Very late HCV relapses - IAPAC · Very late HCV relapses Vincent Soriano Department of Infectious Diseases Hospital Carlos III ... •Carmen de Mendoza •Eva Poveda . Title: Very

Very late HCV relapses

Vincent Soriano

Department of Infectious Diseases

Hospital Carlos III

Madrid, Spain

Definitions • End of treatment response • Sustained virological response • Relapse • Very late relapse: serum HCV-RNA rebound

beyond 24 weeks upon completion of treatment with undetectable viremia.

Differential diagnosis

True relapse vs Re-infection

275 patients with EOT out of 604 treated; HCV rebound in 76 (27.6%)

< w12 w12 – w24 > w24

73

3

HCV rebound at week 36 postreatment with ABT-450, ABT-072 + RBV

• HIV-negative • IL28b-CC • HCV-1a • Non-cirrhotic

Lawitz et al. J Hepatol 2013

Case 1

• 40-year old, Caucasian female • Liver cirrhosis (38 KPa using transient elastography), • IL28B CT alleles • HIV coinfection (CD4=416; HIV-RNA <50 cop/ml; abacavir) • HCV-3a • In year 2005 she was treated for 30 weeks with peginterferon

alpha-2a 180 g/week plus weight-based ribavirin (1000 mg/day; 48 Kg body weight). Serum HCV-RNA was undetectable at the end of treatment as well as at weeks 12 and 24 postreatment. However, serum HCV-RNA was again detectable at the following testing, 44 weeks later.

• Serum HCV-RNA levels at baseline and at rebound were 414,000 and 425,000 IU/ml, respectively.

• Phylogenetic analysis of NS5B gene fragments comparing plasma virus sequences taken at baseline and at rebound showed very close similarity (bootstrap 92%) supporting HCV relapse instead of reinfection.

Case 2 • 66-year old Caucasian male • 72 Kg body weight • null/minimal liver fibrosis (6.8 KPa using transient elastography). • IL28B CT alleles • Negative for HIV • HCV-1b. • The patient was enrolled in an interferon-free phase II trial

conducted in HCV genotype 1 interferon-naive individuals. He was treated with a PI, NNI plus ribavirin for 40 weeks.

• He had undetectable serum HCV-RNA at the end of treatment as well as at weeks 4, 12 and 24 postreatment. However, serum HCV-RNA was again detectable at next testing, 36 weeks after drug discontinuation. Serum HCV-RNA levels at baseline and at rebound were 192,000 and 230,000 IU/ml, respectively.

• Phylogenetic analysis of NS5B gene fragments comparing plasma virus sequences taken at baseline and at rebound showed very close similarity (bootstrap 90%) supporting HCV relapse instead of reinfection.

Translation

HCV NS proteins

NS2

Polyprotein

processing

NS3

NS4B

NS5A NS5B

HCV RNA

Fusion and

uncoating

RNA

replication

NS5A

CypA

NS5B

NS2

NS3

NS4B

Viral

assembly

Transport and

release

NS3/4A protease inhibitors

NS5A inhibitors

NS5B polymerase inhibitors

NS5A inhibitors

replication vesical web

Hypothesis

• Although plasma half-life of HCV-RNA is estimated to be of 45 min, intracellular HCV-RNA half-life may be much longer.

• Intracellular “sequestered” long-lasting HCV-RNA genomes may be the source of relapses upon treatment withdrawal.

• Cells other than hepatocytes might be “hiding” HCV genomes. • The size of this repository as well as the availability of

nucleotides and other factors required for RNA replication could account for the time needed to reappear into the bloodstream after drug withdrawal.

Discussion

• Very late HCV relapses are very rare.

• It may occur with both interferon-based and all-oral DAA. • There is no evidence for predictors of very late HCV relapse.

• Thus, although sustained viral responses at weeks 12 or 24 following completion of HCV therapy may continue to be considered as a major end-point in clinical trials with anti-HCV drugs, it seems worth to advice repeated HCV-RNA testing beyond week 24 postreatment in clinical practice, specially in the absence of liver enzymes normalization or amelioration of hepatic fibrosis, which generally accompany definitive HCV eradication.

Acknowledgements

Clinic

• Pablo Barreiro

• Pablo Labarga

• Jose V Fernandez

• Eugenia Vispo

• Francisco Blanco

Laboratory

• Zulema Plaza

• Rocío Sierra

• Ana Treviño

• Carmen de Mendoza

• Eva Poveda