COMMENTARY

HPV 9: The Latest ACIP Guidance

Sandra Adamson Fryhofer, MD

Disclosures

March 23, 2015

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Hello. I'm Dr Sandra Fryhofer. Welcome to Medicine Matters. The topic: HPV 9—a new human papillomavirus (HPV) vaccination with expanded protection.

Here's why it matters.

Since the Pap test was first introduced in the 1950s, cervical cancer incidence and mortality have dramatically decreased. Cervical cancer screening is one of the greatest cancer prevention achievements of all time. Unfortunately, cervical cancer still affects and kills many American women. Centers for Disease Control and Prevention (CDC) data from the 2012 Behavioral Risk Factor Surveillance System survey published in Morbidity and Mortality Weekly Report reveal that in 2011, a total of 12,109 women developed cervical cancer, and 4092 women died.[1] We now have a new tool for saving lives from cervical cancer: cancer prevention through HPV vaccination.

In June 2006, the Advisory Committee on Immunization Practices (ACIP) made its first recommendation for HPV vaccination: the use of HPV 4 vaccine for females.[2] There are now several HPV vaccines currently available:

  • HPV 2, the bivalent vaccine (Cervarix®), covers types 16 and 18 and is US Food and Drug Administration (FDA) approved only for females (aged 9 through 25 years).[3]

  • HPV 4, the quadrivalent HPV vaccine (Gardasil®), covers HPV strains 6, 11, 16, and 18 and is FDA approved for both males and females aged 9 through 26 years.[4]

  • HPV 9, a nine-valent HPV vaccine, (Gardasil® 9), FDA approved on December 11, 2014, covers types 6, 11, 16, and 18 (just like HPV 4) but also covers five additional high-cancer-risk strains: 31, 33, 45, 52, and 58.[5]

The amount of additional cancer protection from the added serotype coverage depends on cancer site and also varies geographically among countries. In the United States, 66% of cases of cervical cancer are linked to HPV types 16 and 18. An additional 15% of cervical cancer is attributable to the additional five strains. Half of all cases of carcinoma in situ 2 and higher cervical lesions are linked to HPV 16 and 18, but an additional 25% are attributable to the five additional types in the nine-valent vaccine.[6,7] By far, the greatest additional cancer protection is for females—in preventing cervical cancers—as compared with cancer prevention in males.[6,7]

Like HPV 4, HPV 9 vaccine is FDA approved for females aged 9 through 26 years for prevention of cervical, vulvar, vaginal, and anal cancers and precancers and for prevention of genital warts.

The upper age indication for boys is younger. HPV 9 is FDA approved for boys aged 9 through 15 years for prevention of anal cancer and precancer and for prevention of genital warts.[5] The additional serotype protection from the nine-valent vaccine comes with higher price tag (the Merck website shows a $16.08 difference in comparative cost of a one-dose prefilled syringe—HPV 9: $163.86; HPV 4: $147.78/dose).[8]

So how should we incorporate this new expanded coverage yet more expensive HPV 9 vaccine into current vaccination strategies? Can HPV vaccine products be used interchangeably?

HPV 2, HPV 4, or HPV 9 can be used to provide HPV 16 and 18 protection for females, but only HPV 4 and HPV 9 are licensed for use in males. (Note: Draft language from ACIP[9] reads: "Vaccination of females is recommended with HPV 2 or HPV 4 [as long as this formulation is available] or HPV 9. Vaccination of males is recommended with HPV 4 [as long as this formulation is available] or HPV 9." ACIP also acknowledged that use of HPV 9 in males older than 15 years would initially be an off-label use. The vaccine manufacturer has submitted additional data to the FDA about use of the vaccine in older males, so this age range may change in the future.)

Although ACIP does say it's fine to use HPV 9 to complete a series started with HPV 4 for protection against 6, 11, 16, and 18,[9] there is no available information about protection against the five additional strains with fewer than three doses of HPV 9.[5] (Note: There is also no actual study of the interchangeability of the HPV vaccines.[9])

Another important question: Should patients previously vaccinated with HPV 2 or HPV 4 be revaccinated with HPV 9? Let's look at highlights from a study described in the package insert.[5]

Methodology. In a prelicensure clinical study, a group of females aged 12 through 26 years who had previously been vaccinated with three doses of HPV 4 were given either three doses of HPV 9 or saline placebo. The time interval between the last HPV 4 and the first HPV 9 was 12-36 months (section 14.4; page 17).

Safety. The overall safety profile for HPV 9 was similar between those being revaccinated after HPV 4 series and those who were naive to HPV vaccination with one exception: Revaccinated females experienced increased injection site redness and swelling (section 6.1: page 7). The 15-minute observation time after administration still applies.

Immunogenicity. By month 7, seropositivity to all HPV 9 types in the per protocol population ranged from 98.3% to 100% in individuals who were revaccinated with HPV 9. However, geometric mean titers (GMTs) for the five additional serotypes in HPV 9 were 25%-63% of the GMTs in other studies of females who had not previously received HPV 4. The product label states that "the clinical relevance of these differences is unknown... Efficacy of GARDASIL 9 in preventing infection and disease related to HPV Types 31, 33, 45, 52, and 58 in individuals previously vaccinated with HPV 4 has not been assessed" (section 14.4: page 17).

What does ACIP say about revaccination? Expect more guidance from ACIP as more study data become available. (Note: ACIP did not address revaccination with HPV 9 in previously vaccinated persons at the February 2015 ACIP meeting. Note that due to a southern snow storm, the February 2015 ACIP meeting was truncated, so some of the presentations had to be deferred until a later date, possibly at the next ACIP meeting in June 2015.)

For Medicine Matters, I'm Dr Sandra Fryhofer.

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