AIDS PATIENT CARE and STDs CLINICAL AND EPIDEMIOLOGIC RESEARCH

Volume 37, Number 11, 2023

ª Mary Ann Liebert, Inc.
DOI: 10.1089/apc.2023.0170

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Digital Health in Enhancing Antiretroviral Therapy

Adherence: A Systematic Review and Meta-Analysis

Mohd Farizh Che Pa, MSc,1,2 Mohd Makmor-Bakry, PhD,1,3 and Farida Islahudin, PhD1
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Abstract

Adherence to antiretroviral therapy (ART) is essential in determining successful treatment of human immu-
nodeficiency virus (HIV). The adoption of digital health is suggested to improve ART adherence among people
living with HIV (PLHIV). This study aimed to systematically determine the effect of digital health in enhancing
ART adherence among PLHIV from published studies. The systematic search was conducted on Scopus, Web
of Science (WoS), PubMed, Ovid, EBSCOHost, and Google Scholar databases up to June 2022. Studies utilized
any digital health as an intervention for ART adherence enhancement and ART adherence status as study’s
outcome was included. Digital health refers to the use of information and communication technologies to
improve health. Quality assessment and data analysis were carried out using Review Manager (RevMan)
version 5.4. A random-effects model computed the pooled odds ratio between intervention and control groups.
The search produced a total of 1864 articles. Eleven articles were eligible for analysis. Digital health was used
as follows: six studies used short message service or text message alone, three studies used mobile applications,
and two studies used combination method. Four studies showed statistically significant impacts of digital health
on ART adherence, while seven studies reported insignificant results. Results showed studies conducted using
combination approach of digital health produced more promising outcome in ART adherence compared to
single approach. New innovative in combination ways is required to address potential benefits of digital health
in promoting ART adherence among PLHIV.

Keywords: HIV, antiretroviral, adherence, digital technology, digital health

Introduction This strategy sets a target in which 95% of PLHIV know

their status, 95% of diagnosed PLHIV are on antiretroviral

S ince the epidemic began in 1981, a total of 84.2 million

individuals have been infected with human immunode-
ficiency virus (HIV), with *40.1 million deaths reported.1
Recent statistics documented that about 38.4 million people
across the globe are infected with HIV with 1.5 million new
infections diagnosed in 2021.2 In Malaysia, there are 77,903
people living with HIV (PLHIV), with 3564 newly infected
cases in 2019.3 With the increase in the number of PLHIV,
the Joint United Nations Program on HIV and AIDS (UN-
AIDS) has proposed aggressive targets for the global re-
sponse to HIV in 2020 by applying the 95-95-95 strategy.
therapy (ART), and 95% of PLHIV on ART achieve an un-
detectable viral load by 2030.4 To reach the third target,
which specifically refers to PLHIV on ART that achieved
undetectable viral loads, a good adherence to ART is the
main key factor.5
Antiretroviral drugs (ARV) act by interrupting viral rep-
lication processes and are classified based on how they inhibit
the viral cycle. ART is a combination of at least three ARVs,
which is used to prevent HIV replication and hence slow the
disease progression.6 Used as a long-term treatment, the
success of ART is highly dependent on patients establishing

1
Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
2
Department of Pharmacy, Hospital Tuanku Ja’afar, Seremban, Malaysia.
3
Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia.

507
 508
and maintaining high levels of ART adherence.7,8 ART is
currently being advocated not only as a way to delay the onset
of AIDS and improve the health of PLHIV but also as a public
health tool to prevent HIV transmission.9,10 ART effective-
ness demands adherence of at least 95% to achieve viral load
suppression.7,11
Treatment adherence is associated with a multitude of
benefits, including reduced transmission and lower expen-
ditures.12,13 Socioeconomic or environmental factors (such
as income and access to ART medications), demographic
factors (such as age, gender, and ethnic background), social
elements (such as literacy level, use of alcohol/substance, and
stigma), and emotional factors (such as anxiety, stress, ten-
sion, and fear) may also affect patients adherence to ART.14
Nonadherence to HIV therapy may be linked to poor health
and well-being, the development of drug-resistant HIV
strains, treatment failure, a faster progression to AIDS, and
death in PLHIV.15,16
Digital health refers to the use of information and com-
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munication technologies to improve health.17 The im-
plementation of digital health has been classified into
noninternet based [e.g., short message service (SMS) or text
message and phone calls] and internet based (e.g., social
media, e-mail, mobile application and website).18
Most recently, digital health has been used to improve
medication adherence.19 Digital health is known as a cost-
effective way to increase the efficiency of the health care
system, such as improving medication adherence and health
outcomes by utilizing technologies such as computers, in-
ternet, satellite communications, and mobile devices.19
These technologies are also used as appointment reminders,
mobile telehealth and patient monitoring, as well as for
treatment adherence.20 In earlier work, SMS or text message
used as a reminder for 6 months has proven to be successful in
enhancing ART adherence and treatment outcomes among
PLHIV.19
SMS or text message is particularly beneficial because of
its simplicity, low cost, and flexibilty.20 The rate of mobile
phone subscribers in 2013 for developing countries was as
high as 90%,21 which is a key factor supporting the devel-
opment of digital health as a means of improving adherence
outcomes. The success of this particular type of digital
health is further supplemented by declining costs of mobile
devices and internet services. The average price of a
smartphone in the Middle East and Africa has dropped
32.1% between 2013 and 2017 and steadily decreasing.22
Mobile broadband subscriptions have surged by more than
20% globally since 2012, and by more than 30% in devel-
oping countries.22
Previously, two systematic reviews indicate that weekly
text messaging can improve adherence to ART when com-
pared to standard care.23,24 Another review showed the uti-
lization of text message combined with phone calls from
health care providers has demonstrated beneficial impacts on
ART adherence outcomes.25 A later review revealed incon-
clusive findings with wide variation regarding the efficiency
of mobile phone interventions in enhancing adherence to
ART.26 A substantial number of recent articles utilizing
randomized controlled trial (RCT) design, especially on the
mobile applications, justify the demand of an extensive sys-
tematic review to collate and present the overall study de-
signs and findings. Thus, the purpose of this review was to
CHE PA ET AL.
identify and systematically evaluate published research on
the usefulness of digital health in enhancing ART adherence
among PLHIV.
Methods
Search strategy
A systematic review and meta-analysis of published lit-
erature were conducted following the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines for the classification of quality assessment and
data extraction.27 Systematic search of literature was per-
formed from the date of inception until June 30, 2022, on
various databases namely Scopus, Web of Science (WoS),
PubMed, Ovid, EBSCOHost, and Google Scholar.
The screening search was focused on identifying studies
that evaluate the effectiveness of digital health in enhancing
ART adherence among PLHIV. Digital health was included
as any digital technology that was used to enhance medica-
tion adherence, which includes SMS, mobile applications,
e-mail, reminder, and text message. Search keywords were
selected based on Population, Intervention, Comparison, and
Outcome Model. The population was set as PLHIV on ART.
The intervention was any use of digital health. The com-
parison was a formal control group such as standard man-
agement. The outcome was ART adherence measurement as
primary or secondary outcomes.
Medical Subject Heading (MeSH) and terms that were
used to search for relevant publications include ‘‘anti-
retroviral therapy,’’ ‘‘highly active antiretroviral therapy,’’
‘‘human immunodeficiency virus,’’ ‘‘HIV,’’ ‘‘acquired im-
munodeficiency syndrome,’’ ‘‘disruptive technolog*,’’ ‘‘dig-
ital technolog*,’’ ‘‘mobile app*,’’ ‘‘digital app*,’’ ‘‘mobile
healthcare,’’ ‘‘mhealth,’’ ‘‘digital health,’’ ‘‘adherence,’’
‘‘compliance,’’ and ‘‘medication adherence’’ Boolean’s op-
erators such as OR and AND were utilized to narrow the
search. No limitation was applied with regard to the year of
publication during searching. Articles published in English
language were only included. Abstracts and conference pro-
ceedings, editorials, and expert opinion articles were excluded.
Study selection and eligibility criteria
Initial screening was performed, and the title and abstract
of each study were reviewed. Based on the inclusion and
exclusion criteria, the full eligibility of screened abstracts
was assessed. Two reviewers (M.F.C.P. and FI) performed
the screening and all disagreements were resolved by mod-
eration with a third researcher (MMB). Only RCT and ran-
domized factorial trial (RFT)-designed studies that utilized
digital health to enhance ART adherence compared to a
control were included. Studies were included based on the
following criteria:
(1) ART adherence as a primary or secondary outcome.
(2) ART adherence using specific method of adherence
tool.
(3) Reports on adherence level.
(4) Adult patients older than 18 years.
(5) English articles.
The search retrieved 1864 articles. After screening pro-
cess, 24 abstracts were excluded. A full-text review of the
 DIGITAL HEALTH IN ENHANCING ART ADHERENCE 509

remaining 35 potentially eligible articles was conducted.

A total of 11 articles were included in the analysis. The most
common reason for exclusion was labeled under others cat-
egory (n = 12). These include articles that involved patients
younger than 18 years (n = 2), PLHIV with mental illnesses
(n = 2), articles available in abstract only (n = 4), and studies
with viral suppression or viral load level only as an outcome
(n = 4). Other studies were excluded due to qualitative
studies (n = 1), feasibility and acceptability studies (n = 1),
no adherence method was available (n = 3), and non-RCT
studies (n = 7).

Extraction and analysis of the data

Data extraction included study design, aim of study, re-
minder method, population, inclusion and exclusion criteria,
type of adherence measure, type of digital health, duration of
study, and study outcomes. A p values <0.05 was considered
significant.
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A meta-analysis was performed to synthesize the results of

two or more studies that used comparable outcome measures.
The Mantel-Haenszel fixed-effect model was used to gener-
ate odds ratios and 95% confidence intervals for Forest plots.
The chi-square and I2 tests were used to determine hetero-
geneity. Data retrieval using the Web Plot Digitizer version
4.6 web tool28 was utilized for one of the studies, which
describes the results in a graphical form.29 Review Manager
(RevMan) version 5.4 was used to conduct all statistical an-
alyses (The Nordic Cochrane Centre, The Cochrane Colla-
boration, Copenhagen).
Risk of bias assessment
The quality assessment was conducted based on the rec-
ommendation by the Cochrane Handbook of Systematic
Reviews, particularly emphasizing on allocation conceal-
ment, sequence generation, outcome assessment, blinding,
and selective reporting.30 The bias risk for each domain was
rated as low, unclear, or high risk. The total bias risk was
labeled as high if at least one area was at high risk of bias.
Results
A total of 1864 articles were identified. Based on the study
criteria, only 11 articles were included (Fig. 1). Six studies
used SMS or text message alone for reminders, three studies
used mobile applications, and two studies used a combination
method of SMS with phone call or interactive voice response
(IVR; Table 1). Five studies were conducted in the United
States of America31–35 and one each from Malaysia,19 Sin-
gapore,36 China,37 Cameroon,38 India,29 and Uganda.39
Ten studies followed an RCT design (six RCT19,31,32,37–39
and four pilot RCT29,33,34,36) and one study utilized RFT
design.35 The studies were conducted between 2011 and 2018
and published from 2016 to 2020. The total number of par-
ticipants in the included studies was 1785, and the study
sample size varied from 30 to 600 participants per study. The
primary outcomes addressed in the studies included ART
adherence, HIV viral suppression, and usability and feasi-
bility of the technology.
The risk of bias in RCTs was assessed using domains
suggested by the Cochrane Handbook of Systematic Re-
views. All studies reviewed fell under the low-risk category
FIG. 1. PRISMA flow chart of study selection. PRISMA,
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses.
of bias, as shown in Fig. 2. Four studies31,33,37,38 did not
report allocation sequence concealment. One study34 con-
tained a possible contamination bias between control and
intervention participants.
The majority of studies involved male and female par-
ticipants, except for one study that only included MSM
individuals.32 Four studies recruited participants who
have less than 95% adherence at baseline.29,32,34,35 Seven
studies acknowledged recruiting treatment-experienced
patients,29,32–36,38 while another four studies enrolled newly
initiated ART patients.19,31,37,39 Three studies recruited
PLHIV with a history of drug use.32–34
Four studies found that adherence to ART had a statisti-
cally significant and beneficial effect on groups of PLHIV
who were allocated digital health17,29–31 (Table 2). The re-
maining seven studies failed to find a significant difference
between the intervention and control groups.21,23–28
Seven studies were included in the meta-
analysis.19,29,31,32,35,37,38 One study was excluded from meta-
analysis due to non-numerical data reported and data could
not be estimated using a graph digitizer.34 Two studies re-
ported data as percentage of adherence without the exact
number of patients.33,39 Another one study was excluded as
the odds ratio was not estimable as all recruited PLHIV in
both intervention and control group achieved 100% good
adherence at baseline and at the end of the study.36
A meta-analysis was performed on the remaining seven
studies. An odds ratio was used to compare the outcome of
intervention between studies. The odds ratio estimated odds
of poor adherence between control and intervention groups.
The pooled odds ratio was found to be 0.05 ( p = 0.08; Fig. 3)
with statistical heterogeneity (I2 = 82%). Subanalysis was
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Table 1. Details of Included Studies

Difference of
adherence
performance
between group
Authors/publication Study design/reminder Control Intervention (intervention—
year/study site method/intervention Aims Population group (n) group (n) Result control, %)
Haberer et al. RCT, SMS, To explore the effects Rural Uganda, adult, 21 21 (scheduled N/R N/A
(2016)39 (i) scheduled SMS: of SMS plus real- new PLHIV with SMS) and ( p = 0.02)
(Uganda) SMS daily for 1 time adherence social supporters. 20 (triggered
month, weekly. for 2 monitoring on ART SMS)
months, then SMS adherence.
triggered by a
late/missed dose
(within 2 h), SMS to
social supporter if no
signal >48 h.
(ii) triggered SMS:
SMS if no signal
within 2 h from

510
enrolment.
Kalichman RFT contact-matched, To test the independent American, adult PLHIV 149 150 (text UPC 90% adherence B-A = 0% ( p = N/R)
et al. (2016)35 adherence and interactive with <95% adherence (control) message) and score: D-C = -8%
(United States) counselling with text effects of brief self-reported. and 151 150 (contact- A: Control = 43% ( p = N/R)
message, 1 face-to- phone-delivered self- (contact- matched text B:
face counseling on regulation matched message) Intervention = 43%
enrolment, 4 counseling. control) C: Contact-matched
subsequent biweekly To determine the control = 42%
counseling sessions effects of daily D: Contact-matched
through phone, 2 phone-delivered text intervention = 34%
times daily text message on ART
messages on ART adherence.
reminders
Nsagha et al. RCT, SMS, 4 SMS per To assess the African, adult PLHIV 45 45 Adherence score: 20.20
(2016)38 week at equal effectiveness of SMS on ART for at least 1 intervention
(Cameroon) intervals between in improving the month. (64.4%) vs. control
5–7 am and 4–6 pm. ART adherence of (44.2%, p = 0.05).
PLHIV.

(continued)
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Table 1. (Continued)
Difference of
adherence
performance
between group
Authors/publication Study design/reminder Control Intervention (intervention—
year/study site method/intervention Aims Population group (n) group (n) Result control, %)
Abdulrahman RCT, SMS, and To determine the Malaysian, adult, newly 121 121 Adherence score: 8.20
et al. (2017)19 telephone call, effectiveness of started ART, intervention group
(Malaysia) weekly standardized mobile phone completed 4 weeks (92.2%) vs. control
SMS reminder on reminders (SMS and vitamin training. group (54.6%,
Monday with average telephone call p = 0.001).
90-sec telephone call. reminders) and peer
counseling in
improving adherence
and treatment
outcomes among
PLHIV on ART.
Himelhoch et al. Pilot RCT, To determine the African-American, 10 20 N/R N/A
(2017)34 Heart2HAART usability and adult PLHIV with ( p = 0.29).
(United States) android-based mobile feasibility of history of adherence
application, provided Heart2HAART problem and
automated reminders android-based mobile substance users.

511
tailored to ART application among
regimen. PLHIV with history
of substance users.
To evaluate the use of
Heart2HAART
android-based mobile
application as an
adjunct on ART
treatment adherence.
Ruan et al. RCT, interactive SMS, To examine the Chinese, adult PLHIV 50 50 CPCRA adherence 17.00
(2017)37 total of 124 SMS acceptability and started ART not more score: intervention
(China) within 6 modules efficacy of than 3 months. (89.3%) vs. control
were edited, interactive SMS in group (72.3%,
preinstalled, and improving ART p = 0.027).
personalized adherence in PLHIV.
according to PLHIV.
Moore et al. Pilot RCT, text message To evaluate the efficacy Hispanic, non-Hispanic 25 50 N/R N/A
(2018)33 (iTAB), daily of iTAB intervention and Black American,
(United States) personalized, on ART adherence adult PLHIV on ART
bidirectional text among PLHIV who and
messaging system use methamphetamine
iTAB. methamphetamine. abuse or dependence
within 45 days.

(continued)
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Table 1. (Continued)
Difference of
adherence
performance
between group
Authors/publication Study design/reminder Control Intervention (intervention—
year/study site method/intervention Aims Population group (n) group (n) Result control, %)
Horvath et al. RCT, To examine the American, adult MSM 45 45 30-day adherence -3.50
(2019)32 APP+ mobile feasibility and who use stimulants in scores at month-6:
(United States) application, daily acceptability of the the past 6 months, intervention and
reminder from APP+ mobile scored control group
mobile application. application among <excellent (6-point (85.5%) vs.
MSM who use scale) on ART (89.0%, p = 0.39).
stimulants. adherence.
To assess the associated
changes the use of
APP+ mobile
application in self-
reported ART
adherence and
stimulant use.
Pang et al. Pilot RCT, MIST To evaluate the efficacy Singaporean, adult 20 20 Pill count adherence 0
(2020)36 mobile application, of a mobile app, PLHIV on once-daily score: intervention

512
(Singapore) daily reminders sent MIST in improving ART. (100%) vs. control
15 min before the pill adherence to ART (100%, p = 0.84).
time, right on pill among PLHIV.
time, and 30 min
after the pill time.
Sherman et al. RCT, SMS, daily 1-way To determine whether a White, Black, and 49 45 VAS score of >90% -3.70
(2020)31 SMS on ART daily text messaging Hispanic adherence:
(United States) reminders intervention American, adult, new intervention
improves ART PLHIV on ART. (88.6%) vs. control
adherence and (92.3%, p = 0.572)
retention in
treatment.
Swendeman Pilot RCT, IVR call, To measure adherence Indian, adult PLHIV on 179 183 Adherence score: 5.14
et al. (2020)29 and SMS, twice-daily rates and related first- or second-line intervention
(India) IVR call between 9 factors among ART ART, ‡1 missed (84.62%) vs.
am and 9 pm with patients. ART doses in the last control (79.48%,
SMS categorized into To determine daily and 6 month. p-value = N/R,
3 parts: medically weekly IVR calls in stated
related, health improving ART nonsignificant)
promotion, and adherence and
mental health. related outcomes.
AACTG, adult AIDS clinical trial group; ACTG, AIDS clinical trial group; ART, antiretroviral therapy; CPCRA, community programs for clinical research on AIDS; iTAB, individualized texting for
adherence building; IVR, interactive voice response; MEMS, medication event monitoring system; MIST, mobile interactive supervised therapy; MSM, men sex with men; N/A, not available; N/R, not
reported; PLHIV, people living with human immunodeficiency virus; RCT, randomized controlled trial; RFT, randomized factorial trial; SMS, short message service; UPC, unannounced pill count;
VAS, visual analogue scale.
 DIGITAL HEALTH IN ENHANCING ART ADHERENCE 513

higher percentage of other work could be due to the inclusion

of 8 non-RCT studies from a total of 27 studies.
The differences in the PLHIV population between studies
were observed. Three of four studies conducted among new
PLHIV patients who had only been on ART for less than 3
months found that digital health effectively enhanced ART
adherence.19,37,39 Only one of the seven trials enrolling
PLHIV who were already on ART demonstrated a signifi-
cant usage of digital health in improving ART adherence.38
This finding emphasized the crucial function of commenc-
ing intervention earlier before PLHIV developed ART
taking habits.36
Two studies showed no benefit of digital health among the
subpopulation of PLHIV with a history of stimulant used.32,33
These results may suggest that certain components of an in-
dividual’s lifestyle may be more difficult to adjust depending
on their PLHIV background. Digital health may need to be
accompanied with additional components to enhance positive
behavioral changes, such as direct communication with a
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physician other than just reminders from text messages and

FIG. 2. Risk of bias summary of individual study.
carried out to compare the outcome of intervention between
studies that involved single and combination approach of
digital health with statistical heterogeneity, I2 = 50% and
I2 = 86%, respectively (Fig. 3). One study that was conducted
among new PLHIV, who initiated ART, showed improve-
ment in adherence status compared to stable PLHIV.19
Discussion
Along with the industrial revolution, health care technol-
ogy continues to evolve exponentially.40 However, not all
interventions showed positive outcomes on medication ad-
herence. Only 36% (n = 4) of included studies concluded that
digital health significantly enhanced PLHIV adherence to
ART. These data are lower than previously reported at 56%,
specifically in low- and middle-income countries.26 The
mobile applications.22
The efficiency of using mobile applications as reminders is
currently unclear, and more research is needed. Definite
conclusion cannot be drawn as the available studies that used
mobile application as a reminder recruited a small sample
size.32,34,36 In one study, both intervention and control groups
demonstrated 100% adherence to ART at baseline, which left
no possibility for additional improvement.36 Despite this
challenge, the potential use of mobile applications should be
explored as one of the effective ways in enhancing medica-
tion adherence. Quintiles IMS institute for health care in-
formatics reported 23,682 iOS mobile applications
substantially relevant to health were established. In 2015, the
number of iPhone operating system (iOS) mobile applica-
tions related to health surged by more than 100%.22 About
65% of these mobile applications include medication re-
minders and health information.22
The latest innovation in HIV treatment is long-acting ART.
The majority of PLHIV expressed a high level of interest in

Table 2. Summary of Duration of Study and Adherence Measures

Duration
Author/publication year Study year of study Interval of measure Adherence Measure
39
Haberer et al. (2016) 2013–2014 9 Months After 9 months Real-time adherence monitoring
Kalichman et al. (2016)35 2011–2015 12 Months 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, UPC
and 10 months
Nsagha et al. (2016)38 2011 1 Month 0 and 1 month Self-reported
Abdulrahman et al. (2017)19 2014 6 Months 0 and 6 months AACTG adherence questionnaires
Himelhoch et al. (2017)34 N/R 3 Months 0, 6 weeks, and 3 months UPC
Ruan et al. (2017)37 2013–2014 6 Months 0 and 6 months (i) CPCRA
(ii) VAS
Moore et al. (2018)33 2011–2014 6 Weeks After 6 weeks MEMS
Horvath et al. (2019)32 2016–2017 6 Months 0, 2, 4, and 6 months Self-reported
Pang et al. (2020)36 2018 2 Months 0, 1, and 2 months (i) Pill count
(ii) MEMS
(iii) 7-day recall self-report
Sherman et al. (2020)31 2011–2014 6 Months 0, 3, and 6 months VAS
Swendeman et al. (2020)29 2014–2015 6 Months 0, 2, 4, and 6 months (i) Pill count
(ii) ACTG
(iii) ART Card-verified
CD4 cell counts
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FIG. 3. Forest plot result showing ART adherence with digital health intervention. ART, antiretroviral therapy.
long-acting ART, despite its administration through injection
form, and requires monthly visit to hospital. This novel in-
novation is a future improvement to ART regarding adher-
ence challenges, but it may be associated with other issues
among PLHIV.41
This meta-analysis, however, showed no significant dif-
ference in the odds ratio for ART nonadherence between
intervention and control groups. A study conducted among
adolescents living with HIV similarly showed no difference
in ART adherence and clinical outcomes.42 Nevertheless,
subanalysis of digital health in combination approach pro-
duced significant result compared to single approach. Both
studies combined a telephone call or voice message with
SMS or text messages as part of the approach.19,29 According
to a previous meta-analysis and systematic review, a com-
bination of reminder methods was found to be much more
effective than a single reminder method in improving ART
adherence.43,44 Although a combination approach can en-
hance adherence, their efficacy is limited, diminishes over
time, and varies across countries.26
In comparison to the previous work, a Cochrane review
only included two RCTs from Kenya, and concluded text
messages at a weekly interval are effective in enhancing
adherence to ART.23 Another review incorporated three
RCTs and used SMS or text message intervention only.24
Both reviews represented results from Africa and may not be
applicable to other settings. Further, a vast majority of these
reviews only evaluated a single digital health as an inter-
vention, which is SMS or text messages.23,24 A review by
Shah et al., which involved various types of digital health
interventions, including SMS or text messages, voice calls,
mobile applications, and mixed methods, found the effect of
daily SMS or text messages on ART adherence when mea-
sured as standard mean difference.25
The review findings resulted from a meta-analysis on two
studies utilizing similar measure of adherence [Medication
Event Monitoring System (MEMS)]. Due to the various in-
terventions included, the review highlighted the importance
of combination approaches in improving ART adherence.
CHE PA ET AL.
This finding is consistent with the conclusions of Quintana
et al.’s44 and Amankwaa et al.’s45 systematic reviews, which
explored the benefits of multiple approaches. Yet, both re-
views covered a wide range of study designs.44,45 A recent
review found the effect of digital health on ART adherence
was inconclusive and restricted in low- and middle-income
countries.26 This review offers a valuable contribution by
involvement of the new PLHIV and MSM key population in
the included studies. In addition, it encompasses evidence
from both existing reviews and newly published studies that
were not included in earlier systematic reviews.
This systematic evaluation utilized different approaches
compared to previously published works.25,26,44,45 First, ART
adherence was the main focus. Thus, the included studies
should document the type of adherence used and the outcome
of ART adherence assessment. Second, this review may
represent a more comprehensive global perspective ranging
from developed to low-income countries. Third, this review
concentrated only on RCTs that represented high-quality
studies. Finally, this review included studies utilizing the
mobile application as digital health, in addition to SMS or
text messages and IVR-based interventions, which were re-
ported previously.
Although this study has highlighted several important
findings, a few limitations may have influenced the overall
conclusion. These limitations include only English articles
were evaluated, which limit the comparison to other studies
in different languages and populations. In addition, variation
of adherence measures was used such as pill count, visual
analog scale (VAS), MEMS caps, and real-time adherence
monitoring. Moreover, two studies used self-reported data,
which are considered a less sensitive measure of adherence
than MEMS and can lead to overestimation of adherence.
Overall, these available data did not demonstrate any
benefit of digital health as a sole intervention in enhancing
ART adherence among PLHIV. However, combination ap-
proaches showed significant benefits in improving adherence.
New innovative approach in adopting digital health using
combination method is needed to prove its effectiveness. This
 DIGITAL HEALTH IN ENHANCING ART ADHERENCE
review highlighted the lack of studies using mobile applica-
tions and some key populations, such as MSM, substance
abuse, or chemsex. Future studies evaluating the combination
of mobile applications with other technologies are needed to
be explored in larger studies with extended follow-up.
Authors’ Contributions
M.F.C.P.: Writing—original draft (lead); formal analysis
(lead); and writing—review and editing (equal). M.M.B.:
Conceptualization (supporting); methodology (supporting);
and writing—review and editing (equal). F.I.: Con-
ceptualization (lead); methodology (lead); original draft
(supporting); and writing—review and editing (equal).
Author Disclosure Statement
No competing financial interests exist.
Downloaded by 115.164.91.103 from www.liebertpub.com at 12/05/23. For personal use only.
Funding Information
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-profit
sectors.
References
1. World Health Organization (WHO). The Global Health
Observatory. Explore a World of Health. HIV. Available
from: https://www.who.int/data/gho/data/themes/hiv-aids
[Last accessed: March 06, 2022].
2. World Health Organization (WHO). Key Facts HIV 2021.
Available from: https://cdn.who.int/media/docs/default-
source/hq-hiv-hepatitis-and-stis-library/key-facts-hiv-2021-
26july2022.pdf?sfvrsn=8f4e7c93_5 [Last accessed: October
05, 2022].
3. Ministry of Health Malaysia. HIV/STI/Hepatitis C Sec-
tion, Disease Control Division. Global AIDS Monitoring
2020. Available from: https://www.moh.gov.my/moh/
resources/Penerbitan/Laporan/Umum/Laporan_Global_
AIDS_Monitoring_2020_new.pdf [Last accessed: October
17, 2020].
4. Frescura L, Godfrey-Faussett P, Feizzadeh AA, et al.
Achieving the 95 95 95 targets for all: A pathway to ending
AIDS. Ambrose Z. ed. PLoS One 2022;17(8):e0272405;
doi: 10.1371/journal.pone.0272405.
5. Iacob SA, Iacob DG, Jugulete G. Improving the adherence
to antiretroviral therapy, a difficult but essential task for a
successful HIV treatment—Clinical points of view and
practical considerations. Front Pharmacol 2017;8:831; doi:
10.3389/fphar.2017.00831.
6. Aquaro S, Borrajo A, Pellegrino M, et al. Mechanisms
underlying of antiretroviral drugs in different cellular res-
ervoirs with a focus on macrophages. Virulence 2020;
11(1):400–413; doi: 10.1080/21505594.2020.1760443.
7. Paterson DL, Swindells S, Mohr J, et al. Adherence to
protease inhibitor therapy and outcomes in patients with
HIV infection. Ann Intern Med 2000;133(1):21–30; doi: 10
.7326/0003-4819-133-1-200007040-00004.
8. Nachega JB, Hislop M, Dowdy DW, et al. Adherence to
nonnucleoside reverse transcriptase inhibitor-based HIV
therapy and virologic outcomes. Ann Intern Med 2007;
146(8):564–573; doi: 10.7326/0003-4819-146-8-20070
4170-00007.
515
9. Bolsewicz K, Debattista J, Vallely A, et al. Factors asso-
ciated with antiretroviral treatment uptake and adherence:
A review. Perspectives from Australia, Canada, and the
United Kingdom. AIDS Care 2015;27(12):1429–1438; doi:
10.1080/09540121.2015.1114992.
10. Mayer KH, Venkatesh KK. Antiretroviral therapy as HIV
prevention: Status and prospects. Am J Public Health 2010;
100(10):1867–1876; doi: 10.2105/AJPH.2009.184796.
11. Fairley C, Permana A, Read T. Long-term utility of mea-
suring adherence by self-report compared with pharmacy
record in a routine clinic setting. HIV Med 2005;6(5):366–
369; doi: 10.1111/j.1468-1293.2005.00322.x.
12. Gardner EM, Maravi ME, Rietmeijer C, et al. The associ-
ation of adherence to antiretroviral therapy with healthcare
utilization and costs for medical care. Appl Health Econ
Health Policy 2008;6(2–3):145–155; doi: 10.2165/
00148365-200806020-00006.
13. Sax PE, Meyers JL, Mugavero M, et al. Adherence to an-
tiretroviral treatment and correlation with risk of hospital-
ization among commercially insured HIV patients in the
United States. PLoS One 2012;7(2):e31591; doi: 10.1371/
journal.pone.0031591.
14. Abdulrahman SA, Rampal L, Othman N, et al. Socio-
economic predictors of adherence behavior among HIV-
positive patients receiving antiretroviral therapy in Selangor,
Malaysia. Asia Pac J Public Health 2017;29(4):304–314;
doi: 10.1177/1010539517700471.
15. Bangsberg DR. Less than 95% adherence to nonnucleoside
reverse-transcriptase inhibitor therapy can lead to viral
suppression. Clin Infect Dis 2006;43(7):939–941; doi: 10
.1086/507526.
16. Hogg RS, Heath K, Bangsberg D, et al. Intermittent use of
triple-combination therapy is predictive of mortality at
baseline and after 1 year of follow-up. AIDS 2002;16(7):
1051–1058; doi: 10.1097/00002030-200205030-00012.
17. World Health Organization (WHO). Global Strategy on
Digital Health 2020–2025. Geneva: World Health Organi-
zation; 2021. Licence: CC BY-NC-SA 3.0 IGO. Available
from: https://www.who.int/docs/default-source/documents/
gs4dhdaa2a9f352b0445bafbc79ca799dce4d.pdf [Last ac-
cessed: August 22, 2023].
18. Daher J, Vijh R, Linthwaite B, et al. Do digital innovations
for HIV and sexually transmitted infections work? Results
from a systematic review (1996–2017). BMJ Open 2017;7:
e017604; doi: 10.1136/bmjopen-2017-017604.
19. Abdulrahman SA, Rampal L, Ibrahim F, et al. Mobile
phone reminders and peer counseling improve adherence
and treatment outcomes of patients on ART in Malaysia: A
randomized clinical trial. PLoS One 2017;12(5):1–16; doi:
10.1371/journal.pone.0177698.
20. Pérez-Jover V, Sala-González M, Guilabert M, et al. Mo-
bile apps for increasing treatment adherence: Systematic
review. J Med Internet Res 2019;21(6):e12505; doi: 10
.2196/12505.
21. Stephani V, Opoku D, Quentin W. A systematic review of
randomized controlled trials of mHealth interventions
against non-communicable diseases in developing coun-
tries. BMC Public Health 2016;16(1):572; doi: 10.1186/
s12889-016-3226-3.
22. Karageorgos G, Andreadis I, Psychas K, et al. The promise
of mobile technologies for the health care system in the
developing world: A systematic review. IEEE Rev Biomed
Eng 2018;12(c):100–122; doi: 10.1109/RBME.2018
.2868896.
 516
23. Horvath T, Azman H, Kennedy GE, et al. Mobile phone
text messaging for promoting adherence to antiretroviral
therapy in patients with HIV infection. Cochrane Database
Syst Rev 2012;2012(3):CD009756; doi: 10.1002/14651858
.CD009756.
24. Mbuagbaw L, van der Kop ML, Lester RT, et al. Mobile
phone text messages for improving adherence to anti-
retroviral therapy (ART): An individual patient data meta-
analysis of randomised trials. BMJ Open 2013;3:e003950;
doi: 10.1136/bmjopen-2013-003950.
25. Shah R, Watson J, Free C. A systematic review and meta-
analysis in the effectiveness of mobile phone interventions
used to improve adherence to antiretroviral therapy in HIV
infection. BMC Public Health 2019;19(1):915; doi: 10
.1186/s12889-019-6899-6.
26. Demena BA, Artavia-Mora L, Ouedraogo D, et al. A sys-
tematic review of mobile phone interventions (SMS/IVR/
Calls) to improve adherence and retention to antiretroviral
treatment in low-and middle-income countries. AIDS Pa-
tient Care STDs 2020;34(2):59–71; doi: 10.1089/apc.2019
Downloaded by 115.164.91.103 from www.liebertpub.com at 12/05/23. For personal use only.
.0181.
27. Moher D, Liberati A, Tetzlaff J, et al. Preferred Reporting
Items for Systematic Reviews and Meta-Analyses: The
PRISMA statement. Int J Surg 2010;8(5):336–341; doi: 10
.1016/j.ijsu.2010.02.007.
28. Rohatgi A. WebPlotDigitizer—Extract Data from Plots,
Images, and Maps. n.d. Available from: https://automeris
.io/WebPlotDigitizer/citation.html [Last accessed: June
06, 2023].
29. Swendeman D, Fehrenbacher AE, Roy S, et al. A pilot
randomized controlled trial (RCT) of daily versus weekly
interactive voice response calls to support adherence
among antiretroviral treatment patients in India. mHealth
2020;6(May):35; doi: 10.21037/mhealth-19-248a.
30. Higgins JPT, López-López JA, Becker BJ, et al. Synthe-
sising quantitative evidence in systematic reviews of
complex health interventions. BMJ Global Health 2019;
4(Suppl 1):e000858; doi: 10.1136/bmjgh-2018-000858.
31. Sherman EM, Niu J, Elrod S, et al. Effect of mobile text
messages on antiretroviral medication adherence and pa-
tient retention in early HIV care: An open-label, random-
ized, single center study in south Florida. AIDS Res Ther
2020;17(1):1–8; doi: 10.1186/s12981-020-00275-2.
32. Horvath KJ, Lammert S, MacLehose RF, et al. A pilot
study of a mobile app to support HIV antiretroviral therapy
adherence among men who have sex with men who use
stimulants. AIDS Behav 2019;23(11):3184–3198; doi: 10
.1007/s10461-019-02597-3.
33. Moore DJ, Pasipandoya EC, Umlauf A, et al. Individualized
texting for adherence building (iTAB) for methamphetamine
users living with HIV: A Pilot Randomized Clinical Trial.
Drug Alcohol Depend 2018;189(12):154–160; doi: 10.1016/j
.drugalcdep.2018.05.013.
34. Himelhoch S, Kreyenbuhl J, Palmer-Bacon J, et al. Pilot
feasibility study of Heart2HAART: A smartphone appli-
cation to assist with adherence among substance users
living with HIV. AIDS Care 2017;29(7):898–904; doi: 10
.1080/09540121.2016.1259454.
35. Kalichman SC, Kalichman MO, Cherry C, et al. Rando-
mized factorial trial of phone-delivered support counsel-
ing and daily text message reminders for HIV treatment
CHE PA ET AL.
adherence. J Acquir Immune Defic Syndr 2016;73(1):
47–54; doi: 10.1002/9781118702703.ch10.
36. Pang Y, Molton JS, Ooi WT, et al. Preliminary effects of a
mobile interactive supervised therapy intervention on peo-
ple living with HIV: Pilot randomized controlled trial.
JMIR mHealth uHealth 2020;8(3):e15702; doi: 10.2196/
15702.
37. Ruan Y, Xiao X, Chen J, et al. Acceptability and efficacy of
interactive short message service intervention in improving
HIV medication adherence in Chinese antiretroviral
treatment-naı̈ve individuals. Patient Prefer Adher 2017;11:
221–228; doi: 10.2147/PPA.S120003.
38. Nsagha DS, Lange I, Fon PN, et al. A randomized con-
trolled trial on the usefulness of mobile text phone mes-
sages to improve the quality of care of HIV and AIDS
patients in cameroon. Open AIDS J 2016;10:93–103; doi:
10.2174/1874613601610010093.
39. Haberer JE, Musiimenta A, Atukunda EC, et al. Short
message service (SMS) reminders and real-time adherence
monitoring improve antiretroviral therapy adherence in
rural Uganda. AIDS 2016;30(8):1295–1299; doi: 10.1097/
QAD.0000000000001021.
40. Neubeck L, Lowres N, Benjamin EJ, et al. The mobile
revolution-using smartphone apps to prevent cardiovascular
disease. Nat Rev Cardiol 2015;12(6):350–360; doi: 10
.1038/nrcardio.2015.34.
41. Massaroni V, Delle Donne V, Borghetti A, et al. Use of
long-acting therapies for HIV care in Italy: Are people
living with HIV prepared for change? A cross-sectional
study. AIDS Patient Care STDS 2022;36(5):178–185; doi:
10.1089/apc.2022.0030.
42. Mehra N, Tunje A, Hallström IK, et al. Effectiveness of
mobile phone text message reminder interventions to
improve adherence to antiretroviral therapy among ado-
lescents living with HIV: A systematic review and meta-
analysis. PLoS One 2021;16:e0254890; doi: 10.1371/
journal.pone.0254890.
43. Kanters S, Park JJH, Chan K, et al. Interventions to im-
prove adherence to antiretroviral therapy: A systematic
review and network meta-analysis. Lancet HIV 2017;4(1):
e31–e40; doi: 10.1016/S2352-3018(16)30206-5.
44. Quintana Y, Gonzalez Martorell EA, Fahy D, et al. A sys-
tematic review on promoting adherence to antiretroviral
therapy in HIV-infected patients using mobile phone
technology. Appl Clin Inform 2018;9(2):450–466; doi: 10
.1055/s-0038-1660516.
45. Amankwaa I, Boateng D, Quansah DY, et al. Effectiveness
of short message services and voice call interventions for
antiretroviral therapy adherence and other outcomes: A
systematic review and meta-analysis. PLoS One 2018;
13(9):1–20; doi: 10.1371/journal.pone.0204091.
Address correspondence to:
Mohd Makmor-Bakry, PhD
Faculty of Pharmacy
Universiti Kebangsaan Malaysia
Jalan Raja Muda Abdul Aziz
Kuala Lumpur 50300
Malaysia
E-mail: mohdclinpharm@ukm.edu.my