Human papillomavirus (HPV) vaccine policy and evidence-based medicine: Are they at odds?

Figures & data

Table I. Key data on cervical cancer, HPV-16/18 prevalence, and cervical cancer prevention strategies in 22 countries. Data sourced from the World Health Organization (WHO)/Institut Catala d'Oncologia (ICO) Information Centre on HPV and cervical cancer (105).

Country	Incidence per 100,000 women (age-standardized)	Mortality per 100,000 women (age-standardized)	Mortality ranking among all cancers (all ages)	Pap screening coverage (%)	HPV-16/18 prevalence in women with low-/high-grade lesions/cervical cancer (%)	HPV vaccine introduced
Australia	4.9	1.4	17th	60.6 (All women aged 20–69 y screened every 2 y)	3.8/44.6/76.2	Yes
Netherlands	5.4	1.5	16th	59.0 (All women aged > 20 y screened every 5 y)	1.5/61.6/87.9	Yes
US	5.7	1.7	15th	83.3 (All women aged > 18 y screened every 3 y)	7.7/55/76.6	Yes
France	7.1	1.8	15th	74.9 (All women aged 20–69 y screened every 2 y	7.6/63.4/75.6	Yes
Canada	6.6	1.9	14th	72.8 (All women aged 18–69 y screened every 3 y; Annual if at high risk)	11.8/56.2/74.3	Yes
Spain	6.3	1.9	15th	75.6 (All women aged 18–65 y screened every 3 y	2.3/46.9/55.9	Yes
UK and Ireland	7.2	2	16th	80 (All women aged 25–64 y screened every 5 y)	2.4/61.9/79.1	Yes
Israel	5.6	2.1	14th	34.7 (All women aged 18–69 y screened every 3 y)	2.2/44.8/68.5	Yes
Germany	6.9	2.3	13th	55.9 (Women aged 20–49 y screened every 5 y)	1.4/54.1/76.8	Yes
China	9.6	4.2	7th	16.8 (All women aged 18–69 y screened every 3 y)	2.3/45.7/71	No
Viet Nam	11.5	5.7	4th	4.9 (All women aged 18–69 y screened every 3 y)	2.1/33.3/72.6	Yes
Russia	13.3	5.9	7th	70.4 (All women aged 18–69 y screened every 3y)	9.3/56/74	Yes
Brazil	24.5	10.9	2nd	64.8 (All women aged 18–69 y screened every 3 y)	4.3/54/70.7	Yes
Thailand	24.5	12.8	2nd	37.7 (All women aged 15–44 y ever screened	4.1/33.3/73.8	Yes
Pakistan	19.5	12.9	2nd	1.9 (All women aged 18–69 y screened every 3 y)	6/59.3/96.7	Yes
South Africa	26.6	14.5	2nd	13.6 (All women aged 18–69 y screened every 3 y	3.6/58.4/62.8	Yes
India	27	15.2	1st	2.6 (All women aged 18–69 y screened every 3 y)	6/56/82.5	Yes
Cambodia	27.4	16.2	1st	None	3.2/33.3/72.6	Yes
Nepal	32.4	17.6	1st	2.4 (All women aged 18–69y screened every 3 y	6/59.3/82.3	No
Nigeria	33	22.9	2nd	None	4.7/41.3/50	Yes
Ghana	39.5	27.6	1st	2.7 (All women aged 18–69 y screened every 3 y)	4.6/41.3/50	Yes
Uganda	47.5	34.9	1st	None	6.7/37.9/74.1	Yes

Table II. Summary of adverse reactions (ADRs) from HPV vaccines Gardasil and Cervarix. Note that the US FDA Code of Federal Regulation defines a serious adverse drug event as ‘any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect’ (106).

Vaccine	Country	Total n ADRs (ref.)	Doses n (ref.)	Total n ADRs/100,000 doses	Total n serious ADRs (ref.)	Total n serious ADRs/100,000 doses
Gardasil	US	18,727 (7)	35,000,000^a (7)	54	1,498 (7)	4.3
	France	1,700 (34)	4,000,000^a (34)	43	na	–
	Australia	1,534 (39)	6,000,000^a (39)	26	91^c (26,28,29)	1.5^c
	Ireland	314 (33)	90,000^b (33)	349	na	–
Cervarix	Netherlands	575 (32)	192,000^b (32)	299	575 (32)	5.7
	UK	8,798 (23)	3,500,000^b (23)	251	na	–

na = not available.

^aDoses distributed.

^bDoses administered.

^cExcluding 2010 data (unavailable at the time of writing of this report).

Figure 1. The rate of adverse reactions (ADRs) from Gardasil and Cervarix reported through various government-official vaccine surveillance programmes. For the data source, see Table II.

Figure 2. The rate of adverse reactions (ADRs) from Cervarix compared to that of other vaccines in the UK immunization schedule. Data sourced from the report provided by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the Joint Committee on Vaccination and Immunisation in June 2010 (23).

Figure 3. Percentages of reported ADRs associated with HPV vaccines for each system organ class. Data sourced from the Database of the Netherlands Pharmacovigilance Centre Lareb (32), the UK Medicines and Healthcare products Regulatory Agency (MHRA) (62), and the Irish Medicines Board (IMB) (24). The most commonly reported ADRs in the nervous system and psychiatric disorders class were headache, syncope, convulsions, dizziness, hypoaesthesia, paraesthesia, lethargy, migraine, tremors, somnolence, loss of consciousness, dysarthria, epilepsy, sensory disturbances, facial palsy, grand mal convulsion, dysstasia, dyskinesia, hallucination, and insomnia.

Table III. Injectionsite adverse reactions (ADRs) reported in Gardasil clinical trials among 8878 female participants aged 9–26 years, 1–5 days post-vaccination (82).

ADR type	Gardasil(n=5088)%	Aluminum (AAHS)^a (n=3470)%	Saline placebo (n=320)%	Gardasil/saline	Gardasil/AAHS	AAHS/saline
Pain	83.9	75.4	48.6	1.7	1.1	1.6
Swelling	25.4	15.8	7.3	3.5	1.6	2.2
Erythema	24.7	18.4	12.1	2.0	1.3	1.5
Pruritus	3.2	2.8	0.6	3.5	1.1	4.7
Bruising	2.8	3.2	1.6	1.8	0.9	2.0

^aAAHS Control = amorphous aluminum hydroxyphosphate sulfate.

Table IV. Number of girls and women aged 9–26 years who reported a condition potentially indicative of a systemic autoimmune disorder after enrolment in Gardasil clinical trials (82).

Condition	Gardasil (n = 10,706)n (%)	Aluminum (AAHS)^a (n = 9412)n (%)
Arthralgia/arthritis/arthropathy	120 (1.1)	98 (1.0)
Autoimmune thyroiditis	4 (0.0)	1 (0.0)
Coeliac disease	10 (0.1)	6 (0.1)
insulin-dependent	2 (0.0)	4 (0.0)
Diabetes mellitus insulin-dependent	2 (0.0)	2 (0.0)
Erythema nodosum	27 (0.3)	21 (0.2)
Hyperthyroidism	35 (0.3)	38 (0.4)
Hypothyroidism	7 (0.1)	10 (0.1)
Inflammatory bowel disease	2 (0.0)	4 (0.0)
Multiple sclerosis	2 (0.0)	5 (0.1)
Nephritis	2 (0.0)	0 (0.0)
Optic neuritis	4 (0.0)	3 (0.0)
Pigmentation disorder	13 (0.1)	15 (0.2)
Psoriasis	3 (0.0)	4 (0.0)
Raynaud's phenomenon	6 (0.1)	2 (0.0)
Rheumatoid arthritis	2 (0.0)	1 (0.0)
Scleroderma/morphea	1 (0.0)	0 (0.0)
Stevens–Johnson syndrome	1 (0.0)	3 (0.0)
Systemic lupus erythematosus	3 (0.0)	1 (0.0)
Total	245 (2.3)	218 (2.3)

Table V. Key cervical cancer statistics according to the 2010 World Health Organization (WHO)/Institut Catala d'Oncologia (ICO) report on HPV and related cancers (107).

	World	Developing countries (% total)	Developed countries (% total)
Women at risk for cervical cancer (aged ≥15 y)	2,336,986	1,811,867 (77.5)	525,120 (22.5)
Annual number of new cases of cervical cancer	529,828	453,321 (85.6)	76,507 (14.4)
Annual number of cervical cancer deaths	275,128	241,969 (87.9)	33,159 (12.1)
Prevalence (%) of HPV-16 and/or HPV-18 among women with cervical cancer	70.9	71.0	70.8

Figure 4. Correlation between cervical cancer mortality rates and A: Pap test screening coverage; B:HPV-16/18 prevalence in women with high-grade lesions (CIN 2/3, carcinoma in situ (CIS), and high-grade cervical squamous intraepithelial lesions (HSIL)); C: HPV-16/18 prevalence in women with cervical cancer. Data were sourced for 22 countries from World Health Organization (WHO)/Institut Catala d'Oncologia (ICO) Information Centre on HPV and cervical cancer (Table I). The correlation analysis was carried out using GraphPad Prism statistical software to derive Pearson correlation coefficients (r). The level of significance was determined using a two-tailed test. The correlation was considered statistically significant at P <0.05.

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