Scientific Committee on Vaccine Preventable Diseases andScientific Committee on AIDS and STIConsensus Statement on the use of Human Papillomavirus(HPV) Vaccine in prevention of cervical cancer
Introduction
Human Papillomavirus (HPV) vaccine is the first vaccine that has
been successfully developed to prevent a sexually transmitted virus infection,
the persistence of which predisposes to cervical cancer. In 2013, ScientificCommittee on AIDS and Sexually Transmitted Infections (SCAS) and
Scientific Committee on Vaccine Preventable Diseases (SCVPD) of theCentre for Health Protection jointly reviewed the applicability of HPVvaccination in Hong Kong, the conclusions of which were published in theirsubsequent recommendations. By 2016, additional studies and new evidence
concerning the efficacy of HPV vaccines have become available, urging
SCAS and SCVPD to revisit the situation.
2.

This consensus statement summarizes the latest scientificknowledge on HPV infection, its epidemiology and association with cervicalcancer, efficacy and safety of HPV vaccines, the synthesis of which led tothe consensus on the approach to the prevention of HPV infection andcervical cancer, focusing on the situation in Hong Kong. This document
replaces “Recommendation on the use of Human Papillomavirus (HPV)
vaccine” issued by SCAS and SCVPD in 2013.

1Background3.

Human Papillomavirus (HPV) causes cervical cancer and anogenitalwarts. More than 100 HPV genotypes are known today, which can be broadly
categorized as high risk (HR-HPV) and low risk (LR-HPV) types. Genital HRHPV include genotypes 16,18,31,33,35,39,45,51,52,56,58,59,and 68. They arepotentially oncogenic[1, 2] and can cause premalignant and malignant cancers ofcervix, vagina, vulva, anus, penis and upper aerodigestive tract.

LR-HPV

including genotypes 6,11,42,43 and 44 mainly cause genital warts. Majority,
around 90%, of HPV infections are cleared or become suppressed within 1 to 2
years of infection by the host’s own immunity. Persistent infection of HRHPV is a prerequisite for the increased risk of pre-malignant lesions andprogression to malignant cervical cancer.[3]4.

HPV, a highly transmissible virus, is acquired from infected persons

through mainly sexual, particularly vaginal and anal, intercourse. High numberof sex partners is a salient risk factor for HPV transmission.[4] It is estimatedthat the incidence of HPV infection among initially uninfected women could
reach as high as 60% over a 5-year follow-up period[4] and that the probabilityof HPV transmission per coital act ranged from 5% to 100% with a median of40%.[5]5.

There is no published study to support the transmission of genital

HPV through toilet seats, kissing on the mouth, hugging, holding hands, poor
personal hygiene, sharing food or utensils, swimming in pools or hot tubs.

Epidemiology of HPV infection and diseases
6.

By incorporating advanced molecular techniques, epidemiologicaland clinical studies have reported the detection of HR-HPV in practically 100%of cervical cancer tissues.[6]HR-HPV viral DNA was also detected in amajority (70-90%) of pre-cancer lesions or high-grade intraepithelial lesions(CIN II-III)[6] and in a smaller fraction (20-50%) of lower grade lesions (CINI).[6]27.

Worldwide, HPV-16 and HPV-18 are the most frequent HR-HPV

genotypes, amounting to an estimated 53.5% and 17.2% of cervical cancer
respectively.[6] They are followed by HPV-45 (6.7%), HPV-31 (2.9%), HPV33 (2.6%), HPV-52 (2.3%) and HPV-58 (2.2%).[6] Overall, the cumulative
percentage of cervical cancer related to HPV-16 and HPV-18 is 70.7%, rising
to 87.4% when all these seven HPV are included.
8.

LR-HPVs are associated with condylomata acuminata (genital warts)

mainly or papillomatosis. Over 90% of the genital warts have been reported tobe associated with HPV-6 and HPV-11 infection, and rarely with HPV-42.[6, 7]

HPV situation in Hong Kong
9.

In 2013, 503 new cases of cervical cancer were reported to the Hong

Kong Cancer Registry administered by the Hospital Authority, making it theseventh in ranking among all cancers diagnosed in females and the cervicalcancer accounted for 3.6% female cancer in Hong Kong.

According tostatistics from Department of Health, cervical cancer ranked number nine incancer mortality in females in Hong Kong, with 131 (2.3%) reported deaths in2014.
10.

Worldwide, HPV-16,18,45,31 and 33 are the five most prevalent

HR-HPV genotypes associated with cervical cancer. The situation is different
in Hong Kong where HPV-52 and 58 are more prevalent and contribute to ahigher proportion of cervical cancer than Western countries. A meta-analysis
study reported that the attribution of HPV-52 and HPV-58 to cervical cancer in
East Asia was 3.7-4.9 folds higher than elsewhere.[8] A study involving 1924
women in Hong Kong concluded that the overall prevalence of HPV-58 was11.4%, and was 7.6% with invasive cervical cancer.[9]11.

A recent Hong Kong study involving 236 Chinese women who hadreceived cervical cancer treatment revealed that the four most prevalent HPV
genotypes associated with cervical cancer were HPV-16(60.2%), HPV18(21.6%), HPV-52(11.9%) and HPV-58(9.3%).[10] Another study covering
120 cervical cancer patients in Hong Kong also showed similar findings, with3

HPV-16(50.0%), HPV-18(21.7%), HPV-52(12.5%) and HPV-58(8.3%).[11]HPV vaccines
12.

Currently, three HPV vaccines (Appendix), namely Cervarix (2-valent vaccine against HPV-16,18), Gardasil-4 (4-valent vaccine against HPV6,11,16,18)

andGardasil-9(9-valentvaccine

againstHPV-

6,11,16,18,31,33,45,52,58) have been registered in Hong Kong for theprevention of cervical cancer and/or other HPV-related diseases. All threevaccines could prevent infections from HPV-16 and 18, which account for
about 70% of all cervical cancer worldwide. The 9-valent vaccine covers five
additional HR-HPV, viz.

HPV-31,33,45,52,58, which are associated witharound 90% of cervical cancer in worldwide, including Hong Kong. The 4valent and 9-valent vaccines could protect against two LR-HPV, HPV-6 and 11,which are associated with anogenital warts. However, the vaccines have no
therapeutic effect on any existing HPV infections or diseases.

Efficacy of HPV Vaccines
13.

Multiple studies had provided evidence that the first generation 2-valent and 4-valent vaccines had demonstrable efficacy in preventing vaccine
genotype related HPV infection thence the cervical cancer.
14.

Studies suggested the 2-valent vaccine could substantially reduce

the overall burden of CIN 2+ (CIN2, CIN 3 and cervical cancer) by 70.2% 100% in HPV-naive population up to around 6 years’ follow-up.[12, 13] Anotherstudy showed that the 2-valent vaccine induced significantly higher
neutralizing antibody levels as compared with 4-valent vaccine 7.3 years after
vaccination.[12] In an immunogenicity study, anti-HPV-6,11,16,18 antibodies
were shown to remain at high level with seropositive status maintained up to 9years of follow-up after the first dose of the 4-valent vaccine.[14]415.

A 10-year review study published in 2016 confirmed the efficacy ofthe 4-valent vaccine in the prevention of vaccine-related HPV infection andcervical cancer. There was a maximal reduction of 90% for HPV-6,11,16,18
infection, 90% for genital warts, and 90% for high-grade histologically-provencervical abnormalities.[15]16.

In December 2014, Food and Drug Administration in United States(US-FDA) approved a 9-valent HPV vaccine that protects against HPV6,11,16,18,31,33,45,52,58, which is now available in Hong Kong. It includes
the HPV genotypes in the 2-valent and 4-valent vaccine (HPV-6,11,16,18) withfive additional HPV genotypes (HPV-31,33,45,52,58). As HPV-52 and 58 are
relatively commoner in Hong Kong, the 9-valent vaccine could theoreticallyincrease the cervical cancer prevention from around 70% to 90%.
17.

It has been shown from study that the 9-valent HPV vaccine could

result in a 96.7% risk reduction of high grade cervical disease including
cervical cancer and 96% risk reduction of HPV persistent infection.[16]HPV Vaccine Safety
18.

The common side effects of HPV vaccines generally include mild

local reactions following injection, such as erythema, pain and swelling, andsystematic adverse effects such as muscle aches, fever, headache and nausea.
These side effects often subside within days. The vaccine is contraindicated inpersons with a history of immediate hypersensitivity to yeast or any of thevaccine components. Because of limited data, vaccination during pregnancy is
not recommended.
19.

Drug Office of Department of Health (DH) has examined the safetyof all HPV vaccines by reviewing the safety reports collected in Hong Kong
(Department of Health, Hong Kong pharmacovigilance system) andinternational organisations including World Health Organization GlobalAdvisory Committee for Vaccine Safety (WHO-GACVS); EuropeanMedicines Agency’s Pharmacovigilance Risk Assessment Committee (EMAPRAC); Health Canada; United States Centers for Disease Control and5Prevention (US-CDC); United States Food and Drug Administration (US-FDA)
and United States Vaccine Adverse Event Reporting System (US-VAERS). Itis considered that the benefits from HPV vaccination, such as prevention ofcervical cancer, outweigh the risks of potential side effects. An ongoing postmarketing surveillance on safety and effectiveness of the HPV vaccines isessential.

Approach to prevention of HPV infection as a mean to prevent
cervical cancer in Hong Kong
20.

To date, the scientific evidence supports that vaccination against theHPV is effective for individual protection against HPV infections, by thegenotypes covered by the respective vaccine, and thence cervical cancer. The
public health strategy for HPV vaccination in Hong Kong shall be formulated
based on an integration of clinical evidence available internationally,
epidemiological understanding, coupled with the projected population benefits
derived from local studies.
21.

The registered first generation HPV vaccines, i.e., the 2-valent and4-valent vaccine, protects one from high risk HPV-16 and 18 infection, which
together account for about 70% of cervical cancer. The registered second
generation 9-valent HPV vaccine has been shown to be equally efficacious or
not inferior than the first generation vaccines against HPV-16 and 18 infection
and their consequent cervical cancer. The 9-valent vaccine, in view of its
efficacy against HPV-52 and 58, could potentially increase the protection ofcervical cancer to around 90% in Hong Kong, the likelihood of which would
need to be confirmed by longitudinal clinico-epidemiological studies.
22.

Transmission of genital HPV infection is primarily through sexualcontact (both vaginal and anal sex) with an infected person. HPV transmission
can be minimized through the practice of safer sex involving the use of condom,
as well as reducing the number of sex partners. The ideal age of vaccination, ifadministered, should be timed before the commencement of sexual debut. Thevaccines have no therapeutic effect on any pre-existing HPV infections.

623.

Of the three HPV vaccines available in Hong Kong, their benefits inpreventing HPV infection and cervical cancer far outweigh their risks or sideeffects.
24.

HPV vaccines cannot offer a 100% full protection from cervicalcancer.

In this connection, regular cervical cancer screening remains animportant public health strategy which should continue to be recommended toachieve a high population coverage. HPV vaccination does not replace thecervical cancer screening.

Centre for Health Protection
September 2016

The copyright of this paper belongs to the Centre for Health Protection, Department of Health,Hong Kong Special Administrative Region. Contents of the paper may be freely quoted foreducational, training and non-commercial uses provided that acknowledgement be made to theCentre for Health Protection, Department of Health, Hong Kong Special Administrative Region.
No part of this paper may be used, modified or reproduced for purposes other than those statedabove without prior permission obtained from the Centre.

7References[1]

Luckett R, Feldman S. Impact of 2-, 4- and 9-valent HPV vaccines on
morbidity and mortality from cervical cancer. Hum Vaccin
Immunother. 2015 Nov 20:1-11.

[2]

Trottier H, Franco EL. The epidemiology of genital humanpapillomavirus infection. Vaccine. 2006 Mar 30;24 Suppl 1:S1-15.

[3]

Schiffman M, Castle PE, Jeronima J, Rodriguez AC, Wacholder S.
Human papillomavirus and cervical cancer. Lancet. 2007 Sep
8;370(9590):890-907.

[4]

Baseman JG, Koutsky LA. The epidemiology of human papillomavirus
infections. J Clin Virol. 2005 Mar;32 Suppl 1:S16-24.

[5]Burchell AN, Winer RL, de Sanjose S, Franco EL. Epidemiology andtransmission dynamics of genital HPV infection. Vaccine. 2006 Aug31;24 Suppl 3:S3/52-61.

[6]

Castellsague X. Natural history and epidemiology of HPV infection
and cervical cancer. Gynecol Oncol. 2008 Sep;110(3 Suppl 2):S4-7.

[7]

Partridge JM, Koutsky LA. Genital human papillomavirus infection inmen. Lancet Infect Dis. 2006 Jan;6(1):21-31.

[8]

Chan PKS, Ho WCS, Chan MCW, et al. Meta-Analysis on prevalence
and attribution of human papillomavirus type 52 and 58 in cervicalneoplasia worldwide. PLoS One. 2014 Sep 17;9(9):e107573.

[9]

Chan PKS, Lam CW, Cheung TH, et al. Association of humanpapillomavir type 58 variant with the risk of cervical cancer. J NatlCancer Inst. 2002 Aug 21;94(16):1249-53.

[10]

Lau YM, Cheung TH, Yeo W, et al. Prognostic implication of humanpapillomavirus types and species in cervical cancer patients undergoingprimary treatment. PLoS One. 2015 Apr 9;10(4):e0122557.

[11]

Chan PK, Cheung TH, Tam AO, et al. Biases in human papillomavirus
genotype prevalence assessment associated with commonly usedconsensus primers. Int J Cancer. 2006 Jan 1;118(1):243-5.

8

[12]

Schwarz TF. Clinical update of the AS04-adjuvanted humanpapillomavirus-16/18 cervical cancer vaccine, Cervarix. Adv Ther.
2009; Nov;26(11):983-98.

[13]

Schwarz TF. AS04-adjuvanted human papillomavirus-16/18
vaccination: recent advances in cervical cancer prevention. Expert RevVaccines. 2008 Dec;7(10):1465-73.

[14]Nygård M, Saah A, Munk C, et al. Evaluation of the Long-Term AntiHuman Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses
Generated by the Quadrivalent HPV Vaccine. Clin Vaccine Immunol.
2015;Aug(22):943-8.

[15]Garland SM, Kjaer SK, Munoz N, et al. Impact and effectiveness of thequadrivalent human papillomavirus vaccine: a systemic review of ten
years of real-world experience. Clin Infect Dis. 2016 May 26. pii:
ciw354. [Epub ahead of print].

[16]

Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine
against infection and intraepithelial neoplasia in women. N Engl J Med.
2015 Feb 19;372(8):711-23.

9Appendix
The attributes and dosing recommendations of the three registered HPV
vaccines available in Hong Kong
Gardasil-4 (4-valent)
Vaccines

Cervarix (2-valent)(HK-54934)(Vial)

Gardasil-9 (9-valent)(HK-56180)(HK-54935)(Prefilled(HK-64239)

Syringe)
Against HPV

HPV-16,18

HPV-6,11,16,18

HPV-6,11,16,18,31,33,45,52,58

Indicated age

From the age of 9 years

From the age of 9 years

From the age of 9 years(ONLY Female )(Both Female & Male )(Both Female & Male)- Cervical cancer

Yes

Yes

Yes

- Genital Warts

No

Yes

Yes

9-14 years old: 2 doses

9-13 years old: 2 doses

9 years old and above: 3 doses

Diseasesprevention causedby related HPVApproved dosest

regimen in HK(before 31 Oct 2016)15 years old and above:

14 years old and above:

3 doses

3 doses**************
9-14 years old: 2 doses
15 years old and above: 3 dosesst(on or after 31 Oct 2016)10