ProfessorSimone Strasser recently published a paper: Drugs inDevelopment for the Treatment of Chronic Hepatitis B CurrentHepatitis Reports DOI 10.1007/s11901-012-0131-9
Professor Strasser is one of Australia’s top liver specialists,she practises at: AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia
I have read her paper. I will summarise her findings. Pleaseremember, she can only publish what is publicly available. The summary is myown and reflects only my own understanding. For full details, readers must readthe whole paper.
The current goals of therapy include sustainedHBeAg/anti-HBe seroconversion and long-term suppression of HBV DNA. The ultimate goal issustained HBsAg/anti-HBs seroconversion, however this is achieved veryinfrequently. Even more desirable would be the elimination of the majortranscription template, intracellular covalently closed circular DNA (cccDNA),however this is not feasible with current therapies. If cccDNA persists, sodoes the risk of viral reactivation. Mechanisms of cccDNA persistence arepoorly understood but are an area of active research [4].
An ideal treatment of hepatitis B, would be a safe, well toleratedoral therapy with a requirement for a finite duration of exposure, leading tolong-lasting viral control, reversal of liver injury, and prevention ofcirrhosis, liver failure, hepatocellular carcinoma and death. It is likely that elimination of cccDNAwill be required if these goals are to be obtained
New approaches to the treatment of hepatitis B includeclinical trials evaluating combinations of currently approved therapies in long-termcombination, or a finite course of therapy aiming to induce HBsAg loss throughimmunologic mechanisms and thereby long-term HBV control (ClinicalTrials.govidentifier NCT01277601). [Professor Strasser’s hospital is one of the testingcenters]
Clevudine It is unlikely to be more universally approved as the phase3 global development program was halted following the development of a severetoxic myopathy in some patients. The use of clevudine has not been endorsed byAASLD or EASL in their hepatitis B treatment guidelines [1, 2].
Emtricitabine Emtricitabine is a potent nucleoside analogue effective in both HIV and HBV. It is currently approved only for treatment ofHIV. When used as monotherapy, emtricitabine is associated with high rates ofantiviral resistance, and it is therefore always used in combination with other antiviral agents.
As both entecavir and tenofovir used as monotherapy are highlyeffective for treatment naïve patients, the most likely role for combinationtenofovir plus emtricitabine is in treatment-experienced patients with viral breakthrough or incompleteviral suppression with their current regimen.
At this time there is little evidence that tenofovir plus emtricitabineoffers any advantage over tenofovir monotherapy in either treatment naïve ortreatment experienced patients
LB80380 Unless clearly superior efficacy to entecavir and tenofoviris observed, or there is a significant price advantage particularly in theglobal marketplace, it is difficult to see the role for this agent in thecurrent marketplace.
Pradefovir With extensive data and experience supporting the role oftenofovir in treatment of chronic hepatitis B, there would be limited role forthis agent, however its current status is unknown.
GS 7340 Because of greater targeted delivery due to selective intracellularactivation to the pharmacologically active metabolite [36],GS 7340 offers the potential for lower dosing, and therefore lower systemic tenofovir exposure compared to300 mg daily tenofovir. A fixed dose combination of GS-7340 and emtricitabine hasbeen developed and is being studied.
MIV-210 Clinical development of this agent is awaited, however onewould expect it would need to demonstrate significantly improved efficacy overentecavir and tenofovir and at a competitive price to have clinical relevance.
Pegylated Interferon Lambda A dose ranging study of pegylated interferon lambda in patientswith HBeAg positive chronic Hepatitis B is currently enrolling and is due forcompletion in May 2013 (ClinicalTrials.gov identifier NCT01204762). No clinical datain the treatment of patients with hepatitis B are available at this time.
Myrcludex-B The future role of Myrcludex-B in HBV infection is likely tobe in combination with nucleos(t)ide analogues, however clinical trials of thiscompound are not yet underway, but anticipated to commence in 2012.
Bay 41–4109 Bay 41–4109 is a member of theheteroaryldihydropyrimidine family of compounds and inhibits HBV replication bydestabilizing capsid assembly, preventing the formation of viral core particles [44–46]. Bay 41–4109 has been administered for 5days to uPa-SCID mice who were inoculated 10 days earlier with HBV [47]. A 1 log10 copy/mLreduction in HBV DNA level was observed in the treated mice, whereascontrol mice had a 0.5 log10 copy/mLincrease in HBV DNA levels. Viral rebound was observed within 5 days of cessation of treatment. Safety and efficacy studies in humanshave not yet been reported.
REP 9 AC Further results with these intriguing agents are awaited.
GS 9620 It is expected that GS-9620 will enter phase 1 studies in bothhepatitis B and hepatitis C.
Nitazoxanide A large number of clinical trials are underway or completed withnitazoxanide in the treatment of chronic hepatitis C, however no trials inchronic hepatitis B are currently registered with ClinicalTrials.gov.
Conclusion
New nucleos(t)ide analogues and prodrugs would have to offera significant advantage over entecavir and tenofovir to be a worthwhilealternative to current treatments. The development of new interferons withimproved tolerability may offer an advantage over currently availableinterferons, as long as efficacy was comparable or improved. Novel approaches targeting additional components of the hepatitis Blifecycle and the host immune response, offer the potential for finite coursesof treatment with long-term viral control or clearance. Novel agents are inclinical development and their role in the management of chronic hepatitis B isexpected to be defined over the coming years. | 
发表于 2012-6-5 16:22
