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Cervista™ HPV 16/18 for the identification of strains of HPV associated with cervical cancer

Source agency:

ANZHSN

Date of Submission:

01/12/2009

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Cervista™ HPV 16/18

Technology - description:

The new Hologic Cervista HPV 16/18 is a qualitative assay which identifies the presence of DNA sequences to the two specific high-risk genotypes HPV16 and18. It is recommended for use in women aged 30 years or older, or those with questionable cytological results, to gain a better understanding of their risk for cervical cancer. Thus, an ambiguous Pap smear (or an ASC-US smear), which identifies abnormal cells by microscopic examination of cervical cell samples, could be followed by the Cervista™ HPV 16/18, informing the clinician about the presence of high-risk types of HPV and a woman's risk of developing cervical cancer.


The Cervista assay uses a signal amplification method for detection of specific HPV16/18 nucleic acid sequences. The primary reaction occurs on the targeted DNA sequence and a secondary reaction produces a fluorescent signal. In the primary reaction, two types of sequence specific oligonucleotides (oligos) (i.e. a probe oligo and an “Invader” oligo) bind to the DNA target sequence. When these oligos overlap by at least one base pair on the target sequence, an invasive structure forms that acts as a substrate for the Cleavase® enzyme, which cleaves the flap of the probe at the position of the overlap. The cleaved flaps bind to a universal hairpin FRET oligo. Cleavase® recognises this structure and cleaves the FRET oligos, producing a fluorescent signal indicating the presence of a HPV genotype. An internal control is also provided in the kit. A positive result is represented by a FAM fluorescent signal that lies above an empirically derived cut-off value. For each reaction, a negative result is represented by a FAM fluorescent signal that lies below the same empirically derived cut-off value (FDA 2009).

Company or developer:

Hologic™ (Massachusetts, USA)

Reason for database entry:

May reduce the number of women referred on for invasive colposcopy.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Other

Licensing, reimbursement and other approval:

The Cervista™ HPV 16/18 was approved by the United States Food and Drug Administration in March 2009 but does not require Australian TGA approval.

Technology - type(s):

Diagnostics

Technology - use(s):

Diagnostic

Patient Indication & Setting

Patient indications:

All sexually active women who return an ambiguous Pap smear.

Disease description and associated mortality and morbidity:

In 1991 Australia introduced the National Cervical Cancer Screening Program. This program aims to screen all sexually active women in the age group 18-69 yrs, testing is recommended every 2 years. This program has lead to a significant reduction in the incidence of cervical cancer and associated mortality. Cervical cancer is now the 13th most common cancer affecting Australian women, with an age-standardised (world) incidence of 5.9 new cases per 100,000 women in 2005. Cervical cancer is the 19th most common cause of cancer mortality, with an age-standardised (world) mortality of 1.5 deaths per 100,000 women in 2006. This compares favourably with 2002 worldwide figures of an age-standardised (world) incidence of cervical cancer of 16.2 new cases per 100,000 women, and an age-standardised (world) mortality rate from cervical cancer of 9.0 deaths per 100,000 women (AIHW 2009).

A similar trend has been observed in New Zealand after the introduction of a National Cervical Screening Program in 1991. The age-standardised incidence of cervical cancer in 1991 was 12 per 100,000 and in 2002 this rate had decreased to 7 per 100,000. The incidence rate is much higher in Māori women compared to the general population, and was estimated to be 12.4 per 100,000 in 2002. Mortality rates have also decreased with the introduction of a national screening program. Between 1990 and 2001, mortality fell from 5 per 100,000 to 2 per 100,000, a decline of 60 per cent. Mortality in Māori women was also higher than in the general population but has decreased from 11 per 100,000 in 1996 to 6 per 100,000 in 2001 (MoH 2005).

Number of Patients:

The number of colposcopies performed in Australia in the 12-month period from January 2008 to December 2008 was 8,831.

Technology - specialities(s):

Health promotion and protection incl. screening, Gynaecology, women's sexual health, benign breast disease

Technology - setting(s):

Community and primary care

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Additive or complementary technology

Current Technology:

Cervical cancer affects the cells of the cervix and unlike many cancers these cells may show precancerous changes or abnormalities, which may be detected before progression to cancer occurs with screening with the Papanicolaou (Pap) test (AIHW 2009). While the Papanicolaou (Pap) test is problematic and unreliable in many respects it has been the backbone of the most successful cancer reduction program in the Australian health system. The main failing of the Pap test is its sensitivity which has been estimated to be as low as 30 per cent (30-87%), while the specificity – more important for a screening test - is much higher, falling in the range of 86-100 per cent (Nanda et al 2000). Although the success of the Australian Cervical Cancer Screening program is undoubted, reaching 73 per cent of eligible women in each three year period, many women do not participate in the screening for a variety of reasons and the impact of this is evident in the fact that 50 per cent of invasive cervical cancers occur in women not adequately screened (Sasieni et al 1996; van der Graaf et al 1988).

Health Impact:

Women presenting with an ambiguous smear test result may benefit from triaging with an additional test for HPV status. Testing for the 13 or 14 HPV genotypes considered to confer high-risk for the development of cervical cancer would appear to be of some benefit, however further stratification of testing just for the high-risk HPV16 and HPV18 genotypes may reduce the number of women referred on for invasive colposcopy.

Diffusion:

The Cervista™ HPV 16/18 is not currently in use in Australia or New Zealand.

Cost, infrastructure and economic consequences:

The Cervista HPV 16/18 or HPV HR costs approximately $20-25 per test. A ThinPrep® smear test costs approximately $12, however the cost of supplying the ThinPrep® collection vial is only about $2 of this cost (personal communication Hologic Australia).

Ethical, social, legal, political and cultural impact:

It is currently uncertain how the results of the HPV testing will be conveyed to the patient and within what framework the results will be interpreted. Counselling issues and the stigma of being diagnosed with a sexually transmitted disease, without the counselling support of a trained practitioner, are concepts that have been highlighted as reasons against patient access to medical technology outside of established systems.

Evidence & Policy

Clinical evidence and safety:

To date, the only published information in respect to the use of the Cervista HPV 16/18 assay is the safety and effectiveness data provided to the FDA in support of Hologic’s application for FDA approval. A great deal of data has been published since the 2002 and 2003 MSAC applications on the use of assays which are used to detect either the 13 or 14 high-risk HPV genotypes. The most recent of these studies compared the use of the Cervista HPV HR test to PCR with bidirectional DNA sequencing of 189 cervical smear samples. Indeterminate Cervista results were obtained in 2/189 (1.1%) samples. Accuracy of the Cervista assay compared to PCR was 91.4 per cent, 95% CI [86.5, 95.0]. The assay was performed in several pathology centres over different time periods. The inter-run reproducibility agreement (between days and within site) was 98.8 per cent and the inter-site reproducibility agreement (between sites) was 98.7 per cent. In addition, there was no cross-reactivity with DNA obtained from non-oncogenic HPV genotypes or from other infectious agents (Day et al 2009) (level III-2 diagnostic evidence).
Preliminary laboratory-based studies of the Cervista HPV 16/18 demonstrated good precision between operators (94-100%), depending on the DNA copy number or number of HPV positive cells/ml, when the same sample was assayed twice daily and in duplicate over a 21-day period. Reproducibility of the Cervista was assessed at three sites using HPV16, HPV18 and HPV negative DNA extracted and sequenced from cervical samples. Each sample was tested at all three sites on five, non-consecutive days and reproducibility was 100 per cent. Inconclusive results were obtained when samples were contaminated with contraceptive jelly and anti-fungal creams but not with blood, mucous or the PreservCyt® solution. There was no cross-reactivity with DNA obtained from non-oncogenic HPV genotypes or from other infectious agents including Herpes simplex and Chlamydia trachomatis (FDA 2009).
The initial clinical study enrolled 1,514 women, over 18 years (mean age 33.7  11.76 years), with an ASC-US result. All women underwent testing colposcopic examination and testing with the two Cervista assays HPV16/18 and HPV HR using the original ThinPrep® smear sample (level III-1 diagnostic evidence). Cervista HPV 16/18 results were obtained from 1,398 and colposcopy was completed on 1,476 women, however only 1,312 women with a known disease status were available for analysis. The outcomes for these women are summarised in Table 1 (see web link for details).


Three possible outcomes could result from the study: women could be HPV HR positive and HPV 16/18 positive, HPV HR positive and HPV 16/18 negative or HPV HR negative. For women who were CIN 2 by colposcopy/ histology the likelihood ratio of women having the disease and being positive for HPV HR and HPV 16/18 was 3.72. The likelihood ratio of having the disease and being HPV HR positive and HPV 16/18 negative was 0.75 (less likely to have disease) and was 0.16 when HPV HR negative. For women who were CIN 3 by colposcopy/ histology the likelihood ratio of women having the disease and being positive for HPV HR and HPV 16/18 was 4.15. The likelihood ratio of having the disease and being HPV HR positive and HPV 16/18 negative was 0.59 (less likely to have disease) and was 0.0 when HPV HR negative. These results demonstrate that women positive for HPV 16/18 and not just the 14 high-risk genotypes are more likely to have cervical cancer. The sensitivity and specificity of the Cervista HPV 16/18 test in women who were CIN 2 or CIN 3 and had a positive HPV HR result are summarised in Table 2. PCR sequencing was the conducted on the samples that were HPV HR positive. The level of agreement for samples positive for PCR and HPV 16/18 was 94.1 per cent (95% CI [89.8, 96.7]) and for those negative for PCR and negative for HPV 16/18 was 85.7 per cent (95% CI [82.4, 88.4]).
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TABLE 2
CIN 2

Sens 68.8% (44/64),95% CI [56.6, 78.8]
Spec 69.3% (480/693),95% CI [65.7, 72.6]

CIN 3

Sens 77.3% (17/22),95% CI [56.6, 89.9]
Spec 67.3% (495/735),95% CI [63.9, 70.6]
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Preliminary PCR sequencing data was also presented in the FDA submission of an ongoing study recruiting 2,026 women  30 years with a normal Pap smear result (no intraepithelial lesion or malignancy). ThinPrep® smear samples were then tested with Cervista HPV HR and HPV 16/18. It is hoped that at least 1,000 of these women will be followed-up for three years. The level of agreement for samples positive for PCR and HPV 16/18 was 94.4 per cent (95% CI [74.2, 99.0]) and for those negative for PCR and negative for HPV 16/18 was 82.1 per cent (95% CI [77.6, 85.9]).

Economic evaluation:

Although the 2002 MSAC systematic review on the use of HPV testing for women with an ambiguous smear test initially concluded that additional testing was not cost-effective, the cost analysis was found to be sensitive to the prevalence of high grade lesions in women. It was noted that further cost-effectiveness research was required. It would be of interest to source the cost-effectiveness data used to produce the 2009 New Zealand cervical screening guidelines.

Ongoing research:

 

Ongoing or planned HTA:

Although New Zealand have recently adopted HPV testing in conjunction with conventional Pap smears, the cervical cancer screening programme in Australia is not ready to screen women for HPV. Therefore HealthPACT has recommended that further assessment of this technology is no longer warranted.

Web link:

http://www.horizonscanning.gov.au/

References and sources:

AIHW (2009). Cervical screening in Australia 2006-2007, Australian Institute of Health and Welfare and the Australian Government Department of Health and Ageing for the National Cervical Screening Program, Canberra Available from: http://www.aihw.gov.au/publications/can/can-43-10676/can-43-10676.pdf
Day, S. P., Hudson, A. et al (2009). 'Analytical performance of the Investigational Use Only Cervista HPV HR test as determined by a multi-center study', J Clin Virol, 45 Suppl 1, S63-72.
FDA (2009). Cervista™ HPV 16/18 - P080015 [Internet]. United States Food and Drug Administration. Available from: http://www.accessdata.fda.gov/cdrh_docs/pdf8/P080015b.pdf [Accessed 24th September].
Meijer, C. J., Snijders, P. J. & Castle, P. E. (2006). 'Clinical utility of HPV genotyping', Gynecol Oncol, 103 (1), 12-17.
MoH (2005). Cervical screening in New Zealand: A brief statistical review of the first decade., New Zealand Ministry of Health, Wellington. Available from: http://www.nsu.govt.nz/Files/NCSP/NCSP_statistical_review.pdf
Nanda, K., McCrory, D. C. et al (2000). 'Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review', Ann Intern Med, 132 (10), 810-819.
National Screening Unit (2009). Understanding HPV, HPV testing, cervical cancer and the HPV vaccine [Internet]. New Zealand Government. Available from: http://www.nsu.govt.nz/Current-NSU-Programmes/2480.asp [Accessed 30th September].
National Screening Unit (2008). Guidelines for Cervical Screening in New Zealand, New Zealand Ministry of Health, Wellington. Available from: http://www.nsu.govt.nz/Files/NCSP/NCSP_Guidelines_ALL_small(1).pdf
NHMRC (2005). Screening to Prevent Cervical Cancer: Guidelines for the Management of Asymptomatic Women with Screen Detected Abnormalities, National Health and Medical Research Council, Canberra. Available from: http://www.nhmrc.gov.au/publications/synopses/_files/wh39.pdf
Sasieni, P. D., Cuzick, J. & Lynch-Farmery, E. (1996). 'Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. The National Co-ordinating Network for Cervical Screening Working Group', Br J Cancer, 73 (8), 1001-1005.
van der Graaf, Y., Zielhuis, G. A. et al (1988). 'The effectiveness of cervical screening: a population-based case-control study', J Clin Epidemiol, 41 (1), 21-26.
Walboomers, J. M., Jacobs, M. V. et al (1999). 'Human papillomavirus is a necessary cause of invasive cervical cancer worldwide', J Pathol, 189 (1), 12-19.

Notes:

On October 1st 2009, New Zealand released new guidelines for cervical screening, including the recommendation of HPV testing in three clinical situations:
• ASC-US/LSIL triage of women over 30 years. If the HPV test is negative then the woman will have a follow-up smear in one year. If the HPV test is positive, then the woman will be referred for a colposcopy;
• Post treatment of CIN2/3; or
• Management of discordant results (National Screening Unit 2009).
Eight New Zealand pathology laboratories are contracted to provide cytological services for the programme and some of these laboratories will provide HPV testing. Several commercially available HPV tests will be used by these laboratories, rather than a single defined product, and these include Hologic’s Cervista™ HPV HR, Roche’s Amplicor HPV, Abbott’s RealTime High Risk (HR) HPV and the Diagene Capture-II (personal communication NZ National Cervical Screening Programme). All of these assays are qualitative and test for the 13 or 14 high-risk genotypes. HPV testing is not recommended for women under the age of 30 years as HPV infection is common in this age group and is usually self resolving. It is hoped that HPV testing will determine more accurately those women who require further assessment. A negative test indicates that a woman is unlikely to develop cancer in the next few years, however a positive HPV test does not indicate that a woman has cancer (National Screening Unit 2009).
The HPV vaccine has also been introduced in New Zealand and is included on the National Immunisation Schedule at no cost for girls aged 12 years (National Screening Unit 2009).
Recently in Australia, the National Cervical Screening Program has been affected by two major changes in policy and management In 2006, the NHMRC guidelines (NHMRC 2005) were introduced into clinical practice. The guidelines recognised that changes in cervical cells are a result of an infective rather than a neoplastic process. The Guidelines recommend less intervention for women with low-grade squamous intraepithelial lesions, giving HPV infection an opportunity to resolve without treatment. In addition, in 2007, a vaccine against HPV types 16, 18, 6, and 11 was introduced under the National Immunisation Program. The vaccine is expected to lower cervical cancer incidence and mortality rates, however due to the slow progression of cervical cancer the effect of vaccine administration may not be evident for some time (AIHW 2009).