RESEARCH ARTICLE
Reasons for Missing Antiretroviral Therapy:
Results from a Multi-Country Study in
Tanzania, Uganda, and Zambia
Olivier Koole1,2*, Julie A Denison3,4, Joris Menten2, Sharon Tsui3,4, FredWabwire-
Mangen5, Gideon Kwesigabo6, Modest Mulenga7, Andrew Auld8, Simon Agolory8, Ya
Diul Mukadi3, Eric van Praag3, Kwasi Torpey3, Seymour Williams8, Jonathan Kaplan8,
Aaron Zee8, David R Bangsberg9,10, Robert Colebunders2,11
1 London School of Hygiene and Tropical Medicine, Department of Clinical Research, London, United
Kingdom, 2 Institute of Tropical Medicine, Clinical Sciences Department, Antwerp, Belgium, 3 FHI 360,
Social and Behavioral Health Sciences, Durham, North Carolina, United States of America, 4 Johns Hopkins
Bloomberg School of Public Health, Department of International Health, Baltimore, Maryland, United States
of America, 5 Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala,
Uganda, 6 Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania,
7 Tropical Diseases Research Centre, Ndola, Zambia, 8 Division of Global HIV/AIDS, Centers for Disease
Control and Prevention, Atlanta, Georgia, United States of America, 9 Massachusetts General Hospital,
Boston, Massachusetts, United States of America, 10 Harvard Medical School, Boston, Massachusetts,
OPEN ACCESS United States of America, 11 Epidemiology and Social Medicine, University of Antwerp, Antwerp, Belgium
Citation: Koole O, Denison JA, Menten J, Tsui S, * olivier.koole@lshtm.ac.uk
Wabwire-Mangen F, Kwesigabo G, et al. (2016)
Reasons for Missing Antiretroviral Therapy: Results
from a Multi-Country Study in Tanzania, Uganda, and
Zambia. PLoS ONE 11(1): e0147309. doi:10.1371/ Abstract
journal.pone.0147309
Editor: Giuseppe Vittorio De Socio, Azienda
ospedaliero-universitaria di Perugia, ITALY Objectives
Received: August 3, 2015 To identify the reasons patients miss taking their antiretroviral therapy (ART) and the pro-
Accepted: December 31, 2015 portion who miss their ART because of symptoms; and to explore the association between
symptoms and incomplete adherence.
Published: January 20, 2016
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced, distributed, Methods
transmitted, modified, built upon, or otherwise used Secondary analysis of data collected during a cross-sectional study that examined ART
by anyone for any lawful purpose. The work is made
adherence among adults from 18 purposefully selected sites in Tanzania, Uganda, and
available under the Creative Commons CC0 public
domain dedication. Zambia. We interviewed 250 systematically selected patients per facility (
18 years) on
Data Availability Statement: reasons for missing ART and symptoms they had experienced (using the HIV SymptomThe authors confirm
that, for approved reasons, some access restrictions Index). We abstracted clinical data from the patients’medical, pharmacy, and laboratory
apply to the data underlying the findings. Although the records. Incomplete adherence was defined as having missed ART for at least 48 consecu-
patient-level data do not include patient names, this tive hours during the past 3 months.
IRB decision is in the interest of ensuring patient
confidentiality. An individual may email the lead
author (olivier.koole@lshtm.ac.uk) or the CDC Results
division of Global HIV/AIDS science office
(gapmts@cdc.gov) to request the data. Twenty-nine percent of participants reported at least one reason for having ever missed
ART (1278/4425). The most frequent reason was simply forgetting (681/1278 or 53%), fol-
Funding: This research has been supported by the
President’s Emergency Plan for AIDS Relief lowed by ART-related hunger or not having enough food (30%), and symptoms (12%). The
(PEPFAR) through the Centers for Disease Control median number of symptoms reported by participants was 4 (IQR: 2–7). Every additional
PLOS ONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 1 / 15
Reasons for Missing Antiretroviral Therapy
and Prevention (CDC) and the Health Resources& symptom increased the odds of incomplete adherence by 12% (OR: 1.1, 95% CI: 1.1–1.2).
Services Administration (HRSA) under the terms of Female participants and participants initiated on a regimen containing stavudine were more
the contract no. 2006-N-08428 with FHI 360. The
CDC provided technical input into the study design, likely to report greater numbers of symptoms.
data collection, data analysis, data interpretation, and
writing of the manuscript. Conclusions
Competing Interests: The authors have declared Symptoms were a common reason for missing ART, together with simply forgetting and
that no competing interests exist. food insecurity. A combination of ART regimens with fewer side effects, use of mobile
phone text message reminders, and integration of food supplementation and livelihood pro-
grammes into HIV programmes, have the potential to decrease missed ART and hence to
improve adherence and the outcomes of ART programmes.
Introduction
At the end of 2013 two-thirds of the estimated 35 million people globally living with HIV lived
in sub-Saharan Africa.[1] The number of people receiving antiretroviral treatment (ART)
reached about 13 million. Sub-Saharan Africa achieved the greatest increase in ART coverage
by reaching 9 million people, corresponding to about 37% coverage among people living with
HIV in that region.[1,2] The goal of ART is to achieve and sustain viral suppression to achieve
the full clinical and prevention benefits of HIV treatment.[3,4] A systematic review of studies
from low-and middle income countries reported a pooled estimate of viral suppression (<1000
copies/ml) of 78% (95% confidence interval (95% CI):68%-86%) at 12 months after ART initia-
tion.[5]
Achieving viral suppression requires consistent adherence to ART.[6] Factors identified in
the literature as affecting ART adherence include patient characteristics (socio-demographic
and psychosocial factors), patient/provider aspects (patient-provider interactions, trust, and
confidentiality), health-system related factors (waiting time at the clinic, transport), disease
characteristics (HIV-related symptoms), and therapy-related factors (number of pills, medica-
tion side effects).[7,8]
In order to develop effective adherence interventions, it is important to identify the com-
mon reasons people report for not taking their ART. We used data collected during a cross-sec-
tional study conducted in 2011 that examined adherence to ART among adults in three
countries in sub-Saharan Africa: Tanzania, Uganda, and Zambia.[9] In the primary paper we
examined individual and programmatic factors associated with incomplete adherence. We
found that 3% of participants missed two or more consecutive days of their ART in the past
three months, and that having greater versus less self-reported HIV-related symptoms (a
dichotomized variable based on the country-specific median number of symptoms) was signifi-
cantly associated with incomplete adherence. In this secondary analysis we focused on self-
reported reasons for ever missing ART and investigated the role of symptoms in missing ART.
We also explored the association between having experienced specific symptoms and incom-
plete adherence.
Methods
Design and study setting
FromMay to October 2011, a cross-sectional study was conducted among ART patients from
18 purposively selected study sites in Tanzania, Uganda, and Zambia. Site selection has been
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 2 / 15
Reasons for Missing Antiretroviral Therapy
described in an earlier publication [10] and included clinics from different levels in the health
system (ranging from rural health centres to referral hospitals), from different types of health
facilities (public sector, non-governmental organizations (NGOs), or faith-based organiza-
tions), and with different ART provision experiences and adherence strategies.
Inclusion criteria
Patients attending the study sites who were at least 18 years of age at ART initiation, who initi-
ated ART at least six months prior to the interview, and who spoke one of the study languages
were eligible for inclusion.
Data collection and sampling
Based on clinic client flow, participants were selected using a systematic sampling approach
with every fifth patient selected at the larger facilities and every third patient at the smaller clin-
ics. After selection, potential participants were screened for eligibility by trained research inter-
viewers, and, if they consented, interviewed until we obtained a sample of 250 eligible patients
from each facility (4500 patients in total).
Measures
The survey was designed in English and then translated into 10 languages (Swahili for Tanza-
nia; Acholi, Luganda, Lumasaaba, Lunyankore for Uganda; and Bemba, Chewa, Lozi, Nyanja
and Tonga for Zambia) and pretested during the training of the fieldworkers and piloting of
the study-instruments.
The survey contained several measures on self-reported adherence, and questions on psy-
chosocial factors including stigma (Internalized Stigma Scale [11]), depression (Hopkins
Symptoms Checklist [12]), social support (Duke University Functional Social Support ques-
tionnaire [13]), and alcohol abuse (CAGE [14]).
The survey also included a list of 16 reasons for ever missing ART (based on the AACTG
questionnaire) [15] and on symptoms experienced in the four weeks prior to the interview.
Symptoms were collected using a modified HIV Symptom Index that has 20 items scored on a
five point Likert scale.[16] During translation and pre-testing the team modified the responses
from a five point to a four point Likert scale, with 0 representing the absence of that symptom
and 3 indicating that the patient did have the symptom and it bothered them “a lot” resulting
in an index that ranges from 0 to 60. The participant was also asked if they attributed the symp-
tom to their ART.
Based on previous evidence of the importance of treatment interruptions as a predictor of
viral load failure and resistance [17,18], and because missing ART for at least 48 consecutive
hours was the strongest measure related to virological failure during our primary analysis, we
constructed a missed at least 48 consecutive hours measure from two questions about missed
tablets in the past 3 months to define incomplete adherence.[9]
Data regarding ART initiation (ART start dates and regimens, and pre-ART characteristics)
were abstracted from the patient’s medical, pharmacy, and laboratory records using structured
data abstraction forms.
Data management and analysis
All data were double entered in a study database using EpiData Entry 3.1 (EpiData Association,
Odense, Denmark) at the in-country research organizations, and then transferred to the central
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 3 / 15
Reasons for Missing Antiretroviral Therapy
data office at Family Health International 360 (FHI 360) for further cleaning and consistency
checks.
For data analysis, the proportions of reasons for ever missing one’s ART and experiences of
symptoms in the past four weeks are reported. Because of the dependency on self-reported
symptoms, we investigated the relationship between symptoms and incomplete adherence in
the past three months as a purely explorative objective, and therefore limited this analysis to
univariate analysis only. We also explored the association between specific antiretroviral drugs
(nevirapine versus efavirenz, and stavudine versus zidovudine) and symptom burden
(expressed as the HIV Symptom Index score) using multiple linear regression, with backwards
stepwise elimination, including site as a fixed effect. Variables associated with symptom burden
with a p-value<0.10 were considered for multivariable analysis, and variables with a p-value
<0.05 in the multivariable analysis were considered significant.
Ethics statement
The study was reviewed and approved by the institutional review board (IRB) of the U.S. Cen-
ters for Disease Control and Prevention (CDC) and the six partner and national ethical review
committees. The Partners Healthcare IRB ceded review to FHI 360.
Results
A total of 6825 patients were screened for eligibility at the participating sites. Of these 1848
patients were ineligible, and 482 did not provide informed consent. An additional 70 patients
with no data on missed ART for at least 48 consecutive hours were excluded, leaving 4425
patients for the final analysis.
Characteristics of study population
Characteristics at the time of the interview and at ART initiation, stratified by country, are pre-
sented in Table 1. Participants were predominantly female (68%) and had started ART between
2002 and 2011. At ART initiation the median age was 40 years (inter quartile range (IQR):
34–47 years) and the median CD4 cell count was 145 cells/μl (IQR: 75–217). At the time of the
interview, the median time on ART was 4 years (IQR: 2–5 years) and about 45% of participants
had changed their ART regimen since initiation. Twenty-three percent changed from an initial
stavudine (d4T) containing regimen, 13% from an initial nevirapine (NVP) containing regi-
men and 7% from an initial efavirenz (EFV) containing regimen. One-third of patients (32%)
were receiving AZT/3TC/NVP, 17% AZT/3TC/EFV, and 16% d4T/3TC/NVP or TDF/
3TC-FTC/EFV at the time of data collection. About 3% of patients were receiving a second-
line regimen that contained a protease inhibitor.
Incomplete adherence (defined as missed ART for at least 48
consecutive hours during the past 3 months)
About 3% (141/4425) of our study participants had missed taking their ART for at least 48 con-
secutive hours during the past 3 months.
Reasons for ever missing one’s ART
Among all ART patients, 29% of participants reported at least one reason for having ever
missed ART (1278/4425), with only 0.2% (9/4425) missing responses to these questions. About
half of patients who reported ever missing ART (53% or 681/1278) reported they simply forgot,
followed by having too much hunger because of ART or not having enough food (30%), and
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 4 / 15
Reasons for Missing Antiretroviral Therapy
Table 1. Characteristics at interview and at ART initiation of study population in multi-country (Tanzania, Uganda, and Zambia) adherence study,
2011.
Characteristic Tanzania (n = 1469) Uganda (n = 1474) Zambia (n = 1482) Total number of patients (n = 4425)
Gender: n (%)
Male 394 (26.8) 505 (34.3) 520 (35.1) 1419 (32.1)
Female 1075 (73.2) 969 (65.7) 962 (64.9) 3006 (67.9)
At interview
Age (years): median (IQR) 41 (35–47) 39 (34–46) 40 (34–47) 40 (34–47)
Years on ART: median (IQR) 3.2 (2.0–4.6) 3.6 (2.2–5.4) 4.2 (2.5–5.7) 3.6 (2.2–5.3)
CD4 (cells/μL): median (IQR) 372 (243–548) 368 (245–524) 427 (291–588) 391 (255–560)
Missing: n (%) 701 (47.7) 803 (54.5) 700 (47.2) 2204 (49.8)
ART regimen: n (%)
d4T-3TC-NVP 549 (37.4) 11 (0.7) 158 (10.7) 718 (16.2)
AZT-3TC-EFV 389 (26.5) 296 (20.1) 76 (5.1) 761 (17.2)
AZT-3TC-NVP 258 (17.6) 898 (60.9) 253 (17.1) 1409 (31.8)
TDF-3TC/FTC-EFV 114 (7.8) 83 (5.6) 493 (33.3) 690 (15.6)
PI-containing 31 (2.1) 39 (2.6) 66 (4.5) 136 (3.1)
Other 38 (2.6) 134 (9.1) 369 (24.9) 541 (12.2)
Missing 90 (6.1) 13 (0.9) 67 (4.5) 170 (3.8)
Regimen containing: n (%)
EFV 517 (35.2) 382 (25.9) 641 (43.3) 1540 (34.8)
NVP 823 (56.0) 1036 (70.3) 708 (47.8) 2567 (58.0)
d4T 575 (39.1) 23 (1.6) 207 (14.0) 805 (18.2)
AZT 660 (44.9) 1217 (82.6) 347 (23.4) 2224 (50.3)
TDF 123 (8.4) 221 (15.0) 787 (53.1) 1131 (25.6)
Regimen change since ART initiation: n (%)
Yes 663 (45.1) 667 (45.3) 670 (45.2) 2000 (45.2)
No 806 (54.9) 807 (54.7) 812 (54.8) 2425 (54.8)
Change from NVP at initiation: n (%)
Yes 246 (16.7) 141 (9.6) 197 (13.3) 584 (13.2)
No 708 (48.2) 924 (62.7) 504 (34.0) 2136 (48.3)
Not applicable 515 (35.1) 409 (27.7) 781 (52.7) 1705 (38.5)
Change from EFV at initiation: n (%)
Yes 165 (11.2) 59 (4.0) 64 (4.3) 288 (6.5)
No 342 (23.3) 259 (17.6) 495 (33.4) 1096 (24.8)
Not applicable 962 (65.5) 1156 (78.4) 923 (62.3) 3041 (68.7)
Change from d4T at initiation: n (%)
Yes 345 (23.5) 400 (27.1) 256 (17.3) 1001 (22.6)
No 442 (30.1) 6 (0.4) 183 (12.3) 631 (14.3)
Not applicable 682 (46.4) 1068 (72.5) 1043 (70.4) 2793 (63.1)
Change from AZT at initiation: n (%)
Yes 212 (14.4) 82 (5.6) 110 (7.4) 404 (9.1)
No 427 (29.1) 840 (57.0) 256 (17.3) 1523 (34.4)
Not applicable 830 (56.5) 552 (37.4) 1116 (75.3) 2498 (56.5)
At ART initiation
Year of ART initiation: n (%)
2002–2004 10 (0.7) 60 (4.1) 97 (6.5) 167 (3.8)
2005 123 (8.4) 180 (12.2) 192 (13.0) 495 (11.2)
2006 155 (10.6) 152 (10.3) 209 (14.1) 516 (11.7)
(Continued)
PLOS ONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 5 / 15
Reasons for Missing Antiretroviral Therapy
Table 1. (Continued)
Characteristic Tanzania (n = 1469) Uganda (n = 1474) Zambia (n = 1482) Total number of patients (n = 4425)
2007 198 (13.5) 224 (15.2) 254 (17.1) 676 (15.3)
2008 272 (18.5) 219 (14.9) 241 (16.3) 732 (16.5)
2009 315 (21.4) 280 (19.0) 235 (15.9) 830 (18.8)
2010 356 (24.2) 313 (21.2) 240 (16.2) 909 (20.5)
2011 36 (2.5) 43 (2.9) 11 (0.7) 90 (2.0)
Missing 4 (0.2) 3 (0.2) 3 (0.2) 10 (0.2)
WHO clinical stage: n (%)
Stage 1 and 2 414 (28.2) 704 (47.8) 567 (38.3) 1685 (38.1)
Stage 3 659 (44.9) 512 (34.7) 671 (45.3) 1842 (41.6)
Stage 4 274 (18.6) 151 (10.2) 92 (6.2) 517 (11.7)
Missing 122 (8.3) 107 (7.3) 152 (10.2) 381 (8.6)
CD4 (cells/μL): median (IQR) 138 (68–218) 149 (83–211) 147 (75–228) 145 (75–217)
Missing: n (%) 281 (19.3) 296 (20.1) 312 (21.1) 889 (20.1)
ART regimen: n (%)
d4T-3TC-NVP 736 (50.1) 394 (26.7) 396 (26.7) 1526 (34.5)
AZT-3TC-EFV 421 (28.7) 251 (17.0) 77 (5.2) 749 (16.9)
AZT-3TC-NVP 218 (14.8) 668 (45.3) 288 (19.5) 1174 (26.5)
TDF-3TC/FTC-EFV 36 (2.5) 54 (3.7) 403 (27.2) 493 (11.1)
PI-containing 5 (0.3) 16 (1.1) 12 (0.8) 33 (0.8)
Other 51 (3.5) 13 (0.9) 95 (6.4) 159 (3.6)
Missing 2 (0.1) 78 (5.3) 211 (14.2) 291 (6.6)
Regimen containing: n (%)
EFV 507 (34.5) 318 (21.6) 559 (37.7) 1384 (31.3)
NVP 954 (64.9) 1065 (72.3) 701 (47.3) 2720 (61.5)
d4T 787 (53.6) 406 (27.5) 439 (29.6) 1632 (36.9)
AZT 639 (43.5) 922 (62.6) 366 (24.7) 1927 (43.6)
TDF 36 (2.5) 63 (4.3) 409 (27.6) 508 (11.5)
d4T: stavudine; 3TC: lamivudine; NVP: nevirapine; EFV: efavirenz; AZT: zidovudine; TDF: tenofovir; FTC: emtricitabine; PI: protease inhibitor.
doi:10.1371/journal.pone.0147309.t001
feeling sick or uncomfortable because of the ART (12%) (Fig 1). Other frequently cited reasons
included no transport to the pharmacy (11%) and being away from home (3%).
A small number of patients (about 2% of those who ever missed ART or less than 1% of all
patients in the study) have ever missed taking their ART because they were told to stop taking
the drugs by a traditional healer. Of the 4,425 patients in this study, 257 (6%) ever consulted a
traditional healer or herbalist because of HIV, the majority of whom were from Tanzania
(76%).
HIV Symptom Index Score (symptom burden)
Eighty-eight percent of participants reported experiencing at least one symptom during the
past four weeks (Table 2), with responses missing for only a small proportion of participants
(5/4425). The median number of symptoms reported was 4 (IQR: 2–7) with a median HIV
Symptom Index score of 8 (IQR: 3–14). Women reported significantly more symptoms
(median of 4 among women versus 3 among men) and a higher symptom burden (median
HIV Symptom Index score of 8 among women versus 7 among men). More symptoms [5
(IQR: 3–8)] and a higher median HIV Symptom Index score [11 (IQR: 5–17)] were reported in
Uganda (Kruskal Wallis p-value<0.001 for both comparisons).
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Reasons for Missing Antiretroviral Therapy
Female gender and being initiated on a d4T—or NVP—containing ART regimens were
associated with having more symptoms during univariate analysis (Table 3). During multivari-
able analysis, females (coefficient: +1.6, 95%CI: +1.0, +2.2) and participants taking ART regi-
mens containing d4T at initiation (coefficient: +0.9, 95% CI: +0.3, +1.4) remained significantly
associated with a greater symptom burden.
Types of symptoms
Fatigue or loss of energy was the most cited symptom (37%), followed by pain, numbness, or
tingling in the hands or feet (35%), and headache (34%). Feeling sad, down, or depressed was
reported by 30% of participants (Table 2). Of these most frequently reported symptoms, only
pain, numbness, or tingling in the hands or feet was attributed to ART by a substantial propor-
tion of participants with this symptom (33%). Other symptoms that were not as common but
more frequently attributed to ART by at least 30% of participants with that symptom included
trouble remembering (37%), hair loss or changes in hair (35%), nausea or vomiting (34%),
problems with having sex (31%), and skin problems (30%).
Men reported significantly more diarrhoea, skin problems, and problems with having sex
while women reported significantly more fatigue or loss of energy; headache; loss of appetite or
change in the taste of food; fever, chills, or sweats; feeling dizzy or lightheaded; troubles
remembering; nausea or vomiting; feeling sad, down, or depressed; weight loss or wasting; hair
loss or hair change; bloating, pain, or gas; and muscle aches or joint pains (data not shown).
Association between symptoms and incomplete adherence
Every additional symptom increased the odds of incomplete adherence by 10% (odds ratio
(OR): 1.10, 95% CI: 1.05–1.15) (data not shown). Patients who reported at least one symptom
Fig 1. Reasons for patients who ever missed ART in multi-country (Tanzania, Uganda, and Zambia)
adherence study (N = 1278), 2011.
doi:10.1371/journal.pone.0147309.g001
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Reasons for Missing Antiretroviral Therapy
Table 2. Reported symptoms in the past four weeks in multi-country (Tanzania, Uganda, and Zambia) adherence study, 2011.
Tanzania Uganda Zambia Total Attributed to ARVs Severe symptoms (“It
(n = 1469) (n = 1474) (n = 1482) (n = 4425) by patient (n, %) bothers me a lot”) (n, %)
Reporting at least one symptom, n 1193 (81.2) 1389 (94.2) 1325 (89.4) 3907 (88.3)
(%)
Number of symptoms reported, 3 (1–6) 5 (3–8) 4 (2–6) 4 (2–7)
median (IQR)
HIV Symptom Index score, median 6 (2–12) 11 (5–17) 7 (3–13) 8 (3–14)
(IQR)
Symptom, n (%)
Fatigue or loss of energy 360 (24.5) 754 (51.2) 514 (34.7) 1628 (36.8) 308 (18.9) 534 (32.8)
Pain, numbness, or tingling in the 462 (31.4) 662 (44.9) 436 (29.4) 1560 (35.3) 512 (32.8) 583 (37.4)
hands or feet
Headache 394 (26.8) 610 (41.4) 515 (34.8) 1519 (34.3) 233 (15.3) 415 (27.3)
Felt sad, down or depressed 451 (30.7) 518 (35.1) 340 (22.9) 1309 (29.6) 140 (10.7) 467 (35.7)
Muscle aches or joint pains 382 (26.0) 524 (35.5) 284 (19.2) 1190 (26.9) 314 (26.4) 435 (36.6)
Fat deposits or weight gain 378 (25.7) 289 (19.6) 480 (32.4) 1147 (25.9) 326 (28.4) 145 (12.6)
Fevers, chills, or sweats 237 (16.1) 524 (35.5) 374 (25.2) 1135 (25.6) 178 (15.7) 333 (29.3)
Trouble remembering 220 (15.0) 470 (31.9) 419 (28.3) 1109 (25.1) 405 (36.5) 400 (36.1)
Cough or breathing difficulties 208 (14.2) 488 (33.1) 330 (22.3) 1026 (23.2) 128 (12.5) 326 (31.8)
Problems with having sex (such as 316 (21.5) 388 (26.3) 312 (21.1) 1016 (23.0) 317 (31.2) 423 (41.6)
loss of interest or a lack of
satisfaction)
Weight loss or wasting 278 (18.9) 411 (27.9) 321 (21.7) 1010 (22.8) 167 (16.5) 267 (26.4)
Dizzy or lightheaded 250 (17.0) 429 (29.1) 320 (21.6) 999 (22.6) 287 (28.7) 267 (26.7)
Loss of appetite or change in taste 267 (18.2) 341 (23.1) 307 (20.7) 915 (20.7) 252 (27.5) 318 (34.8)
of food
Skin problems (rash, dryness, or 257 (17.5) 381 (25.8) 205 (13.8) 843 (19.1) 255 (30.2) 369 (43.8)
itching)
Difficulty falling or staying asleep 259 (17.6) 327 (22.2) 251 (16.9) 837 (18.9) 204 (24.4) 306 (36.6)
Felt nervous or anxious 248 (16.9) 373 (25.3) 191 (12.9) 812 (18.4) 117 (14.4) 271 (33.4)
Bloating, stomach pain, or gas 249 (17.0) 353 (23.9) 194 (13.1) 796 (18.0) 219 (27.5) 265 (33.3)
Nausea or vomiting 132 (9.0) 203 (13.8) 189 (12.8) 524 (11.8) 176 (33.6) 147 (28.1)
Diarrhea or loose bowl movements 148 (10.1) 146 (9.9) 181 (12.2) 475 (10.7) 100 (21.1) 122 (25.7)
Hair loss or hair change 36 (2.5) 101 (6.9) 42 (2.8) 179 (4.0) 63 (35.2) 60 (33.5)
doi:10.1371/journal.pone.0147309.t002
were more likely to have incomplete adherence (OR: 3.0, 95% CI: 1.2–7.4) (Table 4). About
half of the symptoms from the HIV Symptom Index Score (9/20) were associated with incom-
plete adherence: fatigue or loss of energy (OR: 1.5, 95% CI: 1.0–2.1), fevers, chills, or sweats
(OR: 1.7, 95% CI: 1.2–2.4), nausea or vomiting (OR: 1.7, 95% CI: 1.1–2.7), diarrhoea or loose
bowl movements (OR: 2.2, 95% CI: 1.5–3.4), feeling sad, down, or depressed (OR: 1.5, 95% CI:
1.1–2.1), skin problems (OR: 2.0, 95% CI: 1.4–2.8), cough or breathing difficulties (OR: 1.8,
95% CI: 1.3–2.6), loss of appetite or change in the taste of food (OR: 2.1, 95% CI: 1.4–3.0), and
abdominal pains (OR: 1.6, 95% CI: 1.1–2.3).
Patients who reported feeling sick and uncomfortable because of ART were also more likely
to have incomplete adherence (OR: 3.7, 95% CI: 2.1–6.6).
Discussion
This is the first study to our knowledge to interview more than 4000 patients on their reasons
for ever missing ART and their current experiences with HIV-related symptoms using a
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 8 / 15
Reasons for Missing Antiretroviral Therapy
Table 3. Regression coefficients of factors associated with symptom burden (expressed as HIV Symptom Index Score) in multi-country (Tanzania,
Uganda, and Zambia) adherence study, 2011.
Risk factor Single regression* Multiple regression*
Coefficient (95% CI) P-value Coefficient (95% CI) P-value
Male (versus female) -1.6 (-2.2, -1.0) <0.001 -1.6 (-2.2, -1.0) <0.001
WHO clinical stage at ART initiation (versus WHO stage 1 and 2) 0.138
Stage 3 +0.7 (+0.1, +1.4)
Stage 4 +0.6 (-0.3, +1.6)
Missing +0.7 (-0.3, +1.8)
CD4 cell count at ART initiation (versus 
250 cells/μL) 0.495
< 250 cells/μL -0.1 (-1.4, +0.4)
Missing -0.5 (-1.6, +0.5)
Regimen at ART initiation containing
NVP (versus EFV) +1.0 (+0.3, +1.6) 0.006 NS
d4T (versus AZT) +0.9 (+0.3, +1.4) 0.003 +0.9 (+0.3, +1.4) 0.004
Current age (per 10 years) -0.1 (-0.4, +0.2) 0.479
Duration on ART (per year) +0.1 (-0.1, +0.2) 0.400
CD4 cell count (versus 
250 cells/μL) 0.367
< 250 cells/μL +0.6 (-0.3, +1.5)
Missing -0.1 (-0.7, +0.6)
Current regimen containing
NVP (versus EFV) +0.6 (-0.1, +1.3) 0.115
d4T (versus AZT) +0.7 (-0.2, +1.5) 0.109
*Regression coefficients and P-values calculated using linear regression with site as a fixed effect.
Factors with negative coefficients are associated with a reduced symptom burden; those with a positive coefficient with an increased symptom burden.
d4T: stavudine; NVP: nevirapine; EFV: efavirenz; AZT: zidovudine; CI: confidence interval.
doi:10.1371/journal.pone.0147309.t003
consistent data collection tool across 18 study sites in 3 countries in sub-Saharan Africa. This
paper builds on the study’s primary analysis that found that 3% of participants missed two or
more consecutive days of their ART in the past three months and that having greater numbers
of self-reported symptoms, (defined as more than the country-specific median), was signifi-
cantly related to this measure of incomplete adherence.[9] In this secondary analysis we
focused on specific symptoms and their association with incomplete adherence, and on reasons
for ever missing ART.
This analysis found that about one third of participants (29%) reported ever missing ART.
Simply forgetting was cited as the most common reason for ever missing ART, a result which
concurs with findings from other studies.[19–21] Advances in mHealth technologies are
emerging as an option to address forgetting to take ART. For example, several studies have
found that patients who received text messages have better levels of ART adherence and clinical
indicators, such as lower viral loads and higher CD4 cell counts, compared to patients who did
not receive text messages.[22–24] However, in their network meta-analysis examining direct
and indirect evidence from randomized trials, Mills and colleagues found a large benefit for
weekly but not for daily SMS messages [25], emphasizing the need for tailored mHealth inter-
ventions.[26] Such findings support the inclusion of mobile phone text messaging in the pack-
age of adherence intervention tools, as recommended by the World Health Organization in
their latest guidelines, as well as the need for more research on how to optimize the use of text
messaging.[27] However, the potential of unwanted disclosure if the message is intercepted by
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 9 / 15
Reasons for Missing Antiretroviral Therapy
Table 4. Analysis of individual symptomswith incomplete adherence as outcome (defined as missed ART for at least 48 consecutive hours during
the past 3 months) in multi-country (Tanzania, Uganda, and Zambia) adherence study, 2011.
Total Incomplete adherence Crude Odds Ratio (OR) P-
(n = 4425) (n = 141) (95% CI) * value*
Reporting at least one symptom, n (%) 3907 (88.3) 136 (96.5) 2.95 (1.19–7.35) 0.007
Symptom, n (%)
Fatigue or loss of energy 1628 (36.8) 67 (47.5) 1.45 (1.01–2.06) 0.042
Pain, numbness, or tingling in the hands or feet 1560 (35.3) 57 (40.4) 1.11 (0.78–1.58) 0.562
Headache 1519 (34.3) 61 (43.3) 1.29 (0.91–1.83) 0.162
Felt sad, down or depressed 1309 (29.6) 63 (44.7) 1.49 (1.05–2.12) 0.029
Muscle aches or joint pains 1190 (26.9) 49 (34.8) 1.25 (0.87–1.80) 0.240
Fat deposits or weight gain 1147 (25.9) 37 (26.2) 0.99 (0.66–1.47) 0.950
Fevers, chills, or sweats 1135 (25.6) 52 (36.9) 1.67 (1.16–2.41) 0.007
Trouble remembering 1109 (25.1) 37 (26.2) 1.02 (0.69–1.52) 0.906
Cough or breathing difficulties 1026 (23.2) 51 (36.2) 1.80 (1.25–2.61) 0.002
Problems with having sex (such as loss of interest or a lack 1016 (23.0) 39 (27.7) 1.13 (0.76–1.66) 0.554
of satisfaction)
Weight loss or wasting 1010 (22.8) 39 (27.7) 1.20 (0.81–1.77) 0.362
Dizzy or lightheaded 999 (22.6) 45 (31.9) 1.42 (0.98–2.06) 0.071
Loss of appetite or change in taste of food 915 (20.7) 53 (37.6) 2.05 (1.43–2.95) <0.001
Skin problems (rash, dryness, or itching) 843 (19.1) 48 (34.0) 1.95 (1.35–2.81) <0.001
Difficulty falling or staying asleep 837 (18.9) 38 (27.0) 1.35 (0.91–1.99) 0.145
Felt nervous or anxious 812 (18.4) 38 (27.0) 1.27 (0.85–1.89) 0.256
Bloating, stomach pain, or gas 796 (18.0) 40 (28.4) 1.59 (1.08–2.34) 0.022
Nausea or vomiting 524 (11.8) 28 (19.9) 1.72 (1.11–2.67) 0.020
Diarrhoea or loose bowl movements 475 (10.7) 31 (22.0) 2.24 (1.47–3.43) <0.001
Hair loss or hair change 179 (4.0) 6 (4.3) 1.01 (0.43–2.36) 0.975
*OR and P-value calculated using logistic regression with site as a fixed effect.
OR: odds ratio; CI: confidence interval.
doi:10.1371/journal.pone.0147309.t004
others, and the cost and sustainability of these mHealth interventions in the absence of external
funding, remain important issues.[28]
Having too much hunger because of ART or not having enough food was experienced by
about one-third of participants who reported ever missing ART. The mechanism of ART-
related hunger is unclear, but the possibility of immunological phenomena may play a role.[29]
Food insecurity has been described as an important barrier to adherence and subsequent mor-
tality in impoverished populations.[30–35] The integration of food supplementation into HIV
care programmes has been shown to improve adherence [36], and to have clinical and immu-
nological benefits.[37] In order to address the underlying causes of food insecurity, organiza-
tions are looking for more sustainable long-term solutions to address this issue in the form of
livelihood programmes.[38] The lack of evidence and research on the integration of livelihood
programmes into HIV programmes [38] could be one of the reasons why these programmes
have not been more widely implemented. Further implementation research on how these pro-
grammes should be evaluated, and subsequent cost-effectiveness studies are needed.
Previous studies [19,20] have also found that being away from home for funerals and travel-
ling (and running out of ART while travelling) were common reasons for missing ART. In our
study about 1% of all participants included, or 3% of participants ever missing ART, reported
this as a reason for missing ART. Currently cities and urban areas bear a major part of the
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 10 / 15
Reasons for Missing Antiretroviral Therapy
global HIV burden—in sub-Saharan Africa, nearly half (45%) of people living with HIV reside
in urban areas.[39] Travelling and migration in and out of cities can be a challenge for reten-
tion in care and adherence but also an important factor linking different networks of HIV
transmission.[40] Interventions to provide patients with an adequate supply of ART are critical
to minimizing treatment interruptions during travel.
Lack of money for transport was mentioned by 12% of the participants who ever reported
missing ART and no transport to the pharmacy by 11%. This has also been cited in other stud-
ies as a risk factor for missed medical appointments at the health facility for follow-up and refill
because of competing demands between transport costs and other necessities such as food,
housing, and school fees.[30,41] Further decentralization of ART services, thereby bringing
ART services closer to the patients [42], and involving patients and their families as the model
of Community ART Groups (peer support) has the potential to further reduce transport costs
and thus minimize out-of-pocket payments.[43] In addition, reducing the frequency of follow-
up visits for refills or for routine clinical monitoring may also contribute to reducing the cost
burden of transportation.
A large majority of patients (88%) in this study reported experiencing at least one symptom
from the HIV Symptom Index, and, not surprisingly, the odds of incomplete adherence
increased significantly with each additional symptom, as similarly described elsewhere.[44]
Patients who reported feeling sick and uncomfortable because of ART were about 4 times more
likely to have incomplete adherence, also confirming findings from other studies.[19,45] We
also found that women reported a significantly greater symptom burden (both more symptoms
and severity), as described elsewhere.[46]
Fatigue or loss of energy was the most reported symptom (37%), twice as much as reported
by Bhatt et. al in South Africa [19], but only attributed to ART by 19% of patients with fatigue.
On the other hand, pain, numbness, or tingling in the hands or feet was reported by 35% of
patients, and about one third of the patients who reported this symptom attributed it to ART.
This is comparable with findings from Thailand where 10% and 28% of probable and possible
HIV-associated neuropathy was reported.[47] Peripheral neuropathies are expected to be more
prevalent in settings where d4T is part of the first-line regimen.[48] Fortunately, the latest
WHO recommendations call for the phasing out of d4T-containing regimens and their
replacement by preferably tenofovir-containing regimens.[27] In this study, there was already
clear evidence of this change with the proportion of d4T-containing regimens decreasing from
37% at baseline to 18% at the time of the interview, and tenofovir-containing regimens increas-
ing from 11% (at baseline) to 26% (at the time of the interview).
About one third of the patients (30%) reported feeling sad, down, or depressed in the previ-
ous four weeks based on the HIV Symptom Index. While we cannot conclude that a patient is
suffering from depression based on just one question, this number is surprisingly high and is
consistent with the report of moderate to severe depression symptom severity among people
living with HIV in sub-Saharan Africa. A systematic review, including 23 studies in sub-Saha-
ran Africa, found prevalence estimates of 18% for major depression and 30% for depression
symptoms among HIV-positive patients on ART.[49] In their analysis, patients who reported
depression symptoms were 55% less likely to achieve good adherence compared to those not
reporting depression symptoms. Similarly, in our univariate analysis, participants who
reported feeling sad, down, or depressed were about 50% more likely to report incomplete
adherence. This finding supports the screening for depression among patients with HIV.[49]
However the region’s health system capacity to detect and treat depression is limited.[50] Die-
tary protein supplementation has been suggested as a specific strategy to further reduce depres-
sion in patients on ART, in settings with food insecurity.[29]
PLOSONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 11 / 15
Reasons for Missing Antiretroviral Therapy
Only one-third of participants reported ever missing ART, which may be low given that
other studies have found up to 20% of participants missed taking their ART over just the past
week alone.[51] It is well-established that self-report surveys tend to overestimate actual adher-
ence.[52] However, this overestimate may also introduce a bias by not capturing the reasons
for missed ART among both people willing to disclose, as well as among people unwilling to
disclose incomplete adherence behaviors.
This study was conducted in 2011 before the WHO guidelines to replace d4T-containing
regiments with tenofovir-containing regiments were introduced. [27] As such the factors
related to missing ART may differ among patients on tenofovir-containing regimens.
We found some variability in the proportion of symptoms attributed to ART by patients:
symptoms of peripheral neuropathy, troubles with remembering, nausea and vomiting, skin
problems and problems with having sex were mostly attributed to ART. This could potentially
lead to some bias with less adherent individuals more likely to report symptoms and attribute
them to their ART. The cross-sectional design of the study limits the causal inference of
whether it is incomplete adherence that leads to symptoms or whether it is the symptoms that
are leading to incomplete adherence. Another limitation of the study is the difficulty in attrib-
uting symptoms to ART; some of these symptoms may also arise from the HIV infection itself,
or arise from co- morbidities frequently associated with HIV infection (diabetes, hepatitis C
infection).[53] We were also unable to assess whether ART clients who declined to participate
differed from those participating in the study.
Conclusions
Symptoms were a common reason for missing ART, together with simply forgetting and food
insecurity. Women and participants taking ART regimens containing d4T at initiation experi-
enced greater symptom burden. A combination of ART regimens with fewer side effects, use of
mobile phone text messaging, and integration of food supplementation and livelihood pro-
grammes into HIV programmes, have the potential to decrease missed doses of ART and
hence to improve adherence and the outcomes of ART programmes.
Acknowledgments
Disclaimer
The findings and conclusions in this report are those of the authors and do not necessarily rep-
resent the official position of the CDC, HRSA or any other federal agency or office.
Author Contributions
Conceived and designed the experiments: OK JAD JM ST FWMGKMMAA SA YDM EVP
KT SW JK AZ DRB RC. Analyzed the data: OK JAD JM ST. Wrote the paper: OK JAD JM ST
FWMGKMMAA SA YDM EVP KT SW JK AZ DRB RC.
References
1. UNAIDS. The gap report 2014. 2014. Available: http://www.unaids.org/sites/default/files/en/media/
unaids/contentassets/documents/unaidspublication/2014/UNAIDS_Gap_report_en.pdf. Accessed 22
July 2015.
2. UNAIDS. Ambitious treatment targets: writing the final chapter on the AIDS epidemic. 2014. Available:
http://www.unaids.org/sites/default/files/media_asset/JC2670_UNAIDS_Treatment_Targets_en.pdf.
Accessed 22 July 2015.
PLOS ONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 12 / 15
Reasons for Missing Antiretroviral Therapy
3. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of
HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011 Aug 11; 365(6):493–505. doi: 10.
1056/NEJMoa1105243 PMID: 21767103
4. Loutfy MR, WuW, Letchumanan M, Bondy L, Antoniou T, Margolese S, et al. Systematic review of HIV
transmission between heterosexual serodiscordant couples where the HIV-positive partner is fully sup-
pressed on antiretroviral therapy. PLOS ONE 2013; 8(2):e55747. Available: http://journals.plos.org/
plosone/article?id=10.1371/journal.pone.0055747 Accessed: 2015 July 22. doi: 10.1371/journal.pone.
0055747 PMID: 23418455
5. McMahon JH, Elliott JH, Bertagnolio S, Kubiak R, Jordan MR. Viral suppression after 12 months of anti-
retroviral therapy in low- and middle-income countries: a systematic review. Bull World Health Organ
2013 May 1; 91(5):377–385E. Available: http://www.who.int/bulletin/volumes/91/5/12-112946.pdf.
Accessed 22 July 2015. doi: 10.2471/BLT.12.112946 PMID: 23678201
6. Hogg RS, Heath K, Bangsberg D, Yip B, Press N, O'Shaughnessy MV, et al. Intermittent use of triple-
combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS 2002 May
3; 16(7):1051–8. PMID: 11953472
7. Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000 Jun; 30 Suppl
2:S171–S176. PMID: 10860902
8. Mills EJ, Nachega JB, Bangsberg DR, Singh S, Rachlis B, Wu P, et al. Adherence to HAART: a system-
atic review of developed and developing nation patient-reported barriers and facilitators. PLOSMed
2006 Nov; 3(11):e438. Available: http://www.plosmedicine.org/article/Related/info:doi/10.1371/journal.
pmed.0030438. Accessed 22 July 2015. PMID: 17121449
9. Denison JA, Koole O, Tsui S, Menten J, Torpey K, van PE, et al. Incomplete adherence among treat-
ment-experienced adults on antiretroviral therapy in Tanzania, Uganda and Zambia. AIDS 2015 Jan
28; 29(3):361–71. doi: 10.1097/QAD.0000000000000543 PMID: 25686684
10. Koole O, Tsui S, Wabwire-Mangen F, Kwesigabo G, Menten J, MulengaM, et al. Retention and risk fac-
tors for attrition among adults in antiretroviral treatment programmes in Tanzania, Uganda and Zambia.
Trop Med Int Health 2014 Dec; 19(12):1397–410. doi: 10.1111/tmi.12386 PMID: 25227621
11. Kalichman SC, Simbayi LC, Cloete A, Mthembu PP, Mkhonta RN, Ginindza T (2009) Measuring AIDS
stigmas in people living with HIV/AIDS: the Internalized AIDS-Related Stigma Scale. AIDS Care 21:
87–93. doi: 10.1080/09540120802032627 PMID: 19085224
12. Kaaya SF, Fawzi MC, Mbwambo JK, Lee B, Msamanga GI, Fawzi W (2002) Validity of the Hopkins
Symptom Checklist-25 amongst HIV-positive pregnant women in Tanzania. Acta Psychiatr Scand 106:
9–19. PMID: 12100343
13. BroadheadWE, Gehlbach SH, de Gruy FV, Kaplan BH (1988) The Duke-UNC Functional Social Sup-
port Questionnaire. Measurement of social support in family medicine patients. Med Care 26: 709–
723. PMID: 3393031
14. Samet JH, Phillips SJ, Horton NJ, Traphagen ET, Freedberg KA (2004) Detecting alcohol problems in
HIV-infected patients: use of the CAGE questionnaire. AIDS Res Hum Retroviruses 20: 151–155.
PMID: 15018702
15. Chesney MA, Ickovics JR, Chambers DB, Gifford AL, Neidig J, Zwickl B, et al. Self-reported adherence
to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instru-
ments. Patient Care Committee & AdherenceWorking Group of the Outcomes Committee of the Adult
AIDS Clinical Trials Group (AACTG). AIDS Care 2000 Jun; 12(3):255–66. PMID: 10928201
16. Justice AC, HolmesW, Gifford AL, Rabeneck L, Zackin R, Sinclair G, et al. Development and validation
of a self-completed HIV symptom index. J Clin Epidemiol 2001 Dec; 54 Suppl 1:S77–S90. PMID:
11750213
17. Oyugi JH, Byakika-Tusiime J, Ragland K, Laeyendecker O, Mugerwa R, Kityo C, et al. Treatment inter-
ruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral
therapy in Kampala, Uganda. AIDS 2007 May 11; 21(8):965–71. PMID: 17457090
18. Genberg BL, Wilson IB, Bangsberg DR, Arnsten J, Goggin K, Remien RH, et al. Patterns of antiretrovi-
ral therapy adherence and impact on HIV RNA among patients in North America. AIDS 2012 Jul 17; 26
(11):1415–23. doi: 10.1097/QAD.0b013e328354bed6 PMID: 22767342
19. Bhat VG, Ramburuth M, Singh M, Titi O, Antony AP, Chiya L, et al. Factors associated with poor adher-
ence to anti-retroviral therapy in patients attending a rural health centre in South Africa. Eur J Clin
Microbiol Infect Dis 2010 Aug; 29(8):947–53. doi: 10.1007/s10096-010-0949-4 PMID: 20467769
20. Unge C, Sodergard B, Marrone G, Thorson A, Lukhwaro A, Carter J, et al. Long-term adherence to anti-
retroviral treatment and program drop-out in a high-risk urban setting in sub-Saharan Africa: a prospec-
tive cohort study. PLOS ONE 2010; 5(10):e13613. Available: http://journals.plos.org/plosone/article?
id=10.1371/journal.pone.0013613 Accessed: 2015 July 22. doi: 10.1371/journal.pone.0013613 PMID:
21049045
PLOS ONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 13 / 15
Reasons for Missing Antiretroviral Therapy
21. Barfod TS, Sorensen HT, Nielsen H, Rodkjaer L, Obel N. 'Simply forgot' is the most frequently stated
reason for missed doses of HAART irrespective of degree of adherence. HIV Med 2006 Jul; 7(5):285–
90. PMID: 16945072
22. Lester RT, Ritvo P, Mills EJ, Kariri A, Karanja S, Chung MH, et al. Effects of a mobile phone short mes-
sage service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lan-
cet 2010 Nov 27; 376(9755):1838–45. doi: 10.1016/S0140-6736(10)61997-6 PMID: 21071074
23. Roux P, Kouanfack C, Cohen J, Marcellin F, Boyer S, Delaporte E, et al. Adherence to antiretroviral
treatment in HIV-positive patients in the Cameroon context: promoting the use of medication reminder
methods. J Acquir Immune Defic Syndr 2011 Jul 1; 57 Suppl 1:S40–S43. doi: 10.1097/QAI.
0b013e318222b5c2 PMID: 21857285
24. Finitsis DJ, Pellowski JA, Johnson BT. Text message intervention designs to promote adherence to
antiretroviral therapy (ART): a meta-analysis of randomized controlled trials. PLOS ONE 2014; 9(2):
e88166. Available: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088166.
Accessed 22 July 2015. doi: 10.1371/journal.pone.0088166 PMID: 24505411
25. Mills EJ, Lester R, Thorlund K, Lorenzi M, Muldoon K. Interventions to promote adherence to antiretro-
viral therapy in Africa: a network meta-analysis. Lancet HIV 2014 Dec; 1(3):e104–e111. doi: 10.1016/
S2352-3018(14)00003-4 PMID: 26424119
26. Thirumurthy H, Lester RT. M-health for health behaviour change in resource-limited settings: applica-
tions to HIV care and beyond. Bull World Health Organ 2012 May 1; 90(5):390–2. Available: http://
www.who.int/bulletin/volumes/90/5/11-099317/en/. Accessed 22 July 2015. doi: 10.2471/BLT.11.
099317 PMID: 22589574
27. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infec-
tion. Recommendations for a public health approach 2013.2013. Available: http://apps.who.int/iris/
bitstream/10665/85321/1/9789241505727_eng.pdf?ua=1. Accessed 22 July 2015.
28. Rodrigues R, Bogg L, Shet A, Kumar DS, De CA. Mobile phones to support adherence to antiretroviral
therapy: what would it cost the Indian National AIDS Control Programme? J Int AIDS Soc 2014;
17:19036. Available: http://www.jiasociety.org/index.php/jias/article/view/19036/3934. Accessed 22
July 2015. doi: 10.7448/IAS.17.1.19036 PMID: 25186918
29. Martinez P, Tsai AC, Muzoora C, Kembabazi A, Weiser SD, Huang Y, et al. Reversal of the Kynurenine
pathway of tryptophan catabolismmay improve depression in ART-treated HIV-infected Ugandans. J
Acquir Immune Defic Syndr 2014 Apr 1; 65(4):456–62. doi: 10.1097/QAI.0000000000000062 PMID:
24220289
30. Hardon AP, Akurut D, Comoro C, Ekezie C, Irunde HF, Gerrits T, et al. Hunger, waiting time and trans-
port costs: time to confront challenges to ART adherence in Africa. AIDS Care 2007 May; 19(5):658–
65. PMID: 17505927
31. Musumari PM, FeldmanMD, Techasrivichien T, Wouters E, Ono-Kihara M, Kihara M. "If I have nothing
to eat, I get angry and push the pills bottle away fromme": A qualitative study of patient determinants of
adherence to antiretroviral therapy in the Democratic Republic of Congo. AIDS Care 2013; 25
(10):1271–7. doi: 10.1080/09540121.2013.764391 PMID: 23383757
32. Musumari PM, Wouters E, Kayembe PK, Kiumbu NM, Mbikayi SM, Suguimoto SP, et al. Food insecu-
rity is associated with increased risk of non-adherence to antiretroviral therapy among HIV-infected
adults in the Democratic Republic of Congo: a cross-sectional study. PLOS ONE 2014; 9(1):e85327.
Available: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085327. Accessed 22 July
2015. doi: 10.1371/journal.pone.0085327 PMID: 24454841
33. Singer AW, Weiser SD, McCoy SI. Does Food Insecurity Undermine Adherence to Antiretroviral Ther-
apy? A Systematic Review. AIDS Behav 2014 Aug 6.
34. Weiser SD, Fernandes KA, Brandson EK, Lima VD, Anema A, Bangsberg DR, et al. The association
between food insecurity and mortality among HIV-infected individuals on HAART. J Acquir Immune
Defic Syndr 2009 Nov 1; 52(3):342–9. doi: 10.1097/QAI.0b013e3181b627c2 PMID: 19675463
35. Weiser SD, Palar K, Frongillo EA, Tsai AC, Kumbakumba E, Depee S, et al. Longitudinal assessment
of associations between food insecurity, antiretroviral adherence and HIV treatment outcomes in rural
Uganda. AIDS 2014 Jan 2; 28(1):115–20. doi: 10.1097/01.aids.0000433238.93986.35 PMID:
23939234
36. Cantrell RA, Sinkala M, Megazinni K, Lawson-Marriott S, Washington S, Chi BH, et al. A pilot study of
food supplementation to improve adherence to antiretroviral therapy among food-insecure adults in
Lusaka, Zambia. J Acquir Immune Defic Syndr 2008 Oct 1; 49(2):190–5. doi: 10.1097/QAI.
0b013e31818455d2 PMID: 18769349
37. Mamlin J, Kimaiyo S, Lewis S, Tadayo H, Jerop FK, Gichunge C, et al. Integrating nutrition support for
food-insecure patients and their dependents into an HIV care and treatment program in Western
PLOS ONE | DOI:10.1371/journal.pone.0147309 January 20, 2016 14 / 15
Reasons for Missing Antiretroviral Therapy
Kenya. Am J Public Health 2009 Feb; 99(2):215–21. doi: 10.2105/AJPH.2008.137174 PMID:
19059851
38. Yager JE, Kadiyala S, Weiser SD. HIV/AIDS, food supplementation and livelihood programs in
Uganda: a way forward? PLOS ONE 2011; 6(10):e26117. Available: http://journals.plos.org/plosone/
article?id=10.1371/journal.pone.0026117. Accessed 22 July 2015. doi: 10.1371/journal.pone.0026117
PMID: 22022530
39. UNAIDS. The Cities Report. 2014. Available: http://www.unaids.org/sites/default/files/media_asset/
JC2687_TheCitiesReport_en.pdf. Accessed 22 July 2015.
40. Voeten HA, Vissers DC, Gregson S, Zaba B, White RG, de Vlas SJ, et al. Strong association between
in-migration and HIV prevalence in urban sub-Saharan Africa. Sex Transm Dis 2010 Apr; 37(4):240–3.
doi: 10.1097/OLQ.0b013e3181c3f2d0 PMID: 19959971
41. Tuller DM, Bangsberg DR, Senkungu J, Ware NC, Emenyonu N, Weiser SD. Transportation costs
impede sustained adherence and access to HAART in a clinic population in southwestern Uganda: a
qualitative study. AIDS Behav 2010 Aug; 14(4):778–84. doi: 10.1007/s10461-009-9533-2 PMID:
19283464
42. Koole O, Houben RM, Mzembe T, Van Boeckel TP, KayangeM, Jahn A, et al. Improved retention of
patients starting antiretroviral treatment in Karonga District, northern Malawi, 2005–2012. J Acquir
Immune Defic Syndr 2014 Sep 1; 67(1):e27–e33. doi: 10.1097/QAI.0000000000000252 PMID:
24977375
43. Rasschaert F, Telfer B, Lessitala F, Decroo T, Remartinez D, Biot M, et al. A qualitative assessment of
a community antiretroviral therapy group model in tete, mozambique. PLOS ONE 2014; 9(3):e91544.
Available: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091544. Accessed 22 July
2015. doi: 10.1371/journal.pone.0091544 PMID: 24651523
44. Duran S, Spire B, Raffi F, Walter V, Bouhour D, Journot V, et al. Self-reported symptoms after initiation
of a protease inhibitor in HIV-infected patients and their impact on adherence to HAART. HIV Clin Trials
2001 Jan; 2(1):38–45. PMID: 11590513
45. Al-Dakkak I, Patel S, McCann E, Gadkari A, Prajapati G, Maiese EM. The impact of specific HIV treat-
ment-related adverse events on adherence to antiretroviral therapy: a systematic review and meta-
analysis. AIDS Care 2013; 25(4):400–14. doi: 10.1080/09540121.2012.712667 PMID: 22908886
46. Bonfanti P, Valsecchi L, Parazzini F, Carradori S, Pusterla L, Fortuna P, et al. Incidence of adverse
reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio
Allergia e Infezione da HIV (CISAI) Group. J Acquir Immune Defic Syndr 2000 Mar 1; 23(3):236–45.
PMID: 10839659
47. Sithinamsuwan P, Punthanamongkol S, Valcour V, Onsanit S, Nidhinandana S, Thitivichianlert S, et al.
Frequency and characteristics of HIV-associated sensory neuropathy among HIV patients in Bangkok,
Thailand. J Acquir Immune Defic Syndr 2008 Dec 1; 49(4):456–8. doi: 10.1097/QAI.
0b013e318186eb03 PMID: 19011422
48. Sacktor N, Nakasujja N, Skolasky RL, Robertson K, Musisi S, Ronald A, et al. Benefits and risks of stav-
udine therapy for HIV-associated neurologic complications in Uganda. Neurology 2009 Jan 13; 72
(2):165–70. doi: 10.1212/01.wnl.0000339042.96109.86 PMID: 19139369
49. Nakimuli-Mpungu E, Bass JK, Alexandre P, Mills EJ, Musisi S, RamM, et al. Depression, alcohol use
and adherence to antiretroviral therapy in sub-Saharan Africa: a systematic review. AIDS Behav 2012
Nov; 16(8):2101–18. doi: 10.1007/s10461-011-0087-8 PMID: 22116638
50. WHO. mhGAP: Mental Health Gap Action Programme. 2008. Available: http://whqlibdoc.who.int/
publications/2008/9789241596206_eng.pdf?ua=1. Accessed 22 July 2015.
51. Sarna A, Pujari S, Sengar AK, Garg R, Gupta I, Dam J (2008) Adherence to antiretroviral therapy & its
determinants amongst HIV patients in India. Indian J Med Res 127: 28–36. PMID: 18316850
52. Haubrich RH, Little SJ, Currier JS, Forthal DN, Kemper CA, Beall GN, Johnson D, Dube MP, Hwang
JY, McCutchan JA (1999) The value of patient-reported adherence to antiretroviral therapy in predicting
virologic and immunologic response. California Collaborative Treatment Group. AIDS 13: 1099–1107.
PMID: 10397541
53. Nachega JB, Trotta MP, Nelson M, Ammassari A. Impact of metabolic complications on antiretroviral
treatment adherence: clinical and public health implications. Curr HIV /AIDS Rep 2009 Aug; 6(3):121–
9. PMID: 19589297
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