Title: Electronic reminders for promoting adherence to ART among people living with HIV Contents

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Title: Electronic reminders for promoting adherence to ART among people living with HIV

1. PICO question

Electronic reminders for promoting adherence to ART among people living with HIV P People living with HIV in generalized or concentrated epidemic

I SMS reminders (text messaging); voice messaging; other electronic reminders C No SMS, voice or electronic reminders

O HIV incidence, transmission, mortality, morbidity, access, retention, and other outcomes to be noted in the protocol

2. Search strategy

(01 Jan 1996–05 June 2012)

• PubMed

• EMBASE

• CENTRAL

• PsycINFO

• Web of Science

• WHO Global Health Library Virtual Platform

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This work was commissioned by the World Health Organization and carried out by The University of California, San

(AIM, LILACS, IMEMR, IMSEAR, WPRIM, WHOLIS)

• WHO International Clinical Trials Registry Platform (ICTRP) Also: CROI, IAS, IAC conference abstracts, conference inception to 2012

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3. Flow diagram of screening process

Results from all searches (n = 580)

Duplicates removed (n = 115)

Initial screening by one author

(n = 465)

Clearly irrelevant references removed

(n = 127)

References screened by two authors working independently

(n = 338)

References selected for full-text review

(n = 24)

Ongoing or unpublished

studies identified

(n = 5)

References excluded (n = 314)

References excluded after full-text review

(n = 18)

Ongoing or unpublished study

excluded (n = 1);

Sufficient data for GRADE analysis not

yet obtained (n = 3)

Conference abstract identified

(n = 1)

Studies presently included in GRADE analysis (n = 9), including unpublished data (n = 2) and conference abstract (n = 1)

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4. Evidence summaries

4.1. Mobile phone text messages:

r

andomized controlled

t

rial

s

(RCTs)

All statistics provided are for “non-event”.

Outcome: viral load suppression (follow-up 52 weeks)

• In two trials (Lester 2012, Ikeda 2012) with 52 weeks of follow-up, patients who received daily or weekly mobile phone text messages were at lower risk of viral failure than those receiving standard care (RR 0.67, 95% CI 0.57–0.78). The quality of the evidence is high.

• In one trial (Lester 2010) with 52 weeks of follow-up, patients who received weekly mobile phone text messages were at lower risk of viral failure compared with those receiving standard care (RR 0.83, 95% CI 0.69–0.99). The quality of the evidence is high.

• In one trial (Ikeda 2012) with 52 weeks of follow up, patients who received daily mobile phone text messages were at lower risk of viral failure than those receiving standard care (RR 0.36, 95%

CI 0.25 to 0.51). At 30 weeks, they were at lower risk of viral failure than those receiving standard care (RR 0.53, 95% CI 0.41–0.69). The quality of the evidence is moderate. The evidence quality was downgraded once for imprecision (few events).

Outcome: ART adherence (follow-up 48–52 weeks)

• In two trials (Lester 2010, Pop-Eleches 2011) with 48–52 weeks of follow-up, patients who received mobile phone text messages (whether daily or weekly) were at lower risk of being non- adherent, compared to those receiving standard care (RR 0.82, 95% CI 0.72–0.94). The quality of the evidence is high.

• In two trials (Lester 2010, Pop-Eleches 2011) with 48–52 weeks of follow-up, patients who received weekly mobile phone text messages (whether short or long in length) were at lower risk of being non-adherent than those receiving standard care (RR 0.78, 95% CI 0.68–0.89). The quality of the evidence is high.

• In two trials (Lester 2010, Pop-Eleches 2011) with 48–52 weeks of follow-up, patients who received short weekly mobile phone text messages were at lower risk of being non-adherent than those receiving standard care (RR 0.77, 95% CI 0.66–0.90). The quality of the evidence is high.

• In one trial (Pop-Eleches 2011) with 48 weeks of follow-up, patients who received long weekly mobile phone text messages were at lower risk of being non-adherent (statistically nonsignificant) than those receiving standard care (RR 0.79, 95% CI 0.60–1.04). The quality of the evidence is low. The evidence quality was downgraded twice for imprecision (very few events).

• In one trial (Pop-Eleches 2011) with 48 weeks of follow-up, patients who received short daily mobile phone text messages were at no different risk of being non-adherent (statistically nonsignificant) compared to those receiving standard care (RR 1.0, 95% CI 0.79–1.27). The quality of the evidence is low. The evidence quality was downgraded twice for imprecision (very few events).

• In one trial (Pop-Eleches 2011) with 48 weeks of follow-up, patients who received long daily mobile phone text messages were at no different risk of being non-adherent (statistically nonsignificant) compared to those receiving standard care (RR 0.98, 95% CI 0.77–1.24). The quality of the evidence is low. The evidence quality was downgraded twice for imprecision (very few events).

• In one trial (Mbuagbaw 2012) with 26 weeks of follow-up, patients who received short weekly mobile phone text messages were at no different risk of being non-adherent (statistically nonsignificant) compared to those receiving standard care (RR 0.98, 95% CI 0.57–1.98). The quality of the evidence is moderate. The evidence quality was downgraded once for imprecision (few events).

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• In one trial (da Costa 2012) with 16 weeks of follow-up, patients who received short mobile phone text messages five times each week were at lower risk of being non-adherent (statistically nonsignificant) than those receiving standard care (RR 0.46, 95% CI 0.13–1.71). The quality of the evidence is low. The evidence quality was downgraded twice for imprecision (very few events).

Outcome: pharmacy refills (follow-up 26 weeks)

• In one trial (Mbuagbaw 2012) with 26 weeks of follow-up, there was no difference in the rate of pharmacy refills among patients who received short weekly mobile phone text messages

compared to those receiving standard care (mean difference 0.1 higher, 95% CI 0.29 lower to 0.49 higher). The quality of the evidence is moderate. The evidence quality was downgraded for imprecision (few events).

4.2. Mobile phone text messages: observational studies

Outcome: viral load suppression (follow-up 36 weeks)

• In one observational cohort (Ammassari 2011) with 36 weeks of follow-up, patients who received daily mobile phone text messages were at lower risk of viral failure than those receiving standard care (RR 0.41, 95% CI 0.28–0.61). The quality of the evidence is very low. The evidence quality was downgraded once for imprecision (few events).

Outcome: ART adherence (follow-up 24–36 weeks)

• In two observational cohorts (Ammassari 2011, Dowshen 2012) with 24–36 weeks of follow-up, patients who received daily mobile phone text messages were at lower risk of being non-adherent than those receiving standard care (RR 0.33, 95% CI 0.23–0.46). The quality of the evidence is very low. The evidence quality was downgraded once for imprecision (few events) and once for indirectness (self-reported adherence).

4.3. Pager messages: RCTs

Outcome: ART adherence (follow-up 12 weeks)

• In one trial (Safren 2003) with 12 weeks of follow-up, patients who received pager messages several times daily were, on average, at lower risk of being non-adherent than those receiving standard care (RR 0.38, 95% CI 0.24–0.61). The quality of the evidence is very low. The quality of evidence was downgraded twice for risk of bias (industry sponsor; high loss to follow-up) and twice for imprecision (very few events).

5. Quality of evidence

The Lester and Pop-Eleches trials in Kenya provide high-quality evidence indicating that weekly mobile phone text messaging was efficacious in enhancing adherence among patients recently initiating ART.

The Lester trial also provides high-quality evidence indicating that patients receiving weekly messages had better viral load suppression.

Although the Ikeda trial in Guatemala (also among patients initiating ART) did not directly measure adherence, it provides moderate-quality evidence indicating that patients receiving daily messages on their mobile phones (or songs for patients with low literacy) had better viral load suppression than those in the control group. This would seem to be at odds with low-quality evidence from the Pop-Eleches trial that there was no difference in adherence among patients receiving daily messages.

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The Mbuagbaw trial in Cameroon was in ART-experienced patients. Moderate-quality evidence indicates that weekly messages had no significant effect. The very small da Costa trial in Brazil was also in ART- experienced patients and provides low-quality evidence that patients receiving text messages five times weekly had better ART adherence than those in the control group. Two observational studies (Ammassari 2011, Dowshen 2012) provide very-low-quality evidence indicating that daily messages improved adherence among patients with suboptimal or poor adherence.

The Safren RCT of a pager intervention provides very-low-quality evidence indicating that pager

messages sent several times daily resulted in better adherence in the intervention group than in the control group. The quality of evidence in this trial was downgraded due to industry sponsorship (a proprietary product was used to send the messages), high loss to follow-up and a very small study population.

The GRADE system ranks the quality of evidence on four levels: “high”, “moderate”, “low” and “very low”. Evidence from randomized controlled trials starts at “high” but can be downgraded based on study limitations, inconsistency of results, indirectness of evidence, imprecision or reporting bias. Evidence from observational studies starts at “low” but can be upgraded if the magnitude of treatment effect is very large, if there is a significant dose–response relationship or if all possible confounders would decrease the magnitude of an apparent treatment effect. Evidence from observational studies can also be downgraded.

Table: Effects of the interventions Study Intervention versus

standard care Outcome Measured Effect (non-event) RCTs

Lester 2010

(n = 538) Short weekly messages Viral load

suppression 52 weeks RR 0.83, 95% CI 0.69–0.99 Lester 2010

(n = 538) Short weekly messages >95% adherence 52 weeks RR 0.77, 95% CI 0.63–0.93 Pop-Eleches 2011

(n = 212) Short weekly messages >90% adherence 48 weeks RR 0.78, 95% CI 0.59–1.03 Pop-Eleches 2011

(n = 213) Long weekly messages >90% adherence 48 weeks RR 0.79, 95% CI 0.60–1.04 Pop-Eleches 2011

(n = 209) Short daily messages >90% adherence 48 weeks RR 1.00, 95% CI 0.79–1.27 Pop-Eleches 2011

(n = 211) Long daily messages >90% adherence 48 weeks RR 0.98, 95% CI 0.77–1.24 Da Costa 2012

(n = 21) Short messages 5x/week >95% adherence 16 weeks RR 0.46, 95% CI 0.13–1.71 Ikeda 2012

(n = 226) Short daily messages Viral load

suppression 52 weeks RR 0.36, 95% CI 0.25–0.51 Ikeda 2012

suppression 30 weeks RR 0.53, 95% CI 0.41–0.69 Mbuagbaw 2012

(n = 200) Short weekly messages >95% adherence 26 weeks RR 0.98, 95% CI 0.57–1.98 Safren 2003

(n = 60)

Short messages several

x/day (pager) >95% adherence 12 weeks RR 1.25, 95% CI 0.82–1.90 Observational

Ammassari 2011

suppression 36 weeks RR 0.41, 95% CI 0.28–0.61 Ammassari 2011

n = 145) Short daily messages >95% adherence 36 weeks RR 0.41, 95% CI 0.29–0.58

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This work was commissioned by the World Health Organization and carried out by The University of California, San Dowshen 2012

n = 60) Short daily messages >95% adherence 24 weeks RR 0.02, 95% CI 0.00–0.37

6. Bibliography of included studies

6.1. Mobile phone text-messaging: randomized controlled trials

1. “Cell-POS.” Curioso W et al. at Universidad Peruana Cayetano Heredia. Evaluation of a computer-based system using cell phones for HIV-infected people in Peru. ClinicalTrials.gov # NCT01118767 [personal communication].

2. da Costa TM, Barbosa BJ, E Costa DA, Sigulem D, de Fatima Marin H, Filho AC, et al. Results of a randomized controlled trial to assess the effects of a mobile SMS-based intervention on treatment adherence in HIV/AIDS-infected Brazilian women and impressions and satisfaction with respect to incoming messages. Int J Med Inform 2012;81(4):257-69.

3. Ikeda JM, Barrios R, Lopez-Lopez JB, Hearst N. SMS messaging improves treatment outcome among the HIV-positive Mayan population in rural Guatemala. In: XIX International AIDS Conference, Washington, 22-27 July 2012, #TUPE673 (Poster).

4. Lester RT, Ritvo P, Mills EJ, Kariri A, Karanja S, Chung MH, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010;376(9755):1838-45.

5. Mbuagbaw L et al. [personal communication].

a. Mbuagbaw L, Bonono-Momnougui RC, Thabane L. Considerations in using text

messages to improve adherence to highly active antiretroviral therapy: a qualitative study among clients in Yaounde, Cameroon. HIV/AIDS (Auckland, NZ) 2012;4:45-50.

b. Mbuagbaw L, Thabane L, Ongolo-Zogo P, Lester RT, Mills E, Volmink J, Yondo D, Essi MJ, Bonono-Momnougui RC, Mba R, Ndongo JS, Nkoa FC, Ondoa HA. The Cameroon mobile phone SMS (CAMPS) trial: a protocol for a randomized controlled trial of mobile phone text messaging versus usual care for improving adherence to highly active antiretroviral therapy. Trials 2011 Jan 7;12:5.

6. Pop-Eleches C, Thirumurthy H, Habyarimana JP, Zivin JG, Goldstein MP, de Walque D, et al.

Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS 2011;25(6):825-34.

a. Haberer JE, Kiwanuka J, Nansera D, Wilson IB, Bangsberg DR. Challenges in using mobile phones for collection of antiretroviral therapy adherence data in a resource- limited setting. AIDS and Behavior 2010;14(6):1294-301.

6.2. Mobile phone text-messaging: observational studies

1. Ammassari A, Trotta MP, Shalev N, Tettoni MC, Maschi S, Di Sora F, et al. Timed short messaging service improves adherence and virological outcomes in HIV-1-infected patients with suboptimal adherence to antiretroviral therapy. JAIDS 2011;58(4):e113-5.

2. Dowshen N, Kuhns LM, Johnson A, Holoyda BJ, Garofalo R. Improving adherence to antiretroviral therapy for youth living with HIV/AIDS: a pilot study using personalized,

interactive, daily text message reminders. Journal of Medical Internet Research 2012;14(2):e51.

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6.3. Pager systems: randomized controlled trials

1. Safren SA, Hendriksen ES, Desousa N, Boswell SL, Mayer KH. Use of an on-line pager system to increase adherence to antiretroviral medications. AIDS Care 2003;15(6):787-93.

6.4. Studies for which quantitative data are not currently available and are not graded:

6.4.1. Mobile phone text-messaging: randomized controlled trials

1. Botswana-UPenn Partnership. Steenhoff A et al. Pilot study of text message reminders to improve HIV medication adherence in Botswana. ClinicalTrials.gov # NCT01001741 (unpublished data).

Note: Partial data obtained; see “Results at a glance”. The investigators have not responded to my follow-up requests for additional data; they may send complete data after they present at a meeting in late September 2013. If I am able to obtain these data, I will update the GRADE profiles accordingly.

6.4.2. Automated voice- and picture-messaging: randomized controlled trials

1. De Costa A, Shet A, Kumarasamy N, Ashorn P, Eriksson B, Bogg L, et al. Design of a

randomized trial to evaluate the influence of mobile phone reminders on adherence to first line antiretroviral treatment in South India – the HIVIND study protocol. BMC Medical Research Methodology 2010;10:25

a. Sidney K, Antony J, Rodrigues R, Arumugam K, Krishnamurthy S, D'souza G, De Costa A, Shet A. Supporting patient adherence to antiretrovirals using mobile phone reminders:

patient responses from South India. AIDS Care 2012;24(5):612-7.

Note: The investigators have published qualitative data. The investigators cannot send quantitative data, as it will be in a “locked database” until 2013.

7. Excluded studies with reasons

Reference Reason for exclusion

Andrade AS, McGruder HF, Wu AW, Celano SA, Skolasky RL Jr, Selnes OA, Huang IC, McArthur JC. A programmable prompting device improves adherence to highly active antiretroviral therapy in HIV-infected subjects with memory impairment. Clin Infect Dis 2005;41(6):875-82.

Study population all memory-impaired.

Barnighausen T, Chaiyachati K, Chimbindi N, Peoples A, Haberer J, Newell ML. Interventions to increase antiretroviral adherence in sub-Saharan Africa: a systematic review of evaluation studies. Lancet Infectious Diseases

2011;11(12):942-51.

Systematic review

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Chi BH, Stringer JS. Mobile phones to improve HIV treatment adherence. Lancet 2010;376(9755): 1807–8.

Letter in response to Lester 2010.

Hardy H, Kumar V, Doros G, Farmer E, Drainoni ML, Rybin D, et al. Randomized controlled trial of a personalized cellular phone reminder system to enhance adherence to antiretroviral therapy. AIDS Patient Care STDs 2011; 25(3):153–61.

Control was a different experimental intervention (“beeper”).

Kalichman SC, Kalichman MO, Cherry C, Swetzes C, Amaral CM, White D, et al. Brief behavioral self-regulation

counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial. AIDS Patient Care STDs 2011;25(5):303–10.

Combined with another intervention.

Kelly JD, Giordano TP. Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS 2011;25(8):1137; reply 8-9.

Letter in response to Pop-Eleches 2011.

Mukund Bahadur KC, Murray PJ. Cell phone short messaging service (SMS) for HIV/AIDS in South Africa: a literature review. Stud Health Technol Inform 2010;160(Pt 1):530-534.

Narrative review

NICHD. Belzer ME et al. Pilot study using cell phone interactions to improve medication adherence in adolescents who have previously failed antiretroviral therapy due to non- adherence. ClinicalTrials.gov # NCT01049568 (unpublished data).

Voice calls from “adherence facilitator”

in real time.

Puccio JA, Belzer M, Olson J, Martinez M, Salata C, Tucker D, Tanaka D. The use of cell phone reminder calls for assisting HIV-infected adolescents and young

adults to adhere to highly active antiretroviral therapy: a pilot study. AIDS Patient Care STDs 2006;20(6):438-44.

Voice calls from “adherence facilitator”

in real time.

Reynolds NR, Testa MA, Su M, Chesney MA, Neidig JL, Frank I, et al. Telephone support to improve antiretroviral medication adherence: a multisite, randomized controlled trial.

J Acquir Immune Defic Syndr 2008;47(1):62–8.

Voice calls from nurses in real time.

Saberi P, Johnson MO. Technology-based self-care methods of improving antiretroviral adherence: a systematic review.

PLoS One 2011;6(11):e27533.

Systematic review

Simoni JM, Chen WT, Huh D, Fredriksen-Goldsen KI,

Pearson C, Zhao H, Shiu CS, Wang X, Zhang F. A preliminary randomized controlled trial of a nurse-delivered

medication adherence intervention among HIV-positive outpatients initiating antiretroviral therapy in Beijing, China.

AIDS Behav 2011;15(5):919-29.

Simoni JM, Huh D, Frick PA, Pearson CR, Andrasik MP, Dunbar PJ, Hooton TM. Peer support and pager messaging to promote antiretroviral modifying therapy in Seattle: a

randomized controlled trial. J Acquir Immune Defic Syndr.

2009;52(4):465-473.

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Simoni JM, Pantalone DW, Plummer mean difference, Huang B. A randomized controlled trial of a peer support intervention targeting antiretroviral medication adherence and depressive symptomatology in HIV-positive men and women. Health Psychol 2007;26(4):488–95.

Skinner D, Rivette U, Bloomberg C. Evaluation of use of cellphones to aid compliance with drug therapy for HIV patients. AIDS Care 2007;19(5):605–7.

Vervloet M, Linn AJ, van Weert JC, de Bakker DH, Bouvy ML, van Dijk L. The effectiveness of interventions using electronic reminders to improve adherence to chronic medication: a systematic review of the literature. J Am Med Inform Assoc 2012;19(5):696-704.

Systematic review

Wang H, He G, Li X, Yang A, Chen X, Fennie KP, et al. Self- reported adherence to antiretroviral treatment among HIV infected people in central China. AIDS Patient Care STDs 2008;22(1):71–80.

Cross-sectional survey, no comparator.

Wise J, Operario D. Use of electronic reminder devices to improve adherence to antiretroviral therapy: a systematic review. AIDS Patient Care STDs 2008;22(6):495-504.

Systematic review