Direct Acting Antiviral Therapy After Liver Transplantation

Paul Y. Kwo

Disclosures

Curr Opin Gastroenterol. 2016;32(3):152-158. 

In This Article

Daclatasvir/Sofosbuvir ± Ribavirin

The combination of sofosbuvir and daclatasvir has been shown to be effective post-OLT.[15] One study examined 53 individuals post-OLT who received the NS5A inhibitor daclatasvir with sofosbuvir 400 mg and initial ribavirin dose of 600 mg across a range of genotypes. In the preliminary report, 53 individuals who were post-OLT received daclatasvir and sofosbuvir with overall an SVR rate of 94% (50/53). All three relapses had NS5A resistance variants by population sequencing posttreatment. The overall SVR rate for the genotype 1a cohort was 97%, 90% for 1b, 91% for genotype 3, and 100% for genotype 6, though there was just one patient. Similar to the combination with ledipasvir and sofosbuvir, this was a well tolerated therapy with the treatment-related side-effects primarily related to the use of ribavirin requiring discontinuation of four of 53 individuals with one individual discontinuing therapy because of his significant headache from sofosbuvir, though this patient achieved SVR. And similar to ledipasvir/sofosbuvir, a broad range of immunosuppressive agents were allowed. Another preliminary study has recently reported the results of 130 of 533 liver transplant recipients where patients received 12–24 weeks of sofosbuvir and daclatasvir with or without ribavirin.[16] An overall sustained response rate in this preliminary report of 96% was observed and the intention to treat analysis with two patients experiencing virologic failure, one with genotype 1 and one with genotype 4. These reports when taken together suggest that the combination of sofosbuvir and daclatasvir may be used across a broad range of genotypes posttransplant with the expectation of high sustained response rates.

Sofosbuvir Simeprevir: Genotype 1

The combination of sofosbuvir and simeprevir post-OLT has been shown to be effective in a genotype 1 post-OLT population. As previously noted, there is a drug–drug interaction between cyclosporine and sofosbuvir and this combination is contraindicated because of the simeprevir metabolism inhibition by cyclosporine. A real-world treatment experience was recently reported in patients receiving therapy with sofosbuvir, simeprevir with or without ribavirin.[17] In this report of 151 individuals with outcome data, the majority received sofosbuvir and simeprevir without ribavirin (119) with the remainder receiving ribavirin. The duration of therapy was 12 weeks for most patients, though 15 patients received 24 weeks of therapy. The overall SVR rate was 88% with 11 individuals relapsing (7%). One patient had virologic breakthrough and six were lost to posttreatment follow-up. In this study, the SVR rates were similar between sofosbuvir or simeprevir with or without ribavirin. Three patients with cirrhosis died because of aspiration pneumonia, suicide, and multiorgan failure and there was one episode of acute cellular rejection.

It should be noted that this cohort had many with advanced liver disease with 40% of the cohort reporting a history of hepatic decompensation and 7% had been exposed to protease inhibitors. The current generation of protease inhibitors, while safe in compensated cirrhosis (Child's A) should not be used in those with decompensated liver disease regardless of transplant status. Similar to the other DAA posttransplant studies with ribavirin, anemia was a commonly reported adverse event. There were no safety signals noted for the concomitant use of cyclosporine and simeprevir, though the cohort was small and again, this simeprevir should not be used with cyclosporine-based immunosuppression.

Paritaprevir, Ombitasvir, and Dasabuvir for Genotype 1

The combination of paritaprevir, ombitasvir, and dasabuvir with ribavirin has also been studied in genotype 1 individuals and a recent report examined this combination with ribavirin for 24-week duration.[18] As has been previously discussed, there are drug–drug interactions with ritonavir and the calcineurin inhibitors, tacrolimus, and cyclosporine.

Therefore, when using this regimen for genotype 1 individuals, the tacrolimus is typically dosed at 0.5 mg once weekly or every other week and cyclosporine is reduced to one-fifth of the daily dose. In the 34 individuals who were studied, 85% were genotype 1a with half having F0–F1 and half having F2 fibrosis. An overall SVR rate of 97% was observed with just one relapse noted. Even with the significant drug–drug interaction, both cyclosporine and tacrolimus trough levels were comparable prior to treatment with paritaprevir, ombitasvir, and dasabuvir and on treatment. Four patients experienced a tacrolimus level greater than 15 ng/ml that was because of dosing errors and there were brief increases in creatinine levels that resolved. This therapy was also well tolerated with one patient discontinuing study drug because of adverse events with this individual achieving sustained response. This cohort was recently updated with a naïve genotype 1b cohort that received paritaprevir, ombitasvir, and dasabuvir with no ribavirin for 24 weeks with this genotype 1b cohort achieving SVR in all 13 individuals.

Treatment of Fibrosing Cholestatic Hepatitis C

The combination of sofosbuvir and ribavirin is also highly effective in achieving sustained response in those with severe recurrent hepatitis C post-OLT.[11] In this report, 104 patients were treated, 52 of whom had an early severe recurrence of hepatitis C diagnosed less than 12 months after transplant and 52 had cirrhosis. Of the 92 patients who were assessed (12 were retransplanted), 54% achieved SVR with 59 out of 103 patients assessed for clinical outcomes demonstrating clinical improvement.

In this cohort, the patients could receive sofosbuvir and ribavirin with or without peginterferon and higher sustained response rates were seen in the sofosbuvir and ribavirin group despite the interferon plus sofosbuvir population having less advanced disease than the sofosbuvir and ribavirin population. Those with acute severe early recurrence achieved sustained response at a rate of 73% (35/48) versus those who had compensated and decompensated cirrhosis, who achieved SVR rates at lower rates (19/44, 43%). Similar to the posttransplant report, there were no on treatment failures and sofosbuvir and ribavirin were well tolerated. Of note, 13% of the cohort died, but this cohort was particularly sick with MELD scores as high as 43 and in the cohort with severe acute recurrent hepatitis C, 36 of 52 improved, nine of 52 stabilized, and seven of 52 worsened or died.

Another strategy for fibrosing cholestatic hepatitis C has been to add an NS5a inhibitor to sofosbuvir to treat this population as this DAA class may also be administered safely in those with severe recurrence of hepatitis C and advanced liver disease. A recent report looked at the combination of sofosbuvir and daclatasvir or sofosbuvir and ribavirin in a group of 23 patients with fibrosing cholestatic hepatitis from France and Belgium.[19] Similar to other fibrosing cholestatic hepatitis C cohorts, this group had advanced liver disease with eight having ascites, 15 elevated bilirubin levels and high viral level with a median recurrence to clinically severe hepatitis of 5 months. These individuals received sofosbuvir and daclatasvir (15) or sofosbuvir and ribavirin. Dramatic improvements were seen with median bilirubin reductions that normalized at week 12 of therapy. Twenty two patients had a complete clinical response by week 36 with 96 patients achieving sustained response 12 weeks after treatment. Thus, the addition of daclatasvir or ribavirin to sofosbuvir is another treatment option for patients with fibrosing cholestatic hepatitis C. The combination of ledipasvir and sofosbuvir with ribavirin has also been examined in patients with fibrosing cholestatic hepatitis. These individuals were subset of the recently completed SOLAR-1 and SOLAR-2 studies that evaluated ledipasvir, sofosbuvir, and ribavirin for 12 or 24 weeks. Eleven patients with fibrosing cholestatic hepatitis were documented at 10 sites. As is typical for fibrosing cholestatic hepatitis C cohorts, high bilirubin levels with seen with high viral levels and the overall SVR rate was seen of 100% with 12 and 24-week cohorts both achieving SVR rates of 100%. There was rapid normalization of bilirubin, MELD score with toxicities noted related to the ribavirin use.[20]

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