Effect of mobile telephone reminders on treatment outcome in HIV
A randomised controlled trial
Shet A, DeCosta A, Kumarasamy N, Rodrigues R, Rewari BB, Ashorn P, et al. Effect of mobile telephone reminders on treatment outcome in HIV: evidence from a randomised controlled trial in India. BMJ 2014;349:g5978.
Objective—To assess whether customised mobile phone reminders would improve adherence to therapy and thus decrease virological failure among patients with HIV starting antiretroviral treatment (ART).
Design—Randomised controlled trial among patients with HIV initiating antiretroviral treatment.
Setting—Three diverse healthcare delivery settings in south India: two ambulatory clinics within the Indian national programme and one private HIV healthcare clinic.
Participants—631 HIV, ART naïve, adult patients eligible to initiate first line ART were randomly assigned to mobile phone intervention (n=315) or standard care (n=316) and followed for 96 weeks.
Intervention—The intervention consisted of customised, interactive, automated voice reminders, and a pictorial message that were sent weekly to the patients’ mobile phones for the duration of the study.
Main outcome measures—The primary outcome was time to virological failure (viral load >400 copies/mL on two consecutive measurements). Secondary outcomes included ART adherence measured by pill count, death rate, and attrition rate. Suboptimal adherence was defined as mean adherence <95%.
Results—Using an intention to treat approach we found no observed difference in time to virological failure between the allocation groups: failures in the intervention and standard care arms were 49/315 (15.6%) and 49/316 (15.5%) respectively (unadjusted hazard ratio 0.98, 95% confidence interval 0.67 to 1.47, P=0.95). The rate of virological failure in the intervention and standard care groups were 10.52 and 10.73 per 100 person years respectively. Comparison of suboptimal adherence was similar between both groups (unadjusted incidence rate ratio 1.24, 95% CI 0.93 to 1.65, P=0.14). Incidence proportion of patients with suboptimal adherence was 81/300 (27.0%) in the intervention arm and 65/299 (21.7%) in the standard care arm. The results of analyses adjusted for potential confounders were similar, indicating no significant difference between the allocation groups. Other secondary outcomes such as death and attrition rates, and subgroup analysis also showed comparable results across allocation groups.
Conclusions—In this multicentre randomised controlled trial among ART naïve patients initiating first line ART within the Indian national programme, we found no significant effect of the mobile phone intervention on either time to virological failure or ART adherence at the end of two years of therapy.
Why do the study?
mHealth, the use of mobile technology to support healthcare outcomes, has been endorsed by the European Commission and the World Health Organization, particularly in countries that have resource limited healthcare systems but where mobile phones are ubiquitous among the population. It is believed that mobile technology can be used to enable earlier diagnoses, promote health, and increase accessibility to the results of investigations for patients and healthcare professionals.
Despite this enthusiasm well designed studies exploring the effectiveness of mHealth based interventions are still in their infancy. However, mobile telephone reminders—which are a low cost and effective way of improving attendance at outpatient appointments and aid smoking cessation attempts—have been shown to be effective interventions in some studies. 
Non-adherence to antiretroviral therapies (ART) in patients with HIV is associated with treatment failure (virological failure). The evidence around whether telephone reminder systems improve adherence to ART in patients with HIV is inconclusive. Recent reports from Kenya  led a Cochrane review panel to conclude that mobile phone based reminder systems can be beneficial in HIV treatment, but there is conflicting evidence from similar trials carried out in Brazil and Cameroon.  The authors of this study looked at whether bi-weekly mobile telephone reminders could be used to improve adherence to ART in a resource limited region of India.
What did the authors do?
It is estimated that 2.5 million people in India live with HIV infection. After the same group of authors had separately published studies demonstrating that a sufficient proportion of the HIV population in India had access to mobile telephones and that a telephone reminder improved short term adherence to ART, they designed a partially blinded randomised controlled trial.
Setting and sampling
Patients with documented HIV infection attending ambulatory clinics across three sites in two Indian states were screened for inclusion. ART naïve patients (ie, those who have never used HIV drugs) aged 18-60 years, who required ART as part of their routine care, were eligible for inclusion. Severely ill patients; those with HIV-2 infection; those without access to a mobile phone network; and those with another family member already recruited to the study were excluded.
Randomisation and blinding
Participants were randomly assigned, on a 1:1 basis, to the mobile telephone intervention or control arm. Sequentially numbered opaque sealed envelopes were used to conceal which arm participants were enrolled in. All participants were given a mobile phone, but only those in the intervention arm received reminders. Research and laboratory staff, statisticians, and the study authors, however, were blinded as to who was allocated the intervention.
Mobile telephone intervention and control arms
In brief, an automated motivational voice call was made once a week at a time selected by each participant. The call asked whether the patient had taken his or her prescription the day before, and required a response, dialling “1” for yes or “2” for no. This was followed four days later by a non-interactive neutral pictorial reminder. Both groups received standard care including three counselling sessions before the initiation of ART.
Participants returned for study visits two, eight, and 12 weeks after starting ART, and every 12 weeks thereafter until 96 weeks or the point of virological failure, defined as plasma HIV load >400 copies/mL on two consecutive occasions measured at least one month apart. Adherence, assessed by pill counts was undertaken at each appointment, as were attrition and death rates. Laboratory assessments (CD4 cell count, viral load) were taken every three months. ART was dispensed at the clinic.
Primary outcome and statistical analysis
Intention to treat analyses were employed; that is, all participants who were assigned to the intervention or control arm were included in the analysis regardless of non-adherence, protocol deviations, or withdrawal.
The primary outcome was time to virological failure and was compared in the two arms using Kaplan-Meier survival curves and the log-rank test. Cox regression analyses were performed adjusting for potential confounders including recruitment site, education status, literacy, and employment.
What did they find?
Between July 2010 and August 2011, 1140 patients with HIV were screened for inclusion; 631 participants were enrolled into the study—315 were allocated to the intervention group and 316 to the control group.
The proportion and rate of virological failure was similar in the two groups (figure 1 ). Following adjustment for covariates, there was no significant difference between groups in the time to virological failure (adjusted hazard ratio 0.96 (95% confidence interval 0.64 to 1.43) P=0.85) (see figure).
No differences were seen in the prevalence of suboptimal adherence (defined as < 95% mean pill-count adherence) in the intervention arm (81/300 [27%]) compared with the standard arm (65/299 [22.7%]). Mortality rates were similar between groups; 21/315 (6.7%) and 23/316 (7.3%) patients died in the intervention and standard care groups, respectively.
What does this study mean?
Non-adherence to drugs is one of the major reasons for treatment failure in HIV therapy. Accepting that most patients are non-adherent, at least some of the time, it is important to recognise the difference between partial and complete non-adherence, because the determinants are likely to be different. Partial non-adherence is usually unintentional, and occurs when the patient intends to take the drug but is prevented from doing so by limitations in capacity and resources—for example, “forgetting,” poor comprehension, lack of funds. Complete non-adherence, in contrast, is usually intentional, and occurs when the patient decides not to take the drug as prescribed.
In this study, mobile telephone reminders had no effect on rates of non-adherence, time to, or rates of, virological failure in patients with HIV who were prescribed ART. The non-adherence rates reported in this study are consistent with those from other studies which report that 65-97% of patients adhere to ART >95% of the time.
These negative findings have several potential explanations. First, partial non-adherence, which might be improved with a telephone reminder, may not have a clinically important effect on virological load; whereas, virological failure is likely in patients who have decided not to take their drugs. Intentionally non-adherent patients tend to be sceptical, indifferent, or ambivalent, rather than accepting the need for maintenance therapies. Arguably, a telephone reminder is unlikely to change this complex behaviour.
Second, a person’s behaviour changes as a consequence of the additional attention involved in being observed—the observer or Hawthorne effect. In this study all participants, regardless of whether they were in the intervention arm or not were given a mobile telephone. Therefore, it is conceivable that simply being given a phone was enough to prompt adherence and negate potential differences in partial adherence.
Third, although studies that rely on pill counts are less affected by recall bias than those that use adherence questionnaires, they are subject to “pill dumping,” which is a form of concealment or social desirability bias. Because the study was randomised, however, “pill-dumpers” should have been equally distributed between the intervention and control arms.
Finally, the control group received effective, high quality conventional treatment, including three pre-treatment counselling sessions; therefore there might have been little room for improvement in the intervention over control arm—the so called “ceiling effect.”
Mobile phone communications used as reminders for drug adherence alone did not improve treatment success among participants with HIV. Journals tend to accept studies with a positive outcome, which results in an unrepresentative reflection of completed studies; a concept termed “publication bias.” This study adds to the growing body of negative mHealth research and might help to develop successful applications for mHealth in the future.Neil Chanchlani, foundation year two doctor1, James Goodhand, specialist registrar in gastroenterology2
1Colchester General Hospital, Essex, UK, 2Barts Health NHS Trust, Newham University Hospital, London, UK
Correspondence to: firstname.lastname@example.org
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.
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Cite this as: Student BMJ 2015;23:g7393