Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients

[Guest guest]

Hepatology. 2008 Jul 28;48(6):1769-1778. [Epub ahead of print]

Naturally occurring dominant resistance mutations to hepatitis C virus protease

and polymerase inhibitors in treatment-naïve patients.

Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, Lee B, Heckerman D,

Carlson J, Reyor LL, Kleyman M, McMahon CM, Birch C, Schulze Zur Wiesch J,

Ledlie T, Koehrsen M, Kodira C, AD, Lauer GM, Rosen HR, Bihl F, Cerny A,

Spengler U, Liu Z, Kim AY, Xing Y, Schneidewind A, Madey MA, Fleckenstein JF,

Park VM, Galagan JE, Nusbaum C, BD, Lake-Bakaar GV, Daar ES, son IM,

Gomperts ED, Edlin BR, Donfield SM, Chung RT, Talal AH, n T, Birren BW,

Henn MR, TM.

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical

School, Boston, MA.

Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3)

protease inhibitors in 1000-fold viral load reductions upon treatment,

consistent with their reported reduced replicative fitness in vitro. Recently,

however, an R155K protease mutation was reported as the dominant quasispecies in

a treatment-naïve individual, raising concerns about possible full drug

resistance. To investigate the prevalence of dominant resistance mutations

against specifically targeted antiviral therapy for HCV (STAT-C) in the

population, we analyzed HCV genome sequences from 507 treatment-naïve patients

infected with HCV genotype 1 from the United States, Germany, and Switzerland.

Phylogenetic sequence analysis and viral load data were used to identify the

possible spread of replication-competent, drug-resistant viral strains in the

population and to infer the consequences of these mutations upon viral

replication in vivo. Mutations described to confer resistance to the protease

inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B

polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed

mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the

population, including two patients with possible multidrug resistance.

Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4%

of those infected with genotype 1b carried at least one dominant resistance

mutation. Viral loads were high in the majority of these patients, suggesting

that drug-resistant viral strains might achieve replication levels comparable to

nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C

resistance mutations are common in treatment-naïve patients infected with HCV

genotype 1. Their influence on treatment outcome should further be characterized

to evaluate possible benefits of drug resistance testing for individual

tailoring of drug combinations when treatment options are limited due to

previous nonresponse to peginterferon and ribavirin. (HEPATOLOGY

2008;48:1769-1778.).

PMID: 19026009 [PubMed - as supplied by publisher]

[Guest guest]

Hepatology. 2008 Jul 28;48(6):1769-1778. [Epub ahead of print]

Naturally occurring dominant resistance mutations to hepatitis C virus protease

and polymerase inhibitors in treatment-naïve patients.

Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, Lee B, Heckerman D,

Carlson J, Reyor LL, Kleyman M, McMahon CM, Birch C, Schulze Zur Wiesch J,

Ledlie T, Koehrsen M, Kodira C, AD, Lauer GM, Rosen HR, Bihl F, Cerny A,

Spengler U, Liu Z, Kim AY, Xing Y, Schneidewind A, Madey MA, Fleckenstein JF,

Park VM, Galagan JE, Nusbaum C, BD, Lake-Bakaar GV, Daar ES, son IM,

Gomperts ED, Edlin BR, Donfield SM, Chung RT, Talal AH, n T, Birren BW,

Henn MR, TM.

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical

School, Boston, MA.

Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3)

protease inhibitors in 1000-fold viral load reductions upon treatment,

consistent with their reported reduced replicative fitness in vitro. Recently,

however, an R155K protease mutation was reported as the dominant quasispecies in

a treatment-naïve individual, raising concerns about possible full drug

resistance. To investigate the prevalence of dominant resistance mutations

against specifically targeted antiviral therapy for HCV (STAT-C) in the

population, we analyzed HCV genome sequences from 507 treatment-naïve patients

infected with HCV genotype 1 from the United States, Germany, and Switzerland.

Phylogenetic sequence analysis and viral load data were used to identify the

possible spread of replication-competent, drug-resistant viral strains in the

population and to infer the consequences of these mutations upon viral

replication in vivo. Mutations described to confer resistance to the protease

inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B

polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed

mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the

population, including two patients with possible multidrug resistance.

Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4%

of those infected with genotype 1b carried at least one dominant resistance

mutation. Viral loads were high in the majority of these patients, suggesting

that drug-resistant viral strains might achieve replication levels comparable to

nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C

resistance mutations are common in treatment-naïve patients infected with HCV

genotype 1. Their influence on treatment outcome should further be characterized

to evaluate possible benefits of drug resistance testing for individual

tailoring of drug combinations when treatment options are limited due to

previous nonresponse to peginterferon and ribavirin. (HEPATOLOGY

2008;48:1769-1778.).

PMID: 19026009 [PubMed - as supplied by publisher]