Abstract
Introduction
The introduction of a screening programme for cervical carcinoma in Germany has led to a significant reduction in incidence of the disease. To date, however, diagnosis in Germany has been based solely on cervical cytology, which has been criticised because of a low sensitivity and consequently high rate of false negative results. Because an infection with the human papillomavirus (HPV) previously was found to be a necessary aetiological factor in the development of cervical cancer, there has been some discussion that HPV testing should be included in cervical cancer screening.
Objectives
How do HPV tests compare to cytological tests in terms of sensitivity and specificity, and what are the effects of screening for cervical carcinoma in Germany? Is there health economic evidence that may foster an inclusion of HPV testing into national screening programms?
Methods
A systematic literature review was performed, including studies that compared the HPV test to cervical cytology in terms of sensitivity and specificity in the diagnosis of CIN 2+ (CIN=Cervical Intraepithelial Neoplasia). In addition, a systematic review of the relevant health economic literature was performed to analyze cost-effectiveness in the German setting.
Results
A total of 24 studies fulfilled the inclusion criteria. One study consisted of three substudies. Hence, results of 26 comparisons of HPV and cytology are reported. In 25 of these, the HPV test was more sensitive than cytology, whereas cytology had better specificity in 21 studies. The combination of HPV test and cytology increased sensitivity. Variability in results was considerably larger for cytology than for HPV testing. Results of the economic meta-analysis suggest that in health care settings with already established PAP screening programms, cost-effectiveness strongly depends on screening intervals. In analyses comparing HPV screening to conventional PAP screening with two-yearly intervals, only 25% of the HPV strategies were found to be cost-effective, whereas in comparison with one-, three-, and five-yearly PAP screening, the percentage of overall cost-effective HPV strategies was 83%, 55%, and 92%, respectively. Results for annual screening intervals are based on the assumption of complete screening compliance, which has to be further evaluated in decision analyses in the future adapting to the German health care setting.
Discussion
Including HPV testing in screening procedures for cervical carcinoma could lead to a reduction in false positive results. Doing so would involve one of the following approaches: a) combining the HPV test with cytology, or b) using cytology as triage in HPV-positive women. The most appropriate interval between screening tests and the best age to start or stop screening remains to be determined. At this point a formal health economic decision analyses may help in resolving those questions, additionally incorporating compliance and adherence within different screening scenarios.
Conclusion
Considering medical evidence weighing the question whether HPV testing should be implemented into screening routine may not be if but how to do so. Open questions remain in setting the length of optimal screening intervals, the age range in which to screen, and the combination or sequence of existing cytology and HPV testing. Answers to those questions will be gathered in the very near future through large international clinical trials. Cost-effectiveness of implementing HPV testing is likely to exist in the management of borderline or unclear smears in triage treatment as well as in certain scenarios of primary screening within the German health care setting.
Abstract
Einleitung
Seit der Einführung von Früherkennungsuntersuchungen konnte die Inzidenz von Zervixkarzinomen deutlich reduziert werden. Die Diagnose des Zervixkarzinoms im Rahmen der Früherkennung erfolgt aufgrund einer zytologischen Untersuchung. Die Sensitivität der zytologischen Tests ist problematisch und führt zu einer unbefriedigenden Rate falsch negativer Diagnosen. Als notwendige Voraussetzung für die Entstehung von Zervixkarzinomen gilt eine Infektion mit dem Humanpapillomvirus (HPV). Daher stellt sich die Frage, ob es sinnvoll ist, den Test auf HPV für eine Verbesserung der Früherkennung zu nutzen.
Fragestellung
Wie sind die Gütekriterien des HPV-Tests im Vergleich zu zytologischen Testverfahren zur Diagnose von Zervixkarzinomen und welche Konsequenzen ergeben sich daraus für die Praxis der Früherkennungsuntersuchungen in Deutschland? Gibt es weiterhin ökonomische Argumente und Überlegungen, die eine Einbindung von HPV in das Screening unterstützen würden.
Methodik
Es wurde eine systematische Literaturrecherche durchgeführt. Es wurden Studien eingeschlossen, in denen die Sensitivität und Spezifität von HPV-Tests direkt mit zytologischen Tests verglichen wurde. Als Zielparameter wurde CIN 2+ (CIN=Cervical Intraepithelial Neoplasia) oder eine äquivalente Diagnose definiert. Gesundheitsökonomische Studien sollten eine volle Evaluation vor dem Hintergrund der Fragestellung einer Kosteneffektivität enthalten. Die Bewertung der Qualität medizinischer und gesundheitsökonomischer Studien erfolgt mittels anerkannter Standards zur systematischen Bewertung wissenschaftlicher Studien.
Ergebnisse
Es konnten 24 medizinische Studien identifiziert werden, die alle Einschlusskriterien erfüllten. Eine Studie bestand aus drei Teilstudien, deren Ergebnisse einzeln aufgeführt werden, womit 26 Vergleiche der Testverfahren vorliegen. In 25 von 26 Studien wies der HPV-Test eine höhere Sensitivität auf als der zytologische. In 21 von 26 Studien wies der HPV-Test eine niedrigere Spezifität auf als der zytologische. Die Kombination von HPV- und zytologischem Test führte zu einer Erhöhung der Sensitivität. Die Streuung der Ergebnisse war deutlich geringer beim HPV-Test als bei der Zytologie. Ferner konnten 15 ökonomische Studien identifiziert werden, die für die Fragestellung relevante Daten enthalten, wovon sieben Studien einer ökonomischen Metaanalyse unterzogen wurden. Basierend auf den gesundheitsökonomischen Ergebnissen sollte die Einführung primärer HPV-Screeningverfahren in Settings kosteneffektiv sein, in denen ein PAP-Screening (PAP=Test nach Papanicolaou) weniger häufig als alle zwei Jahre durchgeführt wird. In Settings mit einem zweimal jährlichen PAP-Screening ist es unwahrscheinlich, dass ein HPV-Screening kosteneffektiv ist. Es hat sich gezeigt, dass zwar auch ein HPV-Screening in Settings mit einem jährlichen PAP-Screening kosteneffektiv sein könnte, es werden jedoch weitere Modellierungen empfohlen, um dieses Ergebnis unter Berücksichtigung der Auswirkungen unvollständiger Screeningabdeckung zu stützen.
Diskussion
Die bisherigen medizinischen Studien weisen darauf hin, dass durch eine Integration des HPV-Tests in die Zervixkarzinomfrüherkennung die Rate falsch negativer Diagnosen gesenkt werden könnte. Dabei könnte der HPV-Test in Kombination mit zytologischen Tests oder als alleiniger primärer Test mit anschließender Zytologie für HPV-positive Frauen eingesetzt werden. Offen bleibt aufgrund der bisherigen Studien die genaue Umsetzung innerhalb des Gesundheitswesens, etwa die Häufigkeit bzw. Frequenz des Screenings, Fragen der Compliance oder der genaue Altersbereich, in dem gescreent wird. An dieser Stelle kann die gesundheitsökonomische Forschung die Fragestellung aufgreifen und mittels einer formalen Entscheidungsanalyse bestehende Unsicherheiten aufgreifen.
Schlussfolgerung
Nach Bewertung der medizinischen Evidenz ist die Bewertung der Fragestellung nicht mehr ob, sondern in welcher Weise der HPV-Test genutzt werden sollte. Offene Fragen betreffen insbesondere das Intervall der Früherkennungsuntersuchungen und den Altersbereich, in dem diese angeboten werden. Antworten darauf werden in den kommenden Jahren von einer Reihe derzeit laufender medizinischer Studien zum Einsatz von HPV-Tests im Zervixkarzinomscreening erwartet. Eine Kosteneffektivität ist auf Basis der vorliegenden Daten sowohl beim Einsatz im primären Screening, wie auch im Sekundärscreening bei unklaren Befunden zu vermuten.
Executive Summary
1. Introduction
Screening programmes based on cytology have led to a substantial decrease in the incidence of cervical cancer over the past decades, but have been criticised for their low sensitivity and resulting high false negative rates.
Infection with human papillomavirus (HPV) is a necessary precursor of cervical cancer. In June 2006 the first vaccine against HPV was approved by the US Food and Drug Administration for the prevention of cervical cancer. However, vaccination will not replace cervical cancer screening, due to the fact that the vaccine does not protect against all types of high-risk HPV genotypes.
Whether HPV testing can be used to improve cervical cancer screening has been discussed for a number of years now. In 1999, a systematic review concluded that HPV testing could not be recommended for widespread use in screening programmes. Since then, some large studies on HPV testing have been published, and the Hybrid Capture® (HC I) HPV test has been improved and replaced by the HC II and other testing procedures.
2. Objectives
To compare efficacy and cost-effectiveness of HPV testing and/or cytology in screening for cervical cancer within the German health care setting.
2.1 Medical questions
Can existing cervical cancer screening programmes be improved by including HPV testing?
2.2 Economic questions
Is there health economic evidence for the cost-effectiveness of the introduction of HPV tests to cervical cancer screening?
3. Methodology
We performed a systematic review of English and German literature using the following databases: DAHTA, NHS-CRD-HTA, NHS-EED, IHTA, NHS-CRD-DARE, Cochrane Library-CDSR, MEDLINE, EMBASE, AMED, BIOSIS Previews, MEDIKAT, SERLINE, Cochrane Library–Central, gms, SOMED, CAB abstracts, ISTPB+ISTP/ISSHP, Derwent Biotechnology Ressource, Elsevier BIOBASE, ETHMED, GLOBAL Health, Deutsches Ärzteblatt, MEDLINE Alert, SciSearch, ÄZQ-Leitlinien, CCMed, Social SciSearch, Karger Publisher Database, Kluwer-Verlagsdatenbank, Springer-Verlagsdatenbank, Springer-Verlagsdatenbank PrePrint, Thieme-Verlagsdatenbank.
We included studies that directly compared the sensitivity and specificity of the HPV test and cytology for detecting precancerous lesions in normal-risk populations. HPV was detected using Hybrid Capture® II or polymerase chain reaction (PCR), and cytology could be either conventional or liquid-based. In addition, a systematic review of the relevant health economic literature was performed to analyze cost-effectiveness in the German setting.
4. Results
We identified 3188 studies, with 24 of these fulfilling our inclusion criteria, leading to a total of 126,988 female participants. One study consisted of three substudies. Hence, we report the results of 26 comparisons of HPV and cytology. The studies were performed in both high- and low-resource settings. HC II was used 18 times, PCR seven times, and one study implemented both tests. Conventional cytology was used 19 times, liquid-based cytology four times, and three studies used both tests.
In 25 of the 26 studies included in our systematic review, the HPV test had greater sensitivity than cytology, whereas cytology had better specificity than HPV testing in 21 studies. Sensitivity for HPV testing was over 90% in 50% of the studies, and over 80% in 80% of the studies. Sensitivity for conventional cytology was greater than 90% in only 5% of the studies, and greater than 80% in 13% of the studies. The range and variability of results was considerably larger for cytology than for HPV testing.
15 health economic studies with relevant data were identified. With seven of those a health economic meta-analysis was performed. Due to methodological heterogeneity, the results showed a wide variation. Results of the meta-analysis suggest that in health care settings with already established PAP screening programms, cost-effectiveness strongly depends on screening intervals. In analyses comparing HPV screening to conventional PAP screening with two-yearly intervals, only 25% of the HPV strategies were found to be cost-effective, whereas in comparison with one-, three-, and five-yearly PAP screening, the percentage of overall cost-effective HPV strategies was 83%, 55%, and 92%, respectively. Results for annual screening intervals are based on the assumption of complete screening compliance, which has to be further evaluated in decision analyses in the future considering the German health care setting.
5. Discussion
HPV testing in cervical cancer screening is more sensitive, but also less specific than cytology. Including HPV testing in screening programmes might lead to a decrease in the rate of false negatives and to an extension of the annual screening interval which currently is state of the art in Germany. It is possible to use the HPV test alone as the primary test. However, because a large majority of HPV infected women will not develop cervical cancer, doing so may lead to an increase in colposcopic referrals. Therefore, one US guideline recommends HPV testing in combination with liquid-based cytology. A recently published meta-analysis of European and North American studies suggested that HPV testing may be used as the sole primary test with cytology in triage for HPV infected women.
The most appropriate screening interval and the best age to start or stop screening tests remain to be determined. Ongoing trials of HPV tests in cervical cancer screening will hopefully provide answers to these questions over the next couple of years.
Transferring the results to the German context urges the need for a formal health economic decision analysis. One of the major impact factors will be the implementation of realistic screening participation and adherence rates. This is of paramount importance, since this implicitly raises screening intervals on an average as well a patient individual level. Doing so would allow gathering data input for still missing budget impact analyses within the German setting.
6. Ethical, social, and legal considerations
The vast majority of HPV infected women will never develop cervical cancer. Hence, it is important to inform women with a positive HPV test about their absolute cancer risk to minimise psychological distress.
Accompanied by structured educational efforts the diagnosis of a HPV infection showed no significant difference in psychological distress after a rather short period of time compared to cytology alone.
A positive aspect in the discussion of the pros and cons regarding HPV testing is the possibility of self-testing, which may increase adherence in cervical cancer screening.Taking this into account there additionally may be a window in addressing non-compliant women for participation in screening programmes in the future.
7. Conclusion
Considering medical evidence weighing the question whether HPV testing should be implemented into screening routine may not be if but how to do so. Open questions remain in setting the length of optimal screening intervals, the age range in which to screen, and the combination or sequence of existing cytology and HPV testing. Answers to those questions will be gathered in the very near future through large international clinical trials. Cost-effectiveness of implementing HPV testing is likely to exist in the management of borderline or unclear smears in triage treatment as well as in certain scenarios of primary screening within the German health care setting.