A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation

Abstract

Hepatitis C virus (HCV) infection recurs in liver recipients who are viremic at transplantation. We conducted a randomized, controlled trial to test the efficacy and safety of pretransplant pegylated interferon alpha-2b plus ribavirin (Peg-IFN-α2b/RBV) for prevention of post-transplant HCV recurrence. Enrollees had HCV and were listed for liver transplantation, with either potential living donors or Model for End-Stage Liver Disease upgrade for hepatocellular carcinoma. Patients with HCV genotypes (G) 1/4/6 (n = 44/2/1) were randomized 2:1 to treatment (n = 31) or untreated control (n = 16); HCV G2/3 (n=32) were assigned to treatment. Overall, 59 were treated and 20 were not. Peg-IFN-α2b, starting at 0.75 μg/kg/week, and RBV, starting at 600 mg/day, were escalated as tolerated. Patients assigned to treatment versus control had similar baseline characteristics. Combined virologic response (CVR) included pretransplant sustained virologic response and post-transplant virologic response (pTVR), defined as undetectable HCV RNA 12 weeks after end of treatment or transplant, respectively. In intent-to-treat analyses, 12 (19%) assigned to treatment and 1 (6%) assigned to control achieved CVR (P = 0.29); per-protocol values were 13 (22%) and 0 (0%) (P = 0.03). Among treated G1/4/6 patients, 23 of 30 received transplant, of whom 22% had pTVR; among treated G2/3 patients 21 of 29 received transplant, of whom 29% had pTVR. pTVR was 0%, 18%, and 50% in patients treated for <8, 8-16, and >16 weeks, respectively (P = 0.01). Serious adverse events (SAEs) occurred with similar frequency in treated versus untreated patients (68% versus 55%; P = 0.30), but the number of SAEs per patient was higher in the treated group (2.7 versus 1.3; P = 0.003).

Conclusion: Pretransplant treatment with Peg-IFN-α2b/RBV prevents post-transplant recurrence of HCV in selected patients. Efficacy is higher with >16 weeks of treatment, but treatment is associated with increased risk of potentially serious complications.

Trial registration: ClinicalTrials.gov NCT00135798.

Figure 1

Enrollment flow chart by HCV genotype, showing both intent-to-treat (ITT) and treatment per-protocol (PP) groups. All 32 patients infected with HCV genotypes 2 or 3 were assigned to treatment but only 29 initiated treatment and 3 never received PEGIFN or RBV. Forty seven patients were infected with HCV genotypes 1, 4, or 6, of whom 31 were assigned to treatment and 16 were assigned to untreated control. Two of the patients assigned to treatment never received PEGIFN or RBV and one control was treated. The 8 screen failures are not reflected in this diagram.

Figure 2

The cumulative probability distribution, among treated patients, of time from study enrollment to first HCV RNA negativity for patients who achieved either SVR12 or pTVR, estimated by Kaplan-Meier. Dashed line shows the distribution for patients with HCV genotypes 1/4/6, and solid line for HCV genotypes 2/3.

Figure 3

Percent of treated patients with undetectable HCV RNA at transplant and at week 12 post-LT by genotype. Overall 59% of 44 treated patients were HCV RNA negative at time of transplant and 25% achieved pTVR (RNA negative at post-transplant week 12). Fifty two percent of 23 genotype (G) 1/4/6 and 67% of 21 G 2/3 were RNA negative at transplant (p=0.33); and 22% of G 1/4/6 and 29% of G 2/3 achieved pTVR (p=0.60). PP analyses; whiskers are +/− 1 standard error.

Figure 4

Percent of treated patients with undetectable HCV RNA at transplant and at week 12 post-LT (pTVR) by treatment duration. Virologic response to pre-transplant therapy was linked to treatment duration. Only 25% of the patients treated for less than 8 weeks had undetectable HCV RNA at transplant and none achieved pTVR. In contrast, 64% of patients treated for more than 16 weeks had undetectable HCV RNA at transplant, and 50% achieved pTVR. PP analyses; whiskers are +/− 1 standard error.