Discontinuation of oral antivirals in chronic hepatitis B: A systematic review

Abstract

The possibility of safe discontinuation of therapy with nucleos(t)ide analogues (NAs) remains one of the most controversial topics in the management of chronic hepatitis B. Therefore, we systematically reviewed the existing data on NA discontinuation in this setting and tried to identify factors affecting the probability of posttherapy remission. A literature search was performed in order to identify all published studies including patients who discontinued NAs in virological remission (VR) and were followed for 12 months thereafter. Twenty-five studies with 1716 patients were included. The pooled rates of durable VR remission were 51.4%, 39.3%, and 38.2% at 12, 24, and 36 months, respectively, after NA discontinuation, being relatively higher in initially hepatitis B e antigen (HBeAg)-positive patients (62.5%, 53.4%, 51.5%) than HBeAg-negative patients (43.7%, 31.3%, 30.1%) (P 5 0.064). The weighted probability of durable biochemical remission was 65.4%, being numerically higher in HBeAg-positive than HBeAg-negative patients (76.2% versus 56.7%, P 5 0.130). The weighted probability of hepatitis B surface antigen loss was 2.0%. The rates of durable VR did not significantly differ according to the VR definition (hepatitis B virus DNA <200, < 2000, < 20,000 IU/mL) or duration of on-therapy VR in HBeAg-positive patients, but they were significantly higher in studies with HBeAg-negative patients and on-therapy VR > 24 than £ 24 months (VR at 12 months off-NAs: 75.0% versus 35.6%, P 5 0.005). The weighted probability of durable HBeAg seroconversion was 91.9% and 88.0% at 12 and 24 months, respectively, after NA discontinuation without being affected by the duration of on-therapy VR or consolidation therapy (>6 months in all studies). Conclusion: Durable VR seems to be feasible in a substantial proportion of patients who discontinue long-term NA therapy; on-therapy VR > 24 months offers higher chances of off-NA VR in patients with HBeAg-negative chronic hepatitis B. (HEPATOLOGY 2016;63:1481-1492 T reatment against hepatitis B virus (HBV) has dramatically improved over the last 15 years, but HBV eradication remains a rarely attainable target. (1-3) Pegylated interferon-alfa therapy given for a finite duration of usually 48 weeks can achieve sustained off-therapy responses, with almost half of the responders clearing hepatitis B surface antigen (HBsAg) in the long term. However, only 20%-30% of patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) may achieve sustained off-therapy responses after a course of pegylated interferon-alfa. (1)(2)(3) Many patients are reluctant to start treatment with this agent because interferon-alfa may have severe side effects as well as an unfavorable safety profile. Thus, oral antiviral agents, nucleos(t)ide analogues (NAs), represent the main therapeutic option for the majority of CHB patients. (4) Abbreviations: ALT, alanine aminotransferase; BR, biochemical remission; CHB, chronic hepatitis B; CI, confidence interval; HBeAg, hepatitis B e a...

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…After stopping therapy, HBeAg seroreversion, as well as the development of HBeAg-negative CHB, may also occur (even after NA consolidation treatment), making this endpoint less reliable. 41,42 Hence, continuing oral antiviral therapy irrespective of the HBeAg response until HBsAg loss has become an alternative strategy. Suppression of HBV DNA to undetectable levels is normally associated with normalisation of ALT levels.…”

“…1,56 According to the existing data, HBeAg seroconversion will remain in the majority (approximately 90%) and virological remission defined as HBV DNA \2,000-20,000 IU/ml will be maintained in $50% of such patients at 3 years after NAs cessation. 41 Alternatively, clinicans may choose to continue NA therapy until HBsAg clearance, which represents the safest current treatment endpoint. Long-term, perhaps indefinite, NA therapy is usually given in HBeAg-negative CHB patients, who are considered to be able to safely stop NAs only if they achieve HBsAg loss.…”

“…An important factor affecting the probability of off-NA virological remission appears to be the duration of on-therapy HBV DNA undetectability. 41 According to the existing data, virological remission defined as HBV DNA \2,000-20,000 IU/ml will be maintained in approximately 50% of such patients 3 years after NAs cessation if they have remained for more than two years on virological remission during therapy. 41 Since such findings are based on studies with durations of ontherapy virological remission of [2 to 5 years, 41 the optimal duration of on NAs remission before discontinuation remains unclear.…”

Treatment for hepatitis B in patients with drug resistance

“…Several controlled trials are ongoing to test this approach and identify the ideal candidates of patients for discontinuation of therapy. A recent meta-analysis summarizing the data from available, yet heterogeneous studies reported a virological remission after nucleoside/nucleotide discontinuation in about 38% of the patients (35). From the perspective of drug resistance, this approach is certainly challenging (4).…”

Letter: long‐term safety of nucleoside and nucleotide analogues in HBV‐monoinfected patients

“…After all, two most recent systematic reviews clearly support the safety of this approach. 8,9 Of course substitution of TDF by a newer compound without potential renal and bone side effects would be clinically welcomed. Finally, I wonder why the authors do not make any suggestion for studies applying ab initio TDF doses lower than the currently administered one, at least to patients of older age and/or with comorbidities.…”