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Persistently high loads of human papillomavirus 16 over time were associated with an increased risk for cervical cancer
  1. Joy Melnikow, MD, MPH,
  2. James Nuovo, MD
  1. University of California, Davis Sacramento, California, USA

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 QUESTION: In women with a first normal cervical smear, what is the temporal relation between human papillomavirus (HPV)-16 infection and cervical carcinoma in situ (CIS)?


    Nested case control study of 146 889 women screened from 1969 to 1995.


    Uppsala County, Sweden.


    Women who were <50 years of age at entry (time of first registered smear); were born in Sweden; and had ≥1 cervical smear, a normal first smear, and smears containing β actin. The case group consisted of women who had CIS (n=478; 2081 smears). For each woman with CIS, 5 women in the control group were matched by date of first registered smear and age. Eligible women in the control group were randomly selected from each set of 5 women (n=604; 1754 smears); they had no history of CIS or invasive cervical carcinoma or hysterectomy before the date of diagnosis for the corresponding woman in the case group.

    Assessment of risk factors

    All smears taken after entry were analysed for HPV-16 by using quantitative polymerase chain reaction (5′-exonuclease [Taqman] method). The technician who analysed the smears was blinded to case control status. The level of β actin was also assessed.

    Main outcome measure

    Women with CIS were identified by the National Cancer Registry, and their histological samples were reassessed to confirm the diagnosis.

    Main results

    871 (42%) smears from women with CIS and 117 (7%) smears from women in the control group were positive for HPV-16. The estimated cumulative risk for CIS increased with time since first smear, up to 22.7% (95% CI 12.4% to 31.8%) in women with high viral loads (HPV-16 threshold cycle [Ct] <39.6) and 6.6% (CI 1.7% to 11.2%) in women with medium viral loads (HPV-16 Ct ≤45.6 to ≥39.6) after 15 years. The mean incubation period from first confirmed HPV infection to detection of CIS was >17 years for women with a high viral load and >19 years for women with a medium viral load. The risk for CIS increased with increasing viral load (table).

    Adjusted odds ratios for associations between cervical carcinoma in situ and human papillomavirus (HPV) 16 load at different years before diagnosis (adjusted for levels of β actin)


    In women with a normal first cervical smear, consistently high human papillomavirus 16 loads over the long term were associated with an increased risk for cervical carcinoma in situ.


    Infection with HPV type 16 or 18 has been associated with a higher rate of progression of cervical squamous intraepithelial lesions (SILs) and cancer.1 The ability to identify patients with oncogenic HPV types might lead to improved detection of women who are more likely to develop high grade cervical SILs and cancer. This improved detection could affect management decisions for women with low grade cytological abnormalities. Currently available commercial tests identify the presence of high risk HPV types. Despite the potential value of this technology, recent reports suggest a lack of utility for these qualitative tests in women with low grade cervical SILs. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Epithelial Lesions Triage Study (ALTS) is a large randomised trial of women with recently detected atypical squamous cells of undetermined significance and low grade cervical SILs. High risk HPV DNA was detected in 82.9% of women with low grade cervical SILs, therefore limiting the usefulness of measuring it. Results of the ALTS study for women with atypical squamous cells of undetermined significance are pending.2 Manos et al studied HPV testing combined with ThinPrep in women with atypical squamous cells of undetermined significance and found that the HPV test had a sensitivity of 89.2% and a specificity of 64.1%.3 Other studies have shown sensitivities ≥90% for the second generation, qualitative, high risk HPV test4; however, its false positive rate ranged from 5% to 20%.

    Josefsson et al did a nested case control study on cervical smears of women who developed cervical CIS and those who did not. They measured HPV-16 viral load on archived cervical smears using a quantitative polymerase chain reaction assay available only in research laboratories. They found a strong positive relation between viral load and risk for cervical CIS, but only 283 of 495 women with CIS had any HPV-16 DNA; of those, only 110 women had viral loads in the top 2 quintiles. In the second study based on the same cohort, the time from high HPV-16 viral load to appearance of CIS was determined: a mean time of 17 years. The role for HPV testing in screening for precancerous changes of the cervix remains to be defined. Ultimately, commercially available tests that measure high risk HPV viral load might allow increases in screening intervals for women who test negative. To date, HPV testing has not provided the ability to triage women accurately into high risk and low risk groups. The studies by Josefsson and Ylitalo and their colleagues make some progress toward this goal; however, it is critical to remember that nearly one half of the women with CIS were negative for HPV-16 in their sample. A successful triage would need to measure viral load for several types of high risk HPV.

    In the US, most women who develop cervical cancer have never had a Papanicolaou (Pap) smear, have not had a Pap smear within 5 years of diagnosis, or did not have appropriate follow up of an abnormal smear.5 The problems of screening coverage and adequate follow up of abnormal test results will probably not be solved by advances in HPV technology. Further prospective studies of women with high risk HPV viral load (multiple types) are needed using tests with potential commercial application. Women with both positive and negative results will need to be followed over time to determine whether HPV testing can be used to triage accurately enough to permit longer intervals between tests for women with negative test results. Given the long period between a high HPV viral load test and development of abnormal cells for which effective treatment is available, loss to follow up will probably remain a substantial problem.


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    • Sources of funding: National Institutes of Health; Swedish Cancer Society; Danish National Research Foundation.

    • For correspondence: Dr N Ylitalo, Department of Medical Epidemiology, Karolinska Institute, Box 281, SE-171 77 Stockholm, Sweden. Fax +46 8 8 31 49 57.