Evaluation of an Mhealth Intervention to Increase Adherence to Triage of HPV+ Women
Evaluation of an Mhealth Intervention to Increase Adherence to Triage of HPV+ Women
Cervical cancer remains a serious health problem, particularly in developing countries. It is
 the leading cause of cancer death among women and mainly affects women of low socioeconomic
 status.

 Evidence has shown that HPV-test self-collection can reduce social and health services
 barriers to screening and increase coverage. However, high coverage will not result in a
 decrease of disease burden if women are not diagnosed/treated. The HPV-test indicates whether
 a woman is positive or not, and a triage test is needed to identify HPV-positive women who
 need to perform diagnostic procedures. Several triage methods are available. In Argentina,
 cytology is used as triage method; therefore, all HPV-positive women who have performed
 self-collection at home need to attend health centers to undergo cytology. However, the
 proportion of women who have completed triage is low, therefore new innovative strategies are
 needed to increase attendance to cytology of these women.

 This study will be carried out in Jujuy, one of the Argentinian provinces with highest
 cervical cancer mortality rates and where HPV- self-collection has been introduced as
 programmatic strategy for screening under-users.

 This trial is population-based cluster-randomized study that aims to evaluate the
 effectiveness of a mHealth intervention versus usual care to increase adherence to
 cytological triage among women with HPV-positive self-collected tests.

 An overall number of 240 Community Health Workers (CHWs) from the Primary Health Care System
 (PHCS) of the Province of Jujuy will be randomized into two groups:

 1. mHealth Intervention Group: Women with HPV self-collected tests will receive a mixed
 intervention which includes counseling through an interactive Apps specifically devised
 to increase adherence to triage which will be run on a tablet, and SMS text messages to
 remind them to attend triage. In addition, Heads of CHWs, chiefs of gynecology services
 and CHWs will receive reminders via e-mails and SMS message to contact women if after 60
 days from the HPV-results HPV+ they have not performed triage.

 2. Usual Care Group: Women with HPV self-collected tests receive usual care.

 A database built specifically for the study will be used; it will include data about
 randomization Group, agreement to participate in the study and socio-demographic data. Data
 on HPV-testing and triage will be uploaded importing the data from SITAM, using the Unique
 Identification Number (DNI).

 Data Analysis

 Effectiveness to enhance adherence to cytological triage: Adherence to triage will be
 considered for each CHW. This will be defined as the number of women with triage smears
 within 30, 60 and 90 days. There will be a comparison of the percentage of HPV-positive women
 that did the Pap test within those time intervals in the mHealth intervention group and the
 Usual Care group. The effect of the mHealth intervention against usual care will be estimated
 using a means difference test or a non-parametric test for independent samples.
Description of the problem and study rationale

 Cervical cancer remains a serious health problem, particularly in developing countries. In
 Argentina, every year 5,000 women are diagnosed with cervical cancer and more than 1,800 die
 from the disease 1. In several Latin American countries, it is the leading cause of cancer
 death among women and mainly affects women of low socioeconomic status. This is due in part
 to the difficulties of health policies to promote women's participation in prevention
 programs, namely accessing screening, follow-up and treatment of precancerous lesions.

 Proof of the causal link between HPV and cervical cancer has allowed for the recent
 development of HPV-based screening tests, which detect HPV types considered high-risk. These
 tests have important advantages over the Pap as a screening test: high sensitivity (over
 90%)2 and high negative predictive value3, allowing for a reduction in screening frequency as
 well as for the identification of HPV positive women who, even without presenting a
 precancerous lesion, constitute a high-risk group that requires special follow-up within the
 health system. Very importantly, through self-collection, HPV-testing can reduce barriers to
 screening and increase coverage.4 The method is highly accurate5,6, and is acceptable for
 women in different countries.7-10

 Argentina has become a pioneer in the introduction of new technologies for HPV-based cervical
 cancer prevention. The National Ministry of Health has approved the incorporation of the test
 as a nation-wide screening method. In this context the PI conducted the Jujuy Demonstration
 Project (JDP) to introduce HPV-testing for primary screening.11 This project was part of a
 national strategy to strengthen cervical cancer screening re-launched in 2008,12 which also
 included introduction of HPV vaccination in 2011.13 The JDP is a four-year implementation
 project (2011-2014) to develop, implement and evaluate the programmatic components of an
 HPV-based screening strategy11.

 In addition, in 2012 the PI conducted a population-based cluster randomized trial
 (Self-collection Modality Trial, initials EMA in Spanish). The study was the first carried
 out in a programmatic, real-world context of a low-resource region with the main objective to
 assess the effect on women´s screening uptake of HPV self-collection offered by CHWs during
 home visits and to assess the self-test acceptability by women and CHWs. Our intervention
 resulted in a four-fold increase in screening uptake (85.9% vs 20.2%), showing that offering
 HPV self-collection at home visits through CHWs is an effective strategy to improve cervical
 screening coverage10.

 However, in screening programs, high coverage will not result in a decrease of disease burden
 if women are not diagnosed/treated. Several triage methods are available including cytology,
 visual inspection methods, and colposcopy. In Argentina, cytology is used as triage method;
 therefore, all HPV-positive women who have performed self-collection at home need to attend
 health centers to undergo cytology. However, the proportion of women who have completed
 triage is low; therefore new innovative strategies are needed to increase attendance to
 cytology of these women.

 The aim of the study is to evaluate the effectiveness of a mHealth intervention versus usual
 care to increase adherence to cytological triage in women with HPV-positive self-collected
 test.

 Setting of the study

 The province of Jujuy was selected to develop this study due to the fact that screening based
 on HPV testing as primary test was introduced in 2011. The province of Jujuy has a high
 mortality rate (11.8 x 100.000 women over the 2008-2011 three-year period) and it is one of
 the provinces set as a priority in the National Program of Cervical Cancer Prevention. Since
 2011, HPV-testing is the primary screening test, available for all women aged ≥30 attending
 public health centers and since 2014 HPV- self-collection has been introduced as programmatic
 strategy for screening under-users. The Primary Health Care System (PHC) integrates
 approximately 700 paid full-time CHWs who twice yearly visit approximately 110.000 households
 for health-related tasks as immunization and promotion of maternal/child health. CHW
 performance is evaluated annually and scored as good or sub-optimal by PHC supervisors
 according to achievement of established goals (e.g. number of home visits).10 One hundred
 percent of screening, follow up and treatment in public health system are registered in
 SITAM. SITAM is the national online information system that registers
 screening/diagnosis/treatment events from women attending the public health system.14

 Goals of the study

 A cluster randomized trial will be conducted; it will include a total number of 240 Community
 Health Workers (CHWs) and 7200 women.

 The aim of this study is:

 1. To evaluate the effectiveness of a mhealth intervention versus usual care to increase
 adherence to cytological triage among women with HPV-positive self-collected tests.

 2. To assess the intervention acceptability by women and CHWs.

 Cluster randomized trial

 An overall number of 240 CHWs from the Primary Health Care System (PHCS) of the Province of
 Jujuy will be randomized into two groups that will be named mHealth-Intervention Group (MH)
 and Usual Care Group (UC)

 1. mHealth Intervention Group: Women with HPV self-collected tests will receive a mixed
 intervention which includes counseling through an interactive Apps specifically devised to
 increase adherence to triage which will be run on a tablet, and SMS text messages (SMS
 message) to remind them to attend triage. In addition, Heads of CHWs, chiefs of gynecology
 services and CHWs will receive reminders via e-mails to contact women if after 60 days from
 the HPV-results HPV+ they have not performed triage.

 2. Usual Care Group: Women with HPV self-collected tests receive usual care.

 1. Procedures to carry out in each group:

 • mHealth intervention Group:

 During the home visits that CHWs carry during health rounds, selected CHWs will visit
 every household they are in charge of and will contact women aged 30+ to offer them HPV
 self-collection according to programmatic guidelines. Those women who accept
 self-collection will be invited to participate in the study, providing them the
 necessary information about the goals and activities involved. Eligible women willing to
 participate in the study will be invited to sign an informed consent. The CHW will
 update the F883 template, the standard primary health care form used by CHWs to collect
 socio-demographic and health data of the household and its members. CHWs will use a
 specific questionnaire to collect basic data about inclusion/exclusion criteria.

 Then CHWs will use an APPs specifically designed for the project, run on a tablet, to
 provide women with information about the meaning of the test results, next steps to be
 followed both for positive and negative results, and the importance of adherence to
 triage and diagnostic/treatment procedures if needed.

 An automated system to delivery SMS messages will be developed and linked to SITAM. Once
 the test sample is processed at the HPV laboratory and results registered in SITAM,
 women will receive a SMS message asking them to send a confirmatory reply by text
 messaging which should include its national ID number. Once this confirmatory reply is
 received by the system, women will receive a second SMS message informing them that the
 results are available at the health center, and dates and times to receive them.

 Seven days after the first text message, HPV+ women will receive a reminder to collect
 the test results at the health center. The message will ask women to disregard the
 message in case they have already gone to the health center to get results.

 Sixty-days after the first SMS message, Heads of CHWs, chiefs of gynecology services and
 CHWs will receive an e-mail and SMS message informing them about HPV+ women who have not
 been triaged with cytology, asking them to contact those specific women, with
 information about their name and addresses.

 • Usual care group:

 During the home visits that CHWs carry during health rounds, selected CHWs will visit
 every household they are in charge of and will contact women aged 30+ to offer them HPV
 self-collection according to programmatic guidelines. Those women who accept
 self-collection will be invited to participate in the study, providing them the
 necessary information about the goals and activities involved. Eligible women willing to
 participate in the study will be invited to sign an informed consent. The CHW will
 update the F883 template, the standard primary health care form used by CHWs to collect
 socio-demographic and health data of the household and its members. CHWs will use a
 specific questionnaire to collect basic data about inclusion/exclusion criteria.

 HPV-positive women will receive the visit of the CHW to inform them that they should go
 to the health center to receive results, following standard practices in the provincial
 protocols and guidelines.

 2. Training for CHWs:

 All the CHWs of the province of Jujuy will be informed about the study and a special training
 will be provided for all those who were selected to participate in the study. During the
 training sessions, the goals of the study, the main activities to be carried out and the
 specific tasks that each one of them will have to perform will be explained.

 1. Sample selection and size

 A total of 240 CHWs, who work in the province, will be stratified in four groups
 according to gender and urban/rural setting. A stratified sample of 240 CHWs was
 randomly selected with proportional allocation to strata. Within strata, CHWs were
 randomly assigned (1:1) to study groups. All selected CHWs were informed about the study
 by the PHC heads. We will produce computer-generated random number lists for the CHW
 random selection and the intervention allocation. Blinding of intervention and outcome
 assessments was not feasible.

 The study is designed to have power of more than 0·9 to detect a 20·0% increase in
 triage for the intervention group compared with a 30·0% triage in the control group
 (two-sided alpha=0·05). Based on PHC records13 we estimated that CHWs would enroll an
 average of 30 women in six months, of which 4 will be positive . Correlation induced by
 CHWs is included in sample size calculations assuming an intra-class correlation
 coefficient of 0·10, resulting in a sample of 120 CHWs per arm, and a total of
 approximately 7200 women enrolled.

 2. Database:

 A database built specifically for the study will be used; it will include data about
 randomization Group, agreement to participate in the study and socio-demographic data.
 Data on HPV-testing and triage will be uploaded importing the data from SITAM, using the
 Unique Identification Number (DNI).

 Data entry will be done through specific software that will include range and inter-item
 consistency checks. Entries out of the expected range will not be allowed. Data entry
 will be done by 3 data enters, with re-entry of 20% of questionnaires for quality
 control. Data will be stored in files (TXT, DBF, SQL) compatible with their analysis
 with statistical packages (Stata).

 The data cleaning process will actively search for errors in a planned way. Data
 screening will include searching for four types of oddities: outliers (including
 inconsistencies), strange patterns in distributions, and unexpected analysis results.
 Screening methods will include browsing of data tables after sorting, printouts of
 variables not passing consistency checks, graphical exploration of distribution,
 frequency distributions and cross-tabulations and summary statistics. Once errors have
 been identified, we will go to previous stages of the data flow to see whether the value
 is consistently the same. If no error is found in the data entry phase, we will question
 the interviewer about what may have happened. If possible, we will contact the
 interviewee for repeated measurement.

 Accuracy of previous HPV test reported by the woman will be crossed with information
 from the laboratory database (SITAM). Those women having reported not having a previous
 HPV test, but with a test in the SITAM data base will be excluded from the study.

 Plan for missing data

 Data are exhaustive and complete for all samples arriving to the HPV laboratory. Because
 we define the outcomes as number of Pap smear effectively recorded in the laboratory
 database (SITAM)/ number of women in the study arm, we do not expect to have missing
 data in the main outcome.

 3. Data analysis:

 Data analysis will be done through specific commercial softwares (STATA 10.0 or SPSS 15.0).

 Effectiveness to enhance women adherence to cytological triage

 Adherence to triage will be considered for each CHW. This will be defined as the number of
 women with triage smears within 30, 60 and 90 days. There will be a comparison of the
 percentage of HPV-positive women that did the Pap test within those time intervals in the
 mHealth intervention group and the Usual Care group. The effect of the mHealth intervention
 against usual care will be estimated using a means difference test or a non-parametric test
 for independent samples.
Inclusion criteria:

 -  Women 30 years and older living in a household visited by Community Health Workers
 (CHWs).

 Exclusion criteria:

 -  Women with a previous HPV test.

 -  Women with precancerous lesion or cervical cancer.

 -  Current pregnancy.

 -  Women with Mental disability.