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BMJ 2017;357:j2730 doi: 10.1136/bmj.

j2730 (Published 2017 June 22) Page 1 of 7

Practice

PRACTICE

10 MINUTE CONSULTATION

Discussing human papilloma virus vaccination


1 2
Yan Ling Quah resident physician , Ieera Madan Aggarwal consultant
1
Singhealth Polyclinics, Singapore; 2Department of Gynaecological Oncology, KK Womens and Children's Hospital, Singapore

A mother and her 15 year old daughter come to your clinic. The Antibody titres after vaccination are relatively high. A long term
mothers other daughter, who is 12 years old, recently received follow-up study demonstrated that efficacy of the bivalent
the human papilloma virus (HPV) vaccine at school. The mother vaccine Cervarix after 9.4 years was 95.6% against HPV types
wants to know whether her 15 year old daughter who missed 16 and 18.13 For the quadrivalent Gardasil, no cases of
her HPV vaccination should receive it now. precancerous lesions or genital warts related to HPV 6, 11, 16,
HPV is sexually transmitted. Infection is often asymptomatic. or 18 were detected at five years follow-up.13 Longer term
In some people, however, HPV infection persists and over time studies are needed to establish if booster doses are required.
leads to genital warts or cancer, mainly cervical, but also anal, These trials measured antibody titres as the primary endpoint,
penile, oral, and throat cancers (fig 1). The HPV types 16 and which is a surrogate marker for protection against cancer and
18 together cause 70% of cervical cancers.1-4 precancerous lesions. Evidence on long term immunogenicity
Prophylactic vaccines against HPV are offered as part of the and prevention of cervical cancer is not available. Explain to
national immunisation programme in many countries including patients and their parents that, although the vaccine has been
in the UK.1 These vaccines generate HPV-specific antibodies shown to prevent infection with oncogenic HPV viruses, it is
that bind to the virus and prevent cervical infection. Table 1 not a replacement for routine adult cervical screening.14
shows the three types of vaccines available.
Vaccination coverage globally has been variable. Surveys among
Who may be vaccinated
parents find that the most common reasons for not vaccinating HPV immunisation is usually recommended in adolescent girls
their child include lack of knowledge about the vaccine, a belief before onset of sexual activity, typically in the age group of
that it is not needed, their child is not sexually active, and 9-14 years. See table 2 for country-specific recommendations
concerns about safety.6-8 A healthcare providers regarding age and vaccination schedule.
recommendation is an important factor in parents decision to All girls aged 12-13 years in the UK are offered the quadrivalent
vaccinate their child.9 vaccine Gardasil in school as part of the NHS childhood
What you should cover immunisation programme.10 Girls who have missed vaccination
can be offered a catch-up vaccination up to 18 years of age.16
Initiate a discussion about HPV Vaccination for women over 18 years old is not covered by the
Explore whether the patient or their parents have heard of HPV national programme in the UK, though some countries offer
vaccination and what they know about it. You may ask about vaccination up to 26 years of age.2 The effects of vaccination
the source of their information, whether they have considered in women over this age group have not been sufficiently studied.
vaccination, and any concerns they have. Some countries, including the United States, Canada, and
Australia, also offer vaccination to adolescent boys to prevent
Explain the effects of vaccination HPV related anal and oropharyngeal cancers. Routine
In large randomised controlled trials, both Cervarix and Gardasil vaccination is currently not offered to males in the UK. The
vaccines have been shown to be over 99% effective in effectiveness and feasibility of immunisation of adolescent boys
preventing precancerous lesions associated with HPV types 16 and of men who have sex with men is being studied.17-19
or 18 in young women with no evidence of previous
infection.10-12 Gardasil was additionally 96-100% effective in
preventing anogenital warts.10

Correspondence to: I M Aggarwal Ieera.aggarwal@singhealth.com.sg


This is part of a series of occasional articles on common problems in primary care. The BMJ welcomes contributions from GPs.
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BMJ 2017;357:j2730 doi: 10.1136/bmj.j2730 (Published 2017 June 22) Page 2 of 7

PRACTICE

What you need to know


HPV vaccination protects against infection with oncogenic human papilloma viruses responsible for up to 70% of all cervical cancers
Offer vaccination to adolescent girls in line with the recommended schedule in your country
Explain that vaccination is not a substitute for routine cervical screening, which continues to be an important strategy for prevention
of cervical cancer

Inform about the vaccination schedule for You may explain safe sex practices if the patient inquires about
HPV ways to minimise risk of infection and cancer.
Refer to national guidelines in planning the vaccination schedule
for your patient. Initially, the HPV vaccine was given as three We thank Chung Sze Ryn and Lim Yu Hui for helping us with the
doses (at 0, 2, and 6 months), but recent randomised controlled diagram regarding the sequelae of HPV infection and preventive
trials show that it is as effective when given in two doses (0 and strategies.
6 months) in 9-14 year olds because younger adolescents mount We have read and understood BMJ policy on declaration of interests
a higher immune response.6 20 The vaccine is administered as and declare that we have no relevant interests to declare.
intramuscular injections at least six months (and no longer than
two years) apart.7 8 From the age of 15 years, patients should 1 Bruni L, Barrionuevo-Rosas L, Albero G, et al. Human papillomavirus and related diseases
in the world. ICO Information Centre on HPV and Cancer, 2015.
receive the three dose course.21 The age of starting the 2 Centers for Disease Control and Prevention. HPV Vaccine Information for Clinicians- Fact
vaccination governs the schedule. Sheet. 2012. www.cdc.gov/std/hpv/stdfact-hpv-vaccine-hcp.htm.
3 Kitchener HC, Denton K, Soldan K, Crosbie EJ. Developing role of HPV in cervical cancer
prevention. BMJ 2013;357:f4781. doi:10.1136/bmj.f4781 pmid:23926316.
Explain the safety profile of the vaccine 4 Stillo M, Carrillo Santisteve P, Lopalco PL. Safety of human papillomavirus vaccines: a
review. Expert Opin Drug Saf 2015;357:697-712. doi:10.1517/14740338.2015.
You may highlight to parents that the HPV vaccines contain 1013532 pmid:25689872.
5 Joura EA, Giuliano AR, Iversen OE, et al. Broad Spectrum HPV Vaccine Study. A 9-valent
virus-like particles without any viral DNA and hence are HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med
non-infectious. The World Health Organization Global Advisory 2015;357:711-23. doi:10.1056/NEJMoa1405044 pmid:25693011.
6 Kamerow D. HPV vaccine: effective but underused in the US. BMJ 2016;357:i2060. doi:
Committee for Vaccine Safety (GACVS) regularly reviews 10.1136/bmj.i2060 pmid:27081105.
evidence on safety of HPV vaccines and concluded that both 7 McCarthy M. US falls short of target for vaccinating adolescents against HPV. BMJ
2014;357:g4877. doi:10.1136/bmj.g4877 pmid:25069751.
HPV vaccines are safe and that potential benefits outweigh any 8 Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in
harms.22 younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA
2013;357:1793-802. doi:10.1001/jama.2013.1625 pmid:23632723.
Commonly reported adverse effects include injection site 9 Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human
reactions (pain, swelling, redness), nausea, headache, fever, papillomavirus infection and disease in women: a systematic review of randomized
controlled trials. CMAJ 2007;357:469-79. doi:10.1503/cmaj.070948 pmid:17671238.
muscle or joint pain, and syncope.22-24 Syncope is commonly 10 Centers for Disease Control and Prevention. Human papillomavirus (HPV) vaccine safety.
attributed to vagal nerve stimulation, and the risk can be reduced CDC, 2015. www.cdc.gov/vaccinesafety/vaccines/hpv-vaccine.html.
11 Garland SM, Hernandez-Avila M, Wheeler CM, et al. Females United to Unilaterally
by a 15 minute post-vaccination observation with patients seated Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine
or lying down. As with other vaccines, an anaphylactic reaction against human papillomavirus to prevent anogenital diseases. N Engl J Med
after HPV vaccination is a contraindication for a subsequent 2007;357:1928-43. doi:10.1056/NEJMoa061760 pmid:17494926.
12 FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent
dose. high-grade cervical lesions. N Engl J Med 2007;357:1915-27. doi:10.1056/
NEJMoa061741 pmid:17494925.
Suspected cases of complex regional pain syndrome after HPV 13 De Vincenzo R, Conte C, Ricci C, Scambia G, Capelli G. Long-term efficacy and safety
vaccination were reported in the UK and Japan, which led to of human papillomavirus vaccination. Int J Womens Health 2014;357:999-1010. doi:10.
2147/IJWH.S50365 pmid:25587221.
suspension of HPV vaccine recommendations in Japan in 2013. 14 World Health Organization, International Agency for Research on Cancer. Primary
In December 2012, the UK Medicines and Healthcare products end-points for prophylactic HPV vaccine trials. IARC Working Group Report vol 7. IARC,
Regulatory Agency (MHRA) published a safety assessment 2013.
15 Hanley SJB, Yoshioka E, Ito Y, Kishi R. HPV vaccination crisis in Japan. Lancet
report that concluded there was insufficient evidence of a causal 2015;357:2571. doi:10.1016/S0140-6736(15)61152-7 pmid:26122153.
association with the HPV vaccine.9 25 This was backed by reports 16 Public Health England. Human papillomavirus (HPV): the green book, chapter 18a. 2014.
www.gov.uk/government/publications/human-papillomavirus-hpv-the-green-book-chapter-
in 2013 and 2014 by the GACVS and the European Medicines 18a.
Agency.26 27 17 Mariani L, Venuti A. HPV vaccine: an overview of immune response, clinical protection,
and new approaches for the future. J Transl Med 2010;357:105. doi:10.1186/1479-5876-
8-105 pmid:20979636.
What you should do 18 Stanley M. HPV vaccination in boys and men. Hum Vaccin Immunother 2014;357:2109-11.
doi:10.4161/hv.29137 pmid:25424825.
19 Stanley M, OMahony C, Barton S. HPV vaccination. BMJ 2014;357:g4783. doi:10.1136/
Offer vaccination as per the recommended immunisation bmj.g4783 pmid:25073784.
schedule in your country based on the patients age. This vaccine 20 Kreimer AR, Struyf F, Del Rosario-Raymundo MR, et al. Costa Rica Vaccine Trial Study
Group Authors PATRICIA Study Group Authors HPV PATRICIA Principal
is supplied free of cost in the NHS. In countries where the Investigators/Co-Principal Investigator Collaborators GSK Vaccines Clinical Study Support
vaccine is not offered as part of a national programme, local Group. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine:
costs and availability must be discussed. combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials. Lancet
Oncol 2015;357:775-86. doi:10.1016/S1470-2045(15)00047-9 pmid:26071347.
Reinforce that vaccination is not a substitute for routine cervical 21 European Medicines Agency. PRAC recommendations on signals. Adopted at the PRAC
meeting of 7-10 April 2014. www.ema.europa.eu/docs/en_GB/document_library/PRAC_
cancer screening as it does not protect against all HPV recommendation_on_signal/2014/04/WC500165809.pdf.
subtypes.3 4 About 30% of cervical cancer cases are caused by 22 Holman DM, Benard V, Roland KB, Watson M, Liddon N, Stokley S. Barriers to human
papillomavirus vaccination among US adolescents: a systematic review of the literature.
HPV subtypes not covered by the vaccine. Regular cervical JAMA Pediatr 2014;357:76-82. doi:10.1001/jamapediatrics.2013.2752 pmid:24276343.
smears are still important for early detection and treatment of 23 Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of
pre-invasive cervical abnormalities. a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine
2006;357:5571-83. doi:10.1016/j.vaccine.2006.04.068 pmid:16753240.
Report any side effects on administration of the vaccine, as 24 World Health Organization. Human papillomavirus vaccines: WHO position paper, October
2014. Wkly Epidemiol Rec 2014;357:465-91.pmid:25346960.
safety of the vaccine is continuously being monitored. In the 25 Huygen F, Verschueren K, McCabe C, et al. Investigating reports of complex regional
UK, the MHRA collects data on vaccine safety via the Yellow pain syndrome: an analysis of HPV-16/18-adjuvanted vaccine post-licensure data.
EBioMedicine 2015;357:1114-21. doi:10.1016/j.ebiom.2015.07.003 pmid:26501109.
Card Scheme, where anyone can report a suspected side effect.22

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PRACTICE

Further educational resources


Resources for patients
Public Health England. Immunisation: human papillomavirus (hpv). www.gov.uk/government/collections/immunisation#human-
papillomavirus-(hpv)
NHS Choices. Vaccinations: HPV vaccine. www.nhs.uk/conditions/vaccinations/pages/hpv-human-papillomavirus-vaccine.aspx

Resources for clinicians


Public Health England. Human papillomavirus (HPV): the green book, chapter 18a. www.gov.uk/government/uploads/system/uploads/
attachment_data/file/317821/Green_Book_Chapter_18a.pdf
Centers for Disease Control and Prevention. Human Papillomavirus (HPV). www.cdc.gov/hpv/hcp/index.html

Education into practice


When was the last time you brought up a discussion with a patient regarding vaccination against HPV?
While discussing HPV vaccination with young girls, would you also discuss safe sex practices?
Are you familiar with the HPV vaccination schedule in your country?

How patients were involved in the creation of this article


In the process of writing this article, we asked around 50 teenage girls, most of whom were yet to receive the vaccine, and their mothers
regarding their understanding of HPV vaccination. We noted lack of awareness about the indication for this vaccine, its potential benefits
and adverse effects. A patient reviewed this article and emphasised adding information on adverse effects of the vaccine since that is often
a major concern among parents.

26 MHRA. Cervarix HPV vaccine: safety update at end of 4 years routine use in HPV Published by the BMJ Publishing Group Limited. For permission to use (where not already
immunisation programme. 2012. www.mhra.gov.uk/safety-public-assessment-reports/ granted under a licence) please go to http://group.bmj.com/group/rights-licensing/
CON221607.
permissions
27 Global Advisory Committee on Vaccine Safety, 1213 June 2013. Wkly Epidemiol Rec
2013;357:301-12.pmid:23909011.

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PRACTICE

Tables

Table 1| Types of HPV vaccines2

Vaccine Type Protection against HPV types Licensed for use


Cervarix Bivalent Types 16, 18 (associated with cervical cancer) Females aged 10-25 years
Gardasil Quadrivalent Types 6, 11 (associated with anogenital warts) Females and males aged 9-26 years
Types 16, 18 (associated with cervical cancer)
Gardasil 9 Nonavalent Types 6, 11 (associated with anogenital warts) Females and males aged 9-26 years
Types 16, 18 (associated with cervical cancer)
Types 31, 33, 45, 52, 58 (responsible for ~14% of HPV associated cancers in women and ~4%
of HPV associated cancers in men5)

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Table 2| Recommended HPV vaccination age and dose schedules of various countries

Vaccine type Target age group Dose schedule Special comments


Australia (www.hpvvaccine.org.au)
Quadrivalent Girls and boys 12-13 years old 3 doses (0, 2, 6 months) Used in school-based national HPV
vaccination programme
Austria (www.hpvcentre.net/statistics/reports/AUT.pdf)
Quadrivalent Girls and boys 9 years old 2 doses (0, 6 months) National vaccination programme
Canada (www.immunizebc.ca/diseases-vaccinations/hpv)
Bivalent Girls 9-14 years old 2 doses (0,6 months)
Girls 15-<27 years old 3 doses (0,1,6 months)
Women 27 years old with high risk
Quadrivalent Girls and boys 9-13 years old 2 doses (0, 6 months or 0, 12 months)
Girls and boys 14-<27 years old 3 doses (0, 2, 6 months)
Women and men 27 years old with high risk
MSM <27 years old
Nonavalent Girls and boys 9-<27 years old 3 doses (0,2,6 months)
Women and men 27 years old with high risk
MSM <27 years old
Denmark (www.ssi.dk/English/PublicHealth/Vaccination/The%20Danish%20Childhood%20Vaccination%20Programme/Q%20and%20A/HPV%20Vaccination.
aspx)
Bivalent Girls 12-13 years old 2 doses (0, 6 months) Part of childhood immunisation
programme
Grils 14-18 years old 3 doses (0,2,6 months)
Hong Kong (www.cervicalscreening.gov.hk/english/hum/hum_ccv.html)
Bivalent Girls 9-14 years old 2 doses (0, 6 months)
Girls 15 years old 3 doses (0, 1, 6 months)
Quadrivalent Girls and boys 9-13 years old 2 doses (0, 6 months)
Girls and boys 14 years old 3 doses (0, 2, 6 months)
Nonavalent Girls and boys 9-14 years old 2 doses
Girls and boys 15 years old and above 3 doses
Japan (government withdrew recommendation for HPV vaccine in 2013 due to controversies15)
Korea (www.hpvcentre.net/statistics/reports/KOR.pdf)
Bivalent Girls 11-12 years old 3 doses (0, 1, 6 months) Part of national immunisation
programme
Girls 9-14 years old (alternative) 2 does (0, 6 months)
Quadrivalent Girls 11-12 years old 3 doses (0, 2, 6 months)
Girls 9-13 years old (alternative) 2 doses (0, 6 months)
Malaysia (www.myhealth.gov.my/en/immunisation-schedule/)
Quadrivalent Girls 13 years old 2 doses (0, 6 months) Part of national HPV immunisation
programme
Singapore (www.healthhub.sg/live-healthy/312/HPV_immunisation_FAQ)
Bivalent Girls 9-13 years old 2 doses (0, 6 months)
Girls 14- 25 years old 3 doses (0, 1, 6 months)
Quadrivalent Girls 9-13 years old 2 doses (0, 6 months)
Girls 14-26 years old 3 doses (0, 2, 6 months)
South Africa (www.hpvcentre.net/statistics/reports/ZAF.pdf)
Bivalent Girls 9-14 years old 2 doses (0, 5-7 months)
Girls 15 years old and above 3 doses (0, 1, 6 months)
Quadrivalent Girls and boys 9-13 years old 2 doses (0, 6 months)
Girls and boys 14 years old and above 3 doses (0, 2, 6 months)
Sweden, www.norrbotten.se/upload/pv/stpv/HPV-vaccination/Vaccination_blad_HPV_foraldrar_engelska.pdf
Quadrivalent Girls 10-12 years old 3 doses (0, 2, 6 months) Part of national school-based
vaccination programme
Taiwan (http://shmc.osa.ntu.edu.tw/en/policlinic/policlinic4)

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PRACTICE

Table 2 (continued)

Vaccine type Target age group Dose schedule Special comments


Bivalent Girls 10-25 years old 3 doses (0, 1, 6 months)
Quadrivalent Girls 9-26 years old 3 doses (0, 2, 6 months)
UK (www.nhs.uk/Conditions/vaccinations/Pages/hpv-human-papillomavirus-vaccine.aspx)
Quadrivalent Girls 12-13 years old 2 doses (0, 6 months) For girls 12-13 years old, part of
NHS childhood vaccination
Girls 15 years old 3 doses (0, 2, 6 months)
programme
US (www.cdc.gov/hpv/hcp/index.html)
Quadrivalent and nonavalent Girls and boys 11-12 years old 2 doses (6-12 months apart) or 3 doses (0, 2, If 2 doses <5 months apart, 3rd dose
Girls and boys 15 years old 6 months) to be given
11-12 years is recommended age of
vaccination

MSM = Men who have sex with men.

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PRACTICE

Figure

Fig 1 Sequelae of HPV infection and preventive strategies

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