Control de la ejecución

I took a systematic approach to the following literature review including a comprehensive systematic search of databases, systematic application of exclusion and inclusion criteria and systematic narrative synthesis of findings. This was not a formal systematic review because of lack of dual study inclusion/exclusion and data extraction. In addition, I did not undertake hand searching of key journals, or searches of conference proceedings or theses.

Four electronic databases were searched: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and ISI Web of Knowledge/Science. A comprehensive search strategy was developed using the following indexing terms (MeSH) to search Medline and Embase: ‘papillomavirus vaccines.mp. or exp Papillomavirus Vaccines/’, ‘human papilloma virus vaccines.mp.’, ‘human papilloma virus.mp.’, ‘hpv.mp.’, ‘exp Vaccination/ or exp Mass Vaccination/ or vaccination.mp.’, ‘exp Immunization/ or immunisation.mp. or exp Immunization Programs/’, ‘immunization.mp.’, ‘vaccin*.mp.’, ‘great britain.mp. or exp Great Britain/’, ‘exp Europe/ or europe.mp.’, ‘uptake.mp.’. I used similar search terms in both Medline and Embase. The terms and search strategies used were adapted accordingly for the other two databases, CINAHL and Web of Knowledge/Science. The search strategy for each database is presented in Appendix 1 (including Table 1, Table 2 and Table 3). Abstracts were saved using EndNote basicX7. There were no restrictions placed on the language of publication.

The PRISMA4 flow diagram in Appendix 1 depicts the flow of information through the different phases of this review. It maps out the number of records identified, included and excluded, and the reasons for exclusions. The review inclusion criteria were in

4

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relation to the populations, interventions, outcomes and types of studies. Inclusion criteria in relation to outcome and interventions were uptake of HPV vaccine (both quadrivalent and bivalent vaccine) provided in any setting (public/private healthcare sector as well as public/ private education sector) in Europe. Only studies conducted in Europe were considered for review because of several reasons. European countries introduced the HPV immunization programme almost at the same time around 2007 – 2008. The implementation of the HPV programme was supported by exchange of experience between European countries. The UK is part of Europe and it was intended to make a comparison between the HPV programme rolled out in the UK and the other European countries. Studies were eligible if HPV vaccine uptake one dose or two doses or all three doses in young women aged 9-26 years were reported. The searches were carried out between 2011 and 2012 and included literature dating from 2007 to 2012. The search was limited to 2007 because the HPV vaccination programme was firstly implemented in some European countries at that time. No restrictions were set according to study design. Both quantitative and qualitative studies were included. The review exclusion criteria were in relation to any country which implemented the HPV vaccination programme but was not in Europe (for example, the US, Australia, Canada and the developing countries in other parts of the world).

Studies reporting attitudes/intention to receive the HPV vaccine were excluded as well as those studies related to awareness/knowledge about HPV vaccine, epidemiology of HPV infection, genital warts, cervical cancer, cervical cancer screening, only HPV vaccine, HPV vaccine and boys, cost effectiveness of HPV vaccine and modeling analyses, HPV vaccine and media, STIs, vaccination/immunization, sexual health. Study selection was conducted in two stages: Initially, I assessed titles and abstracts of all identified studies according to the above mentioned inclusion criteria. Then, I included and I assessed twelve relevant full texts in English. The review is based on

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these twelve studies of uptake of HPV vaccine in Europe. I undertook a narrative synthesis because of heterogeneity of study design, participants, and outcomes.

Some studies reported vaccination rates while others looked at the factors associated with the uptake. A summary of HPV vaccination uptake across European countries indicates that the uptake of one or more doses of HPV vaccine by routine and catch-up cohorts at local and national level varied from 4% to 81% between 2007 and 2010 (Table 8) although WHO recommended coverage of 70% of the target population (World Health Organization, 2008).

Table 8. Uptake of HPV vaccine in European countries by dose, by age group and by year Location Number of doses Proportion of vaccinated girls/adolescent females

Age range Year

Portugal (Dorleans et al., 2010) Not reported 81% 56% 13 years old 17 years old 2009 2009 United Kingdom (Dorleans et

al., 2010)

Not reported

80% 12-13 years old 2009

32% 13-17 years old 2009

Denmark (Dorleans et al., 2010) Not reported 58% 73% 12 years old 15-17 years old 2010 2010 Italy (Dorleans et al., 2010) Not

reported

56% 11 years old 2009

Belgium - Flanders (Lefevere et al., 2011)

1 dose 53% 12-18 years old 2007-2009

Netherlands (Rondy et al., 2010)

1 dose 49.9% 13-16 years old 2009

Switzerland - Geneva (Jeannot et al., 2011)

3 doses 41.6% 11-21 years old 2007-2009

France - Paris (Rouzier and Giordanella, 2010)

3 doses 43% 14-23 years old Not

reported France (Lutringer-Magnin et al., 2011) Not reported 38% Not reported 2008-2010

Norway (Dorleans et al., 2010)

Not reported

30% 12 years old 2010

Luxemburg (Dorleans et al., 2010) Not reported 17% 29% 12 years old 13-18 years old 2009 2009 Sweden (Dahlstrom et al.,

2010)

Not reported

13% Not reported Not

reported Greece - Athens (Sakou et al.,

2011)

Not reported

11.9% 11-19 years old Not reported Austria (Schneider, 2010) Not

reported

4% Not reported Not

reported ()=reference

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The review presents the results of studies which addressed common determinants of HPV vaccine uptake.

Two studies showed a significant association between age and the HPV vaccine uptake [1 dose (p-value=0.000) (Rondy et al., 2010) and 3 doses (p-value<0.001) (Rouzier and Giordanella, 2010)]. A study (Lefevere et al., 2011) reported that the hazard of HPV vaccination (1 dose) was higher for older girls (20 years old) (HR5=19.39; CI=17.47- 21.52) than younger girls (13 years old) (HR1=0.23; CI=0.20-0.25). However, two studies (Fagot et al., 2011; Jeannot et al., 2011) showed lower HPV vaccine uptake (3 doses) in catch-up cohorts than in routine cohorts.

Four studies using correlation and multivariate analyses reported a significant association between ethnicity (measured by UK Census or country of birth) and low HPV vaccine uptake (1-2 doses) in routine and catch-up cohorts (Rondy et al., 2010; Roberts et al., 2011; Widgren et al., 2011; Kumar and Whynes, 2011). Two out of four studies showed imprecise effects of ethnicity because of small number of participants (Roberts et al., 2011; Widgren et al., 2011). One study out of four (population based) (Rondy et al., 2010) found a significant association of low HPV vaccine uptake (1 dose) and ethnicity (measured by country of birth). The lowest uptake was reported for girls having both parents born in a different country than the country of residence (p- value=0.000).

Four studies found a significant association between uptake of HPV vaccine and uptake of MMR (Rondy et al., 2010; Roberts et al., 2011; Widgren et al., 2011; Kumar and Whynes, 2011). Only one out of four studies (Rondy et al., 2010) adjusted for confounders and showed that the likelihood of HPV vaccine uptake was 6.26 higher for

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those who have received a previous MMR6 (NHS Choices, 2013a) (measles, mumps and rubella) than those who have not received it (CI=5.87-6.68; p-value=0.000).

Two studies showed a significant association between low uptake of the HPV vaccine (2 doses) and deprivation (measured by IMD) in routine (Roberts et al., 2011) and catch-up cohorts (Kumar and Whynes, 2011). Similarly, one study reported a significant association of low HPV vaccine uptake (1 dose) and socioeconomic level (based on income estimation at postcode level) (p-value=0.000) (Rondy et al., 2010). Another study found that the hazard of the HPV vaccination (1 dose) was higher for girls with a higher socioeconomic level (based on median income of the neighborhood) (HR=1.10; CI=1.07-1.12) (Lefevere et al., 2011).

Included studies were critically appraised according to Cochrane methodology to identify the strengths and the factors which may have introduced bias or limited the generalizability of the results. The strength of the studies came from the use of an HPV vaccine register (Rondy et al., 2010; Widgren et al., 2011), the measures to increase response rate (Rondy et al., 2010), the techniques to increase the validity of the findings [i.e., triangulation (Mortensen, 2010)], the adjustment for confounders (Rondy et al., 2010; Lefevere et al., 2011; Roberts et al., 2011; Widgren et al., 2011; Chadenier et al., 2011) and large sample size including eligible girls for the HPV vaccine (between 435 and 4.2 million).

Methodological problems included variation in reported HPV vaccine uptake: unknown dose (Mortensen, 2010; Sakou et al., 2011; Dorleans et al., 2010), 1 dose (Rondy et al., 2010; Lefevere et al., 2011; Widgren et al., 2011), 2 doses (Roberts et al., 2011; Kumar

6

MMR is a vaccine that protects against three infectious diseases – measles, mumps and rubella. The vaccine is given routinely to children in two doses and is administered as a single injection. The first dose is administered when babies are 12 and 13 months old and the second dose is given to pre school children aged 3- 5 years. In case of measles outbreak it is reccomemnded that MMR vaccine should be given to babies who are over 6 months old to older children and adults.

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and Whynes, 2011; Brabin et al., 2008), and 3 doses [(Rouzier and Giordanella, 2010; Fagot et al., 2011; Jeannot et al., 2011; Chadenier et al., 2011). Some studies were conducted soon after the start of the programme (Roberts et al., 2011; Brabin et al., 2008) and reported the initiation of HPV vaccination with one-two doses although WHO guidelines indicate that three doses are effective. Reporting of the HPV vaccine uptake rates varied e.g. using reimbursement data (Rouzier and Giordanella, 2010; Lefevere et al., 2011; Fagot et al., 2011), a local health authority dataset (Chadenier et al., 2011), a PCT7 (Roberts et al., 2011; Kumar and Whynes, 2011; Brabin et al., 2008), or a state health office (Jeannot et al., 2011), introducing the possibility of bias. Reimbursement data might not indicate the actual uptake. The use of aggregate data (Rondy et al., 2010; Kumar and Whynes, 2011) could introduce an ecological fallacy.

There was inconsistency of classification of ethnicity across studies because of insufficient data (not recorded in health system) or different definitions across countries (Rondy et al., 2010; Roberts et al., 2011; Widgren et al., 2011). Varying measures of socioeconomic level were used based on area indicators (Rondy et al., 2010; Lefevere et al., 2011; Roberts et al., 2011; Kumar and Whynes, 2011; Brabin et al., 2008). No study measured socioeconomic level by individual income, education or occupation.

Although studies were large, some findings could not be generalized beyond the study population because of limitations of datasets [missing data, loss of follow up for 3 doses

7

Primary care trusts (PCTs) were organizational structures of NHS and were responsible for management, delivery of and access to health and social care services to people in their geographic area according to people’s needs. PCTs controlled 80% of the NHS budget (NHS Choices, 2013b). It planned and purchased healthcare services for local populations (NHS England, 2014). A range of services were provided at primary care level through GPs, dentists, opticians, pharmacists, screening, mental health services, NHS walk-in centres, NHS Direct, patient transport (including accident and emergency). PCTs commissioned hospital services also.

There were 152 PCTs in England. In April 2013, they were replaced with 211 Clinical Commissioning Groups (CCG) (NHS England, 2014). and local area teams (LATs). which have taken the responsibility to commission hospital and community NHS services for the people in their area (NHS Choices, 2013b).

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(Rondy et al., 2010; Fagot et al., 2011; Widgren et al., 2011)] or participants’ low response rate (Roberts et al., 2011).

In summary, the quality of included studies limits the conclusions which could be drawn about the determinants of the HPV vaccine uptake and their effect size. There were inconsistent results related to the association between the HPV vaccine uptake and girls’ age and ethnicity. It appeared consistently that low HPV vaccine uptake was associated with deprivation and childhood vaccination uptake respectively.

There was a gap in literature related to the influence of ethnicity on HPV vaccine uptake due to inconclusive evidence.

2.4. Summary

Human papillomavirus is considered the commonest agent of STIs. It affects a high proportion (70%) of sexually active women and men during their lifetime, usually shortly after sexual debut. Almost all cervical cancer cases are linked with genital infection with HPV. Two HPV types (16 and 18) are thought to be responsible for 70% of cervical cancer cases worldwide. The period between infection with HPV and the development of cervical cancer varies from one year to one decade.

The European Medicines Agency has licensed two HPV vaccines: a quadrivalent vaccine and a bivalent vaccine which are safe, effective and cost-effective for prevention of cervical cancer for females aged 9 to 26. Only quadrivalent vaccine protects additionally against most genital warts in females and males and cancers of the vulva, vagina, and anus. Ideally, females should be vaccinated before the onset of sexual activity with three doses of vaccine. Currently it is known that the duration of vaccine-induced immunity is “at least” 5 - 6 years. Vaccinating girls is more cost effective than vaccinating boys.

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In Europe, the vaccine was implemented at national level based on evidence related to burden of disease, safety, efficacy, effectiveness (anticipated impact on precancerous and cancerous lesions) and cost-effectiveness of vaccine, existence or lack of cervical cancer screening and vaccine acceptability by adolescents and their parents as well as by health professionals. European countries adopted HPV vaccination policies, which vary in relation to target population, vaccine delivery strategies and health services infrastructure. Two target populations were established for HPV vaccination, which was integrated in the national immunization programme: a routine and a catch-up group. The routine and catch-up HPV vaccination was provided in the public sector (i.e., in schools, health professionals’ practices, public health clinics) and/or in the private sector, but only in some countries was it free of charge.

A literature review that addressed common determinants of the HPV vaccine uptake showed the HPV vaccine uptake a gap in relation to the influence of ethnicity and girls’ age on HPV vaccine uptake due to inconclusive evidence.

In the next chapter, I discuss access to health services with emphasis on barriers faced by different ethnic groups mostly in the UK.

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CHAPTER 3: PART 1 PRINCIPLES AND