FDA Approves Merck's GARDASIL 9 for the Prevention of Certain HPV-Related Head and Neck Cancers
Friday, June 12, 2020 6:40 pm ET see press release below
In The Lancet HIV, Helen Kelly and colleagues8 have added clarification on the relationship between HIV treatment and anal cancer risk. In their systematic review and meta-analysis of dozens of mostly cross-sectional studies, the associations between ART and measures of immune status with prevalent anal HR-HPV infection and consequent anal lesions are summarised. They report that receipt of ART, a prolonged duration of treatment, an undetectable HIV viral load, and increased nadir and current CD4 cell counts were all associated with a decreased prevalence of anal HR-HPV. It should be noted that a substantial proportion of patients with prevalent anal HR-HPV might represent acute self-limiting infections rather than the long-term infections that precede cancer.6 Thus, associations with prevalent anal HR-HPV do not necessarily reflect cancer risk.
Kelly and colleagues also report on the relationship between ART and anal cancer precursors, such as high-grade squamous intraepithelial lesions (HSIL). There is much more methodological variability in studies reporting on such outcomes because of the variation between study sites in the accuracy of diagnosing anal HSIL. Nevertheless, people with undetectable HIV viral load had a significantly decreased prevalence of HSIL, and this relationship was stronger if the viral suppression was sustained. HSIL prevalence was not associated with current CD4 counts but was found to be decreased in patients with increased nadir CD4 counts.
Kelly and colleagues interpreted these data as suggesting that early ART might lead to improved control of anal HR-HPV infection and reduced progression to HSIL and to anal cancer.
We identified 6777 studies, of which 5377 were excluded before full-text review. 122 studies providing estimates for 130 distinct populations matched the inclusion criteria. The populations comprised 417 006 people living with HIV (women, men who have sex with men, and men who have sex with women). 41 (32%) population estimates were not stratified by sex or sexual orientation. People living with HIV receiving ART had 35% lower high-risk HPV prevalence than ART-naive people (crude odds ratio [OR] 0⋅65, 95% CI 0⋅54-0⋅79; I2 12⋅1%, p=0⋅31) in 18 studies, and prolonged ART use was associated with a 10% reduction per year in high-risk HPV prevalence in two studies (adjusted OR 0⋅90, 0⋅85-0⋅95; I2 0%, p=0⋅88). People living with HIV with undetectable PVL had lower HSIL-AIN2+ prevalence than those with detectable PVL (crude OR 0⋅84, 0⋅72-0⋅98; I2 0%, p=0⋅80) in 16 studies, particularly if sustained for more than 1 year (crude OR 0⋅62, 0⋅47-0⋅81; I2 0%, p=0⋅51). ART was not associated with anal cancer incidence when adjusted for years living with HIV in three studies (adjusted hazard ratio [HR] 1⋅11, 95% CI 0⋅68-1⋅80; I2 0%, p=0⋅57), but ART users with sustained undetectable HIV PVL had 44% lower risk of anal cancer than those without (adjusted HR 0⋅56, 0⋅44-0⋅70; I2 0%, p=0⋅94) and for each increase in nadir CD4 cell counts of 100 cells per μL, there was a 40% decrease in anal cancer incidence (crude HR 0⋅60, 0⋅46-0⋅78; I2 21⋅7%, p=0⋅26).
Effective ART use and early initiation at high nadir CD4 counts might reduce anal high-risk HPV infection and anal cancer risk. Although most studies were cross-sectional in design and few adjusted for potential confounders, this analysis provides comprehensive estimates of the effect of ART and HIV-related factors on the natural history of anal HPV-related disease in people living with HIV.
Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial. Lancet Sept 5 2027 - Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0⋅5 cases per 10 000 person-years in the 9vHPV and 19⋅0 cases per 10 000 person-years in the qHPV groups, representing 97⋅4% efficacy (95% CI 85⋅0-99⋅9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine.
The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.
GARDASIL 9 produced similar antibody protection against the four HPV types in GARDASIL. Antibodies to the HPV types targeted by GARDASIL 9 persisted through five years following vaccination. Geometric mean titer ratios (GARDASIL 9/GARDASIL) for HPV6/11/16/18 varied minimally over time. The two vaccines had similar adverse event profiles; injection-site adverse events were more common with GARDASIL 9; most were mild-to-moderate in intensity. A paper detailing these results was also published online on September 5 in The Lancet.
The study included 133,082 females (66,541 vaccinated and 66,541 unvaccinated) stratified by the number of HPV vaccine doses and the vaccine initiation age. Among those aged 15 to 19 years, the hazard ratio (HR) for high‐grade cytology for the 3‐dose group was 0.84 (95% confidence interval [CI], 0.73‐0.97), whereas the HRs for histologically confirmed preinvasive cervical disease for 1, 2, and 3 doses were 0.64 (95% CI, 0.47‐0.88), 0.72 (95% CI, 0.54‐0.95), and 0.66 (95% CI, 0.55‐0.80), respectively.
The receipt of 1, 2, or 3 doses of an HPV vaccine by females aged 15 to 19 years was associated with a lower incidence of preinvasive cervical disease in comparison with unvaccinated females, and this supports the use of any HPV vaccination in reducing the burden of the disease.
FDA Approves Merck's GARDASIL 9 for the Prevention of Certain HPV-Related Head and Neck Cancers
Friday, June 12, 2020 6:40 pm ET
GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) Now Approved for the Prevention of HPV-Related Cervical, Vaginal, Vulvar, Anal, Oropharyngeal and Other Head and Neck Cancers
KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded indication for GARDASIL9 for the prevention of oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58. The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The trial is currently underway.
"At Merck, working to help prevent certain HPV-related cancers has been a priority for more than two decades," said Dr. Alain Luxembourg, director, clinical research, Merck Research Laboratories. "Today's approval for the prevention of HPV-related oropharyngeal and other head and neck cancers represents an important step in Merck's mission to help reduce the number of men and women affected by certain HPV-related cancers."
GARDASIL 9 is a vaccine indicated in females 9 through 45 years of age for the prevention of cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by human papillomavirus (HPV) Types 16, 18, 31, 33, 45, 52, and 58; cervical, vulvar, vaginal, and anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.
GARDASIL 9 is indicated in males 9 through 45 years of age for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.
GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant].
Both men and women can be at risk for HPV-attributable oropharyngeal cancer; however, this cancer affects men five times more than women.1 For most people, HPV clears on its own. But, for those who don't clear the virus, it can cause certain cancers. Oropharyngeal cancer can arise as a result of HPV infection in the oropharynx, which includes the soft palate, side and back wall of the throat, tonsils, and back one-third of the tongue. According to a recent model published by the U.S. Centers for Disease Control and Prevention (CDC), HPV-attributable oropharyngeal cancer has surpassed cervical cancer as the most prevalent type of HPV-related cancer in the U.S.1
1 The CDC analyzed data from the U.S. Cancer Statistics (USCS) to assess the incidence of HPV-associated cancers and to estimate the annual number of cancers caused by HPV, overall and by state, during 2012 to 2016.
The estimated number of HPV-attributable cancers was calculated by multiplying the average number of HPV-associated cancers by the percentage of HPV-attributable cancers diagnosed from 1993 to 2005, before HPV vaccination was available in the U.S.
The detection of HPV DNA in an HPV study is not enough to determine that HPV caused the cancer.
Not all cervical and oropharyngeal cancers are caused by HPV.
Important Information About GARDASIL 9
GARDASIL 9 does not eliminate the necessity for vaccine recipients to undergo screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers as recommended by a healthcare provider.
GARDASIL 9 has not been demonstrated to provide protection against diseases caused by:
•HPV types not covered by the vaccine
•HPV types to which a person has previously been exposed through sexual activity
Not all vulvar, vaginal, anal, oropharyngeal and other head and neck cancers are caused by HPV, and GARDASIL 9 protects only against those vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58.
GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is not a treatment for external genital lesions; cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers; or cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), or anal intraepithelial neoplasia (AIN).
Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients.
Select Safety Information for GARDASIL 9
GARDASIL 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant].
Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following HPV vaccination. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.
Safety and effectiveness of GARDASIL 9 have not been established in pregnant women.
The most common (≥10%) local and systemic adverse reactions in females were injection-site pain, swelling, erythema, and headache. The most common (≥10%) local and systemic reactions in males were injection-site pain, swelling, and erythema.
The duration of immunity of GARDASIL 9 has not been established.
Dosage and Administration for GARDASIL 9
GARDASIL 9 should be administered intramuscularly in the deltoid or anterolateral area of the thigh.
•For individuals 9 through 14 years of age, GARDASIL 9 can be administered using a 2-dose or 3-dose schedule. For the 2-dose schedule, the second dose should be administered 6-12 months after the first dose. If the second dose is administered less than 5 months after the first dose, a third dose should be given at least 4 months after the second dose. For the 3-dose schedule, GARDASIL 9 should be administered at 0, 2 months, and 6 months.
•For individuals 15 through 45 years of age, GARDASIL 9 is administered using a 3-dose schedule at 0, 2 months, and 6 months.
About HPV and HPV-related Cancers and Diseases
According to the CDC, an estimated 14 million new HPV infections occur every year in the United States. HPV is so common that 80% of people who are sexually active get HPV at some point in their life. For most people, HPV clears on its own; but for those who don't clear the virus, it could cause certain cancers and diseases. There is no way to know which people who have HPV will develop cancer or other health problems. GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) helps protect against seven HPV types that cause the majority of HPV-related cancers in the United States. Persistent HPV infection can also lead to pre-cancerous lesions that may require additional follow-up procedures. With the exception of cervical cancer, there is no routinely recommended screening for the detection of HPV-related cancers.
For more than 125 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world's most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals - including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases - as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
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Please see the Prescribing Information for GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) at
and the Patient Information for GARDASIL9 at
Source: Merck & Co., Inc.