Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation

Firpi, Roberto J.; Zhu, Haizhen; Morelli, Giuseppe; Abdelmalek, Manal F.; Soldevila-Pico, Consuelo; Machicao, Victor I.; Cabrera, Roniel; Reed, Alan; Liu, Chen; Nelson, David R.

doi:10.1002/lt.20532

Cited by 143 publications

(133 citation statements)

References 25 publications

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“…25 Studies that have demonstrated a beneficial effect of CsA on HCV have only been able to do so in genotype 1, generally in conjunction with interferon. [26][27][28][29][30] We used a forward genetics approach to investigate the mechanism of CsA inhibition of the HCV replicon. CsA selected for mutations in NS5A and NS5B.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine-resistant mutant HCV in vitro. The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P < 0.0001) or only NS5B (P ‫؍‬ 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY

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Section: Discussionmentioning

confidence: 99%

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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“…As co-treatment with IFN and CsA has been shown to achieve greater inhibition of HCV replication and higher SVR rates compared to IFN alone [104] . Furthermore, SVR after IFN therapy has been found to be higher with CsA compared to tacrolimus (46% vs 27%; P = 0.03) [105] . In a pilot study [106] , 38 patients with HCV recurrence receiving PEG IFN α2a and Ribavirin were randomized to continue tacrolimus or to be switched to CsA.…”

Section: Calcineurin Inhibitorsmentioning

confidence: 99%

Strategies to reduce hepatitis C virus recurrence after liver transplantation

Ciria

Pleguezuelo²,

Khorsandi³

et al. 2013

WJH

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Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not retransplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pretransplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of posttransplant HCV recurrence and strategies to reduce its impact on our patients.

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“…62 A meta-analysis of studies comparing the 2 calcineurin inhibitors found a patient and graft survival benefit associated with tacrolimus as maintenance immunosuppression. 63 Conversely, some reports have shown that cyclosporine may have an inhibitory effect on HCV replication that requires concomitant administration of interferon 64 ; however, a prospective, randomized, pilot study revealed no significant difference in sustained viral response compared with those who received tacrolimus. 65 The impact of mycophenolate mofetil on recurrence of HCV appears to be neutral or beneficial to long-term outcomes.…”

Section: Lines Of Managementmentioning

confidence: 99%

Untitled

2014

Exp Clin Transplant

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Liver retransplant is the only treatment for patients with irreversible graft failure. However, given the severe shortage of organs, there is an ethical question of equity in the distribution of this resource. Liver retransplant is more expensive and is associated with lower patient/graft survival rates than equivalent rates after primary transplant. Both primary nonfunction and hepatic artery thrombosis account for nearly all cases of early liver retransplant. Late indications of liver retransplantinclude chronic rejection, biliary complications, or recurrence of primary disease such as hepatitis C, autoimmune hepatitis, and primary sclerosing cholangitis. Donor data are not available when a patient is listed for liver retransplant; therefore, prognostic factors related to the recipient is a more practical way of making the decision to offer liver retransplant is made. In the Model of End-stage Liver Disease era liver retransplant for "late" indications is more complex and selection criteria are more stringent. We review the literature for predictive factors influencing outcome of liver retransplant, especially in those with recurrent disease.

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Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation

Cited by 143 publications

References 25 publications

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

Strategies to reduce hepatitis C virus recurrence after liver transplantation

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