PLOS GLOBAL PUBLIC HEALTH

RESEARCH ARTICLE

Concurrent HPV DNA testing and a visual

inspection method for cervical precancer
screening: A practical approach from Battor,
Ghana
Kofi Effah ID1, Ethel Tekpor1, Comfort Mawusi Wormenor1, Joseph Emmanuel Amuah1,2,
Nana Owusu Essel ID3*, Bernard Hayford Atuguba1, Gifty Belinda Klutsey1, Edna Sesenu1,
Georgina Tay1, Faustina Tibu1, Seyram Kemawor ID1, Isaac Gedzah1, Esu Aku
Catherine Morkli1, Stephen Danyo1, Patrick Kafui Akakpo4
a1111111111
1 Catholic Hospital, Battor, via Sogakope, Volta Region, Ghana, 2 School of Epidemiology and Public
a1111111111
Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada, 3 Department of Emergency
a1111111111 Medicine, College of Health Sciences, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,
a1111111111 AB, Canada, 4 Department of Pathology, University of Cape Coast, School of Medical Sciences, Clinical
a1111111111 Teaching Center, Cape Coast, Ghana

* [email protected]

OPEN ACCESS Abstract

Citation: Effah K, Tekpor E, Wormenor CM, Amuah
JE, Essel NO, Atuguba BH, et al. (2023) Concurrent Cytology-based cervical cancer screening programs have been difficult to implement and
HPV DNA testing and a visual inspection method scale up in developing countries. Thus, the World Health Organization recommends a ‘see
for cervical precancer screening: A practical and treat’ approach by way of hr-HPV testing and visual inspection. We aimed to evaluate con-
approach from Battor, Ghana. PLOS Glob Public
Health 3(4): e0001830. https://doi.org/10.1371/
current HPV DNA testing and visual inspection in a real-world low-resource setting by compar-
journal.pgph.0001830 ing the detection rates of concurrent visual inspection with dilute acetic acid (VIA) or mobile
Editor: Edina Amponsah-Dacosta, University of
colposcopy and hr-HPV DNA testing to standalone hr-HPV DNA testing (using the careHPV,
Cape Town, SOUTH AFRICA GeneXpert, AmpFire, or MA-6000 platforms). We further compared their rates of loss to fol-
Received: January 3, 2023
low-up. This retrospective, descriptive cross-sectional study included all 4482 women sub-
jected to cervical precancer screening at our facility between June 2016 and March 2022. The
Accepted: March 27, 2023
rates of EVA and VIA ‘positivity’ were 8.6% (95% CI, 6.7–10.6) and 2.1 (95% CI, 1.6–2.5),
Published: April 20, 2023 respectively, while the hr-HPV-positivity rate was 17.9% (95% CI, 16.7–19.0). Overall, 51
Peer Review History: PLOS recognizes the women in the entire cohort tested positive on both hr-HPV DNA testing and visual inspection
benefits of transparency in the peer review (1.1%; 95% CI, 0.9–1.5), whereas a large majority of the women tested negative (3588/4482,
process; therefore, we enable the publication of
all of the content of peer review and author
80.1%) for both and 2.1% (95% CI, 1.7–2.6) tested hr-HPV-negative but visual inspection ‘pos-
responses alongside final, published articles. The itive’. In total, 191/275 (69.5%) participants who tested hr-HPV positive on any platform, as a
editorial history of this article is available here: standalone test for screening, returned for at least one follow-up visit. In light of factors such as
https://doi.org/10.1371/journal.pgph.0001830
poor socioeconomic circumstances, additional transportation costs associated with multiple
Copyright: © 2023 Effah et al. This is an open screening visits, and lack of a reliable address system in many parts of Ghana, we posit that
access article distributed under the terms of the
standalone HPV DNA testing with recall of hr-HPV positives will be tedious for a national cervi-
Creative Commons Attribution License, which
permits unrestricted use, distribution, and cal cancer prevention program. Our preliminary data show that concurrent testing (hr-HPV
reproduction in any medium, provided the original DNA testing alongside visual inspection by way of VIA or mobile colposcopy) may be more
author and source are credited. cost-effective than recalling hr-HPV-positive women for colposcopy.
Data Availability Statement: All relevant data are
within the paper, and relevant datasets can be

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

accessed at: https://doi.org/10.6084/m9.figshare. Introduction

21801268.v2.
Globally, about half a million women develop cervical cancer annually [1] with over 85% of
Funding: The authors received no specific funding
cases occurring in developing countries, making it the second most frequent cause of cancer
for this work.
deaths [2]. Cervical precancer screening remains a key strategy in reducing the global disease
Competing interests: The authors have declared burden. In developing countries, however, infrastructural challenges, lack of trained person-
that no competing interests exist.
nel, high costs, and long waiting times for test results make cytological screening ill-suited [3].
To achieve comprehensive cervical cancer control, human papillomavirus (HPV) vaccination
and effective precancer screening programs remain at the forefront, followed by treatment of
any identified precancerous or cancerous lesions [4, 5]. In this regard, it is essential to distin-
guish between the concepts of cervical cancer elimination and HPV eradication. However, in
pushing the overall agenda, the objective is to institute a target (tailored according to a coun-
try’s existing health structures and economic circumstances), that, if reached, cervical cancer
would no longer be considered a public health concern [5].
Although cytology-based cervical cancer screening programs have demonstrated usefulness
in reducing attributable mortality rates in the developing world, they have been relatively
more difficult to implement and scale up in developing countries like Ghana. This has been
ascribed to lack of trained cytopathologists and pathology services and poor infrastructure for
patient follow-up [6, 7]. As viable alternatives, visual inspection with dilute acetic acid (VIA)
and HPV DNA testing have gained popularity in screening programs in low-resource settings.
In such settings, the World Health Organization (WHO) conditionally recommends screen-
and-treat algorithms by way of HPV testing and VIA [8]. These recommendations were based
on the following pieces of low-quality evidence available on the accuracies of these methodolo-
gies: recommendation 2–preferably screening with VIA, followed by cryotherapy (or loop elec-
trosurgical excision procedure [LEEP] if ineligible) over HPV screening followed by
cryotherapy (or LEEP if ineligible); recommendation 6–preferably perform HPV testing fol-
lowed by VIA and cryotherapy (or LEEP) or HPV testing with cryotherapy (or LEEP); and rec-
ommendation 7–preferably screen via HPV testing, followed by VIA with cryotherapy (or
LEEP) over screening with VIA and treatment with cryotherapy (or LEEP) [8].
VIA is not expensive and can be performed by lay-trained healthcare professionals, and
VIA-positive women can undergo treatment within the same visit, reducing the need to recon-
tact patients and the resulting loss to follow-up. Despite these advantages, the performance of
the procedure varies according to provider experience, with wide ranges of sensitivity (41–92%)
and specificity (49–98%) for the detection of histologically-confirmed high-grade cervical pre-
cancerous lesions (CIN2+) [9, 10]. In addition, VIA findings are less reliable among meno-
pausal patients [11]. In primary screening for precancerous lesions, HPV DNA testing has been
shown to outperform cytology or VIA in decreasing cervical cancer incidence and mortality in
a single screen [12, 13], with a sensitivity of 89.7% (range, 86.4–93.9) and specificity of 88.2%
(range, 86.2–90.1) for detecting CIN2+ lesions [14]. However, women with transient high-risk
HPV (hr-HPV) infection are at risk of overtreatment; thus, under ideal conditions, only women
with progressive hr-HPV infection should be triaged for treatment [15].
At the Cervical Cancer Prevention and Training Centre (CCPTC), Battor, Ghana, primary
screening via HPV DNA testing is employed using a number of platforms: AmpFire, GeneX-
pert, MA-6000, and previously careHPV. Visual inspection methods such as VIA and mobile
colposcopy with the Enhanced Visual Assessment (EVA) system are options also available to
clients. Various screening models of concurrent hr-HPV DNA technologies and visual inspec-
tion methods have yet to be evaluated for their general performance and comparative advan-
tages and disadvantages specific to a low-resource setting. There is a gap in knowledge in this
area of cervical cancer screening, particularly in low-resource settings. For a country with no

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

functional national cervical cancer screening guidelines, this study of concurrent HPV DNA
and VIA testing in a secondary-level healthcare facility could potentially generate a wealth of
information, that could shape the future of cervical cancer screening by formulating a strategy
that works best for our setting.
The present study aimed to evaluate the existing recommendations of the WHO pertaining
to visual inspection and HPV DNA testing algorithms for cervical cancer screening in a real-
world low-resource setting. Specifically, we aimed to determine the detection rates of concur-
rent (combined) VIA or EVA mobile colposcopy and hr-HPV DNA testing in comparison to
standalone hr-HPV DNA testing; to evaluate the rate of loss to follow-up in this cohort; and to
discuss our approach to triaging hr-HPV-positive patients at our center.

Materials and methods

Ethical considerations
The Research Ethics Committee of the Catholic Hospital, Battor, granted ethical approval for
this study (approval no. CHB-ERC-002/07/19). The need for informed consent was waived on
account of the retrospective nature of the study.

Study setting, design, and overview

The CCPTC was established in May 2017 and started training health workers in cervical cancer
prevention skills (including how to perform VIA and colposcopy) in September 2017. Stand-
alone HPV DNA testing was the main cervical precancer screening method. The algorithm
used at the CCPTC for cervical precancer screening with HPV DNA testing has been pub-
lished previously [16]. In November 2017, to enable trainees acquire more practical experi-
ence, VIA became a routine procedure at no extra cost to clients. It was at this time that the
CCPTC started to gain experience with concurrent HPV DNA testing and visual inspection
procedures using the algorithm presented in S1 Fig. Although VIA was performed at no addi-
tional cost, women had to pay from their pockets to undergo EVA mobile colposcopy and hr-
HPV DNA testing. This made it possible to compare concurrent HPV DNA testing and visual
inspection methods (VIA or mobile colposcopy) with standalone HPV DNA testing in a rou-
tine clinical setting. One hundred and thirty-five women who opted for and performed self-
sampling were included in the standalone HPV DNA testing group as no visual inspection
method was performed.
The present retrospective, descriptive cross-sectional study included all 4482 women sub-
jected to cervical precancer screening via HPV DNA testing in combination with a visual
inspection method (VIA or EVA colposcopy) and 1574 women subjected to standalone hr-
HPV DNA testing at the CCPTC, Battor, between June 1, 2016 and March 31, 2022. All data
on the women and their screening statuses were captured and stored securely in databases
managed by the CCPTC. All personal data were de-identified prior to the analyses.

Variables and outcomes

We captured and analyzed data pertaining to sociodemographic characteristics of the screened
women, including age, marital status, parity, monthly income, education level, and religious
faith. We also collected data regarding self-reported risk factors such as HIV and smoking sta-
tus. The outcomes of interest were a positive hr-HPV DNA test determined using any of the
four platforms and/or the presence of clinically relevant lesion(s) on visual inspection (using
VIA or mobile colposcopy).

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Cervical sample collection and HPV DNA screening

During the screening visit, all women were counseled on the benefits of cervical screening and
its associated risks and possible outcomes. In the dorsal lithotomy position, a speculum was
placed to expose the cervix and to obtain cervical specimens with a sterile brush or dry cotton
swab for laboratory processing and typing. Women who opted to undergo hr-HPV DNA test-
ing with self-samples were instructed on Evalyn self-sample brush (Rovers Medical Devices B.
V., Oss, Netherlands) use. The Evalyn brushes were capped after sample collection, stored in a
dry area at room temperature, and returned to our central laboratory for processing within
seven days.
HPV DNA testing was performed using careHPV (Qiagen GmBH, Hilden, Germany) [17],
GeneXpert (Cepheid, Sunnyvale, CA, USA) [18], AmpFire (Atila BioSystems, Inc., Mountain
View, CA, USA) [16, 19], or MA-6000 (Sansure Biotech Inc., Hunan, China) [20], depending
on the period of testing. Each test was performed strictly according to the manufacturer’s
protocol.

HPV DNA detection

careHPV utilizes a powerful and fast procedure to detect HPV DNA in cervical specimen col-
lected into careHPV collection medium. The platform is designed to detect HPV 16/18/31/33/
35/39/45/51/52/56/58/59/66/68 without distinction [17]. GeneXpert also detects HPV DNA in
PreserCyt or ThinPrep liquid specimens. It specifically identifies HPV 16 and 18/45 and collec-
tively identifies genotypes 31/33/35/39/51/52/56/58/59/66/68 as ‘other’ hr-HPV types [18].
Both AmpFire and MA-6000 detect HPV DNA in cervicovaginal samples (collected using dry
brushes, swabs, or PreservCyt/ThinPrep) and specifically identify genotypes 16 and 18 and col-
lectively identify genotypes 31/33/35/39/45/51/52/53/56/58/59/66/68 [19, 20]. Even though
both AmpFire and MA-6000 offer full genotyping options, these are more expensive and have
a low throughput, and so are not generally performed at our facility.

Screening via visual inspection methods

VIA was performed by locally trained nurses under the supervision of a specialist gynecologist.
The cervix was inspected after applying 5% acetic acid, waiting for 90–120 seconds, and look-
ing over carefully for abnormal changes under a 100 W incandescent light source [7]. VIA pos-
itivity was defined as the presence of well-defined opaque aceto-whitening at the
transformation zone.
Mobile colposcopy was performed using the EVA system (MobileODT, Tel Aviv, Israel), a
platform built around a smartphone interface with an online image storage portal. The appli-
cation is used to control the mobile colposcope and upload colposcopic images for review by a
gynecologist [16, 21]. Nurses recorded details pertaining to colposcopic adequacy, the type of
transformation zone, and the presence of any cervical or vaginal lesions.
Upon cervical screening by EVA colposcopy or VIA, the result of the examination was clas-
sified using the Rio 2011 Colposcopy Nomenclature of the International Federation for Cervi-
cal Pathology and Colposcopy (IFCPC) [22]. In keeping with this nomenclature, each
woman’s screening status was classified as one of the following:
1. Inadequate conditions for colposcopic assessment, inflammation
2. Adequate conditions for colposcopic assessment, transformation zone type 1
3. Adequate conditions for colposcopic assessment, transformation zone type 2

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

4. Adequate conditions for colposcopic assessment, transformation zone type 3; only limited
assessment of the transformation zone is possible.

Definitions of transformation zone types

Type 1: The entire circumference of the squamocolumnar junction is visible; fully ectocervical.
Type 2: The entire circumference of the squamocolumnar junction is visible; partly or fully
endocervical.
Type 3: The entire circumference of the squamocolumnar junction is not visible; partly or
fully endocervical.

Statistical analysis
Descriptive statistics were generated for all sociodemographic and clinical variables. Percent-
ages and counts were used to describe all categorical variables and prevalence estimates, along-
side their binomial exact 95% confidence intervals (CIs). Continuous variables are described
as means with their standard deviations (SDs) or medians with their interquartile ranges,
depending on the level of skewness. Overall rates of positivity on EVA colposcopy, VIA, and
hr-HPV testing are presented and disaggregated by HIV status and test platform. All statistical
analyses were performed using Stata 15 (StataCorp LLC, College Station, TX, USA).

Results
Sociodemographic and clinical details of participants
A total of 4482 women underwent concurrent cervical precancer screening via HPV DNA test-
ing and visual inspection (VIA or EVA colposcopy) during the study period. The sociodemo-
graphic, clinical, and screening characteristics of the study participants are presented in Table 1.
The mean age at screening was 39.3 (SD, 9.4) years, with a majority of women being married
(51%) or having a steady partner (22%). Almost 1 in 4 (23.1%) of the women screened had com-
pleted tertiary education and almost 1 in 10 (10.8) had no formal education. As self-reported
risk factors, most participants had never smoked (99.5%) and were HIV negative (54%). The
HIV positivity rate among 2538 women with available information on HIV status was 5.0%.

Overall and subgroup analyses of hr-HPV DNA detection rates

Overall, at screening, 800 of 4482 participants (17.9%; 95% CI, 16.7–19.0) tested hr-HPV posi-
tive, whereas 69 of 801 (8.6%; 95% CI, 6.7–10.6) women who underwent EVA colposcopy
were ‘positive’ and 76 out of 3681 women (2.1%; 95% CI, 1.6–2.5) who underwent VIA were
‘positive’. The corresponding rates tended to be higher among HIV-positive women (10.5%,
7.5%, and 42.5% positivity rates on EVA colposcopy, VIA, and hr-HPV DNA testing, respec-
tively) (Table 1). When disaggregated according to test platform, MA-6000 showed the highest
hr-HPV detection rate of 24.6% (95% CI, 21.6–27.7), followed by GeneXpert (19.0%; 95% CI,
12.6–25.5), AmpFire (16.6%; 95% CI, 15.3–17.9), and careHPV (13.4%; 95% CI, 9.6–17.2).

Overall screening outcomes and treatment of study participants

In the subgroup of 3681 women who underwent VIA, 3106 were hr-HPV negative, among
whom 55 (1.8%) were VIA ‘positive’ (Fig 1). Among 575 hr-HPV-positive women (15.6%) in the
same subgroup, 21 (3.7%) were VIA ‘positive’. Eight of these women were treated based on hr-
HPV-negative and VIA-positive results: thermal coagulation in 3 and LEEP in 5. Two women
were treated based on hr-HPV-positive and VIA-positive results: thermal coagulation and LEEP

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

Table 1. Sociodemographic and clinical characteristics of women (n = 4482) who underwent concurrent cervical
precancer screening via HPV DNA testing and visual inspection.
Characteristic Estimate
Age, mean (SD) 39.3 (9.4)
Marital status, n (%)
Single 667 (14.9)
Has a steady partner 987 (22.0)
Married 2295 (51.2)
Divorced 307 (6.9)
Widowed 206 (4.6)
Missing 20 (0.5)
Number of children, median (IQR) 1 (0, 2)
Highest level of education, n (%)
No formal education 483 (10.8)
Elementary education 842 (18.8)
Secondary education 2006 (44.8)
Tertiary education 1034 (23.1)
Vocational/technical/other 114 (2.5)
Missing 3 (0.1)
Religious faith, n (%)
Christian 3998 (89.2)
Islam 269 (6.0)
African traditional religion 22 (0.5)
Other 7 (0.2)
None 5 (0.1)
Missing 181 (4.0)
Smoker, n (%) 20 (0.5)
HIV status, n (%)
Positive 127 (2.8)
Negative 2411 (53.8)
Unknown 1944 (43.4)
Earns income, n (%)
Yes 3851 (85.9)
No 440 (9.8)
Missing 191 (4.2)
EVA positive, % (95% CI) 8.6 (6.7–10.6)
EVA positive, % (95% CI) [among 86 HIV positive women] 10.5 (4.0–16.9)
VIA positive, % (95% CI) 2.1 (1.6–2.5)
VIA positive, % (95% CI) [among 41 HIV positive women] 7.3 (0.0–15.3)
hr-HPV positive, % (95% CI) 17.9 (16.7–19.0)
hr-HPV positive, % (95% CI) [among HIV 127 positive women] 42.5 (33.9–51.1)
hr-HPV positive by test platform, % (95% CI)
careHPV 13.4 (9.6–17.2)
GeneXpert 19.0 (12.6–25.5)
AmpFire 16.6 (15.3–17.9)
MA-6000 24.6 (21.6–27.7)

hr-HPV, high-risk human papillomavirus

SD, standard deviation
IQR, interquartile range
VIA, visual inspection with dilute acetic acid
CI, confidence interval.

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

Fig 1. Flow chart for concurrent screening with hr-HPV DNA testing and VIA. VIA, visual inspection with dilute acetic acid; hr-
HPV, high-risk human papillomavirus; LEEP, loop electrosurgical excision procedure.
https://doi.org/10.1371/journal.pgph.0001830.g001

in 1 each. In the hr-HPV-negative VIA positive group, histopathology following LEEP revealed
no dysplasia in 3 women and CIN2 in 2 women. In the hr-HPV-positive VIA positive group, his-
topathology revealed no dysplasia in the only woman subjected to LEEP (Fig 1).
Within the subgroup of 801 (17.9%) women subjected to concurrent hr-HPV DNA testing
and EVA colposcopy, 39 (4.9%) showed an abnormal lesion on EVA colposcopy but tested hr-
HPV negative, whereas 195 (24.3%) tested hr-HPV positive but EVA ‘negative’ and 30 (3.7%)
tested hr-HPV positive and EVA ‘positive’ (Fig 2). Six out of 39 women who tested hr-HPV
negative and EVA positive were treated: three each by way of thermal coagulation or LEEP.
Histopathology following LEEP for these 3 women showed no dysplasia. Seventeen out of 30
women were treated based on hr-HPV positivity and EVA positivity: thermal coagulation in 6
and LEEP in 11. Histopathology following LEEP revealed CIN2 lesions in 5 women, CIN3
lesions in 2 women, and no dysplasia in the remaining four women (Fig 2).

Outcomes of women subjected to concurrent hr-HPV testing and visual

inspection by test combination and follow-up after standalone hr-HPV
testing
Table 2 shows the distributions of screening outcomes stratified according to method and plat-
form combinations. The highest rate of positivity on both hr-HPV DNA testing and visual
inspection was recorded for GeneXpert +EVA (4.7%; 95% CI, 1.5–10.6), followed by AmpFire
+ EVA (4.5%; 95% CI, 2.5–7.4), careHPV + EVA (3.9%; 95% CI, 1.6–7.9), and MA-6000
+ EVA (2.5%; 95% CI, 0.8–5.7). Overall, 51 women in the entire cohort showed positive results
on both hr-HPV DNA testing and a visual inspection method (1.1%; 95% CI, 0.9–1.5), whereas
a large majority (80.0%; 95% CI, 78.8–81.2) of the women showed negative findings on both

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

Fig 2. Flow chart for concurrent screening with hr-HPV DNA testing and EVA colposcopy. hr-HPV, high-risk human
papillomavirus; LEEP, loop electrosurgical excision procedure.
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hr-HPV testing and visual inspection. Again, 191 (69.5%) of 275 women who tested hr-HPV
positive on any platform applied, as a standalone test for screening, returned for at least one
follow-up visit within the study period (Table 3).

Discussion
Our study aimed to evaluate the detection rates of concurrent hr-HPV DNA testing and visual
inspection by way of EVA mobile colposcopy or VIA in comparison to standalone hr-HPV DNA

Table 2. Distributions of results of concurrent hr-HPV testing and visual inspection screening stratified by method.
hr-HPV + hr-HPV + hr-HPV – hr-HPV – Total
Visual inspection – Visual inspection + Visual inspection + Visual inspection –
careHPV + VIA, n (%) 8 (5.9) 1 (0.7) 3 (2.2) 123 (91.1) 135
careHPV + EVA, n (%) 26 (14.6) 7 (3.9) 10 (5.6) 135 (75.8) 178
GeneXpert + VIA, n (%) 5 (14.3) 0 (0.0) 0 (0.0) 30 (85.7) 35
GeneXpert + EVA, n (%) 17 (15.9) 5 (4.7) 6 (5.6) 79 (73.8) 107
AmpFire + VIA, n (%) 429 (14.6) 9 (0.3) 36 (1.2) 2466 (83.9) 2940
AmpFire + EVA, n (%) 89 (28.5) 13 (4.2) 13 (4.2) 197 (63.1) 312
MA-6000 + VIA, n (%) 112 (19.6) 11 (1.9) 16 (2.8) 432 (75.7) 571
MA-6000 + EVA, n (%) 63 (30.9) 5 (2.5) 10 (4.9) 126 (61.8) 204
Total, n (%) 749 (16.7) 51 (1.1) 94 (2.1) 3588 (80.1) 4482

VIA, visual inspection with dilute acetic acid

hr-HPV
high-risk human papillomavirus.

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

Table 3. Distributions of hr-HPV test results and follow-up rates following standalone hr-HPV testing stratified
by platform.
hr-HPV + hr-HPV – hr-HPV + cases who returned for follow-up
careHPV, n (%) 166 (15.1) 933 (84.9) 104 (62.7)
GeneXpert, n (%) 28 (11.6) 213 (88.4) 25 (89.3)
AmpFire, n (%) 39 (31.7) 84 (68.3) 27 (69.2)
MA-6000, n (%) 42 (37.8) 69 (62.2) 35 (83.3)
Total, n (%) 275 (17.5) 1299 (82.5) 191 (69.5)
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testing among 4482 women who presented for cervical precancer screening at the CCPTC, Bat-
tor. This work will provide information and more options to the WHO recommendation of a ‘see
and treat’ approach to cervical cancer screening in low-resource settings because it is cost-effec-
tive and reduces loss to follow-up [7, 8, 23]. To the best of our knowledge, the present work is the
first to document an evaluation of concurrent cervical precancer screening as an alternative to the
see and treat approach advised by the WHO for resource-limited countries.
One of the most important contributions of the study was to evaluate retention in care, per-
haps one of the greatest challenges in cervical cancer screening programs worldwide. When
standalone hr-HPV DNA testing was performed, 69.5% (191/275) of hr-HPV-positive women
returned for follow-up evaluation via visual inspection (colposcopy), despite various efforts
made to reach all of them. This finding demonstrates that without performing concurrent
visual inspection (colposcopy or VIA) within the same visit as when a cervicovaginal sample
was taken for hr-HPV testing, as many as 30.5% of hr-HPV-positive women would be lost to
follow-up. This high rate of loss to follow-up is multifactorial, and despite exerting reasonable
efforts to reduce loss to follow-up, some barriers remained that might best be elucidated
through qualitative research. Ghana remains a vibrant mobile phone market in the sub-Saha-
ran region, with recent surveys showing that 83% of all adults own a mobile phone and that
there are approximately 130 mobile service subscribers per 100 population [24, 25]. Although
the country has a high penetration of mobile phone services, it may be difficult to get hr-HPV-
positive women to screening centers on multiple occasions due to additional costs associated
with transportation. Further, even though attempts have been made in recent times to imple-
ment a digital addressing system for houses in many cities and towns in Ghana in addition to
street naming [26], many Ghanaians do not have permanent addresses, making a call-recall
system for a national cervical cancer prevention program difficult to implement. Further, in
similar low-resource settings, a lack of understanding of cervical cancer as a disease, the
screening process, and its outcomes, linked with poor socioeconomic circumstances and low
levels of male partner support have been identified as hampering adherence to follow-up after
an initial positive screening test [27, 28]. Thus, besides national policies, at the facility level, it
may be useful to intensify information-education-communication activities, in addition to
incentivizing providers and screen-positive attendees to complete the continuum of cancer
care. All these factors contribute to loss to follow-up, and make a case for a single visit
approach to cervical cancer screening in Ghana and other low (middle) income countries. The
training program offered at the CCPTC for nurses and midwives across Ghana and beyond
provides most women screened with hr-HPV DNA testing the opportunity to undergo VIA in
a single visit and in the same setting (when the HPV sample was taken). In addition, it allows
trainees to have hands-on experience in performing VIA, while giving attendees the opportu-
nity to have a one-time visit without paying additional fees for VIA. In light of the foregoing,
we posit that concurrent testing, where available, may be more cost-effective than waiting for
hr-HPV DNA results to recall hr-HPV-positive women for colposcopy.

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Another considerable challenge was highlighted in our data: namely, 2.1% (94/4482) of our
study participants showed negative results on hr-HPV testing but ‘positive’ results on visual
inspection (colposcopy or VIA). The corresponding rates were 4.9% (39/801) for the EVA
colposcopy group and 1.5% (55/3681) for the VIA group. These women represent a very
important group because these data show that if hr-HPV DNA testing had been performed as
a standalone test, and only hr-HPV-positive women had been recalled for colposcopy/VIA,
potentially precancerous cervical lesions would have been missed. This proportion would fur-
ther be expected to be greater among high-risk groups such as women living with HIV [29]. In
total, 14.9% (14/94) of these women with cervical lesions underwent treatment: 6 in the EVA
colposcopy group and 8 in the VIA group. In this group of hr-HPV-negative visual inspection
‘positive’ women, 6 were treated with thermal coagulation (thus, no tissue was obtained for
histopathology) while 8 were treated with LEEP. The histopathology reports for the 8 women
who underwent LEEP were no dysplasia (n = 6) and CIN2 (n = 2). Many factors determined
who got treated and the type of treatment (ablation–thermal coagulation or excisional–LEEP).
LEEP was recommended for large lesions that cover >75% of the ectocervix or extend into the
endocervical canal. There was also the option of conservative management (follow-up) for
women with minor changes on colposcopy and who were unlikely to be lost to follow-up,
while prompt treatment was recommended for women with major changes. In the 2011
Colposcopy Nomenclature of the IFCPC, minor changes (Grade 1) refer to thin acetowhite
epithelium, irregular, geographic border, fine mosaic, and fine punctuation. Major changes
(Grade 2) refer to dense acetowhite epithelium, rapid appearance of aceto-whitening, cuffed
gland openings, coarse mosaic, coarse punctuation, sharp border, and the presence of an inner
border sign or ridge sign [30]. Representative colposcopic images obtained from women who
tested EVA ‘positive’ and hr-HPV DNA positive on the careHPV, GeneXpert, AmpFire, and
MA-6000 platforms are shown in S2–S5 Figs.
Further, we observed a disparity between the positivity rates for VIA and EVA colposcopy.
While the VIA ‘positivity’ rate was 2.1 (95% CI, 1.6–2.5), the EVA colposcopy ‘positivity’ rate
was 8.6% (95% CI, 6.7–10.6), representing a clear difference of 6.5% (95% CI, 4.6–8.5;
p<0.0001). In addition to the established relatively more operator-dependent nature of VIA
[7, 10, 17, 29], this observed difference may be attributable to the magnification offered by the
mobile colposcope, rendering small lesions not visible to the naked eye on VIA visible during
colposcopy.

Strengths and limitations

The main strengths of this study lay in its relatively large sample size, allowing us to stratify
prevalence and detection rates without loss of statistical power, as well as its novelty as the first
study, to the best of our knowledge, to evaluate a concurrent cervical precancer screening algo-
rithm in Ghana. However, our study had a number of limitations, from which future studies
can draw to improve generalizability to similar low-resource settings. First, this work was done
in a routine clinical setting at Catholic Hospital, Battor. As this was not a funded project, the
women paid from their pockets to get screened and treated. When offered the choice of treat-
ment approach (thermal coagulation or LEEP), many, who could not afford biopsies, LEEP,
and the cost of histopathology opted to undergo ablation. When thermal coagulation was cho-
sen, no tissue was obtained for histopathology. Thus, we were unable to present the histopath-
ological results for many of the cervical lesions seen and followed up or treated by ablation.
Again, because we were unable to perform full genotyping for hr-HPV positive women, we
could neither distinguish among recognized, probable (HPV 66 and 68), or potential (HPV
53) hr-HPV genotypes nor account for the bias that could have arisen from using multiple

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

testing platforms. In addition, the criterion for adjudging positivity on VIA or mobile colpos-
copy is commonly the presence of aceto-whitening. Aceto-whitening may be due to immature
metaplasia, inflammation, subclinical papillomavirus infection, or CIN. Biopsies for histopa-
thology would have been useful to confirm precancerous (CIN2+) lesions. This work could
also not address the proportion of hr-HPV negatives who were visual inspection method
(VIA/colposcopy) negative but had lesions in the endocervical canal, that is for women with
transformation zone type 3. This is because pap smears and/or endocervical curettage were
not taken for this group of women. Further studies are needed to identify the exact proportion
of precancerous lesions that are hr-HPV DNA negative but positive on visual inspection or
negative on visual inspection because the lesions are in the endocervical canal. Evidence sug-
gests that this group may not constitute a clinically important group if clinically validated HPV
assays are used. However, we wish to create awareness among health workers in low-resource
settings that HPV assays available (such as those used in our study) may be less sensitive than
the gold standard and other validated assays. Thus, the increasing popularity of such platforms
in low-resource settings makes this group increasingly important. Again, our findings on the
level of education of these women suggest that they were more likely to have a tertiary level of
education (23.1%) than the general female population (10.4%) of Ghana according to the 2021
Population and Housing Census [31]. This suggests that the results of our research may not be
generalizable to the entire female population of Ghana. Last, the completeness of medical rec-
ords and missing data represented minor challenges. To mitigate these, we reviewed all data
sources in-depth to minimize the effects of missingness on our estimates and included ‘missing
data’ as an outcome measure for all relevant variables.

Conclusion
Based on our study population, prevailing poor socioeconomic circumstances, additional
transportation costs associated with multiple screening visits, and lack of a reliable address sys-
tem in many parts of Ghana, we posit that standalone HPV DNA testing with recall of hr-HPV
positives will be tedious for a national cervical cancer prevention program. Our preliminary
data show that concurrent testing (hr-HPV DNA testing along with visual inspection by way
of VIA or mobile colposcopy) may be more cost-effective than recalling hr-HPV-positive
women for colposcopy. In addition to building significant levels of capacity and strengthening
existing health systems, a concurrent approach, where available, may better address the entire
continuum of cervical cancer screening and improve loss to follow-up in low-resource
countries.

Supporting information
S1 Fig. Algorithm for screening with concurrent HPV DNA testing and visual inspection
at the CCPTC.
(TIF)
S2 Fig. Colposcopy images of a 41-year-old woman, para 2. careHPV testing was performed
concurrently with EVA colposcopy: (A) before applying acetic acid and (B) after applying ace-
tic acid. careHPV–positive; EVA transformation zone type 3, dense aceto-whitening more
anteriorly; treatment–LEEP; histopathology, CIN2.
(TIF)
S3 Fig. Colposcopy images of a 37-year-old woman, para 2. GeneXpert testing was per-
formed concurrently with EVA colposcopy: (A) before applying acetic acid and (B) after apply-
ing acetic acid. GeneXpert–positive (others, P3); EVA transformation zone type 3,

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

circumferential aceto-whitening, dense at the 1–3 o’clock position; treatment–LEEP; histopa-

thology, CIN2.
(TIF)
S4 Fig. Colposcopy images of a 37-year-old woman, para 0. AmpFire hr-HPV testing was
performed concurrently with EVA mobile colposcopy: (A) before applying acetic acid and (B)
after applying acetic acid. AmpFire–positive for HPV 18; EVA–leukoplakia with circumferen-
tial dense aceto-whitening; treatment–LEEP; histopathology, CIN 3.
(TIF)
S5 Fig. Colposcopy images of a 26-year-old woman, para 0+1. MA-6000 HPV DNA testing
was performed concurrently with EVA colposcopy. MA-6000–positive for ‘other’ HPV type
(s); EVA–adequate, transformation zone type 1, thin aceto-whitening on the anterior and pos-
terior cervical lips; treatment–thermal coagulation.
(TIF)

Acknowledgments
The authors acknowledge all the workers in the main laboratory of Catholic Hospital, Battor,
and the laboratory at the CCPTC as well as the staff at the CCPTC and the Department of
Obstetrics and Gynecology, Catholic Hospital, Battor who contributed in various ways toward
the screening and management of these women. The authors also thank the Catholic Hospital,
Battor for its support.

Author Contributions
Conceptualization: Kofi Effah, Ethel Tekpor, Comfort Mawusi Wormenor, Joseph Emmanuel
Amuah, Patrick Kafui Akakpo.
Data curation: Kofi Effah, Ethel Tekpor, Comfort Mawusi Wormenor, Joseph Emmanuel
Amuah, Nana Owusu Essel, Bernard Hayford Atuguba, Gifty Belinda Klutsey, Edna Sesenu,
Georgina Tay, Faustina Tibu, Seyram Kemawor, Isaac Gedzah, Esu Aku Catherine Morkli,
Stephen Danyo.
Formal analysis: Kofi Effah, Ethel Tekpor, Comfort Mawusi Wormenor, Joseph Emmanuel
Amuah, Nana Owusu Essel, Esu Aku Catherine Morkli, Stephen Danyo.
Investigation: Kofi Effah, Ethel Tekpor, Gifty Belinda Klutsey, Edna Sesenu, Georgina Tay,
Faustina Tibu, Seyram Kemawor, Isaac Gedzah, Stephen Danyo.
Methodology: Ethel Tekpor, Joseph Emmanuel Amuah.
Project administration: Kofi Effah.
Resources: Kofi Effah.
Software: Joseph Emmanuel Amuah.
Supervision: Kofi Effah.
Validation: Kofi Effah.
Writing – original draft: Kofi Effah, Ethel Tekpor, Comfort Mawusi Wormenor, Joseph
Emmanuel Amuah, Nana Owusu Essel, Patrick Kafui Akakpo.
Writing – review & editing: Kofi Effah, Ethel Tekpor, Comfort Mawusi Wormenor, Joseph
Emmanuel Amuah, Nana Owusu Essel, Patrick Kafui Akakpo.

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PLOS GLOBAL PUBLIC HEALTH Concurrent cervical precancer screening

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