O118 : Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis

Yurdaydın, Cihan; İdilman, Ramazan; Choong, Ingrid; Kalkan, Çağdaş; Keskın, Onur; Karakaya, Muhammed Fatih; Tüzün, Ali; Karataylı, Ersin; Bozdayı, Mithat; Cory, David G.; Glenn, Jeffrey S.

doi:10.1016/s0168-8278(15)30137-9

Cited by 17 publications

(10 citation statements)

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“…Results were compared to the proof-of-concept study results (lonafarnib alone) [50] and to the HIDIT-2 [48] PEG+TDF results. The boost with ritonavir 100 mg or the combination with PEG-alpha-2a 180 µg/week improved the antiviral efficacy with a viral load decrease of 2 log and reduced digestive side effects [53].…”

Section: Chronic B-delta Hepatitismentioning

confidence: 98%

“…It blocks the assembly and the package during the HDV replication and had been reported to decrease HDV replication [52]. A dose-study to evaluate the virological impact, with a boost with ritonavir (100 mg) or with PEG-alpha2a at 1 and 2 months has been reported [53]. Results were compared to the proof-of-concept study results (lonafarnib alone) [50] and to the HIDIT-2 [48] PEG+TDF results.…”

Section: Chronic B-delta Hepatitismentioning

confidence: 99%

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Hepatitis Delta Virus: Epidemiology, Natural Course and Treatment

Sultanik¹,

Pol²

2016

J Infect Dis Ther

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The hepatitis delta virus (HDV) is a defective hepatotropic virus that affects only patients with hepatitis B virus (HBV) infection. These 2 viruses share the same routes of transmission (parenteral, sexual, and mother to child). The hepatitis delta virus infection may result in acute hepatitis, including fulminant presentation or spontaneously resolving infection, and chronic infection. The prognosis depends on the chronology of the 2 infections, co-infection (higher risk of fulminant hepatitis) or super-infection (frequent evolution to chronicity). The harmfull impact of HIVassociated infection is today debated even if HDV antibodies are present in 12% and 4% of HIV/HBV co-infected and HBV-mono-infected patients respectively. HDV may be treated by interferon, the unique treatment, but relapse is observed in 50% of cases after discontinuation of therapy: only 25% of treated patients achieved a sustained virologic response. Entry HBV/HDV inhibitors (Myrcludex) and prenylation inhibitors are awaited encouraging progress in treating HDV infection. The treatment is recommended in patients with significant fibrosis; viral suppression may result in fibrosis stabilization or reversal which may be also observed in the absence of complete viral eradication. The prevention of hepatitis delta virus infection is based on hepatitis B virus vaccination

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Section: Chronic B-delta Hepatitismentioning

confidence: 98%

Section: Chronic B-delta Hepatitismentioning

confidence: 99%

Hepatitis Delta Virus: Epidemiology, Natural Course and Treatment

Sultanik¹,

Pol²

2016

J Infect Dis Ther

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“…No treatment discontinuation occurred in the treatment groups. Ritonavir boosting can further increase the antiviral effect of lonafarnib [28] .…”

Section: New Therapeutic Strategiesmentioning

confidence: 99%

Chronic Hepatitis D; at a Standstill?

Rizzetto

2016

Dig Dis

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Chronic hepatitis D (CHD) is a severe liver disease with worldwide distribution caused by the hepatitis D virus (HDV). Therapy of CHD is at a standstill. It still relies on interferon (IFN), introduced empirically in the 1980s; results are limited. With the peghilated IFNs that are now in use, only 25% of CHD reach a sustained viral response, that is, clear the HDV-RNA 6 months after stopping therapy. However, HDV remains infectious and ready to reactivate at very low titers undetectable by current assays, if the HBsAg persists in serum; relapses of hepatitis D post-therapy are frequent and further diminish the therapeutic response. The major obstacle to CHD therapy is the minimalist nature of the HDV. It does not encode for any enzymatic function but is replicated by host RNA polymerases deceived to recognize the viral RNA as it were a cellular DNA; therefore, it has no replicative machinery of its own to be targeted by antivirals. The only help required from hepatitis B virus (HBV) is the HBsAg coat to attach to hepatocytes and assembly in the virion; HBV antivirals that decrease HBV-DNA but leave HBsAg unaffected are of no avail in CHD. Novel therapeutic strategies are under evaluation. Myrcludex B, a peptidic inhibitor of HBV entry, was used with some success in vitro in the mouse to block the Na⁺-tauro chocolate cotransporting polypeptide and prevent entry of the HD virion into hepatocytes. The nuclei acid polymer REP-2139 was shown to distinctly diminish serum HBsAg and HDV-RNA by blocking HBsAg entry and inhibiting its intracellular synthesis. Prenylation of the large HD-antigen is critical for its interaction with the HBsAg in the assembly of the virion. A proof of concept study in humans has shown that the prenylation inhibitor lonafarnib reduced HDV-viremia.

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“…Following the discovery of NCTP as the major HBV receptor on hepatocytes [96], drug discovery for HBV/HDV is expected to rapidly move steps forward, and clinical trials with new molecules, including entry HBV/HDV inhibitors (i.e., myrcludex) or prenylated inhibitors that block HDV assembly (i.e., lonafarnib) are ongoing [97,98].…”

Section: Hepatitis Delta Misdiagnosismentioning

confidence: 99%

Emerging Challenges in Managing Hepatitis B in HIV Patients

et al. 2015

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Roughly 10 % of HIV-positive individuals worldwide have concomitant chronic hepatitis B virus (HBV) infection, with large differences between geographical regions and/or risk groups. Hepatitis B is a preventable infection with vaccines. However, it cannot be eradicated once acquired, resembling HIV and in contrast with HCV. In developed countries, hepatitis B exhibits particular features in the HIV population. First, HBV infection is less frequently misdiagnosed than in the general population. Second, nucleos(t)ide analogs active against HBV are widely used as part of antiretroviral combinations and are taken by most HIV patients. Lastly, as the HIV population ages given the success of antiretroviral therapy, non-AIDS co-morbidities are becoming a major cause of disease, for which specific drugs are required, increasing the risk of interactions and hepatotoxicity. Furthermore, concern on HBV reactivation is rising as immunosuppressive drug therapies are increasingly been used for cancers and other non-malignant conditions. In this scenario, new challenges are emerging in the management of hepatitis B in HIV-positive individuals. Among them, major interest is focused on failures to suppress HBV replication, HBV breakthroughs and reactivations, the meaning of isolated anti-HBc, screening for liver cancer, and the complexity arising when hepatitis viruses C and/or D are additionally present. This review will focus on these challenges and the major advances in HBV coinfection in HIV.

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O118 : Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis

Cited by 17 publications

References 0 publications

Hepatitis Delta Virus: Epidemiology, Natural Course and Treatment

Hepatitis Delta Virus: Epidemiology, Natural Course and Treatment

Chronic Hepatitis D; at a Standstill?

Emerging Challenges in Managing Hepatitis B in HIV Patients

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