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Cancer Epidemiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Cancer Epidemiology
The International Journal of Cancer Epidemiology, Detection, and Prevention
journa l homepage: www.cancerepidemiology.net
$
European Code against Cancer 4th Edition: Infections and Cancer
a a,1 a a
Patricia Villain , Paula Gonzalez , Maribel Almonte , Silvia Franceschi ,
b,c d a a a,
Joakim Dillner , Ahti Anttila , Jin Young Park , Hugo De Vuyst , Rolando Herrero *
a
International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
b
Department of Laboratory Medicine, Karolinska Institutet, Nobels väg 12A, 171 77 Stockholm, Sweden
c
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 77 Stockholm, Sweden
d
Finnish Cancer Registry, Unioninkatu 22, FI-00130 Helsinki, Finland
A R T I C L E I N F O A B S T R A C T
Article history: Of the 2,635,000 new cancer cases (excluding non-melanoma skin cancers) occurring in the European
Received 22 May 2015
Union (EU) in 2012, it is estimated that approximately 185,000 are related to infection with human
Received in revised form 1 October 2015
papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV), and Helicobacter pylori (H. pylori).
Accepted 6 October 2015
Chronic infection with these agents can lead to cancers of the cervix uteri, liver, and stomach,
Available online xxx
respectively. Chronic infection with HCV can also lead to B-cell non-Hodgkin lymphoma. Human
immunodeficiency virus (HIV) infection continues to be of major public health importance in several EU
Keywords:
countries and increases cancer risk via HIV-induced immunosuppression. The fourth edition of the
Cancer vaccines
European Code Against Cancer presents recommendations on effective and safe preventive interventions
Human papillomavirus vaccines
in order to reduce the risk of infection-related cancers in EU citizens. Based on current available
Hepatitis B vaccines
Hepatitis B/C treatments evidence, the fourth edition recommends that parents ensure the participation of their children in
‘ ’
Helicobacter pylori vaccination programs against HBV (for newborns) and HPV (for girls). In the Questions and Answers
HIV (Q&As) section about vaccination and infections in the website for the European Code Against Cancer,
Cervical cancer
individuals who are at risk of chronic HBV or HCV are advised to seek medical advice about testing and
Hepatocellular carcinoma (HCC)
obtaining treatment when appropriate. Individuals most at risk of HIV are advised to consult their doctor
Gastric cancer
or healthcare provider to access counselling and, if needed, testing and treatment without delay.
Europe
Information about H. pylori testing and treatment is also provided as testing might currently be offered in
some high-risk areas in Europe. The rationale and supporting evidence for the recommendations on
vaccination in the European Code Against Cancer, and for the main recommendations on vaccination and
infection in the Q&As, are explained in the present review.
ã 2015 International Agency for Research on Cancer; Licensee ELSEVIER Ltd https://creativecommons. org/licenses/by-nc-nd/3.0/igo/
1. Introduction
The population-attributable fraction (PAF) for cancer-related
infections in more highly developed countries has been estimated
to be 7.4% [1]. In 2012, approximately 195,000 of 2,635,222 new
$
cancer cases (excluding non-melanoma skin cancers) occurring in
This is an Open Access article published under the CC BY NC ND 3.0 IGO license
which permits users to download and share the article for non-commercial the European Union (EU) [2] are estimated to be infection-related
purposes, so long as the article is reproduced in the whole without changes, and
[1]. Human papillomaviruses (HPVs), hepatitis B virus (HBV),
provided the original source is properly cited. This article shall not be used or
hepatitis C virus (HCV), and Helicobacter pylori (H. pylori) account
reproduced in association with the promotion of commercial products, services or
for approximately 95% of these cases [1]. Because of the
any entity. There should be no suggestion that IARC endorses any specific
fi
organisation, products or services. The use of the IARC logo is not permitted. This immunosuppression induced by human immunode ciency virus
’
notice should be preserved along with the article s original URL. (HIV), this virus should be also considered a cause of infection-
* Corresponding author.
related cancers in the EU. Current available evidence has been
E-mail address: [email protected] (R. Herrero).
1 reviewed here to recommend – in the fourth edition of the
Permanent address: Proyecto Epidemiológico Guanacaste, Fundación
European Code Against Cancer and related ‘Questions and
INCIENSA, Solarium bodega 8C, Liberia, Guanacaste, Costa Rica.
http://dx.doi.org/10.1016/j.canep.2015.10.006
1877-7821/ã 2015 International Agency for Research on Cancer. Licensee ELSEVIER Ltd https://creativecommons.org/licenses/by-nc-nd/3.0/igo/
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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CANEP 930 No. of Pages 19
2 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
Answers’ (Q&A) – effective and safe interventions for EU citizens to regional disparities still exist, with high rates in Central and
reduce their risk of infection-related cancers. Eastern countries of the EU (ASIR 28.6 in Romania, 26.1 in
Lithuania, 24.5 in Bulgaria, 16.1 in Slovakia and 12.2 in Poland)
2. Human papillomaviruses compared to other EU countries where the estimated ASIR was 10.6
(Denmark) or lower (Fig. 1) [18]. Mortality rates follow a similar
2.1. Role in cancer pattern (Fig. 1) [18].
Twelve HPV types – HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 2.2. HPV vaccines
and 59 – were classified by the International Agency for Research
on Cancer (IARC) Monographs Program as Group 1 (i.e., firmly 2.2.1. Scientific justification of the European Code Against Cancer
established) human carcinogens, and a few other types were recommendation
classified as probably or possibly carcinogenic [3]. Cancers caused
by HPV include all cancers of the cervix, most anal cancers (88%), 2.2.1.1. Efficacy and safety of HPV vaccines. Two prophylactic
and less well identified portions of vaginal (70%), vulvar (43%), vaccines against HPV are currently marketed internationally and in
penile (50%), and oropharyngeal cancers (26%) [1,4]. HPV16 and the EU/European Economic Area (EEA) (which as of July
18 account together for about 70% of cervical cancers in every 2013 includes EU-28 and Iceland, Lichtenstein and Norway);
world region [5]. In HPV-positive cancers of other anatomical sites, these include the bivalent vaccine produced by GlaxoSmithKline
1
HPV16 is also the most common HPV type, being found in about (Cervarix ), and the quadrivalent vaccine produced by Merck
1
60% of vaginal [6], 80% of anal [7], 60% of penile [8] and 95% of (Gardasil ), both of which originally had a three-dose schedule for
oropharyngeal [9] cancers. HPV6 and 11 have been classified as girls (see below).
Group 3 agents (i.e. “not classifiable as to its carcinogenicity to The two vaccines are based on virus-like particles (VLPs)
humans”) by the IARC Monographs Program, but are responsible produced by expression in insect cells (bivalent vaccine) or yeast
for almost 100% of genital warts and recurrent respiratory (quadrivalent vaccine) of the HPV L1 gene, encoding the main
papillomatosis [3,10]. component of the viral capsid. These VLPs are not infectious but are
The natural history and molecular mechanisms involved in highly antigenic: they produce a strong antibody response that
cervical carcinogenesis are well understood [10,11], and effective prevents infection by neutralizing infectious virions in the mucosa
screening methods exist to detect precancerous lesions of the at the time of contagion [19]. The bivalent vaccine includes
cervix (see Armaroli et al., this issue, 2015). HPV is considered a HPV16 and 18 VLPs and is produced with a complex adjuvant
necessary cause of cervical cancer [3]. Cervical HPV infection is system (ASO4) consisting of monophosphoryl lipid A and alum.
primarily transmitted by mucosal contact, usually during sexual The quadrivalent vaccine, produced with alum adjuvant, includes
intercourse. It is very common in young women after the onset of HPV16 and 18 VLPs and also HPV6 and 11 VLPs.
sexual activity, with peak prevalence among women under For the first time in 2009, the World Health Organization
25 years of age [11–13]. The majority of HPV infections, often (WHO) recommended the introduction of HPV vaccination into
associated with minor epithelial abnormalities, clear spontane- national immunization programs, targeting 9–13-year-old girls
ously within a few years [12,13]. Persistent HPV infection may lead (i.e. before the onset of sexual activity) with a three-dose regimen
to precancerous lesions – cervical intraepithelial neoplasia (CIN) 2 [20]. Evidence available up to September 2008 from the three main
and 3 – around the mean age of 35–42 years, a proportion of which randomized controlled trials (RCTs) at that time (i.e. FUTURE 1 and
will progress, if not treated, to invasive cervical cancer over a FUTURE 2 for the quadrivalent vaccine; PATRICIA for the bivalent
period of 10–20 years [11–13]. The risk for persistence and vaccine) and immunobridging studies were used to support this
progression to cancer precursor lesions varies by HPV type, host recommendation. Immunogenicity studies showing that antibody
factors and the presence of cofactors [12,13]. Cofactors include response to the two licensed vaccines is stronger in adolescent girls
smoking, immunosuppression, high parity and hormonal con- (aged 10–14 years) than in young adult women (aged 15–25 years)
traceptive use [3,14–16]. By specifically targeting women at the age [21–23] permitted bridging of efficacy data to adolescent girls.
of risk of developing CIN 2/3 and cervical cancers, well-organized Recently, WHO updated its HPV vaccines position paper [24] to
cervical cancer screening programs have been able to prevent four recommend a two-dose regimen with increased flexibility in the
out of five cervical cancers [17] (Armaroli et al., this issue 2015). interval between doses (see below).
Compared to other HPV-related cancers, cervical cancer is the The evidence on HPV vaccination was updated in the European
most common [4]. It is the fourth most common cancer in women Code Against Cancer using the methodology described in greater
worldwide, with an estimated 528,000 new cases and detail in this issue (see Minozzi et al., this issue 2015). The Medline,
266,000 deaths in 2012, of which 87% occurred in the more Embase, PsycINFO and Cochrane Library databases were searched
poorly developed regions [18]. The estimated age-standardized to identify systematic reviews (SRs) on the efficacy and safety of
mortality rate (ASMR) ranged from about 2/100,000 in developed HPV vaccines in women; two SRs were selected [25,26]. Additional
1
regions (such as Western Europe ) to more than 20/100,000 in scientific publications identified by the experts were also included
some less developed regions [18]. (as detailed below) to complete the evidence. Due to the relatively
Cytology-based cervical cancer screening has resulted in a low number of RCTs on efficacy and safety of HPV vaccines in men,
substantial reduction in cervical cancer incidence in the EU, with individual studies on this topic were directly searched using the
an age-standardized incidence rate (ASIR) in 2012 of 9.6/100,000 Cochrane Central Register of Controlled Trials (CENTRAL), and six
(33,679 new cases and 13,136 deaths). However, important articles [27–32] were selected from the publications retrieved.
In women, the totality of the evidence reviewed is in line with
the WHO recommendation with regard to both efficacy and safety;
1
As defined by the WHO, countries in Western Europe include: Andorra, Austria, both vaccines were shown to be safe, generally well tolerated, and
Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, almost 100% effective in preventing persistent cervical HPV16/
Luxembourg, Malta, Monaco, Netherlands, Norway, Portugal, San Marino, Spain,
18 infections and associated precancerous lesions – CIN2 or 3 (CIN2
Sweden, Switzerland, and the United Kingdom. Countries in Central Europe include:
+) and adenocarcinoma in situ (AIS) – among young women (mean
Albania, Bosnia & Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Hungary,
age of approximately 20–22 years) not previously infected at the
Former Yugoslav Republic of Macedonia, Montenegro, Poland, Romania, Serbia,
Slovakia, Slovenia and Turkey. time of vaccination [25,33–37]. No results from longitudinal
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx 3
Fig. 1. Estimates of cervical cancer incidence and mortality in the 28 member states of the European Union. Age-standardized rates (ASR) in 2012, adjusted to the World
standardized population (W). Adapted from Ferlay et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France:
International Agency for Research on Cancer; 2013. Available at: http://globocan.iarc.fr (accessed on 26.03.2015).
follow-up studies are yet available on the magnitude of the effects types [27,31]. RCT results and immunobridging studies [22,27,31]
on cervical or other cancers. strongly suggest that, as in women, it would be more effective to
The vaccines were also shown to prevent infections and CIN1+ vaccinate young men before they become sexually active.
in women >25 and 45 years [38–40] who are naïve to the vaccine- RCTs conducted essentially prior to vaccine licensure provide
related HPV types, but the frequency of CIN2/3 was much lower in evidence of an excellent safety profile for both vaccines [27–29]
this age group than among younger women. (reviewed in [46]). Pooled analysis of safety data from the
In non-cervical sites, the quadrivalent vaccine has been shown quadrivalent vaccine RCTs [47] or the bivalent vaccine [48] showed
to prevent the majority of vulvar and vaginal HPV infections and no significant difference between the vaccinated and the control
lesions associated with HPV16 and 18, as well as genital warts group in terms of occurrence of serious adverse events or deaths.
caused by HPV6 and 11, as reviewed recently [19]. The bivalent Further data are also available from passive and active post-
vaccine has been shown to prevent anal, oral and vulvar HPV16/ licensure safety surveillance of HPV vaccines. This is an important
18 infections in young women [41–43]. component of the overall safety assessment of vaccines, as rare or
Both vaccines also afford limited protection against non- unexpected adverse events can be detected which may not have
vaccine HPV types phylogenetically related to HPV16 and 18. A been evident in clinical trials due to their limited sample size.
6-month cross-protection has been reported against Passive surveillance activities are designed to systematically
HPV31 persistent infection for the quadrivalent vaccine and collect post-vaccination adverse events [49,50]. For HPV vaccines,
against HPV31, 33, 45 and 51 persistent infections for the bivalent the minor adverse events most commonly reported through
vaccine among HPV-naïve women [25,26,35,44,45]. Efficacy passive surveillance are injection site reactions, headache and
against persistent infections with types 31 and 45 seemed to dizziness [46,51,52]. Moreover, while a variety of serious outcomes
decrease in bivalent vaccine trials with increased follow-up [26], and deaths have been reported, none has been attributed to the
suggesting a waning of cross-protection over time. The significance vaccines [46].
of early protection against these additional types is not clear and Active surveillance activities involve population-based post-
needs to be monitored over the long term. licensure clinical studies [49]. Concerns have been raised that HPV
Among young men (16–26 years of age) naïve to vaccine-related vaccines might be associated with such adverse events as
HPV types, the quadrivalent vaccine has been shown to prevent miscarriages, syncope, anaphylaxis, venous thromboembolism
persistent anogenital infection with HPV vaccine types, external and autoimmune diseases such as multiple sclerosis, cerebral
genital lesions including penile, perianal, or perineal intraepithe- vasculitis, Guillain–Barré syndrome or chronic pain conditions, but
lial lesions, including genital warts [28]. The quadrivalent vaccine these safety outcomes have been evaluated in population-based
has been demonstrated to prevent anal intraepithelial neoplasia studies and, to date, no association between HPV vaccines and such
among men who have sex with men [30]. The quadrivalent and conditions has been identified [46,51]. These results have been
bivalent HPV vaccines were highly immunogenic for all vaccine corroborated by reviews of safety data conducted by a number
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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4 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
ofrecognized advisory bodies such as the Institute of Medicine of follow-up, no significant difference in efficacy against HPV16/
which reviewed data on quadrivalent vaccine safety in 2011 [53], 18 persistent infection was observed when one or two doses of
and the WHO Global Advisory Committee on Vaccine Safety vaccine were administered, compared to the recommended three-
(GACVS) which has repeatedly reviewed data on both HPV dose protocol [64]. In addition, several studies have shown that the
vaccines, most recently in March 2014 [54]. The GACVS immunogenicity of two doses of both vaccines, particularly among
Committee has remained reassured by the safety profile of the girls aged 9–14 years and when the doses are separated by
HPV vaccines, and noted the importance of continued surveil- 6 months, is not inferior to that of three doses among women aged
lance and epidemiological investigation with an emphasis on the 15–25/26 years, for which vaccine efficacy has been proven [65,66].
collection of high-quality data. Such data are essential for The Strategic Advisory Group of Experts (SAGE) on immunization
interpretation of any adverse events which may occur following for the WHO has recently reviewed the evidence related to HPV
HPV vaccination. As highlighted in their 2014 report, interpreta- vaccination schedules for both bivalent and quadrivalent vaccines.
tion requires due diligence and great care; allegations of harm Results from a systematic review comparing the effects of two-
being raised on the basis on “anecdotal observations and reports dose and three-dose HPV vaccination [67] were the basis for the
in the absence of biological or epidemiological substantiation” WHO’s recommendation of a two-dose vaccination schedule with
may lead to unacceptable harm when “as a result, safe and a 6-month interval for both the bivalent and the quadrivalent
effective vaccines cease to be used” [54]. As an example of such vaccines if administered before age 15. There is no maximum
harm, the media coverage of adverse events of HPV vaccines in recommended interval between doses, but if the interval between
November 2013 in France raised concerns about HPV vaccine doses is shorter than 5 months a third dose is recommended at
safety, and had a negative impact on vaccination coverage; the least 6 months after the first dose. The WHO also recommends
proportion of mothers who did not wish to vaccinate their girls prioritizing vaccination of the primary target population of young
increased significantly after November 2013: 23% in September– girls 9–13 years of age (for full details of the WHO position see
November versus 35% in December 2013 [55]. [24]).
2.2.1.2. Duration of protection: long-term effect and 2.2.1.4. State of HPV vaccination in Europe. As of early 2014,
effectiveness. The longest duration of efficacy of the vaccines 21 countries (Austria, Belgium, Bulgaria, Czech Republic, Denmark,
reported to date is approximately 8–10 years for a three-dose Finland, France, Germany, Greece, Ireland, Italy, Latvia,
vaccine schedule [56]. Studies – including linkage to cancer Luxembourg, Malta, the Netherlands, Portugal, Romania,
registries – are ongoing to monitor the population impact of HPV Slovenia, Spain, Sweden and the United Kingdom) of the 28 EU
vaccination. Cross-sectional studies of women aged 18–24 years Member States have included HPV vaccination in their national
who received Pap screening in family planning clinics throughout immunization schedules [68,69]. The age group targeted by these
Australia showed a 77% decrease in prevalence of HPV types programs varies from one country to another, but it commonly
targeted by the quadrivalent vaccine from the period before includes 11–13-year-old girls [68,69]. Currently available data on
(2005–2007) to the period after the vaccine was widely three-dose HPV vaccination coverage in the EU indicate that
implemented (2009–2010) [57]. The impact of HPV vaccination coverage varies widely between countries and is rarely optimal; for
on the incidence of genital warts has been reported also for example, coverage is low in Luxembourg (17%) and France (29%),
Australia [58,59] and recently for Sweden [60], showing a dramatic medium in Italy (66%) and in the Netherlands (56%), and high in
reduction in the incidence of genital warts in the HPV-vaccinated some countries such as the United Kingdom (80%) and Portugal
cohorts. It will probably be possible to determine the attributable (81%) [68]. Variance in coverage across the EU can be explained by
reduction in the incidence of cervical and other HPV-related different vaccine implementation policies and/or different
cancers only after several decades. reporting systems [69,70]. Modelling suggests that additional
HPV vaccination does not eliminate the need for effective implementation of catch-up vaccination for girls older than the
cervical cancer screening in the HPV-vaccinated cohorts (Armaroli primary target population may not enhance the long-term
et al., this issue 2015), mainly because the vaccines do not protect population effectiveness of vaccination against HPV16/
against all oncogenic HPV types. However, vaccination has the 18 infection. It may, however, shorten the period within which
potential to greatly decrease the intensity, cost, and morbidity population effectiveness is reached by 2–5 years [71]. Of the 21 EU
associated with screening, and in the future the impact on countries mentioned above, 11 (Belgium, Denmark, Finland,
screening may be even greater; the FDA has in December France, Italy, Luxembourg, the Netherlands, Portugal, Romania,
2014 approved the HPV9-valent vaccine (Merck, Gardasil 9), Sweden and the United Kingdom) have also introduced catch-up
which is produced using the same technology and adjuvant as the programs. In several of these 11 countries, catch-up is offered to
quadrivalent vaccine and includes HPV16, 18, 6, 11, 31, 33, 45, 52 girls and women aged around 14–18 years who have not previously
and 58 VLPs [61]. Sanofi Pasteur has recently (June 2015) received been vaccinated [68].
approval from the European Medicines Agency (EMA) for The EMA has also granted marketing authorizations for
1 1
marketing Gardasil 9 in the EU [62]. This vaccine has the potential Cervarix and Gardasil in the EU/EEA for a two-dose schedule
to prevent approximately 90% of cervical, vulvar, vaginal and anal administered by injection at a 6-month interval for girls aged 9–
cancers in women caused by the vaccine HPV types. 14 and 9–13 years respectively. If the respective vaccines are
By specifically targeting young girls for vaccination before HPV administered at an older age, the three-dose schedule should be
infection, and women for screening at the age of risk of used (for full details see [72,73]). Some countries, such as France
developing cervical cancers, these two strategies have the and the UK, have already implemented a two-dose HPV vaccina-
potential to yield a greater benefit when implemented together tion policy. With the exception of Austria [74], vaccinating mid-
rather than separately; however, their implementation should be adult women (>26 years) is not routinely practiced in the national
coordinated in a comprehensive cervical cancer prevention immunization programs; the cost-benefit ratio in this age range is
program [63]. reduced, in part because of the lower incidence of lesions among
women infected by HPV later in life and the lower risk of
2.2.1.3. Number of doses. A study nested in the Costa Rica vaccine progression of these lesions [75,76].
trial was the first to suggest the efficacy of fewer than the Based on results from RCTs and immunobridging studies, the
recommended three doses of the bivalent HPV vaccine: at 4 years national advisory committees on immunization in Australia [77],
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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Canada [78] and the US [79] have recommended including 2.2.2. Key points for the general public, healthcare providers and
vaccination of young men in routine vaccination schedules. Except health policy makers
in Austria [74], vaccination of boys is not currently offered in any Based on the above evidence, the European Code Against Cancer
public health vaccination program in the EU, as it has not been recommends (to parents): “Ensure your children take part in
shown to be cost-effective because of the much lower burden of vaccination programs for human papillomavirus (HPV) (for
HPV-related cancers in men compared to women [80]. It is worthy girls)” (Box 1, no.11).
of note, however, that modelling studies suggest that vaccination
of boys might impact on cervical cancer burden by reducing HPV In the questions and answers (Q&As) dealing with vaccination
circulation in women, especially if high vaccine coverage is not and infections on the European Code Against Cancer website [81],
achieved in girls [71]. However, HPV models are being reassessed the Working Group on Infections and Vaccination in the European
at the moment in some EU countries to take into account new Code Against Cancer project provides additional information that
assumptions: i.e. the new two-dose vaccination schedule and price would be of particular relevance for parents, boys and girls, and
reduction of HPV vaccines. Some EU countries may include young women interested in learning more about what they could
adolescent males and/or men in their current HPV vaccination do to lower the risk of cancer from HPV infection. Key messages
programs in a near future. include:
WHO recommends HPV vaccination for girls aged 9–13. This is
because sexual activity usually begins at later ages, and most
girls (9–13 years old) are therefore unlikely to have already been
Box 1. European Code Against Cancer. infected.
HPV vaccination is highly effective in boys but is currently
12 ways to reduce your cancer risk
offered in only one public health program in the European Union.
1. Do not smoke. Do not use any form of tobacco.
At the moment, parents can choose to have their adolescent sons
2.Make your home smoke free. Support smoke-free
vaccinated at their own expense in consultation with their doctor
policies in your workplace.
or healthcare provider.
3. Take action to be a healthy body weight.
The current vaccines are highly effective in preventing infections
4.Be physically active in everyday life. Limit the time you
with HPV types 16 and 18, the types that cause most cervical and
spend sitting.
5. Have a healthy diet: anal cancers, but they do not prevent infection with all the types
Eat plenty of whole grains, pulses, vegetables and of HPV that may cause cancer. It is very important to remember
fruits. that vaccination will profoundly diminish screening intensity
Limit high-calorie foods (foods high in sugar or fat) but vaccinated women will still need to participate in cervical
and avoid sugary drinks. cancer screening.
Avoid processed meat; limit red meat and foods high
in salt.
6.If you drink alcohol of any type, limit your intake. Not
3. Hepatitis B and hepatitis C viruses
drinking alcohol is better for cancer prevention.
7.Avoid too much sun, especially for children. Use sun
3.1. Role in cancer
protection. Do not use sunbeds.
8.In the workplace, protect yourself against cancer-
HBV and HCV target the liver and replicate in hepatocytes. They
causing substances by following health and safety
instructions. have been classified by the IARC Monographs Program as Group 1
9.Find out if you are exposed to radiation from naturally human carcinogens [3], and chronic HBV and/or HCV infection are
high radon levels in your home. Take action to reduce the most important causes of hepatocellular carcinoma (HCC)
high radon levels. worldwide with an estimated PAF of 77% [82–84]. People who
10. For women:
become chronically infected with HBV and/or HCV (also known as
’
Breastfeeding reduces the mother s cancer risk. If you carriers) are at higher risk of developing chronic liver disease,
can, breastfeed your baby.
progressing from chronic hepatitis to fibrosis, cirrhosis, and finally
Hormone replacement therapy (HRT) increases the
HCC. Hepatitis B or C carriers generally have no noticeable
risk of certain cancers. Limit use of HRT.
symptoms until the liver has been significantly damaged. Cirrhosis
11. Ensure your children take part in vaccination pro-
can be considered a pre-cancerous stage, being found in 80–90% of
grammes for:
patients with HCC [85]. Chronic HCV infection is also a risk factor
Hepatitis B (for newborns)
for B-cell non-Hodgkin lymphoma (NHL) [3]. Direct HCV infection
Human papillomavirus (HPV) (for girls).
of B cells may be involved in this oncogenic process as peripheral-
blood B cells from HCV carriers have been shown to be infected
12. Take part in organized cancer screening programmes
for: with HCV [86]. However, HCV-associated NHL is rare, with an
estimated PAF of 8% worldwide [82].
Bowel cancer (men and women)
HCC represents approximately 80–85% of primary liver cancers
Breast cancer (women)
(PLCs) globally. PLC, roughly equivalent to rates of HCC, is
Cervical cancer (women).
predominant in men, being the fifth most common cancer in that
gender (554,000 cases in 2012, 7.5% of total cancer cases
The European Code Against Cancer focuses on actions
worldwide) and the ninth most common in women (228,000
that individual citizens can take to help prevent cancer.
cases in 2012, 3.4% of total cases) [18]. On account of high lethality,
Successful cancer prevention requires these individual
HCC is the second most common cause of death from cancer
actions to be supported by governmental policies and
actions. worldwide (746,000 deaths in 2012, 9.1% of total deaths) [18]. Most
of the burden of HCC is confined to developing countries; in 2012,
83% of new cases occurred in less developed regions. The regions of
high incidence are Eastern and South-Eastern Asia (ASIR of 31.9/
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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CANEP 930 No. of Pages 19
6 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
100,000 and 22.2/100,000, respectively) for men, and Eastern Asia In Europe, as observed worldwide, when comparing one
and Western Africa (10.2 and 8.1, respectively) for women [18]. In geographic region to another, the contribution of chronic HBV/
the EU, by contrast, estimated incidence rates in men are low in the HCV infection to the etiology of HCC varies between countries [88].
North (AISR of 2.4 and 4.6/100000, respectively, in the Netherlands This variation is linked to the prevalence of chronic HBV/HCV
and the UK) and intermediate in the South (Italy: 11; Portugal: 8.6; infection, which varies widely between the countries in the
Spain: 9.9); some EU countries in the West and East – such as European Union/European Free Trade Association (EU/EFTA) (as of
France (11.3), Luxembourg (10.3) and Romania (9.2) – also have July 2013: EU-28 and Iceland, Lichtenstein, Norway and Switze-
intermediate rates (Fig. 2) [18]. For women in the EU, the estimated land) [89]. Some countries, such as the Northern countries and the
ASIR ranges from 0.9 in the Netherlands to 3.6 in Italy [18]. Given UK, can be considered at low risk for chronic HCV or/and HBV
the very poor prognosis of liver cancer, the geographical patterns of infection (estimated prevalences <1%) and at lower risk for
HCC incidence and mortality are quite similar [18]. infection-related HCC (Fig. 3) [88,89]. For example, in Sweden
+ +
Worldwide, the relative contributions of the major risk factors about 15% of HCC cases are anti-HCV and 3% are HBsAg , while 82%
for HCC – i.e. HBV and/or HCV chronic infection, consumption of are negative for both viruses. In Belgium and the UK about 25% are
+ +
aflatoxin-contaminated maize and groundnuts, and heavy alcohol anti-HCV and 20% are HBsAg , while 45% are negative and 10%
consumption – vary by geographic region [83,84]. Alcohol- positive for both viruses [88,89]. High-risk countries for chronic
associated liver cirrhosis (Scoccianti et al., this issue 2015) is the HBV infection are Greece (estimated prevalence 2.1%) and Romania
+
most important risk factor for HCC in populations with low (5.6%); in Greece about 56% of HCCs are HBsAg and 16% are anti-
+
prevalence of HBV and HCV, as in the United States and Northern HCV , while 25% are negative and 3% positive for both viruses
Europe [84,87]. Aflatoxin exposure is a major risk factor in East and (Fig. 3) [88,89]. High-risk countries for chronic HCV infection are
Southeast Asia and in sub-Saharan Africa, where regulatory control South Italy (i.e. Sicily: 10.4%) and Romania (3.5%) (Fig. 3) [88,89].
is weak [84]. In areas where chronic HBV or HCV infection In the EU/EFTA region, about 4.5 million (HBV) and 5.5 million
endemicity is high – hepatitis B surface antigen (HBsAg) (HCV) adults are carriers [90]. These figures are likely under-
prevalence 8% and anti-HCV >3.5% respectively – chronic HBV estimates; most hepatitis B or hepatitis C carriers are currently
and/or HCV infection is a major risk factor for HCC [83]. The undiagnosed as chronic infection is usually asymptomatic until the
prevalence of chronic HBV infection is highest (HBsAG prevalence late stages of liver damage. Moreover, people at high risk of being
8%) in Southeast Asia, China and sub-Saharan Africa and is also carriers, such as migrant groups from endemic countries and
high in the southern parts of Eastern and Central Europe. elderly people, are generally under-represented in the statistics.
Prevalence of chronic HCV infection is highest (anti-HCV 10%) Reported data suggest that the prevalence of chronic HBV and/or
in Pakistan, Egypt, and Mongolia, and is also high in some parts of HCV infections is higher in migrants from endemic countries than
China, Italy and Japan [84]. in the general population in the EU/EFTA [91]. In some Southern
European countries like Italy, Spain and Portugal, the burden of
Fig. 2. Estimates of liver cancer incidence in men in the 28 member states of the European Union. Age-standardized rates (ASR) in 2012, adjusted to the World standardized
population (W). Adapted from Ferlay et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International
Agency for Research on Cancer; 2013. Available at: http://globocan.iarc.fr (accessed on 26.03.2015).
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx 7
Fig. 3. Hepatitis B and hepatitis C prevalence (%) in the general population by country in Europe, 2000–2009. (a) Hepatitis B surface antigen (HBsAg) prevalence (%). (b)
Hepatitis C (anti-HCV antibody) prevalence (%). From Hahné et al. BMC Infectious Diseases 2013, 13:181 available at http://www.biomedcentral.com/1471-2334/13/181.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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8 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
chronic liver disease related to hepatitis is increasing due to the infection with HBV is primary prevention through vaccination.
ageing unvaccinated population (hepatitis B) and to injecting drug There is no vaccine available against HCV infection. Hepatitis B
use (hepatitis C) [92]. vaccines are composed of highly purified preparations of HBsAg.
The first vaccines, available in 1982, were plasma-derived. Since
3.1.1. Hepatitis B virus 1986, these vaccines have been replaced by recombinant hepatitis
HBV is a DNA virus transmitted by exposure to infected blood B vaccine, which is obtained by expressing HBsAg in yeast or
and other body fluids, including semen and vaginal fluids. Around mammalian cells. Aluminum phosphate or aluminum hydroxide is
the time of birth, HBV is transmitted to babies by carrier mothers, used as an adjuvant. Hepatitis B vaccine is available as monovalent
and this is the main route of transmission in highly endemic formulations or in fixed combination with other vaccines,
regions. During childhood, transmission can occur between including diphtheria–tetanus–pertussis (DTP), Haemophilus
children living in close proximity, although the exact route is influenzae type b, hepatitis A, and inactivated polio.
unclear. In adult life, the virus can spread through sexual contact or Since 1997, WHO has recommended hepatitis B vaccination for
by use of contaminated needles. The age of infection is critically all newborns, and the last updated position paper was published in
important in determining whether the infection can become 2009 [98]. The WHO recommended that all infants receive the
chronic [84]; HBV-infected newborns have an 80–90% probability hepatitis B vaccine (monovalent) as soon as possible after birth,
of developing chronic infection; children infected in the first preferably within 24 h, independently of whether the country has
5 years of life have a 20–50% probability of becoming carriers, high, medium or low endemicity; two or three additional
while those infected in adult life have a probability of <10% of monovalent or combined vaccine doses – at 1 and 6 months of
developing chronic infection. Conversely, the risk of developing age in most countries – are given in addition to the birth dose to
acute hepatitis, ranging from no symptoms at all to severe illness complete immunization.
(fever, jaundice and lethargy), is approximately one third in adult The evidence on efficacy and safety of HBV vaccination was
infections, but rare in children [84]. updated with a systematic search of the Medline, Embase,
Chronic infection is characterized by serum persistence PsycINFO and Cochrane Library databases up to January 2013;
(>6 months) of HBsAg. The risk of progression to liver disease is two SRs [99,100] were selected based on the European Code
associated with active HBV replication, determined by tests for Against Cancer methodology. Neither of these reviews reported
HBeAg and levels of HBV DNA [85]. There are various mechanisms chronic hepatitis B, liver cirrhosis or HCC incidence or mortality
by which HBV may promote carcinogenesis: (1) integration of HBV outcomes but reported either anti-HB level [99] or occurrence of
DNA into the host genome that alters the function of endogenous hepatitis B infection [100]. Ortqvist’s SR [99] showed efficacy, but
genes or induces chromosomal instability; (2) accumulation of no meta-analysis was performed. Mathew’s SR [100] showed
genetic damage due to hepatic inflammation mediated by virus- contradictory results on efficacy depending on the method used to
specific T cells; and (3) induction of oxidative stress by expression perform data analysis. The evidence available since the last WHO
of viral proteins HBx and HBs [93]. position paper is therefore summarized below using individual
studies.
3.1.2. Hepatitis C virus Effectiveness studies have been performed in highly HBV
HCV is an RNA virus with a highly variable genome. The endemic countries or regions with high rates of HCC. Surveys on
distribution of HCV genotypes and sub-genotypes depends on the seroprevalence of HBsAg in children carried out before and after
geographic region, and in Europe HCV1b is the main one [94]. HCV introduction of immunization programs show a significant
infection occurs mainly from contaminated blood or blood reduction in the rate of chronic infection among immunized
products. Before the 1990s, when widespread screening of the children. In China, where the immunization program was
blood supply for HCV contamination began in developed countries, introduced in 1992, the prevalence of HBsAg positivity in children
hepatitis C was commonly spread through blood transfusions and younger than 5 years decreased from 9.7% in 1992 to 1.0% in 2006
blood products. The risk of HCV transmission through donated [101]. In Taiwan, since implementation of vaccination in 1984,
blood is now very small in Europe and most developed countries, seroprevalence in children decreased from 10% in 1984 to 0.9% in
and most new infections with HCV occur by sharing needles or 2009 [102]. Comparison of vaccinated birth cohorts with
other equipment to inject drugs. Diagnostic procedures and unvaccinated ones in studies with 25–30 years of follow-up time
treatments in healthcare facilities with inadequate infection have shown the effectiveness of hepatitis B immunization in
control practices may also be a source of infection. This is the lowering mortality from fulminant hepatitis and incidence of HCC
reason why hepatitis C epidemics can be concentrated in certain in Taiwan [103], Qidong City (China) [104], Japan [105], and Alaska
high-risk populations, for example among people who inject drugs [106]. The studies’ results are summarized below.
and/or in general populations in certain areas. More rarely, HCV In Taiwan, the birth cohort born in 1981–1984, which received
can also be acquired from sexual and household contacts [84]. HCV HBV vaccines at preschool ages instead of early infancy, had
infection can be both acute and chronic. Unlike HBV, the risk of significantly lower HCC mortality and incidence than those born in
chronic infection with HCV does not decrease when infection 1977–1980 (RR 0.70, 95%CI 0.59–0.83 of HCC mortality; RR 0.73,
occurs in adults. About 15% of those initially infected will develop 95%CI 0.63–0.85 of HCC incidence) [103].
acute hepatitis which is generally asymptomatic, and spontane- In Qidong City, China, a controlled neonatal HBV vaccination
ously clear the virus. The remaining 85% will become carriers [95]. trial began in 1983 and ended in November 1990. After the end of
Chronic infection is characterized by serum persistence the trial, vaccination of newborns continued without interruption.
(>6 months) of HCV RNA and HCV antibodies [96]. Approximately Compared with 1980–1983, the age-specific liver cancer incidence
20% of HCV carriers will develop HCC by the age of 75 years [97]. rates in 2005–2008 significantly decreased 1.9-fold at ages 0–19,
14-fold at ages 20–24, 9-fold at ages 25–29, 4-fold at ages 30–34,
3.2. Interventions 1.5-fold at ages 35–39, 1.2-fold at ages 40–44 and 1.4-fold at ages
45–49, but increased at older ages. The reduction at ages below
3.2.1. Hepatitis B virus vaccines 25 reflect the combined effects of interventions to reduce aflatoxin
exposure and neonatal HBV vaccination [104].
3.2.1.1. Scientific justification of the European Code Against Cancer A nationwide prevention program utilizing immunoprophy-
recommendation. The most effective intervention against laxis for high-risk newborn babies against maternal HBV
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transmission was introduced in Japan in January 1986. The number 3.2.1.2. Key points for the general public, healthcare providers and
of patients with HBV-positive HCC and the ratio of HBV-positive health policy makers..
HCC to hepatoblastoma decreased over the study period. There Based on the above evidence, the European Code Against Cancer
was a significant decrease in HBV-positive HCC during the last recommends (to parents): “Ensure your children take part in
study periods (2001–2008) compared with HBV-negative HCC vaccination programs for hepatitis B (for newborns)” (Box 1,
(P < 0.001) [105]. no.11).
A universal newborn immunization with hepatitis B
vaccine was initiated in 1984 among Alaskan native people; In the Q&A section [81], the Working Group on Infections and
the incidence of HCC in persons below 20 years of age Vaccination also provided additional information that would be of
decreased from 3/100,000 in 1984–1988 to zero in 1995–1999, particular relevance for parents interested in learning more about
and no cases have occurred since 1999 (test for trend overall, what they could do to lower the risk of liver cancer from hepatitis B
P < 0.001) [106]. infection (see also Section 3.2.2.3). A point considered by the
Only two RCTs initiated during the 1980s examine HCC as an Working Group to be particularly relevant is:
outcome. They were conducted in areas where the high incidence
of liver cancer was attributable to endemic HBV infection, but also In a few EU countries (the United Kingdom and some Nordic
to dietary exposure to aflatoxin. The Gambian Hepatitis Interven- countries) vaccination against hepatitis B is offered only to high-
tion Study (GHIS) was conducted from 1986 to 1990 in Gambia risk newborns (i.e. newborns of mothers who are HBV-positive).
(Africa) [107]; 24 years after vaccination, vaccine efficacy against However, parents living in one of these countries may wish to
chronic infection with hepatitis B virus was 95.1% (95% CI 91.5– consider having their children vaccinated at their own expense in
97.1%) [108]. The latest estimates [109] indicate that the consultation with their doctor or other healthcare provider.
evaluation of the protective efficacy of HBV vaccine against
HCC should be measurable from 2017. The Qidong Hepatitis B
Intervention Study (QHBIS), an RCT of neonatal HBV vaccination, 3.2.2. The “test and treat” intervention
was conducted between 1983 and 1990 in Qidong County (China) Because the disease is often asymptomatic and left untreated,
[110]. This population-based, cluster randomized, controlled trial people with chronic HBV and/or HCV infection remain infectious to
included 39,292 newborns who were randomly assigned to the others and are themselves at risk of serious liver disease such as
vaccination group in which 38,366 participants completed the liver cirrhosis or HCC. Various drugs for treatment of chronic HBV
HBV vaccination series and 34,441 newborns who were randomly or HCV infection have received marketing authorization approval.
assigned to the control group in which the participants received Efficacy and safety of these drugs have been reviewed recently by a
neither a vaccine nor a placebo. However, 23,368 (67.8%) number of recognized advisory bodies to produce the following
participants in the control group received catch-up vaccination evidence-based guidelines or recommendations:
at age 10–14 years. At 30-year follow-up, the incidence rate of
primary liver cancer (PLC) and the mortality rates of infant WHO: guidelines for the screening, care and treatment of people
fulminant hepatitis were significantly lower in the vaccination with hepatitis C infection (2014) [114];
group than in the control group, with a risk reduction estimated National Institute for Health and Care Excellence (NICE):
to be 84% (95% CI 23–97%) and 60% (95% CI 34–86%) respectively Hepatitis B and C testing: people at risk of infection (2012) [115];
[111]. The estimated efficacy of catch-up vaccination on NICE: hepatitis B (chronic) diagnosis and management (2013)
HBsAg seroprevalence in early adulthood was substantially [116];
weaker than that of the neonatal vaccination. Limitations of European Association for the Study of the Liver (EASL):
the study results include the small number of individuals with management of chronic hepatitis B infection (2012) [117];
PLC, the large number of participants lost to follow-up, and the EASL: recommendations on treatment of hepatitis C (2014)
large proportion of participants who did not provide serum [118];
samples at follow-up. US Preventive Services Task Force (USPSTF): screening for
Since its availability in 1982, more than 1 billion doses of HBV hepatitis B virus infection in non-pregnant adolescents and
vaccine have been used worldwide; so far no serious safety adults (2014) [119].
concerns regarding the HBV vaccines have been reported by any
national or international (i.e. Global Alliance for Vaccines and In summary, these guidelines recommend (1) to offer HBV and
Immunization, GAVI) surveillance system authority. No safety HCV serology testing to individuals from high-risk groups (Table 1);
concern was highlighted either through exhaustive review of (2) to assess carriers of HBV and HCV for antiviral treatment (i.e.,
scientific evidence such as the one published in 2013 by the selection of antiviral drugs to be used, duration of treatment, and
Institute of Medicine in the USA [112]. subsequent monitoring of patients, genotyping being recom-
In the EU, only four countries (Denmark, Finland, Sweden and mended only for chronic HCV infection); and (3) to offer adequate
the UK) have not introduced immunization against hepatitis B treatment to individuals with evidence of active infection or liver
into their childhood immunization programs on account of the damage. NICE, EASL, and WHO guidelines also provide detailed
historically low prevalence of HBV infection in the general recommendations and guidance to health professionals regarding
population. These countries opted instead for systematic high- protocols for treatment of carriers, taking into account patient
coverage surveillance of pregnant women to identify carrier assessment (e.g., severity of liver disease; previous treatment
mothers, and administration of HBV vaccination only to new- failure, and genotyping for chronic HCV infection). The NICE
borns whose mother was infected. A survey of hepatitis B recommendations also take into account evidence of cost-
immunization programs was performed in 2008–2009 in 25 EU effectiveness. A summary of the evidence regarding efficacy and
members [113]. Based on this survey, of the 20 countries with a safety of the main currently available drugs that are described in
childhood immunization program, 18 countries had the first the above guidelines is provided in the following paragraphs.
hepatitis B vaccine dose scheduled at birth or 2–3 months after Specific recommendations on which treatment to use are not
birth, and two countries vaccinated only schoolchildren. Of those provided since this was not the aim of European Code Against
18 countries, 11 provided catch-up programs for older children or Cancer project; treatment depends on patient assessment and the
teenagers [113]. recommendations in place in a specific country.
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Table 1
Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) carriers: high-risk groups.
a b
Groups at increased risk of being chronic HBV carriers compared to the general Groups at increased risk of being chronic HCV carriers compared to the general
population population
People not vaccinated as newborns against HBV and included in one or more of People who have ever injected drugs
the categories below
People born or brought up in a country with an intermediate or high prevalence People who received a blood transfusion or blood products before the 1990s
(2%) of chronic hepatitis B. This includes all countries in Africa, Asia, the Recipients of potentially infected blood products or invasive procedures in
Caribbean, Central and South America, Eastern and Southern Europe, the Middle healthcare facilities with inadequate infection control practices
East and the Pacific islands. In the EU, this includes some countries such as Greece
and Romania
Babies born to mothers who are HBV carriers People born or brought up in a country with an intermediate or high prevalence
(2%) of chronic hepatitis C. US-born people not vaccinated as infants whose
parents were born in regions with a very high prevalence of HBV infection (8%),
such as sub-Saharan Africa and Central and Southeast Asia. In the EU, this
includes countries such as Italy (particularly Southern Italy and Sicily), and
Romania
People who have ever injected drugs Babies born to HCV-infected mothers
Men who have sex with men People with HCV-infected sexual partners
Anyone who has ever had unprotected sex People with HIV infection
Anyone (especially babies and children under the age of 10) subject to close People born in countries and regions outside the EU with a high prevalence of
contacts with carriers (i.e. where there is a risk of transmitting the infection HCV infection, such as Eastern and South-Eastern Asia
through blood or body fluids). This could include the family members, close
friends, household contacts or sexual partners of someone known to be
chronically infected with hepatitis B
Healthcare workers People who have used intranasal drugs (e.g. through sharing of inhalation
equipment for cocaine)
People who have had tattoos or piercings
Healthcare workers
a
Adapted from National Institute for Health and Care Excellence 2012 [115].
b
Adapted from World Health Organization 2014 [114], National Institute for Health and Care Excellence 2012 [115] and European Association for The Study of the Liver 2014
[118].
3.2.2.1. Chronic hepatitis B: available treatments. The progression 3.2.2.2. Chronic hepatitis C treatment available or under
of HBV-related liver disease is associated with HBV DNA levels in development. Successful eradication of HCV by treatment is
the blood. Unlike HCV treatment, treatments against chronic defined as achievement of sustained virological response (SVR),
hepatitis B can control but do not cure HBV infection, owing to the i.e. absence of viremia 18 or 24 weeks after cessation of all antiviral
persistence of HBV in the hepatocyte genome. Antiviral therapy medication, which is associated with a reduction of cirrhosis,
suppresses HBV replication, ensuring long-term suppression of the incidence reduction of HCC and liver-related death [129–131].
viral load. This is associated with histological improvement and Since the introduction of indirect antiviral drugs, INFa
reversal of fibrosis and cirrhosis, and thereby the likelihood of monotherapy in 1990 and ribavirin (RBV) in combination with
serious clinical disease is reduced [120–123]. PEG-INFa in 2002, research has focused on developing more
Seven antiviral drugs falling into two groups are licensed in effective antiviral treatments that target HCV directly, are orally
most European countries for treatment of chronic HBV infection: administered, safe and effective across all genotypes, and that
interferons (interferon alpha, INFa and pegylated (PEG)-INFa), and achieve high SVR rates.
oral nucleos(t) ide analog (NA) polymerase inhibitors (lamivudine, In 2011, telaprevir or boceprevir, the first generation of
adefovir, entecavir, telbivudine and tenofovir). PEG-INFa, enteca- inhibitors of the HCV NS3/4A serine protease, were approved by
vir, and tenofovir are licensed as first-line treatments and regulatory agencies – the US Food and Drug Administration (FDA),
recommended as such in most current guidelines [117]. the EMA, and others – for treatment of patients infected with
Two SRs show that, compared to no treatment, INFa treatment chronic HCV genotype 1 in a triple-therapy regimen with RBV and
significantly decreased the incidence of liver cirrhosis, liver cancer INFa. This treatment has been reported to be more effective than
and liver-related death [124,125]. However, in Jin’s [125], the effect the combination of RBV and PEG-INFa alone achieving a 60–70%
on liver cancer is less significant when the Bayesian meta-analysis SVR and a 75% reduced risk of HCC [132]. Unfortunately, this
approach was used to combine data (RR 0.27, 95% CI 0.06, 1.03) treatment is associated with more adverse events than the dual
compared to the Der Simonian–Laird approach (RR 0.47, 95% CI therapy, is expensive, requires several months’ duration, and has a
0.26, 0.85). Compared to the first generation of NAs, development high pill burden.
of resistance and relapse after treatment cessation seem to be Since 2011, a number of new antiviral compounds – such as
significantly lower with entecavir and tenofovir [117,126]. No direct simeprevir, sofosbuvir and ledispasvir – has been developed, and
evidence on the efficacy of entecavir/tenofovir in preventing or some additional compounds are currently in various stages of
delaying HCC is available because these drugs are relatively new, development, including marketing authorization assessment. The
and HCC development takes several decades. However, indirect main characteristics of these new products as reported in the
evidence of cancer prevention is available, as reviewed recently literature are shorter treatment duration, easier administration
[127,128]. protocol (i.e. a single daily oral administration), fewer side effects,
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and SVR rates of >90%. Simeprevir, a new generation of NS3/4A In Europe, gastric cancer incidence varies by region: in 2012,
inhibitors, has been recently licensed as part of a combination the estimated ASIR was 11.7/100,000 (for men) and 5.9/100,000
treatment regimen with RBV and PEG-INFa. Evidence has shown (for women) in Southern Europe, 20.3 (men) and 8.9 (women) in
that simeprevir is effective against HCV genotype 1 excluding the Central and Eastern Europe, and 7.4 (men) and 3.7 (women) in
genotype 1a NS3 Q80K polymorphism [133–137]. Sofosbuvir, Northern Europe [18]. H. pylori prevalence follows a similar
inhibitor of the HCV NS5B RNA polymerase, has recently been pattern: prevalence of the infection was generally higher in
approved by the FDA and the EMA, and is effective and safe in countries in Southern Europe (e.g. 84.2%, 18–30 years of age, in
combination with either RBV alone or with RBV and PEG-INFa for Portugal [146], 58.0%, 18–69 years of age, in Italy [147]) and
treatment of genotypes 1–6 [138–140]. Inhibitors of the HCV in Central and Eastern Europe (e.g. 61.7%, <17 years of age, in
protein NS5A, such as ledipasvir, have recently been reviewed Bulgaria [148]) than in Northern European countries (e.g. 11.0%,
[141] and seem to be very promising new treatments. They are 25–50 years of age on average in Sweden [148] and 27.6%, 40–49
active against all HCV genotypes, require once-daily dosing, and years of age in the UK [149].
show resistance profiles that do not overlap with those of other H. pylori infection is strongly associated with socioeconomic
anti-HCV medicines. Marketing authorization application was conditions [150], and transmission appears to occur through close
made to the FDA and the EMA in February 2014 for a once-daily personal contact, particularly within the family [3] and typically in
fixed-dose combination of ledipasvir with sofosbuvir [142,143]. early childhood. Once established, infection usually persists
While the cost of new drugs is currently the major obstacle to their throughout life unless it is treated. The prevalence of H. pylori
large-scale use, the manufacturing of these drugs is not per se infection has decreased in recent decades, particularly among
expensive, opening the way to rapid price decline particularly in children in developed countries, probably reflecting improvements
the public sector use [144] in hygiene [151,152].
3.2.2.3. Key points for the general public, healthcare providers and 4.2. Intervention: H. pylori eradication
health policy makers. In the Q&A section [81], based on the above
evidence, the Working Group on Infections and Vaccination in the Several randomized trials conducted mainly in high-risk
European Code Against Cancer project provided further populations in Asia have produced evidence indicating that H.
information that would be of particular relevance for adults pylori eradication reduces the risk of developing gastric precan-
interested in learning more about what they could do to lower the cerous lesions and cancer [153]. In 2012, Ma and colleagues
risk of liver cancer from hepatitis B and C. Key messages include: reported the long-term follow-up results of a randomized trial in
H. pylori-seropositive adults drawn from a general population in
Individuals in high-risk groups for chronic HBV and/or HCV China. By 15 years after randomization the OR of gastric cancer for
infection should consult their doctor or other healthcare H. pylori eradication was 0.61, 95% CI 0.38–0.96 [154]. A meta-
provider to get a HBV or HCV test and be advised about analysis of six randomized trials estimated a relative risk of
treatment options, if tested positive. Effective treatments are stomach cancer as 0.66 (95% CI 0.46–0.95) in asymptomatic
available that will reduce the risk of developing liver cancer. infected individuals [155].
To prevent HCV transmission, individuals are advised to avoid There are treatments available containing combinations of
injections and use oral treatments, when available and possible, antibiotics and acid-inhibitors taken for 7–14 days that can safely
especially when traveling to countries in which medical care is eradicate the infection in more than 80% of cases, depending on the
suboptimal. It is also recommended to avoid body piercing, antibiotic resistance patterns of H. pylori within the population
tattooing or acupuncture, if there is any doubt about the safety/ [156].
hygiene of the procedure. Absence of proper needle handling is No screening program for systematically detecting and treating
common in countries or regions outside Europe with limited H. pylori is currently in place because important uncertainties
economic resources and during times of political or social regarding potential benefits and harms of such programs remain
upheaval. [157,158]; important questions inherent to the implementation of
any screening programs (e.g. program costs, feasibility, appropriate
target groups for intervention, and to the potential harm of mass
4. H. pylori therapy with antibiotics) must first be resolved before implement-
ing large-scale programs. In Europe, important data are likely to
4.1. Role in cancer and situation in Europe emerge from RCTs that are currently in progress or about to begin
in the region. An example is the Gastric Cancer Prevention Study by
H. pylori was classified by the IARC Monographs Program as a Predicting Atrophic Gastritis (GISTAR), which was launched in
Group 1 carcinogen in 1994; this classification was maintained in 2013 in Latvia to evaluate new intervention strategies for gastric
2009 after more recent evidence was reviewed [3]. Approximately cancer prevention in high-risk areas in East Europe.
89% of non-cardia gastric cancer cases, representing 78% of all
gastric cancer cases worldwide, are now estimated to be 5. Human immunodeficiency virus
attributable to chronic H. pylori infection [145]. Chronic H. pylori
infection can also cause low-grade B-cell MALT gastric lymphoma, 5.1. Role in cancer and situation in Europe
which is rare, representing less than 2% of all gastric cancers [3,82].
Even if the recently observed decline in gastric cancer incidence The progression of disease related to human immunodeficiency
rates is assumed to continue, the global burden in 2030 is expected virus (HIV) is well documented: acute infection stage, clinical
to remain the same due to demographic change. Gastric cancer is latency, and AIDS (acquired immunodeficiency syndrome). AIDS is
the fifth most common malignancy in the world, but it is the third a life-threatening condition defined by severe immune dysfunc-
leading cause of death in both sexes, accounting for 8.8% of the tion.
total deaths from cancer worldwide in 2012. The highest mortality HIV-positive individuals have an increased cancer risk. Ad-
rates were reported in East Asia (ASMR of 24 and 9.8/100,000 for vanced-stage HIV disease is characterized by immunosuppression,
men and women, respectively) and the lowest in North America which is a risk factor for many malignancies [82]. There are three
(2.8 and 1.5/100,000 for men and women, respectively) [18]. AIDS-defining cancers: Kaposi sarcoma, NHL, and cervical cancer.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
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CANEP 930 No. of Pages 19
12 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
In contrast to the general population, a majority of lymphomas in Regional Office for Europe has pointed out that HIV infection is still
HIV-infected people are caused by the Epstein–Barr virus [3]. HIV- a major public health issue in several countries in the EU/EEA. In
infected persons also have elevated risks of other virus-related 2013, 29,157 new HIV diagnoses were reported in EU/EEA
cancers – notably anal cancer, hepatocellular carcinoma, and countries, a rate of 5.7/100,000 population. The countries with
Hodgkin lymphoma – and a higher prevalence of lifestyle- the highest rates of new HIV cases were Estonia (24.6), Latvia
associated risk factors, including smoking and alcohol consump- (16.8), Portugal (10.4), Belgium (10.0), Luxemburg (9.9) and the UK
tion leading to increased risk of cancers of the head, neck and lung (9.4). The lowest rates were reported in Slovakia (1.5) and Croatia
[3]. Overall, the risk of non-AIDS-defining cancers in HIV-infected (2.0) [161]. There are no clear signs of overall decrease in HIV
people is double that of the general population [159]. Before the incidence due to continuing transmission in specific populations
introduction of highly active antiretroviral therapy (HAART) in the (Fig. 4) [161]. In 2013, in the EU/EEA region, the majority of new
mid-1990s, the life expectancy of people with HIV was severely HIV diagnoses were men who have sex with men (42%) (MSM)
compromised. However, the availability of HAART has led to a followed by heterosexuals (33%), one third of those being migrants
striking increase in survival. from countries or areas where there is a generalized HIV epidemic
At the end of 2011, it was estimated that around 900,000 people (i.e. sub-Saharan Africa) [161]. Transmission due to injecting drug
1
were living with HIV/AIDS in Western and Central Europe with an use accounted for 5% of new HIV diagnoses, and transmission
estimated prevalence of 0.2% in adult population (15–49 years) mode was unknown for nearly 20% of new diagnoses [161].
[160]. The estimated prevalence in adults was generally higher in The number of HIV diagnoses among MSM have increased by
countries from Southern Europe (e.g. 0.7% in Portugal, 0.4% in Italy 33% since 2004 (Fig. 4b) [161]. When information on CD4 cell
and Spain) than in other European countries (e.g. 0.3% in UK, 0.1% in counts were reported by countries, nearly half (47%) of all newly
3
Finland, Germany, Croatia, Czech Republic and Slovakia; and <0.1% infected individuals had a CD4 cell count <350/mm , 27% of those
in Croatia or Czech Republic) [160]. being diagnosed with severe immunosuppression (CD4 <200/
3
A recent surveillance report prepared jointly by the European mm ) [161]. This population would have benefited from earlier HIV
Centre for Disease Prevention and Control (ECDC) and the WHO testing and HAART treatment (see below).
Fig. 4. (a) Rate of reported HIV diagnoses, by year of diagnosis, in the European Union and European Economic Area (EU/EEA). (b) Number of HIV diagnoses, by transmission
mode and year of diagnosis, adjusted for reporting delay, in the EU/EEA (excluding Estonia, Italia, Poland and Spain), 2004–2013. Note that “Other/undetermined” reflects
missing data, i.e., information on the probable source of infection was not available. From European Centre for Disease Prevention and Control/WHO Regional, Office for
Europe: HIV/AIDS surveillance in Europe 2013.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx 13
5.2. The “test and treat” intervention be asymptomatic and detected by testing – is associated with
reduced risk for AIDS-related events or death and HIV transmission
There is no vaccine to prevent HIV infection and no cure for to uninfected sexual partners [163,164]. Based on these results,
chronic infection. Interventions provided to HIV-infected people both the USPTF and WHO issued recommendations in 2013 about
include HAART treatment and counselling to reduce high-risk testing (see below). More recently, in 2014, the US Department of
behaviors. Health and Human Services (HHS) recommended treatment for all
To evaluate HAART efficacy in preventing cancer in HIV-positive HIV-infected individuals regardless of the patient’s CD4 cell count.
or AIDS patients, a systematic review was conducted, and However, the strength of this HHS recommendation varies by
25 primary studies published after 2007 were selected (see patients’ pre-treatment CD4 cell count, based on available
Minozzi et al., this issue 2015). Of these, 19 are retrospective cohort scientific evidence; the recommendation is “strong” for
3
studies comparing the pre-HAART to the HAART periods. The CD4 count <500 cells/mm , but “moderate” for CD4 count
3
review showed that (1) the rate of AIDS-defining cancers (i.e. >500 cells/mm [165,166].
Kaposi sarcoma, NHL, and invasive cervical cancer) has continued On the basis of earlier treatment benefits, and the high
to fall since the introduction of HAART, and (2) survival for NHL and percentage in the US (about 20–25%) of HIV-positive persons
Kaposi sarcoma has increased significantly. HAART prevents about unaware of their positive status, the USPSTF has recommended HIV
two thirds of the cancers – particularly Kaposi sarcoma and NHL – “screening” (in actual fact, voluntary testing) of all adolescents and
in HIV-infected persons [159]. For non-AIDS-defining cancers, the adults aged 15–65 years at normal risk and younger adolescents
results are less clear and more conflicting: some studies found a and older adults at increased risk to identify asymptomatic but
significant increase in overall incidence after the introduction of infected persons in US settings [167] (Fig. 5). In the absence of
HAART, whereas others found no significant differences between sufficient evidence to determine optimum time intervals for HIV
pre-HAART and HAART periods. The importance of preventing testing, the USPSTF suggested that “one reasonable approach
even moderate levels of HIV-induced immunosuppression is being would be one-time screening of adolescent and adult patients to
increasingly appreciated, notably for the prevention of HPV- identify persons who are already HIV-positive, with repeated
associated cancers [162]. screening of those who are known to be at risk for HIV infection,
Recent SRs commissioned by the USPTF and WHO have shown those who are actively engaged in risky behaviors, and those who
that earlier treatment of HIV-positive individuals – i.e. at live in or receive medical care in a high-prevalence setting” (i.e. a
3
CD4 count 500 cells/mm , when individuals are more likely to geographic location or community with an HIV seroprevalence of
Fig. 5. Screening for HIV: clinical summary of the US Preventive Services Task Force recommendation. From V.A. Moyer. Screening for HIV: US Preventive Services Task Force
Recommendation Statement, Ann Intern Med 2013, 159: 51–60.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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CANEP 930 No. of Pages 19
14 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
Table 2
a
Summary of HIV testing and counselling recommendations in asymptomatic individuals for low-level and concentrated epidemics , WHO recommendation.
Who to test When to test
Partners of people with HIV As soon after partner diagnosis as possible
For the negative person in serodiscordant couples, offer re-testing every 6–12 months
Families of index cases (adults and adolescents) As soon as possible after the family member is diagnosed
Key populations (adults and adolescents): people who inject drugs, men Every 6–12 months
who have sex with men, transgender people and sex workers
Pregnant women At the first antenatal care visit
Infants and children <18 months old Early infant diagnosis at 4–6 weeks for all infants whose mothers are living with HIV or if
maternal HIV status is unknown; determine the final infant HIV infection status after
18 months and/or when breastfeeding ends
Adapted from Table 5.3 in “Summary of HIV testing and counselling recommendations for low- level and concentrated epidemics”, World Health Organization, consolidated
guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach (June 2013).
a
Low-level HIV epidemic: epidemics in which the prevalence of HIV infection has not consistently exceeded 1% in the general population nationally or 5% in any
subpopulation; concentrated HIV epidemic: HIV has spread rapidly in one or more defined subpopulations but is not well established in the general population. Numerical
proxy: HIV prevalence is consistently over 5% in at least one defined subpopulation but is less than 1% among pregnant women in urban areas.
at least 1% [167]). It is worthy of note, however, that the USFTP Individuals most at risk for HIV infection are men who have sex
recommend voluntary testing on the basis of risk assessment (see with men, sex workers, injection drug users, people from a
Fig. 5 “risk assessment”) in settings where the prevalence of country with high rates of HIV (e.g. sub-Saharan Africa) or
undiagnosed HIV infections 0.1% [167]. WHO also recommended individuals who have unprotected sex without being sure that
HIV testing in asymptomatic individuals to initiate treatment in their partner is HIV-negative. Individuals most at risk should
3
HIV-positive individuals at CD4 count 500 cells/mm [164]. The consult their healthcare provider to access counselling, testing,
population targeted by the WHO testing recommendation was and, if the test is positive, to start treatment without delay. If the
defined on the basis of HIV prevalence; in low-prevalence HIV test is positive, delaying treatment allows the virus to spread in
settings, i.e. <1% in the general population, WHO recommends the body and damage the patient’s health, in addition to
(voluntary) HIV testing and counselling to “key populations that increasing the risk of infecting sexual partners. If the test is
include both vulnerable and most-at-risk populations”, and gives negative, the healthcare provider will advise on whether
intervals for testing (Table 2) [164]. In generalized HIV epidemics repeated testing is needed based on the individual’s HIV risk
(i.e. HIV prevalence 1% in the general population) WHO (see above). The tests used nowadays can usually tell whether a
recommends (voluntary) HIV testing and counselling to every- person has HIV within a month of infection. The most common
body. tests require only a small amount of blood or saliva.
Based on (a) the benefits of timely detection and treatment for
cancer prevention, (b) recommendations for HIV testing in low-
prevalence settings, and (c) figures obtained in the EU/EEA, the Conflict of interest
Working Group on Infections and Vaccination in the European
Code Against Cancer project recommended that: in terms of HIV- J. Dillner’s institution has received research grants from Merck/
related cancers prevention, individuals in the groups most at risk SPMSD for monitoring long-term follow-up of effects of HPV
for HIV infection and transmission in the EU/EEA (i.e. MSM, vaccines in populations. He declares no personal remuneration. M.
injection drugs users, and migrants from countries or settings with Almonte received non-monetary support from QIAGEN to attend
generalized HIV epidemics) but also individuals from other most the 27th International Papillomavirus Conference (Berlin, 2011).
at-risk populations (e.g. sex workers [164]), should be aware of She declares no personal remuneration. The other authors declare
their HIV status and get treatment if needed. This is in accordance no conflict of interest.
with the ECDC recommendation, which concluded in their
2014 report that “key populations are the cornerstones of HIV Acknowledgements
prevention in most EU/EEA countries” [161]. However, as there is
no clear decrease in the trends of HIV transmission in the EU/EEA, The European Code Against Cancer project was co-funded by
with heterosexual transmission still remaining the second most the European Union [grant agreement numbers: 2011 53 05; 2010
common mode of HIV transmission, the Working Group also 53 04 and 2007IARC01] and the International Agency for Research
considered that it is important to extend the above recommenda- on Cancer. The authors alone are responsible for the views
tion to all individuals who are or have engaged in risky behaviors expressed in this manuscript.
such as having unprotected sex or being injection drug users. Time The authors thank Dr. Lawrence von Karsa, co-principle
intervals for HIV testing should be based on individual risk investigator of the project to revise the European Code Against
assessment and counselling. Cancer, for reviewing the manuscript and for providing helpful
comments. We would like to thank also Sir Andrew Hall, previously
5.3. Key point for the general public, healthcare providers and health at the Infectious Disease Epidemiology Unit, Department of
policy makers. Epidemiology and Population Health, London School of Hygiene
and Tropical Medicine, for his valuable contribution to the
In the Q&A section [81], based on the above evidence, the development of the European Code Against Cancer, and acknowl-
Working Group on Infections and Vaccination in the European edge his wish to not co-author this article consequent to his
Code Against Cancer project provides additional information that retirement. We also thank S. Minozzi, C. Bellisario, E. Biagioli, M.
would be of particular relevance for all adolescents and adults Cinquini, S. Gianola, M. Gonzalez Lorenzo, D. Puricelli Perin and P.
interested in learning more about what they could do to lower the Villain for skillful performance of the systematic reviews used in
risk of cancer from HIV infection. A key message is: this paper.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
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CANEP 930 No. of Pages 19
P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx 15
References [19] J.T. Schiller, X. Castellsague, S.M. Garland, A review of clinical trials of human
papillomavirus prophylactic vaccines, Vaccine 30 (Suppl. 5) (2012)
F123–F138.
[1] C. De Martel, J. Ferlay, S. Franceschi, J. Vignat, F. Bray, D. Forman, M. Plummer,
[20] World Health Organization, Human papillomavirus vaccines, WHO Position
Global burden of cancers attributable to infections in 2008: a review and
Paper, Wkly Epidemiol Rec. 84 (2009) 118–131.
synthetic analysis, Lancet Oncol. 13 (2012) 607–615.
[21] C. Pedersen, T. Petaja, G. Strauss, H.C. Rumke, A. Poder, J.H. Richardus, B.
[2] J. Ferlay, E. Steliarova-Foucher, J. Lortet-Tieulent, S. Rosso, J.W. Coebergh, H.
Spiessens, D. Descamps, K. Hardt, M. Lehtinen, G. Dubin, Immunization of
Comber, D. Forman, F. Bray, Cancer incidence and mortality patterns in
early adolescent females with human papillomavirus type 16 and 18 L1 virus-
Europe: estimates for 40 countries in 2012, Eur. J. Cancer 49 (2013)
1374–1403. like particle vaccine containing AS04 adjuvant, J. Adolesc. Health 40 (2007)
564–571.
[3] IARC, Monographs on the Evaluation of Carcinogenic Risks to Humans
[22] S.L. Block, T. Nolan, C. Sattler, E. Barr, K.E. Giacoletti, C.D. Marchant, X.
Volume 100B: A Review of Human Carcinogens: Biological Agents, (2012).
Castellsague, S.A. Rusche, S. Lukac, J.T. Bryan, P.F. Cavanaugh Jr, K.S. Reisinger,
[4] D. Forman, M.C. de, C.J. Lacey, I. Soerjomataram, J. Lortet-Tieulent, L. Bruni, J.
Comparison of the immunogenicity and reactogenicity of a prophylactic
Vignat, J. Ferlay, F. Bray, M. Plummer, S. Franceschi, Global burden of human
quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like
papillomavirus and related diseases, Vaccine 30 (Suppl. 5) (2012) F12–F23.
particle vaccine in male and female adolescents and young adult women,
[5] N. Li, S. Franceschi, R. Howell-Jones, P.J. Snijders, G.M. Clifford, Human
Pediatrics 118 (2006) 2135–2145.
papillomavirus type distribution in 30,848 invasive cervical cancers
[23] G. Perez, E. Lazcano-Ponce, M. Hernandez-Avila, P.J. Garcia, N. Munoz, L.L.
worldwide: variation by geographical region, histological type and year of
Villa, J. Bryan, F.J. Taddeo, S. Lu, M.T. Esser, S. Vuocolo, C. Sattler, E. Barr, Safety,
publication, Int. J. Cancer 128 (2011) 927–935.
immunogenicity, and efficacy of quadrivalent human papillomavirus (types
[6] L. Alemany, M. Saunier, L. Tinoco, B. Quiros, I. Alvarado-Cabrero, M. Alejo, E.A.
6, 11, 16, 18) L1 virus-like-particle vaccine in Latin American women, Int. J.
Joura, P. Maldonado, J. Klaustermeier, J. Salmeron, C. Bergeron, K.U. Petry, N.
Cancer 122 (2008) 1311–1318.
Guimera, O. Clavero, R. Murillo, C. Clavel, V. Wain, D.T. Geraets, R. Jach, P.
[24] World Health Organization, Human papillomavirus vaccines: WHO position
Cross, C. Carrilho, C. Molina, H.R. Shin, V. Mandys, A.M. Nowakowski, A. Vidal,
paper, October 2014, Wkly. Epidemiol. Rec. 89 (2014) 465–491.
L. Lombardi, H. Kitchener, A.R. Sica, C. Magana-Leon, M. Pawlita, W. Quint, I.G.
[25] B. Lu, A. Kumar, X. Castellsague, A.R. Giuliano, Efficacy and safety of
Bravo, N. Munoz, S.S. de, F.X. Bosch, Large contribution of human
prophylactic vaccines against cervical HPV infection and diseases among
papillomavirus in vaginal neoplastic lesions: a worldwide study in
women: a systematic review & meta-analysis, BMC Infect. Dis. 11 (2011) 13.
597 samples, Eur. J. Cancer 50 (2014) 2846–2854.
[26] T. Malagon, M. Drolet, M.C. Boily, E.L. Franco, M. Jit, J. Brisson, M. Brisson,
[7] L. Alemany, M. Saunier, I. Alvarado-Cabrero, B. Quiros, J. Salmeron, H.R. Shin,
Cross-protective efficacy of two human papillomavirus vaccines: a
E.C. Pirog, N. Guimera, G. Hernandez-Suarez, A. Felix, O. Clavero, B. Lloveras,
systematic review and meta-analysis, Lancet Infect. Dis. 12 (2012) 781–789.
E. Kasamatsu, M.T. Goodman, B.Y. Hernandez, J. Laco, L. Tinoco, D.T. Geraets,
[27] T. Petaja, H. Keranen, T. Karppa, A. Kawa, S. Lantela, M. Siitari-Mattila, H.
C.F. Lynch, V. Mandys, M. Poljak, R. Jach, J. Verge, C. Clavel, C. Ndiaye, J.
Levanen, T. Tocklin, O. Godeaux, M. Lehtinen, G. Dubin, Immunogenicity and
Klaustermeier, A. Cubilla, X. Castellsague, I.G. Bravo, M. Pawlita, W.G. Quint,
safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in
N. Munoz, F.X. Bosch, S.S. de, Human papillomavirus DNA prevalence and
healthy boys aged 10–18 years, J. Adolesc. Health 44 (2009) 33–40.
type distribution in anal carcinomas worldwide, Int. J. Cancer 136 (2015)
98–107. [28] A.R. Giuliano, J.M. Palefsky, S. Goldstone, E.D. Moreira Jr., M.E. Penny, C.
Aranda, E. Vardas, H. Moi, H. Jessen, R. Hillman, Y.H. Chang, D. Ferris, D.
[8] C. Miralles-Guri, L. Bruni, A.L. Cubilla, X. Castellsague, F.X. Bosch, S.S. de,
Rouleau, J. Bryan, J.B. Marshall, S. Vuocolo, E. Barr, D. Radley, R.M. Haupt, D.
Human papillomavirus prevalence and type distribution in penile carcinoma,
Guris, Efficacy of quadrivalent HPV vaccine against HPV Infection and disease
J. Clin. Pathol. 62 (2009) 870–878.
in males, N. Engl. J. Med. 364 (2011) 401–411.
[9] R. Herrero, X. Castellsague, M. Pawlita, J. Lissowska, F. Kee, P. Balaram, T.
[29] E.D. Moreira Jr., J.M. Palefsky, A.R. Giuliano, S. Goldstone, C. Aranda, H. Jessen,
Rajkumar, H. Sridhar, B. Rose, J. Pintos, L. Fernandez, A. Idris, M.J. Sanchez, A.
R.J. Hillman, D. Ferris, F. Coutlee, E. Vardas, J.B. Marshall, S. Vuocolo, R.M.
Nieto, R. Talamini, A. Tavani, F.X. Bosch, U. Reidel, P.J. Snijders, C.J. Meijer, R.
Haupt, D. Guris, E.I. Garner, Safety and reactogenicity of a quadrivalent
Viscidi, N. Munoz, S. Franceschi, Human papillomavirus and oral cancer: the
human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in
International Agency for Research on Cancer multicenter study, J. Natl.
older adolescents and young adults, Hum. Vaccine 7 (2011) 768–775.
Cancer Inst. 95 (2003) 1772–1783.
[30] J.M. Palefsky, A.R. Giuliano, S. Goldstone, E.D. Moreira Jr., C. Aranda, H. Jessen,
[10] M.L. Gillison, L. Alemany, P.J. Snijders, A. Chaturvedi, B.M. Steinberg, S.
R. Hillman, D. Ferris, F. Coutlee, M.H. Stoler, J.B. Marshall, D. Radley, S.
Schwartz, X. Castellsague, Human papillomavirus and diseases of the upper
Vuocolo, R.M. Haupt, D. Guris, E.I. Garner, HPV vaccine against anal HPV
airway: head and neck cancer and respiratory papillomatosis, Vaccine 30
infection and anal intraepithelial neoplasia, N. Engl. J. Med. 365 (2011)
(Suppl. 5) (2012) F34–F54.
1576–1585.
[11] F.X. Bosch, V. Tsu, A. Vorsters, D.P. Van, M.A. Kane, Reframing cervical cancer
[31] R.J. Hillman, A.R. Giuliano, J.M. Palefsky, S. Goldstone, E.D. Moreira Jr., E.
prevention. Expanding the field towards prevention of human
Vardas, C. Aranda, H. Jessen, D.G. Ferris, F. Coutlee, J.B. Marshall, S. Vuocolo, R.
papillomavirus infections and related diseases, Vaccine 30 (Suppl. 5) (2012)
F1–11. M. Haupt, D. Guris, E.I. Garner, Immunogenicity of the quadrivalent human
papillomavirus (type 6/11/16/18) vaccine in males 16 to 26 years old, Clin.
[12] A.B. Moscicki, M. Schiffman, S. Kjaer, L.L. Villa, Chapter 5: updating the
Vaccine Immunol. 19 (2012) 261–267.
natural history of HPV and anogenital cancer, Vaccine 24 (Suppl. 3) (2006)
S3-42–S3-51. [32] S.E. Goldstone, H. Jessen, J.M. Palefsky, A.R. Giuliano, E.D. Moreira Jr, E. Vardas,
C. Aranda, R.J. Hillman, D.G. Ferris, F. Coutlee, J.B. Marshall, S. Vuocolo, R.M.
[13] A.B. Moscicki, M. Schiffman, A. Burchell, G. Albero, A.R. Giuliano, M.T.
Haupt, D. Guris, E. Garner, Quadrivalent HPV vaccine efficacy against disease
Goodman, S.K. Kjaer, J. Palefsky, Updating the natural history of human
related to vaccine and non-vaccine HPV types in males, Vaccine 31 (2013)
papillomavirus and anogenital cancers, Vaccine 30 (Suppl. 5) (2012) F24–F33.
3849–3855.
[14] P. Appleby, V. Beral, G.A. Berrington de, D. Colin, S. Franceschi, A. Goodill, J.
[33] S.K. Kjaer, K. Sigurdsson, O.E. Iversen, M. Hernandez-Avila, C.M. Wheeler, G.
Green, J. Peto, M. Plummer, S. Sweetland, Carcinoma of the cervix and tobacco
Perez, D.R. Brown, L.A. Koutsky, E.H. Tay, P. Garcia, K.A. Ault, S.M. Garland, S.
smoking: collaborative reanalysis of individual data on 13,541 women with
Leodolter, S.E. Olsson, G.W. Tang, D.G. Ferris, J. Paavonen, M. Lehtinen, M.
carcinoma of the cervix and 23,017 women without carcinoma of the cervix
Steben, F.X. Bosch, J. Dillner, E.A. Joura, S. Majewski, N. Munoz, E.R. Myers, L.L.
from 23 epidemiological studies, Int. J. Cancer 118 (2006) 1481–1495.
Villa, F.J. Taddeo, C. Roberts, A. Tadesse, J. Bryan, R. Maansson, S. Lu, S.
[15] P. Appleby, V. Beral, G.A. Berrington de, D. Colin, S. Franceschi, A. Goodhill, J.
Vuocolo, T.M. Hesley, A. Saah, E. Barr, R.M. Haupt, A pooled analysis of
Green, J. Peto, M. Plummer, S. Sweetland, Cervical cancer and hormonal
continued prophylactic efficacy of quadrivalent human papillomavirus
contraceptives: collaborative reanalysis of individual data for 16,573 women
(Types 6/11/16/18) vaccine against high-grade cervical and external genital
with cervical cancer and 35,509 women without cervical cancer from
lesions, Cancer Prev. Res. (Phila) 2 (2009) 868–878.
24 epidemiological studies, Lancet 370 (2007) 1609–1621.
[34] N. Munoz, S.K. Kjaer, K. Sigurdsson, O.E. Iversen, M. Hernandez-Avila, C.M.
[16] X. Castellsague, M. Pawlita, E. Roura, N. Margall, T. Waterboer, F.X. Bosch, S.S.
Wheeler, G. Perez, D.R. Brown, L.A. Koutsky, E.H. Tay, P.J. Garcia, K.A. Ault, S.M.
de, C.A. Gonzalez, J. Dillner, I.T. Gram, A. Tjonneland, C. Munk, V. Pala, D. Palli,
Garland, S. Leodolter, S.E. Olsson, G.W. Tang, D.G. Ferris, J. Paavonen, M.
K.T. Khaw, R.V. Barnabas, K. Overvad, F. Clavel-Chapelon, M.C. Boutron-
Steben, F.X. Bosch, J. Dillner, W.K. Huh, E.A. Joura, R.J. Kurman, S. Majewski, E.
Ruault, G. Fagherazzi, R. Kaaks, A. Lukanova, A. Steffen, A. Trichopoulou, D.
R. Myers, L.L. Villa, F.J. Taddeo, C. Roberts, A. Tadesse, J.T. Bryan, L.C. Lupinacci,
Trichopoulos, E. Klinaki, R. Tumino, C. Sacerdote, A. Mattiello, H.B. Bueno-de-
K.E. Giacoletti, H.L. Sings, M.K. James, T.M. Hesley, E. Barr, R.M. Haupt, Impact
Mesquita, P.H. Peeters, E. Lund, E. Weiderpass, J.R. Quiros, M.J. Sanchez, C.
of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated
Navarro, A. Barricarte, N. Larranaga, J. Ekstrom, M. Hortlund, D. Lindquist, N.
genital diseases in young women, J. Natl. Cancer Inst. 102 (2010) 325–339.
Wareham, R.C. Travis, S. Rinaldi, M. Tommasino, S. Franceschi, E. Riboli,
[35] R. Herrero, S. Wacholder, A.C. Rodriguez, D. Solomon, P. Gonzalez, A.R.
Prospective seroepidemiologic study on the role of Human Papillomavirus
Kreimer, C. Porras, J. Schussler, S. Jimenez, M.E. Sherman, W. Quint, J.T.
and other infections in cervical carcinogenesis: evidence from the EPIC
Schiller, D.R. Lowy, M. Schiffman, A. Hildesheim, Prevention of persistent
cohort, Int. J. Cancer 135 (2014) 440–452.
human papillomavirus infection by an HPV16/18 vaccine: a community-
[17] IARC, Cervix Cancer Screening, IARC Handbooks of Cancer Prevention, vol.10,
based randomized clinical trial in Guanacaste, Costa Rica, Cancer Discov. 1
IARC Press, Lyon, 2005, pp. 1–302.
(2011) 408–419.
[18] J. Ferlay, I. Soerjomataram, M. Ervik, R. Dikshit, S. Eser, C. Mathers, M. Rebelo,
[36] M. Lehtinen, J. Paavonen, C.M. Wheeler, U. Jaisamrarn, S.M. Garland, X.
D.M. Parkin, D. Forman, F. Bray, GLOBOCAN 2012 v1.0, Cancer Incidence and
Castellsague, S.R. Skinner, D. Apter, P. Naud, J. Salmeron, S.N. Chow, H.
Mortality Worldwide: IARC CancerBase No. 11 [Internet], International
Kitchener, J.C. Teixeira, J. Hedrick, G. Limson, A. Szarewski, B. Romanowski, F.
Agency for Research on Cancer, Lyon, France, 2013 Available from: http://
Y. Aoki, T.F. Schwarz, W.A. Poppe, N.S. De Carvalho, M.J. Germar, K. Peters, A.
globocan.iarc.fr (accessed on 26.03.2015).
Mindel, S.P. De, F.X. Bosch, M.P. David, D. Descamps, F. Struyf, G. Dubin,
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
G Model
CANEP 930 No. of Pages 19
16 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or [53] Institute of Medicine of the National Academies, Adverse Effects of Vaccines:
greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the Evidence and Causality, (2011) Available from: http://iom.
randomised, double-blind PATRICIA trial, Lancet Oncol. 13 (2012) 89–99. nationalacademies.org/Reports/2011/Adverse-Effects-of-Vaccines-
[37] A.C. Rodriguez, D. Solomon, R. Herrero, A. Hildesheim, P. Gonzalez, S. Evidence-and-Causality.aspx (accessed on 27.03.2015).
Wacholder, C. Porras, S. Jimenez, M. Schiffman, Impact of human [54] Global Advisory Committee on Vaccine Safety (GACVS), Statement on the
papillomavirus vaccination on cervical cytology screening, colposcopy, and Continued Safety of HPV Vaccination, (2014) Available from: http://www.
treatment, Am. J. Epidemiol. 178 (2013) 752–760. who.int/vaccine_safety/committee/topics/hpv/
[38] P.L. McCormack, Quadrivalent human papillomavirus (types 6, 11, 16, 18) GACVS_Statement_HPV_12_Mar_2014.pdf (accessed on 26.03.2015).
recombinant vaccine (gardasil((R))): a review of its use in the prevention of [55] J. Gaudelus, R. Cohen, A. Martinot, J.P. Stahl, T. Lery, D.M. Le, F. Denis, [HPV
premalignant anogenital lesions, cervical and anal cancers, and genital warts, vaccination is still difficult to implement], Med. Mal. Infect. 44 (2014)
Drugs 74 (2014) 1253–1283. 289–291.
[39] X. Castellsague, N. Munoz, P. Pitisuttithum, D. Ferris, J. Monsonego, K. Ault, J. [56] D. Ferris, R. Samakoses, S.L. Block, E. Lazcano-Ponce, J.A. Restrepo, K.S.
Luna, E. Myers, S. Mallary, O.M. Bautista, J. Bryan, S. Vuocolo, R.M. Haupt, A. Reisinger, J. Mehlsen, A. Chatterjee, O.E. Iversen, H.L. Sings, Q. Shou, T.A.
Saah, End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV Sausser, A. Saah, Long-term study of a quadrivalent human papillomavirus
(types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age, vaccine, Pediatrics 134 (2014) e657–e665.
Br. J. Cancer 105 (2011) 28–37. [57] S.N. Tabrizi, J.M. Brotherton, J.M. Kaldor, S.R. Skinner, E. Cummins, B. Liu, D.
[40] S.R. Skinner, A. Szarewski, B. Romanowski, S.M. Garland, E. Lazcano-Ponce, J. Bateson, K. McNamee, M. Garefalakis, S.M. Garland, Fall in human
Salmeron, M.R. Del Rosario-Raymundo, R.H. Verheijen, S.C. Quek, D.P. da papillomavirus prevalence following a national vaccination program, J.
Silva, H. Kitchener, K.L. Fong, C. Bouchard, D.M. Money, A. Ilancheran, M.E. Infect. Dis 206 (2012) 1645–1651.
Cruickshank, M.J. Levin, A. Chatterjee, J.T. Stapleton, M. Martens, W. Quint, M. [58] T.R. Read, J.S. Hocking, M.Y. Chen, B. Donovan, C.S. Bradshaw, C.K. Fairley, The
P. David, D. Meric, K. Hardt, D. Descamps, B. Geeraerts, F. Struyf, G. Dubin, near disappearance of genital warts in young women 4 years after
Efficacy, safety, and immunogenicity of the human papillomavirus 16/ commencing a national human papillomavirus (HPV) vaccination
18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim programme, Sex Transm. Infect. 87 (2011) 544–547.
follow-up of the phase 3, double-blind, randomised controlled VIVIANE [59] J.M. Brotherton, M. Fridman, C.L. May, G. Chappell, A.M. Saville, D.M. Gertig,
study, Lancet 384 (2014) 2213–2227. Early effect of the HPV vaccination programme on cervical abnormalities in
[41] A.R. Kreimer, P. Gonzalez, H.A. Katki, C. Porras, M. Schiffman, A.C. Rodriguez, Victoria, Australia: an ecological study, Lancet 377 (2011) 2085–2092.
D. Solomon, S. Jimenez, J.T. Schiller, D.R. Lowy, L.J. van Doorn, L. Struijk, W. [60] A. Leval, E. Herweijer, A. Ploner, S. Eloranta, S.J. Fridman, J. Dillner, C. Young, E.
Quint, S. Chen, S. Wacholder, A. Hildesheim, R. Herrero, Efficacy of a bivalent Netterlid, P. Sparen, L. Arnheim-Dahlstrom, Quadrivalent human
HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a papillomavirus vaccine effectiveness: a Swedish national cohort study, J.
nested analysis within the Costa Rica Vaccine Trial, Lancet Oncol. 12 (2011) Natl. Cancer Inst. 105 (2013) 469–474.
862–870. [61] U.S. Food and Drug Administration (FDA), Human Papillomavirus 9-valent
[42] R. Herrero, W. Quint, A. Hildesheim, P. Gonzalez, L. Struijk, H.A. Katki, C. Vaccine (Gardasil 9), (2015) Available from: http://www.fda.gov/
Porras, M. Schiffman, A.C. Rodriguez, D. Solomon, S. Jimenez, J.T. Schiller, D.R. BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm426445.htm
Lowy, L.J. van Doorn, S. Wacholder, A.R. Kreimer, Reduced prevalence of oral (accessed on 25.03.2015).
human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a [62] European Medicines Agency (EMA), Summary of the European Public
randomized clinical trial in Costa Rica, PLoS One 8 (2013) e68329. Assessment Report (EPAR) for Gardasil 9, (2015) Available from: http://www.
[43] K.A. Lang Kuhs, P. Gonzalez, A.C. Rodriguez, L.J. van Doorn, M. Schiffman, L. ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/
Struijk, S. Chen, W. Quint, D.R. Lowy, C. Porras, C. DelVecchio, S. Jimenez, M. 003852/human_med_001863.jsp (accessed on 05.08.2015).
Safaeian, J.T. Schiller, S. Wacholder, R. Herrero, A. Hildesheim, A.R. Kreimer, [63] A. Anttila, M. Arbyn, H. De Vuyst, J. Dillner, L. Dillner, S. Franceschi, J. Patnick,
Reduced prevalence of vulvar HPV16/18 infection among women who G. Ronco, N. Segnan, E. Suonio, S. Törnberg, L. von Karsa (Eds.), European
received the HPV16/18 bivalent vaccine: a nested analysis within the Costa Guidelines for Quality Assurance in Cervical Cancer Screening, Second
Rica vaccine trial, J. Infect. Dis. 210 (2014) 1890–1899. edition, Supplements, Office for Official Publications of the European Union,
[44] J. Paavonen, P. Naud, J. Salmeron, C.M. Wheeler, S.N. Chow, D. Apter, H. Luxembourg, 2015.
Kitchener, X. Castellsague, J.C. Teixeira, S.R. Skinner, J. Hedrick, U. Jaisamrarn, [64] A.R. Kreimer, A.C. Rodriguez, A. Hildesheim, R. Herrero, C. Porras, M.
G. Limson, S. Garland, A. Szarewski, B. Romanowski, F.Y. Aoki, T.F. Schwarz, W. Schiffman, P. Gonzalez, D. Solomon, S. Jimenez, J.T. Schiller, D.R. Lowy, W.
A. Poppe, F.X. Bosch, D. Jenkins, K. Hardt, T. Zahaf, D. Descamps, F. Struyf, M. Quint, M.E. Sherman, J. Schussler, S. Wacholder, Proof-of-principle evaluation
Lehtinen, G. Dubin, Efficacy of human papillomavirus (HPV)-16/18 AS04- of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine, J.
adjuvanted vaccine against cervical infection and precancer caused by Natl. Cancer Inst. 103 (2011) 1444–1451.
oncogenic HPV types (PATRICIA): final analysis of a double-blind, [65] E. Lazcano-Ponce, M. Stanley, N. Munoz, L. Torres, A. Cruz-Valdez, J. Salmeron,
randomised study in young women, Lancet 374 (2009) 301–314. R. Rojas, R. Herrero, M. Hernandez-Avila, Overcoming barriers to HPV
[45] C.M. Wheeler, S.K. Kjaer, K. Sigurdsson, O.E. Iversen, M. Hernandez-Avila, G. vaccination: non-inferiority of antibody response to human papillomavirus
Perez, D.R. Brown, L.A. Koutsky, E.H. Tay, P. Garcia, K.A. Ault, S.M. Garland, S. 16/18 vaccine in adolescents vaccinated with a two-dose vs. a three-dose
Leodolter, S.E. Olsson, G.W. Tang, D.G. Ferris, J. Paavonen, M. Steben, F.X. schedule at 21 months, Vaccine 32 (2014) 725–732.
Bosch, J. Dillner, E.A. Joura, R.J. Kurman, S. Majewski, N. Munoz, E.R. Myers, L. [66] S.R. Dobson, S. McNeil, M. Dionne, M. Dawar, G. Ogilvie, M. Krajden, C.
L. Villa, F.J. Taddeo, C. Roberts, A. Tadesse, J. Bryan, L.C. Lupinacci, K.E. Sauvageau, D.W. Scheifele, T.R. Kollmann, S.A. Halperin, J.M. Langley, J.A.
Giacoletti, M. James, S. Vuocolo, T.M. Hesley, E. Barr, The impact of Bettinger, J. Singer, D. Money, D. Miller, M. Naus, F. Marra, E. Young,
quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus- Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses
like particle vaccine on infection and disease due to oncogenic nonvaccine in young women: a randomized clinical trial, JAMA 309 (2013) 1793–1802.
HPV types in sexually active women aged 16-26 years, J. Infect. Dis. 199 [67] M. D’Addario, P. Scott, S. Redmond, N. Low, HPV vaccines: systematic review
(2009) 936–944. of literature on alternative vaccination schedules, in: Evidence-based
[46] K.K. Macartney, C. Chiu, M. Georgousakis, J.M. Brotherton, Safety of human recommendations on human papillomavirus (HPV) schedules: Background
papillomavirus vaccines: a review, Drug Safety 36 (2013) 393–412. paper for SAGE discussions, World Health Organization, Geneva (2014) .
[47] S.L. Block, D.R. Brown, A. Chatterjee, M.A. Gold, H.L. Sings, A. Meibohm, A. [68] H. De Vuyst, R. Howell-Jones, D. Levy-Bruhl, P. Giorgi Rossi, S. Franceschi,
Dana, R.M. Haupt, E. Barr, G.M. Tamms, H. Zhou, K.S. Reisinger, Clinical trial Implementation of vaccination against human papillomavirus in Europe (S3),
and post-licensure safety profile of a prophylactic human papillomavirus in: A. Anttila, M. Arbyn, H. De Vuyst, J. Dillner, L. Dillner, S. Franceschi, J.
(types 6, 11, 16, and 18) l1 virus-like particle vaccine, Pediatr. Infect. Dis. J. 29 Patnick, G. Ronco, N. Segnan, E. Suonio, S. Törnberg, L. von Karsa (Eds.),
(2010) 95–101. European Guidelines for Quality Assurance in Cervical Cancer Screening,
[48] M.G. Angelo, M.P. David, J. Zima, L. Baril, G. Dubin, F. Arellano, F. Struyf, Pooled Second edition, Supplements, Office for Official Publications of the European
analysis of large and long-term safety data from the human papillomavirus- Union, Luxembourg, 2015.
16/18-AS04-adjuvanted vaccine clinical trial programme, [69] K.M. Elfstrom, J. Dillner, L. Arnheim-Dahlstrom, Organization and quality of
Pharmacoepidemiol. Drug Safety 23 (2014) 466–479. HPV vaccination programs in Europe, Vaccine 33 (2015) 1673–1681.
[49] J. Bonhoeffer, S. Black, H. Izurieta, P. Zuber, M. Sturkenboom, Current status [70] B. Owsianka, M. Ganczak, Evaluation of human papilloma virus (HPV)
and future directions of post-marketing vaccine safety monitoring with focus vaccination strategies and vaccination coverage in adolescent girls
on USA and Europe, Biologicals 40 (2012) 393–397. worldwide, Przegl. Epidemiol. 69 (2015) 53–55.
[50] MHRA (Medicines and Healthcare Products Regulatory Agency), Yellow Card [71] I. Baussano, J. Dillner, F. Lazzarato, G. Ronco, S. Franceschi, Upscaling human
Scheme, (2014) Available from https://yellowcard.mhra.gov.uk/ (acessed on papillomavirus vaccination in high-income countries: impact assessment
26.02.2015). based on transmission model, Infect. Agent Cancer 9 (2014) 4.
[51] M.G. Angelo, J. Zima, S.F. Tavares Da, L. Baril, F. Arellano, Post-licensure safety [72] European Medicines Agency (EMA), Summary of the European Public
surveillance for human papillomavirus-16/18-AS04-adjuvanted vaccine: Assessment Report (EPAR) for Cervarix, (2015) Available from: http://www.
more than 4 years of experience, Pharmacoepidemiol. Drug Safety 23 (2014) ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/
456–465. 000721/human_med_000694.jsp&mid=WC0b01ac058001d124 (accessed
[52] B.A. Slade, L. Leidel, C. Vellozzi, E.J. Woo, W. Hua, A. Sutherland, H.S. Izurieta, on 27.03.2015).
R. Ball, N. Miller, M.M. Braun, L.E. Markowitz, J. Iskander, Postlicensure safety [73] European Medicines Agency (EMA), Summary of the European Public
surveillance for quadrivalent human papillomavirus recombinant vaccine, Assessment Report (EPAR) for Gardasil, (2015) Available from: http://www.
JAMA 302 (2009) 750–757. ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
G Model
CANEP 930 No. of Pages 19
P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx 17
000703/human_med_000805.jsp&mid=WC0b01ac058001d124 (accessed [96] H.J. Alter, L.B. Seeff, Recovery, persistence, and sequelae in hepatitis C virus
on 27.03.2015). infection: a perspective on long-term outcome, Semin. Liver Dis. 20 (2000)
[74] European Centre for Disease Prevention and Control, Introduction of HPV 17–35.
Vaccines in EU countries – An Update, (2012) Available from: http://ecdc. [97] C.F. Huang, W.L. Chuang, M.L. Yu, Chronic hepatitis C infection in the elderly,
europa.eu/en/publications/_layouts/forms/Publication_DispForm.aspx? Kaohsiung J. Med. Sci. 27 (2011) 533–537.
List=4f55ad51-4aed-4d32-b960-af70113dbb90&ID=677 (accessed on [98] World Health Organization, Hepatitis B vaccines. Position paper, Weekly
03.11.2015). Epidemiol. Rec. 40 (2009) 405–420.
[75] T.A. Westra, M.H. Rozenbaum, R.M. Rogoza, H.W. Nijman, T. Daemen, M.J. [99] A. Ortqvist, M. Blennow, R.M. Carlsson, L.A. Hanson, A. Lindberg, L. Lindqvist,
Postma, J.C. Wilschut, Until which age should women be vaccinated against M. Magnusson, L. Nilsson, A. Norlund, O. Nyren, P. Olcen, P. Olin, S.A.
HPV infection? Recommendation based on cost-effectiveness analyses, J. Silfverdal, J. Sawe, A. Soderstrom, B. Trollfors, Vaccination of children–a
Infect. Dis. 204 (2011) 377–384. systematic review, Acta Paediatr. Suppl. 99 (2010) 1–192.
[76] E.F. Rodriguez, J.P. Reynolds, S.M. Jenkins, S.M. Winter, M.R. Henry, A. Nassar, [100] J.L. Mathew, D.R. El, P.J. Mathew, E.H. Boxall, J. Brok, Hepatitis B immunisation
Atypical squamous cells of undetermined significance in patients with HPV in persons not previously exposed to hepatitis B or with unknown exposure
positive DNA testing and correlation with disease progression by age group: status, Cochrane Database Syst. Rev. (2008) CD006481.
an institutional experience, Int. J. Clin. Exp. Pathol. 5 (2012) 428–435. [101] F. Cui, L. Li, S.C. Hadler, F. Wang, H. Zheng, Y. Chen, X. Gong, Y.J. Hutin, K.L.
[77] PBAC (The Pharmaceutical Benefits Advisory Committee)-Australian Cairns, X. Liang, W. Yang, Factors associated with effectiveness of the first
Government (Depatment of Health), November 2011 PBAC Meeting dose of hepatitis B vaccine in China: 1992–2005, Vaccine 28 (2010) 5973–
Outcomes – Positive Recommendations, (2011) Available from: http://www. 5978.
pbs.gov.au/info/industry/listing/elements/pbac-meetings/pbac-outcomes/ [102] Y.H. Ni, M.H. Chang, J.F. Wu, H.Y. Hsu, H.L. Chen, D.S. Chen, Minimization of
2011-11/positive-recommendations (accessed on 27.03.2015). hepatitis B infection by a 25-year universal vaccination program, J. Hepatol.
[78] NACI (National Advisory Committee on Immunization), Update on Human 57 (2012) 730–735.
Papillomavirus (HPV) Vaccines (an Advisory Committee Statement), Canada [103] C.J. Chiang, Y.W. Yang, S.L. You, M.S. Lai, C.J. Chen, Thirty-year outcomes of the
Communicable Disease Report (CCDR) vol. 38(2012) Available from: http:// national hepatitis B immunization program in Taiwan, JAMA 310 (2013) 974–
www.phac-aspc.gc.ca/publicat/ccdr-rmtc/12vol38/acs-dcc-1/assets/pdf/ 976.
12vol-38-acs-dcc-1-eng.pdf (accessed on 26.03.2015). [104] Z. Sun, T. Chen, S.S. Thorgeirsson, Q. Zhan, J. Chen, J.H. Park, P. Lu, C.C. Hsia, N.
[79] CDC (Centers for Disease Control and Prevention), Human Papillomavirus Wang, L. Xu, L. Lu, F. Huang, Y. Zhu, J. Lu, Z. Ni, Q. Zhang, Y. Wu, G. Liu, Z. Wu, C.
Vaccination: Recommendations of the Advisory Committee on Qu, M.H. Gail, Dramatic reduction of liver cancer incidence in young adults:
Immunization Practices (ACIP), (2014) Available from: http://www.cdc.gov/ 28 year follow-up of etiological interventions in an endemic area of China,
mmwr/preview/mmwrhtml/rr6305a1.htm (accessed on 26.03.2015). Carcinogenesis 34 (2013) 1800–1805.
[80] A.R. Giuliano, A.G. Nyitray, A.R. Kreimer, C.M. Pierce Campbell, M.T. [105] H. Tajiri, H. Tanaka, S. Brooks, T. Takano, Reduction of hepatocellular
Goodman, S.L. Sudenga, J. Monsonego, S. Franceschi, EUROGIN 2014 carcinoma in childhood after introduction of selective vaccination against
roadmap: differences in human papillomavirus infection natural history, hepatitis B virus for infants born to HBV carrier mothers, Cancer Causes
transmission and human papillomavirus-related cancer incidence by gender Control 22 (2011) 523–527.
and anatomic site of infection, Int. J. Cancer 136 (2015) 2752–2760. [106] B.J. McMahon, L.R. Bulkow, R.J. Singleton, J. Williams, M. Snowball, C. Homan,
[81] IARC, The European Code Against Cancer (ECAC), (2014) Available from: A.J. Parkinson, Elimination of hepatocellular carcinoma and acute hepatitis B
http://cancer-code-europe.iarc.fr (accessed on 12.03.2015). in children 25 years after a hepatitis B newborn and catch-up immunization
[82] S. Franceschi, R. Herrero, Infections, in: B.W. Stewart, C.P. Wild (Eds.), World program, Hepatology 54 (2011) 801–807.
Cancer Report 2014, International Agency for Research on Cancer, 2014, pp. [107] The Gambia Hepatitis Study Group, The Gambia Hepatitis Intervention Study,
105–114. Cancer Res. 47 (1987) 5782–5787.
[83] N.D. Theise, Liver cancer, in: B.W. Stewart, C.P. Wild (Eds.), World Cancer [108] M. Mendy, I. Peterson, S. Hossin, T. Peto, M.L. Jobarteh, A. Jeng-Barry, M.
Report 2014, International Agency for Research on Cancer, 2014, pp. 105–114. Sidibeh, A. Jatta, S.E. Moore, A.J. Hall, H. Whittle, Observational study of
[84] C.J. Chen, W. Chen, S. Franceschi, S.A. Hall, W.T. London, K.A. McGlynn, C.P. vaccine efficacy 24 years after the start of hepatitis B vaccination in two
Wild, H. Gelband, Liver Cancer, in: H. Gelband, P. Jha, R. Sankaranarayanan, S. Gambian villages: no need for a booster dose, PLoS One 8 (2013) e58029.
Horton (Eds.), Cancer, University of Washington, Department of Global [109] S. Viviani, P. Carrieri, E. Bah, A.J. Hall, G.D. Kirk, M. Mendy, R. Montesano, A.
Health, Seattle, 2014. Plymoth, O. Sam, M. Van der Sande, H. Whittle, P. Hainaut, 20 years into the
[85] H.B. El-Serag, Epidemiology of viral hepatitis and hepatocellular carcinoma, Gambia Hepatitis Intervention Study: assessment of initial hypotheses and
Gastroenterology 142 (2012) 1264–1273.e1. prospects for evaluation of protective effectiveness against liver cancer,
[86] F. Forghieri, M. Luppi, P. Barozzi, R. Maffei, L. Potenza, F. Narni, R. Marasca, Cancer Epidemiol Biomarkers Prev. 17 (2008) 3216–3223.
Pathogenetic mechanisms of hepatitis C virus-induced B-cell [110] Z. Sun, Y. Zhu, J. Stjernsward, M. Hilleman, R. Collins, Y. Zhen, C.C. Hsia, J. Lu, F.
lymphomagenesis, Clin. Dev. Immunol. 2012 (807351) (2012) . Huang, Z. Ni, Design and compliance of HBV vaccination trial on newborns to
[87] P. Boffetta, M. Hashibe, V.C. La, W. Zatonski, J. Rehm, The burden of cancer prevent hepatocellular carcinoma and 5-year results of its pilot study, Cancer
attributable to alcohol drinking, Int. J. Cancer 119 (2006) 884–887. Detect. Prev. 15 (1991) 313–318.
[88] S.A. Raza, G.M. Clifford, S. Franceschi, Worldwide variation in the relative [111] C. Qu, T. Chen, C. Fan, Q. Zhan, Y. Wang, J. Lu, L.L. Lu, Z. Ni, F. Huang, H. Yao, J.
importance of hepatitis B and hepatitis C viruses in hepatocellular Zhu, J. Fan, Y. Zhu, Z. Wu, G. Liu, W. Gao, M. Zang, D. Wang, M. Dai, C.C. Hsia, Y.
carcinoma: a systematic review, Br. J. Cancer 96 (2007) 1127–1134. Zhang, Z. Sun, Efficacy of neonatal HBV Vaccination on liver cancer and other
[89] S.J. Hahne, I.K. Veldhuijzen, L. Wiessing, T.A. Lim, M. Salminen, M. Laar, liver diseases over 30-Year Follow-up of the Qidong Hepatitis B intervention
Infection with hepatitis B and C virus in Europe: a systematic review of study: a cluster randomized controlled trial, PLoS Med. 11 (2014) e1001774.
prevalence and cost-effectiveness of screening, BMC Infect. Dis.13 (2013) 181. [112] Institute of Medicine, The Childhood Immunization Schedule and Safety:
[90] V.D. Hope, I. Eramova, D. Capurro, M.C. Donoghoe, Prevalence and estimation Stakeholder Concerns, Scientific Evidence, and Future Studies, The National
of hepatitis B and C infections in the WHO European Region: a review of data Academies Press, Washington, DC, 2013.
focusing on the countries outside the European Union and the European Free [113] D. O’Flanagan, S. Cotter, J. Mereckiene, Hepatitis B Vaccination in Europe
Trade Association, Epidemiol. Infect. 142 (2014) 270–286. November 2008–March 2009 (VENICE project), (2009) Available from:
[91] European Centre for Disease Prevention and Control, Assessing the Burden of http://venice.cineca.org/Report_Hepatitis_B_Vaccination.pdf (accessed on
Key Infectious Diseases Affecting Migrant Populations in the EU/EEA, (2014) 06.08.2015).
Available from: http://ecdc.europa.eu/en/publications/_layouts/forms/ [114] World Health Organization, Guidelines for the Screening, Care and Treatment
Publication_DispForm.aspx?List=4f55ad51-4aed-4d32-b960- of Persons with Hepatitis C Infection, (2014) Available from: http://www.
af70113dbb90&ID=1099 (accessed on 03.11.2015). who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (accessed on
[92] A. Hatzakis, D.P. Van, K. Alcorn, C. Gore, M. Benazzouz, S. Berkane, M. Buti, M. 03.11.2015).
Carballo, M.H. Cortes, S. Deuffic-Burban, A. Dominguez, M. Donoghoe, A.N. [115] National Institute for Health and Care Excellence (NICE), Hepatitis B and C
Elzouki, B.N. Ben-Alaya, G. Esmat, R. Esteban, M. Fabri, K. Fenton, D. Goldberg, Testing: People at Risk of Infection, NICE Guidelines [PH43], (2012) Available
I. Goulis, C. Hadjichristodoulou, T. Hatzigeorgiou, O. Hamouda, S. Hasurdjiev, from: https://www.nice.org.uk/guidance/ph43 (accessed on 05.11.2015).
S. Hughes, A. Kautz, M. Malik, S. Manolakopoulos, M. Maticic, G. [116] National Institute for Health and Care Excellence (NICE), Hepatitis B
Papatheodoridis, R. Peck, A. Peterle, G. Potamitis, D. Prati, F. Roudot-Thoraval, (chronic): Diagnosis and Management, NICE Guidelines [CG165], (2013)
T. Reic, A. Sharara, M. Shennak, G. Shiha, D. Shouval, M. Socan, H. Thomas, M. Available from: https://www.nice.org.uk/guidance/cg165 (accessed on
Thursz, M. Tosti, C. Trepo, A. Vince, E. Vounou, L. Wiessing, M. Manns, The 05.11.2015).
state of hepatitis B and C in the Mediterranean and Balkan countries: report [117] European Association for the Study of the Liver (EASL), EASL clinical practice
from a summit conference, J. Viral. Hepat. 20 (Suppl. 2) (2013) 1–20. guidelines: management of chronic hepatitis B virus infection, J. Hepatol. 57
[93] M. Tarocchi, S. Polvani, G. Marroncini, A. Galli, Molecular mechanism of (2012) 167–185.
hepatitis B virus-induced hepatocarcinogenesis, World J. Gastroenterol. 20 [118] European Association for the Study of the Liver (EASL), EASL
(2014) 11630–11640. recommendations on treatment of hepatitis C, J. Hepatol. 61 (2014) 373–395.
[94] E. Gower, C.C. Estes, S. Hindman, K. Razavi-Shearer, H. Razavi, Global [119] M.L. LeFevre, Screening for hepatitis B virus infection in nonpregnant
epidemiology and genotype distribution of the hepatitis C virus infection, J. adolescents and adults: U.S. Preventive Services Task Force recommendation
Hepatol. (2014) . statement, Ann. Int. Med. 161 (2014) 58–66.
[95] A. Arzumanyan, H.M. Reis, M.A. Feitelson, Pathogenic mechanisms in HBV- [120] Y.F. Liaw, Impact of therapy on the outcome of chronic hepatitis B, Liver Int.
and HCV-associated hepatocellular carcinoma, Nat. Rev. Cancer 13 (2013) 33 (Suppl. 1) (2013) 111–115.
123–135.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
G Model
CANEP 930 No. of Pages 19
18 P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx
[121] E.R. Schiff, S.S. Lee, Y.C. Chao, Y.S. Kew, F. Bessone, S.S. Wu, W. Kryczka, Y. Al-Assi, G.M. Subramanian, D. An, M. Lin, J. McNally, D. Brainard, W.T.
Lurie, A. Gadano, G. Kitis, S. Beebe, D. Xu, H. Tang, U. Iloeje, Long-term Symonds, J.G. McHutchison, K. Patel, J. Feld, S. Pianko, D.R. Nelson, Sofosbuvir
treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in for hepatitis C genotype 2 or 3 in patients without treatment options, N. Engl.
patients with chronic hepatitis B, Clin. Gastroenterol. Hepatol. 9 (2011) J. Med. 368 (2013) 1867–1877.
274–276. [140] S. Zeuzem, G.M. Dusheiko, R. Salupere, A. Mangia, R. Flisiak, R.H. Hyland, A.
[122] P. Marcellin, E. Gane, M. Buti, N. Afdhal, W. Sievert, I.M. Jacobson, M.K. Illeperuma, E. Svarovskaia, D.M. Brainard, W.T. Symonds, G.M. Subramanian,
Washington, G. Germanidis, J.F. Flaherty, R.A. Schall, J.D. Bornstein, K.M. J.G. McHutchison, O. Weiland, H.W. Reesink, P. Ferenci, C. Hezode, R. Esteban,
Kitrinos, G.M. Subramanian, J.G. McHutchison, E.J. Heathcote, Regression Sofosbuvir and ribavirin in HCV genotypes 2 and 3, N. Engl. J. Med. 370 (2014)
of cirrhosis during treatment with tenofovir disoproxil fumarate for 1993–2001.
chronic hepatitis B: a 5-year open-label follow-up study, Lancet 381 (2013) [141] J.M. Pawlotsky, NS5A inhibitors in the treatment of hepatitis C, J. Hepatol. 59
468–475. (2013) 375–382.
[123] T.T. Chang, Y.F. Liaw, S.S. Wu, E. Schiff, K.H. Han, C.L. Lai, R. Safadi, S.S. Lee, W. [142] N. Afdhal, K.R. Reddy, D.R. Nelson, E. Lawitz, S.C. Gordon, E. Schiff, R. Nahass,
Halota, Z. Goodman, Y.C. Chi, H. Zhang, R. Hindes, U. Iloeje, S. Beebe, B. Kreter, R. Ghalib, N. Gitlin, R. Herring, J. Lalezari, Z.H. Younes, P.J. Pockros, A.M. Di
Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and Bisceglie, S. Arora, G.M. Subramanian, Y. Zhu, H. Dvory-Sobol, J.C. Yang, P.S.
continued histological improvement in patients with chronic hepatitis B, Pang, W.T. Symonds, J.G. McHutchison, A.J. Muir, M. Sulkowski, P. Kwo,
Hepatology 52 (2010) 886–893. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection, N.
[124] G.L. Wong, K.K. Yiu, V.W. Wong, K.K. Tsoi, H.L. Chan, Meta-analysis: reduction Engl. J. Med. 370 (2014) 1483–1493.
in hepatic events following interferon-alfa therapy of chronic hepatitis B, [143] K.V. Kowdley, S.C. Gordon, K.R. Reddy, L. Rossaro, D.E. Bernstein, E. Lawitz, M.
Aliment Pharmacol. Ther. 32 (2010) 1059–1068. L. Shiffman, E. Schiff, R. Ghalib, M. Ryan, V. Rustgi, M. Chojkier, R. Herring, A.
[125] H. Jin, N. Pan, Y. Mou, B. Wang, P. Liu, Long-term effect of interferon treatment M. Di Bisceglie, P.J. Pockros, G.M. Subramanian, D. An, E. Svarovskaia, R.H.
on the progression of chronic hepatitis B: Bayesian meta-analysis and meta- Hyland, P.S. Pang, W.T. Symonds, J.G. McHutchison, A.J. Muir, D. Pound, M.W.
regression, Hepatol. Res. 41 (2011) 512–523. Fried, Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without
[126] J. Petersen, M. Buti, Considerations for the long-term treatment of chronic cirrhosis, N. Engl. J. Med. 370 (2014) 1879–1888.
hepatitis B with nucleos(t) ide analogs, Expert Rev. Gastroenterol. Hepatol. 6 [144] K. van de Vooren, A. Curto, L. Garattini, Pricing of forthcoming therapies for
(2012) 683–694. hepatitis C in Europe: beyond cost-effectiveness? Eur. J. Health. Econ. 16
[127] M. Sherman, Does hepatitis B treatment reduce the incidence of (2015) 341–345.
hepatocellular carcinoma? Hepatology 58 (2013) 18–20. [145] M. Plummer, S. Franceschi, J. Vignat, D. Forman, C. De Martel, Global burden
[128] C.M. Fernandez-Rodriguez, M.L. Gutierrez-Garcia, Prevention of of gastric cancer attributable to Helicobacter pylori, Int. J. Cancer 136 (2015)
hepatocellular carcinoma in patients with chronic hepatitis B, World J. 487–490.
Gastrointest. Pharmacol. Ther. 5 (2014) 175–182. [146] J. Bastos, B. Peleteiro, R. Barros, L. Alves, M. Severo, P.M. de Fatima, H. Pinto, S.
[129] N. Kimer, E.K. Dahl, L.L. Gluud, A. Krag, Antiviral therapy for prevention of Carvalho, A. Marinho, J.T. Guimaraes, A. Azevedo, V.C. La, H. Barros,
hepatocellular carcinoma in chronic hepatitis C: systematic review and N. Lunet, Sociodemographic determinants of prevalence and incidence of
meta-analysis of randomised controlled trials, BMJ Open 2 (2012) . Helicobacter pylori infection in Portuguese adults, Helicobacter 18 (2013)
[130] A.G. Singal, M.L. Volk, D. Jensen, A.M. Di Bisceglie, P.S. Schoenfeld, A sustained 413–422.
viral response is associated with reduced liver-related morbidity and [147] R.M. Zagari, L. Fuccio, M.A. Wallander, S. Johansson, R. Fiocca, S. Casanova, B.Y.
mortality in patients with hepatitis C virus, Clin. Gastroenterol. Hepatol. 8 Farahmand, C.C. Winchester, E. Roda, F. Bazzoli, Gastro-oesophageal reflux
(2010) 280–288.e1. symptoms, oesophagitis and Barrett’s oesophagus in the general population:
[131] A.J. van der Meer, B.J. Veldt, J.J. Feld, H. Wedemeyer, J.F. Dufour, F. Lammert, A. the Loiano–Monghidoro study, Gut 57 (2008) 1354–1359.
Duarte-Rojo, E.J. Heathcote, M.P. Manns, L. Kuske, S. Zeuzem, W.P. Hofmann, [148] World Gastroenterology Organisation Global Guidelines, Helicobacter pylori
R.J. de Knegt, B.E. Hansen, H.L. Janssen, Association between sustained in Developing Countries, (2010) Available from: http://www.
virological response and all-cause mortality among patients with chronic worldgastroenterology.org/guidelines/global-guidelines/helicobacter-
hepatitis C and advanced hepatic fibrosis, JAMA 308 (2012) 2584–2593. pylori-in-developing-countries/helicobacter-pylori-in-developing-
[132] R.L. Morgan, B. Baack, B.D. Smith, A. Yartel, M. Pitasi, Y. Falck-Ytter, countries-english (accessed on 05.11.2015).
Eradication of hepatitis C virus infection and the development of [149] P. Moayyedi, A.T. Axon, R. Feltbower, S. Duffett, W. Crocombe, D. Braunholtz, I.
hepatocellular carcinoma: a meta-analysis of observational studies, Ann. Int. D. Richards, A.C. Dowell, D. Forman, Relation of adult lifestyle and
Med. 158 (2013) 329–337. socioeconomic factors to the prevalence of Helicobacter pylori infection, Int. J.
[133] M.W. Fried, M. Buti, G.J. Dore, R. Flisiak, P. Ferenci, I. Jacobson, P. Marcellin, M. Epidemiol. 31 (2002) 624–631.
Manns, I. Nikitin, F. Poordad, M. Sherman, S. Zeuzem, J. Scott, L. Gilles, O. Lenz, [150] C. Porras, J. Nodora, R. Sexton, C. Ferreccio, S. Jimenez, R.L. Dominguez, P.
M. Peeters, V. Sekar, S.G. De, M. Beumont-Mauviel, Once-daily simeprevir Cook, G. Anderson, D.R. Morgan, L.H. Baker, E.R. Greenberg, R. Herrero,
(TMC435) with pegylated interferon and ribavirin in treatment-naive Epidemiology of Helicobacter pylori infection in six Latin American countries
genotype 1 hepatitis C: the randomized PILLAR study, Hepatology 58 (2013) (SWOG Trial S0701), Cancer Causes Control 24 (2013) 209–215.
1918–1929. [151] J.Y. Yim, N. Kim, S.H. Choi, Y.S. Kim, K.R. Cho, S.S. Kim, G.S. Seo, H.U. Kim, G.H.
[134] I.M. Jacobson, G.J. Dore, G.R. Foster, M.W. Fried, M. Radu, V.V. Rafalsky, L. Baik, C.S. Sin, S.H. Cho, B.H. Oh, Seroprevalence of Helicobacter pylori in South
Moroz, A. Craxi, M. Peeters, O. Lenz, S. Ouwerkerk-Mahadevan, G. De La Rosa, Korea, Helicobacter 12 (2007) 333–340.
R. Kalmeijer, J. Scott, R. Sinha, M. Beumont-Mauviel, Simeprevir with [152] M. Oona, M. Utt, I. Nilsson, O. Uibo, T. Vorobjova, H.I. Maaroos, Helicobacter
pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with pylori infection in children in Estonia: decreasing seroprevalence during the
chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, 11-year period of profound socioeconomic changes, Helicobacter 9 (2004)
randomised, double-blind, placebo-controlled trial, Lancet 384 (2014) 233–241.
403–413. [153] E.R. Greenberg, J.Y. Park, Effectiveness of Helicobacter pylori eradication, in: I.
[135] M. Manns, P. Marcellin, F. Poordad, E.S. de Araujo, M. Buti, Y. Horsmans, E. A.R.C. Helicobacter working group (2014) (Ed.), Helicobacter pylori
Janczewska, F. Villamil, J. Scott, M. Peeters, O. Lenz, S. Ouwerkerk- eradication as a strategy for preventing gastric cancer, International Agency
Mahadevan, G. De La Rosa, R. Kalmeijer, R. Sinha, M. Beumont-Mauviel, for Research on Cancer (IARC Working Group Reports, No. 8), Lyon, France,
Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in 2014, pp. 64–71.
treatment-naive patients with chronic hepatitis C virus genotype 1 infection [154] J.L. Ma, L. Zhang, L.M. Brown, J.Y. Li, L. Shen, K.F. Pan, W.D. Liu, Y. Hu, Z.X. Han,
(QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial, S. Crystal-Mansour, D. Pee, W.J. Blot, J.F. Fraumeni Jr., W.C. You, M.H. Gail,
Lancet 384 (2014) 414–426. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on
[136] X. Forns, E. Lawitz, S. Zeuzem, E. Gane, J.P. Bronowicki, P. Andreone, A. Horban, gastric cancer incidence and mortality, J. Natl. Cancer Inst. 104 (2012) 488–
A. Brown, M. Peeters, O. Lenz, S. Ouwerkerk-Mahadevan, J. Scott, G. De La 492.
Rosa, R. Kalmeijer, R. Sinha, M. Beumont-Mauviel, Simeprevir with [155] A.C. Ford, D. Forman, R.H. Hunt, Y. Yuan, P. Moayyedi, Helicobacter pylori
peginterferon and ribavirin leads to high rates of SVR in patients with HCV eradication therapy to prevent gastric cancer in healthy asymptomatic
genotype 1 who relapsed after previous therapy: a phase 3 trial, infected individuals: systematic review and meta-analysis of randomised
Gastroenterology 146 (2014) 1669–1679. controlled trials, BMJ 348 (2014) g3174.
[137] S. Zeuzem, T. Berg, E. Gane, P. Ferenci, G.R. Foster, M.W. Fried, C. Hezode, G.M. [156] J.P. Gisbert, E.R. Greenberg, Potential regimens for the mass eradication of
Hirschfield, I. Jacobson, I. Nikitin, P.J. Pockros, F. Poordad, J. Scott, O. Lenz, M. Helicobacter pylori infection, in: IARC Helicobacter working group (2014)
Peeters, V. Sekar, S.G. De, R. Sinha, M. Beumont-Mauviel, Simeprevir (Ed.), Helicobacter pylori eradication as a strategy for preventing gastric
increases rate of sustained virologic response among treatment-experienced cancer, International Agency for Research on Cancer (IARC Working Group
patients with HCV genotype-1 infection: a phase IIb trial, Gastroenterology Reports, No. 8), Lyon, France, 2014, pp. 95–110.
146 (2014) 430–441.e6. [157] P. Malfertheiner, F. Megraud, C.A. O’Morain, J. Atherton, A.T. Axon, F. Bazzoli,
[138] E. Lawitz, A. Mangia, D. Wyles, M. Rodriguez-Torres, T. Hassanein, S.C. G.F. Gensini, J.P. Gisbert, D.Y. Graham, T. Rokkas, E.M. El-Omar, E.J. Kuipers,
Gordon, M. Schultz, M.N. Davis, Z. Kayali, K.R. Reddy, I.M. Jacobson, K.V. Management of Helicobacter pylori infection–the Maastricht IV/Florence
Kowdley, L. Nyberg, G.M. Subramanian, R.H. Hyland, S. Arterburn, D. Jiang, J. Consensus Report, Gut 61 (2012) 646–664.
McNally, D. Brainard, W.T. Symonds, J.G. McHutchison, A.M. Sheikh, Z. [158] IARC Helicobacter pylori Working Group, Helicobacter pylori Eradication as a
Younossi, E.J. Gane, Sofosbuvir for previously untreated chronic hepatitis C Strategy for Preventing Gastric Cancer, International Agency for Research on
infection, N. Engl. J. Med. 368 (2013) 1878–1887. Cancer (IARC Working Group Reports, No. 8), Lyon, France, 2014 Available
[139] I.M. Jacobson, S.C. Gordon, K.V. Kowdley, E.M. Yoshida, M. Rodriguez-Torres, from: http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.php
M.S. Sulkowski, M.L. Shiffman, E. Lawitz, G. Everson, M. Bennett, E. Schiff, M.T. (accessed on 03.11.2015).
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006
G Model
CANEP 930 No. of Pages 19
P. Villain et al. / Cancer Epidemiology xxx (2015) xxx–xxx 19
[159] S. Franceschi, M. Lise, G.M. Clifford, M. Rickenbach, F. Levi, M. Maspoli, C. [163] R. Chou, S. Selph, T. Dana, C. Bougatsos, B. Zakher, I. Blazina, P.T. Korthuis,
Bouchardy, S. Dehler, G. Jundt, S. Ess, A. Bordoni, I. Konzelmann, H. Frick, M. Screening for HIV: systematic review to update the 2005 U.S. Preventive
Dal, L. aso, L. Elzi, H. Furrer, A. Calmy, M. Cavassini, B. Ledergerber, O. Keiser, Services Task Force recommendation, Ann. Int. Med. 157 (2012) 706–718.
Changing patterns of cancer incidence in the early- and late-HAART periods: [164] World Health Organization, Consolidated Guidelines on the Use of
the Swiss HIV Cohort Study, Br. J. Cancer 103 (2010) 416–422. Antiretroviral Drugs for Treating and Preventing HIV Infection:
[160] Joint United Nations Programme on HIV/AIDS (UNAIDS), 2012-UNAIDS Recommendations for a Public Health Approach, (2013) Available from:
Report on the Global AIDS Epidemic, (2012) Available from: http://www. http://www.who.int/hiv/pub/guidelines/arv2013/en/ (accessed on
unaids.org/en/resources/documents/2012/ 03.11.2015).
20121120_UNAIDS_Global_Report_2012 (accessed on 03.11.2015). [165] Panel on Antiretroviral Guidelines for Adults and Adolescents, Guidelines for
[161] European Centre for Disease Prevention and Control/WHO Regional Office for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents,
Europe, HIV/AIDS Surveillance in Europe 2013, (2014) Available from: http:// (2015) Available from: http://aidsinfo.nih.gov/guidelines/html/1/adult-and-
ecdc.europa.eu/en/publications/_layouts/forms/Publication_DispForm. adolescent-treatment-guidelines/0/ (accessed on 03.11.2015).
aspx?List=4f55ad51-4aed-4d32-b960-af70113dbb90&ID=1217 (accessed on [166] U.S. Department of Health and Human Services, Guide for HIV/AIDS Clinical
03.11.2015). Care–2014 Edition, (2014) Available from: http://hab.hrsa.gov/
[162] G. Clifford, B. Bertisch, S. Franceschi, Clifford et al. respond to biological and deliverhivaidscare/2014guide.pdf (accessed on 03.11.2015).
clinical insights from epidemiologic research into HIV, HPV, and anal cancer, [167] V.A. Moyer, Screening for HIV: U.S. Preventive Services Task Force
Am. J. Epidemiol. 178 (2013) 888–889. Recommendation Statement, Ann. Int. Med. 159 (2013) 51–60.
Please cite this article in press as: P. Villain, et al., European Code against Cancer 4th Edition: Infections and Cancer, Cancer Epidemiology
(2015), http://dx.doi.org/10.1016/j.canep.2015.10.006