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Evolution of hepatitis C virus quasispecies during repeated treatment with the
NS3/4A protease inhibitor telaprevir
#MMPMID25712364
Susser S
; Flinders M
; Reesink HW
; Zeuzem S
; Lawyer G
; Ghys A
; Van Eygen V
; Witek J
; De Meyer S
; Sarrazin C
Antimicrob Agents Chemother
2015[May]; 59
(5
): 2746-55
PMID25712364
show ga
In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV)
infections, the rapid reselection of resistance-associated variants (RAVs) is
well known in patients with repeated exposure to the same class of antiviral
agents. For chronic hepatitis C patients who have experienced virologic failure
with direct-acting antiviral drugs, the potential for the reselection of
persistent RAVs is unknown. Nine patients who received 14 days of telaprevir
monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years
later. In four patients with virologic failure with both telaprevir-containing
regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease
gene were performed before and at treatment failure (median coverage, 4,651
reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no
isolates were found harboring RAVs at the baseline time points. While
population-based sequencing uncovered similar resistance patterns (V36M plus
R155K for subtype 1a and V36A for subtype 1b) in all four patients after the
first and second telaprevir treatments, deep sequencing analysis revealed a
median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the
resistant strains, together with large phylogenetic differences between viral
quasispecies, making the survival of resistant isolates highly unlikely. In
contrast, in a comparison of the two baseline time points, the median number of
nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8),
reflecting the natural evolution of the NS3 gene. In patients with repeated
direct antiviral treatment, a continuous evolution of HCV quasispecies was
observed, with no clear evidence of persistence and reselection but strong signs
of independent de novo generation of resistance. Antiviral therapy for chronic
viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV),
faces several challenges. These viruses have evolved survival strategies and
proliferate by escaping the host's immune system. The development of
direct-acting antiviral agents is an important achievement in fighting these
infections. Viral variants conferring resistance to direct antiviral drugs lead
to treatment failure. For HIV/HBV, it is well known that viral variants
associated with treatment failure will be archived and reselected rapidly during
retreatment with the same drug/class of drugs. We explored the mechanisms and
rules of how resistant variants are selected and potentially reselected during
repeated direct antiviral therapies in chronically HCV-infected patients.
Interestingly, in contrast to HIV and HBV, we could not prove long-term
persistence and reselection of resistant variants in HCV patients who failed
protease inhibitor-based therapy. This may have important implications for the
potential to reuse direct-acting antivirals in patients who failed the initial
direct antiviral treatment. (The phase IIIb study described in this paper is
registered at ClinicalTrials.gov under registration number NCT01054573.).
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