Feasibility and Acceptability of HPV Self-Collection Cervical Cancer Screening and Treatment in Botswana
Condition: Human Papillomavirus Infection; Cervical Cancer
MeSH terms: Papillomavirus Infections; Uterine Cervical Neoplasms
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): HPV self collection, followed by visual assessment of the cervix for treatment (VAT) and treatment
Intervention type(s): Diagnostic Test
Intervention description(s): Women who test HPV positive are offered visual assessment for treatment, with treatment method (cryotherapy, LEEP, or biopsy) based on visual assessment findings.
Intervention model: Single Group Assignment
Intervention model description: This is a prospective cohort study of women in an HPV self-collection screen-and-treat strategy for cervical cancer prevention to assess collection, triage and treatment through a service delivery model using descriptive, quantitative methods, and formative, qualitative research with providers and women.
Methods to assess feasibility of the service model are electronic medical record (EMR) documentation of women's progression from eligibility for and receipt of services through each step of the HPV self-collection screen-and-treat strategy, from self-collection through test results to treatment of precancer, including referral for suspect cancer.
Acceptability will entail: a) in-depth interviews with health providers, community mobilizers, health facility staff and managers and b) in-depth interviews and surveys with women who receive services as well as women that are eligible and decline services.
Masking: None (Open Label)
Primary purpose: Screening
Keywords: human papillomavirus; cervical cancer; self-collection