RESEARCH ARTICLE

Discontinuation from Antiretroviral Therapy:

A Continuing Challenge among Adults in HIV
Care in Ethiopia: A Systematic Review and
Meta-Analysis
Hailay Abrha Gesesew1,2*, Paul Ward1, Kifle Woldemichael Hajito2, Garumma
Tolu Feyissa3,4, Leila Mohammadi5, Lillian Mwanri1

a1111111111 1 Public Health, Flinders University, Adelaide, Australia, 2 Epidemiology, Jimma University, Jimma, Ethiopia,
3 Joanna Briggs Institute, Adelaide University, Adelaide, Australia, 4 Department of Health Education and
a1111111111
Behavioral Sciences, Jimma, Ethiopia, 5 Gus Fraenkel Medical Library, Flinders University, Adelaide,
a1111111111 Australia
a1111111111
a1111111111 * hailushepi@gmail.com

Abstract
OPEN ACCESS

Citation: Gesesew HA, Ward P, Hajito KW, Feyissa

Background
GT, Mohammadi L, Mwanri L (2017)
Discontinuation from Antiretroviral Therapy: A Discontinuation of antiretroviral therapy (ART) reduces the immunological benefit of treat-
Continuing Challenge among Adults in HIV Care in ment and increases complications related to human immune-deficiency virus (HIV). How-
Ethiopia: A Systematic Review and Meta-Analysis.
ever, the risk factors for ART discontinuation are poorly understood in developing countries
PLoS ONE 12(1): e0169651. doi:10.1371/journal.
pone.0169651 particularly in Ethiopia. This review aimed to assess the best available evidence regarding
risk factors for ART discontinuation in Ethiopia.
Editor: Matt A Price, International AIDS Vaccine
Initiative, UNITED STATES

Received: June 28, 2016 Methods

Accepted: December 20, 2016 Quantitative studies conducted in Ethiopia between 2002 and 2015 that evaluated factors
associated with ART discontinuation were sought across six major databases. Only English
Published: January 20, 2017
language articles were included. This review considered studies that included the following
Copyright: © 2017 Gesesew et al. This is an open
outcome: ART treatment discontinuation, i.e. ‘lost to follow up’, ‘defaulting’ and ‘stopping
access article distributed under the terms of the
Creative Commons Attribution License, which medication’. Meta- analysis was performed with Mantel Haenszel method using Revman-5
permits unrestricted use, distribution, and software. Summary statistics were expressed as pooled odds ratio with 95% confidence
reproduction in any medium, provided the original intervals at a p-value of <0.05.
author and source are credited.

Data Availability Statement: All relevant data are

Results
within the paper and its Supporting Information
files. Nine (9) studies met the criteria of the search. Five (5) were retrospective studies, 3 were
Funding: The authors received no specific funding case control studies, and 1 was a prospective cohort study. The total sample size in the
for this work. included studies was 62,156. Being rural dweller (OR = 2.1, 95%CI: 1.5–2.7, I2 = 60%),
Competing Interests: The authors have declared being illiterate (OR = 1.5, 95%CI: 1.1–2.1), being not married (OR = 1.4, 95%CI: 1.1–1.8),
that no competing interests exist. being alcohol drinker (OR = 2.9, 95%CI: 1.9–4.4, I2 = 39%), being tobacco smoker (OR =
Abbreviations: ART, antiretroviral therapy; BMI, 2.6, 95%CI: 1.6–4.3, I2 = 74%), having mental illness (OR = 2.7, 95%CI: 1.6–4.6, I2 = 0%)
body mass index; HIV, human immunodeficiency and being bed ridden functional status (OR = 2.3, 95%CI: 1.5–3.4, I2 = 37%) were risk

PLOS ONE | DOI:10.1371/journal.pone.0169651 January 20, 2017 1 / 19

 Meta-Analyses of ART Discontinuation among PLHIV

virus; JBI-MAStARI, Joanna Briggs Institute Meta- factors for ART discontinuation. Whereas, having HIV positive partner (OR = 0.4, 95%CI:
Analysis of Statistics Assessment and Review 0.3–0.6, I2 = 69%) and being co-infected with Tb/HIV (OR = 0.6, 95%CI: 0.4–0.9, I2 = 0%)
Instrument; LTFU, lost to follow up; MAT,
Medication-Assisted Therapies; PLHIV, people
were protective factors.
living with HIV; Tb, tuberculosis.
Conclusion
Demographic, behavioral and clinical factors influenced ART treatment discontinuation.
Hence, we recommend strengthening decentralization of HIV care services in remote
areas, strengthening of ART task shifting, application of seek-test-treat-succeed model, and
integration of smoking cession strategies and mental health care into the routine HIV care
program.

Background
Since its emergence in the 1980s, the human immunodeficiency virus (HIV) has infected peo-
ple of all ages, sexes, races and income status, leading to poor health and socio-economic out-
comes across the world[1]. Since recognition of the acquired immune deficiency syndrome
(AIDS) epidemic, almost 78 million people have been infected and about half of these people
have died[2]. By the end of 2015, globally, 38.8 million (37.6–40.4 million) people were living
with HIV[3].
Africa, Asia and Latin America were the major continents affected by the disease[4]. Sub-
Saharan Africa (SSA) is the home for 76% of the global morbidity and 75% of the global mor-
tality[3]. In 2015, Ethiopia had 39, 140 new HIV infections, 768, 040 people living with HIV,
and 28, 650 HIV/AIDS deaths [3].
The advent of anti-retroviral therapy (ART), known to prolong the life of HIV patients,
was a significant achievement[5]. If the quality of life and survival of people living with HIV
(PLHIV) are to be improved, further effort needs to be made to ensure ART retention and its
positive outcomes[6]. Discontinuation from ART (hereon in referred to as discontinuation) is
the major contributor to attrition, and further to poor quality of life and death [7–13]. Discon-
tinuation is defined as interruptions to ART due to LTFU, defaulting, transferring out and
stopping medication while remaining in care[14]. Discontinuation reduces the immunological
benefit of treatment and increases HIV-related complications, including AIDS-related re-
admission, morbidity, mortality and drug resistance [14–19].
Discontinuation is known to be a significant problem across the globe[20–22], and Ethiopia
is no exception. Studies conducted in Aksum St Marry Hospital[8], Mizan Aman General Hos-
pital[10], Jimma University Specialized Hospital[23] and University of Gondar[24] reported
that the proportion of LTFU was 9.8%, 26.7%, 28% and 31.4%, respectively. Additionally, a ret-
rospective study from Ethiopia reported that retention of patients in care was a major chal-
lenge and varied across health facilities[25].
Primary studies conducted in Ethiopia reported socio-demographic, behavioral, clinical
and institutional factors as contributors to discontinuation[7–10]. However, different studies
showed conflicting association, and the existence of additional factors challenging interven-
tions. Furthermore, the risk factors for discontinuation are still poorly understood in many
developing countries including Ethiopia.
The absence of a clear and uniform definition of discontinuation is also another challenge.
A study from five East African countries revealed the existence of 14 different definitions of
ART defaulting were in use[26]. Currently, the definition of LTFU in Ethiopia is also not

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 Meta-Analyses of ART Discontinuation among PLHIV

uniform, and has included a patient discontinuing from ART for more than one[8], two[9],
three[10,27–29] or twelve[30] months. Additional studies have considered a ‘defaulter’ when a
patient discontinues from ART for more than two months [7,23].
Until a better understanding of these risk factors is gained, attempts to increase retention
rates will be ad hoc and likely to be cost ineffective. As far as is known, there is no published
systematic review and meta-analysis on this topic. Additionally, the lack of high quality data
on the association between discontinuation and its risk factors is a challenge preventing
national HIV/AIDS control programs from providing accurate data to inform tailored inter-
vention strategies. This study examined risk factors for discontinuation from ART among
PLHIV adults in Ethiopia.

Methods and Participants

This review has been reported using PRISMA reporting guidelines for systematic review[31]
(S1 Table).

Study protocol
A protocol for this study has been published elsewhere[32].

Study design
A systematic review and meta-analysis was performed on studies conducted in English lan-
guage in Ethiopia between 2002 and 2015. We selected 2002 as a start date for the search
because this was when ART has been introduced in Ethiopia.

Types of participants
The detail of the study participants has been described in the published protocol[32].

Types of exposures
The review considered studies that examined risk factors for discontinuation including: age,
sex, educational status, place of residence and matrimonial status, disclosure, partner’s HIV
status, mental status, smoking tobacco and drinking alcohol, tuberculosis HIV (Tb/HIV) co-
infection, isoniazid (INH) prophylaxis provision, cotrimoxazole or opportunist infection (OI)
prophylaxis provision, presence of side effects, baseline CD4 counts, baseline WHO clinical
stage, baseline functional status, baseline body mass index (BMI) level, baseline hemoglobin
level and regimen substitution, distance from the facility and facility type.

Types of outcome measures

The review considered studies that included discontinuation. Patients were considered ‘dis-
continued’ when they had been on ART and had missed at least one clinical appointment
(one month) but had not yet been classified as “dead” or “transferred out”, or when they had
stopped treatment due to any reason while they have remained in care.

Search methods for identification of studies

An initial limited search of Google Scholar, MEDLINE, CINAHL and SCOPUS was under-
taken followed by an analysis of the text words contained in the title and abstract, and of the
index terms used to describe the article. A second search using all identified keywords and
index terms was undertaken across the following databases: MEDLINE, PubMed, CINAHL,

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 Meta-Analyses of ART Discontinuation among PLHIV

SCOPUS, ProQuest and Web of Science. Finally, bibliographies of all articles were reviewed to
identify for additional relevant studies. Studies published in English between 2002 and 30
December 2015 were considered for inclusion in this review. The key words for this review
included discontinuation, LTFU, defaulting, retention, attrition, stopping medication, inter-
ruption and Ethiopia. Full search strategy can be found in S1 Table.

Selection of studies and quality appraisal

The types of studies to be included in the review has been described in the published protocol
[32]. The selected papers were assessed by two independent reviewers, HAG and GTF, for
methodological validity prior to inclusion in the review using standardized critical appraisal
instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and
Review Instrument (JBI-MAStARI) (S1 doc, S2 Table). Any disagreements between the
reviewers were resolved through discussion. The appraisal form comprises 9 questions about
the quality of the study for which articles receive values representing the extent to which they
met the following criteria: Yes, No, Unclear and Not applicable. For cohort studies, appraisal
based on "has bias been minimized in relation to selection of cases and of controls" was inter-
preted as "has bias been minimized in relation to selection of exposed and of unexposed
adults living with HIV/AIDS". Risk of bias was also assessed based on Agency for Healthcare
Research and Quality (AHRQ) criteria[33]. Authors of primary studies were contacted to clar-
ify missing or unclear data. Articles were retained if at least one search term for the outcome
concept was found. Articles that did not meet all eligibility criteria were excluded and reasons
were noted (Fig 1).

Data extraction
The data extraction procedure has been described in the published protocol[32]. Authors of
five studies were contacted via e-mail and requested to extract row by column tables: number
of patients being reported discontinuation from ART treatment vs. not, and exposures of
interest.

Data syntheses
The quantitative data were abstracted into an Excel 2007 spreadsheet and included details of
study design, outcome and its measurement, sample size, number of participants with and
without the event by the exposures of interest and summary of the study. Clinical heterogene-
ity was assessed by the authorship team and was acceptable to add each outcome to meta-anal-
ysis. Statistical heterogeneity was assessed statistically using the standard Chi-square and I2
tests, with significant heterogeneity detected at the P value < 0.05. Meta-analyses were con-
ducted separately for discontinuation and each exposure of interest using RevMan-5 Software
[34]. Meta-analysis was considered if I2 was below 85%[35]. Mantel Haenszel statistical
method was used to calculate effect sizes, and forest plots to describe for the meta-analyses of
exposures of interest with the event.
Pooled odds ratio (OR)[36] estimates and their 95% confidence intervals (CI) were calcu-
lated using random or fixed effect meta-analysis based on the degree of heterogeneity[35].
However, when the number of studies that reported the exposure of interest was small (n<5),
only fixed effect model was considered irrespective of the level of heterogeneity[37,38]. Pooling
was considered when at least two studies assessed the outcome and the exposure of interest.
Publication bias was assessed using funnel plot.

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 Meta-Analyses of ART Discontinuation among PLHIV

Fig 1. PRISMA 2009 flow diagram. This figure presents the results of the systematic search and reasons of exclusion.
doi:10.1371/journal.pone.0169651.g001

Results
Description of articles
One thousand two hundred and nineteen (1219) potential studies including from literature
search (1216) and bibliographic review (3) were identified. Fig 1 reports the results of the
search and reasons of exclusion. A total of nine studies were included to assess the association
between discontinuation and at least one of the aforementioned exposures of interest.
Table 1 presents the main characteristics and outcomes of reviewed studies[7–10,23,28–
30,39]. Studies were conducted from across Ethiopia and the majority of them were from the
northern (4) and southern (3) part of the nation. All studies had relatively high sample size

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 Meta-Analyses of ART Discontinuation among PLHIV

Table 1. Characteristics of included articles (n = 9).

Author Year Sample Study design Outcome of Measurement Setting Summary
size (n) interest
Deribe et al. 2008 1094 Case control Defaulting Individuals who had missed two or Jimma, South west Not taking hard drugs (cocaine, cannabis
[23] more clinical appointments (i.e. had not Ethiopia and IV drugs) (AOR = 0.02, 95%CI:
been seen for the last two months) 0.003–0.17), excessive alcohol
consumption (AOR = 6, 95%CI: 3.3–
11.1), being bedridden (AOR = 5.7, 95%
CI: 1.6–20.2), living outside Jimma town
(AOR = 2.2, 95%CI: 1.4–3.5) and having
an HIV negative (AOR = 3.5, 95%CI:
1.1–11.1) or unknown (AOR = 1.7, 95%
CI: 1.02 = 2.9) HIV status partner were
associated with defaulting ART.
Asefa et al. 2013 236 Case control Defaulting Cases were individuals who had Nekemtie, South west Living far from the facility (AOR = 4.1,
[7] missed two or more clinical Ethiopia 95%CI: 1.86–9.42), being dependent for
appointments (i.e. had not been seen source of food (AOR = 13.9, 95%CI:
for the last two months) 4.23–45.99], not being mentally at ease
(AOR = 4.7, 95%CI: 1.65–13.35], having
HIV negative partner (AOR = 5.1, 95%CI:
1.59–16.63), having a partner who hadn’t
been tested for HIV or unknown
(AOR = 2.8, 95%CI: 1.23–6.50] and fear
of stigma (AOR = 8.3, 95%CI: 2.88–
23.83) had statistically significant
association with LTFU compared to their
counterparts.
Wubshet 2013 2461 Retrospective LTFU Adult patients who were three months Gondar, Northwest Reasons for non-deaths losses include:
et al.[39] cohort late for their appointment to pick-up Ethiopia stopping antiretroviral treatment due to
their antiretroviral drugs different reasons, 135(53.36%), and
relocation to another antiretroviral
treatment program by self- transfer, 118
(46.64%).
Berheto 2014 2133 Retrospective LTFU Not taking ART refill for a period of Mizan, Southwest Patients with regimen substitution
et al.[10] cohort three months or longer from the last Ethiopia (HR = 5.2, 95% CI: 3.6–7.3), non-
attendance and not yet classified as isoniazid (INH) prophylaxis (HR = 3.7,
‘dead’ or ‘transferred-out’ 95% CI: 2.3–6.2), adolescent (HR = 2.1,
95% CI: 1.3–3.4), and had a baseline
CD4 count < 200 cells/mm3 (HR = 1.7,
95% CIs: 1.3–2.2) were at higher risk of
LTFU. WHO clinical stage 3 (HR = 0.6,
95% CIs: 0.4–0.9) and 4 (HR = 0.8, 95%
CI: 0.6–1.0) patients at entry were less
likely to be LTFU than clinical stage 1
patients
Tadesse 2014 520 Retrospective LTFU Patients who had missed one or more Axum, Northern The independent predictors of LTFU of
et al.[8] cohort clinical appointments Ethiopia patient were being smear positive
pulmonary Tb (AHR = 2.05, 95% CI:
1.02, 4.12), male gender (AHR = 2.73,
95%CI: 1.31, 5.66), regiment AZT-
3TC-NVP (AHR = 3.47, 95%CI:
1.02,11.83) and weight 60kg
(AHR = 0.24, 95% CI: 0.06,0.96).
Bucciardini 2015 512 Prospective LTFU1, 1
patients who missed scheduled visit to South Tigray, North Active Tb (HR = 1.72, 95% CI: 1.23–
et al.[28] cohort Stopped the same health facility more than three Ethiopia 2.41) and gender (HR = 1.64, 95% CI:
treatmen2 months after the last visit; 2patients 1.10–2.56) were also significantly
known to have discontinued ART for associated with attrition.
any reasons
Dessalegn 2015 727 Case control LTFU Patients who had missed two or more Wukro, Northern Presence of bereavement concern
et al.[9] clinical appointments Ethiopia (AOR = 0.1, 95%CI: 0.01–0.3), not being
provided with isoniazide prophylaxis
(AOR = 3.04, 95%CI: 1.3–7.3), and
presence of side effects (AOR = 12.3,
95%CI: 4.9–31.4) were found to be
associated with increased odds for being
LTFU
Melaku et al. 2015 53,300a Retrospective LTFU If patients were not recorded as dead, Ethiopia Younger age, female gender, never
[30] longitudinal transferred, or initiating ART, and if being married, no formal education, low
they did not have a recorded visit for 12 CD4+ cell count, and advanced WHO
months or more with no subsequent clinical stage were associated with
visit increased LTFU
(Continued)

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 Meta-Analyses of ART Discontinuation among PLHIV

Table 1. (Continued)

Author Year Sample Study design Outcome of Measurement Setting Summary

size (n) interest
Teshome 2015 1173 Retrospective LTFU If he or she failed to visit the health Southern, Nations, The competing-risk regression model
et al.[29] cohort facility for more than 3 months after the Nationalities and showed that body mass index > = 18.5 vs
last appointment date. Peoples Region, <18.5(AHR = 0.6, 95%CI: 0.4–0.9), WHO
South Ethiopia clinical stage late vs early (AHR = 1.4,
95%CI: 1.02–1.9), isoniazid prophylaxis
no vs yes (AHR = 1.9, 95%CI = 1.1–3.2),
age 26–39 vs 15–25 years (AHR = 0.6,
95%CI: 0.4–0.8), facility type health
center vs hospital (AHR = 0.7, 95%CI:
0.5–0.9), and educational status 20+ vs
no (AHR = 0.6, 95%CI: 0.4–0.7) were
independently associated with LTFU.

doi:10.1371/journal.pone.0169651.t001

and the total sample size was 62,156. The studies were analytical in type including: three case
control studies[7,9,23], five retrospective cohort studies[8,10,29,30,39] and one prospective
cohort study[28]. The majority of the studies (n = 7)[8–10,28–30,39] assessed factors associ-
ated with LTFU and the remaining two studies[7,23] assessed defaulting. One study that
assessed LTFU[28] also assessed ‘stopped treatment’.

Methodological quality
Three case-control studies[7,9,23] met seven out of nine JBI critical appraisal criteria, and six
cohort studies[8,10,28–30,39] met eight out of nine JBI critical appraisal criteria. S2 Table pres-
ents outcome of the quality appraisal of each studies.
In addition, summary of risk of bias of the included studies was assessed based on Agency
for Healthcare Research and Quality (AHRQ) criteria (S3 Table). The extent of risk bias was
almost similar, and the studies had ‘low risk’ bias in the majority of areas. Due to inapplicabil-
ity of design nature of the studies, they had ‘unclear risk’ judgment in a few criteria assessing
the bias.

Measurement of discontinuation from ART

Measures of discontinuation were based on LTFU, defaulting or stopping medication. Four
studies[10,28,29,39] considered LTFU when HIV positive patients on ART treatment had
missed three or more monthly clinical appointments and not yet been classified as “dead” or
“transferring out”. One study[8] measured LTFU when adult patients were one month late for
their appointment to pick-up their antiretroviral drugs whereas one other study[9] defined
LTFU when patients had missed two or more clinical appointments. Another study[30]
defined LTFU if they did not have a records of patients’ visit for 12 months or if there were no
more subsequent visit.
The remaining two studies[7,23] measured defaulting, and both considered ‘defaulter’ for
individuals who had missed two or more clinical appointments. One study[28] assessed
‘stopped treatment’ and defined ‘stopped treatment’ when HIV positive patients who have been
on ART treatment but have stopped treatment due to any reason while they remained in care.

Factors associated with discontinuation from ART among adults living

HIV/AIDS
Socio-demographic determinants. The following socio-demographic factors were ana-
lyzed to assess their relationship with discontinuation: age, sex, place of residence, marital

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 Meta-Analyses of ART Discontinuation among PLHIV

status and educational status. All studies assessed the relationship of age with discontinuation.
All studies have measured the association of age and discontinuation, and 3 studies[10,30,39]
found that patient’s age had significant association with discontinuation. Similarly, all studies
have assessed the relationship between sex and discontinuation, and four studies[8,28,30,39]
found a significant association. Two[23,39] of the four studies[7,9,23,39] that assessed the asso-
ciation between place of residence and discontinuation reported a significant association. Out
of the six studies[7–9,23,29,30] that assessed correlation between marital status and discontin-
uation, only Melaku and colleagues [30] reported significant association. Seven studies[7–
9,23,28–30] assessed the association between educational status and discontinuation, and only
Melaku and colleagues [30] found statistical association.
Behavioral determinants. The following behavioral factors were the reported to be
influential to discontinuation: disclosure, partner’s HIV status, mental status, smoking
tobacco and drinking alcohol. Asefa and colleagues [7] and Deribe and colleagues [23] dis-
cussed the association of tobacco use with discontinuation, however their odds were non-sig-
nificant. Both studies also assessed the correlation of alcohol with discontinuation, of which
Deribe and colleagues found a statistical difference. Two [7,23] of the three studies [7,9,23]
that assessed association of partner’s HIV status and discontinuation observed significant
association. Dessalegn and colleagues [9] and Teshome and colleagues [29] studied the asso-
ciation of HIV disclosure status with discontinuation, however both found non-statistical
association.
Clinical determinants. The following clinical factors were reported about their associa-
tion with discontinuation: mental status, Tb/HIV co-infection, INH prophylaxis provision,
cotrimoxazole or OI prophylaxis provision, presence of side effects, baseline CD4 counts, base-
line WHO clinical stage, baseline functional status, baseline BMI level, baseline hemoglobin
level and regimen substitution. Asefa and colleagues [7] and Deribe and colleagues [23]
reported that having mental health problem was a risk factor for defaulting, and both reported
statistically significant association. Among the three studies[7,9,29] that assessed the associa-
tion between ART side effects and discontinuation, Dessalegn and colleagues[9] informed sta-
tistical significance. Seven studies[7–10,23,29,39] measured the correlation between baseline
functional status and discontinuation, and only Berheto and colleagues [10] and Deribe and
colleagues [23] reported the statistical significance.
Of the seven studies[7,8,10,23,28,29,39] that assessed the association between Tb status or
being on Tb treatment and discontinuation, three[8,28,39] studies reported statistical differ-
ence. None of the four studies[7,8,10,23] that assessed the relationship between OI treatment
or cotrimoxazole prophylaxis and discontinuation reported statistical significance. All studies
assessed the correlation between baseline CD4 counts and discontinuation, and two studies
[10,30] found statistical significance. WHO clinical stage as a factor for discontinuation was
also assessed by six studies[9,10,28–30,39], and three of them[10,29,40] reported a statistical
significance. All three studies[9,10,40] that assessed the relationship between INH prophylaxis
and discontinuation reported statistical significance. Berheto and colleagues [10] and Dessa-
legn and colleagues [9] assessed the association between ART regimen substitution and dis-
continuation, but only Berheto and colleagues[10] reported significant association between
these variables.
Institutional determinants. Distance to the health care facility[7,9] and the facility type
[28,29] were the reported institutional factors influencing discontinuation. Asefa and col-
leagues[7] reported the presence of significant association between distance and discontinua-
tion, and Bucciardini and colleagues [28] and Teshome and colleagues [29] reported the
presence of significant association between the facility type and discontinuation.

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 Meta-Analyses of ART Discontinuation among PLHIV

Fig 2. Forest plot of meta-analytic association between age and discontinuation from ART. It shows that the risk of
ART discontinuation is not different by age.
doi:10.1371/journal.pone.0169651.g002

Meta analysis of factors affecting ART discontinuation

This meta-analysis identified determinants of discontinuation among adults living with HIV
using proportions of the factors for the response variable assessed in primary studies[7–
10,23,28–30,39]. Random effects meta-analysis model was considered for studies having mod-
erate heterogeneity level when combined, whereas, fixed effect model was used for studies hav-
ing low or no heterogeneity level[35]. However, when the number of studies reporting the
exposure of interest was small (n<5), only fixed effect model was considered irrespective of
the level of heterogeneity[37,38]. ART side effect was excluded from the meta-analysis because
studies[7,23] reporting this variable showed severe heterogeneity (I2 = 90%). The Mantel
Haenszel statistical method was used to calculate effect sizes and forest plots for the meta-
analyses of socio-demographic, behavioral, clinical and institutional factors are shown in Figs
2–13.
Of the socio-demographic variables, rural dwellings (Fig 4; OR = 2.1, 95%CI: 1.5–2.7, I2 =
60%), no literacy status (Fig 5; OR = 1.5, 95%CI: 1.1–2.1) and being not married (Fig 6;
OR = 1.4, 95%CI: 1.1–1.8) had higher odds of discontinuation than their comparator. Among
the behavioral factors influencing for discontinuation, partners’ HIV positive status was found
a protective factor (Fig 7; OR = 0.4, 95%CI: 0.3–0.6, I2 = 69%) where as alcohol drinking (Fig
8; OR = 2.9, 95%CI: 1.9–4.4, I2 = 39%) and tobacco smoking (Fig 9; OR = 2.6, 95%CI: 1.6–4.3,
I2 = 74%) were found risk factors. Of the clinical factors, Tb/HIV co-infection was associated
with lower odds of discontinuation (Fig 10; OR = 0.6, 95%CI: 0.4–0.9, I2 = 0%). Where as,

Fig 3. Forest plot of meta-analytic association between sex and discontinuation from ART. It shows that the risk of
ART discontinuation is not different by sex.
doi:10.1371/journal.pone.0169651.g003

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 Meta-Analyses of ART Discontinuation among PLHIV

Fig 4. Forest plot of meta-analytic association between residence and discontinuation from ART. It shows that the risk of
ART discontinuation is higher for rural than urban.
doi:10.1371/journal.pone.0169651.g004

Fig 5. Forest plot of meta-analytic association between level of education and discontinuation from ART. It shows that the
risk of ART discontinuation is higher for patients with no literacy status than literates.
doi:10.1371/journal.pone.0169651.g005

having bedridden functional status (Fig 11; OR = 2.3, 95%CI: 1.5–3.4, I2 = 37%) and having
mental illness (Fig 12; OR = 2.7, 95%CI: 1.6–4.6, I2 = 0%) were another risk factors. As shown
in Fig 10, the article by Tadesse and colleagues [8] was removed from the meta-analysis calcu-
lation to prevent the introduction of significant heterogeneity.

Fig 6. Forest plot of meta-analytic association between marital status and discontinuation from ART. It shows that the risk
of ART discontinuation is higher for not-married than married.
doi:10.1371/journal.pone.0169651.g006

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 Meta-Analyses of ART Discontinuation among PLHIV

Fig 7. Forest plot of meta-analytic association between partners’ HIV status and discontinuation from ART. It shows that
the risk of ART discontinuation is lower for patients with HIV positive partner than HIV negative/unknown partner.
doi:10.1371/journal.pone.0169651.g007

Fig 8. Forest plot of meta-analytic association between alcohol drinking and discontinuation from ART. It shows that the
risk of ART discontinuation is higher for alcohol drinkers than non-drinkers.
doi:10.1371/journal.pone.0169651.g008

Fig 9. Forest plot of meta-analytic association between tobacco smoking and discontinuation from ART. It shows that the
risk of ART discontinuation is higher for cigarette smokers than non-smokers.
doi:10.1371/journal.pone.0169651.g009

Fig 10. Forest plot of meta-analytic association between Tb/HIV co-infection and discontinuation from ART. It shows that
the risk of ART discontinuation is lower for Tb/HIV co-infected patients than HIV alone.
doi:10.1371/journal.pone.0169651.g010

PLOS ONE | DOI:10.1371/journal.pone.0169651 January 20, 2017 11 / 19

 Meta-Analyses of ART Discontinuation among PLHIV

Fig 11. Forest plot of meta-analytic association between baseline functional status and discontinuation from ART. It
shows that the risk of ART discontinuation is higher for patients with bedridden than working functional status.
doi:10.1371/journal.pone.0169651.g011

Fig 12. Forest plot of meta-analytic association between mental status and discontinuation from ART. It shows that the risk of
ART discontinuation is higher for patients with mental status than their comparator.
doi:10.1371/journal.pone.0169651.g012

Fig 13. Forest plot of meta-analytic association between cotrimoxazole or opportunistic infections prophylaxis and
discontinuation from ART. It shows that the risk of ART discontinuation is not different by the status of cotrimoxazole or
opportunistic infections prophylaxis.
doi:10.1371/journal.pone.0169651.g013

Discussion
Studies examining retention in HIV care in Ethiopia have identified discontinuation as a key
challenge for patient retention[11–13]. Studies in the current systematic review and meta-anal-
ysis[7–10,23,28–30,39] have identified a number of determinants. In Ethiopia, even though a
large number of HIV-infected patients discontinue after engagement with ART treatment,

PLOS ONE | DOI:10.1371/journal.pone.0169651 January 20, 2017 12 / 19

 Meta-Analyses of ART Discontinuation among PLHIV

little research has been published as demonstrated by the low number of articles (nine studies)
over a 13-year period included in this meta-analysis. This systematic review and meta-analysis
identified studies conducted in three regional states of Ethiopia. The current study identified
that being a rural dweller, being illiterate, being not married, being alcohol drinker, being
tobacco smoker, having mental illness and being bed ridden functional status were risk factors
for ART discontinuation, whereas, having HIV positive partner and being co-infected with
Tb/HIV were protective factors for ART discontinuation.
The setting where the participant lived had significant influence to discontinuation with
rural dwellers being more likely to discontinue compared to their urban counter parts. This
finding was not a surprise as could be attributed to factors such as accessibility of the health
care and availability of the transportation services[41,42]. It is therefore, plausible to hypothe-
sise that strengthening decentralization and service integration of HIV care in remote areas
would be a key for patient retention[43]. This hypothesis is also currently supported by WHO
recommendations[44] of task shifting. The ART task shifting has commonly been practiced
with tasks being shifted from doctors to health officers or nurses. This act has been observed to
reduce patient attrition and also stated to be viable approach in rural areas. In additional to
WHO recommendation, the task shifting was corroborated by a nationwide study in Ethiopia
confirming that ART provision in health centers, based on health officers and nurses, is feasi-
ble, effective and acceptable[45]. Community engagement in HIV care continuum can also
address the gap in inequity, particularly in rural-urban arena[46]. It is for this reason that a
new model called seek-test-treat-succeed model—a model that aims at seeking out of HIV-
infected individuals, offering them HIV testing and treatment, and providing support to
retain—for HIV care has been promoted[47]. In addition, addressing long-term physical barri-
ers such as roads and transportation facilities could also improve ART treatment retention
[48–50].
The risk of discontinuation among patients with low literacy status was about two times
higher when compared to the risk among literates. Several studies have suggested that improv-
ing knowledge of HIV care as an intervention could influence the retention of HIV positive
people[51,52]. Furthermore, according to the seek-test-treat-succeed model, literate HIV
infected people[53] have the capacity to provide almost 40% of HIV service-related tasks[54]
and could lead to retention and re-engagement into care[47].
The risk of discontinuation among bedridden patients was two times higher when com-
pared to the risk among working or ambulatory status. This poor baseline functional status
might be due to late presentation for HIV care, a big challenge in the HIV care continuum
[55]. Tobacco smokers also had high risk of discontinuation. Smoking has been noted to
have a number of toxic effects that induce inflammation and weakening of the immunity,
leading to failure to thrive and hindering patients from taking HIV care services continu-
ously[56]. In addition, smokers are more likely to expose to risky sexual behaviors and this
might facilitate to poor HIV/AIDS prognosis and subsequently deter from seeking HIV care
services[57]. Thus, interventions for smoking cession such as Medication-Assisted Thera-
pies (MAT) with behavioral counseling[58] and group behavior therapy programs[59]
among HIV infected population should be instituted and be integrated with comprehensive
HIV care.
Patients with mental illness had high probability of discontinuation than their comparator.
It is well recognised that HIV and mental illness cause a serious bidirectional and synergistic
combination of illness in which HIV escalates lifetime prevalence of mental illness, and mental
illness increases the risk of HIV infection [60]. In addition, stigma and discriminating among
HIV positive people with mental health issues can deter them from HIV care seeking[60]. This
indicates the need for the inclusion of mental health into routine HIV care program.

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 Meta-Analyses of ART Discontinuation among PLHIV

The meta-analysis association suggests that having unknown or negative HIV partner was
associated with higher odds of discontinuation than having HIV positive partner. The plausi-
ble justification might be due to negligence of counseling related to partner by health profes-
sionals[61]. It is therefore necessary to trace LTFU patients and design strict counseling for
them and their partners. Additionally, it is necessary to invite patients with their partners
because partners play key role in supporting patients in their HIV care continuum. Tb/HIV
co-infection was associated with lower odds of discontinuation, a finding supported by a
previous systematic review from sub-Saharan Africa[61]. It is plausible to hypothesize that if
patients have Tb/HIV co-infection, they may attend and continue the care due to the fear of
sequel of both diseases and this might have influence in retaining HIV patients in HIV care.
However, further exploration is needed to examine the role of Tb/HIV co-infection in HIV
care retention when compared to patients with HIV alone.
The current evidence on determinants of discontinuation has several important gaps. Mea-
sures for LTFU and defaulting were disparate to be analyzed systematically. This limitation is
suggestive of weaknesses in definition of discontinuation which continues to lack a ‘gold stan-
dard’ measurement method[62]. All the studies were conducted in the three major regional
states of Ethiopia named Tigray, Amhara and Oromiya in which HIV prevalence was below
2% compared to other regions such as Gambella with higher prevalence of 6.5%[63]. It is possi-
ble that regions with higher prevalence could have dissimilar risk factors for discontinuation
and as such urgent attention would be warranted to establish these.
Another gap relates to the outcome status of discontinuation. Only Wubshet and colleague
[39] reported the number of patients who died, survived and returned to HIV care after LTFU.
Previous research reported that only 14% and 60% of LTFU patients re-engaged to HIV care at
three and six months respectively[64], and those patients who re-engaged accessed the care
after their health had deteriorated[65]. This shows a significant oversight for the need of future
research involving the role and benefits of establishing the community-tracking system[66].
Finally, the majority of articles were retrospective cohort studies. For this reason, potential
risk factors of discontinuation such as HIV related stigma were not assessed. Thus, primary
studies, which may include qualitative study designs, are encouraged to explore the factors of
discontinuation.
Findings of the current systematic review and meta-analysis highlight an imperative need
to continue planning, implementing and evaluating intervention modalities aimed at improv-
ing retention in HIV care. To date, interventions such as reminding patients with mobile
phones, text messaging and diary cards, and arranging treatment supporters have targeted the
improvement of ART adherence[67,68]. Strengthening and adapting these interventions for
improving patient retention could also be very effective.
Interpretations of the current study findings should consider the following important limi-
tations. As stated, only one of the included studies in this review was prospective. This implies
that meta-analytic findings can be viewed as an association and may not be causally related.
The search strategy was limited to English language- a common example of reporting bias[69].
A funnel plot to detect publication bias in studies included in the meta-analysis was not
reported due to the limited number of studies per each exposure (n<10)[69]. Geographic
skewness and inclusion of few studies could influence the generalizability of the findings.
Transferred out cases were excluded. However, we acknowledged that patients who were
transferred out could continue the care in another institution resulting in overestimate of the
proportion of discontinuation.
Some of the studies did not explicitly report absolute numbers of patients who discontinued
by exposures of interest. Efforts to contact authors of the corresponding studies were fruitless
and hence, we have been unable to report findings of meta-analytic association of the following

PLOS ONE | DOI:10.1371/journal.pone.0169651 January 20, 2017 14 / 19

 Meta-Analyses of ART Discontinuation among PLHIV

variables: WHO clinical stage of HIV, CD4 level, regimen substitution, hemoglobin level, INH
prophylaxis and facility type. We focused the systematic review on HIV positive adults, but
such analysis should be followed by another work to assess risk factors for discontinuation
among children. Regimen wise, studies included in the current meta-analysis were about dis-
continuation from first line ART treatments and this may limit the transferability of the find-
ings to second line ART drugs.

Conclusion
Our review identified several risk factors for ART discontinuation. Therefore, addressing the
above determinants using multiple retention strategies is crucial to reduce attrition rate due to
discontinuation. In addition, the retention strategies should involve multi-levels i.e. at individ-
ual-, system- and structural-level barriers.

Supporting Information
S1 doc. JBI Critical Appraisal instruments. It shows the critical appraisal checklist for each
study designs.
(DOCX)
S2 doc. JBI Data extraction instruments. It shows the data extraction checklist for each study
designs.
(DOCX)
S1 Table. Full searching strategy by databases. It shows the detailed searching strategy across
data bases.
(DOCX)
S2 Table. Assessment of methodological quality (n = 9). It shows the result of the methodo-
logical quality assessment.
(DOCX)
S3 Table. Risk of Bias Assessment within the studies (n = 9). It shows the result of the risk
bias assessment.
(DOCX)

Acknowledgments
We acknowledge the authors of included studies for partaking their data for the meta-analysis.
We are grateful to Dr. Pamela Lyon, Visiting Research Fellow in Southgate Institute for Health,
Society and Equity at Flinders University for editing draft of the manuscript. This systematic
review was conducted for the partial fulfillment of a PhD in Public Health at Faculty of Medi-
cine, Nursing and Health Sciences, Flinders University. The authors did not receive any spe-
cific grant for this research.

Author Contributions
Conceptualization: HAG PW KWH GTF L. Mohammadi L. Mwanri.
Data curation: HAG PW KWH GTF L. Mohammadi L. Mwanri.
Formal analysis: HAG.
Methodology: HAG PW KWH GTF L. Mohammadi L. Mwanri.

PLOS ONE | DOI:10.1371/journal.pone.0169651 January 20, 2017 15 / 19

 Meta-Analyses of ART Discontinuation among PLHIV

Project administration: HAG.

Validation: HAG PW KWH GTF L. Mohammadi L. Mwanri.
Visualization: HAG PW KWH GTF L. Mohammadi L. Mwanri.
Writing – original draft: HAG.
Writing – review & editing: HAG PW KWH GTF L. Mohammadi L. Mwanri.

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