The trial is registered with the Pan-African Clinical Trials Registry http://pactr.org
as PACTR201011000261458 and with clinical trials.gov as NCT01247181.
Partial funding for this study was obtained from an international postdoctoral research fellowship awarded by the Canadian Institutes of Health Research (CIHR) HIV Clinical Trials Network (CTN) to the principal investigator.
Using a 1:1 allocation ratio, patients at the Yaoundé Central Hospital (YCH) Accredited Treatment Centre (ATC) will be randomized to either receive a text message reminder to take their medication or not (Figure : Consolidated Standards of Reporting Trials-CONSORT diagram of study design). Both groups of patients will benefit from the usual care provided in this centre which includes adherence counseling and rarely, home visits.
Consolidated Standards of Reporting Trials-CONSORT diagram of study design.
This is a parallel group design evaluating the effects of adding weekly SMS text messages using mobile phones to usual care (intervention) versus usual care alone (control) among HIV positive patients on HAART. Eligible and consenting patients will be randomized to intervention and control arms using 1:1 allocation ratio by opaque sealed envelope method. A computer generated randomization list will be generated using random block sizes of 2, 4 and 6, by the Father Sean O'Sullivan Research Centre Biostatistics Unit at St Joseph's Healthcare/McMaster University. The allocation codes will then be put in sequentially numbered opaque sealed envelopes and administered by the trained Research Staff at YCH ATC centre. Trained interviewers - blinded to group allocation - will collect data using a pretested data collection form containing socio-demographic data, clinical information and adherence rates at baseline, 3 and 6 months. The data analyst will also be blinded to group allocation.
Cameroon is a sub-Saharan central African country, made of ten provinces and a population of 18 million inhabitants [18
]. The Centre and capital province has a population of about 3.2 million inhabitants. The adult prevalence rate of HIV in the country is 5.1% [19
]. Subjects will be recruited from the YCH ACT. This is an urban centre in the heart of the capital city, Yaoundé. The adult prevalence of HIV in the Centre province is 4.7%. The YCH is a tertiary level general teaching hospital with a capacity of 381 beds. It employs nearly 800 staff including 95 doctors and 270 nurses [20
]. The ACT has a very high recruitment rate of approximately 40 new cases per week and caters for 6500 regular clients. It is the largest HIV clinic in the country and offers enormous potential for recruitment.
Participants: inclusion/exclusion criteria
We will include subjects who are aged above 21 years, own a mobile phone and can read text messages, and who have been on HAART for at least a month. Informed consent is a prerequisite for participating in the study, and will be provided orally and in writing.
We will exclude participants who have been on HAART for less than a month, are aged less than 21 years. Participants who have used HAART for at least one month are chosen so that we can calculate a baseline figure for adherence.
We will send a short text message to the participants in the intervention group in both French and English. The content of the message will be motivating and will act both as a reminder and a cue to action (Figure : Example of a text message). The message will also contain a phone number they can call back if they need help. The content will be varied so as to retain participants' attention throughout the period of the study and to explore the various aspects of behavior change. The program secretary will have a list of phone numbers to which he/she will send the messages every week and will use the 'delivery report' function to ensure that the messages have been delivered. One message will be sent per week in the morning of a chosen day. The average cost for text messages on any networks is 50 CFA Frs. CFA (≈0.1 USD). Text messaging will be provided as an add-on to usual care which includes regular HAART counseling and occasional home visits.
In the control arm, patients will receive the usual care provided to all patients of the ATC which includes regular HAART counseling and occasional home visits. They will be given a number to call if they have questions. They will not receive any text messages, but they will be interviewed at baseline, 3 months and 6 months.
The primary objective of this trial is to investigate the effect of adding the SMS to usual care versus usual care alone in improving and maintaining adherence to HAART in HIV positive patients on HAART at 3 and 6 months. There are several methods used to evaluate or measure adherence to medications, each with advantages and disadvantages [21
]. Thus, there is no gold standard in measuring medication adherence [21
]. The common approach is to use multiple methods to compare or assess the robustness of the estimates of adherence. For this study, we will use three commonly used measures of adherence - namely Visual Analogue Scale (VAS), Pharmacy Refill Data (PRD), and Self Report (SR). We will use VAS as the primary method of measuring adherence. The VAS is highly correlated with more objective methods like using Microelectronic Monitoring System (MEMS) caps [24
]. VAS method has also been widely used in several RCTs evaluating different interventions including mobile text messaging to enhance adherence to HAART [8
]. PRD and SR will be used to fill any missing data on VAS.
The secondary objectives include comparing clinical outcomes such as weight, body mass index (BMI), opportunistic infections (OI), Cluster Designation (CD) 4 count, viral load and quality of life between the groups. These comparisons will be performed at 3 and 6 months.
Our primary outcome will be adherence rates, measured using VAS. SR and PRD will also be used to supplement VAS (Table ).
Overview of outcome measures
Our Secondary endpoints will be;
• Clinical: Weight, BMI, opportunistic infections
• Biological: CD4 count, viral load
• Quality of life (QOL): Measured with the SF-12 QOL assessment form [25
• All cause mortality
The trial will run for six months, with outcome assessment at baseline, 3 months and 6 months.
The sample size calculation is based on the test of the null hypothesis that the rates of adherence to HAART in the two groups (intervention and control) are equal. The primary measure of effect is the rate of adherence to ART treatment as measured by using the VAS over 6 months. The criterion for significance (alpha) has been set at 0.05. The test is 2-tailed, which means that an effect in either direction will be interpreted. The sample size was calculated using the WINPEPI (PEPI- for-windows) version 9.5 software [26
]. With the proposed sample size of 82 in each of the two groups (i.e. assuming a 1:1 allocation ratio), the study will have power of 80% to yield a statistically significant result using a chi-squared test (assuming an intention-to-treat principle for the analysis) of the relative risk at alpha = 0.05. This computation assumes an adherence rate of 80% (for the intervention group) versus 60% (for the control group) at 6 months. These estimates are reflective of estimates from similar studies investigating SMS effect on drug adherences [27
] and were modified to account for the type of intervention and patients for this study. We adjusted the sample size for a potential attrition rate of 20% (due to drop-outs) based on attrition rates to care in this centre. Therefore, the required sample size is 198 patients (99 per group). At the YCH ATC, on average, there are about 120 patients put on HAART per month. We estimate that about 90% will have mobile phones and would be eligible to participate in the study. Of these, it is expected that approximately 75% would be willing to participate in the study and will provide consent to participate in the trial. The expected period for recruitment will be one month to obtain 198 patients needed for the trial. It is feasible to recruit 198 patients in one month because we will also recruit from the large pool of old patients. Our study is designed to detect a 20% increase in adherence.
The analysis and reporting of the results with follow the CONSORT guidelines [28
]. The statistician/data analyst will be blinded to the study group. The process of patient selection and flow throughout the study will be summarized using a flow-diagram. The analysis results of patient demographics and baseline outcome variables (both primary and secondary) will be summarized using descriptive summary measures: expressed as mean (standard deviation) or median (minimum-maximum) for continuous variables and number (percent) for categorical variables. We will adopt an intention-to-treat principle to analyze all outcomes, meaning that data from participants will be analyzed according to the group to which they were randomized even if they do not receive the allocated intervention. We will also use multiple-imputation [29
] to handle missing data. We will use the T-test for comparing groups on continuous outcomes and the chi-squared test for binary outcomes. All statistical tests will be performed using two-sided tests at the 0.05 level of significance. The Bonferroni method will be used to adjust the level of significance for testing for secondary outcomes to keep the overall level at alpha = 0.05. For all group comparisons, the results will be expressed as effect (or risk ratio for binary outcomes), corresponding two-sided 95% confidence intervals and associated p-values. P-values will be reported to three decimal places with values less than 0.001 reported as <0.001. Adjusted analyses using the following baseline covariates (age, gender, education, duration on HAART, HIV staging, nutritional status (BMI) and the presence or not of an opportunistic infection (OI)) will be performed using regression techniques to investigate the residual impact of key baseline characteristics on the outcomes. Goodness-of-fit will be assessed by examining the residuals for model assumptions and chi-squared test of goodness-of-fit. All analyses will be performed using SPSS (Statistical Package for the Social Sciences) version 16.0 for Windows.
Adherence will be measured both as a continuous outcome (change in adherence) and as a binary outcome i.e. adherent (95% of pills taken) or non adherent (< 95% of pills taken). In literature, adherence data can be handled in a number of ways. The measures can be reported as the number of doses respected or can be combined into a composite score [21
]. Even though combined measures are more correlated to clinical response, they are not very practical [22
]. The data from the various adherence measures will not be merged. We will report the effects of the intervention on all the measures of adherence used, and compare them for discrepancies.
• Adherence rates:
We will use this opportunity to calculate the rates of adherence to HAART in the YCH ATC. The context of adherence to HAART in Cameroon has changed greatly over time and the rates reported in literature were subject to cost (which has been dropping over time), availability, accessibility, study design, technique used to measure adherence and study setting. These rates vary from 10% to 97% [30
]. This study will provide a more accurate and current estimate of adherence in Cameroon.
• Safety: Data will be collected on issues that may arise from the use of text messages to improve adherence.
• Health worker experiences: Self-administered questionnaires will be used to assess health worker perceptions of the intervention in terms of long term use, additional workload and benefits to care. The applicability of such an intervention will depend largely on its acceptability by health workers.
The trial will be conducted in compliance with the local protocol and applicable regulatory requirements in Cameroon. The study has been approved by Cameroon National Ethics Committee. Any deviations from the protocol will be reported and explained. The study will be conducted in accordance with the Helsinki declaration [33
] and other established clinical practice guidelines for research on human subjects. Research personnel will approach all potentially eligible patients who fulfill eligibility criteria for consent. All patients must sign a consent form to participate in the trial.