Compassionate-Use Regimen of Sofosbuvir + RBV ± PegIFN Active, Well Tolerated in Patients With Severe HCV Recurrence After Liver Transplantation

Provided by Clinical Care options

 

Capsule Summary

Date posted: 11/4/2013

• Observational study^[1]

Summary of Key Conclusions

• Sofosbuvir plus ribavirin (RBV), with or without peginterferon (pegIFN), well tolerated and active in patients with severe HCV recurrence after liver transplantation
  • Marked clinical improvement and/or disease stabilization in majority of patients (75%)
  • More than one half of patients (56%) achieved SVR12
  • Liver function tests improved during treatment
• Substantial mortality due to disease progression (25%)
• Sofosbuvir-containing regimens well tolerated, with only 1 serious adverse event attributed to treatment

Background

• Recurrent HCV infection of allograft unavoidable if HCV RNA not suppressed to undetectable levels before liver transplantation
  • Severe recurrence common (eg, fibrosing cholestatic hepatitis)^[2]
  • Recurrent infection may result in graft loss and poor short-term outcomes^[2]
• Limited treatment options for patients with severe HCV recurrence after liver transplantation
  • Interferon-based treatment poorly tolerated with limited efficacy and frequent unfavorable interactions of HCV protease inhibitors with immunosuppressive drugs
• Sofosbuvir: HCV NS5B polymerase inhibitor
  • Administered orally once daily
  • Broad activity against genotypes 1-6
  • High genetic barrier to resistance
  • No food effects or significant drug interactions with immunosuppressive agents
  • Favorable safety, tolerability to date in more than 3000 patients
• Current compassionate-use study analyzed efficacy and safety of sofosbuvir plus RBV, with or without pegIFN, in patients with severe recurrent HCV following liver transplantation^[1]

Summary of Study Design

• Patients enrolled in sofosbuvir compassionate-use program included in analysis
  • Individual requests for sofosbuvir use based on patient medical history and clinical assessment
  • All patients who received treatment had severe HCV recurrence, including fibrosing cholestatic hepatitis
• Patients treated with sofosbuvir 400 mg/day plus RBV for ≤ 48 weeks; pegIFN could be added at physician’s discretion
• Current report includes 44 patients treated with sofosbuvir plus RBV with or without pegIFN

Baseline Characteristics

Characteristic	Sofosbuvir + RBV (n = 32)	Sofosbuvir + RBV + PegIFN (n = 12)
Mean age, yrs (range)	56 (27-71)	57 (45-66)
Male, n (%)	21 (65)	10 (83)
Mean HCV RNA, log10 IU/mL (range)	7.6 (1.4-10.0)	7.0 (1.3-7.5)
HCV genotype, n (%)
1a	9 (28)	5 (42)
1b	17 (53)	3 (25)
2	0 (0)	1 (8)
3	4 (13)	1 (8)
4	0 (0)	1 (8)
Mixed	2 (6)	1 (8)
Mean laboratory values
Bilirubin, mg/dL (range)	7.9 (0.4-27.1)	2.6 (0.4-5.1)
Albumin, g/L (range)	3.2 (1.3-12.2)	3.4 (2.0-4.8)
INR (range)	1.4 (0.9-3.9)	1.2 (1.0-1.6)
ALT, IU/L (range)	124 (13-717)	81 (8-197)
AST, IU/L (range)	223 (14-1331)	112 (36-270)
Histologically documented fibrosing cholestatic hepatitis, n (%)	15 (47)	5 (33)
Mean MELD score (range)	16 (6-43)	13 (8-22)
Mean time from liver transplantation, mos (range)	40 (3-178)	31 (5-124)

INR, international normalized ratio; MELD, Model for End-Stage Liver Disease.

Description of Current Analysis

• Data collected on patient characteristics, clinical assessments, laboratory abnormalities, and serious adverse events
• Decompensation events included episodes of hepatic encephalopathy, ascites, and liver-related laboratory values
• Recommended timing of assessments
  • Baseline
  • On-treatment Weeks 4, 12, 24, 36, and 48
  • Posttreatment Weeks 4, 12, and 24
• Undetectable HCV RNA defined as lower limit of detection or lower limit of quantification, depending on treatment center
• Intent-to-treat analysis

Main Findings

• 24 of 44 patients (55%) completed treatment (48 weeks in 1 patient, 36 weeks in 4 patients, 24 weeks in 19 patients)
  • 5 patients (11%) discontinued treatment early
  • 7 patients (16%) died prior to completing treatment due to progressive liver disease or associated complications
  • 8 patients (18%) still receiving treatment
• On-treatment virologic response occurred early (ie, by Week 4) in majority of treated patients and rate of response continued to increase over time during treatment

Undetectable HCV RNA During Treatment	Sofosbuvir + RBV (n = 32)	Sofosbuvir + RBV + PegIFN (n = 12)
Wk 4	69	67
Wk 12	91	75
Wk 24	83*	64†

*3 patients who terminated treatment early not counted in denominator.
^†1 patient who terminated treatment early not counted in denominator.

Overall, 69% of patients attained SVR4; 56% attained SVR12

Deaths and posttreatment relapse accounted for nearly all cases of virologic failure

Virologic Outcome, n (%)	Sofosbuvir + RBV	Sofosbuvir + RBV + PegIFN	All Patients
Wk 4 posttreatment	(n = 27)	(n = 9)	(N = 36)
SVR4	20 (74)	5 (56)	25 (69)
Virologic failure
Relapse	1 (4)	1 (11)	2 (6)
Nonresponse	0	1 (11)	1 (3)
Death	6 (22)	2 (22)	8 (22)
Wk 12 posttreatment	(n = 20)	(n = 8)	(N = 28)
SVR12	12 (60)	4 (50)	15 (56)
Virologic failure
Relapse	2 (10)	2 (25)	4 (15)
Nonresponse	0 (0)	1 (13)	1 (4)
Death	6 (30)	1 (13)	7 (26)

• Overall, 64% demonstrated improvement of decompensation events; 11% showed stabilization of events
• Marked improvements in liver function tests observed during treatment, including reductions in ALT, bilirubin, and international normalized ratio
• Hemoglobin levels decreased during treatment, likely in association with RBV
• MELD score also decreased during treatment
• Large proportion of patients experienced serious adverse events during treatment, majority attributed to disease progression and not to therapy
  • 1 treatment-related serious adverse event in sofosbuvir plus RBV arm involved neutropenia
  • 3 serious adverse events leading to treatment discontinuation involved acute renal failure, deep vein thrombosis, and multifocal hepatoma (1 event of each)

Safety Outcome, n (%)	Sofosbuvir + RBV (n = 32)	Sofosbuvir + RBV + PegIFN (n = 12)
Any serious adverse event	16 (50)	5 (42)
Treatment-related serious adverse event	1 (3)	0 (0)
Serious adverse event leading to treatment discontinuation	1 (3)	2 (17)

 

References

1. Forns X, Fontana RJ, Moonka D, et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 1084.

2. Crespo G, Mariño Z, Navasa M, Forns X. Viral hepatitis in liver transplantation. Gastroenterology. 2012;142:1373-1383.

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