Sustained Efficacy Of Gardasil Against Early Cervical Lesions, Precancerous Vulvar And Vaginal Lesions, And Genital Warts In Large Phase III Studies

Main Category: Cervical Cancer / HPV Vaccine
Also Included In: Immune System / Vaccines
Article Date: 14 Mar 2008 - 4:00 PST

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A combined analysis of three phase II/III clinical studies which enrolled more than 18,000 young women* confirmed that the quadrivalent (6,11,16,18) vaccine Gardasil®† had a sustained efficacy of 96%‡ against early cervical lesions (CIN1§), 99%** against genital warts and 100%††against early and precancerous vulvar and vaginal lesions (VIN‡‡1 and 2/3, VaIN§§1 and 2/3) caused by the virus types targeted by the vaccine.

These new data were presented at the 20thEuropean Congress of Obstetrics and Gynaecology in Lisbon, Portugal.1 They add to the efficacy results against precancerous cervical lesions (CIN2/3 and AIS) already presented last month2 while post-marketing surveillance and monitoring continue.

"The new data confirm the benefit that quadrivalent vaccination can provide in addition to cervical cancer prevention both for women's health and for health authorities," comments lead investigator Prof. Charles Lacey, from the Hull York Medical School, University of York, UK. "Gardasil® offers a wide spectrum of protection against genital diseases caused by HPV and both an early and sustained protection which translates into rapid individual and long-lasting socio-economic benefit".

In light of the sustained high efficacy of Gardasil®, the independent Data and Safety Monitoring Board (DSMB) of the two large phase III studies in young women (FUTURE I & II) recommended that these studies be terminated as soon as feasible in order to offer women in the placebo group the opportunity to be vaccinated with Gardasil®.

In Europe***, approximately 25% of early cervical lesions are caused by human papillomavirus (HPV) types 16 and 18 (~200,000 cases every year) and 10% more are due to HPV 6 and 11 (~80,000 cases).3,4 †††

Although type 6 and 11-related early cervical lesions usually do not progress to cancer, screening cannot distinguish them from type 16 and 18-related lesions which may progress to cancer. They require the same medical follow up‡‡‡and may lead to the same anxiety in women.

* 16 to 26 years, not exposed to the four human papillomavirus (HPV) types (6,11,16,18) targeted by Gardasil® before vaccination
† Gardasil® (Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed))
‡ 95% CI [91,4; 98,4], through a mean follow up of up to four years after the start of vaccination
§ Cervical Intraepithelial Neoplasia grade 1
** 95% CI [96,2; 99,9]
†† respectively 95% CI [85,9; 100,0] and 95% CI [82,6; 100,0]
‡‡ Vulvar Intraepithelial Neoplasia grade 1 and 2/3 respectively
§§ Vaginal Intraepithelial Neoplasia grade 1 and 2/3 respectively
*** European Union member states (except Romania and Bulgaria) plus Iceland, Norway & Switzerland
††† Calculation based on 1998 US data and population data obtained from http://www.PopulationData.net. Calculation of HPV-related lesions is determined as follows: annual incidence of lesions multiplied by EU female population and prevalence of virus types.
‡‡‡ Including repeated testing, colposcopy (visual examination of the cervix to determine the cause of abnormalities) and diagnostic biopsies (the removal of a sample of tissue (cells of the cervix) for examination under a microscope to assist in diagnosis).

Virus types 6 and 11 also cause 90% of genital warts (about 225,000 cases annually in Europe).5,6,7,§§§ Genital warts can cause anxiety which may impact personal relationships.8 Even if effective in the short term, physically ablative therapies are painful, and recurrence rates can be high as only the visible lesion is excised while the infection persists.9,10,11

These lesions, in particular early cervical lesions and genital warts develop much faster than cervical cancer, often within a few months after exposure to the virus.12,13

It is estimated that 30,000 new cases of pre-cancerous vulvar and vaginal lesions related to human papillomavirus are diagnosed each year in Europe.14,15,16,17 An increasing incidence of pre-cancerous vulvar lesions and vulvar cancer has been noted over the past 30 years.18,19 The incidence of vulvar carcinoma in situ increased by 400% in the United States between 1973 and 2000; invasive vulvar cancer increased by 20% during the same period.20

*** About the studies

The FUTURE I and II studies (protocols 013 and 015) are phase III, prospective, double-blind, placebo-controlled randomised studies conducted in 16 countries. Over 17,000 women participated in the trials. They were aged 16 to 26 and received three doses of either Gardasil® or placebo at day 1, month 2, and month 6. FUTURE I evaluated the incidence of pre-cancerous and early cervical lesions (CIN 1-3), pre-cancerous and early vulvar and vaginal lesions (VIN1-3 and VaIN1-3) and external genital warts caused by the HPV 6, 11, 16 and 18. FUTURE II evaluated the prevention of pre-cancerous cervical lesions (CIN 2/3) and non-invasive cancers (AIS) caused by HPV types 16 and 18.

The phase II clinical trial (protocol 007) was a double-blind, placebo-controlled randomised study, in which 1,106 women were enrolled. They were aged 16 to 23 years and received three doses of either Gardasil® or placebo at day 1, month 2, and month 6.

The phase II/III combined analysis is representative of 18,150 women (16-26 years) enrolled in one of the three studies and randomised to receive either Gardasil® (n = 7,864) or placebo (n = 7865) at day 1, and month 2 and 6 and were followed for up to 4 years after the start of vaccination. Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing taken at regular 6 or 12-month intervals, and collection of cervicovaginal specimens. Colposcopy referral was algorithm-based (except for protocol 007). Biopsies were HPV typed and were given histological diagnoses by a blinded gynaecologic pathology panel. Follow-up for the current analysis was 4 years post-dose 1. Analyses were carried out in a per protocol population that included subjects who received all 3 doses, had no major protocol violations, were sero- and PCR-negative at day 1 and DNA negative day 1 to month 7 to the HPV vaccine types.

Notes

Since its first approval in 2006, Gardasil® has been approved in 93 countries and launched in 76 of them. More than 20 million doses have been distributed worldwide.

Current UK indication of Gardasil®

Gardasil®, human papillomavirus vaccine [types 6,11,16,18] (recombinant, adsorbed), can be given to children and adolescents 9 to 15 years and adult females 16 to 26 years of age and is indicated for the prevention of cervical carcinoma (cervical cancer), high grade cervical dysplasia CIN2/3 (precancerous cervical lesions), high grade vulvar dysplastic lesions VIN 2/3 (precancerous vulvar lesions) and external genital warts (condyloma acuminata) caused by human papillomavirus types 6, 11, 16 and 18.

§§§ In women alone, boys and men not yet considered.² Calculation obtained by extrapolation of the UK genital wart 2007 incidence (Health Protection Agency) to the population of the 27 states of the European Union (Eurostat 2007).

About Sanofi Pasteur MSD

Sanofi Pasteur MSD is a joint venture between sanofi pasteur, the vaccine division of sanofi-aventis, and Merck & Co., Inc. Combining innovation and expertise, Sanofi Pasteur MSD is the only company in Europe dedicated exclusively to vaccines. Sanofi Pasteur MSD is able to draw on the research expertise of sanofi pasteur and Merck & Co., Inc., together with their teams throughout the world, to focus on the development of new vaccines for Europe, which aim to extend protection to other diseases and perfect existing vaccines in order to improve the acceptability, efficacy and tolerability of vaccination.

References

1. Lacey CJN, et al. Continued efficacy of quadrivalent HPV (types 6/11/16/18) L1 VLP Vaccine in preventing cervical or external genital disease: 4 years of follow up. Poster presentation at the 20th European Congress of Ostetrics and Gynaecology (EBCOG), 4-8 March, 2008, Lisbon, Portugal.

2. Joura EA et al. Sustained protection by quadrivalent HPV (type 6, 11, 16, 18) vaccine through 4 years against HPV 6/11/16/18-related cervical intraepithelial neoplasia grade 2/3 (CIN2/3) and adenocarcinoma in situ (AIS) of the cervix; Abstract presented at the 19th International Congress on Anti-Cancer Treatment (ICACT), 5-8 February 2008, Paris, France.

3. Clifford GM et al. Human papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1157-1164.

4. Insinga RP et al. Diagnoses and outcomes in cervical cancer screening : A population-based study. Am J Obstet Gynecol 2004;191:105- 113.

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6. von Krogh G. Management of anogenital warts (condylomata acuminata). Eur J Dermatol 2001;11:598-603.

7. UK Health Protection Agency. CDR Weekly 2003;3(44).

8. Maw RD et al. An international survey of patients with genital warts: Perceptions regarding treatment and impact on lifestyle. Int J STD AIDS 1998 ;9 :571-578.

9. Beutner KR and Wiley DR. Recurrent external genital warts: A literature review. Papillomavirus Rep 1997;8:69-74.

10. Clinical Effectiveness Group (Association for Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases. National guideline for the management of anogenital warts. (last visit 18.08.06).

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13. Winer RL, Koutsky LA Human Papillomavirus through the Ages J Inf Dis 2005;19:1787-1789

14. Dodge JA, Eltabbakh GH, Mount SL et al. Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia. Gynecol Oncol 2001;83:363-369.

15. van Beurden M, ten Kate FJW, Smits HL et al. Multifocal intraepithelial neoplasia grade III and multicentric lower genital tract neoplasia is associated with transcriptionally active human papillomavirus. Cancer 1995;75:2879-2884.

16. Hording U, Junge J, Poulson H et al. Vulvar intraepithelial neoplasia III: A viral disease of undetermined progressive potential. Gynecol Oncol 1995;56:276-279.

17. Jones RW. Vulval intraepithelial neoplasia: Current perspectives. Eur J Gynaecol Oncol 2001;22:393-402.

18. Joura EA et al. Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women. J Reprod Med 2000; 45: 613-15.

19. Jones RW et al. Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997; 90: 448-52.

20. Judson PL et al. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006; 107: 1018-22.

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