Am J Cancer Res 2012;2(2):192-203
Original Article
Physical state and viral load as predictive biomarkers for persistence and
progression of HPV16-positive cervical lesions: results from a population based
long-term prospective cohort study
Anna Manawapat, Frank Stubenrauch, Rainer Russ, Christian Munk, Susanne Krüger Kjær, Thomas Iftner
Medical Virology, Section Experimental Virology, University Hospital of Tübingen, Elfriede-Aulhorn Str. 6, 72076 Tübingen;
Department of Virus, Hormones and Cancer. Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49,
DK-2100 Copenhagen, Denmark; Gynecologic Clinic, The Juliane Marie Center, Rigshospitalet, University of Copenhagen,
Blegdamsvej 9, DK-2100, Denmark; Gendata, Margarethenstrasse 38, 4053 Basel, Switzerland; James Cook University
Townsville, Australia.
Received November 25, 2011; accepted January 3, 2012; Epub February 15, 2012; Published February 28, 2012
Abstract: Persistent infection with a high risk (hr) human papillomavirus (HPV) has been established as the main cause of
cervical cancer and high-grade cervical intraepithelial neoplasia (CIN3). Because most infections are transient, testing for hrHPV
lacks specificity and has a low positive predictive value. It has been suggested that additional parameters like viral load and
physical status of the viral genome could improve the effectiveness of HPV-based screening. We investigated the association
between HPV16 viral load and physical state with viral persistence or risk of incident CIN3 or worse in a population-based
prospective cohort study comprising 8656 women (20-29 years). All participants had two gynecological examinations two years
apart and were followed through the nationwide Danish Pathology Data Bank (median follow-up: 12.9 yrs). Seventynine cervical
swabs from women with a persistent HPV16 infection were available for analysis. For comparison we selected a random
age-matched sample of transiently HPV16 infected women (N=91). Persistently infected women with incident CIN3 or cancer
(CIN3+; N=31) were compared to women with normal cytology during follow up (non-progressors; N=39). Quantitative real-time
PCR for HPV16E6, E2 and IFNb1 was done to determine the HPV16 viral load and the E2/E6 ratio was used as a surrogate
marker for integration. Women with normal cytology who became persistently HPV16 infected had a significantly lower HPV16
load at baseline than women who cleared the infection (median 4.72 copies/cell versus median 20.0 copies/cell, respectively;
p=0.0003). There was no difference in viral load at enrollment between women who progressed to CIN3+ and women who
stayed cytologically normal (p=0.85). At the second examination viral load tended to be higher in women who progressed, but the
difference was not statistically significant (p=0.39). The E2/E6 ratio was shown to be lower in the persistently infected group
(p<0.0001) already at the first examination, but no difference between non-progressors and CIN3+ cases was observed at any of
the two examinations (p=0.61 and 0.86). Lower viral load and integration of the viral genome are predictive for the persistence of
HPV16 DNA, but not for the progression of a persistent HPV16 infection to CIN3+ in women with normal cytology.
(AJCR0000095).
Keywords: Cervical cancer, HPV, viral load, viral integration
Address all correspondence to:
Eberhard Karls-University of Tuebingen Medical Faculty
University Hospital Tuebingen
Institute of Medical Virology
Section Experimental Virology
Elfriede-Aulhorn-Str. 6
D-72076 Tübingen
Germany
Phone ++49 (0)7071 29-80246
Fax ++49 (0)7071 29-5419
E-mail: thomas.iftner@med.uni-tuebingen.de
Original Article
Physical state and viral load as predictive biomarkers for persistence and
progression of HPV16-positive cervical lesions: results from a population based
long-term prospective cohort study
Anna Manawapat, Frank Stubenrauch, Rainer Russ, Christian Munk, Susanne Krüger Kjær, Thomas Iftner
Medical Virology, Section Experimental Virology, University Hospital of Tübingen, Elfriede-Aulhorn Str. 6, 72076 Tübingen;
Department of Virus, Hormones and Cancer. Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49,
DK-2100 Copenhagen, Denmark; Gynecologic Clinic, The Juliane Marie Center, Rigshospitalet, University of Copenhagen,
Blegdamsvej 9, DK-2100, Denmark; Gendata, Margarethenstrasse 38, 4053 Basel, Switzerland; James Cook University
Townsville, Australia.
Received November 25, 2011; accepted January 3, 2012; Epub February 15, 2012; Published February 28, 2012
Abstract: Persistent infection with a high risk (hr) human papillomavirus (HPV) has been established as the main cause of
cervical cancer and high-grade cervical intraepithelial neoplasia (CIN3). Because most infections are transient, testing for hrHPV
lacks specificity and has a low positive predictive value. It has been suggested that additional parameters like viral load and
physical status of the viral genome could improve the effectiveness of HPV-based screening. We investigated the association
between HPV16 viral load and physical state with viral persistence or risk of incident CIN3 or worse in a population-based
prospective cohort study comprising 8656 women (20-29 years). All participants had two gynecological examinations two years
apart and were followed through the nationwide Danish Pathology Data Bank (median follow-up: 12.9 yrs). Seventynine cervical
swabs from women with a persistent HPV16 infection were available for analysis. For comparison we selected a random
age-matched sample of transiently HPV16 infected women (N=91). Persistently infected women with incident CIN3 or cancer
(CIN3+; N=31) were compared to women with normal cytology during follow up (non-progressors; N=39). Quantitative real-time
PCR for HPV16E6, E2 and IFNb1 was done to determine the HPV16 viral load and the E2/E6 ratio was used as a surrogate
marker for integration. Women with normal cytology who became persistently HPV16 infected had a significantly lower HPV16
load at baseline than women who cleared the infection (median 4.72 copies/cell versus median 20.0 copies/cell, respectively;
p=0.0003). There was no difference in viral load at enrollment between women who progressed to CIN3+ and women who
stayed cytologically normal (p=0.85). At the second examination viral load tended to be higher in women who progressed, but the
difference was not statistically significant (p=0.39). The E2/E6 ratio was shown to be lower in the persistently infected group
(p<0.0001) already at the first examination, but no difference between non-progressors and CIN3+ cases was observed at any of
the two examinations (p=0.61 and 0.86). Lower viral load and integration of the viral genome are predictive for the persistence of
HPV16 DNA, but not for the progression of a persistent HPV16 infection to CIN3+ in women with normal cytology.
(AJCR0000095).
Keywords: Cervical cancer, HPV, viral load, viral integration
Address all correspondence to:
Eberhard Karls-University of Tuebingen Medical Faculty
University Hospital Tuebingen
Institute of Medical Virology
Section Experimental Virology
Elfriede-Aulhorn-Str. 6
D-72076 Tübingen
Germany
Phone ++49 (0)7071 29-80246
Fax ++49 (0)7071 29-5419
E-mail: thomas.iftner@med.uni-tuebingen.de
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American Journal of Cancer Research
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