Al-Mahtab Mamun, Bazinet Michel, Vaillant Andrew
Bangabandhu Sheikh Mujib Medical University, Shahbagh Road, Dhaka-1000, Bangladesh.
Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec, Canada H4P 2R2.
PLoS One. 2016 Jun 3;11(6):e0156667. doi: 10.1371/journal.pone.0156667. eCollection 2016.
Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2-7 log reductions of serum HBsAg, 3-9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10-1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which may improve the effect of immunotherapy. NAPs may be a potentially useful component of future combination therapies for the treatment of chronic hepatitis B.
ClinicalTrials.gov NCT02646163 and NCT02646189.
先前的体内研究表明，核酸聚合物（NAPs）可能通过阻止乙肝表面抗原（HBsAg）从受感染的肝细胞中释放，从而降低血液中循环的HBsAg水平，且这种作用可能具有临床益处。在两项针对HBeAg阳性慢性乙型肝炎病毒（HBV）感染患者的临床研究中对NAP治疗进行了评估。REP 101研究检测了8例患者接受REP 2055单药治疗的情况，REP 102研究检测了12例患者接受REP 2139-Ca单药治疗的情况，其中9例患者过渡到聚乙二醇化干扰素α2a或胸腺素α1的短期联合治疗。在两项研究中，NAP单药治疗均伴随着血清HBsAg下降2 - 7个对数、血清HBV DNA下降3 - 9个对数以及血清抗HBsAg抗体的出现（10 - 1712 mIU/ml）。在REP 102研究中，9例过渡到免疫治疗（聚乙二醇化干扰素或胸腺素α1）联合治疗的患者中有8例出现HBsAg消失，并且所有9例患者在治疗停药前血清抗HBsAg抗体滴度均大幅升高。在停用REP 2055治疗后的52周内，8例患者中有3例未观察到血清病毒血症反弹（HBV DNA>1000拷贝/ml，HBsAg>1IU/ml）。其中2例患者的血清病毒血症抑制进一步维持了290周和231周。在REP 102研究中过渡到联合治疗的9例患者停用所有治疗后，8例患者在停药后实现了HBV DNA<116拷贝/ml。7例患者在12至123周内出现病毒反弹，但在随访135周和137周时，仍有2例患者未出现病毒反弹。REP 2055观察到的给药耐受性问题在REP 2139-Ca中很少见，但REP 2139-Ca治疗伴有脱发、吞咽困难和味觉障碍，这些被认为与试验地点流行的重金属暴露有关。这些初步研究表明，NAP在治疗期间可引发重要的抗病毒反应，这可能会改善免疫治疗的效果。NAPs可能是未来慢性乙型肝炎治疗联合疗法中一个潜在有用的组成部分。
ClinicalTrials.gov NCT02646163和NCT02646189。
