To the Editors:
Suboptimal adherence to antiretroviral therapy (ART) is a leading cause of HIV treatment failure.1 Novel interventions targeted at patients with suboptimal adherence are necessary to assure that all HIV-infected persons share the benefits of pharmacotherapy. The use of mobile phone technologies in promoting health behaviors is well documented.2 Short messaging service (SMS) has been utilized successfully as a health promotion tool in diverse contexts, and a number of studies have demonstrated the efficacy of SMS interventions in promoting adherence to ART and outpatient clinical appointments.3–5 As an adherence intervention tool, SMS offers a number of advantages including near universal coverage, low cost, instant delivery, and potential for individualized interventions. Studies in both HIV-negative and HIV-positive subjects show high rates of sustained willingness to receive health-related SMS reminders.6
We designed a multicenter study to investigate the efficacy of a novel intervention: timed SMS reminders. Timed SMS describes the automated delivery of a reminder text message at the time of ART dosing. The efficacy of timed SMS in promoting antiretroviral adherence has not previously been demonstrated. We conducted a single-arm open-label study to investigate the efficacy of timed SMS reminders in improving ART adherence and viroimmunological outcomes amongst suboptimally adherent HIV-infected adults in Italy. The primary outcome was change in self-reported adherence measures over time. Secondary outcomes included change in the proportion of subjects with HIV-1 RNA levels <50 copies per milliliter and the perceived utility of the intervention. The planned intervention and follow-up time was 9 months.
Patients receiving HIV care at participating sites were screened for trial eligibility using a validated self-administered adherence questionnaire.7 The following 4 measures of adherence comprised the assessment: (1) proportion of ART doses taken over the preceding month as measured by a visual analogue scale; (2) any missed doses over the past week; (3) variations in dosing schedule >2 hours over the past week; and (4) self-initiated drug interruptions of 2 or more days over the last 3 months. Inclusion in the trial was offered to patients reporting any degree of suboptimal adherence on any measure. Additional inclusion criteria were as follows: age >18 years, receiving ART at time of screening, and access to a mobile phone. The sole exclusion criterion was illiteracy.
During the 9-month intervention period, SMS reminders were sent at the time ART dosing, every day including weekends and holidays. SMS reminders were content neutral and contained no mention of HIV, AIDS, ART, or medications. SMS reminders were programmed for automated delivery through a centralized database composed of an anonymous list of subjects, subject cell phone numbers, and dosing schedules. If an SMS could not be delivered within 6 hours of the planned dosing time, delivery was aborted to avoid confusion in dosing schedule. The SMS provider was blinded to the study protocol and hypothesis.
Study subjects were evaluated at baseline, 3, 6, and 9 months. An identical self-administered adherence questionnaire was completed at each study visit. ART was prescribed at the discretion of the clinician as part of routine clinical care. Confirmation of each subject's ART regimen and dosing schedule was performed at baseline and at each follow-up visit. Viral load and CD4+ cell count measurements were performed at 3-month intervals, unless otherwise clinically indicated. All subjects continued to receive adherence support as part of routine standard of care, including counseling sessions and psychological support programs already in place at all participating clinical centers. Differences between baseline and subsequent evaluations were assessed by the mean of a paired t test for continuous variables and the McNemar test for categorical variables.
The study was designed by the Italian National Institute for Infectious Diseases “L. Spallanzani” Instituto Nationale Malottic Infective in collaboration with Network Persone Sieropositive-Italia Onlus, a patient advocacy group. All subjects provided written informed consent. The study was conducted according to the Good Clinical Practice Guidelines of the European Union and the principles of the Helsinki Declaration. The study was approved by the Institutional Review Boards of all participating centers.
One hundred forty-five patients were found eligible for participation, provided written informed consent, and had at least 1 follow-up visit. Subjects were predominantly male (72.8%), older (mean age, 44 years), and treatment experienced (76.9% on second-line or third-line regimens). Median CD4+ cell count at baseline was 384 cells per milliliter (range 238–555) and median HIV-1 RNA level was 1.80 log10 copies per milliliter (range: 1.60–3.25 log10 copies/mL). Figure 1 shows baseline and follow-up adherence measures. A significant improvement in the proportion of ART doses taken over the preceding month was noted at all study time points. At baseline, mean monthly self-reported adherence by visual analogue scale was 78.8% (mean: SD ± 22.6%), and increased to 94.2% (mean: SD ± 12.1%), 93.9% (mean: SD ± 12.7%), 94.9% (mean SD ± 9.0%) at months 3, 6, and 9, respectively (P < 0.001 for all comparisons). A significant improvement in the proportion of subjects with undetectable HIV RNA viral load was also observed at all time points (Fig. 1). At baseline, 42.3% of subjects had an undetectable HIV RNA viral load, whereas this proportion increased to 76.8%, 71.5%, 76.2% at month 3, 6, and 9, respectively (P < 0.001). The perceived utility of the intervention was high with more than 90% of subjects reporting that timed SMS reminders helped them remember to take their medications and maintain a correct dosing schedule “quite a lot” or “a lot”.
Identification of new, effective, and broad-based interventions to improve adherence to ART are needed, particularly in the suboptimally adherent patient. Our study is the first to demonstrate the efficacy of a novel timed SMS reminder adherence intervention. In our study, timed SMS was associated with significant increases in self-reported adherence and rates of virological suppression. The positive effect of the intervention was sustained over the 9-month study period. Nearly all participants found the intervention to be highly useful. In summary, timed SMS is an efficient, low-cost, universally accessible intervention to increase ART adherence and improve virological outcomes. More research is needed to define the optimal target populations, the durability of the intervention, cost-effectiveness, and complementarity with other adherence promoting strategies.
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