Gardasil HPV Vaccine Reduces Occurrence of Genital Warts and Cervical Dysplasia

Countries that widely use a quadrivalent human papillomavirus (HPV) vaccine have seen up to a 90% reduction in HPV infections and decreases in the incidence of genital warts and cervical cell abnormalities that can lead to cancer, according to an analysis of nearly 60 studies from 9 countries presented at the European Research Organization on Genital Infection and Neoplasia and published in the May 26 edition of Clinical Infectious Diseases.

HPV is among the most common sexually transmitted infections. While the immune system can often control and eliminate the virus, persistent infection with certain types (e.g., 6 and 11) can cause genital warts, while other types (e.g., 16 and 18) can trigger abnormal cell growth (dysplasia or neoplasia) that can progress toanal, cervical, and other genital cancers.

HPV vaccination programs are major public health initiatives worldwide. Three vaccines are approved in the U.S.: the bivalent Cervarix (active against HPV types 16 and 18), the original quadrivalent Gardasil (6, 11, 16, and 18), and the newer 9-valent Gardasil 9 (6, 11, 16, 18, 31, 33, 45, 52, and 58). Vaccination is recommended for adolescents and young adult women and men, but coverage is low in some areas, in part due to concern about encouraging sex among young people.

Suzanne Garland from Royal Women's Hospital in Australia and colleagues assessed the global effect of quadrivalent vaccination on HPV infection and disease. They searched the PubMed and Embase literature databases for peer-reviewed articles published from January 2007 through February 2016, looking for observational studies reporting the impact of vaccination on HPV infection, anogenital warts, and cervical cancer or precancerous lesions. After screening more than 900 articles, 58 met the inclusion criteria.

They found that over the past decade the impact of HPV vaccination in real-world settings has become "increasingly evident," especially among girls vaccinated before HPV exposure in countries with high vaccine uptake.

Studies showed maximum reductions of approximately 90% for infection with HPV types 6/11/16/18, approximately 90% for genital warts, approximately 45% for low-grade cervical cell abnormalities, and approximately 85% for high-grade cervical abnormalities most likely to progress to cancer. Decreases were greatest in younger age groups who were less likely to already be infected when vaccinated. They did not see a reduction in cervical cancer itself, as most vaccinated women have not yet reached the age at which it typically develops.

"The full public health potential of HPV vaccination is not yet realized," the researchers concluded. "HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage."

Below is an edited excerpt from a Merck press release describing the findings in more detail.

Systematic Review of 58 Publications of Real-World Use of GARDASIL Presented at EUROGIN Congress

Studies Published over the Last 10 Years Report Reductions in Cervical Pre-cancers and Other HPV-related Diseases

Kenilworth, N.J. -- June 16, 2016 -- Merck (NYSE:MRK), known as MSD outside of the United States and Canada, announced today that in a systematic review conducted of the global impact and effectiveness of GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant], substantial reductions were observed in HPV 6/11/16/18-related infection, genital warts, Pap abnormalities, and cervical pre-cancers. This evaluation of 58 effectiveness and impact studies published during the past 10 years examined the use of GARDASIL in routine vaccination programs in Australia, Europe, North America and New Zealand, and will be presented for the first time during an oral session at the European Research Organization on Genital Infection and Neoplasia (EUROGIN) congress in Austria. A paper detailing this review was also published online on June 14 in the journal Clinical Infectious Diseases (CID).

Following introduction of vaccination programs with GARDASIL, the earliest impact of the vaccine was seen in the reduction of genital warts. Reductions in genital warts were observed in all nine countries included in this review (based on 28 publications), with declines occurring as early as one year after vaccine introduction in Australia and Germany. Reductions in HPV 6/11/16/18 infection, assessed in 14 publications from five countries (Australia, Belgium, Germany, Sweden and the United States), were also observed shortly after vaccination; for example, reductions in HPV 6/11/16/18 infection were seen within four years in several studies from Australia and the United States. Subsequently, as successive birth cohorts began cervical screening, reductions in cervical pre-cancers were observed within 3-5 years of vaccine program implementation in Australia, Canada, Denmark, Sweden and the United States.

GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] is indicated for use in females 9 through 26 years of age for the prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. GARDASIL is also approved for use in males 9 through 26 years of age for the prevention of anal cancer caused by HPV types 16 and 18, for the prevention of anal dysplasias and precancerous lesions caused by HPV types 6, 11, 16 and 18, and for the prevention of genital warts caused by HPV types 6 and 11. GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

The review identified 58 studies published from January 2007 through February 2016 that met the pre-specified criteria for assessment of the real-world impact of vaccination with GARDASIL on HPV-related disease. These studies were conducted in nine different countries (Australia, Denmark, Sweden, Belgium, Germany, France, United States, Canada, and New Zealand) with varying degrees of HPV vaccination coverage, among populations of different ages, and used different study methods and disease endpoints. Studies reporting only on the bivalent HPV vaccine were excluded. GARDASIL was predominantly, but not exclusively, used in all publications reviewed. Short-term endpoints (reduction in HPV infection and genital warts) and medium-term endpoints (reduction in Pap abnormalities and cervical pre-cancers) were assessed. Cervical cancer, however, was not identified because most vaccinated cohorts have not yet reached ages when cervical cancer is typically diagnosed. Thus the anticipated benefit of vaccination on certain HPV-related cancer rates cannot be fully determined yet, because of the long latency periods following exposure to HPV.

In this review of the studies, decreases in the prevalence of HPV 6/11/16/18 infections, genital warts, Pap abnormalities, and cervical pre-cancers were observed among females in their teens and 20s subsequent to the introduction of GARDASIL. Decreases were generally highest in younger populations, reflecting a lower likelihood of pre-existing HPV infection at time of vaccination, supporting global recommendations for routine use of HPV vaccine in adolescents.

"Based on this comprehensive review of studies published during the past 10 years since the licensure of GARDASIL, reductions in HPV infections as well as reductions in the prevalence of HPV 6/11/16/18-related diseases, as noted by decreases in Pap abnormalities, cervical pre-cancers, and genital warts, were detected within four years after vaccine introduction," said Professor Suzanne Garland, MD, director of microbiological research and head of clinical microbiology and infectious diseases, The Royal Women's Hospital, Victoria, Australia, who will present these data at EUROGIN and is lead author on the CID publication.

"Despite the progress we have made with Pap screening and vaccination, cervical cancer and other HPV-related diseases are still a public health issue in both developed and developing nations, which underscores the need for comprehensive HPV vaccination programs in adolescents before they’re at risk of contracting the virus," added Garland.

Results varied depending on the vaccine coverage (percent of the population who had been vaccinated), breadth of the immunization program (the age range of those vaccinated and whether catch-up vaccination was included), the number of doses received, the study design, and the disease outcome assessed. The overall impact on the population was greatest in countries that achieved high vaccination rates soon after the introduction of GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant] and in the youngest cohorts.

For example, in Australia, a country with 3-dose vaccination coverage of 73 percent among adolescent females, prevalent HPV 6/11/16/18-related infection decreased by 86 percent in females 18-24 years of age after three doses within six years of vaccine introduction, compared to unvaccinated women during the same timeframe. Furthermore, a 92.6 percent reduction in genital warts diagnosed among females <21 years of age was observed four years after the vaccine program was initiated. Within four years of vaccine introduction in Australia, reductions in cervical pre-cancers were seen in females 11-27 years old at the start of the vaccination program in 2007 and who received all three vaccine doses, with declines ranging from 57 percent in females 15-18 years old to 5 percent in females 23-27 years old. Reductions in disease endpoints were generally lower in older individuals and in countries with lower vaccine coverage. For example, in the same Australian study where a 92.6 percent reduction in genital warts was observed in females <21 years of age, the reduction in genital warts in females 21-30 years of age was 72.6 percent. Reductions in genital warts were <50 percent in teens 15-19 years old in France and Germany where vaccine coverage was much lower than Australia.

"These data reinforce that GARDASIL is important in the fight against cervical cancer and certain other HPV-related cancers and diseases, however the full public health potential of HPV vaccination of males and females is not yet realized even after a decade of use," said Jacques Cholat, MD, president of Merck Vaccines. "Increasing HPV vaccination rates and access to the vaccine has the potential to make an even greater impact globally."

Systematic review of 58 peer-reviewed publications

This review synthesized available data assessed through a systematic search of PubMed and Embase for peer-reviewed manuscripts from January 2007 through February 2016. The search identified observational studies that reported on the impact or effectiveness of GARDASIL on HPV infection, genital warts, cervical abnormalities and pre-cancers. Both vaccine effectiveness and impact aim at evaluating ‘real-life benefit’ and are typically measured through observational studies. Vaccine impact denotes the population-prevented fraction of infection or disease and is assessed by comparing prevalence or incidence in the vaccine era to a comparable population from the pre-vaccine era or by measuring population-level trends over time. Vaccine effectiveness corresponds to the proportion of infection or disease prevented among vaccinated individuals, and is estimated by comparing the incidence in vaccinated versus unvaccinated individuals within similar populations. After screening 903 papers, 58 publications from nine countries met the pre-specified inclusion criteria.

See full press release for important information about GARDASIL

About HPV and related cancers and diseases

In the United States, human papillomavirus (HPV) will infect most sexually active males and females in their lifetime. According to the CDC, there are approximately 14 million new genital HPV infections in the United States each year, half of which occur in people 15 through 24 years of age. For most people, HPV clears on its own, but for others who don't clear the virus, it could lead to cancers and other diseases in males as well as females, and there is no way to predict who will clear the virus.

In women, HPV causes virtually all cervical cancer cases of which an estimated 70 percent are caused by HPV types 16 and 18. Each day another 35 women are diagnosed with cervical cancer in the United States -- about 12,900 women per year. HPV also causes approximately 70-75 percent of vaginal cancer cases and approximately 30 percent of vulvar cancer cases. HPV types 16 and 18 cause an estimated 65% of HPV-related vaginal cancer cases and 75% of HPV-related vulvar cancer cases. Additionally, there are an estimated 3 million abnormal Pap results, many of which are caused by HPV, that require follow-up each year in the United States.

HPV causes approximately 85-90 percent of anal cancers in both males and females, and HPV types 16 and 18 cause an estimated 85 percent of those cases. According to the American Cancer Society, an estimated 2,600 men and 4,600 women in the United States will be diagnosed with anal cancer in 2015, and overall rates have been increasing. There is no routine screening recommended for the general population to screen for anal cancer.

HPV causes approximately 90 percent of genital warts in both males and females. There are approximately 360,000 cases of genital warts each year in the United States. Treatment of genital warts can be painful, and they may recur after treatment, especially in the first three months. Approximately 3 out of 4 people get them after having genital contact with someone who has genital warts.

About Merck

For 125 years, Merck has been a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook, YouTube and LinkedIn.

6/30/16

Reference

SM Garland, SK Kjaer, N Muñoz, et al. Impact and Effectiveness Of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of Ten Years of Real-World Experience. Clinical Infectious Diseases. May 26, 2016 (online ahead of print).

Other Source

Merck. Systematic Review of 58 Publications of Real-World Use of GARDASIL Presented at EUROGIN Congress. Press release. June 16, 2016.