Vaccine 26S (2008) M43M52

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

ICO Monograph Series on HPV and Cervical Cancer: Asia Pacic Regional Report

Human Papillomavirus Infection and Cervical Cancer Prevention in India,

Bangladesh, Sri Lanka and Nepal
Rengaswamy Sankaranarayanan a, , Neerja Bhatla b , Patti E. Gravitt c , Partha Basu d ,
Pulikattil O. Esmy e , K.S. Ashrafunnessa f , Yasantha Ariyaratne g ,
Aarati Shah h , Bhagwan M. Nene i
a

Screening Group, International Agency for Research on Cancer, Lyon, France

Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi, India
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
d
Department of Gynaecological Oncology, Chittaranjan National Cancer Institute, Kolkata, India
e
Division of Radiotherapy & Oncology, Christian Fellowship Community Health Centre, Ambilikkai, Tamil Nadu, India
f
Department of Obstetrics & Gynaecology, Bangabandhu Sheik Mujib Medical University (BSMMU),
Shahbag, Dhaka, Bangladesh
g
National Cancer Control Programme, Government Cancer Institute, Maharagama, Sri Lanka
h
Bhaktapur Cancer Care Centre, Dudhpati, Bhaktapur, Nepal
i
Tata Memorial Centre Rural Cancer Project, Nargis Dutt Memorial Cancer Hospital, Barshi, Maharashtra, India
b
c

a r t i c l e
Keywords:
Asia Pacic
HPV
Epidemiology
South Asia
HPV vaccination
Cervical screening
HPV testing
Cytology
Visual screening
Cancer control

i n f o

a b s t r a c t
Although one-third of the world cervical cancer burden is endured in India, Bangladesh, Nepal and Sri
Lanka, there are important gaps in our knowledge of the distribution and determinants of the disease in
addition to inadequate investments in screening, diagnosis and treatment in these countries. Prevalence
of human papillomavirus (HPV) infection among the general populations varies from 714% and the agespecic prevalence across age groups is constant with no clear peak in young women. This observation
may be the result of a low clearance rate of incident infections, frequent re-infection/reactivation, limited
or no data in target high-risk age groups (teenagers), and sexual behavioural patterns in the population.
High-risk HPV types were found in 97% of cervical cancers, and HPV-16 and 18 were found in 80% of cancers
in India. Beyond research studies, demonstration projects and provincial efforts in selected districts, there
are no serious initiatives to introduce population-based screening by public health authorities in these
countries. Cervical cancer is a relatively neglected disease in terms of advocacy, screening and prevention
from professional or public health organizations. Cytology, HPV testing and visual screening with acetic
acid (VIA) or Lugols iodine (VILI) are known to be accurate and effective methods to detect cervical cancer
and could contribute to the reduction of disease in these countries. While HPV vaccination provides hope
for the future, several barriers prohibit the introduction of prophylactic vaccines in these countries such
as high costs and low public awareness of cervical cancer. Efforts to implement screening based on the
research experiences in the region offer the only currently viable means of rapidly reducing the heavy
burden of disease.
2008 Elsevier Ltd. All rights reserved.

1. Introduction
India, Bangladesh, Nepal and Sri Lanka together contribute
around one-third of the global cervical cancer burden, yet control
measures are neither uniformly nor vigorously implemented in this
vast region [1]. In the general population, data show high prevalence of human papillomavirus (HPV) infection (>10%). Information

Corresponding author. Tel.: +33 472738599; Fax: +33 472738518.

E-mail address: sankar@iarc.fr (R. Sankaranarayanan).
0264-410X/$ see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2008.05.005

related to selected reproductive health indicators and cancer information systems in these countries are given in Table 1 [24]. The
median age at marriage for girls ranges from 16 years (Bangladesh)
to 22 years (Sri Lanka). The proportion of married girls by the age
of 15 ranges between 5% (Sri Lanka) and 27% (Bangladesh) and the
median age at rst child birth varies between 18 years (Bangladesh)
and 23 years (Sri Lanka). Human immunodeciency virus (HIV)
prevalence varies between <100 per 100,000 in Bangladesh and
Sri Lanka to 747 per 100,000 in India. The prevailing scenario of
cervical cancer burden, epidemiology of HPV infection and cervical
cancer and prospects for prevention by screening and vaccination

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R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

Table 1
Data on selected reproductive health indicators for India, Bangladesh, Nepal and Sri Lanka
Indicator

India

Bangladesh

Nepal

Sri Lanka

Median age at marriage in girls

Premarital sexual activity in girls
Mean age at sexual debut in girls
Married girls by the age of 15
Median age at rst child
HIV prevalence (per 100,000)
Population cancer registries
Population cervical screening programs

18
6%
18
24%
19
747
18
none

16
2%

27%
18
<100
none
none

17
<1%
17
14%

447
none
none

22
2%
14
5%
23
<100
none
none

HIV: Human immunodeciency virus. Sources of data: [24].

in India, Bangladesh, Sri Lanka and Nepal are briey reviewed in

this article.

2. Incidence and mortality of cervical cancer

2.1. India
India has a population of approximately 1.2 billion and accounts
for a signicant burden of cervical cancer in the Indian subcontinent. Information on cancer patterns and burden in India is
based on the projections from 18 population-based cancer registries covering approximately 4% of the population, including three
rural registries in different regions, but with a particular concentration in South India (Fig. 1). Age-standardized cervical cancer
incidence rates range from 9 to 40 per 100,000 women in various regions of India [3,4]. The estimated age-standardized cervical
cancer incidence and mortality rates around 2002 were 30.7 and
17.8 per 100,000 women respectively [1]. The peak incidence was
observed in older women 70 years of age. Almost one-fourth of the
worlds total burden of cervical cancer and 90% of the estimated
149,000 cervical cancers in the Indian sub-continent occur in India
(Table 2) [1]. The impact of control measures in India will substan-

tially reduce the global burden. The number of maternal deaths

and cervical cancer cases is almost equal in India [5]. There is considerable awareness, advocacy and investment to reduce maternal
deaths (undoubtedly an extremely justiable investment) among
policy makers, governments, professional societies (including the
Federation of Obstetric & Gynaecology Societies of India (FOGSI),
perhaps the largest professional organization in the world), social
organizations and womens movements. It is paradoxical that there
is very limited awareness on cervical cancer as a threat to the
health of middle-aged women in the most productive period of
their life.

2.2. Bangladesh
Bangladesh has approximately 150 million inhabitants and is
one of the most densely populated countries in the world. Currently,
no population-based cancer registry exists and mortality data are
incomplete; hence there are no data on cervical cancer incidence or
mortality rates. Previous hospital-based studies showed that cervical cancer constituted about one-quarter of all female cancers
[6,7]. The estimated age-standardized cervical cancer incidence
and mortality rates around 2002 were 27.6 and 14.8 per 100,000

Fig. 1. Location of population-based cancer registries and cervix screening/HPV research projects in South Asian countries.

R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

M45

Table 2
Maternal deaths and cervical cancer burden in South Asian countries
Country

Maternal deathsa

Maternal mortality ratio (per 100,000 live births)

Cervical cancer casesb

Cervical cancer deathsb

India
Bangladesh
Nepal
Sri Lanka

136,000
16,000
6,000
300

540
380
740
92

132,000
13,000
2,150
1,550

74,100
6,600
1,100
840

Sources of data: [1,5].

a
Estimated in the year 2000 (approximately).
b
Estimated in the year 2002 (approximately).

women respectively [1]. It is estimated that annually 13,000 cases

and 6,600 cervical cancer deaths occur in Bangladesh (Table 2)
[1].

thapur and Bharatpur indicate that cervical cancer accounts for

20% of all female cancers. Most cases present in advanced clinical
stages.

2.3. Sri Lanka

3. HPV epidemiology

Sri Lanka has a population of about 20 million people where

1,550 invasive cervical cancers and 850 deaths are estimated to
occur annually [1]. In comparison, 300 maternal deaths occur annually (Table 2) [5]. Since there is no population-based cancer registry
in Sri Lanka, actual incidence rates of cancer in any specied populations are not known and mortality data are incomplete. The
estimated 2002 age-standardized cervical cancer incidence and
mortality rates were 17.2 and 9.5 per 100,000 women respectively [1]. There is a centralized effort to collect hospital-based data
from major hospitals in the country coordinated by the National
Cancer Control Program (NCCP) ofce at the Ministry of Public
Health. According to these data, cervical cancer is the second most
common cancer among women in Sri Lanka. These gures constituted 12.6% of the 7,374 cancer notications during the year
2005; 928 cases were recorded in 2005 as compared to 747 in
2001, and more than three-fourths were stage IIb or worse disease. A strategy must be developed as a priority to address the
immediate problem of late stage cervical disease and invasive
cancers.

3.1. India

2.4. Nepal
Nepal has a population of about 28 million people. Annually
2,150 invasive cervical cancers and 1,100 deaths are estimated to
occur in Nepal compared to 6,000 maternal deaths in the country (Table 2) [1,5]. There is no population-based cancer registry
and actual incidence rates of cancer are not known for any region
of the country. Mortality data are incomplete and unreliable. The
estimated age-standardized cervical cancer incidence and mortality rates around 2002 are 26.4 and 14.1 per 100,000 women
respectively [1]. Hospital-based statistics from Kathmandu, Bhak-

The available information on HPV epidemiology is mostly based

on research studies addressing cervical screening and HPV infection
in selected locations in India (Fig. 1). The prevalence of highrisk HPV (HR-HPV) infection has been studied among apparently
healthy populations in various regions of India. The HR-HPV prevalence rates varied between 713%, but were mostly above 10%
(Table 3). The most common HPV types reported were (in descending order) HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68
[813]. Overall HPV prevalence in India was similar to the high-risk
areas in Latin America, but lower than that observed in some parts
of sub-Saharan Africa [9].
In a hospital-based case-control study, 27.7% of 210 normal
women were positive for any HPV type and 21.7% were positive
for HR-HPV types [14]. In a population-based study involving 651
women in Ballabgarh, a rural area near Delhi, 7.1% were positive for
HR-HPV using polymerase chain reaction (PCR) line-blot assay. A
population-based, cross-sectional survey in married women aged
1659 years was conducted in rural Dindigul district [8]. The prevalence of any HPV type was 16.9% in the general population, of which
14.0% (252/1,799) were among women without cervical abnormalities and 73.9% (68/92) among those with cytological abnormalities.
Age-standardized proportions were 17.5%, 15.2% and 64.9%, respectively. The prevalence of HR-HPV infection was 12.5%, with multiple
HPV types detected in one-fth of the infected women [8,9]. The
prevalence of HR-HPV infection was 9.6% (172/1,799) among cytologically normal women. The most common types in this study
were HPV-16 (3.8%), followed by 56 (1.5%), 31 (1.2%), 33 (1.2%), and
18 (1.0%). Women who were widowed (odds ratio (OR): 1.7), separated or divorced (OR: 2.3) or manual workers (OR: 1.3) had high

Table 3
Prevalence of high-risk HPV infection in the general population in India
Study site (year of report)

Number of women
(age range in years)

% positive for
high-risk HPV types

Age-standardized
cervical cancer
incidence rate (per
100,000 women)

Dindigul district, Tamil Nadu (2005) [8,9]

Osmanabad district, Maharashtra (2005) [10]
Kolkata, Mumbai, Trivandrum (2005) [11]
Hyderabad, Andhra Pradesh (2005) [12]
Manipur (2007) [13]
Sikkim (2007) [13]
West Bengal (2007) [13]

1,891 (1659)
27,212 (3059)
18,085 (2565)
185 (3059)
692
415
1,112

12.5
10.4
7.0
10.3
7.4
12.5
12.9

40
30

15.8
22.8
25

HPV: human papillomavirus.

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R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

Table 4
Prevalence of high-risk HPV types in cervical cancer specimens in India
Study site (year of report)

Number of cases

HPV positive
n (%)

% positive
HPV-16

% positive
HPV-18

Madurai (1998) [17]

Mumbai (2002) [18]
Chennai (2003) [14]
Hyderabad (2005) [12]
Kolkata, Mumbai, Trivandrum (2005) [11]
Delhi (2006) [19]
Vellore (2006) [20]
Kolkata and Nagpurc

43
337
191
41
51
106
119
93

30 (70)
258 (77)a
190 (99)
36 (88)
38 (75)b
104 (98)
113 (95)
72 (77)

53

59
67

74
60
60

13

12
19

14
14
11

Sources of data: [11,12,14,1720].

a
HPV-16 and 18 only.
b
HPV testing by Hybrid Capture 2 (HC2).
c
Unpublished data.

HPV positivity while education was inversely associated with HPV

infection (women with high school or college education OR: 0.6)
[8].
Among 27,212 women aged 3059 years in Osmanabad district,
10.4% of the women were positive for HR-HPV DNA (by Hybrid
Capture 2 (HC2), Qiagen Gaithersburg, Inc., MD, USA (previously
Digene Corp.)), 12% of whom had cervical intraepithelial neoplasia
(CIN) lesions of grade 23 or invasive cancer [10]. In a multi-centre,
cross-sectional study that involved 18,085 women aged 2565
years recruited from three cities in India, evaluated the accuracy of
HPV testing (by HC2) in detecting CIN2-3 lesions in which 7% were
HR-HPV positive and 12.8% of these had CIN2-3 lesions or invasive
cancer [11].
Unlike most populations in developed countries, HPV prevalence was constant across age groups in India, with no clear peak
in young women [810]. In the Osmanabad district study the
prevalence of HR-HPV types in the 3039, 4049 and 5059 age
groups were 9.8%, 10.4% and 12.2%, respectively [10]. In the multicentre cross-sectional study in India, these were 7.0%, 6.8% and
7.5%, respectively [11]. The population-based study in Dindigul,
which included a broad age range of women 1625 years, did
not nd any peak prevalence in the younger age group [8]. Low
clearance of incident infections, frequent re-infection/reactivation,
underrepresentation of teenagers in the study samples and sexual
behavioural patterns in the population may be responsible for the
constant, steady prevalence of HPV infection in different age groups
in India.
Unfortunately, no prospective data from the region are available
to test these hypotheses, though a population-based prospective
natural history study, using one-year sampling intervals, is currently underway in Hyderabad. It is also notable that all studies
are restricted in enrolment to married women due to the cultural taboo of genital tract sampling of an unmarried woman.
Cultural inuences specic to rural India might also factor into
the lack of a peak in HPV prevalence when restricting analyses
to married women. Based on data from the latest National Family Health Survey (20052006), there was a noticeable gap in the
age at marriage between women and men, with 52.5% of rural
Indian women reporting marriage before age 18, while only 36.5%
of men reported marriage before age 21 [15]. Furthermore, there
was greater age discordance in married couples (22% of men are
older than their wives by 6 years or more) and this was associated
with an increased probability of the husband reporting extramarital
sexual relationships [16]. Few studies have addressed the prevalence of pre-marital sexual contacts in rural India, though formative
research conducted in rural Andhra Pradesh indicates that this
may be a signicant factor inuencing age at rst HPV exposure.
Determining the age that accurately reects rst exposure will be

critical to the formulation of a coherent HPV vaccination strategy

in India.
The prevalence of HPV types in cervical cancer specimens,
analyzed by PCR or HC2, varied between 7599% in hospitalbased cross-sectional studies in different regions of India (Table 4)
[11,12,14,1720]. HPV-16 or 18 were the most common in all regions
with some difference in the HPV types subsequently, but no substantial difference in the type attributable fraction. This HPV type
distribution is more similar to that seen in Europe than in Southeast Asia [21]. In a study in Madurai, HPV DNA was detected in 70%
of the 43 samples analyzed: HPV-16 in 23 cases (53%), HPV-18 in
four cases (13.3%), and HPV-33 in one case (3.3%) [17]. A hospitalbased case-control study in Chennai found 23 different HPV types
among 190 of 191 cervical cancer cases; HPV-16 (58.6%) and 18
(12.0%) were the most common types detected and multiple infections were found in 30 cases (15.7%) [14]. HPV infection of any type
was associated with a 498-fold increased risk for cervical cancer in
this study; those infected with HPV-18 had a higher risk for cervical
cancer (OR: 3.9) compared to women infected with HPV-16, multiple infections did not increase risk. Illiteracy (OR: 4.8), no toilet
(OR: 4.8) or running water inside the house (OR: 2.0), not washing
genitals after sexual intercourse (OR: 4.5), age at rst sexual intercourse <15 years (OR: 2.2), more than two lifetime sexual partners
(OR: 4.0) and widowhood (OR: 8.3, possibly due to the prevailing
sexual behaviour) were associated with increased risk of cervical
cancer [14].
In a study of 106 cervical cancer biopsy specimens from north
India, 98.1% were positive for HR-HPV types among which 12 different HPV types were detected [19]. Eighteen HPV types were
identied in cervical cancer specimens in a study in Vellore [20].
Furthermore, in a study evaluating 59 cervical cancer specimens
from Kolkata and 34 from Nagpur, HPV DNA was detected in 72
cases.
Overall in India, 79.5% of cervical cancer specimens contained
HPV-16 and/or 18 DNA (Fig. 2) [8,12,14,17,19,20,22]. HPV-16 was the
most common type in all regions, with a frequency varying between
5074% followed by HPV-18 (1220%), clearly indicating that HPV16 or 18 were present in more than three-fourths of the cases
(Table 4). The prevalence of HR-HPV types exceeded 80% for CIN2-3
cases and 30% for CIN1 cases in hospital-based studies with a small
number of high-grade CIN cases (less than 12) [12,20]. In a multicentre, cross-sectional study, HPV DNA was detected (by HC2)
in 38/51 (74.5%) histologically conrmed invasive cancer cases,
75/89 (84.3%) CIN3 cases, 50/99 (50.5%) CIN2 cases and 101/481
(21.0%) CIN1 cases [11]. Theoretically, an HPV vaccine with 100%
efcacy in preventing HPV-16 and 18 infections could potentially
reduce the cervical cancer burden by more than 60%, assuming
100% coverage.

R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

M47

Fig. 2. The ve of most frequent HPV types in women with cervical cancer [12,14,17,19,20,22] and with normal cytology [8,23,24] in India.

3.2. Bangladesh
Information on HPV type-specic prevalence in women with
and without cervical lesions is not available for Bangladesh and
there have been no systematic population-based studies to estimate HPV prevalence. In a hospital-based study, 96.7% of 120
cervical cancer cases, 83.3% of 36 cases of CIN2-3 (high-grade
squamous intraepithelial lesions (HSIL)) cases and 4.1% of 120 control women were HPV positive (by HC2). Those belonging to low
socio-economic groups and having lower levels of education were
seven times more likely to develop cervical cancer compared to
higher education and income groups [25,26]. In Bangladesh, typespecic HPV prevalence data for cervical cancer is being collected
by collaborative efforts of the International Epidemiologic Study of
Worldwide Distribution of type-specic HPV DNA.
3.3. Sri Lanka
Information is not available on HPV type-specic prevalence in women without cervical lesions, from either population
or hospital-based studies. In a small hospital-based study in
2006, HPV-16 DNA was detected by PCR in 11 of 15 cases
of cervical squamous cell carcinoma and 3 of 15 healthy control women; HPV-18 was detected in three of the 15 cervical
cancer cases and none of the controls [27]. Research studies
to address the prevalence of HPV types in Sri Lankan populations are urgently needed, given the glaring lack of such
data.
3.4. Nepal
There are no data on the prevalence of HPV infection in the
general population or on the prevalence of different HPV types
in cervical cancer and CIN cases in Nepal. An HPV prevalence
study supported by the International Agency for Research on Cancer (IARC) in collaboration with the BP Koirala Cancer Centre in
Bharathpur has completed recruitment and results from this study
will soon be available. There is very little awareness on the impor-

tance of cervical cancer and the causal role played by persistent

HPV infection in cervical carcinogenesis.
4. Prospects for HPV vaccination
4.1. India
The prospects for HPV vaccination in public health services have
to be judged in the backdrop of the realities for intensely advocated
and essential Expanded Program of Immunization (EPI) vaccines,
which are perceived as extremely high priority vaccines. Coverage
for three doses of the diphtheria and tetanus toxoids and pertussis
(DTP3) and of polio vaccines for the year 2005 was estimated at 60%
by the World Health Organization-United Nations Childrens Fund
(WHO-UNICEF) (Table 5) and 90% by national estimates; coverage
for hepatitis B vaccine for the same year was barely 8% by WHO
estimates and 68% by national estimates [28]. The low coverage
for these vaccines is surprising given the high awareness among
parents, health care providers and policy makers, state funding,
availability of infrastructure for storage and delivery and the fact
that childhood immunization is relatively more successful among
the public health programs in India. India reported 2,587 cases of
tetanus and 676 cases of polio in 2006 [28].
The HPV vaccine is not yet licensed or marketed in India, but
a major obstacle to its introduction is likely to be its prohibitive
cost. To illustrate the magnitude of the cost of an HPV vaccine,
the current costs of three doses of HPV vaccines in Europe are
150 times higher than the entire cost of the EPI vaccines in India.
Research into less expensive second-generation prophylactic HPV
vaccines is promising. Subunit (capsomere) vaccines can be more
cheaply manufactured in E. coli and require no cold-chain. Monovalent vaccines, based on the L2 protein, offer broader protection
across the genotype spectrum. Needle-free delivery systems are
also under development. Indias biotechnology sector is leading
the way in this research by producing the rst good manufacturing
practices (GMP)-grade L2 and capsomere vaccines in collaboration
with international researchers.
There are certain unique socio-cultural issues associated with
the HPV vaccine because it targets a sexually transmitted infection

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R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

Table 5
Coverage among target populations vaccinated by EPI vaccine antigens in South Asian countries in 2005
Vaccine

India (730 USD)a

Bangladesh (470 USD)a

Sri Lanka (1,160 USD)a

Nepal (270 USD)a

BCG
DPT3
Polio3
MCV
Hib
Hepatitis B

75%
59%
58%
58%

8%

99%
88%
88%
81%

62%

99%
99%
99%
99%

99%

87%
75%
78%
74%

41%

EPI: Expanded Program of Immunization; BCG (tuberculosis): bacille Calmette-Gurin, DPT3: diphtheria, pertussis (whooping cough) and tetanus, three doses of triple
vaccine; Polio 3: three doses of oral polio vaccine; MCV: measles containing vaccine; Hib: Haemophilus inuenza B. WHO-UNICEF estimates [28].
a
Gross national income per capita (US dollars).

(STI) and primarily targets female adolescents and young adults to

prevent a disease generally considered a disease of the aged. These
issues will signicantly inuence the willingness of: 1) health policy makers to introduce the vaccine in the health system; 2) health
care providers to recommend HPV vaccination; 3) parents to have
their children vaccinated; and 4) adolescent and young girls to
receive vaccination. Parental awareness and attitude towards the
HPV vaccine are likely to be major determinants of acceptability in
India. An ongoing survey in Eastern India among educated urban
men and women (N = 121), with at least one girl child and belonging to middle or high socio-economic group, revealed that 72% had
never heard of HPV. Only 46% of parents were in favour of vaccinating their daughters against an STI; however, after going through
a brief information sheet about the HPV vaccine, 80% agreed to
vaccination. About 62% of those who accepted the vaccine did not
agree that vaccination would be construed as parental consent for
children to engage in sexual practice, while 20% were unsure. The
most common reason for not accepting the vaccine was uncertainty
about the safety of a new vaccine. The physicians recommendation was found to be the most important factor inuencing their
decision.
In the realistic policy scenario, a perceived urgent necessity to
introduce HPV vaccines is highly unlikely given the backdrop of
practically nonexistent public demand to introduce HPV vaccines
and the very low awareness of the viral aetiology of cervical cancer and the possibility of preventing it by vaccination. On the other
hand, India has a large and rapidly expanding middle-income population. Once the HPV vaccine is licensed in India, it may disseminate
through private practice for afuent sections of the society, but
it will have little impact on cervical cancer burden unless the
socially disadvantaged high-risk populations are covered through
public health services. HPV vaccine clinical trials for both globally
licensed vaccines are either ongoing or planned in India and the rst
safety/immunogenicity results are expected in 2008. A new large
multi-centre study involving around 16,000 girls aged 1018 years
to evaluate the effectiveness and safety of two- versus three-doses
HPV vaccine in preventing cervical cancer has been planned and
is expected to commence recruitment of participants in late 2008.
It is expected that the ndings from the above studies and future
reductions in costs of the vaccine may catalyze a wider rollout of
HPV vaccine in the public health domain in due course. Both schoolbased and campaign-based approaches seem likely to facilitate the
HPV vaccine rollout.

adolescent girls. HPV vaccines are not yet licensed for use in
Bangladesh. The high cost of the vaccine coupled with several
unanswered questions regarding the duration of immunogenicity,
cross-protection against HPV types not included in the vaccine and
uncertainty about its long-term impact on preventing cervical cancer will be major impediments for introducing HPV vaccination
here as in India. Environmental disasters such as ood and other
causes of death such as diarrheal diseases, respiratory tract infections and high maternal mortality concern politicians and policy
makers more than deaths caused by cervical cancer. In the short
term, a study should be developed to assess the prospects for HPV
vaccination including the barriers and accelerating factors within
the social structure of Bangladesh. It is pertinent to note here that
the hepatitis B vaccine was introduced as part of EPI in 2003 and
the coverage is estimated to have increased from 5% in 2004 to 62%
in 2005 [28].
4.3. Sri Lanka
Sri Lanka has a very successful EPI program that has achieved
more than 99% coverage for bacille Calmette-Gurin (BCG) vaccine for tuberculosis (TB) disease, diphtheria, pertussis (whooping
cough) and tetanus (DPT), polio, hepatitis B, and measles containing vaccines (Table 5) [28]. The possibility of introducing the HPV
vaccine as a part of the public health services is hindered by the
unaffordable costs, lack of internal advocacy, lack of awareness of
the role of HPV in cervical carcinogenesis and a number of technical
issues related to long-term immunogenicity, cross-protection and
effectiveness in reducing invasive cancer. HPV vaccines are not currently licensed in Sri Lanka. If that happens, it may be prescribed
to a limited extent in private care of the afuent sections of the
community, but this will have limited impact on disease burden.
Further developments in HPV vaccination and reduction in costs
will have a major bearing on the introduction of HPV vaccines in
public health programs of Sri Lanka.
4.4. Nepal
Given the fact that the estimated coverage of the target population by EPI vaccines in 2005 in Nepal was just above 75%, and the
prohibitive costs of HPV vaccines, there is little or no prospect of
introducing HPV vaccines at this unaffordable price tag and with a
variety of uncertainties in public health services (Table 5) [28].

4.2. Bangladesh

5. Cervical cancer screening

There is very little awareness among the general population,

health care professionals and policy makers in Bangladesh about
HPV infection, the availability of the HPV vaccine and cervical cancer prevention. Therefore, educational efforts to inform
the stakeholders are a critical requirement when considering the
prospects of introducing HPV vaccination for adolescent and pre-

5.1. India
There are no organized screening programs in any province
or region of India. In the absence of a state policy on cervical
cancer prevention, screening of asymptomatic women is practically absent, even among otherwise well-organized health care

R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

M49

Table 6
Cervical screening test characteristics of the cross-sectional studies in India

Testing
method

Number of
studies

Number of
women tested

Test positive

VIA
VILI
VIAM
Cytology
HPV testing

6
5
3
5
4

32,192
26,444
16,900
22,663
18,085

4,951
4,568
2,399
1,406
1,273

CIN 2-3

Invasive Cancer

Test +

Test

Test +

Test

310
273
147
206
125

122
59
82
149
63

76
48
55
55
38

19
11
13
19
13

Sensitivity (%) for CIN 23

Specicity (%) for CIN 23

Value (95% CI)

Range in studies

Value (95% CI)

Range in studies

73.2 (69.277.0)
82.1 (77.985.8)
68.0 (62.473.3)
60.8 (56.065.5)
68.2 (61.974.1)

63.085.4
75.387.1
64.675.0
36.678.0
50.080.0

85.6 (85.286.0)
83.7 (83.284.1)
86.8 (86.287.3)
94.9 (94.695.1)
93.8 (93.494.1)

76.190.9
74.189.3
83.389.5
88.799.2
91.794.6

CIN: cervical intraepithelial neoplasia; VIA: visual inspection with 35% acetic acid; VILI: Visual inspection with Lugols iodine; VIAM: magnied (2x4X) visual inspection
with 35% acetic acid; CI: Condence interval. Sources of data: [11,3537].

programs of the industrial and military sectors. Beyond research

studies, demonstration projects and provincial efforts in selected
districts there are no serious efforts to introduce population-based
screening by public health authorities in almost the entire country.
The large burden and suffering from cervical cancer are often underappreciated and there is no effective advocacy for cervical cancer
screening and prevention from the general public or professional
organizations, such as FOGSI, as well as the general gynaecology,
primary care and cancer control community. Hence, prevention of
cervical cancer continues to be largely neglected in India. A major
thrust in the National Cancer Control Program has been to detect
early stage invasive cancer by early clinical detection/diagnosis and
treatment. At the national policy level, the most cost-effective control option of screening for CIN and preventing invasive cancer is
yet to be seriously pursued in India.
Conventional cytology is offered sporadically to women in
selected urban areas attending health services for other reasons,
but not as routine screening of asymptomatic women. According
to a WHO Health Survey in 2002 2.6% of 4,586 women aged 1869
years, ever had a Pap smear [29]. It is estimated that less than 1.5
million smears are opportunistically taken annually. In recent years,
HPV DNA testing (by HC2) is increasingly used in the private sector,
though it is likely that less than 50,000 HPV tests are carried out
annually.
Colposcopy and treatment facilities for precancerous lesions are
not available in most areas of India and doctors and gynaecologists
are mostly not used to providing routine cervical screening or other
preventive health care services. There are large gaps in provider
knowledge and practices, due to limited training and reorientation
opportunities. For screen-positive women and those with precancerous lesions, availability and access are limited to appropriate
diagnostic (e.g., colposcopy) and treatment (e.g., cryotherapy, loop
electrosurgical procedure (LEEP), laser, etc.) services. Most women
with CIN are often inappropriately managed by hysterectomy in
many urban and rural areas. Facilities for management of invasive
cervical cancer by radiotherapy and chemotherapy are more widely
developed compared to colposcopy and management of precancerous lesions. Policy makers, social advocates and the general
population are largely unaware of the potential for early detection
of cervical precancerous lesions and the prevention of cervical cancer. Although task forces have deliberated the problem of cervical
cancer and have made recommendations, organized mass screening is not yet a reality in India.
The difculties in implementing an organized cervical cytology screening in India and other low-resource countries have
prompted several Indian researchers to evaluate affordable and
effective alternative screening approaches to facilitate evolution
and implementation of cost-effective screening in due course [30].
These studies are briey reviewed.
The accuracy of conventional cytology, HPV testing by HC2
method, visual inspection with acetic acid (VIA) and visual inspec-

tion with Lugols iodine (VILI) in the early detection of CIN2-3

lesions has been addressed in several cross-sectional studies
[11,3138]. The results from major multi-centre, cross-sectional
studies are given in Table 6 [11,3338]. These studies indicate
that with quality assurance and good training of providers, cytology, HPV testing and visual tests had similar sensitivity to detect
high-grade lesions. However, a potential bias exists for VIA studies
in view of colposcopically directed biopsies used as the reference standard, the sensitivity for VIA in the Indian studies varied
between 56 to 88% [35]. A higher sensitivity for high-grade CIN was
demonstrated with HPV testing in North American and European
studies (pooled average 98%) whereas the sensitivity in India was
lower (range 5080%) [11,39]. A certain amount of bias in reference
diagnosis, due to the use of colposcopic biopsy based gold standard,
cannot be ruled out for this discrepancy [39]. The range in sensitivities between the study centres was widest for cytology; HPV DNA
testing was the most reproducible test [11,37].
Recognizing the importance of developing rapid, simple,
accurate and affordable HPV test formats suitable for use in lowresource settings, has resulted in ongoing efforts by the START
project (Screening Technologies to Advance Rapid Testing) to
develop such tests. The START project was conceived and coordinated by PATH (Seattle, WA, USA) in collaboration with the Cancer
Institute of the Chinese Academy of Medical Sciences (CICAMS),
Beijing, China; the Tata Memorial Centre (TMC), Mumbai, India;
Nargis Dutt Memorial Cancer Hospital (NDMCH), Barshi, India; the
International Agency for Research on Cancer (IARC), Lyon, France
and industrial partners and funded by the Bill and Melinda Gates
Foundation. A rapid batch test format, based on HC technology, targets oncogenic HPV types and another assay targets the detection
of the E6 protein of oncogenic HPV types in a lateral ow strip-test
format. The commercial availability of these tests is eagerly awaited.
The efcacy and cost-effectiveness of new paradigms in cervical
screening such as a single lifetime screening with VIA, cytology or
HPV testing in preventing invasive cervical cancer has been evaluated in randomised, controlled trials [10,40,41]. Compliance to
attend screening visits, as well as follow-up and treatment, is a
major problem in developing countries. A single visit approach has
been evaluated in which screening, colposcopy of screen-positive
women, directing biopsies and treatment of CIN by cryotherapy are
carried out in the same session in order to enhance adherence to
diagnosis and treatment of screen-positive women [10,40,42]. In a
cluster-randomized trial in Dindigul district in India, of the 49,311
eligible women aged 3059 years in the VIA group, 31,343 (63.6%)
were screened during 20002003; 30,958 women in the control
group received routine care. A signicant 25% reduction in cervical cancer incidence and 35% reduction in mortality were reported
seven years after the beginning of screening in this study (Table 7)
[40].
In the Osmanabad district cluster-randomized controlled trial,
the efcacy and cost-effectiveness of a single round of screening

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R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

Table 7
Cervical cancer incidence and mortality from a randomized controlled trial in the Dindigul district cervical screening cluster, India (20002006)
Endpoint

VIA group

Control group

Adjusted hazard ratioa (95% CI)

Total number of women

Number screened
Number screen positive
Cervical cancer cases
Age-standardized incidence rate (per 100,000)
Cervical cancer deaths
Age-standardized mortality rate (per 100,000)

49,311
31,343
3,088
167
75.2
83
38.3

30,958
951

158
99.1
92
54.9

0.75 (0.590.95)

0.65 (0.470.89)

VIA: visual inspection with acetic acid; CI: Condence interval. Source of data: [40].
a
Adjusted for cluster design, age, education, marital status and parity.

by VIA (34,000 women), cytology (32,000 women), or HPV testing

(34,000 women) as compared to a control group (31,400 women)
receiving routine care plus health education on cervical cancer prevention in incidence and mortality has been investigated [10]. The
screening rounds were completed during 20002003. More than
70% of the women in the different groups were screened; the detection rate of high-grade lesions was similar in all intervention arms:
0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing (Table 8).
Updated results from this study will be available in 2008. Factors
inuencing participation in screening and treatment in the above
studies have been addressed [43,44]. The cure rates for cryotherapy
and LEEP for CIN in these studies exceed 85%; minor side effects and
complications were reported in less than 10% of women and these
treatments are judged to effective, safe and acceptable to women
[42].
In a cost-effectiveness study of different cervical screening
approaches in India and other developing countries, screening
women once a lifetime, at the age of 35 years, with a one- or
two-visit screening strategy involving VIA or HPV testing reduced
the lifetime risk of cancer by approximately 2536% and cost less
than 500 US dollars per year of life saved. The relative cancer risk
declined by an additional 40% with two screenings (at 35 and 40
years of age), resulting in a cost per year of life saved that was less
than each countrys per capita gross domestic product - a very costeffective result [45]. The ndings and experiences from the Indian
screening studies [10,11,3146] have substantially contributed to
the development of guidelines and training manuals for global use
[4750].
5.2. Bangladesh
Until recently, there were no organized or opportunistic cervical
screening programs in Bangladesh. Cervical smears were sporadically taken in medical college hospitals and large hospitals in urban
areas. According to a WHO Health Survey in 2002, 0.4% of 2,964
women aged 1869 years ever had a Pap smear [51]. It is estimated
that less than 50,000 smears are taken annually.
Cognizant of the inability to introduce a good quality cervical cytology screening program in the country due to formidable
technical and logistic challenges, the Government of Bangladesh
and Bangabandhu Sheikh Mujib Medical University (BSMMU) with
the support of the United National Population Fund (UNFPA) are
currently developing a cervical cancer screening program. The
screening program targets women aged 30 years and above, and is
based on VIA provided by trained health workers, paramedics and
nurses in primary care at the maternal and child welfare centres
and district hospitals with referral of VIA-positive women to nearby
medical college hospitals for investigation and treatment of women
with CIN and cancer. This program has been successfully piloted in
16 districts, currently expanded to 31 districts, and is planned to
soon cover all 64 districts in the country. More than 80,000 women
have already been screened through this program. Colposcopy clin-

ics at BSMMU and 14 medical colleges offer diagnosis and treatment

services (cryotherapy or LEEP) to screen-positive women as outpatient procedures. Recently ten master trainers from different
regions of Bangladesh were trained in India and 36 gynaecologists
received extensive colposcopy training at BSMMU to support the
large training and human resources requirements of this program.
Several courses have been conducted in Bangladesh to train service
providers in VIA, colposcopy and treatment of CIN using training
and service delivery manuals [4850]. Culturally sensitive educational efforts to inform and motivate women regarding prevention
opportunities, and to educate and reorient health care professionals, are currently ongoing.
5.3. Sri Lanka
There are no organized cervical screening programs in Sri Lanka.
Cervical smears are opportunistically taken from women attending major government hospitals, centrally processed and reported
in Colombo. According to a WHO Health Survey in 2002, 1.3% of
3208 women aged 1869 years ever had a Pap smear [51]. During 2006, around 44,000 cervical smears were processed in public
services in the country. Cumulatively during 20012006, around
135,000 cervical smears were reported. About 5% of the smears
had low-grade squamous intraepithelial neoplasia (LSIL) or worse
reports. However, it is not clear if the smear-positive women ever
received diagnosis and treatment. There is a great need to develop
and implement an appropriate early detection policy. Efforts are
currently underway to develop a population-based cancer registry
and to evaluate different cervical screening methods to guide the
development of such a policy. There is an urgent need to invest and
educate service providers in cervical screening and management
of CIN and to organize colposcopy, cryotherapy and LEEP treatment
services in the country.
5.4. Nepal
There is no organized cervical screening program in any part
of Nepal. Cervical smears are taken sporadically among women
attending major government hospitals in Kathmandu and other
large towns. According to a WHO Health Survey in 2002, 2.4% of
4,300 women aged 1869 years ever had a Pap smear [52]. It is
unlikely that more than 20,000 smears are taken annually throughout the country. Among 1,106 women tested with cervical cytology
in a hospital-based study in Kathmandu, smears from 75 women
had CIN1 features, eight had CIN2, six had CIN3 and eleven invasive cancers [53]. In another hospital-based study involving 800
women, 4.8% of the smears were reported as CIN or invasive cancer [54]. In recent years, colposcopy and CIN treatment services
have been organized in Kathmandu, Bhakthapur, Bharathpur and
Banepa as part of studies involving 15,000 women aged 3059 years
to evaluate visual screening and treatment of CIN. In the study in
Bharathpur, the detection rate of CIN3 lesions and cancer was 5

R. Sankaranarayanan et al. / Vaccine 26S (2008) M43M52

M51

Table 8
Input and intermediate outcome measures in the Osmanabad district randomized controlled trial of cytology, VIA and HPV testing in India
Endpoint

Cytology group

VIA Group

HPV group

Control group

Eligible women (3059 years)

Screening coverage
Test positivity
Detection rate of CIN1
Detection rate of CIN2/3
Detection rate of cancer
Treatment rate of CIN1
Treatment rate CIN2/3

35,193
73%
7%
2.0%
1.0%
0.3%
46%
88%

36, 874
72%
14%
5.6%
0.7%
0.3%
34%
88%

36, 938
74%
10%
2.3%
0.9%
0.2%
31%
83%

33, 696
6%a

CIN: cervical intraepithelial neoplasia; VIA: visual inspection with acetic acid. Source of data: [10].
a
Proportion of women seeking screening services and screened with cytology.

per 1,000 women screened (personal communication: Dr Binuma,

2008), which is similar to rates observed in India [10,40]; however
in Bhakthapur and Banepa, the frequency of CIN3 was much lower
at 1 per 1,000 women, indicating possible under-diagnosis. Efforts
are underway to train a large number of nurse providers in primary care on visual screening techniques and to develop referral
centres in district hospitals where screen-positive women can be
investigated and treated for CIN. Cervical cancer treatment facilities are available in Kathmandu, Bhakthapur and Bharathpur. There
is an enormous scope for implementing early detection of cervical
neoplasia in Nepal.
6. Conclusions
The current scenario of cervical cancer prevention in the
Indian sub-continent provides glimpses of the striking gap in
our knowledge on the distribution and determinants of disease
in vast regions, glaring inadequacy or nonexistent investment
in prevention and early detection, in spite of existing options
and opportunities in controlling invasive cervical cancer. Cervical
cancer incidence needs to be documented in representative populations in Bangladesh, Nepal and Sri Lanka in order to obtain accurate
national estimates of disease burden in these countries. This is
effectively done by developing population-based cancer registries.
HPV prevalence surveys in the general population and among cervical cancer cases, natural history, and vaccine introduction studies
are needed to inform public health strategies in prevention by vaccination.
Investigating and proving the usefulness of innovative dose
regimes such as two-dose HPV vaccine regimen and efforts to
reduce the costs of the vaccine are important in the context of introducing HPV vaccines. School-based and pulse vaccination using
a campaign approach are most helpful for HPV vaccine rollout.
While HPV vaccination provides hope for the future, public and
professional education and the deployment of screening programs
provide the means of controlling the current heavy burden of disease.
VIA based screening is clearly the most feasible screening
approach as of now in India, Bangladesh, Nepal and Sri Lanka.
Neglecting and delaying planned investments in screening programs will result in the disease burden continuing unabated and
many poor women in these countries will miss opportunities for
preventing cervical cancer for several decades to come. Although
HPV testing is a more accurate, reproducible and objective screening test as compared to visual and cytology screening for cervical
neoplasia, the current high costs and cumbersome technology
behind it preclude its wider use. The eventual availability of a rapid,
accurate and affordable HPV test should facilitate the wider use of
HPV testing in screening programs. Investments today in VIA based
screening programs will eventually facilitate the smooth introduction of the inexpensive and rapid HPV tests in the future when

they are widely commercially available. Professional and womens

organizations can play a major role in advocating cervical cancer
prevention by educating planners and governments and by catalyzing urgent investments. Findings from research studies and
demonstration projects provide important leads for introducing
screening and HPV vaccination programs in a phased manner to
control the current high burden of disease.
Disclosed potential conict of interest
PG: Advisory Board (Roche Molecular Systems, Merck & Co.,
Inc.); Consultant (TriPath); Research Grants (Roche Molecular Systems, Merck & Co., Inc.); Speakers Bureau (Merck & Co., Inc.).
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