AASLD: Treating Before Transplant Cuts HCV Recurrence

AASLD: Treating Before Transplant Cuts HCV Recurrence

MedPage Today

November 06, 2009


BOSTON -- In patients with advanced liver disease related to hepatitis C, a course of pegylated interferon and ribavirin (Rebetol) before liver transplant may help them avoid recurrence of infection, a researcher said here.


Nearly 30% of patients receiving the drugs showed no signs of the hepatitis C virus (HCV) three months after receiving a new liver, reported Gregory T. Everson, MD, of the University of Colorado in Denver.


He presented results of a prospective, semirandomized component of a larger study called A2ALL at the American Association for the Study of Liver Diseases meeting.


"This experience supports the concept that pretransplant therapy can prevent allograft reinfection," he said.

Action Points


* Explain to interested patients that hepatitis C virus infection can persist after liver transplant.



* Explain that the pretransplant drug regimen used in this study had significant toxicities and did not benefit all patients.



* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.


Not surprisingly, the best results were achieved in patients whose HCV viral loads were reduced to undetectable levels at the time of transplant, Everson reported. Among 14 patients in whom this was achieved, eight remained virus free at the post-transplant evaluation.


Duration of the pretreatment regimen was also a significant predictor of post-transplant response, Everson reported.


Some 44% of patients who received the interferon-ribavirin treatment for more than 15 weeks before transplant had a postprocedure response, compared with 18% of those treated for 10 to 15 weeks and 15% of those getting the drugs for less than 10 weeks (P=0.04).


Other factors -- such as baseline HCV viremia, viral genotype, type of donor (live versus dead), and toxicity-related dose limitations -- were not significantly associated with post-transplant response, although the study may not have been powered adequately to detect such associations.


Of the 79 patients enrolled in the trial, 47 with HCV genotypes 1, 4, 5, or 6 were randomized in a 2:1 ratio to receive the pretransplant drug regimen or no treatment. All of the 32 other patients with HCV genotypes 2 or 3 received the treatment.


The treatment consisted of starting doses of 0.75 mcg/kg/week of pegylated interferon-alfa-2b (PEGIntron) and 600 mg/day of ribavirin, which were both escalated as tolerated over several weeks to standard target levels.


Median treatment duration was 11.4 weeks for the 44 dead-donor candidates and 14.6 weeks for the 35 able to receive live-donor organs.


Transplant was actually performed in 41 patients, 25 of whom were dead-donor candidates.


Everson characterized the effectiveness of the pretransplant drug regimen as "limited."


He said it should be considered only for selected patients, particularly those with relatively less severe disease.


In the trial, those were the patients who were live-donor candidates along with the dead-donor candidates who received a so-called MELD upgrade because of hepatocellular carcinoma.


"If you take all the patients with HCV going to liver transplant, many of them are too sick to treat with [pegylated interferon] and ribavirin," he said.


Data from the study indicated that the treatment was significantly toxic. Three-quarters of the treated patients suffered serious adverse events, compared with half of untreated patients (P=0.04). These were seen both before and after transplant.


However, mortality rates were the same in treated and untreated patients, at about 15%.


Everson said it might be possible in the future to try pretreatment in sicker patients when direct antiviral drugs for HCV become available.


In the meantime, he said, patients who can tolerate the treatment need to stay on it for at least 12 weeks.


The study was funded by the National Institutes of Health.


Everson reported relationships with Schering-Plough and Ortho Biotech. Other co-authors reported relationships with Roche, Salix, Gilead, Vertex, Pfizer, GlaxoSmithKline, Amgen, Bayer, Novartis, and Human Genome Sciences, among others.


Primary source: Hepatology

Source reference:

Everson G, et al "Interim analysis of a controlled trial of pretransplant peginterferon alfa-2b/ribavirin (PEG/RBV) to prevent recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) in the Adult-to-Adult Liver Transplantation (A2ALL) Study" Hepatology 2009; 50: 302A.

--------------------

Interim analysis of a controlled trial of pre-transplant peginterferon alfa-2b/ribavirin (PEG/RBV) to prevent recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) in the Adult-to-Adult Liver Transplantation (A2ALL) Study

G. T. Everson1; N. Terrault2; A. S. Lok3; R. S. Brown4; S. Saab5; M. L. Shiffman6; A. M. Al-Osaimi7; L. M. Kulik8; B. W. Gillespie9; J. E. Everhart10

1. Department of Medicine, University of Colorado, Aurora, CO, USA.

2. Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

3. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

4. Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.

5. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

6. Department of Medicine, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA, USA.

7. Department of Medicine, University of Virginia, Charlottesville, VA, USA.

8. Department of Medicine, Northwestern University, Chicago, IL, USA.

9. Biostatistics, University of Michigan, Ann Arbor, MI, USA.

10. Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.




Background: Recurrent HCV after LT is inevitable and may lead to graft loss. Preventing re-infection is desirable but PEG/RBV is poorly tolerated by patients with advanced disease. Aims: To assess the safety of pre-LT PEG/RBV and to determine whether undetectable HCV RNA at LT reduces HCV recurrence after LT.

Methods: 79 pts were enrolled; 44 candidates for only deceased donor LT (DDLT) and 35 candidates for either living donor LT (LDLT) or DDLT. Pts with HCV genotypes 1, 4, 5, or 6 were randomized 2:1 to PEG/RBV (N=31) or no treatment (N=16). All pts with HCV genotypes 2 or 3 (N=32) were treated. Initial doses of PEG 0.75 µg/kg wkly and RBV 600 mg/d were increased as tolerated to standard target doses. Erythropoietin alfa (EPO) and G-CSF were permitted. All analyses were performed on a per-protocol basis (58 treated, 21 controls). The primary endpoint was post-LT virologic response (pTVR) defined as undetectable HCV RNA 12 wks post-LT.

Results: Median age was 56 (range 27 to 69), 75% male, 81% Caucasian, and 6% African American. Median model for end-stage liver disease (MELD) scores, without exception for HCC, were 10 (7-22) for DDLT candidates and 12 (7-20) for LDLT/DDLT candidates. Median treatment duration was 11.4 (1-32) wks for DDLT and 14.6 (5-21) wks for LDLT/DDLT recipients. HCV RNA ranged from 1.95 to 7.48 log10 IU/ml; and, 59% were infected with HCV genotypes 1, 4, 5, or 6. 31% achieved target doses of PEG/RBV and 72% used EPO or G-CSF. Virologic responses are displayed in the table by HCV genotype and type of transplant. 14 pts had negative HCV RNA at LT and at least 12 wks of post-LT followup - 8/14(57%) achieved pTVR. Pre-transplant treatment for ≥ 12 wks predicted pTVR (p=0.004). Percentages of pts with adverse events (AE), serious adverse events (SAE), and mortality pre- and post-LT were (treated vs. control) 95% vs. 67%, (p=0.003), 66% vs. 43% (p=0.07), and 12% vs. 14% (p=0.72).

Conclusions: HCV recurrence was prevented in patients who had undetectable HCV RNA at LT and ≥ 12 wks pre-LT PEG/RBV treatment. Factors favoring pTVR included HCV genotypes 2/3 and LDLT, likely due to the ability to control the timing of LT. New antiviral drugs with more rapid and effective viral suppression and strategies to reduce AEs and SAEs are needed.

Picture 1.png