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Eurosurveillance, Volume 7, Issue 51, 18 December 2003
Articles

Citation style for this article: Arthur G. HART study findings suggest a bigger role for human papillomavirus testing in cervical cancer screening. Euro Surveill. 2003;7(51):pii=2351. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=2351

HART study findings suggest a bigger role for human papillomavirus testing in cervical cancer screening

Gilly Arthur (gilly.arthur@hpa.org.uk), Health Protection Agency Communicable Disease Surveillance Centre, London, England.

Oncogenic types of human papillomavirus (HPV) are the underlying cause of almost all cervical cancer and its precursors (1). Human papillomaviruses are sexually transmitted and data suggests that prevalence of high risk HPV in women attending routine cervical screening in the UK in the 1990s was 6-7% (2,3) . High risk (HR) oncogenic types of HPV can be detected through DNA testing of epithelial cells obtained during routine cytological screening. However HPV testing has not yet been introduced into routine cytological screening programmes in Europe and the focus has been on cytological screening rather than on the underlying sexually transmitted disease. The perceived wisdom, drawn from ten years of trials on triage in cervical screening, has cytology as the first step. More recently, in the USA, HR HPV testing has been advocated as a triage step to improve the sensitivity of CIN2 detection. Drafts of new European guidelines (European Cervical Cancer Screening Network website, http://www.cancer-network.de/cervical/index.html) recognize HPV as causal and include a section on HPV testing. They advocate further research to better define the performance indicators of HPV DNA testing (alone and with cytology) before launching any new screening approaches.

A recent paper presents findings from the recently published HART (HPV in Addition to Routine Testing) study (4), and argues for initial screening of high risk HPV before triaging positive cases with cytology. The HART study is a multicentre randomised controlled trial of 11 085 women (aged 30-60 years) comparing, for women with minimal abnormalities (a borderline smear or positive HR HPV test and negative cytology), strategies of immediate colposcopy versus viral and cytological surveillance. The study confirmed previous findings that HR HPV testing can raise sensitivity of CIN2 detection by 20% compared with cervical cytology but also increases the false positive rate by 5%. The researchers found that, for those with minimal abnormalities, it was safe to repeat testing at 12 months rather than resort to colposcopy immediately and suggested the possibility of lengthened screening intervals for low risk women (negative by cytology and HPV) from 3 to 5 years. In women positive for HPV at baseline, who later had virological and cytological surveillance, a significant proportion (45% with negative cytology and 35% with borderline cytology) had cleared their HPV infections by the retest after 6-12 months. No CIN2 was found in these groups nor in women with an initial negative HPV test with borderline or mild dyskaryosis on cytology. The authors concluded that HPV positive women with normal or borderline cytology (about 6% of women screened) could be managed with repeat testing at 12 months, improving detection rates of CIN2 without increasing colposcopy referral rates. They also provocatively advocate for initial screening with HPV test followed by triaging of those HPV positive cases with cytology.

This study had number of limitations. The abnormality rate was 25% lower than the national average possibly limiting the general applicability of the results. Also compliance with follow-up was only approximately 70%. A further important limitation of the trial is its concurrent design in which all women received both tests, such that it did not compare HPV testing with cytology as separate screening modalities. Further randomised controlled trials are required to assess the duration of protection conferred by a negative HPV result and the efficacy of a Pap-centred triage approach before any conclusions can be drawn regarding HPV as a lone initial screening tool. In Europe the triaging of women after baseline borderline smears is different to the USA, with the guidelines suggesting a usual approach of repeat testing at 6 months rather than immediate colposcopy (5). The impact of this study’s findings in terms of suggesting deferring colposcopy in those with mild dyskaryosis (and HPV negative) may therefore have different significance for the European guidelines.

There have been very few randomised controlled trials of HPV testing in population screening. These have generally focused on triage (the management of patients with borderline or mildly dyskaryotic smears (ASCUS-atypical squamous cells of undetermined significance)) rather than on initial screening. In the USA, a recent trial ASCUS -LSIL (low grade squamous intra-epithelial lesions) Triage Study (ALTS))(6,7) prompted changes in their guidelines for cervical screening to highlight the usefulness of HPV testing in triaging women with equivocal smears but not advocating it as initial screening test. These changes were published as two consensus statements by the American Medical Association (8,9) and were reviewed in a previous issue of Eurosurveillance (10). New technologies in cervical screening including the role of HPV testing are being studied in Europe under the auspices of the European Cervical Cancer Screening Network and their progress can be reviewed on their website (as above).

If the HART study findings are borne out by further randomised controlled trials, a radical shift towards STI detection and away from cytological screening will be required. This will create a powerful new focus for STI prevention for women and their partners and could have a major impact on other STI prevention activities. The European Surveillance of STI (ESSTI) network, a collaboration of 14 member states (and Norway) has been established to address issues of sexually transmitted infection surveillance, prevention and care issues across Europe (11-13). ESSTI has been highlighting the growing concern that STIs are rising rapidly in Europe(14). This additional momentum to tackle the problem would be welcomed by the ESSTI network.

References:
  1. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189: 12-9.
  2. Cuzick J, Szarewski A, Terry G, Ho L, Hanby A, Maddox P. Human papillomavirus testing in primary cervical screening. Lancet 1995; 345: 1533-6.
  3. Cuzick J, Beverley E, Ho L, Terry G, Sapper H, Mielzynska I. HPV testing in primary screening of older women. Br J Cancer 1999; 81: 544-8.
  4. Cuzick J, Szarewski A, Cubie H, Hulman G, Kitchener H, Luesley D et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 2003; 362: 1871-6.
  5. European Commission DG V F.2 'Europe against cancer' programme/Committee on Quality Assurance TaEotEFoCSQ. European Guidelines for Quality Assurance in Cervical Cancer Screening, CSRSG. De Wolf CTE, editor. 1997. (http://crsg.ubc.kun.nl/quate/guidelines/entire.html).
  6. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003; 188: 1383-92.
  7. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med 2003; 127: 946-9.
  8. Wright TC, Jr., Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002; 287: 2120-9.
  9. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002; 287: 2114-9.
  10. Lowndes C. Promising results from trials of vaccines against human papillomavirus (HPV) and herpes simplex virus type 2 (HSV-2) genital infections. Eurosurveillance Weekly 2002; 6 (51): 19/12/2002. (http://www.eurosurveillance.org/ew/2002/021219.asp)
  11. Fenton K, Lowndes C, Cooper J. Heterogeneity in European STI Surveillance Systems: Is Harmonisation Possible? For the European Surveillance of STIs (ESSTI) Network, editor. 2003.
  12. Fenton K, Boccia D, Lowndes C, van de Laar M, Van Veen M, Hamouda O et al. The recent epidemiology of infectious syphilis in Western Europe. on behalf of the ESSTI network, editor. 2003.
  13. Lowndes C, Cooper J. First meeting of the European Surveillance of STIs (ESSTI) network collaborative group. Eurosurveillance Weekly 2003; 7 (15): 10/04/2003. (http://www.eurosurveillance.org/ew/2003/030410.asp)
  14. Fenton K, Lowndes C, for the European Surveillance of Sexually Transmitted Infections (ESSTI) Network. Recent trends in the epidemiology of sexually transmitted infections in the European Union. Sex Transm Infect In press 2003

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