Immunological dysfunction during or after antiviral therapy for recurrent hepatitis C reduces graft survival

Sharma, Pratima; Hosmer, Amy; Appelman, Henry D.; McKenna, Barbara J.; Jafri, Mohammad S.; Sullivan, Patti; Fontana, Robert J.; Lok, Anna S.

doi:10.1007/s12072-013-9436-1

Cited by 13 publications

(8 citation statements)

References 33 publications

(34 reference statements)

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“…The lower observed SVR rates are attributed to the use of immunosuppressant agents that enhance viral replication and the need for frequent antiviral dose reductions (50 to 70%) and early antiviral treatment discontinuation (20 to 40%) (12,14). Furthermore, there are increasing reports of immune-mediated allograft dysfunction due to PEG-IFN that may not only require early discontinuation of treatment, but also lead to premature graft failure and/or death (15–17). However, since LT recipients who achieve SVR have a significantly improved survival compared to non-responders, there is an urgent unmet medical need to develop safer and more effective therapies for LT recipients (18, 19).…”

Section: The First Generation Hcv Protease Inhibitors: Boceprevir Andmentioning

confidence: 99%

Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting

Tischer

Fontana

2014

Journal of Hepatology

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Preliminary studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C have demonstrated dramatic increases in tacrolimus, cyclosporine, and the mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldepravir are 2nd generation protease inhibitors which may have improved efficacy and tolerability profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based therapies are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.

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Section: The First Generation Hcv Protease Inhibitors: Boceprevir Andmentioning

confidence: 99%

Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting

Tischer

Fontana

2014

Journal of Hepatology

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“…The second important observation of this study is that the combination of sofosbuvir and ribavirin therapy had a favorable safety profile in this population, with no deaths, graft losses, episodes of rejection or immunological dysfunction observed. In contrast, interferon-based treatments have been associated with post-treatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT recipients [25][26][27]. The safety profile of sofosbuvir and ribavirin is in contrast with that recently reported in two multicenter studies of telaprevir or boceprevir with peginterferon and ribavirin, with both studies reporting near universal need for dose reductions of interferon and ribavirin related to adverse events and treatment-related , sofosbuvir exposure was minimally altered in the post-transplant setting in the context of concomitant cyclosporine-based therapy in contrast to the results of a prior drug-drug interaction study, where a high dose of cyclosporine (600mg) produced a 4.5-fold increase in sofosbuvir exposure, which was not considered clinically meaningful 17.…”

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confidence: 99%

Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation

et al. 2015

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“…Although ACR is frequent after LT, the response to boluses of corticosteroids is successful in >80% of patients and the rates of chronic rejection remain low under current tacrolimus‐based immunosuppression protocols . The risk of chronic rejection and graft loss is increased in case of repeated episodes of severe ACR unresponsive to steroids and when ACR occurs late (>3 months after LT) . Such rather rare conditions are usually restricted to a subpopulation of patients with autoimmune liver diseases .…”

Section: Analysis Of Biopsy‐proven Acr As An Efficacy Endpoint For Rctsmentioning

confidence: 99%

Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal

et al. 2016

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Biopsy-proven acute cellular rejection (ACR) is the primary efficacy endpoint in most randomized trials evaluating immunosuppression in liver transplantation. However, ACR is not a major cause of graft loss, and a certain grade of immune activation may be even beneficial for long-term graft acceptance. Validated criteria to select candidates for liver biopsy are lacking, and routine clinical practice relies on liver tests, which are inaccurate markers of ACR. Indeed, both the agreement among clinicians to select candidates for liver biopsy and the correlation between the clinical suspicion of ACR and histological findings are poor. In randomized trials evaluating immunosuppression protocols, this concern grows exponentially due to the open-label and multicenter nature of most studies. Therefore, biopsy-proven ACR is a suboptimal efficacy endpoint given its limited impact on prognosis and the heterogeneous diagnosis, which may increase the risk of bias. Chronic rejection and/or graft loss would be more appropriate endpoints, but would certainly require larger studies with prolonged surveillances. An objective method to select candidates for liver biopsy is therefore urgently needed, and only severe episodes of histological ACR should be considered as potentially harmful. Emerging surrogate markers of ACR and antibody-mediated rejection require further investigation to determine their clinical role.

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Immunological dysfunction during or after antiviral therapy for recurrent hepatitis C reduces graft survival

Cited by 13 publications

References 33 publications

Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting

Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting

Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation

Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal

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