The effect of an interactive weekly mobile phone messaging on retention in prevention of mother to child transmission (PMTCT) of HIV program: Study protocol for a randomized controlled trial (WELTEL PMTCT)

Background: Improving retention in prevention of mother to child transmission (PMTCT) of HIV programs is critical to optimize maternal and infant health outcomes, especially now that lifelong treatment is immediate regardless of CD4 cell count). The WelTel strategy of using weekly short message service (SMS) to engage patients in care in Kenya, where mobile coverage even in poor areas is widespread has been shown to improve adherence to antiretroviral therapy (ART) and viral load suppression among those on ART. The aim of this study is to determine the effect of the WelTel SMS intervention compared to standard care on retention in PMTCT program in Kenya. Methods: WelTel PMTCT is a four to seven-centers, two-arm open randomized controlled trial (RCT) that will be conducted in urban and rural Kenya. Over 36 months, we plan to recruit 600 pregnant women at their first antenatal care visit and follow the mother-infant pair until they are discharged from the PMTCT program (when infant is aged 24 months). Participants will be randomly allocated to the intervention or control arm (standard care) at a 1:1 ratio. Intervention arm participants will receive an interactive weekly SMS ‘How are you?’ to which they are supposed to respond within 24 h. Depending on the response (ok, problem or no answer), a PMTCT nurse will follow-up and triage any problems that are identified. The primary outcome will be retention in care defined as the proportion of mother-infant pairs coming for infant HIV testing at 24 months from delivery. Secondary outcomes include a) adherence to WelTel; (b) adherence to antiretroviral medicine; (c) acceptance of WelTel and (d) cost-effectiveness of the WelTel intervention. Discussion: This trial will provide evidence on the effectiveness of mHealth for PMTCT retention. Trial results and the cost-effectiveness evaluation will be used to inform policy and potential scale-up of mHealth among mothers living with HIV.

The WelTel PMCT study is a 4–7 center two-arm open randomized controlled trial in which the intervention is allocated in a 1:1 ratio (Fig. 1 trial design). WelTel PMTCT trial design The study is in western Kenya and involves 4–7 facilities that are among over 192 facilities providing PMTCT services located in the catchment of Academic Model Providing Access to Health Care (AMPATH) – a large HIV Comprehensive Care Program run under the auspices of Moi University School of Medicine, located in Eldoret. These facilities implement Option B+ regimen of PMTCT. The approximate coverage of mobile phones in western Kenya is around 78 % [19]. The research setting has been carefully selected to represent urban and rural mixes that have high antenatal HIV percentage prevalence (10–15 %), about twice that of the national prevalence of 6 %. The study population will consist of: (i) pregnant women living with HIV aged 18 and over presenting at ANC for a first visit in the current pregnancy at the selected clinics; and (ii) newborns delivered to these women living with HIV. Women who will be pregnant and will be diagnosed with HIV infection will be referred to a male or female research assistant to complete a checklist for eligibility. Determination of HIV infection will be based on two repeated Determine or Colloidal Gold tests for women newly diagnosed during the current pregnancy, or, based on referral from the comprehensive care clinic for those with known HIV infection and on antiretroviral therapy (ART) or pre-ART). Individuals must fulfill all the inclusion criteria, provide consent to participate and complete an interviewer-administered questionnaire before they are randomized to either the control and intervention groups. Participants in the intervention group will register their phone numbers in the WelTel system (online or via SMS) and then receive a weekly short text message question in Kiswahili “Mambo?” (Kiswahili for “How are you?”) asking about their general wellbeing (Fig. 2). The message will be sent on a fixed day of the week and will allow the patient to respond within 24 h either that they are well for example “ok” or “sawa” or that they have a problem (for example “problem” or “shida”). A female study coordinator will be in charge of centrally monitoring the WelTel SMS platform, which automatically sends the messages and registers responses from the participants and categorizes them. All participants who respond “problem” or who do not respond will be directly linked to a regular PMTCT nurse at the woman’s clinic to assist with identified problems. Problems that cannot be immediately resolved by the nurse follow routine procedures at the clinic and are normally referred to the PMTCT clinical officer at the respective facility who will then decide if the patient needs to visit the facility or should receive a follow up phone call. The study coordinator will follow up with the respective PMTCT nurses to record action taken, which is entered directly into the WelTel platform logs as notes. Patients who will not respond to the SMS within 24 h will be traced (first by telephone then at households) within the defaulter tracing outreach program in routine PMTCT care. At enrollment, the participants will be informed that the weekly SMS support service does not replace routine clinic services, and that all appointments made by PMTCT staff should be honored and all emergencies should be handled by usual means. A WelTel SMS platform technician will handle all technical problems that may arise. WelTel SMS intervention Retention in PMTCT care is defined as the proportion of women living with HIV and their HIV-exposed infants that remain in care until infants are aged 24 months measured from when the pair is enrolled in the program from the woman’s first visit at ANC until 24 months after birth. The primary outcome of the study is defined as the proportion of mother-newborn retained in PMTCT care at 24 months; assuming i) a power of 80 %, ii) a two-sided test (alpha = 0.05), iii) and based on prior knowledge, a proportion retained in the control group of about 30 %, a sample size of 300 participants in each arm for a total of 600 subjects, with 5 % dropout rate (i.e. women who decide to withdraw from the study) in both the control and intervention arms was estimated to detect a 11 % difference (the smallest detectable difference) in the primary outcome between the intervention and control arms that is the difference that it would be important to detect is 11 %, computed as the proportion retained in the intervention arm minus the proportion retained in the control arm i.e. the proportion retained in the intervention group minus the proportion retained in the control group. Calculations were performed using Stata 14.1. A PMTCT nurse at the selected clinics will inform all consecutive pregnant women identified as living with HIV at their first ANC visit about the study. The PMTCT nurse will then refer these clients to the research assistant who will assess their eligibility and provide detailed information about the study. Individuals who are eligible will be invited to participate in the study and the research assistant will seek their consent. Participants in the intervention arm who own or have access to mobile phones will be registered directly onto the WelTel platform with their phone number. Eligible and consenting patients will be randomized to the intervention and control arms using a 1:1 allocation ratio. To ensure balance between the arms throughout the trial, we adopted a permuted-block randomization scheme. The block size will be concealed until the trial is over. Randomization will be performed separately at each clinic. We will use opaque sealed envelopes to assign participants to the intervention and control arms. The randomization list was be generated at the Karolinska Institutet (Stockholm, Sweden) by an independent statistician. An interviewer- facilitated baseline questionnaire will be administered after recruitment and allocation. Questions record information on participants’ social and demographic characteristics; time of HIV diagnosis, time on ARV, disclosure of HIV status, HIV care and social support, mobile phone use as well as costs for accessing care. Follow up visits will occur at 6 and 24 months postpartum, at which time research assistant will administer the follow-up questionnaire. The follow up questionnaire will capture information on participants’ missed appointments, engagement with health workers and satisfaction with care, mobile phone access and using the WelTel intervention, and health related status/quality of life using the EuroQol 5-dimensional (EQ-5D) utility scores and twelve item short form survey (SF-12) standardized tools. To investigate quality of life, we will first develop a patient generated index (PGI) to identify areas in the women’s lives that are affected by their HIV infection during pregnancy and nursing period; periods when the risk of transmitting HIV is high. A PGI is an individualized patient reported instrument that allows the respondent to state, weight and rate areas of importance to the patients’ lives that are affected by their illness. The PGI will also enable the investigators to assess the validity of the EQ5D and SF12 in this population and context. All outgoing and incoming text messages will be automatically recorded on the WelTel platform. The platform also captures all of the “problems” noted by participants, instances of non-response, and actions taken in relation to participants’ ‘problem’ responses and non-responses. Platform data will be backed up every 7 days. All questionnaires will be paper-based and the data manager will then enter data into a database at the central office on an ongoing basis. A data manager will check the forms for completeness and quality will be verified by re-checking a random sample of 10 % of the data. Any problems that arise will be resolved promptly. Participant files will be stored in a locked office at the trial sites. Data on attendance, HIV care clinical indicators like viral load and CD4 cell count as well as treatment regimen will be collected medical records. We will also collect information on demographic characteristics (age, education level, marital status and parity) of all screened patients/potential trial participants. Qualitative research using in –depth interviews will also be performed to discover ‘how’ and ‘why’ the intervention works to improve retention in PMTCT program. Purposive sampling will be used to identify participants for qualitative interviews. Face-to-face interactions will be used to build trust during the interview process and to enhance free interaction between the researcher and the participants [20]. All conversations will be recorded with permission from the respondents and the interviews will be performed at a place and in a language preferred by the respondent. All qualitative research tools will be developed in English, then translated to Kiswahili, and then back translated to English. The interview guide will be available in both languages. Baseline participants’ characteristics will be reported separately by treatment arm. Baseline characteristics include: age, parity (nulliparous versus previous birth), marital status (single, married or cohabiting, divorced/widowed), ARV exposure (experienced vs. naive), duration of known HIV diagnosis (newly vs. previously diagnosed), age (18–29, 30–39, 40–49, ≥50 years of age), phone ownership (owned vs. shared), level of education (none, primary, secondary, post-secondary), distance from clinic (≤1 h vs. >1 h), number of children born after HIV diagnosis, on ARV at enrolment (yes, no), time on ARV at enrolment (≤6 months, 7–12 months, ≥13 months) and HIV status disclosure (yes, no). We will report the mean (standard deviation [SD]) or median (first quartile, third quartile) for continuous variables, and count and percentages for categorical variables. All analyses are by intention-to-treat i.e. according to the study group to which women were originally allocated regardless of subsequent intervention received and per protocol. Other more statistical methods will be used to take into account switching. For the primary outcome, we will compare the proportion of mothers living with HIV and their HIV-exposed infants in the program at 24 months post-birth in the intervention vs. control arm using both parametric (Chi-Square) and exact (Fisher) statistical tests. Secondary outcomes will also be compared between arms, with t-tests for normally distributed variables, Mann Whitney-U tests for non-normally distributed variables, and Chi-Square and Fisher exact tests for categorical variables. The relative risk (RR) for PMTCT retention with 95 % confidence intervals will be computed and the number needed to treat to prevent one non-retained mother-infant pair will also be estimated. Concerning the secondary outcomes, average treatment effects (ATE) will be computed for continuous outcomes and RRs for categorical outcomes. For both primary and secondary outcomes, log-linear or linear regression models will be used to provide effect estimates adjusted for potential imbalances in baseline participants’ characteristics, if required. We will repeat the analysis of primary and secondary outcomes within such subgroups (in relation to socio-demographics) to assess the homogeneity of the intervention effect across pre-determined subgroups of patients. Stratified RRs and ATEs will be computed. Regression models, which include the intervention allocation and subgroup-defining variables and their interaction, will be applied to assess effect modification across groups; all statistics tests will be run based on two side p-values and values <0.05 will be considered statistically significant. All statistical analyses will be again performed with Stata version 14.1 (Stata Corporation, College Station, TX, USA). Qualitative data will be analyzed using content analysis, guided by Graneheim and Lundman [21]. First, the transcribed material is read a number of times to get a general sense of the material by a group of researchers. Using the open code software for qualitative research, meaning units, which are key phrases in the text, are identified, condensed and outlined. Codes will then be ascribed to each meaning unit. The codes will be compared and grouped into sub-categories. This comparison will be performed consistently to identify emerging categories that will be further compared, re-organized and merged into sub-themes and one overarching theme. The coding and analysis process will be deductive in nature and involve key members of the research team. We will perform an economic evaluation to assess WelTel SMS from a healthcare payer perspective. The primary outcome of the cost effective analysis (CEA) will be the incremental cost per additional mother-infant pairs that remain in PMTCT until infant is aged 24 months. A secondary outcome is averted infant HIV-infections at cessation of breastfeeding. For the cost-utility analysis the outcome will be quality adjusted life years (QALYs), based on responses to the SF-12 and EQ5D. For both analyses (CEA and CUA) we will report the incremental cost-effectiveness ratios (ICERs) that will be computed as the ratio of the incremental costs to provide WelTel SMS over usual care and incremental effects e.g. cost per additional mother-infant pairs that remain in PMTCT until infant is aged 24 months, cost averted infant HIV-infections at cessation of breastfeeding and cost per QALY. A secondary analysis will also consider the incremental cost per averted deaths by bringing infants lost to follow up back and enabling treatment. Thus, we will determine ICER for cost per averted deaths. Deterministic sensitivity analysis will be to address uncertainty.

N/A

• Dima Health