本帖最后由 StephenW 于 2020-7-8 16:01 编辑
Addition of Nucleic Acid Polymers Improves Outcomes of Patients With HBV Infection by Kristine Novak Addition of nucleic acid polymers (NAPs), which inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles, to tenofovir disoproxil fumarate (TDF) and pegIFN therapy significantly increased rates of HBsAg loss and seroconversion, and functional cure, after therapy, researchers report in Gastroenterology. [img]https://ci5.googleusercontent.com/proxy/ioUpFezSVbwhv9wAwaU6sCkYT71WEnWAjsBtrxlHYpv35UGxJcNrKdbNnwR8RnuH06jl2ShAu32WGJE_RUNYFyf5QIZo80nSzHNcGL5fNv4_K8YE35mYZyNGnA-0DdsVhxldmOnrfjUNkk5g0aMny47nd9lE-wUH5kTrirUwgKeiaqzQQkbTWg=s0-d-e1-ft#https://i1.wp.com/journalsblog.g ... g?fit=900%2C448&;ssl=1[/img]
NAPs inhibit virus entry into cells and/or virus assembly by interacting with viral protein and cell factors. Although inhibition of HBV entry has been reported for some early-stage NAPs, REP-2139 and REP-2165 affect formation of subviral particles.Chronic HBV infection causes progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma. There are 292 million persons infected worldwide and 870,000 associated deaths annually, so HBV infection presents a significant global medical burden. Nucleos(t)ide analogues (NUCs), including TDF, suppress viral replication and related liver disease but must be taken lifelong, whereas pegIFN is associated with loss of hepatitis B s antigen (HBsAg) in only about 10% of patients, even when combined with NUCs. The NAP REP 2139 blocks assembly of subviral particles in hepatocytes containing covalently closed circular DNA (cccDNA) or integrated HBV DNA via an as-yet unidentified cellular target (see figure). This NAP reduced HBV replication in livers of ducks within 2 weeks, cleared serum HBsAg and eventually reduced HBV DNA, which were maintained after the ducks were no longer given the agent. In a previous, smaller study, administration of a REP 2139 precursor to HBeAg-positive patients with chronic HBV infection resulted in reductions in HBsAg , HBsAg and HBeAg seroconversion, and HBV DNA clearance. However, long-term virologic control similar to inactive chronic HBV (HBV DNA < 2000 IU/mL, normal alanine aminotransferase) occurred in only 3 of 8 participants, persisting to 5 years in 2 of 8 participants. One of these participants had a functional cure (HBV DNA target not detected, HBsAg below the lower limit of quantification, and normal level of alanine aminotransferase). Michel Bazinet et al performed an open-label, phase 2 trial
of the safety and efficacy of the NAPs REP 2139 or REP 2165 (a bioequivalent variant of REP 2139 with accelerated clearance), combined with TDF and pegIFN, in patients with chronic HBV infection who were negative for hepatitis B e antigen. Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of TDF + pegIFN + REP 2139-Mg or REP 2165-Mg (experimental therapy) weekly, or 24 weeks of control therapy (TDF + pegIFN), followed by 48 weeks of experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. During the first 24 weeks, significantly higher proportions of patients in the NAP groups had decreases in HBsAg to below 1 IU/mL and HBsAg seroconversion compared with controls. Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. At the time patients completed the TDF + pegIFN + NAP regimen (48 weeks), HBsAg levels were 0.05 IU/mL or lower in 24/40 participants. During 48 weeks of follow up, virologic control persisted in 13 of the 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants, with persistent HBsAg seroconversion. PegIFN-induced thrombocytopenia and neutropenia did not differ significantly between patients given NAPs vs controls. Higher proportions of patients in the NAP groups had increases in levels of transaminases, and increases were greater, compared with controls, but did not cause symptoms. The increases correlated with initial decrease in HBsAg, and normalized during therapy and follow up. In an editorialassociated with the article David Durantel and Tarik Asselah call for large, multicenter studies, with longer follow-up periods, to determine if seroconversion is sustained. The editorial authors state that it is unclear whether PEG-IFN is needed in the NAP regimen; TDF and NAP without PEG-IFN was not studied. Studies of flares during treatment are also needed—the flares in this study were safe and associated with beneficial outcomes. Competing therapies being developed include small interfering RNAs, and small molecule HBs-RNA destabilizer.
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发表于 2020-7-8 15:56