Development of a Two-stage Cervical Cancer Screening Algorithm for Botswana
Phase: NA
Conditions: Cervical Cancer, HIV/AIDS
Sponsor: Beth Israel Deaconess Medical Center

(CCI) Committee on Clinical Investigations 
Page 1 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date: 
09/27/2017 
 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
Development of a two-stage cervical cancer screening 
algorithm for Botswana 
Principal Investigator 
Rebecca Luckett 
 
 
 
B1. 
PURPOSE OF PROTOCOL 
Cervical cancer screening programs vary across settings and there is no clear guidance for effective screening 
programs for HIV-positive women. Evaluating the performance of algorithms that include human 
papillomavirus (HPV) DNA testing as first stage screening in high HIV prevalence settings like Botswana is 
essential for establishing an evidence-based strategy for cervical cancer screening in HIV-positive women.  
The proposed study seeks to evaluate sensitivity, specificity, and positive predictive value (PPV) of two 
different two-stage cervical cancer screening algorithms for HIV-positive women in Botswana: HPV followed 
by Papanicolaou (Pap) smear, and HPV followed by visual inspection with acetic acid (VIA). The specific aims 
are: 
1. To determine the sensitivity, specificity, and PPV of a two-stage screening algorithm that utilizes HPV 
testing followed by Pap smear for the detection of high-grade cervical dysplasia, using colposcopy with 
histology as the gold standard. 
2. To determine the sensitivity, specificity, and PPV of a two-stage screening algorithm that utilizes HPV 
testing followed by VIA for the detection of high-grade cervical dysplasia, using colposcopy with 
histology as the gold standard.   
 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Cervical cancer is the fourth leading cause of cancer death in women worldwide and is the leading cause of 
cancer death in women in Botswana.i,ii,iii The disease burden in Botswana is impacted by the high prevalence of 
HIV (22% among people aged 15-49 years), which is a well-established risk factor for cervical cancer.iv,v,vi 
Cervical cancer is largely preventable and treatable where screening programs and treatment are 
available.vii,viii,ix,x The majority of cervical cancers are associated with infection with high-risk HPV subtypes 
(HPV).xi,xii,xiii Among HIV-positive women, persistent HPV positivity and infection with multiple subtypes are 
strong risk factors for cervical cancer.xiv HPV prevalence is variable, ranging from 15-45%, with higher 
prevalence in HIV-positive women.xv,xvi,xvii HPV 16, 18, and 45 are the high-risk subtypes most commonly 
associated with cervical cancer in Africa. In Botswana, HPV subtype prevalence in HIV positive women with 
high grade precancerous cervical lesions include 16, 18, 35, 58, 61; infections with multiple subtypes is 
common.xviii,xix,xx,xxi,xxii 
Cervical cancer screening strategies are most effective when based on local evidence and tailored to the 
population and resource infrastructure.xxiii,xxiv Available screening tests include HPV testing, cytology [liquid-
based or Pap smear], and VIA. HPV testing has a high sensitivity (93-100%) and specificity (80-90%), but low 
PPV (12-23%) for pre-invasive disease.xxv,xxvi,xxvii,xxviii  Cytology is operator dependent, with variable sensitivity 
(43-94%) and specificity (78-98%), but PPV of up to 90%.xxix,xxx,xxxi VIA sensitivity (17-100%) and specificity 
(8-95%) also are variable, and in resource-poor settings without HPV testing or histopathology can reduce 
cervical cancer mortality.xxxii,xxxiii,xxxiv There is increasing evidence that primary HPV testing is the most 
effective screening strategy. xxxv,xxxvi,xxxvii,xxxviii Primary testing with HPV alone, followed by treatment, creates a 
high likelihood of overtreatment and harm to women who desire future fertility. In addition, primary HPV 
testing followed by colposcopy is not feasible in settings like Botswana where there are an insufficient number 
of trained colposcopists. To address these two issues, two-stage screening strategies, consisting of HPV testing 
followed by either cytology or VIA, have been advocated.xxxix,xl,xli HPV testing followed by cytology results in 
increased sensitivity and specificity.xlii In a single study from Cameroon in a population with a high prevalence 

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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date: 
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of HIV (14.2%), HPV testing followed by Pap smear has been shown to have superior sensitivity and specificity 
compared to HPV testing followed by VIA.xliii 
 
Botswana’s screening strategy is similar to low-resource countries in the region. Given logistical and 
implementation challenges associated with a pathology-dependent screening test,xliv a screen-and-treat approach 
with VIA was introduced in Botswana in 2011.xlv Currently the standard of care in Botswana is for women to be 
screened either with a Pap smear or VIA alone. If she has an abnormal Pap smear result, she is referred for 
colposcopy; if she has an abnormal VIA result she is either offered cryotherapy or a loop electrosurgical 
excision procedure, depending on the size of the lesion.  In developed countries, screening protocols have 
incorporated HPV DNA testing as it has a higher sensitivity in detecting women at risk of developing cervical 
cancer. Botswana plans to roll out HPV DNA testing as it has unique resources that allow for a more resource-
intensive and effective strategy. However, because HPV DNA testing is sensitive but not specific, HPV testing 
alone would result in overtreatment of women who are unlikely to develop cervical cancer. Fortunately, 
pathology services have improved dramatically since 2011, and Pap smear may be an appropriate follow-up 
after a positive HPV test. VIA is also becoming more available nationally. An efficient, high-impact, two-stage 
strategy with primary HPV testing followed by either Pap or VIA can now be introduced nationally to reduce 
overtreatment and potential harm to women. Comparing these two strategies will provide essential data to 
inform national cervical cancer screening policy in Botswana and the surrounding region. 
 
 

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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date: 
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B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
Study Population and HPV Screening 
The proposed study will enroll 300 women for HPV testing in order to evaluate 81 HPV-positive women (see 
Sample Size calculations below). The first 100 enrollments will be nested within an existing cross-sectional 
pilot study designed to determine the uptake, acceptability, and feasibility of testing women for HPV using self-
collected samples. The goal of this 100-person pilot study is to inform the future scale-up of primary HPV 
screening, by answering the question of whether self-collected swabs are as good as provider-collected swabs. 
These 100 participants will self-collect a vaginal specimen and undergo a concomitant provider-collected 
specimen for HPV testing; a provider-collected approach will be used for the subsequent 200 women who enroll 
for this proposed study. Co-enrollment with the existing pilot study leverages the existing study and facilitates 
use of the same staff and resources to ultimately accrue 300 women at minimal cost. 
 
Research question 
Which two-stage cervical cancer screening algorithm is more effective for HIV-positive women in Botswana: 
HPV followed by Papanicolaou (Pap) smear or HPV followed by visual inspection with acetic acid (VIA)? 
 
Study Procedures 
For all 300 participants, HPV testing will be performed with either the commercially-available Cepheid Xpert 
HPV Assay or the commercially-available Roche Cobas HPV Assay for provider- and participant-collected 
samples, as per the protocol of the HPV pilot study. The pilot study currently utilizes a Cepheid GeneXpert 
machine on loan from the National Health Laboratory (NHL), and the duration of its availability is unknown. 
Should the GeneXpert machine become unavailable, the Roche Cobas machine at the NHL will be used for 
HPV testing. After the HPV pilot study ends, the remaining 200 participants will be enrolled and screened in a 
similar manner using a provider-collected approach. This study introduces Pap smear collection for all 
participants at the time of provider-collected HPV specimen. Pap smear will be prepared using standard 
technique at the site of collection. 
Participants who test HPV-negative will have their Pap smear sent to the NHL for staining and 
pathologist evaluation. If the Pap smear is abnormal, they will be referred to colposcopy per current Botswana 
Cervical Cancer guidelines.  
Per the protocol of the HPV pilot study, participants who test HPV-positive will be asked to return for 
colposcopy and will undergo further diagnosis and treatment for cervical cancer per national guidelines. 
Participants who have positive HPV screening will have: 1) Pap smear sent to the NHL for review and 2) VIA 
at the colposcopy visit but performed prior to colposcopy. At the second visit - prior to the colposcopy – a 
trained nurse will conduct VIA using the Botswana standard protocol. After application of acetic acid to the 
cervix, the nurse will record visual results as positive or negative. If VIA is positive based on assessment of the 
lesion(s), the nurse will record a recommendation for either cryotherapy or loop electrosurgical excision 
procedure (LEEP). Since all of these HPV-positive participants will undergo colposcopy, the participants will 
not be informed of the VIA results, as neither cryotherapy nor LEEP will be administered based on the VIA 
results.  Rather, the participants will proceed to colposcopy as planned in the HPV pilot study (and as will be 
continued for the women participating only in this study) and results of colposcopy will determine further 
diagnosis and treatment. This design leverages the existing HPV pilot study and enables us to assess the utility 
of both HPV/Pap and HPV/VIA two-stage algorithms while providing the highest-quality follow-up to cervical 
cancer screening abnormalities in Botswana.  
 
Participants will thus have a total of two study-related encounters if they are HPV positive—one for initial 
screening and the one for the second-stage of screening and colposcopy. Participants who are HPV negative 
will only have the one study-related initial screening visit. Participants will also be asked if they want to be 
contacted in the future regarding participation in future research related to cervical screening and treatment.  If 
the participant agrees, they will check yes for future contact in the consent form.   

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Study Description – Part B 
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The study site is only in Botswana; however, statistical analysis will be done with support from staff at BIDMC.  
 
A detailed data monitoring and safety plan has been developed.  All adverse events will be reviewed by the PI 
and co-investigators. All serious adverse events will be reviewed by the PI, co-investigators and a designated 
safety monitor, Dr. Surbhi Grover. 
 
 
B. 
Statistical Considerations 
Sample Size 
The goal of a two-stage algorithm is to increase PPV while maintaining sensitivity and specificity, and thus 
reduce overtreatment. Sample size assumptions were based on preliminary data, existing literature, and patient 
behavior regarding clinical follow-up. Among the first 25 women recruited in the parent study, the incidence of 
HPV-positivity was 30%. In a population with relatively high HIV prevalence, the PPV of an HPV-positive test 
for high-grade cervical dysplasia was 24%.xlvi  Our sample size calculation was targeted to detect an 
improvement in PPV of 25% between HPV testing alone and either two-stage algorithm (a PPV of 49% for the 
two-stage algorithms). Assuming a two-sided test and an alpha of 0.05, a sample size of 81 participants will 
yield over 80% power to detect the specified difference. Clients receiving care at the Infectious Disease Care 
Clinic (IDCC) tend to return for clinical follow-up appointments, because they come to IDCC each month to 
obtain their free anti-retroviral medications. Clients seeking care at the gynecology outpatient clinic may be less 
integrated into routine care. Thus, we anticipate that approximately 10% of HPV-positive participants will not 
return for colposcopy. The proposed study will aim to enroll 300 participants to yield 90 who are HPV 
positive—81 of whom we expect to return for colposcopy. 
 
Data analysis 
All data will be analyzed using SAS 9.4 (Cary, NC) at Beth Israel Deaconess Medical Center.  Descriptive 
statistics will be presented as mean with standard deviation, median with interquartile range, or proportion, 
based on data type and distribution. Data will be compared using the appropriate parametric or non-parametric 
test for continuous variables and Chi-square or Fisher’s exact test for categorical variables. All tests will be two-
sided and a p-value <0.05 will be considered statistically significant.   
 
We will calculate sensitivity, specificity and PPV of HPV/Pap smear and HPV/VIA to detect high-grade 
cervical dysplasia amongst HPV-positive participants. We will also evaluate associations between HPV type, 
cytology, VIA result, and histopathology results. 
 

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Study Description – Part B 
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C. 
Subject Selection 
Inclusion and Exclusion Criteria  
Inclusion criteria for the study are:  
1) ≥25 years of age 
2) HIV-positive 
3) Competent to understand study procedures and give informed consent.  
 
Exclusion criteria are:  
1) Currently pregnant (as diagnostic procedures for cervical cancer are often deferred during pregnancy) 
2) Currently menstruating or having persistent vaginal discharge 
3) Previous hysterectomy 
4) Previous diagnosis of cervical cancer 
 
 
  
 
 

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B4. 
POSSIBLE BENEFITS 
Participants will benefit from this study by being tested for HPV, which is a test not currently available in 
regular care in Botswana. Participants who test positive for HPV may be identified as at higher risk for 
cervical cancer earlier than standard care, which may allow for more timely management.  
 
Potential benefits to Botswana include determination of the effectiveness of two–stage screening 
algorithms for cervical cancer. Two-stage screening strategies have been widely adopted in other settings 
as they increase the specificity and positive predictive value of pre-invasive cervical disease, and thus 
reduce over-treatment of insignificant screening findings. The study will provide valuable operational data 
as the country prepares to scale up HPV testing as part of its Comprehensive Prevention and Control 
Strategy. Finally, study results will serve to estimate the prevalence of HPV subtypes, which may inform 
HPV vaccination policies and assessments. 
 
 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
The potential risks encountered during the study are: 1) HPV screening, 2) Sample collection, 3) 
Colposcopy and 4) Loss of confidentiality 
 
1) HPV screening: The major risk for participants in this study is the concern and worry they might 
experience while awaiting HPV test results. Participants will receive counseling before and after HPV 
screening to answer questions that they may have or allay any worries.  Participants who test positive for 
HPV might feel uncomfortable, anxious or depressed about their result and there may be stigma 
associated with their diagnosis. Trained personnel will give counseling to both participants and their 
partners to assist with any of these issues. All participants with HPV infection will receive standard of care 
follow-up and treatment as outlined. 
 
2) Specimen collection: There may be some temporary discomfort associated with self-collected and 
provider-collected vaginal swabs.  Study personnel will be trained how to minimize any adverse events and 
any such event that occurs will be reported to both the Site Coordinator and the Principal Investigator. 
 
3) Colposcopy: Current standard of care in Botswana for patients with Pap smear results of high grade or 
persistent low grade are referred for colposcopy. Based on this standard of care, we are referring all 
patients with positive HPV results to colposcopy. Colposcopy allows for evaluation of the cervix under a 
microscope to detect any abnormal lesions. Patients with abnormal lesions will undergo biopsy as 
indicated in routine colposcopy procedure. Though colposcopy can be uncomfortable, it is a routine step 
in cervical cancer screening, as follow-up for abnormal results, and the benefit of diagnosing cervical 
cancer or pre-invasive cervical disease outweigh the risk of the procedure. 
 
4) Loss of confidentiality: To protect patient privacy, all data will be handled in a confidential manner. 
Moreover, participants will be assigned a unique study identification number. The analytic dataset will only 
contain de-identified data. 
 
 
 
Minimizing/alleviating risk:  
Informed consent and strict confidentiality will be rigorously enforced to minimize risks to participants 
and their partners.  All study personnel will receive training in the informed consent process.    

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Participants will be provided with a phone number whereby a member of the clinic staff and the Principal 
Investigators, Dr Rebecca Luckett and Dr. Doreen Ramogola-Masire, may be contacted to answer 
questions or in case of emergency, psychological distress or any questions regarding their informed 
consent. 
 
Risk/Benefit Ratio: 
Any woman seeking cervical cancer screening in Botswana will require a pelvic exam for any available 
screening modality currently available in Botswana (Pap and VIA), and thus provider-collected HPV 
testing does not introduce a new discomfort. The benefits to the participants of more sensitive diagnosis 
of pre-invasive cervical disease with HPV testing outweigh the discomfort of sample collection. 
 
In this study, patients who are HPV positive will be referred for colposcopy. The benefit of colposcopy 
for the patient is evaluation of an abnormal cervical cancer screening test with the opportunity for 
diagnosis.  It is standard of care for detection of pre-invasive and invasive cervical disease following an 
abnormal screening test in many settings.  While it may be slightly more uncomfortable than a pelvic exam 
in the case that a biopsy is taken, it does not pose a risk of serious physical injury to a patient. While it may 
introduce an element of anxiety or psychological distress, measures will be taken to address any patient 
concerns prior to and during the procedure.  The benefit of diagnosis of cervical disease outweighs the 
risk of the procedure. 
 
Finally, the pelvic exam for colposcopy will be slightly longer due to the introduction of nurse evaluation 
with VIA prior to colposcopy. This discomfort is brief and temporary. The benefit to determining the 
effectiveness of VIA is essential for guiding national cervical cancer screening guidelines in Botswana, and 
will benefit a larger population in the long-run.  
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
Participants will be recruited from patients presenting for care at the HIV treatment and gynecology 
outpatient clinics at Princess Marina Hospital (PMH), the tertiary care referral hospital in the capital of 
Botswana, Gaborone  All women over the age of 25 who present to the clinics during study implementation 
will be informed that there is a study evaluating cervical cancer screening with primary HPV testing, and will 
be given information about HPV and cervical cancer.  
 
Patients will not pay to participate in this study.  All testing, procedures and office visits will be covered by 
the study. 
 
Consent 
Study personnel will invite interested women to a private clinic room and will thoroughly explain the study 
and the informed consent document. Information provided will include other available screening 
modalities in Botswana and the positive and negative predictive value of each screening modality.  
Additionally, patients will be given information about the utility of two-stage screening algorithms in terms 
of increasing the specificity of screening, and thus reducing overtreatment. After verification of eligibility, 
and potential participant confirmation of on-going interest in participation, a written, informed consent 
will be administered. 
 
The process of obtaining informed consent will be finished before collection of data or specimens. Study 
personnel will exclude any potential participant who is unable to understand the informed consent.  
 

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Consent forms will be kept in a locked office in Gaborone. All study staff involved in recruiting and 
consenting participants will have completed the Human Research Subjects certification program before 
the beginning of the study. Participants will be provided with contact information for Principal 
Investigators, Dr Rebecca Luckett and Dr. Doreen Ramogola-Masire, for any questions or concerns. 
 
 
Subject Protection 
Study participants will be assured that their participations is completely voluntary and will not affect their 
clinical care.  Patients declining participation will still receive standard screening from their provider, 
including VIA or a Pap smear. Only patients who can provide informed consent will be included.  
 
B7. 
STUDY LOCATION 
Privacy & Physical Setting 
 
Patients will be consented in a private consultation room in the clinic at which they are seeking care at 
Princess Marina Hospital. 
 
Examinations will be performed in private examination rooms at Princess Marina Hospital. Participants 
will only be contacted on the telephone number that they provide to the study. Prior to discussing study 
issues over the phone the patient will be asked if they are in a suitable location to receive results. All 
specimens will be stored at Princess Marina Hospital and data will be de-identified for data analysis. Data 
analysis will occur at BIDMC. 
 
 
B8. 
DATA SECURITY 
We will keep all electronic data in a password protected database, stored on a password protected device. 
Any paper with study data will be kept in a locked office belonging to a member of the study team. All 
data will be reported in aggregate such that participants cannot be identified.  
 
 

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B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
 
B10 
Dissemination of Research Results 
 
We plan to share the results of these findings with the Ministry of Health of Botswana so that the 
valuable information gathered can be utilized to guide national cervical cancer prevention programming.  
We also plan to present the data at national and international meetings and publish the results in a peer-
reviewed journal. 
 
                                                 
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xxxiii Mustafa, ibid. 
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