Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population?
Abstract Background and Aim: The presence of four or more amino acid substitutions within the interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) genotype 1b NS5A gene determines sensitivity to interferon (IFN) monotherapy in Japanese patients. Resistance of HCV genotype 1 to IFN-alpha has been attributed to the functional inhibition of a RNA dependent protein kinase (PKR) by the HCV NS5A PKR binding domain (PKRBD), which includes the ISDR. The ability of the ISDR and PKRBD sequence to predict a response to IFN-alpha and ribavirin combination therapy was investigated in an Australian population.


METHODS
The sequence of the PKRBD of NS5A, including the ISDR, for the dominant quasi-species of HCV was determined in 37 genotype 1 (genotype 1a: n = 26, genotype 1b: n = 11) and 13 genotype 3a infected patients.


RESULTS
The number of PKRBD amino acid substitutions in HCV genotype 1 infected patients with a sustained virological response was significantly higher than that in patients with a non-response to treatment (P = 0.047). It was found that only 2/37 HCV genotype 1 infected patients had four or more amino acid substitutions relative to the prototype ISDR sequence (HCV-J). Importantly, a sustained virological response was not found in any of the HCV infected patients who had a prototype ISDR genotype 1 sequence (n = 5).


CONCLUSIONS
There are relatively few amino acid mutations within the ISDR of this Western Australian patient population. Patients infected with a HCV genotype 1 prototype sequence should be counseled before receiving combination IFN-alpha and ribavirin therapy as they have a poor response to treatment.
Macquillan
Gerry C
GC
Department of Medicine, University of Western Australia, Crawley, Western Australia, Australia. gerrymacquillan@hotmail.com
Niu
Xianwa
X
Speers
David
D
English
Suzanne
S
Garas
George
G
Harnett
Gerry B
GB
Reed
William D
WD
Allan
Jane E
JE
Jeffrey
Gary P
GP
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use; D001315:Australia; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase