Feasibility and Acceptability of HPV Self-Collection Cervical Cancer Screening and Treatment in Botswana
Feasibility and Acceptability of HPV Self-Collection Cervical Cancer Screening and Treatment in Botswana
Aims of the Study: To assess feasibility and acceptability of introducing HPV testing of
 self-collected vaginal specimens (self-collection for HPV) of women age 30-49 years, followed
 by visual assessment of the cervix for treatment (VAT) and treatment of women testing HPV
 positive at a district hospital, surrounding clinics and communities in Botswana.

 Background and Rationale:

 High HIV prevalence correlates with high rates of precancerous and cancerous changes on the
 cervix, and Botswana has the third highest HIV prevalence rate (22.2%) in the world. In
 Botswana, cervical cancer is the leading cause of cancer and cancer-related deaths among
 women. While the Government of Botswana has made cervical cancer a public health priority,
 and has provided cytology-based screening (Pap smears) for the past 20 years and in recent
 years began also offering VIA coupled with immediate cryotherapy for eligible precancerous
 lesions in a screen-and-treat (S&T) approach, the program still encounters multiple
 challenges. These include delays in reporting/receiving cytology results, referral
 bottlenecks for specialist care, and ultimately far fewer women being screened and treated
 than set targets. In response, in 2012 Botswana's Ministry of Health and Wellness (MoHW)
 developed a National Cervical Cancer Prevention Programme (NCCPP) Comprehensive Prevention
 and Control Strategy that includes implementing a demonstration project to gauge
 acceptability and obtain lessons that will be used in planning the roll-out of this screening
 method.

 As a result, the MoHW is exploring human papillomavirus (HPV) testing as a primary screening
 method with the future service delivery in mind through HPV testing, specifically using
 self-collected samples, as a primary screening method. HPV testing is more sensitive and
 reliable for the detection of cervical precancer and cancer than Pap testing and VIA. This
 increased sensitivity translates into two important benefits: 1) earlier detection of
 significant precancerous lesions that if treated results in a ~50% reduction in the incidence
 of cervical cancer within 4-5 years compared to Pap testing and 50% reduction in related
 deaths within 8 years compared to Pap testing and VIA and 2) lower cancer risk for many years
 for those with a negative result, which permits screening at an extended interval of 5-10
 years. The Xpert HPV test, which will be used in this study, has high sensitivity (100%) and
 relatively high specificity (81.5%) for CIN. HPV tests run on the GeneXpert® machine allow
 multiple tests (four in the model to be used in this study) to be run in an hour.
A. Study Objectives:

 Research Question 1. Is it feasible to implement HPV self-collection for cervical cancer
 prevention at a District Hospital, four surrounding clinics, and in the community among women
 eligible for cervical cancer screening per national guidelines, followed by VAT triage of HPV
 positive women at the clinic; and then treatment at the clinic or hospital?

 -  What is the HPV positivity rate (prevalence) for women age 30 - 49 years and
 disaggregated by HIV status and clinic location?

 -  What are the screening-to-treatment completion rates with this strategy for women with
 HPV-positive test, by HIV status and clinic location?

 -  Can at least 75% of women doing HPV self-collection receive their results within 3
 weeks self-collection?

 -  Can at least 75% of women with an HPV positive result undergo VAT within 3 weeks of
 receiving their HPV result?

 -  Can at least 90% of women with an HPV positive result undergo VAT and receive
 treatment within 3 months of initial HPV self-collection?

 Research Question 2a, 2b. Do (2a) health care providers, community health workers, laboratory
 personnel, and managers and (2b) women consider the HPV self-collection, VAT and treatment
 acceptable? For each group of these participants, what are some of the enablers and the
 barriers to implementing an HPV self-collection screen-and-treat strategy?

 B. Overview of Methods:

 Research Question 1: Service Delivery Model The methods are prospective documentation of
 women's progression from eligibility for and receipt of services through each step of the HPV
 self-collection screen-and-treat strategy for cervical cancer prevention. This documentation
 and aggregation across client will involve client-level longitudinal data collected
 electronically from the time of HPV self-collection through test results to treatment of
 precancerous, including referral for suspect cancer cases as needed.

 Research Question 2a and 2b:

 Qualitative Research with Providers and Other Stakeholders:

 The methods are in-depth interviews to be conducted with health providers, community
 mobilizers, health facility staff, and facility and district managers.

 Mixed Method Research with Women: The methods are a combination of in-depth interviews and
 surveys to be conducted with women who receive services through each step of the HPV
 self-collection screen-and-treat strategy for cervical cancer prevention as well as women
 that are eligible and decline to do HPV self-collection.

 C. Sample sizes and justifications by Research Question:

 Hypothesis 1: Of eligible women who accept to do HPV self-collection, >75% will receive their
 HPV test results within 3 weeks. Summary from a statistical calculation: A sample size of
 1022 women produces a two-sided 95% confidence interval with a width equal to 0.05 (5%
 precision on either side) when the sample proportion is 0.80

 Research Question 1: Service Delivery Model

 The study will include all women who meet eligibility criteria, consent and perform HPV
 self-collection up to 1,022 women. This will occur during a six-month enrollment period at
 the district hospital, four clinics or communities serviced by the clinics. By health
 facility, the break down is:

 -  Scottish Livingstone Hospital: 204 women

 -  Clinic 1: Lephephe: 103 women at the facility + 103 in the community

 -  Clinic 2: Thamaga 103 women at the facility + 103 in the community

 -  Clinic 3: Kopong: 203 women at the facility

 -  Clinic 4: Phuthadikobo: 203 women at the facility

 Justification for Sample Size:

 -  The sample size of 1,022 is large enough to be meaningful to show the MoHW whether the
 HPV self-collection screen-and-treat strategy is feasible and acceptable.

 -  At any one time, up to 4 HPV tests can be run in the 1 GeneXpert machine dedicated for
 HPV tests, to be located at Scottish Livingstone Hospital. Processing takes 1 hour. Over
 6 months, this is approximately 2 tests per working hour.

 -  The proportion of women who test HPV positive will result in the number of women to
 receive VAT and treatment.

 -  Based on historical data on women receiving treatment following VIA screening, we expect
 at least 85% of HPV-positive cases to be eligible for cryotherapy, which can be provided
 on the same day as the VAT. The sample size of 1,022 women will result in treatment
 services that are feasible to offer at Scottish Livingstone Hospital and Phuthadikobo
 Clinic.

 Research Question 2a: Qualitative Research with Providers and Other Stakeholders.

 In-depth interviews will be conducted at the district hospital and up to 4 clinics with the
 following persons: 2 VIA nurses, 1 doctor performing LEEP, 3 district management official, 6
 facility or unit in-charges, 2 laboratory staff and 10 community mobilizers. Some participant
 types only work at district hospital while others are at the clinics. Up to 24 interviews
 will be conducted with providers and district authorities.

 Research Question 2b: Qualitative and Survey Research with Women Among the women who do HPV
 self-collection, we will recruit clients from each facility or stated community, to
 participate in an in-depth interview. Among the women who test HPV positive and completes
 VAT, we will recruit two clients from each facility where the client is attached. Clients who
 fit the eligibility requirements, will be purposively recruited after completing her HPV
 self-collection, on a day when the interviewer is present at the facility in order to
 minimize burden and number of contacts with the client.

 The qualitative sample size for questions 2a (24) and 2b (27) is a total of 51 interviews
 (Providers, Staff, Managers, and Clients). The sample size for RQ 2a is determined by the
 limited number of Providers, Staff, and Managers. The qualitative sample size for the number
 of women is determined to include women who may represent the variability of women's
 perceptions and experiences relevant to HPV self-testing and follow-up care to achieve
 saturation of themes.

 D. Implementation In Research Question 1: Service Delivery Model, Step 1: Eligibility
 Assessment, Consent, Enrollment, and HPV Self-collection

 -  Health care worker informs and educates women attending clinics at SLH, at the Health
 Clinics, and in the community about cervical cancer, its prevention including HPV
 self-collection. Study staff recruit and screen women for eligibility for HPV
 self-collection at the facilities and this data is documented on the Eligibility
 Assessment Form, the Electronic Client Record 1 (ECR 1).

 -  Research nurse obtains informed consent of women who meet the study inclusion criteria
 and consent to HPV self-collection, and signature is collected within the Electronic
 Client Record as part of ECR 1.

 -  Research nurse collects basic demographic and contact information, including woman's
 telephone number(s) to allow for follow up with results. Research nurse asks the woman,
 and documents, if she prefers to be contacted with results by phone or in person at the
 facility.

 -  If HIV status is not known (no prior HIV testing or last documented HIV test result was
 negative but more than 12 months ago), research nurse recommends HIV testing and is
 excluded from the study until HIV status is documented by HIV testing and recorded on
 ECR 2.

 -  Research nurse provides HPV self-collection kit with a sampling brush (a broom-like
 device) and a PreservCyt solution vial to the woman and she is instructed on proper
 collection technique. The woman goes to a designated private area to self-collect the
 vaginal specimens and rinse the self-collection brush into the vial and caps the vial.

 -  The woman takes the vial of self-collected specimen to the research nurse who labels the
 specimen and records this information as well as the "ease of use" questions in the
 Electronic Client Record (ECR 2).

 Step 2: Storage and transport of Self-collected specimens

 -  At hospital, self-collected specimens are HPV tested immediately, or, if not able to
 tested immediately that day, are stored at 2 - 30°C and tested later.

 -  In the community, study staff take the self-collected specimens to the study health
 clinic on the same day as collection.

 -  At the health clinic, the specimens are stored at 2 - 30°C.

 -  The specimens are transported at 2 - 30°C to SLH using the normal health clinic lab
 specimen transport mechanisms and schedule. Frequency of transport depends on the
 clinic, e.g., daily in some cases, but at least once a week

 Step 3: HPV tests are run on GeneXpert® DX machine at hospital and results recorded in ECR

 Step 4: The woman receives her HPV test results

 -  Senior Research Nurse or Research Assistant enters the HPV test of diagnosis into the
 electronic record data system (ECR 3), which can then be viewed by other study nurses at
 the study health clinic.

 -  Senior Research Nurse or Research Assistant notifies woman of HPV positivity/negativity
 in person or by phone, according to her preference, as noted in Step 1, and notification
 is documented in the ECR

 -  If the test is HPV positive, the woman is scheduled for a visit to a SLH VIA Clinic for
 VAT - possibly on same day.

 -  If the test is HPV negative, the woman is told her test is normal and should be retested
 in 3 year (HIV positive status) or 5 years (HIV negative status).

 Step 5: VAT Note: Where VAT findings are eligible for cryotherapy, VAT (Step 5) and Treatment
 with cryotherapy (Step 6) mostly will occur during the same visit

 • HPV-positive women will receive VAT. Nurses, midwives, and doctors, previously trained in
 VIA and cryotherapy, perform VAT and triage every client who is HPV-positive to determine
 treatment method and document findings in the electronic client record (ECR 4: VAT Result and
 ECR 6: Referral Result).

 Possible VIA findings:

 -  VIA-negative (no lesion seen) - eligible for cryotherapy

 -  VIA-positive - eligible for cryotherapy: not suspicious for cancer, small lesion (meets
 standard eligibility criteria for cryotherapy); or

 -  VIA-positive - not eligible for cryotherapy: Large lesion, not eligible for cryotherapy,
 referred to the LEEP Clinic at SLH; or

 -  Suspicious for cancer: referred to Colposcopy/LEEP Clinic at SLH for further management.

 Step 6: Treatment

 -  Following VAT, women eligible for cryotherapy are offered immediate treatment and
 treatment is performed according to standards. Treatment is documented in the electronic
 client record (ECR 4: VAT Result).

 -  Following VAT, women with large lesions are referred to the SLH LEEP Clinic, where LEEP
 is performed according to standards. Treatment is documented in the electronic client
 record (ECR 6: Referral Result and ECR 4: VAT Result).

 -  Following VAT, women with suspect cancer are referred to the SLH Colposcopy/LEEP Clinic,
 where biopsies are obtained and further management is arranged. Management is documented
 in the electronic client record (ECR 6: Referral Result).

 -  Following treatment, healthcare worker counsels the woman on findings, self-care, and
 warning signs and to return in one year for rescreening

 In Research Question 2a, the qualitative interviewer will meet with the consenting provider
 or other stakeholder in a private room. The interview will cover the experiences and opinions
 of providers, staff and managers on the various features in using the HPV test and
 self-collection, and other implementation considerations such as impact of the program on the
 quality of services and potential uptake within the community. These interviews will be
 conducted towards the end of the 6 month implementation period, to allow for participants to
 develop opinions and fully answer questions related to sustainability. Interviews with
 providers, community mobilizers, stakeholders and other Ministry employees will be conducted
 in English or Setswana, depending on the participant preference, and last up to an hour in
 length.

 In Research Question 2b, in a private room, the qualitative interviewer will meet with
 consenting women who accept HPV self-collection and with consenting women who are HPV
 positive and return for VAT. The Senior Research Nurse or Research Assistant will meet with
 consenting women in a private to conduct surveys on women who are eligible but do not accept
 to do HPV self-collection, and women who are HPV positive but do not return for VAT within
 two weeks of receiving their results. Surveys will assess their reasons for not accepting
 self-testing for HPV or not returning for VAT. Interviews and Surveys under Research Question
 2b will be fit into the same Service Delivery Model previously described.

 E. Data Analysis Data analysis will be descriptive with no statistical testing planned since
 the research questions are descriptive. We will report confidence intervals around mean
 values of indicators, also median and interquartile range, when appropriate.

 Qualitative data will be transcribed, and translated. Analysts will come up with an initial
 codebook, a list of draft codes based on our field guide questions and anticipating some
 themes and sub-themes from reading the literature.

 Each transcript will be coded and considered for analysis in the same way. We will allow for
 and encourage addition of emergent codes. Once we code all transcripts, we will divide up the
 codes into code families. After reading through passages in a code family, we will create a
 display matrix following the framework analysis approach. In this display, each participant
 is a row and each theme and sub-theme is a column, cells refer to specific quotes; this will
 allow for comparisons of the narratives among different types of participants. This visual
 matrix allows the analyst to move back and forth between different levels of abstraction and
 facilitates cross-case and within-case analyses.

 The final phase of analysis, abstraction and interpretation will follow these steps: a)
 categorization, in which the researcher takes note of, and may write memos to document, the
 range and diversity of views, underlying dimensions of themes and creates categories; b)
 mapping linkages and connections and allowing for creation of typologies; and c) explanation,
 which involves accounting for the patterns of association in the data, and considering
 alternative explanations.

 F. Protection of participants Clients' non-participation in any aspect of the study or
 withdrawal from our study will NOT affect their health care or their employment. Information
 that we gain from the quantitative, qualitative, or analysis components will not be shared
 with any individual or organization (i.e. government authorities, NGO representatives) except
 in aggregate form, and the results will have no participant identifiers.

 A separate database that links the national ID numbers/passport number and client's name the
 unique study ID numbers will be kept in a separate password protected, electronic database
 that only study staff will be able to access. Study team members will clearly explain the
 purpose of the study to the facility representatives and other participants, as well as
 obtain written informed consent from participants for participation in the service delivery
 process and in the qualitative interviews. Data collectors will be trained to be sensitive
 and to answer any questions. A strategy for keeping data confidential will be developed and
 followed.

 All individual recruitment of any woman or provider participant will occur in a space at the
 facility, or community, that allows for audio and visual privacy (not in open view or in a
 place where others can overhear the conversation). The research nurse will be trained to seek
 a private space for the recruitment To ensure that the data will be kept confidential and
 secure, data collection team/interviewers will be trained on issues of ethics and will sign
 confidentiality agreements to ensure that they do not share the completed data collection
 tools outside study team. The completed notes from interviews and will be sealed in envelopes
 immediately after the completion of data collection. Electronically entered data will be
 password protected upon entry. Paper-based and electronic data, including audio files, will
 be kept safe in locked containers and transported to the Jhpiego offices in Gaborone. Audio
 files and transcripts of the de-identified key informant interviews will be stored in a
 password protected, compressed folder, which will be upload to a password-protected Dropbox
 folder, a web-based software application to share files with data analysts at Jhpiego
 Botswana and Baltimore. Hard copies of data will be kept in locked cupboards. The data will
 be entered in an electronic database accessible only to authorized assessment personnel.

 G. Risks or Discomforts to Participants HPV test self-collection is the main focus of the
 investigation in this study. This study will use the standard of care treatments available in
 Botswana for women who test HPV positive. The VIA used in VAT and treatment are not under
 investigation. We do not foresee adverse events. It is possible that there could be
 misunderstandings about the HPV self-collection at the community level; therefore we will
 make sure that community leaders and members are sensitized to the purpose and procedures of
 the study at the facility and community level.

 An adverse event would be considered a disclosure of client information due to the study. As
 precautions will be taken to protect client information with confidentiality (as described
 above), adverse events are unlikely. The study team will follow up on each enrolled
 participant's case to make sure each woman has received services. If we learn of any adverse
 event with an enrolled participant, we will follow up to learn the nature of the problem.

 The PI, Dr. John Varallo, Jhpiego, will be in constant communication with the
 Jhpiego-Botswana Country Team on the progress of the study and will contact the MOHW and the
 JHSPH IRB in case of any problems. They will try to quickly resolve any problems that arise.
The District Health Management Team (DHMT), estimates that in 2011 there were 31,574 women
 30-49 years of age on the Kweneng East catchment area, serviced by Scottish Livingstone
 Hospital and the 4 selected Health Clinics.

 Women will be clients of the health facility at one of the clinics (described below under
 recruitment), may come to the facility for cervical cancer screening after having been
 contacted by a community mobilizer, or women attending a community health campaign event
 (in the community).

 Participants under Research Question 1: 1022 women Participants under Research Question 2a:
 24 providers and other stakeholders Participants under Research Question 2b: 27 women for
 in-depth interviews; 250 women for structured surveys.

 Inclusion Criteria: Service Delivery Model

 -  Age 30 to 49 years,

 -  Not screened recently/never screened before, defined as:

 -  No prior history of cervical cancer screening: Pap smear, VIA or HPV testing), or

 -  Prior screening, but result unknown and no treatment

 -  Prior screening occurred more than 5 years ago for HIV negative women or 3 years
 ago for HIV positive women

 -  HIV status is known (HIV positive result, or documented HIV negative result is less
 than 12 months ago).

 -  No history of prior abnormal screening or treatment/procedure on her cervix due to
 abnormal screening

 -  No history of cervical cancer

 -  Not currently pregnant; not less than 6 weeks postpartum

 -  Intact uterus/ no prior hysterectomy with a cervix present

 -  Accesses services in Kweneng East District study catchment area

 -  Able and willing to provide consent

 Inclusion Criteria: Qualitative Research with Providers and Other Stakeholders

 -  Working as one of the cadres in Sampling Table 1 at the time of the interview.

 -  Working in cervical cancer prevention currently.

 -  Manager agrees the participant can take part in interview.

 -  Has been trained by the study regarding HPV self-collection and VAT.

 -  Willing to participate in in-depth interview and gives informed consent.

 Exclusion Criteria:

 -  Woman does not meet the criteria for inclusion age 29 years or younger and age 50
 years or older.

 -  Screened for cervical cancer in last 3 years if HIV positive, or in the last 5 years
 if HIV negative.

 -  Had an abnormal cervical cancer screening and/ or treatment of cervix ,

 -  History of cervical cancer HIV status unknown,

 -  Pregnant (self-report or by pregnancy test confirmation.

 -  Less than 6 weeks postpartum, prior hysterectomy,

 -  Unable to participate and give informed consent.

 -  Not interested in HPV self-collection.

 -  Unwilling to give informed consent