Evaluation of a mHealth Intervention to Increase Adherence to Triage of Self-collected HPV+ Women (ATICA Project)
Evaluation of a mHealth Intervention to Increase Adherence to Triage of Self-collected HPV+ Women (ATICA Project)
Cervical cancer is a serious public health problem reflecting social and gender inequalities
 in health. Currently, new technologies based on HPV DNA detection allow HPV self-collection,
 increasing screening coverage. In a self-collection based strategy, triage becomes a key step
 in the prevention process, as it is the first method to identify HPV+ women who will need
 diagnostic and treatment procedures. However, high adherence to triage is difficult to
 obtain, which is not surprising given that adherence to follow-up and treatment is a
 generalized problem in cervical cancer programs.

 Specific aims of the study are: 1. To evaluate the effectiveness of an innovative
 multi-component mHealth intervention to increase adherence to triage among women with HPV+
 self-collected tests compared to usual care. 2. To evaluate the implementation strategy and
 identify barriers and facilitators to implementation of the multi-component mHealth
 intervention.

 The study design will follow the structure of an effectiveness-implementation hybrid type I
 trial, and will use mix-method approach. A cluster randomized trial including 200 Community
 Health Workers (CHWs) (clusters) and 4000 women will be used to evaluate the effectiveness of
 the multi-component mHealth intervention to increase adherence to cytology triage at 120 days
 after positive HPV testing. The intervention will include SMS messages sent to HPV+ women to
 inform them when results are available, and subsequent SMS messages as reminders. For those
 HPV+ women who did not have a triage within 60 days of the HPV test result, CHWs will receive
 an e-mail and SMS message so they can visit these women for in-person counseling. For the
 implementation evaluation, CFIR will be used to guide qualitative data collection and
 analysis of factors that influence implementation. RE-AIM will be used to assess the Reach,
 Effectiveness, Adoption, Implementation and Maintenance of the Intervention.

 Results of this project will provide evidence on the effectiveness of the multi-component
 mHealth intervention to increase triage of HPV+ women, but it could be adapted to increase
 compliance of diagnoses/treatment of other health problems. Findings from the implementation
 evaluation will be applicable to programs that are planning to incorporate HPV
 self-collection. In addition, the use of CFIR and RE-AIM in this innovative study will serve
 as a model of work, constituting an important advance in the use of Implementation Science in
 the Region.
Cervical cancer is a disease of health and gender inequalities, and is primarily a cancer of
 poor, socially vulnerable women. Even though it is almost entirely preventable, in Latin
 America it is the leading cause of cancer death among women.1 In Argentina, it is the second
 cause of female cancer death: every year 5,000 women are diagnosed with cervical cancer and
 more than 1,800 die from the disease.1 In this country, and generally across Latin America,
 high mortality is related to problems in the continuity of the prevention process, including
 low screening coverage and loss to follow-up, diagnosis, and treatment.2,3 New screening
 tests detect the presence of high-risk types of HPV which cause cervical cancer. HPV tests
 have important advantages over the Pap as a primary screening test, including higher
 sensitivity (over 90%)4 and a high negative predictive value,5 which allow reduced screening
 frequencies. Very importantly, through self-collection strategies, HPV testing can reduce
 barriers to screening and increase coverage.6 HPV self-collection is highly accurate,7 and is
 acceptable among women in different countries.8-11 However, HPV screening identifies women
 who are HPV+ (around 10%). Triage tests for HPV+ women determine those who need additional
 diagnostic procedures. While several triage methods are available for detecting precancerous
 lesions, including cytology and colposcopy,12 to date most such triage methods require HPV+
 women to attend health centers to determine appropriate follow-up. Although adherence to
 follow-up and treatment is a widespread problem for cervical cancer programs in Latin
 America,2 evidence for interventions to improve adherence to follow-up is lacking.

 The introduction of self-administered HPV testing in Jujuy has been successful in increasing
 primary cervical cancer screening coverage. Yet the proportion of self-collected HPV+ cases
 who currently undertake cytological triage within 120 days of screening is low (about 30%),
 which hinders the impact of the increased HPV screening coverage attained.

 Aims of the study

 1. To evaluate the effectiveness of a mHealth intervention targeted to women and health
 providers to increase adherence to cytological triage among self-tested HPV+ women
 compared to usual practice.

 2. To identify and understand the processes and factors which contribute to the success of
 the mHealth intervention strategy (or lack thereof).

 Setting The research will take place in the province of Jujuy, located in Northwest
 Argentina. Eighty-five percent of Jujuy's population lives in urban areas and the rate of
 mobile phone penetration was 82% of urban households in 201113 Jujuy has a high cervical
 cancer mortality rate (10.6 per 100.000 women during 2012-2014).

 The Jujuy public health system includes a main hospital and 300 primary health care centers.
 For the uninsured, health services are provided free of cost. The Primary Health Care System
 (PHC) integrates approximately 700 paid full-time community health workers (CHWs) who twice
 yearly visit approximately 110,000 households for health-related tasks such as immunization
 and promoting maternal and child health.

 Study design The study design follows the structure of an effectiveness-implementation hybrid
 type I trial14 and uses a mix-methods approach.

 It combines a cluster randomized trial to evaluate the effectiveness of a multi-component
 mHealth intervention with a mixed methods approach involving quantitative and qualitative
 evaluations of the implementation using the RE-AIM15 and Consolidated Framework for
 Implementation Research (CFIR)16 frameworks.

 The study will integrate quantitative and qualitative methods and follow Greene's typology of
 mixed-methods for convergence and complementarity.17 A formative research will be carried out
 to develop the framing and content of SMS messages (qualitative secondary method).

 Then a pragmatic cluster randomized trial will be carried out to measure the effectiveness of
 the multi-component mHealth intervention in improving triage adherence among HPV+ women
 (quantitative primary method for Specific Aim 1).

 Finally, during the post-intervention phase (Implementation evaluation for Specific Aim 2), a
 quantitative survey will be carried out to measure acceptability of the strategy by CHWs
 (quantitative secondary method), and semi-structured interviews (qualitative secondary
 methods) will be conducted among health authorities and health professionals,18 to receive
 feedback on their own perspectives and opinions about the intervention.19 HPV+ women will
 also be interviewed via a structured questionnaire (quantitative secondary method) to collect
 information about acceptability of the intervention, reasons for triage
 adherence/non-adherence, and their views about the strategy.

 Formative research. Focus group discussions (FGD) will be carried out to explore women's
 opinions about how to frame and phrase SMS messages. Barriers women face in accessing triage
 will be explored, and the resulting information will be used to develop strategies CHWs can
 use to address them during the intervention. Drawing from FGD results, SMS messages will be
 designed and pilot tested with a validation protocol that has already been used in
 Argentina.20 Development of Automated Messaging system: an Automated System (AS) will be
 developed, which will then send SMS messages and e-mails based on data from the national
 Screening Information System (SITAM). This AS will will work in an asynchronous manner. In
 order to avoid sending a SMS message to the wrong person, an identity verification process
 will be initiated. Only matching data will be classified as "valid" and receive subsequent
 SMS messages. E-mails sent to CHWs will not include personal information about women, but a
 secure link to registries of women to be viewed in SITAM. SMS messages and e-mails will
 comply with security procedures.

 Intervention: cluster-randomized trial. Approximately 200 CHWs from Jujuy's PHC will be
 randomized into two groups: 1) mHealth Intervention (MH) Group: Women with positive
 self-collected tests will receive a multi-component intervention. HPV+ women will receive
 periodic SMS messages during the first month after registration of self-collection test
 result in SITAM, notifying them that test results are available and they should go to the
 health center. In addition, CHWs will receive an e-mail and SMS message prompting them to
 visit those HPV+ women who, at 60 days since availability of the HPV result in SITAM, have
 not attended triage. CHWs will be asked to confirm receipt of the e-mail for monitoring
 project processes. Within 15 days of being notified, CHWs will visit these HPV+ women, for an
 in-person reminder and counseling about the importance of attending health centers and have
 triage performed. 2) Usual Care (UC) Group: Women with positive self-collected tests will
 receive usual care, i.e., women opting for self-collection will be instructed to go the
 health center in 30 days to pick up results.

 Hypothesis: Adherence to triage will be higher in the MH intervention group compared to women
 receiving UC.

 Study procedures. CHWs from both groups will identify eligible women and invite them to
 participate in the study during their routine home visits. Once women have performed HPV-self
 collection, CHWs will screen for eligibility criteria, including use of mobile phones. Those
 women who use a mobile phone will be explained the study objectives and will be invited to
 participate in the study. Women accepting to participate will be asked to provide a telephone
 number. Based on previous studies,21,22 the investigators expect approximately 85% of women
 will provide a telephone number; with 70% providing their own personal mobile phone.

 MH Group: CHWs will carefully explain participants the sequence of SMS messages to be
 received depending on the Test results, and how they should proceed after reception of the
 SMS messages. If the woman does not have a personal phone, she will be asked if she is
 willing to be contacted and receive the proposed SMS messages on a shared phone. CHWs will
 inform women about the nature and content of the SMS messages to be received. They will also
 explain that if they have not performed triage 60 days after a positive test results they
 will come back for an in-person visit. Therefore, consent to participate also means women
 agreement to be contacted and to receiving SMS messages, even if phones are shared by several
 family members.

 Upon SITAM registration of the HPV result, a first SMS message will be sent requiring women a
 confirmatory reply with their id number. This confirmatory approach to assure a patient's
 identity has been used and proved effective in other studies.22,23 After confirmation, women
 will receive a second SMS message with different information depending on their HPV status:
 if HPV-, they will be informed about the result and date of next screening; if HPV+, they
 will be informed that test results are available at the health center. Women will know in
 advance that this SMS message will mean they are HPV+. During the first four weeks after
 registration of a HPV result in SITAM, a SMS message will be sent weekly unless a Pap result
 is registered in SITAM. Sixty days after the date of registration of the HPV test result in
 SITAM, CHWs will receive an e-mail and SMS message informing them that there are HPV+ women
 who have not had Pap triage (if this is the case). The e-mail will contain a secure link to
 the list of HPV+ women to be visited. CHWs will be asked to confirm receipt of the e-mail for
 monitoring project processes. CHWs will visit these HPV+ women within 15 days of being
 notified, for an in-person reminder and counseling about the importance of attending health
 centers and have triage performed. CHW visit information will be recorded, including visit
 attempts, date of visit and issues addressed during counseling.

 UC care group: Once women have agreed to participate in the project, CHWs will provide UC
 counseling using specific24 standard provincial protocol and materials. They will inform
 women that they should go to the health center in a month to get their test results.

 Randomization and sample size: All CHWs (clusters) (approximately 700) of the Jujuy province
 offer self-collection and will be eligible to participate in the study. After classifying
 them into four groups according to gender and urban/rural setting, a stratified sample of 240
 CHWs will be randomly selected with allocation proportional to strata. Selected CHWs will be
 invited to participate in the study following the order defined by the random list until 200
 are enrolled. Enrolled CHWs will be randomly allocated to the MH or the UC group (3:2 ratio).
 Blinding of intervention and outcome assessments is not feasible due to the characteristics
 of the study. Primary outcome: The target sample size (120 CHWs in the MH group and 80 CHWs
 in the UC group, each one providing 2 HPV+ women) will have 97% power to detect a 20% triage
 difference between the two groups when the control group has a 30% triage in a 120-days
 period (two-sided test, alpha=0.05). Correlation induced by the CHWs was included in power
 calculations assuming an intra-class correlation coefficient of 0.10. Secondary outcome:
 Under the same assumptions, the proposed sample size will have 90% power to detect a
 difference of 10% in triage between groups when the control group has a 15% triage by day 60.

 Analysis plan: All analysis will be conducted in an intention-to-treat basis, i.e. an
 enrolled woman with a positive HPV result will be considered in the study group assigned to
 her CHW, regardless of adherence of the CHW to the intervention or the number of SMS messages
 delivered to the woman. The effect of the multi-component mHealth intervention on the primary
 outcome will be assessed using a generalized estimating equations approach. The model, logit
 link, and binomial distribution will include trial group as fixed effect and CHWs as the
 clustering variable. Potential modification of the effect of the intervention due to
 rural/urban location of the woman and CHW gender will be evaluated, additionally including
 these factors and their interactions with study group in the former model. Baseline women
 factors will be compared between groups. Factors showing clear unbalance between arms will be
 included in the model proposed above to adjust for potential confounding. The same approach
 will be used to estimate the intervention effect on the secondary outcome. An interrupted
 time series approach will be used to explore the differential impact of each component of the
 intervention (SMS messages to women from day 1-59, SMS message and e-mail to CHWs by day 60)
 on the total number of women with triage at each week. Baseline for each woman will be
 defined as the day the HPV tests results are recorded in SITAM. Segmented regression will be
 used to assess the trend of the outcome in each period (1-59; 60-120 days) and any potential
 discontinuity (change in level or profile) in the time series of the intervention group
 compared to the control group. A linear model accounting for the autocorrelation of the data
 and including period (1-59; 60-120 days), intervention indicator (yes/no), and functions of
 time before and after the breakpoint (date when the second component starts) will be fitted.
 Given that the number of HPV+ women with triage is not expected to follow a linear trend with
 time, smooth functions (spline) of time will be used to model the relation between outcome
 and time in each study group. Under the assumption that the trend in the outcome would remain
 unchanged in the absence of the second component, this approach will allow investigators to
 describe the counterfactual curve expected in the intervention group had the second component
 not been implemented. Analyses will be conducted using STATA and/or SAS. The trial will
 follow the CONSORT extension for cluster randomized trials reporting guidelines.25
Inclusion Criteria:

 In the Randomized Controlled Trial we will recruit a minimum of 4000 women, aged 30 and
 older living in the province of Jujuy, Argentina.

 Inclusion criteria are:

 1. Having performed self-collection of HPV-testing.

 2. Mentally competent to understand the consent form.

 3. Able to communicate with study staff.

 4. Being able to provide a mobile phone telephone number.

 Exclusion Criteria:

 -  Current pregnancy.

 -  Women with Mental disability.