Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial

Bazinet, Michel; Pântea, Victor; Cebotarescu, Valentin; Cojuhari, Lilia; Jimbei, Pavlina; Albrecht, Jeffrey H.; Schmid, Peter; Gal, Frédéric Le; Gordien, Emmanuel; Krawczyk, Adalbert; Mijočević, Hrvoje; Karimzadeh, Hadi; Roggendorf, Michael; Vaillant, Andrew

doi:10.1016/s2468-1253(17)30288-1

Cited by 209 publications

(263 citation statements)

References 40 publications

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“…Therapy of chronic hepatitis B and HBV/HDV coinfection with REP 2139 combined with pegIFN has shown promising results in several trials . A significant reduction or complete loss of HBsAg, and subsequent seroconversion to anti‐HBs was observed.…”

Section: Discussionmentioning

confidence: 99%

“…The lead NAP compound, REP 2139, achieves multilog reduction or loss of HBsAg in chronic HBV mono‐infection and chronic HBV/hepatitis delta virus (HDV) coinfection. This HBsAg clearance is associated with seroconversion to anti‐HBs, reduction in HBV DNA and elimination of HDV RNA in HDV coinfected patients . REP 2139‐mediated HBsAg clearance appears to synergistically potentiate the host response to pegIFN, resulting in profound increases in anti‐HBs, therapeutic liver flares and the functional control of HBV and HDV infection persisting after termination of combination therapy.…”

Section: Introductionmentioning

confidence: 99%

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Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Mijočević

Karimzadeh

Seebach

et al. 2018

Journal of Viral Hepatitis

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Summary The treatment of patients suffering from HBeAg‐positive chronic hepatitis B with REP 2139‐Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti‐HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139‐Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the “a” determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre‐S/S open reading frame (ORF) was sequenced and pre‐S1, pre‐S2 and S amino acid sequences were analysed. We found no major differences between pre‐S1, pre‐S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the “a” determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre‐S/S ORF has no direct influence on response to REP 2139‐Ca therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Mijočević

Karimzadeh

Seebach

et al. 2018

Journal of Viral Hepatitis

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“…cccDNA was then amplified using specific primers and established conditions . The number of vge per cell was calculated as described …”

Section: Methodsmentioning

confidence: 99%

“…However, this model also has limitations, given that monitoring of host immune responses remains difficult in the absence of commercial tools allowing the analysis of duck innate, humoral, and cellular immune responses, and there is no development of fibrosis or liver inflammation in this model. Interestingly, the antiviral activity of NAP monotherapy observed in the chronic DHBV model closely emulates the effects of NAPs in HBV infection in clinical trials, validating the preclinical performance of NAP‐based therapy in DHBV‐infected ducks as a reliable predictor of the effects of NAPs in HBV‐infected patients.…”

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confidence: 99%

Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks

et al. 2018

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Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)‐infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV‐infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti‐DHBsAg antibodies were monitored by enzyme‐linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow‐up by immunohistochemistry. On‐treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (>3 log) and cccDNA (>2 log), which were tightly correlated with the clearance of DHBsAg in the liver. Conclusion: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (Hepatology 2018;67:2127‐2140).

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“…Relapse could still be observed after the use of interferon (IFN) α−2α9 or pegylated IFN α−2α 10. Whereas there are three novel therapeutic approaches currently available for chronic HDV infection namely lonafarnib,11 REP2139-Ca12 and Myrcludex B,5 there is no study published in the literature which has evaluated the global burden of HDV infection. Reliable estimates are needed to establish the updated prevalence of HDV infection.…”

Section: Introductionmentioning

confidence: 99%

Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis

Chen

Shen

et al. 2018

Gut

300

321

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Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial

Cited by 209 publications

References 40 publications

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks

Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis

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