Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in HCV/HIV�Coinfected Subjects Treated with Interferon�Based Regimens

[Guest guest]

http://www.journals.uchicago.edu/doi/abs/10.1086/650490

The Journal of Infectious Diseases 2010;201:712–719

© 2010 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2010/20105-0012$15.00

MAJOR ARTICLE

Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in

HCV/HIVâ€Coinfected Subjects Treated with Interferonâ€Based Regimens

E. Sherman,1

D. Rouster,1

Stanford,1

T. Blackard,1

Norah Shire,2

Margaret Koziel,3

n s,5

T. Chung,4 and the

AIDS Clinical Trials Group 5071 Study Team

1University of Cincinnati College of Medicine, Cincinnati, Ohio; 2Infectious

Disease Epidemiology, Merck & Co, Inc, North Wales, Pennsylvania; 3Department of

Medicine, Beth Israel Deaconess Medical Center, and 4Harvard Medical School,

Massachusetts General Hospital, Boston; 5Division of Gastroenterology,

University of California–San Francisco, San Francisco

Background.Coinfection with hepatitis C virus (HCV) and human immunodeficiency

virus (HIV) has emerged as a major cause of morbidity and mortality due to liver

disease. Interferonâ€based therapy response rates have been disappointingly

low. Baseline HCV complexity and the relationship between complexity and viral

kinetic parameters has not been well described in HCV/HIVâ€coinfected subjects.

Methods.A subset of patients enrolled in the AIDS Clinical Trials Group 5071

trial underwent sampling to evaluate viral kinetics and changes in HCV

complexity. Early kinetic parameters, baseline complexity, and treatment

outcomes—including rapid viral response (RVR), early viral response (EVR), and

sustained viral response (SVR)—were evaluated. HCVâ€monoinfected subjects

were matched to HCV/HIVâ€coinfected subjects.

Results.Baseline complexity was determined in 108 HCV/HIVâ€coinfected subjects

and in 13 HCVâ€monoinfected control subjects. Quasispecies complexity was a

mean of 2.24 bands for HCV/HIVâ€coinfected subjects and a mean of 1.90 bands

for HCVâ€monoinfected subjects ( ). Lower baseline complexity was associated

with EVR ( ) and approached statistical significance for SVR. In patients who

underwent viral kinetic modeling, a decrease in complexity was associated with

RVR ( ) and was independent of the correlation between firstâ€phase viral

decline efficiency and RVR.

Conclusion.Baseline HCV complexity is an independent predictor of EVR in

HCV/HIVâ€coinfected subjects. A decrease in complexity occurs by 4 weeks after

the initiation of interferonâ€based therapy and is associated with RVR. These

findings may enhance the predictive modeling of treatment outcome in

HCV/HIVâ€coinfected patients.

Received 17 July 2009; accepted 6 October 2009; electronically published 27

January 2010.

Reprints or correspondence: Dr E. Sherman, Gould Professor of Medicine,

Div of Digestive Diseases, University of Cincinnati College of Medicine, 231

Albert Sabin Way, Cincinnati, OH 45267â€0595 (.sherman@...).

Potential conflicts of interest: K.E.S.'s institution receives research funding

from Roche; M.P. is a consultant for Roche, clinical care options; and R.T.C.

receives research support from Roche. All other authors report no potential

conflicts.

Financial support: National Institute of Allergy and Infectious Diseases AIDS

Clinical Trials Group (grants AI25897, AI068636, and U01 AI38858); National

Institute of Diabetes and Digestive and Kidney Diseases (award K24 DK070528 to

K.E.S.). Roche Laboratories provided study drug and hepatitis C virus RNA

monitoring kits.

[Guest guest]

http://www.journals.uchicago.edu/doi/abs/10.1086/650490

The Journal of Infectious Diseases 2010;201:712–719

© 2010 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2010/20105-0012$15.00

MAJOR ARTICLE

Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in

HCV/HIVâ€Coinfected Subjects Treated with Interferonâ€Based Regimens

E. Sherman,1

D. Rouster,1

Stanford,1

T. Blackard,1

Norah Shire,2

Margaret Koziel,3

n s,5

T. Chung,4 and the

AIDS Clinical Trials Group 5071 Study Team

1University of Cincinnati College of Medicine, Cincinnati, Ohio; 2Infectious

Disease Epidemiology, Merck & Co, Inc, North Wales, Pennsylvania; 3Department of

Medicine, Beth Israel Deaconess Medical Center, and 4Harvard Medical School,

Massachusetts General Hospital, Boston; 5Division of Gastroenterology,

University of California–San Francisco, San Francisco

Background.Coinfection with hepatitis C virus (HCV) and human immunodeficiency

virus (HIV) has emerged as a major cause of morbidity and mortality due to liver

disease. Interferonâ€based therapy response rates have been disappointingly

low. Baseline HCV complexity and the relationship between complexity and viral

kinetic parameters has not been well described in HCV/HIVâ€coinfected subjects.

Methods.A subset of patients enrolled in the AIDS Clinical Trials Group 5071

trial underwent sampling to evaluate viral kinetics and changes in HCV

complexity. Early kinetic parameters, baseline complexity, and treatment

outcomes—including rapid viral response (RVR), early viral response (EVR), and

sustained viral response (SVR)—were evaluated. HCVâ€monoinfected subjects

were matched to HCV/HIVâ€coinfected subjects.

Results.Baseline complexity was determined in 108 HCV/HIVâ€coinfected subjects

and in 13 HCVâ€monoinfected control subjects. Quasispecies complexity was a

mean of 2.24 bands for HCV/HIVâ€coinfected subjects and a mean of 1.90 bands

for HCVâ€monoinfected subjects ( ). Lower baseline complexity was associated

with EVR ( ) and approached statistical significance for SVR. In patients who

underwent viral kinetic modeling, a decrease in complexity was associated with

RVR ( ) and was independent of the correlation between firstâ€phase viral

decline efficiency and RVR.

Conclusion.Baseline HCV complexity is an independent predictor of EVR in

HCV/HIVâ€coinfected subjects. A decrease in complexity occurs by 4 weeks after

the initiation of interferonâ€based therapy and is associated with RVR. These

findings may enhance the predictive modeling of treatment outcome in

HCV/HIVâ€coinfected patients.

Received 17 July 2009; accepted 6 October 2009; electronically published 27

January 2010.

Reprints or correspondence: Dr E. Sherman, Gould Professor of Medicine,

Div of Digestive Diseases, University of Cincinnati College of Medicine, 231

Albert Sabin Way, Cincinnati, OH 45267â€0595 (.sherman@...).

Potential conflicts of interest: K.E.S.'s institution receives research funding

from Roche; M.P. is a consultant for Roche, clinical care options; and R.T.C.

receives research support from Roche. All other authors report no potential

conflicts.

Financial support: National Institute of Allergy and Infectious Diseases AIDS

Clinical Trials Group (grants AI25897, AI068636, and U01 AI38858); National

Institute of Diabetes and Digestive and Kidney Diseases (award K24 DK070528 to

K.E.S.). Roche Laboratories provided study drug and hepatitis C virus RNA

monitoring kits.

[Guest guest]

http://www.journals.uchicago.edu/doi/abs/10.1086/650490

The Journal of Infectious Diseases 2010;201:712–719

© 2010 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2010/20105-0012$15.00

MAJOR ARTICLE

Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in

HCV/HIVâ€Coinfected Subjects Treated with Interferonâ€Based Regimens

E. Sherman,1

D. Rouster,1

Stanford,1

T. Blackard,1

Norah Shire,2

Margaret Koziel,3

n s,5

T. Chung,4 and the

AIDS Clinical Trials Group 5071 Study Team

1University of Cincinnati College of Medicine, Cincinnati, Ohio; 2Infectious

Disease Epidemiology, Merck & Co, Inc, North Wales, Pennsylvania; 3Department of

Medicine, Beth Israel Deaconess Medical Center, and 4Harvard Medical School,

Massachusetts General Hospital, Boston; 5Division of Gastroenterology,

University of California–San Francisco, San Francisco

Background.Coinfection with hepatitis C virus (HCV) and human immunodeficiency

virus (HIV) has emerged as a major cause of morbidity and mortality due to liver

disease. Interferonâ€based therapy response rates have been disappointingly

low. Baseline HCV complexity and the relationship between complexity and viral

kinetic parameters has not been well described in HCV/HIVâ€coinfected subjects.

Methods.A subset of patients enrolled in the AIDS Clinical Trials Group 5071

trial underwent sampling to evaluate viral kinetics and changes in HCV

complexity. Early kinetic parameters, baseline complexity, and treatment

outcomes—including rapid viral response (RVR), early viral response (EVR), and

sustained viral response (SVR)—were evaluated. HCVâ€monoinfected subjects

were matched to HCV/HIVâ€coinfected subjects.

Results.Baseline complexity was determined in 108 HCV/HIVâ€coinfected subjects

and in 13 HCVâ€monoinfected control subjects. Quasispecies complexity was a

mean of 2.24 bands for HCV/HIVâ€coinfected subjects and a mean of 1.90 bands

for HCVâ€monoinfected subjects ( ). Lower baseline complexity was associated

with EVR ( ) and approached statistical significance for SVR. In patients who

underwent viral kinetic modeling, a decrease in complexity was associated with

RVR ( ) and was independent of the correlation between firstâ€phase viral

decline efficiency and RVR.

Conclusion.Baseline HCV complexity is an independent predictor of EVR in

HCV/HIVâ€coinfected subjects. A decrease in complexity occurs by 4 weeks after

the initiation of interferonâ€based therapy and is associated with RVR. These

findings may enhance the predictive modeling of treatment outcome in

HCV/HIVâ€coinfected patients.

Received 17 July 2009; accepted 6 October 2009; electronically published 27

January 2010.

Reprints or correspondence: Dr E. Sherman, Gould Professor of Medicine,

Div of Digestive Diseases, University of Cincinnati College of Medicine, 231

Albert Sabin Way, Cincinnati, OH 45267â€0595 (.sherman@...).

Potential conflicts of interest: K.E.S.'s institution receives research funding

from Roche; M.P. is a consultant for Roche, clinical care options; and R.T.C.

receives research support from Roche. All other authors report no potential

conflicts.

Financial support: National Institute of Allergy and Infectious Diseases AIDS

Clinical Trials Group (grants AI25897, AI068636, and U01 AI38858); National

Institute of Diabetes and Digestive and Kidney Diseases (award K24 DK070528 to

K.E.S.). Roche Laboratories provided study drug and hepatitis C virus RNA

monitoring kits.

[Guest guest]

http://www.journals.uchicago.edu/doi/abs/10.1086/650490

The Journal of Infectious Diseases 2010;201:712–719

© 2010 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2010/20105-0012$15.00

MAJOR ARTICLE

Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in

HCV/HIVâ€Coinfected Subjects Treated with Interferonâ€Based Regimens

E. Sherman,1

D. Rouster,1

Stanford,1

T. Blackard,1

Norah Shire,2

Margaret Koziel,3

n s,5

T. Chung,4 and the

AIDS Clinical Trials Group 5071 Study Team

1University of Cincinnati College of Medicine, Cincinnati, Ohio; 2Infectious

Disease Epidemiology, Merck & Co, Inc, North Wales, Pennsylvania; 3Department of

Medicine, Beth Israel Deaconess Medical Center, and 4Harvard Medical School,

Massachusetts General Hospital, Boston; 5Division of Gastroenterology,

University of California–San Francisco, San Francisco

Background.Coinfection with hepatitis C virus (HCV) and human immunodeficiency

virus (HIV) has emerged as a major cause of morbidity and mortality due to liver

disease. Interferonâ€based therapy response rates have been disappointingly

low. Baseline HCV complexity and the relationship between complexity and viral

kinetic parameters has not been well described in HCV/HIVâ€coinfected subjects.

Methods.A subset of patients enrolled in the AIDS Clinical Trials Group 5071

trial underwent sampling to evaluate viral kinetics and changes in HCV

complexity. Early kinetic parameters, baseline complexity, and treatment

outcomes—including rapid viral response (RVR), early viral response (EVR), and

sustained viral response (SVR)—were evaluated. HCVâ€monoinfected subjects

were matched to HCV/HIVâ€coinfected subjects.

Results.Baseline complexity was determined in 108 HCV/HIVâ€coinfected subjects

and in 13 HCVâ€monoinfected control subjects. Quasispecies complexity was a

mean of 2.24 bands for HCV/HIVâ€coinfected subjects and a mean of 1.90 bands

for HCVâ€monoinfected subjects ( ). Lower baseline complexity was associated

with EVR ( ) and approached statistical significance for SVR. In patients who

underwent viral kinetic modeling, a decrease in complexity was associated with

RVR ( ) and was independent of the correlation between firstâ€phase viral

decline efficiency and RVR.

Conclusion.Baseline HCV complexity is an independent predictor of EVR in

HCV/HIVâ€coinfected subjects. A decrease in complexity occurs by 4 weeks after

the initiation of interferonâ€based therapy and is associated with RVR. These

findings may enhance the predictive modeling of treatment outcome in

HCV/HIVâ€coinfected patients.

Received 17 July 2009; accepted 6 October 2009; electronically published 27

January 2010.

Reprints or correspondence: Dr E. Sherman, Gould Professor of Medicine,

Div of Digestive Diseases, University of Cincinnati College of Medicine, 231

Albert Sabin Way, Cincinnati, OH 45267â€0595 (.sherman@...).

Potential conflicts of interest: K.E.S.'s institution receives research funding

from Roche; M.P. is a consultant for Roche, clinical care options; and R.T.C.

receives research support from Roche. All other authors report no potential

conflicts.

Financial support: National Institute of Allergy and Infectious Diseases AIDS

Clinical Trials Group (grants AI25897, AI068636, and U01 AI38858); National

Institute of Diabetes and Digestive and Kidney Diseases (award K24 DK070528 to

K.E.S.). Roche Laboratories provided study drug and hepatitis C virus RNA

monitoring kits.