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
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.