The cytochrome P450 3A4 inhibitor, RTV, allows a lower LNF dose to be used while achieving higher levels of postabsorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG-IFNα achieved more substantial and rapid HDV-RNA reduction, compared to historical responses with PEG-IFNα alone. Twelve weeks of LNF can result in posttreatment HDV-RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. (Hepatology 2018;67:1224-1236).

Viral response to interferon increases with treatment duration and favorably affects the natural course of disease. Interferon treatment duration has to be individualized with careful post-treatment assessment.

In this study of patients with cirrhosis and healthy controls from the United States and Turkey, a diet rich in fermented milk, vegetables, cereals, coffee, and tea is associated with a higher microbial diversity. Microbial diversity was associated with an independently lower risk of 90-day hospitalizations. (Hepatology 2018;68:234-247).

Background and Aims Proof‐of‐concept studies demonstrated lonafarnib (LNF), a first‐in‐class oral prenylation inhibitor, efficacy in patients infected with HDV. The lonafarnib with ritonavir for HDV‐2 (LOWR‐2) study’s aim was to identify optimal combination regimens of LNF + ritonavir (RTV) ± pegylated interferon alpha (PEG‐IFNα) with efficacy and tolerability for longer‐term dosing. Here we report the safety and efficacy at end of treatment for up to 24 weeks. Approach and Results Fifty‐five patients with chronic HDV were consecutively enrolled in an open‐label, single‐center, phase 2 dose‐finding study. There were three main treatment groups: high‐dose LNF (LNF ≥ 75 mg by mouth [po] twice daily [bid] + RTV) (n = 19, 12 weeks); all‐oral low‐dose LNF (LNF 25 or 50 mg po bid + RTV) (n = 24, 24 weeks), and combination low‐dose LNF with PEG‐IFNα (LNF 25 or 50 mg po bid + RTV + PEG‐IFNα) (n = 12, 24 weeks). The primary endpoint, ≥2 log10 decline or < lower limit of quantification of HDV‐RNA from baseline at end of treatment, was reached in 46% (6 of 13) and 89% (8 of 9) of patients receiving the all‐oral regimen of LNF 50 mg bid + RTV, and combination regimens of LNF (25 or 50 mg bid) + RTV + PEG‐IFNα, respectively. In addition, multiple patients experienced well‐tolerated transient posttreatment alanine aminotransferase increases, resulting in HDV‐RNA negativity and alanine aminotransferase normalization. The proportions of grade 2 and 3 gastrointestinal adverse events in the high‐dose versus low‐dose groups were 49% (37 of 76) and only 22% (18 of 81), respectively. Conclusions LNF, boosted with low‐dose RTV, is a promising all‐oral therapy, and maximal efficacy is achieved with PEG‐IFNα addition. The identified optimal regimens support a phase 3 study of LNF for the treatment of HDV.

These data suggest that cessation of NA treatment is a viable option after a reasonable treatment duration in patients with HBeAg-negative CHB and that HBsAg clearance may become an achievable target in these patients.