To Stop or Not to Stop: Response After Nucleos(t)ide Analogue Withdrawal Among Patients With Chronic Hepatitis B

Hepatitis B virus (HBV) infection is a major global public health concern with high morbidity and mortality due to progression of liver disease to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Nucleos(t)ide analogues (NAs) are highly effective in viral suppression however, most patients require lifelong treatment, and hepatitis B surface antigen (HBsAg) loss, or “functional cure” is rare on therapy. NA withdrawal results in higher rates of HBsAg loss but remains controversial because of the possibility of HBV flares. This thesis aims to investigate long-term outcomes after NA cessation and determine prognostic factors among virally supressed chronic hepatitis B (CHB) patients who were hepatitis B e antigen (HBeAg)-negative at end of therapy. The first study found that Caucasians with HBsAg levels <1,000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a 4-year predicted probability of HBsAg loss of >30%, although the risk of hepatic decompensation and HCC persisted. The second study found that patients who remained off-therapy without HBsAg loss for one year had mildly active disease, even if they did not meet the criteria for retreatment. The third study found that there were no significant differences in the rates of HBsAg loss between patients who discontinued tenofovir disoproxil fumarate (TDF) compared with entecavir (ETV) however, virological relapse occurred earlier in the TDF-treated group and rates of clinical relapse were also relatively higher in this group. The fourth study showed that the risk of hepatic decompensation was higher among cirrhotics and patients who were HBeAg-positive at the start of therapy. The fifth study described patients who were referred for liver transplantation (LT) after NA cessation. The fourth and fifth studies collectively highlighted that patients should be very carefully assessed prior to NA discontinuation and timely re-initiation of treatment is crucial to avoid adverse outcomes. In conclusion, NA withdrawal can lead to HBsAg loss, but virological relapse is universal and a sustained response off therapy may not be comparable to on-therapy viral suppression. Thus, if NA withdrawal is considered, strict and frequent monitoring is critical to prevent severe complications and liver-related deaths. Non-cirrhotic, Caucasian patients with low HBsAg levels are likely the best candidates for NA withdrawal.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2025

Author dc:creator

• Hirode, Grishma

Advisor dc:contributor.advisor

• Janssen, Harry LA

• antiviral
• cirrhosis
• discontinuation
• functional cure
• hepatitis b
• therapy

Handle dc:identifier.uri

https://hdl.handle.net/1807/145134

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/145134