patients with chronic hepatitis B

Abstract

Background/AimsLittle is known about the effect of early flares on response during first-line tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB). The aim of this study was to investigate the incidence and outcome of early alanine aminotransferase (ALT) flare in treatment-naive patients with CHB during long-term TDF monotherapy. MethodsOne hundred eighty-one treatment-naive CHB patients were treated with a 300-mg once-daily dose of TDF for more than 12 weeks. Virological markers of hepatitis B virus (HBV) and biochemical data were measured at baseline and every 4-12 weeks during the therapy. The proportion of patients with undetectable HBV DNA level (< 100 copies/mL) was noted. ResultsThe median age was 48.3 years and 122 patients (67.4%) were men. Hepatitis B envelope antigen (HBeAg) was positive in 101 patients (55.8%). No patient had cirrhosis. The median follow-up duration was 45 weeks (12-155 weeks). ALT flare (>5 × upper limit of the normal range) occurred in seven patients (3%) without viral breakthrough within the first 8 weeks after the start of TDF monotherapy. Among them, six patients were HBeAg-positive and one patient was HBeAg-negative. All cases of early ALT flares resolved within 4 weeks and virologic response was observed in all patients without interruption or discontinuation of treatment. ConclusionsContinuous TDF monotherapy was effective and safe in treatment-naive patients with CHB who experienced early ALT flares followed by a decrease in HBV DNA level.

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.…”

“…[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. 3,6,9 Nucleic acid polymers (NAPs) selectively block the assembly / secretion of HBV subviral particles (SVP) 15,16 from hepatocytes harbouring cccDNA or integrated HBV DNA, 17 allowing clearance of serum HBsAg by host mediated processes.…”

“…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 .…”

Is alanine aminotransferase flare-up in nucleos(t)ide analogue treatment of chronic hepatitis B a promising, rather than a devastating, sign?

“…According to a study by Seo et al [ 11 ], 7 of 181 CHB patients (3%) showed early ALT flare (>10×ULN) without viral breakthrough during administration of TDF, and all of them recovered without decompensation and were able to maintain virological response. Although TDF is one of the highly potent NUCs that induce rapid reduction of viral load, a few subjects taking TDF showed early ALT flare without transient decompensation [ 12 , 13 ].…”

“…In conclusion, Seo et al [ 11 ] showed that early ALT flare on highly potent NUC was relatively safe and led to successful virological responses in compensated CHB patients. In addition, to achieve partial immune reconstitution by NUCs, additional immune therapy is expected to completely eliminate HBV in the liver in further investigations.…”