Clinical Perspectives on the Role of the Human Papillomavirus Vaccine in the Prevention of Cancer

Justin M. Julius, Pharm.D.; Lois Ramondeta, M.D.; Katherine A. Tipton, Pharm.D.; Lincy S. Lal, Pharm.D., Ph.D.; Karen Schneider, M.D.; Judith A. Smith, Pharm.D.; FCCP, FISOPP

Disclosures

Pharmacotherapy. 2011;31(3):280-297.

Bridging Studies for Older Populations

Although HPV VLP vaccines are meant to target young people before exposure, they have been shown to offer protection against one oncogenic HPV type (either HPV-16 or HPV-18) in female patients who are infected with the other oncogenic HPV type.^[60,61] Thus, vaccine manufacturers and regulatory agencies in other countries sought to expand the vaccine indication to females aged 26 years and older. With age simply representing likelihood of previous sexual intercourse and HPV exposure, women of advanced age with few or no sexual partners may also gain protection from vaccination; thus, it is logical not to deny vaccines to these populations.

A bridging study was conducted to evaluate vaccine-induced immune responses in two age cohorts outside those used in the clinical efficacy trials.^[82] Women aged 26–45 years and those aged 46–55 years were compared with girls and women aged 15–25 years with respect to seroconversion rates and antibody levels after vaccination with the bivalent vaccine. In all age groups, women who were seronegative initially achieved seroconversion for both HPV-16 and HPV-18 1 month after the third dose of vaccine. A decrease in geometric mean antibody titers was observed with increasing age, again forcing the issue of waning protection and need for even more frequent boosters in these age groups.

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Cite this: Clinical Perspectives on the Role of the Human Papillomavirus Vaccine in the Prevention of Cancer - Medscape - Mar 01, 2011.

Table 1. Incidence and Mortality of Human Papillomavirus–Related Cancers
Cancer Type	U.S. Cases in 2010^a	U.S. Deaths in 2010^a	No. (%) of Cases Caused by HPV^b	Potential No. of Deaths Related to HPV^c
Women
Cervical⁷	12,200	4210	12,200 (100)	4210^d
Anal¹⁹	3260	440	2934 (90)	396
Vulvar, vaginal¹⁹	6200	1700	2480 (40)	680
Oropharynx²⁸	11,120	2450	4448 (40)	980
Men
Anal¹⁹	2000	280	1800 (90)	252
Penile¹⁹	1250	310	500 (40)	124
Oropharynx²⁸	36,540	7880	14,616 (40)^d	3152
Total	72,570	17,270	38,978 (54)	9794

HPV = human papillomavirus.
^aBased on data from the American Cancer Society: Cancer Facts & Figures 2010.27
^bProportions of disease related to HPV are based on consensus of published literature.
^cAssumes proportional mortality in HPV- and non–HPV-related disease.
^dAlthough cervical cancer associated with HPV results in the most deaths in the United States, it is estimated that a greater number of cases of cancers of the head and neck result from HPV.

Table 2. Summary of the Available Clinical Trial Data by Prespecified Patient Populations for the Two Types of Human Papillomavirus Vaccines
No. of Patients, Duration of Follow-up	End Point	Prespecified Patient Population
No. of Patients, Duration of Follow-up	End Point	According to Protocol	Modified Intent-to-Treat	Intent-to-Treat
Quadrivalent vaccine
552 patients, 36 mo⁵⁸	Persistent infection HPV-16 or HPV-18 at 4 mo	96 (83–100)	94 (83–98)	NR
	CIN1+ related to HPV-16 or HPV-18	NR	100 (31–100)	NR
5455 patients, 3 yrs⁵⁹	CIN1+ related to HPV-16	100 (65–100)	94 (62–100)	73 (31–91)
	CIN1+ related to HPV-18	100 (< 0–100)	100 (41–100)	89 (20–100)
	CIN1+ related to HPV-16 or HPV-18	100 (94–100)	98 (92–100)	55 (40–66)
	CIN2+ regardless of HPV type	NR	NR	20 (8–31)
12,167 patients, 3 yrs⁶⁰	CIN2+ related to HPV-16	97 (84–100)	94 (82–99)	42 (22–56)
	CIN2+ related to HPV-18	100 (61–100)	100 (74–100)	79 (49–93)
	CIN2+ related to HPV-16 or HPV-18	98 (75–100)	95 (85–99)	44 (26–58)
	CIN2+ regardless of HPV type	NR	NR	17 (1–31)
Bivalent vaccine
18,644 patients, 3 yrs⁶¹	Persistent infection HPV-16 or HPV-18 at 6 mo	NR	NR	80.4 (70.5–87.4)
	Persistent infection HPV-16 or HPV-18 at 12 mo	NR	NR	75.9 (47.7–90.2)
	CIN2+ related to HPV-16	95.7 (82.9–99.6)	95.9 (86.2–98.4)	NR
	CIN2+ related to HPV-18	86.7 (39.7–98.7)	91.6 (64.6–99.2)	NR
	CIN2+ related to HPV-16 or HPV-18	92.9 (79.9–98.3)	94.5 (86.2–98.4)	52.8 (37.5–64.7)
	CIN2+ regardless of HPV type	NR	70.2 (54.7–80.9)	30.4 (16.4–42.1)

Data are percentages (95% confidence intervals for quadrivalent vaccine, 96.1% confidence intervals for bivalent vaccine). Although efficacy was high for all evaluated end points in the according-to-protocol and modified intent-to-treat populations, results from the intent-to-treat population showed a low percentage of patients who showed immunity to the strains covered as well as all HPV types.
HPV-16 or -18 = human papillomavirus type 16 or 18; CIN1+ or 2+ = cervical intraepithelial neoplasia grade 1 or 2; NR = not reported in the primary research report.

Table 3. Summary of Common and Serious Adverse Drug Events Associated with Human Papillomavirus Vaccination
Adverse Event	Frequency (%)^a
Quadrivalent vaccine⁵⁴
Common adverse events
Dermatologic
Erythema	16.7–24.7
Pain at injection site	61.5–83.9
Injection site pruritis	3.2
Swelling at injection site	13.9–25.4
Gastrointestinal
Nausea	2–6.7
Neurologic
Dizziness	1.2–4
Other
Fever	8.2–13
Serious adverse events^b	—
Syncope, appendicitis, pancreatitis, asthma, bronchospasm, disseminated encephalomyelitis, Guillain-Barré syndrome, transverse myelopathy syndrome, venous thromboembolism
Bivalent vaccine⁵⁵
Common adverse events
Dermatologic
Erythema	48
Pain at injection site	91.8
Swelling at injection site	44.1
Rash	9.8
Gastrointestinal symptoms	27.8
Musculoskeletal
Arthralgia	20.8
Myalgia	49.1
Neurologic
Headache	53.4
Other
Fatigue	55
Serious adverse events^b	—
Syncope, immune hypersensitivity reaction, angioedema

^aData were derived from manufacturer's data contained in the package insert.
^bSerious adverse events include those reported in clinical trials as well as postmarketing surveillance conducted through the national Vaccine Adverse Event Reporting System (https://vaers.hhs.gov/about/index).

Table 4. Comparison of Pharmacoeconomic Studies Conducted in the United States
Study Year	Study Assumptions
Study Year	Patient Age at Vaccination (yrs)	Cost QALY (2007 U.S. $)^a	Efficacy (%)	Population Covered (%)	Duration of Immunity	Current Screening Utilization (%)
2004⁸⁶	12	26,700	90	100	Lifelong	90
2007⁸⁷	12	3,150	100	70	Lifelong	NR
2007⁸⁸	12	4,300	100	70	Lifelong	NR
2008⁸⁹	12	43,600	100	75	Lifelong	95
	12	144,100	100	75	10 yrs	95
	18	97,300	100	75	Lifelong	95
	21	120,400	100	75	Lifelong	95
	25	152,700	100	75	Lifelong	95

QALY = quality-adjusted life-year.
^aPrices were adjusted from study reports based on yearly Consumer Price Index. A variety of estimated vaccination costs have been published in the United States since the development of human papillomavirus virus-like particle vaccines based on various study assumptions and modeling. All of the studies in this table had a societal perspective and used a Markov model.

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