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R E S E A R C H A R T I C L E Open Access
Longitudinal adherence to antiretroviral
drugs for preventing mother-to-child
transmission of HIV in Zambia
Sumiyo Okawa
1
, Mable Chirwa
2,3
, Naoko Ishikawa
4*
, Henry Kapyata
2,3
, Charles Yekha Msiska
2,3
, Gardner Syakantu
5
,
Shinsuke Miyano
4
, Kenichi Komada
3,4
, Masamine Jimba
1
and Junko Yasuoka
1
Abstract
Background: Adherence to antiretroviral (ARV) drugs is essential for eliminating new pediatric infections of human
immunodeficiency virus (HIV). Since the Zambian government revised the national guidelines based on option A
(i.e., maternal zidovudine and infant ARV prophylaxis) of the World Health Organization’s 2010 guidelines, no studies
have assessed adherence to ARVs during pregnancy up to the postpartum period. This study aimed to examine
adherence to ARVs and identify the associated risk factors.
Methods: A prospective cohort study was conducted in the Chongwe district from June 2011 to January 2014.
Self-reported adherence to ARVs was examined during pregnancy and at one week, six weeks, and 24 weeks
postpartum among 321 HIV-positive women. The probability of remaining adherent to ARVs was estimated using
the Kaplan-Meier method, and the risk factors for non-adherence were identified using the Cox proportional hazard
regressions—treating loss to follow-up as non-adherence. The statuses of HIV in HIV-exposed infants were assessed
in January 2014.
Results: During the study period, 326 infants were born to HIV-positive women, 262 (80.4 %) underwent HIV
testing, and 11 (3.4 %) had their HIV infection detected at the time that they had the latest HIV testing as of
January 2014. The ARV adherence rate was 82.5 % during pregnancy, 84.2 % at one week postpartum, 81.5 % at six
weeks postpartum, and 70.5 % at 24 weeks postpartum. The probability of remaining adherent to ARVs was 0.61 at
day 50, 0.35 at day 100, 0.18 at day 200, and 0.06 at day 300. Attending a referral health center (HC) was a risk
factor for non-adherence compared with attending rural HCs that provided HIV care/treatment (adjusted hazard
ratio [aHR] 0.71, 95 % confidence interval [CI] 0.57–0.88) and those that did not provide HIV care/treatment (aHR
0.58, 95 % CI 0.46–0.74). A new diagnosis of HIV infection compared to a known HIV-positive status before
pregnancy was another risk factor for non-adherence (aHR 1.24, 95 % CI 1.03–1.50).
Conclusions: Maintaining adherence to ARVs through pregnancy to the postpartum period remains a crucial
challenge in Zambia. To maximize the treatment benefits, adherence to ARVs and retention in care should be
improved at all health facilities.
Keywords: Prevention of mother-to-child transmission of HIV (PMTCT), Antiretroviral (ARV), Adherence, Pregnancy,
Zambia
* Correspondence: n-ishikawa@it.ncgm.go.jp
4
National Center for Global Health and Medicine, 1-21-1 Toyama,
Shinjuku-ku, Tokyo 162-8655, Japan
Full list of author information is available at the end of the article
© 2015 Okawa et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Okawa et al. BMC Pregnancy and Childbirth (2015) 15:258
DOI 10.1186/s12884-015-0697-7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Background
The global epidemic of human immunodeficiency virus
(HIV) has affected the lives of millions of children. In
2013, about 240,000 children were newly infected with
HIV, with the majority of pediatric HIV infections being
attributed to mother-to-child transmission [1]. In an at-
tempt to eliminate new pediatric HIV infections, the
World Health Organization (WHO) revised the guidelines
for preventing mother-to-child transmission of HIV
(PMTCT) in 2010 [2].
The guidelines recommended two options for antiretro-
viral (ARV) prophylaxis. In option A, pregnant women
begin zidovudine (AZT) at 14 gestational weeks and con-
tinue it during pregnancy, while their infants receive nevira-
pine (NVP) throughout the breastfeeding period. In option
B, pregnant women receive triple ARV prophylaxis from
14 weeks of pregnancy to the end of the breastfeeding
period, while their infants receive NVP for the first four to
six weeks. In both options, lifelong antiretroviral therapy
(ART) is recommended for all women with a CD4 cell
count ≤350 cells/mm
3
or those in the WHO clinical stage 3
or 4. It is expected that ARV prophylaxis can reduce the
risk of HIV transmission from 35 to 5 % among breastfeed-
ing infants [2]. In 2013, WHO released new consolidated
guidelines on the use of ARVs, in which two options for
PMTCT, option B and B+ were recommended [3]. In op-
tion B+, all women initiate lifelong triple ARVs regardless
of their WHO clinical stage or CD4 cell count [3].
Optimal adherence to ARVs is essential to protect chil-
dren from acquiring HIV, maintain maternal health, and
minimize the risk of drug resistance [4]. According to a
meta-analysis on ARV adherence in the PMTCT pro-
gram, 74 % of pregnant women in low-, middle-, and
high-income countries achieved adequate adherence,
and the ARV adherence rate was higher during preg-
nancy than the postpartum period [5].
In sub-Saharan Africa, only a few studies have
assessed ARV adherence during pregnancy and the
postpartum period [6–13]. In these studies, disclosure
of the HIV status was a major factor that affected ad-
herence among pregnant women [6–9, 13]. Other risk
factors for non-adherence included a younger maternal
age, lack of income-generating activity, early enrollment
in the PMTCT services, experiences of discrimination,
and lack of treatment support [6, 7, 9, 13].
ARV adherence is affected by the loss of patient
follow-up [14, 15], and a loss to follow-up has been
commonly observed in the PMTCT program in sub-
Saharan Africa [16–18]. The effects of loss to follow-
up on ARV adherence will become more serious in
the longitudinal ARV regimen newly introduced in
the WHO’s 2010 guidelines. However, few studies
have examined longitudinal ARV adherence and the
effects of the loss to follow-up.
Zambia is one of the countries seriously affected by
HIV, with an estimated HIV prevalence of 12.6 % among
the adult population in 2013 [19]. The national guide-
lines for PMTCT were revised based on option A of the
WHO 2010 guidelines, which were implemented across
the country at the time that the present study was con-
ducted [20]. In accordance with the WHO 2013 guide-
lines, the Zambian government has been shifting to
option B+, which is gradually being introduced at quali-
fied heath facilities. In 2011, the majority of pregnant
women (97 %) attended an antenatal clinic and under-
went HIV testing, and 85 % of HIV-positive pregnant
women received ARVs; however, only 36 % of infants
born to HIV-positive women received ARVs [19]. The
mother-to-child transmission rate was 12 % in 2012
[19]. However, the availability of HIV care/treatment ser-
vices is limited. In 2010, there were 1784 health facilities
in the country, and only 453 (25.4 %) offered HIV care/
treatment services [21]. By 2012, about 110 facilities in-
troduced HIV care/treatment services [19].
Before introducing the WHO 2010 guidelines, several
studies have examined the uptake of ARVs among HIV-
positive women and their infants in Zambia [22–28]. Ac-
cording to these studies, the maternal factors associated
with a missed ARV dose were a longer interval between
HIV testing and delivery [23], no high school-level educa-
tion, lower newborn birth weight [24], maternal age be-
tween 26 and 30 years, multi-gravidity, fewer antenatal
clinic visits, vaginal delivery, single-dose NVP regimen
versus ART regimen [28], illiteracy, and no history of prior
fetal or infant death [22]. In addition, the first diagnosis of
HIV infection during pregnancy is a crucial factor that af-
fects ARV adherence [29]. According to the new guide-
lines, ARV adherence and ART initiation can be affected
by the availability of HIV care/treatment services, wherein
PMTCT services are provided [30]. However, few studies
have focused on these factors that affect ARV adherence
in the PMTCT program in Zambia.
To date, no studies have examined the long-term ARV
adherence under the 2010 national guidelines in Zambia.
An evaluation of longitudinal ARV adherence would
provide a platform to examine the feasibility of the
WHO 2013 guidelines. This study aimed to assess ARV
adherence from pregnancy to 24 weeks postpartum by
considering the effect of loss to follow-up, and identify
risk factors for non-adherence to ARVs.
Methods
Study setting
This prospective cohort study was conducted in
Chongwe district, Zambia from June 2011 to January
2014. At the beginning of the study, there were 39 health
facilities across the district. This study included the
western part of the district as the study site where the
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Chongwe referral health center (HC) and 19 rural HCs
are operated. All of the facilities have implemented the
PMTCT program under the 2010 national guidelines,
and only six provided HIV care/treatment. The Chongwe
referral HC was equivalent to a district hospital, and it
supervised the 19 rural HCs with regards to the imple-
mentation of the PMTCT and HIV care/treatment
programs.
Of these health facilities, 11 were selected as the study
sites. First, we selected all facilities that offered PMTCT
services and HIV care/treatment, including one referral
HC and five rural HCs. The HIV care/treatment was pro-
vided daily at the Chongwe referral HC and fortnightly at
the five rural HCs. Then of 14 rural HCs, we selected five
rural HCs that did not provide HIV care/treatment. At
these facilities, women eligible for ART were referred to
the Chongwe referral HC or one of the five rural HCs that
provided HIV care/treatment. The five rural HCs with no
HIV care/treatment were selected based on the following
inclusion criteria: located within 20 km from a neighbor-
ing health facility offering HIV care/treatment, and deliv-
ery care was provided. Finally, 11 health facilities were
included in the study.
Data collection
HIV-positive women were recruited by nurses or trained
volunteers when they attended PMTCT services from
pregnancy (median 10 weeks before delivery) to the post-
partum period (median six weeks after delivery). During
the study period, we enrolled 360 women in the study,
and analyzed 321 eligible women. Then, 39 women were
excluded for the following reasons: 29 missed key data;
eight had an abortion or stillbirth during pregnancy; and
two were not breastfeeding at recruitment.
During the study period, participants had a maximum
of four interviews at the following periods: during preg-
nancy (first observation), one week postpartum (second
observation), six weeks postpartum (third observation),
and 24 weeks postpartum (forth observation). The cutoff
points for the follow-up observations were set at five
weeks postpartum for the second observation, 23 weeks
postpartum for the third observation, and 52 weeks
postpartum for the fourth observation. All observations
were completed either at the fourth observation, at the
end of the interview survey (October 1, 2012), or at
52 weeks postpartum. The time points for the postpar-
tum observations were decided by considering the tim-
ing of routine PMTCT visits [20].
Structured questionnaires were developed based on
standardized questionnaires produced by the WHO [31],
2007 Zambia Demographic and Health Survey [32], and
Adult AIDS Clinical Trials Group [33, 34]. Through
face-to-face interviews, participants provided their age,
educational level, marital status, type of health facility
(referral HC, rural HCs with HIV care/treatment, or
rural HCs without HIV care/treatment), travel time from
home to the health facility, HIV status at enrollment in
the PMTCT program, timing of study enrollment (preg-
nancy or postpartum), ARV regimen (ARV prophylaxis
or ART), breastfeeding status, internalized stigma (i.e.,
feeling bad about being HIV-positive), and attitude about
taking ARVs with three items (taking ARVs can prevent
HIV transmission to the baby; taking ARVs makes me
healthier; and if I do not take ARVs properly, the
ARVs will not work). Agreement with the three ques-
tions was regarded as having a positive attitude to-
wards ARVs.
As for the partners’characteristics, participants provided
their experience with couple HIV testing and counseling
(CHTC), disclosure of their HIV status to their partner,
HIV status of the partner, and experience with domestic
violence (e.g., verbal abuse, physical abuse, and/or being
forced to leave home) [35]. If a woman reported any of
the three types of domestic violence, it was defined as hav-
ing experienced domestic violence.
Using the PMTCT-related register, we assessed the HIV
status and survival status of infants who were born to the
study participants as of January 2014. During the study
period, these infants were recommended to undergo HIV
testing at six weeks, six months, 12 months, and
18 months of age at the study sites. We examined each
date of HIV testing that the infants had ever undergone. If
an infant had undergone HIV testing more than once,
their latest HIV status was used in the analysis. However,
we were not able to confirm the breastfeeding status at
the time that the infants underwent HIV testing because a
number of information was missing in the register.
Definition of the study outcome
This study examined adherence to ARVs as the primary
outcome. To measure adherence to ARVs, we used the
self-report questionnaire developed by Adult AIDS Clin-
ical Trials Group [36]. Despite the potential risk of over-
estimation, the self-report measurements have been
validated [37], and they are widely used in resource-
limited settings [5]. During the study period, we used
the national PMTCT guidelines based on the option A
of WHO 2010 guidelines [20]. Eleven HCs prescribed
AZT for women not eligible for treatment during preg-
nancy and NVP syrup for HIV-exposed infants during
the postpartum period under the PMTCT program,
whereas triple ARV drugs for women on ART were pre-
scribed from pregnancy to the postpartum period under
the HIV care/treatment service program at the Chongwe
referral HC or at the five rural HCs offering HIV care/
treatment.
Corresponding to the national protocol, ARV adher-
ence was measured differently between women on ARV
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prophylaxis and those on ART. For women on ARV
prophylaxis, maternal adherence was assessed during
pregnancy, and infant adherence was assessed during the
postpartum period. For those on ART, maternal adher-
ence was measured over the assessment period.
For both groups of women, non-adherence was de-
fined as having missed any prescribed drug or having
failed to follow the prescribing schedule at least once in
the four days preceding the interview [7, 38]. Medication
interruption was also defined as non-adherence if it was
detected during the interview (primary definition).
For the women on ARV prophylaxis, the assessment
of ARV adherence was completed on cessation of breast-
feeding and confirmation of the HIV-negative status of
their infants, as there was no longer a risk of HIV trans-
mission to their infants. However, women on ART con-
tinued the assessment of ARV adherence regardless of
the breastfeeding status, as they require lifelong ART.
Additionally, the authors expected that a number of
participants would be lost to follow-up and would likely
not adhere to ARVs during the period of loss to follow-
up [15]. To include participants lost to follow-up in the
analysis, we adopted a broader definition of non-
adherence in which delayed or missed scheduled visits
and reported infant deaths were treated as non-
adherence (secondary definition).
Statistical analysis
In the descriptive analysis, the chi-square test was per-
formed to assess proportional differences in the categor-
ical variables. The ARV adherence rate was calculated at
four observed periods among the women who had
attended the scheduled interviews, which did not include
the women who had missed scheduled visits (primary
definition).
The probability of remaining adherent to ARVs was esti-
mated using the Kaplan-Meier method, which applies the
secondary definition of ARV adherence using the time
from the start of an observation to the detection of non-
adherence to ARVs or interruption of ARV administration
due to loss to follow-up (an event). However, study partic-
ipants may repeat the events during the assessment
period, and the observed record could contain interval-
censored records. To analyze multiple events, the recur-
rent event model was used in the analysis [39]. In this
model, the censorship point adopted the midpoint of the
previous observation and the current non-adherence
events (the main model), as a non-adherent event was
likely to have occurred before it was detected [40]. Obser-
vations were also censored at the midpoint between the
previous observation and the cutoff point of the present
observation if a participant was lost to follow-up. Changes
in the ARV regimen from ARV prophylaxis to ART were
treated as a time-dependent variable.
The proportional hazards assumption was tested using a
log-log survival plot and Schoenfeld residuals. The Cox
proportional hazard regression model was subsequently
tested to identify the risk factors for non-adherence to
ARVs in a backward stepwise model-building procedure.
The final model-building process assigned independent
variables to two groups: those regarded as essential in the
study (i.e., age, educational level, marital status, health fa-
cility type, and timing of HIV diagnosis) were retained re-
gardless of their significance, and other potential
confounders were retained if the p-value was <0.05. In the
Cox proportional hazard models, the potential correla-
tions within individuals were adjusted using robust vari-
ance estimates.
Sensitivity analyses were performed to test the effect of
the time definitions and ARV regimen on the study out-
come. Regarding the effect of the time definition, an alter-
native model was developed in which crude cutoff points
were applied to censorship to estimate the time to detect
a non-adherent event. Subsequently, we assessed any dif-
ferences in the hazard ratios between censorship at the
midpoint (the main model) and at the crude cutoff point
(the alternative model). Similarly, adherence to ARVs
among those on ARV prophylaxis and those on ART were
analyzed separately to examine any differences in the haz-
ard ratios between the two ARV regimens.
The statistical analysis was performed using Stata SE,
version 12 (Stata Corp., College Station, TX).
Ethical considerations
This study was approved by the Institutional Ethics
Committee of the National Center for Global Health
and Medicine, the Research Ethics Committee of the
University of Tokyo, and Biomedical Research Ethics
Committee of the University of Zambia. Written in-
formed consent was obtained from all participants at re-
cruitment. When a participant was found to have any
physical or psychosocial problems (e.g., domestic vio-
lence) through the interview, she was referred to health
workers for further follow-up.
Results
Basic characteristics of the study participants
Table 1 shows the basic characteristics of the 321 HIV-
positive women. The referral HC enrolled 130 women
(40.5 %); the five rural HCs with HIV care/treatment en-
rolled 106 (33.0 %) women; and the five rural HCs with-
out HIV care/treatment enrolled 85 women (26.5 %).
Half of the women (49.8 %) were recruited in the study
during pregnancy. The median age was 29 years (inter-
quartile range [IQR] 24–34), 105 (32.7 %) had achieved
an educational level higher than primary school (eight
years), and 272 (84.7 %) were married or living with a
partner. The median time required to access the nearest
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Table 1 Basic characteristics of study participants
Characteristics Overall Referral HC
a
Rural HCs with HIV care/treatment Rural HCs without HIV care/treatment p-value
‡
N(%) 321 130 (40.5) 106 (33.0) 85 (26.5)
Age
Median (IQR
b
) 29 (24–34) 30 (24–33) 30.5 (26–34) 28 (22–35)
≤29 163 (50.8) 64 (49.2) 48 (45.3) 51 (60.0) 0.1
≥30 158 (49.2) 66 (50.8) 58 (54.7) 34 (40.0)
Educational level
≤Primary 216 (67.3) 76 (58.5) 81 (76.4) 59 (69.4) 0.01
≥Secondary 105 (32.7) 54 (41.5) 25 (23.6) 26 (30.6)
Marital status
Married/living with partner 272 (84.7) 112 (86.2) 95 (89.6) 65 (76.5) 0.04
Other 49 (15.3) 18 (13.9) 11 (10.4) 20 (23.5)
Travel time to health facility
Median (IQR
b
) 60 (30–90) 30 (20–60) 90 (60–120) 60 (35–120)
≤59 min 134 (41.7) 84 (64.6) 21 (19.8) 29 (34.1) <0.01
≥60 min 187 (58.3) 46 (35.4) 85 (80.2) 56 (65.9)
HIV status at PMTCT enrolment
Already known HIV status 162 (50.5) 68 (52.3) 68 (64.2) 26 (30.6) <0.01
Newly diagnosed 159 (49.5) 62 (47.7) 38 (35.9) 59 (69.4)
ARV regimen at study enrolment
ARV prophylaxis 167 (52.0) 66 (50.8) 49 (46.2) 52 (61.2) 0.1
ART 154 (48.0) 64 (49.2) 57 (53.8) 33 (38.8)
Timing of study enrolment
During pregnancy 160 (49.8) 55 (42.3) 62 (58.5) 43 (50.6) 0.05
After delivery 161 (50.2) 75 (57.7) 44 (41.5) 42 (49.4)
Baseline ARV adherence
Adherent 254 (79.1) 102 (78.5) 89 (84.0) 63 (74.1) 0.2
Non-adherent 67 (20.9) 28 (21.5) 17 (16.0) 22 (25.9)
Internalized stigma
Yes 107 (33.3) 46 (35.4) 31 (29.3) 30 (35.3) 0.6
No 214 (66.7) 84 (64.6) 75 (70.8) 55 (64.7)
Attitude on taking ARV
Positive 278 (86.6) 114 (87.7) 90 (84.9) 74 (87.1) 0.8
Negative 43 (13.4) 16 (12.3) 16 (15.1) 11 (12.9)
Couple HIV testing and counseling
Received 129 (40.2) 33 (25.4) 60 (56.6) 36 (42.4) <0.01
Never received 192 (59.8) 97 (74.6) 46 (43.4) 49 (57.7)
Disclosed HIV status to partner
Disclosed 258 (80.4) 109 (83.9) 88 (83.0) 61 (71.8) 0.07
Never disclosed 63 (19.6) 21 (16.2) 18 (17.0) 24 (28.2)
HIV status of partner
Positive 134 (41.7) 58 (44.6) 48 (45.3) 28 (32.9) 0.03
Negative 52 (16.2) 13 (10.0) 23 (21.7) 16 (18.8)
Unknown 135 (42.1) 59 (45.4) 35 (33.0) 41 (48.2)
Okawa et al. BMC Pregnancy and Childbirth (2015) 15:258 Page 5 of 10
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health center was 60 min (IQR 30–90). About half of the
women (49.5 %) were newly diagnosed as HIV-positive
during the current pregnancy, and 154 women (48.0 %)
were already receiving ART at enrollment to the study.
During the baseline interview, 67 women (20.9 %)
were non-adherent to ARVs. One-third (33.3 %) reported
internalized stigma, and 278 (86.6 %) showed positive at-
titudes towards taking ARVs. Moreover, 129 women
(40.2 %) had undergone CHTC, and 258 (80.4 %) had
disclosed their HIV status to their partners. Of all the
women, 134 (41.7 %) reported that their partners were
HIV-positive, 52 (16.2 %) were HIV-negative, and 135
(42.1 %) had an unknown HIV status. Sixty-two women
(19.3 %) reported that they had recently experienced do-
mestic violence.
Self-reported adherence to ARVs at four observation
points
Table 2 shows the proportion of adherence to ARVs
among the women who made the scheduled visits (pri-
mary definition). The ARV adherence rate was 82.5 %
(95 % confidence interval [CI] 76.5–88.5 %) during preg-
nancy, 84.2 % (95 % CI 78.5–89.8 %) at one week post-
partum, 81.5 % (95 % CI 76.1–86.9 %) at six weeks
postpartum, and 70.5 % (95 % CI 62.3–78.7 %) at
24 weeks postpartum. At the 24 weeks postpartum
follow-up, five women reported cessation of breastfeed-
ing. However, they were included in the analysis as all of
them were undergoing ART.
Probability of remaining adherent to ARVs
Figure 1 shows the probability of remaining adherent to
ARVs in all participants, in which loss to follow-up and
infant death were treated as non-adherence (secondary
definition). The probability of remaining adherent to
ARVs was 0.61 (95 % CI 0.56–0.66) at day 50, 0.35 (95 %
CI 0.30–0.39) at day 100, 0.18 (95 % CI 0.14–0.21) at
day 200, and 0.06 (95 % CI 0.04–0.09) at day 300.
Risk factors for non-adherence to ARVs
Before running the Cox proportional hazard models, the
proportional hazard assumption was evaluated using
a log-log survival plot and Schoenfeld residuals, which
showed no significance in the global test (p= 0.8). Over-
all, the model appeared to meet the proportional hazard
assumption. Finally, the risk factors for non-ARV adher-
ence using the secondary definition were estimated using
the Cox proportional hazard models (Table 3).
In the main final model, the women attending rural
HCs providing HIV care/treatment (adjusted hazard ra-
tio [aHR] 0.71, 95 % CI 0.57–0.88) and the women at-
tending rural HCs not providing HIV care/treatment
(aHR 0.58, 95 % CI 0.46–0.74) were more likely to be
adherent than those attending the referral HC. Women
newly diagnosed as HIV-positive during pregnancy (aHR
1.24, 95 % CI 1.03–1.50) were more likely to be non-
adherent than those with a known HIV status before
pregnancy.
Table 1 Basic characteristics of study participants (Continued)
Domestic violence
Experienced 62 (19.3) 28 (21.5) 21 (19.8) 13 (15.3) 0.5
Not experienced 259 (80.7) 102 (78.5) 85 (80.2) 72 (84.7)
a
HC: health center
b
IQR: interquartile range
‡
p-value for Chi-square test
Table 2 Adherence to ARVs at four observation points
a
Observation points Overall Adherent
nn %95%CI
Pregnancy 160 132 82.5 (76.5–88.5)
1 week postpartum 164 138 84.2 (78.5–89.8)
6 weeks postpartum 200 163 81.5 (76.1–86.9)
24 weeks postpartum 122 86 70.5 (62.3–78.7)
a
Self-reported adherence to ARVs for the four days prior to the interview
(primary definition)
Fig. 1 Probability of remaining adherent to ARVs. Definition of
non-adherence to ARVs (secondary definition) includes: missed
doses; not following prescribed schedule; missed visiting for
scheduled interview; loss to follow up; and infant deaths
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Sensitivity analysis
This study performed two sensitivity analyses to assess
the following effects on the study outcome: 1) the time
definition, and 2) ARV regimen. For the time definition,
we utilized two models for the censorship definitions.
The main model used a midpoint between the date of
the previous observation and the cutoff points of the
current observation, whereas the alternative model used
a crude cutoff point. A comparison between the two
models showed that the health facility type was a signifi-
cant predictor in both models. Although the sensitivity
analysis indicated that the definition of time affected the
CIs of the HIV status at PMTCT enrollment, it did not
show changes in the direction of the hazard ratios. Fur-
thermore, a comparison between the two ARV regimens
showed that the health facility type was a significant fac-
tor in both regimen groups, whereas the HIV status at
PMTCT enrollment was a significant factor in the ART
regimen group only.
Mother-to-child transmission of HIV
Table 4 shows the preliminary results of the HIV testing
among infants born to the study participants. During the
study period, the participants had delivered 326 infants,
including five sets of twins. Although the breastfeeding
status could not be confirmed, 262 infants (80.4 %)
underwent HIV testing at the median age of 10.4 weeks
(IQR 6.5–28.6), which was the time that they had the
latest HIV testing, and 11 (3.4 %) were diagnosed as
HIV-positive by January 2014.
Discussion
In this study, the self-reported ARV adherence rate (pri-
mary definition) was over 80 % from pregnancy to six
weeks postpartum, but it decreased to 70 % at 24 weeks
postpartum. Using the broader definition, which treated
the loss to follow-up as non-adherence (secondary defin-
ition), the probability of remaining adherent to ARVs de-
creased considerably over the assessment period. The risk
factors for non-adherence to ARVs were identified using
the secondary definition, which included attending the re-
ferral HC and having a new diagnosis of HIV infection
during the current pregnancy. Potential confounders such
as the timing of study enrollment and the ARV regimen
(ARV prophylaxis/ART) did not affect the study outcome.
The small sample size may be one of the reasons for this
finding. Eighty percent of the infants had undergone HIV
testing, and 3.4 % were HIV-positive, although their
breastfeeding status was unknown.
This study observed poor longitudinal adherence to
ARVs in the PMTCT program. Similar findings were
also reported in studies conducted in other sub-Saharan
African countries [5–9]. An extended ARV regimen was
the major revision in the WHO 2010 guidelines [2]. The
poor longitudinal ARV adherence highlights critical chal-
lenges to implementing the WHO 2010 guidelines. An-
other explanation for this finding would be that this
study was conducted shortly after the introduction of
the new guidelines; thus, the extended regimen may not
have been familiar at the operational level.
In particular, women attending the referral HC showed
poorer adherence to ARVs than those attending rural
HCs. In previous studies, easier access to health facilities
was found to facilitate better ARV adherence [10]. In this
study, women attending the referral HC reported a
shorter travel time to the health facility than those at-
tending rural HCs, which did not seem to influence their
adherence. Potential reasons could be a poor quality of
PMTCT services provided at the referral HC, which
would be attributed to a large number of PMTCT clients
per health worker. For example, only a quarter of the
participants attending referral HC reported that they
attended CHTC, whereas >40 % attended CHTC at
Table 3 Risk factors for non-adherence to ARV
Variables Main-final model
aHR
a
95 % CI
Age
≤29 1.00
≥30 0.99 (0.82–1.19)
Educational level
≤Primary 1.00
≥Secondary 0.91 (0.75–1.11)
Marital status
Married/living with partner 1.00
Other 1.03 (0.80–1.34)
Facility type
Referral HC 1.00
Rural HCs with HIV care/treatment 0.71 (0.57–0.88)
Rural HCs without HIV care/treatment 0.58 (0.46–0.74)
HIV status at PMTCT enrolment
Already known HIV status 1.00
Newly diagnosed 1.24 (1.03–1.50)
Cox proportional hazard regressions
a
aHR: adjusted hazard ratio
Table 4 Preliminary results of the HIV testing among HIV-
exposed infants
HIV status Number Percent
HIV positive 11 (3.4)
HIV negative 251 (77.0)
Unknown 64 (19.6)
As of January 2014
Okawa et al. BMC Pregnancy and Childbirth (2015) 15:258 Page 7 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
other rural HCs. The gap in CHTC attendance may
affect their adherence to ARVs [41–43] and the loss to
follow-up [26]. A higher number of HIV patients per
health workers can also increase the risk of loss to
follow-up at the facility [44].
Furthermore, in rural HCs, the limited availability of la-
boratory and clinical services did not affect women’sad-
herence to ARVs. This may be because the fewer number
of PMTCT clients at rural HCs may allow health workers
to provide effective adherence support. Similarly, a study
conducted in Malawi reported that continuous follow-up
by community health workers has contributed to
utilization and retention in the PMTCT program [45].
Regarding the service provision system at the time of
implementing this study, the women needed to be trans-
ferred to other health facilities with HIV care/treatment
services. However, only 25 % of health facilities offered
HIV care/treatment services in Zambia in 2010 [21].
Such limited availability of the HIV care/treatment could
be an obstacle for the transfer of HIV-positive women to
the HIV care/treatment, which would result in loss to
follow-up and treatment interruption [46]. The Zambian
government has been expanding option B+ across the
country since 2013, and all target facilities of the study
have introduced option B+ by August 2015. In option B
+, women attending rural HCs without HIV care/treat-
ment services will face the challenge of continuing ART
even after completing the PMTCT program. To imple-
ment option B+ across the country, effective planning is
required to expand the HIV care/treatment services to
all rural HCs simultaneously.
In this study, the women newly diagnosed as HIV-
positive were more likely to be non-adherent than those
with a known HIV status before pregnancy. A similar find-
ing was reported in a previous study [29]. This implies
that women who are newly diagnosed as HIV-positive
have specific characteristics. First, the newly diagnosed
women have to handle the physical and psychosocial chal-
lenges such as giving birth to a child with a risk of HIV in-
fection, disclosing their HIV status to family members,
following the daily routine of medication, and experien-
cing the side effects of ARVs [10, 47]. Second, they may
not completely understand the importance of ARV adher-
ence because they are more likely to be diagnosed during
the asymptomatic stage; thus, they are less likely to experi-
ence the efficacy of ARV drugs [29, 48]. Third, they may
have some misconceptions or negative impressions of
HIV treatment [47].
In newly diagnosed women, psychosocial support
and health education would be essential interventions
to overcome multiple challenges and establish good
adherence to ARVs. Thus, it would be important to
ensure referral of the newly diagnosed HIV-positive
women to HIV care/treatment services where they are
able to receive comprehensive care and support that
may not be provided in the PMTCT program. How-
ever, only six facilities provided HIV care/treatment
services at the study site, which is common in other
parts of Zambia. This suggests that further effort is
required to strengthen the linkage between the
PMTCT and HIV care/treatment programs [46].
To mitigate psychosocial challenges following ante-
natal HIV diagnosis, women should be encouraged to
undergo HIV testing before pregnancy. This will re-
duce the number of pregnant women who are not
aware of their HIV status until the first antenatal
visit. Furthermore, early awareness of their HIV status
would encourage women to abstain from risky sexual
behavior, which would reduce the risk of HIV trans-
mission to their children and partners [49]. Moreover,
this approach would provide the benefit of primary
HIV prevention among the population of reproductive
age. In this study, however, half of the participants
did not know their HIV status, and 40 % did not
know their partners’HIV status. Similarly, nearly
70 % of HIV-positive men and 50 % of HIV-positive
women in Zambia are reported to have never been
tested before their first HIV-positive diagnosis [32].
Thus, the promotion of regular testing of all sexually
active women of reproductive age would increase the
benefits associated with PMTCT strategies.
This study has several limitations. First, the small
sample size may limit the statistical power and affect
the study findings, and it may affect the generalizability
of our findings. Second, variation in the timing of study
enrollment may cause selection bias even though we
statistically adjusted and confirmed that the study out-
come was not affected by the timing of study enroll-
ment.Third,thisstudyusedasinglemeasurementof
self-reported ARV adherence, which was potentially af-
fected by recall bias and social desirability bias. Forth,
this study may have overestimated the incidence of
non-adherence due to use of a broad definition of ARV
adherence. However, this is an operational research
using intention-to-treat analysis, which was designed to
observe the standard practice of the PMTCT program.
Finally, given the observational nature of this analysis,
theresultsmaybebiasedowingtotheunmeasured
confounders at the individual, facility, or community
level.
Conclusions
The PMTCT program in Zambia is facing a crucial
operational challenge of poor adherence to ARVs over
the high-risk period of mother-to-child transmission.
All health facilities should strengthen the support for
ARV adherence and retention in care from pregnancy
to the cessation of breastfeeding.
Okawa et al. BMC Pregnancy and Childbirth (2015) 15:258 Page 8 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Abbreviations
HIV: Human immunodeficiency virus; WHO: World Health Organization;
PMTCT: Prevention of mother-to-child transmission of HIV;
ARV: Antiretroviral; AZT: Zidovudine; NVP: Nevirapine; ART: Antiretroviral
therapy; HC: Health center; CHTC: Couple HIV testing and counseling;
IQR: Interquartile range; aHR: Adjusted hazard ratio.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
SO conducted the study design and analysis, supervised data collection,
and drafted the manuscript. MC participated in the study design,
supervised data collection, and drafted the manuscript. NI conducted
the study design, supervised data collection, and drafted the manuscript.
HK participated in the study design and supervised data collection. CYM,
GS, SM, and KK supervised data collection. MJ and JY supervised the
study design and data analysis, and helped to draft the manuscript.
All authors reviewed and approved the final manuscript.
Acknowledgements
The authors would like to acknowledge the Scaling up of Quality HIV/AIDS
Care Service Management Project (SHIMA Project), Zambia Ministry of Health,
Japan International Cooperation Agency, and National Center for Global
Health and Medicine for all their support provided to facilitate this study.
We would like to express our great appreciation to Assistant Professor Stuart
Gilmour and Professor Kenji Shibuya at Department of Global Health Policy,
Graduate School of Medicine, The University of Tokyo, and Dr. Shinya
Tsuzuki, Mr. Paul Kalichini, and Mr. Seishi Kobayashi for their technical
support.
Author details
1
Department of Community and Global Health, Graduate School of
Medicine, The University of Tokyo, Tokyo, Japan.
2
Chongwe District
Community Health Office, Chongwe, Zambia.
3
Ministry of Health
Zambia-Japan International Cooperation Agency SHIMA project, Lusaka,
Zambia.
4
National Center for Global Health and Medicine, 1-21-1 Toyama,
Shinjuku-ku, Tokyo 162-8655, Japan.
5
Ministry of Health, Lusaka, Zambia.
Received: 29 January 2015 Accepted: 6 October 2015
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