Viral response and safety following discontinuation of treatment with the core inhibitor vebicorvir and a nucleos (t)ide reverse transcriptase inhibitor in patients with HBeAg positive or negative chronic hepatitis B virus infection

Abstract

Background and aims: Vebicorvir (VBR) is a 1st-generation core inhibitor being developed for chronic HBV infection (cHBV). In Study 201, NrtI-suppressed eAg pos or eAg neg cHBV patients (pts) with F0- F2 fibrosis were randomized to VBR or placebo +NrtI for 24 wks. Eligible pts then received VBR+NrtI in Study 211. VBR+NrtI resulted in deep on-treatment viral suppression assessed by high sensitivity assays. VBR+NrtI was discontinued if total HBV nucleic acid (DNA +pgRNA) was <20 U/ml and eAg negative or levels ≤5 IU/ml for ≥6 mths at Wk 52 or later. Here we report off-treatment (off-Rx) viral response and safety after VBR+NrtI discontinuation (DC) in Study 211. Method: The primary end point in Study 211 was sustained virologic response (SVR; HBV DNA <20 IU/ml, COBAS TaqMan v2.0) 24 wks off treatment. eAg and sAg were measured by Abbott Architect (LLOQ = 0.11 IU/ml, 0.05 IU/ml, respectively) and crAg by Lumipulse G (LOD = 1 kU/ml). Safety was assessed by adverse events (AEs) and labs. NrtI was restarted per protocol-specified criteria or investigator/pt preference. Results: Of the pts in Study 211, 18 of 43 eAg pos and 23 of 26 eAg neg pts discontinued VBR+NrtI. In these 41 pts, the mean age was 46 yrs, 71% male, 78% Asian, 80% on TFV and 20% on ETV. At time of DC, the mean duration of VBR treatment was 76 wks and NrtI was 6 yrs; the eAg pos pts had mean eAg 1.1 IU/ml, crAg 247 kU/ml and sAg 6595 IU/ml and the eAg neg pts had mean crAg 7.0 kU/ml and sAg 2808 IU/ml. No pt achieved SVR. Of the 18 eAg pos pts, 17 (94%) relapsed early at off-treatment (off-Rx) Wk 4 and 1 pt (6%) relapsed at off-Rx Wk 12. Of the 23 eAg neg pts, 16 (70%) relapsed early at off-Rx Wk 4, and 3 (13%) and 4 (17%) pts relapsed later at off-Rx Wk 12 and 16, respectively. Univariate logistic regression identified ETV use (p < 0.001) and lower crAg (p = 0.03) as associated with later relapse after off-Rx Wk 4. The current mean time off-Rx was 19 wks with 29/41 (71%) pts restarting NrtI with subsequent decline in HBV DNA. Off-Rx, 14/41 (34%) pts had AEs, most Grade 1 or 2. The most common AE was ALT elevation in 4/41 (10%) pts. No pt had confirmed ALT flare (≥10xULN) or hepatic decompensation. Two unrelated SAEs were reported, hemorrhage following surgery and seizure. Conclusion: While VBR+NrtI DC was well-tolerated, SVR was not achieved. Data suggest crAg level may be important in future DC criteria. Other studies with VBR+NrtI in multi-drug combinations will evaluate potential finite treatment regimens.