Download Strategies to reduce the risk of virus

Annals of Oncology 11: 1091-1096, 2000
© 2000 Khmer Academic Publishers. Printed in the Netherlands
Review
Strategies to reduce the risk of virus-related cancers
S. Franceschi
Epidemiology Unit, Centro di Riferimento Oncologico, Aviano, Italy; Current address- the International Agency for Research on Cancer,
Lyon, France
vaccination aimed at cancer prevention is already a reality or
a possibility. Whereas HBV vaccination already emerged as
Background: Experimental and epidemiological evidence has one of the most cost-effective ways to reduce adult cancer
established an association between at least eight viruses and mortality, for HPV vaccination some technical problems still
various cancer sites. Recent estimates (at least 10% of cancer await a solution. For other infectious agents (e.g., HCV, HIV)
worldwide) have revealed that viruses, together with tobacco prospects for a vaccine are not immediate.
and diet, account for the largest proportion of cancer in the
Conclusions: In order to apply new knowledge on viruses
world.
to cancer prevention, large vaccination trials are warranted.
Results: Improvements in the detection of viruses and bio- These will have to be large (many thousands of people),
markers of chronic infection have led to the identification of prolonged (5-10 years), and match scientific excellence with a
strong associations with cancer, particularly for human papil- feasible design. Mistrust between scientists and the public will
lomavirus (HPV), hepatitis B virus (HBV), and human immu- have to be prevented by means of absolute openness in sciennodeficiency virus (HIV). For some cancer viruses (e.g., HIV tific information and economical interests involved.
and hepatitis C virus, HCV), the spectrum of malignancies
involved has still to be well defined. For HBV and HPV, Key words: cancer, HBV, HCV, HIV, HPV, vaccination, viruses
Summary
Introduction
The elucidation of the role of a few human cancer
viruses has been one of the major breakthroughs in
cancer research in the last 20 years. Progress has been
made possible by improvements in the detection of
certain viruses (or subgroups of) and biomarkers of
chronic infection [1]. In their estimate of proportions of
cancer deaths attributed to various factors in the US,
Doll and Peto [2] assigned 10% to infections, with 1% as
a lower confidence limit. However, only two specific
human cancer viruses, Epstein-Barr virus (EBV) and
hepatitis B virus (HBV) were mentioned [2]. As of 2000,
experimental and epidemiological evidence has firmly
established an association between various cancer sites
and at least eight viruses, in addition to a few parasites
(Schistosomes and liver flukes), and one bacterium,
Helicobacter pylori [3-7]. Approximately 15% of cancers
worldwide (i.e., nine million new cases in 1990), 23% in
developing countries, are now attributed to infectious
agents [8]. Most of this burden is related to viral infections (i.e., 10% worldwide, 17% in developing countries).
Infectious agents represent, therefore, with tobacco
and diet [2, 8, 9], priorities in cancer prevention. Strategies to reduce the risk of virus-related cancers include:
1) research into the strength of the association between
viruses and cancer and the spectrum of cancer sites
involved, in order to set priorities; 2) behavioural
changes (e.g., safe sex, avoidance of breast feeding, etc.);
3) avoidance of infection by screening for cancer viruses
in traditional sources (e.g., blood and blood derivatives,
cervical smears, etc.) or carriers (e.g., pregnant women,
organ donors, etc.); 4) active host immunization through
prophylactic and therapeutic vaccines [1, 10]; and 5) antiviral treatment to prevent chronic carrier status [11].
In the following, I will not deal in detail with all viral
infections related to cancer in humans nor with all
prevention strategies above. Indeed, strategy 3) is routinely performed for known cancer viruses which can
be parenterally transmitted whereas strategy 5) is still
hampered by the limitations of antiviral drugs [11]. I will,
however, consider, by means of examples, some of the
most important achievements and future challenges of
strategies 1) and 4).
Strength of virus-cancer link
Virologists chiefly classify established human tumour
viruses as direct or indirect carcinogens (also referred
to as cofactors), chiefly on the basis of knowledge of
specific viral oncogenes [1]. From an epidemiologist's
viewpoint, viral infections would be usefully classified
by the consistency and strength of their association with
cancer, as expressed by relative risk (RR) estimates from
case-control and cohort studies. This classification has
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Table I. Relation between selected human viruses and various cancer
sites by relative risk (RR) level.
Relative risk
Virus
Very high
>1000
> 100
HIV-1
HIV-1
> 100
Kaposi's sarcoma
Non-Hodgkin's
lymphoma
HPV 16, Cervical cancer
18, etc.
~20
HBV
-20
HCV
Moderate
~10
2-10
2-10
Undefined,
but elevated
HIV-1
HIV-1
HTLV-I
EBV
HHV-8
Undefined
Cancer
Not yet
identified
Comments
CofactorofHHV-8
CofactorofEBV
Squamous-cell and
adenocarcinomas.
Other anogenital
cancers
Hepatocellular
carcinoma
Hepatocellular
carcinoma
Hodgkin's disease
Cervical and anal
cancer
T-cell leukemia/
lymphoma
Burkitt's lymphoma
Hodgkin's disease
Non-Hodgkin's
lymphoma
Nasopharyngeal
carcinoma
Kaposi's sarcoma
Primary effusion
lymphoma
Lymphomas and
leukaemias
Bladder
Skin
Table 2. Increases in relative risk (RR) estimates for HPV and cervical
lesions as detection techniques improved.
Study (location)
Viral detection RR
Franceschi et al., Genital warts
1983 (UK)
Comment
5.8 Cytological abnormalities;
compared to other
sexually-trasmitted
diseases
Reeves et al,
1989 (Latin
America)
Filter in situ
hybridization,
HPV 16, 18
Munozet al.,
1992 (Spain and
Columbia)
PCR, any HPV
Ngelangel et al.,
1998
(Philippines)
PCR, any HPV 156
111
Squamous-cell carcinoma
Adenocarcinoma
PCR, HPV 16 506
549
Squamous-cell carcinoma
Adenocarcinoma
9.1 Cervical cancer
28.8 Cervical cancer
CofactorofHPV
Endemic in Japan,
the Caribbean, and
West Africa
Malaria as cofactor
In immunodepressed
individuals
Suggested by
epidemiological
evidence
been attempted in Table 1. It is important to bear in
mind that an RR is greatly influenced by background
risk in a given population (i.e., the prevalence and importance of other risk factors), especially when a virus is
an indirect cause of cancer (i.e., neither sufficient nor
necessary). An RR is also affected by the accuracy with
which the relevant agent or biomarker of chronic infection can be detected. Thus low RR for certain viruses
may be attributable to the importance of other risk
factors in certain populations or to a lack of sensitivity
or specificity of available tests.
Human papillomavirus (HPV) provides an outstanding example of the gradual discovery of an important
human cancer virus [5]. The relationship between a
woman's promiscuity (and her partners' number of partners) and cervical cancer has been known for decades
[2]. Virtually all sexually transmitted agents, most notably
herpes simplex type II, were taken into consideration
before suspecting HPV. First isolations of novel virus
types (HPV 16 and 18) directly from cervical cancer date
back to 1983 [1], but, earlier, in the absence of better
markers of HPV-status, the risk of cervical intra-epithelial neoplasm was compared in women with genital
warts (as a proxy of HPV-carriage) and women with
genital herpes, trichomoniasis, and gonorrhoea [12].
Genital warts were associated with an RR of 5.8 compared to other sexually transmitted agents.
Less than two decades later, polymerase chain reaction (PCR)-based tests targeting different open reading
frames of HPV were able to identify the virus in 99.7%
of approximately 1000 cervical cancer specimens from
22 countries worldwide [13, 14]. Selected studies at
Table 2 show the steady increase in the magnitude of
HPV-associated RRs as methods for viral detection
improved and the most oncogenic HPV types were
identified [15, 16]. In one of the most recent studies [17],
HPV-16 was associated with a RR of 506 (95% confidence interval (CI): 178-1436) for squamous-cell carcinoma of the cervix (i.e., one of the most elevated RRs
ever found for any cancer risk factor). The same was
found for adenocarcinoma of the cervix, most notably
for HPV 18 (RR = 549; 95% CI: 44-6912).
Following the recognition of the central role of HPV in
cervical cancer aetiology, HPV testing is being evaluated
as an adjunct to Pap smear in screening programs. Main
purposes may be HPV typing (for prognostic purposes),
avoidance of over-treatment or, in HPV-negative middleaged women, avoidance of further screening [10]. The
most recent commercially available HPV diagnostic test
(Hybrid Capture II) uses hybridization and a cocktail of
HPV-specific probes to detect and type (high-risk vs.
low-risk) HPV [18]. For the time being, however, it is
unclear how HPV testing will alter the usual clinical
care for a positive Pap smear or whether it will make
screening more cost-effective.
Aside viruses whose link with cancer is well quantified,
Table 1 includes several instances where the computation
of a precise RR is not possible. Such an estimate has
been, so far, hampered by the complicated pattern of
infection involved in cancer causation (e.g., EBV) or by
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the novelty of virus discovery (e.g., human herpes in addition to disrupted immunosurveillance, chronic
virus 8, HHV-8) [7]. Finally, the fourth group in Table 1 antigen stimulation and cytokine dysregulation conincludes some cancer sites for which an infectious agent tribute to cancer onset.
has not been identified as yet, but is strongly suspected
Marked increases in Kaposi's sarcoma (KS, with RR
on account of either a peculiar geographic cancer distri- in the order of 1000) and NHL (with RR in the order of
bution (e.g., childhood leukaemia [19]) or of an associa- 100) were among the earliest features of the AIDS
tion with recurrent infections (bladder [20]) or immune epidemic (Table 1) [6]. In the largest study so far [28]
impairment (e.g., non-Hodgkin's lymphoma (NHL), from the US, the RR for NHL after AIDS was 112.9
non-melanomatous skin cancer [21]). Such malignancies, (95% CI: 103.6-123.4). The striking associations between
albeit not yet susceptible to prevention strategies, should HHV-8 and KS [7] and between EBVand certain NHLs
also be a research priority since long awaited advances [7] suggest that the role of HIV may be indirect. Indeed,
in agent identification may soon become available.
the incidence of KS and NHLs increases markedly as
HIV-related immunosuppression progresses.
Initial reports of Hodgkin's disease (HD) in patients
Spectrum of virus-cancer link
with HIV/AIDS came from case-series [29] and were
taken with skepticism since no clear excess of HD had
For many viral infections the full spectrum of associated previously emerged among iatrogenically immunomalignancies has still to be clarified. This particularly suppressed patients [21]. Registry-linkage studies, from
applies to two important viruses: hepatitis C virus the US, Italy, and Australia showed, for HD in people
with HIV/AIDS, consistent RRs of approximately 10
(HCV)andHIV-l.
HCV has infected an estimated 170 million people and [30]. In the largest US study [28], the RR for HD after
is the major cause of parenterally transmitted hepatitis AIDS was 7.6 (95% CI: 4.1-13.1).
worldwide [4]. Only 20%-30% of new HCV infections
Excesses in people with HIV/AIDS have been represent with clinically apparent hepatitis, although 75%- ported also for squamous-cell carcinoma of the anus,
85% of infected persons develop a persistent infection particularly among homosexual men in North America
[22]. HCV does not integrate in host genome and, there- and northern Europe [5], and of the conjunctiva in Africa
fore, hepatocellular carcinoma is thought to result from [31]. With respect to invasive cervical cancer, marked
prolonged liver necrosis and regeneration. HCV-specific increases in HIV-infected women have emerged in studies
cytoxic T-lymphocytes (CTL) compartmentalize to the in southern Europe, e.g., RR = 15.5, 95% CI: 4.0-40.1
liver in chronic infection and the response is polyclonal [30] and 12.8, 95% CI: 6.6-22.4 [32]. In the US, women
and multispecific [23]. It is not clear as yet whether CTL with HIV/AIDS showed an approximately five-fold
response protects against disease or whether it causes increased risk of invasive cervical cancer [33], but pretissue damage. HCV genome and its replicative inter- invasive cervical lesions were greatly increased [28].
mediate have been detected in peripheral blood mono- Higher RRs in southern Europe than in the US may be
nuclear cells of patients with chronic infection. The attributable to the higher proportion of intravenous
persistence of HCV in these cells may chronically stim- drug users and/or less widespread screening for cervical
cancer (and, therefore, less frequent diagnosis at preulate B-lymphocytes [24].
HCV increases significantly the risk of hepatocellular invasive stages). The impact of HIV on cervical cancer in
carcinoma. In a meta-analysis of 32 case-control studies high-risk developing countries is not clear as yet. In
[25], the RR for anti-HCV ab or HCV-RNA positivity Uganda, the incidence of cervical cancer increased by
was 11.5 (95% CI: 9.9-13.3), i.e., similar to the one two-fold from 1960-1971 to 1995-1997 [31], but the RRs
for HBsAg positivity (13.7; 95% CI: 12.2-15.4). The RR in HIV-positive women from case-control studies were
was more elevated (16.8; 95% CI: 11.9-24.1) in studies not significantly elevated [5],
in Japan and the Mediterranean countries, where HCV
By and large, the involvement of a broader spectrum
infection is more frequent than HBV infection among of tissues or sites than originally suspected seems a
hepatocellular carcinoma patients. An association of characteristic of several well-established cancer viruses.
HCV with NHL has also been reported [26, 27]. A 51- HPV, besides causing anogenital malignancies, is susfold elevated risk (95% CI: 9.3-286) emerged for extra- pected to be implicated in some carcinomas of the upper
nodal NHL of the liver and salivary glands in an Italian aerodigestive tract [34, 35] and, perhaps, of the skin [5].
EBV is implicated in epithelial as well as lymphatic
case-control study [27].
malignancies,
whereas HHV-8 is strongly associated
In respect to HIV, as of the end of 1999, approxiwith
a
rare
type
of NHL (primary effusion lymphoma),
mately 34 million people were living with HIV infection
in
addition
to
KS
[7].
or AIDS world-wide. Retroviruses HIV-1 and 2 cause a
steady decline of immunity, particularly cellular immunity
[6]. Thus, the AIDS epidemic is going to represent an
unprecedented source of information on immunity and Cancer prevention through vaccines
cancer since follow-up studies of patients receiving
organ or bone marrow transplants have involved only a The close link between certain cancer sites and viral
few thousand subjects [21]. In HIV infection, however, infections opens the possibility of using vaccinations in
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Table 3. Open issues in the development of prophylactic HPV vaccines.
cheap and produce a strong and long-lasting immunological response. In fact, the burden of exposure for
Issue
Comments
sexually transmitted agents such as HPV can be especially
heavy and prolonged. As shown by experience with
Ideally, prophylactic and therapeutic
Type of vaccine
HBV, routine immunization of infants and/or adolesAt least 30 oncogenic types exist, but HPV
HPV types to be
cents,
girls and boys, appears to be, in the long-term, the
16 accounts for 50%, HPV 18, 31, and 45
included
sole effective immunization strategy (Table 3).
for further 30% of cervical cancers
A few prophylactic HPV vaccines are already availRoute of administration Ideally, through genital mucosae
able
[36]. The presence of viral oncogenes in HPVs
Ideally infants, girls and boys
Target population
posed
theoretical obstacles to the development of a
Cost
It should be low, perhaps using bacterial
prophylactic
vaccine that carries the viral genome.
vectors or transgenic plants
Therefore, efforts have been aimed at developing subunit
vaccines (i.e., virus-like particles, VLPs). The VLPs were
cancer prevention, and, perhaps, treatment. Such possible obtained by expression of the major HPV capsid protein
vaccinations include: 1) prophylactic vaccination, with LI, alone or in combination with L2. Systemic vaccinathe aim to prevent or modify primary viral infection; tion with VLPs has resulted in 90%-100% protection
2) post-infection vaccination, with the aim to modify against species-specific papillomavirus in three animal
the existing immune status of an infected individual; and models (rabbits, cattle, and dogs) and in a few early3) therapeutic vaccination, targeted against viral anti- phase human clinical trials (against HPV) (6,11, and 16)
[36]. These experiences have opened the door to phase
gens expressed in tumour cells.
For two viruses in the group showing the most ele- III randomized trials in the year 2000.
Several therapeutic HPV vaccines are also available
vated RRs in Table 1 (i.e., HBVand HPV), prophylactic
vaccination aimed at cancer prevention is already a and are being used in phase I—II trials [36]. The aim of
reality or a possibility [36]. For HBV a vaccine based on therapeutic vaccines would be to induce cellular immunity
HBsAg particles produced by recombinant DNA tech- against cells expressing viral proteins, in order to induce
nology is available at a relatively low cost ($1 per dose) the regression of pre-malignant and malignant cervical
[36]. Vaccination at birth or in early childhood prevented lesions. They thus target E6 and E7 oncoproteins of
70%-85% chronic carriers in China, but 90% in Africa, HPV 16 and 18. Some of the vaccines are peptide based
where perinatal transmission is less common [4]. Pro- whereas others are based on a recombinant vaccinia
tection has been shown to persist up to age nine [37], i.e., vector expressing E6 and E7 [5]. Chimeric (or combined)
when the risk of carriage substantially declines. The only vaccines will contain both LI or L1-L2 and E6 or E7
large-scale comparative study, started in The Gambia in proteins, and thus they should allow prevention as well
1986 on about 60,000 infants [38] has not yet provided as regression of cervical lesions [36].
For other viruses related to cancer, prospects for a
estimates of HBV vaccination efficacy to prevent cancer.
However, 6-10 years after the institution of Taiwan's vaccine are not immediate. HCV, for instance, shares
program of universal HBV vaccination, the incidence with HIV an extreme genetic heterogeneity, including
of childhood hepatocellular carcinoma declined signifi- hypervariable regions. Patients tend to harbour a mix of
cantly [39]. In West Africa it has been estimated that $30 viral genomes and those who clear natural infection can
can prevent one chronic carrier and $130 one hepato- be re-infected [41].
An HIV-1 vaccine offers the best long-term hope to
cellular carcinoma [40].
The rationale for developing an HPV vaccine includes control the AIDS pandemic, especially in developed
the frequency of the HPV infection world-wide (it has countries [42]. Although small-scale clinical trials of
been estimated that at least 50% of sexually active adults HIV-1 vaccines have been underway since 1987, the first
have had a genital HPV infection), and the well-docu- phase III efficacy trials started only in 1998 in the US
mented role of humoral and cellular immunity in the (5400 volunteers) and Thailand (2500 volunteers). Vaccontrol of HPV lesions [36]. However, several issues cines in such trials are based on the envelope glycoprotein
remain open, as briefly outlined at Table 3. The ideal gp 120, but other candidate vaccines use live recombinant
vaccine against HPV should target different viral anti- vectors and, more recently, DNA immunization [41]. On
gens, in order to have potentials for preventing and account of the disease severity, even an HIV-1 vaccine
clearing HPV infection and, possibly, induce tumour with a partial efficacy or one able to modify infection
regression. Although HPV 16 predominates in severe (i.e., reduce viral load), albeit not to induce sterilizing
cervical lesions and carcinomas (approximately 50%), immunity, may also merit to be considered [42].
Vaccination strategies with recombinant subunit viral
at least a dozen other types (including 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59 and 68) can be found, accounting, proteins (e.g., gp 350) and live recombinant virus
for about 30% additional cases. Thus, a polyvalent vac- vectors are also being developed against EBV [7]. In the
cine would be preferable. Since the principal aim of HPV absence of a satisfactory animal system, however, EBV
vaccines is to prevent genital infection, optimal routes of vaccines will have to be evaluated directly in human
administration to elicit protection in the genital mucosa trials, after immunogenicity and toxicity have been aswill have to be identified. Finally, vaccine should be sessed in animals.
1095
Concluding remarks
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Technological progresses have overcome former inaccuracies in the detection of viruses and virus carrier
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effective vaccination is the potential for involvement of
large populations, at costs possibly affordable by less
wealthy countries, and without a need to tackle deeply
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Received 10 April 2000; accepted 3 August 2000.
Correspondence to •
S. Franceschi, MD
Unit of Field and Intervention Studies
International Agency for Research on Cancer
150, Cours Albert Thomas
69372 Lyon Cedex 08
France
E-mail: [email protected]