7a Fee ART

BUILDING NEW KNOWLEDGE SUPPLEMENT
Predictors of loss to follow-up among

children in the first and second
years of antiretroviral treatment
in Johannesburg, South Africa
Mazvita Sengayi1,2*, Ntabozuko Dwane2, Edmore Marinda2,
Nosisa Sipambo1, Lee Fairlie1 and Harry Moultrie1,2
1
Wits Reproductive Health and HIV Research Institute, Faculty of Health Sciences, University of the
Witwatersrand, Johannesburg, South Africa; 2School of Public Health, Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg, South Africa
Background: Ninety percent of the worlds 2.1 million HIV-infected children live in sub-Saharan Africa, and
2.5% of South African children live with HIV. As HIV care and treatment programmes are scaled-up, a rise in
loss to follow-up (LTFU) has been observed.
Objective: The aim of the study was to determine the rate of LTFU in children receiving antiretroviral
treatment (ART) and to identify baseline characteristics associated with LTFU in the first year of treatment.
We also explored the effect of patient characteristics at 12 months treatment on LTFU in the second year.
Methods: The study is an analysis of prospectively collected routine data of HIV-infected children at the
Harriet Shezi Childrens Clinic (HSCC) in Soweto, Johannesburg. Cox proportional hazards models were
fitted to investigate associations between baseline characteristics and 12-month characteristics with LTFU in
the first and second year on ART, respectively.
Results: The cumulative probability of LTFU at 12 months was 7.3% (95% CI 7.18.8). In the first 12 months
on ART, independent predictors of LTFU were age B1 year at initiation, recent year of ART start, mother as
a primary caregiver, and being underweight (WAZ 52). Among children still on treatment at 1 year from
ART initiation, characteristics that predicted LTFU within the second year were recent year of ART start,
mother as a primary caregiver, being underweight (WAZ 52), and low CD4 cell percentage.
Conclusions: There are similarities between the known predictors of death and the predictors of LTFU in the
first and second years of ART. Knowing the vital status of children is important to determine LTFU.
Although HIV-positive children cared for by their mothers appear to be at greater risk of becoming LTFU,
further research is needed to explore the challenges faced by mothers and other caregivers and their impact on
long-term HIV care. There is also a need to investigate the effects of differential access to ART between
mothers and children and its impact on ART outcomes in children.
Keywords: HIV; antiretroviral treatment; children; loss to follow-up; South Africa
Received: 31 July 2012; Revised: 13 November 2012; Accepted: 13 November 2012; Published: 24 January 2013
ub-Saharan Africa is home to 90% of the worlds

2.1 million HIV-infected children. Of all the people
living with HIV in sub-Saharan Africa, 10% are
children (1). In South Africa at the end of 2009, 330,000
children were infected with HIV and the prevalence
of HIV in children aged between 2 and 14 years was
2.5% (1.93.5%) (2, 3). The number of patients receiving
antiretroviral treatment (ART) at PEPFAR-supported
government sites in South Africa increased nearly 20-fold
in 5 years from 33,500 in 2005 to 632,000 in 2009 (4).
In the same period, paediatric ART programmes in

South Africa have seen an over 50-fold increase in
average monthly patient enrolments from 2 to 106 (5).
The impact of this rapid expansion of ART programmes
on quality of care is a cause of concern.
The study of loss to follow-up (LTFU) and other
treatment outcomes in HIV care has been used to
monitor and improve programme effectiveness, using
patient retention as a measure of quality of care (6).
While children in HIV care programmes have a much
Glob Health Action 2013. # 2013 Mazvita Sengayi et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-169
Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, and reproduction
in any medium, provided the original work is properly cited.
Citation: Glob Health Action 2013, 6: 19248 - http://dx.doi.org/10.3402/gha.v6i0.19248
(page number not for citation purpose)
Mazvita Sengayi et al.
higher retention than adults, a rise in LTFU has been

observed as paediatric HIV care programmes scaleup (79). A trend of increasing LTFU over time was
observed in a pooled analysis of the 16 paediatric HIV
care programmes in sub-Saharan Africa which form
the Kids Antiretroviral Treatment in Lower-Income
Countries (KIDS-ART-LINC) Collaboration. The risk
of LTFU was 2.8% (95% CI 1.94.1) at 6 months, 4.6%
(95% CI 3.46.2) at 1 year, and 8.4% (95% CI 6.510.7)
at 2 years (7).
Most children initiating ART in resource-poor settings
start treatment at advanced stages of illness leading
to high mortality rates especially in the first 3 months
of ART initiation (1, 1012). These early deaths if
unreported may be misclassified as early LTFU. The
risk factors of LTFU in the first year and second year of
ART may differ. It is therefore important to examine the
risk factors of LTFU in the first year on ART and explore
whether these differ with predictors of LTFU after
surviving the first year on ART. This is potentially useful
in making recommendations for patient retention in
paediatric HIV care programmes.
The aim of the present study was to determine the rate
of LTFU in children receiving ART and to identify
baseline characteristics associated with LTFU in the first
year on treatment. We also explored the effect of patient
characteristics at 12 months on LTFU in the second year
on treatment.
Methods
Study population
The study is an analysis of prospectively collected routine
data of HIV-infected children at the Harriet Shezi
Childrens Clinic (HSCC) in Soweto. The HSCC is a large
urban paediatric HIV treatment clinic situated at the
Chris Hani Baragwanath Academic Hospital, a referral
hospital in Johannesburg. Since 1 April 2004, HSCC
has treated children with government-funded ART. All
children enrolled at HSCC are HIV-infected and ART
is started based on current South African national guidelines. The 2004 national guidelines recommended ART
for HIV-positive children with recurrent (two admissions
per year) or prolonged (4 weeks) hospitalization, WHO
clinical stage 3 and 4, or CD4 cell percentage B20% in
children under 18 months and B15% for older children
(13). The 2010 treatment guidelines recommend ART
initiation for all HIV-positive children aged B1 year,
for children aged 15 years with clinical stage 3 or 4 or
CD4 525% or absolute CD4 count B750 cells/mm3, and
for children 5 years with clinical stage 3 or 4 or CD4
B350 cells/mm3 (14). Ethical approval for this study was
granted by the University of Witwatersrand Committee
for Research on Human Subjects.
170
All children B12 years of age who started ART at

HSCC between 1 April 2004 and 30 October 2011 were
included in the study. Twelve years was used as a cut-off
because older children might have unique predictors of
LTFU compared to younger children, and may be able
to attend clinic visits on their own. Only children with a
minimum follow-up time of 6 months before date of
database closure were included in the study. The date
of database closure was 30 April 2012. Children with
follow-up time of B1 day (who never returned to the
clinic after the day of initiation) were excluded from the
analysis.
Procedures
A child was defined as LTFU if their last date of
contact with the clinic was 6 months before the date
of database closure (30 April 2012), and they were not
known to have died or transferred. Baseline exposure
variables were as follows: age, sex, year of ART initiation;
primary caregiver relationship; anthropometric measures
(weight-for-age Z score (WAZ); height-for-age Z score
(HAZ) and weight-for-height Z score (WHZ)); WHO
clinical stage; CD4 cell percentage; immune suppression
(as defined by the 2006 WHO classification of HIVassociated immunodeficiency in children using CD4 cell
count and age) (15); log10 of plasma HIV viral load;
and ART regimen. Age was categorised into the following
categories: B1 year, 1 to B3 years, 3 to B5 years, and
5 years to 12 years. Updated 12-month characteristics
were used to investigate LTFU in the second year on
ART. The United Nations General Assembly Special
Session (UNGASS) on HIV/AIDS recommends reporting of 12-month outcomes of patients on ART and
yearly thereafter as indicators of programme retention
(16). This guided the selection of the 12-month cut-off
in the analysis.
Statistical analysis
Continuous variables were tested for the assumption of
normality using histograms and normal quantile plots.
Categorical variables were described using frequencies;
normally distributed continuous variables in terms of
mean and standard deviation; non-normal continuous
variables in terms of median and inter-quartile range.
Time-to-event analysis was the primary method of
analysis. In the analysis for LTFU in the first year on
ART, person-time accrued from date of ART initiation
to the earliest of (1) date of last visit, or (2) date at
12 months from ART initiation, or (3) date of database
closure (30 April 2012). Cumulative probabilities of
LTFU and period incidence rates were calculated.
KaplanMeier curves were plotted and were compared
using log rank tests. Cox proportional hazards models
were fitted to investigate associations between baseline
characteristics and LTFU. Global tests (using Schoenfeld
Loss to follow-up in children
and scaled Schoenfeld residuals) were used to test for

validity of the proportional hazards assumption. Similarly, in the analysis of LTFU in the second year on ART,
person-time accrued from 12 months post ART initiation
to the earliest of (1) date of last visit, or (2) date at 24
months from ART initiation, or (3) date of database
closure (30 April 2012). Variables included in the multivariate models were age, year of ART start, primary
caregiver relationship, WAZ, and CD4 cell percentage.
These variables were selected based on findings of
other studies (5, 7, 8, 17), WHZ and HAZ were excluded
for collinearity with WAZ, and regimen was excluded
because the age at initiation determined regimen selection
(13, 14).
Stata version 11 (Stata Corporation, College Station,
Texas, USA) software package was used for all statistical
analyses.
Results
Cohort description
A total of 4,266 children enrolled between 1 April 2004
and 30 October 2011 were included in the study. A flow
chart of children included in the study is shown in Fig. 1.
Characteristics at baseline and at 12 months on treatment
and the proportion of missing data for each variable
are presented in Table 1. The median age was 4.2 years
(IQR 1.47.4), and 48.7% (2078) of them were female.
The majority of children (52.2%) had mothers as their
primary caregivers at ART initiation. More than twothirds of children had advanced/severe immunodeficiency
(68.6%) at the start of treatment, and 73.7% had WHO
clinical stage 3 or 4 disease. The mean CD4 cell percentage was 14.5% (SD 9.3) at baseline, and the mean
log10 of HIV plasma viral load was 11.4 copies per
millilitre (SD 2.6). Baseline regimens had either a
protease inhibitor (PI) backbone (47.4%) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) backbone (44.2%). At 12 months after starting treatment,
49.1% of the children in care were female and 52% had
mothers as their caregivers. The proportion of children
with advanced/severe immune suppression dropped to
48.1%, the mean log10 of plasma viral load dropped
to 5.8 copies/mL (SD 3.6), and the mean CD4 cell
percentage was 23.6 (SD 9.5).
LTFU in the first year on ART
In the first year on ART, a total of 323 children were lost
to follow-up (7.6%). There were a total of 3832.8 childyears of follow-up, and the overall incidence of LTFU in
the first 12 months was 8.4 per 100 child-years (95% CI
7.69.4). The incidence of LTFU was highest in the first
3 months on ART with a period incidence rate of 13.6 per
100 child-years (95% CI 11.616.1). The cumulative
probability of LTFU at 12 months was 7.3% (95% CI
7.18.8). There were 113 reported deaths and 202 known

transfers in the first year (Fig. 1).
Age group, year of ART initiation, primary caregiver relationship, WAZ, and CD4 cell percentage were
included in the multivariable Cox model to identify independent predictors of LTFU in the first year (Table 2).
Older children were less likely to become LTFU than
infants [HR 0.5 (95% CI 0.30.8) and HR 0.6 (0.40.9)
for children aged 3 to B5 years and 512 years, respectively]. Children initiating ART in 200608 were twice
as likely to become LTFU as those who initiated in 2004
05 [HR 2.1 (1.23.5)], and those initiating ART between
2009 and 2011 were five times more likely to become
LTFU [HR 4.9 (2.98.2)]. Children whose biological
mother was their primary care giver had the highest
risk of LTFU. Having a grandmother [HR 0.1 (0.040.3)],
other relatives [HR 0.6 (0.40.9)], or non-family caregivers [HR 0.4 (0.20.8)] as primary caregivers at baseline
was significantly associated with a lower risk of LTFU
than being cared for by the childs mother. Kaplan Meier
plots also showed the increased risk of LTFU in children
cared for by their mothers (Fig. 2). Severely underweight
children (WAZ B3) were over three times more likely to
become LTFU than well-nourished children [HR 3.6
(2.55.3)]. CD4 cell percentage had no effect on risk of
LTFU in the first year [HR 1.0 (0.991.0)].
LTFU in the second year on ART

At the end of 12 months from the start of ART, 3,460
children (81.1%) were still in care at HSCC. These
children contributed a total of 3,064.4 child-years and
the overall incidence of LTFU in the second year on
ART was 5.0 per 100 child-years (95% CI 4.25.8). The
cumulative probability of LTFU at the end of the second
year was 4.9% (95% CI 4.25.7). There were 32 reported
deaths and 294 known transfers in the second year
(Fig. 1).
Table 3 shows adjusted and unadjusted hazard ratios
for the effect of characteristics at 12 months treatment on
LTFU in the second year. Age group at 12 months was
not significantly associated with LTFU in the second year
on ART. Children initiating ART in 200608 were twice
as likely to become LTFU as those who initiated in 2004
05 [HR 1.9 (1.13.1)], and those initiating ART between
2009 and 2011 were nearly three times more likely to
become LTFU [HR 2.7 (1.64.5)]. Children cared for by
their grandmothers [HR 0.3 (0.10.6)] and other relatives
[HR 0.6 (0.30.8)] had a lower risk of LTFU than those
cared for by their biological mothers. Children who were
still severely underweight after 1 year on ART were three
times more likely to become LTFU than those who were
well-nourished [HR 2.9 (1.94.5)]. The hazard of LTFU
decreased by 3% for every unit increase in CD4 cell
percentage [HR 0.97 (0.960.99)].
171
5118 children started

ART at HSCC
between 01 April
2004 and 30 April 2012
461 excluded: age>12 at ART
initiation
187 excluded: started ART <6 months
before database closure (30 April
2012)
204 excluded: follow -up time = zero
(never returned after initiation)
4266 children included
in the study
113 reported deaths

in the
first year
202 known
transfers in the
first year
323 Lost to follow
up in the
first year on ART
3460 In care at the end

of 12 months
from ART initiation
32 Reported deaths
in the second
year on ART
294 Known
transfers in the
second year on ART
152 Lost to follow
up in the second
year on ART
2643 on ART at the end

of 24 months
from initiation
Fig. 1. Flow chart of HIV-infected children initiating ART at HSCC between 01 April 2004 and 30 April 2012.
Sensitivity analyses
Missing CD4 cell percentage values at baseline were
imputed using the multivariate normal method, and the
multivariate Cox model for the first year was re-run using
the imputed values and compared with the multivariate
Cox model using the original data, and similar results
were obtained (Table 4). The multivariate Cox models
were also re-run using age and year of start as continuous
variables and compared with the Cox models with
categorised age and year of start using likelihood ratio
tests (Tables 4 and 5). There were no significant differences in models. Tests for linear trend confirmed a
linear relationship between year of ART start and LTFU
in the first and second year (Tables 4 and 5). Age group
172
had a linear relationship with LTFU in the second year

on ART (Table 5).
Discussion
As in other paediatric HIV care programmes in subSaharan Africa (8, 10), the majority of children initiated
ART at advanced stages of disease having WHO stage
3 or 4 and advanced or severe immune suppression.
Incidence of LTFU in this study was 8.4 and 5.0 per
100 child-years in the first and second year of ART,
respectively.
In the first year on ART the incidence rate of LTFU
was highest in the first 3 months. This mirrors the
previously reported high rate of death in the first
Table 1. Overall cohort characteristics at baseline (N4,266) and at 12 months on treatment (N3,640)
Baseline
Characteristic
12-month characteristics
%
Sex
Male
2188
51.3
1760
50.9
Female
2078
48.7
1700
49.1
B1 year
823
19.3
1 to B3 years
3 to B5 years
949
634
22.3
14.9
998
587
28.8
17.0
5 to 12 years
1860
43.6
1875
54.2
Median age, years (IQR)
4.2 (1.47.4)
Age
5.2 (2.48.5)
Year of starting ART

200405
969
22.7
865
25.0
200608
1742
40.8
1548
44.7
200911
1555
36.5
1047
30.3
Mother
2226
52.2
1800
52.0
Grandmother
641
15.0
594
17.2
Other family
827
19.4
741
21.4
Primary caregiver
Foster/institution/neighbour/guardian
301
7.1
256
7.4
Data missing
271
6.4
69
2.0
2 (not underweight)

2 to 3 (moderately underweight)
3112
461
73.0
10.8
2430
543
70.2
15.7
Weight-for-age Z score
B3 (severely underweight)
369
8.7
426
12.3
Data missing
324
7.6
61
1.8
Mean WAZ (standard deviation)
0.1 (2.6)
Height-for-age Z score
2 (no stunting)
68.2
2850
2 to 3 (moderate stunting)
90
2.1
126
3.6
B3 (severe stunting)
39
0.9
46
1.3
Data missing
1226
28.7
438
12.6
Mean HAZ (standard deviation)
2.7 (3.2)
Weight-for-height Z score
2 (no wasting)
2911
0.8 (2.1)
82.4
1.9 (2.8)
1273
29.8
1145
33.1
2 to 3 (moderate wasting)
421
9.9
406
11.7
B3 (severe wasting)
832
19.5
841
24.3
Data missing
1740
40.8
1068
30.9
Mean (standard deviation)
2.2 (2.2)
Immune suppression
Mild
Advanced/severe
2.2 (2.1)
263
2927
6.2
68.6
1639
1663
47.4
48.1
1076
25.2
158
4.6
1/2
621
14.6
558
16.1
3/4
3144
73.7
2815
81.4
Data missing
501
11.7
87
1327
31.11
2701
78.1
1883
44.14
617
17.8
Data missing
WHO clinical stage
CD4 cell percentage

]15%
B15%
2.5
173
Table 1 (Continued)
Baseline
Characteristic
Data missing
1056
14.5 (9.3)
12-month characteristics
%
24.75
N
142
%
4.1
23.6 (9.5)
Log10 of plasma viral load (copies/mL)

Data missing
1158
11.4 (2.6)
27.1
177
5.1
5.8 (3.6)
Initial regimen
NNRTI-based
1884
44.2
1251
36.2
PI-based
Data missing
2024
350
47.4
8.4
1405
804
40.6
23.2
Definitions of immune suppression according to the 2006 WHO classification of HIV-associated immunodeficiency in children by age and
CD4%: (children B1 year: mild CD4% of 3035%, advancedCD4% of 2529%, severeCD4% B25%; children 1 to B3 years:
mildCD4% of 2530%, advanced CD4% of 2025%, severeCD4% B20%; children 3 to B5 years: mild CD4% of 2025%,
advanced CD4% of 1519%, severeCD4% B15%; children 5 years: mildCD4 cell count 350499 cells/mm3, advanced CD4
cell count 200349 cells/mm3, severeCD4 cell count B200 cells/mm3 or CD4% B15%) (14).
WHO: World Health Organization; NNRTI: non-nucleoside reverse transcriptase inhibitor (efavirenz or niverapine); PI: protease inhibitor
(lopinavir/ritonavir).
90 days on ART (18) and may be partly attributable to

unreported early mortality. The cumulative probability of
LTFU at 12 months was 7.3% (95% CI 7.18.8). This is
comparable with the 1-year LTFU rate of 7% reported by
the International epidemiologic Databases to Evaluate
AIDS in Southern Africa (IeDEA-SA) study in a pooled
analysis of 10 paediatric ART programmes from South
Africa, Malawi, Mozambique, and Zimbabwe (10). The
incidence of LTFU in Asian children on ART with an
average follow-up time of 3 years was found to be lower
at 4.2 per 100 person-years (19). In the first 12 months on
ART, independent predictors of LTFU were age B1 year
at initiation, recent year of ART, having ones biological
mother as a primary caregiver, and being underweight
(WAZ 52). The risk of LTFU increased progressively
Fig. 2. KaplanMeier estimates of cumulative probability

of LTFU by caregiver relationship during the first year and
second year on ART.
174
in successive enrolment calendar periods with those

initiated between 2009 and 2011 having the highest
LTFU. This increase in LTFU in children enrolled in
more recent years is consistent with findings of studies
of ART outcomes in similar settings (8, 17). This might
reflect the effect of rapid scale-up and subsequently
higher workloads on quality of care. A study of temporal
trends in four South African provinces which comprised
smaller, rural paediatric cohorts did not demonstrate
the same progressive increase in LTFU in subsequent
calendar cohorts as shown in this study (5). This suggests
that the increase in LTFU might be related to rapid ART
scale-up in large urban cohorts where the impact of high
workloads on quality of care would be significant.
Haitian children who were LTFU had lower baseline
median WAZ (3, IQR 3.7 to 1.8) than those
retained in care (20). WAZ is a marker of disease severity
associated with mortality in the HSCC cohort (18).
Among children who were still in care at 12 months
since ART initiation, 12-month characteristics which
predicted LTFU were recent year of ART, having ones
biological mother as a primary caregiver, and being
underweight (WAZ 52). The hazard of LTFU in the
second year decreased by 3% for every unit increase
in CD4 cell percentage. Baseline CD4 cell percentage
had no effect on LTFU in the first year on ART,
but children who still had a low CD4% after 12 months
on ART were more likely to get LTFU in the second
year. This may be explained by possible suboptimal
adherence and consequent higher risk of death in
children with a poor immune response at 12 months.
Table 2. Baseline characteristics associated with LTFU in the first year on ART
Characteristic
Unadjusted HR (95% CI)
Adjusted HR* (95% CI)
Sex
Male
Female
0.94 (0.761.17)

0.580
Age at ART initiation

B1 year
1 to 3 years
0.79 (0.611.04)
B0.093
1
1.15 (0.791.69)
0.458
3 to B5 years
0.30 (0.190.45)
B0.001
0.47 (0.270.83)
0.009
5 to 12 years
0.31 (0.240.42)
B0.001
0.61 (0.410.93)
0.020

200405
200608
2.48 (1.563.93)
B0.001
2.05 (1.213.49)
1
0.008
200911
6.28 (4.059.75)
B0.001
4.90 (2.928.20)
B0.001
Primary caregiver
Mother
Grandmother
0.13 (0.070.26)
B0.001
0.12 (0.040.31)
1
B0.001
Other family
0.45 (0.320.63)
B0.001
0.57 (0.370.88)
0.011
0.43 (0.250.76)
0.003
0.38 (0.180.82)
0.013
2 (not underweight)
3.38 (2.524.53)
B0.001
1
2.71 (1.903.88)
B0.001
4.83 (3.616.49)
B0.001
3.64 (2.515.27)
B0.001
2 (no stunting)
11.10 (7.2816.93)
B0.001
15.17 (8.5227.02)
B0.001
2 (no wasting)
0.89 (0.581.37)
0.592
B3 (severe wasting)
0.43 (0.280.67)
B0.001
Immune suppression
Mild
Advanced/severe
0.49 (0.330.71)
WHO clinical stage

1/2
3/4

B0.001
1
1.37 (0.951.98)
0.090
CD4 cell percentage
1.04 (1.021.05)
B0.001
1.10 (1.041.16)
B0.001
1.01 (0.991.02)
0.212
Initial regimen
NNRTI-based
PI-based
2.45 (1.883.21)

B0.001
*N 3078 for adjusted model.

Definitions of immune suppression according to the 2006 WHO classification of HIV-associated immunodeficiency in children by age
and CD4%: (children B1 year: mild CD4% of 3035%, advanced CD4% of 2529%, severeCD4% B25%; children 1 to B3 years:
mild CD4% of 2530%, advanced CD4% of 2025%, severeCD4% B20%; children 3 to B5 years: mild CD4% of 2025%,
advanced CD4% of 1519%, severeCD4% B15%; children 5 years: mildCD4 cell count 350499 cells/mm3, advanced CD4
cell count 200349 cells/mm3, severeCD4 cell count B200 cells/mm3 or CD4% B15%) (14).
175
Table 3. The effect of 12-month characteristics on LTFU in the second year on ART
Characteristic
Unadjusted HR (95% CI)
Adjusted HR* (95% CI)
Sex
Male
Female
1.15 (0.831.8)
0.399
Age at 12 months on ART

1 to B3 years
3 to B5 years
0.82 (0.531.29)
0.397
1
1.19 (0.741.91)
0.471
5 to 12 years
0.58 (0.410.83)
0.003
0.88 (0.581.35)
0.566

200405
200608
1.91 (1.193.08)
0.007
1.85 (1.123.07)
1
0.017
200911
2.84 (1.734.66)
B0.001
2.68 (1.584.55)
B0.001
Primary caregiver
Mother
Grandmother
0.23 (0.120.46)
B0.001
1
0.30 (0.150.59)
Other family
0.41 (0.260.67)
B0.001
0.49 (0.300.82)
0.006
0.63 (0.331.20)
0.155
0.59 (0.281.21)
0.150
0.001
2 (not underweight)
2.09 (1.373.18)
0.001
1
1.97 (1.283.04)
0.004
3.51 (2.385.18)
B0.001
2.93 (1.914.47)
B0.001
2 (no stunting)
5.05 (2.609.81)
B0.001
13.52 (6.1929.55)
B0.001
2 (no wasting)
0.55 (0.281.09)
0.081
B3 (severe wasting)
0.64 (0.391.03)
0.068
Immune suppression
Mild
Advanced/Severe
1.74 (1.232.46)
0.002
WHO clinical stage

1/2
3/4
1.46 (0.882.43)
0.140
CD4 cell percentage
0.98 (0.960.99)
0.007
1.17 (1.121.21)
B0.001
0.97 (0.960.99)
0.004
Regimen at 12 months
NNRTI-based
PI-based
1.43 (0.932.20)
0.099
*N3,283 in adjusted model.
Definitions of immune suppression according to the WHO classification of HIV-associated immunodeficiency in children by age and
CD4%: (children B1 year: mildCD4% of 3035%, advanced CD4% of 2529%, severeCD4% B25%; children 1 to B3 years:
mildCD4% of 2530%, advanced CD4% of 2025%, severeCD4% B20%; children 3 to B5 years: mild CD4% of 2025%,
advanced CD4% of 1519%, severe CD4% B15%; children 5 years: mildCD4 cell count 350499 cells/mm3, advanced CD4
cell count 200349 cells/mm3, severe CD4 cell count B200 cells/mm3 or CD4% B15%) (14).
176
Table 4. Sensitivity analyses: LTFU in the first year

Model B (imputed CD4%
Model C (age and year of
missing values)
start as continuous)
Model A (original)
Characteristic
HR (95% CI)
HR (95% CI)
B1 year
1 to B3 years
1.15 (0.791.69)
0.458
0.89 (0.661.21)
0.452
3 to B5 years
0.47 (0.270.83)
0.009
0.39 (0.240.63)
B0.001
5 to 12 years
0.61 (0.410.93)
0.020
0.49 (0.350.69)
B0.001
HR (95% CI)
0.93 (0.880.97)
0.002
1.36 (1.261.47)
B0.001
Age at HAART initiation

1
Age (as continuous variable)

200405
200608
2.05 (1.213.49)
0.008
2.08 (1.273.39)
1
0.003
200911
4.90 (2.928.20)
B0.001
4.67 (2.907.50)
B0.001

(as a continuous variable)
Primary caregiver
Mother
Grandmother
Other family
0.12 (0.040.31)
0.57 (0.370.88)
B0.001
0.011
1
0.18 (0.090.37)
0.64 (0.450.93)
B0.001
0.018
0.12 (0.040.31)
0.57 (0.370.87)
1
B0.001
0.010
Non-family
0.38 (0.180.82)
0.013
0.49 (0.270.87)
0.015
0.40 (0.190.86)
0.019
2
2 to 3
2.71 (1.903.88)
B0.001
2.96 (2.194.00)
B0.001
2.75 (1.923.93)
B0.001
B3
3.64 (2.515.27)
B0.001
4.06 (3.015.49)
B0.001
3.57 (2.485.18)
B0.001
1.01 (0.991.02)
0.212
1.01 (0.991.02)
0.443
1.01 (0.991.02)
0.383
CD4 cell percentage
Likelihood ratio test between Model A and Model C showed that there was no difference between the model (p0.449).
Tests for linear trend for age group were significant (pB0.001) and so were tests for departure from linear trend (pB0.001) suggesting a
more complex relationship between age group and LTFU in the first year.
Tests for linear trend for year of ART initiation were significant (pB0.001) and those for departure from linear trend were not significant
(p0.935), hence there was a linear relationship between year of ART start and LTFU.
Those who had higher CD4 cell percentage at 12 months

were probably more adherent and less likely to suffer
opportunistic diseases that may lead to death and
LTFU.
The finding that children with their biological mothers
as primary caregivers at baseline and at 1 year were more
likely to be LTFU can be explained by the possibility that
a number of these mothers may have died during the
follow-up period resulting in the children becoming
LTFU. Keeping HIV-positive mothers alive by effective
ART has been shown to reduce under-five childhood
mortality to levels seen in children of HIV-negative
mothers (21). While it is likely that these mothers were
enrolled in ART programmes themselves, it is possible
that they might not be accessing ART due to the
differences in the eligibility criteria for ART in adults
and children in South Africa (13, 14, 22). At the time of
the study, women would be initiated on ART if their

CD4 count were 5200 cells/mm3 or if they had a WHO
stage 4 condition according to the 2004 guidelines (13).
According to the 2010 ART guidelines women can access
treatment at CD4 5200 cells/mm3 except in pregnancy
and active tuberculosis, where therapy is started at
CD4 5350 cells/mm3 (22). The paradox becomes that
children are eligible for ART in South Africa at earlier
disease stages than their non-pregnant mothers, with
possible negative consequences on childrens treatment
outcomes. The adoption of the WHO Option B plus for
prevention of mother to child transmission (PMTCT),
which offers the best protection of maternal health by
starting all pregnant HIV-infected women on ART for life
(23), may positively impact childrens outcomes.
Another explanation could be misclassification of
mothers as caregivers since the caregiver status might
177
Table 5. Sensitivity analyses: LTFU in the second year

Model E (age and year of
Model D (original)
Characteristic
start as continuous)
HR (95% CI)
3 to B5 years
1.19 (0.741.91)
0.471
5 to 12 years
0.88 (0.581.35)
0.566
HR (95% CI)
0.94 (0.890.99)
0.047
1.21 (1.101.34)
B0.001
Age at 12 months
1 to B3 years
Age (as continuous variable)

Year of Starting ART
20042005
20062008
1.85 (1.123.07)
0.017
20092011
2.68 (1.584.55)
B0.001

(as a continuous variable)
Primary caregiver
Mother
Grandmother
0.30 (0.150.59)
0.001
1
0.32 (0.160.64)
0.001
Other family
Foster/Institution/Neighbour/Guardian
0.49 (0.300.82)
0.59 (0.281.21)
0.006
0.150
0.54 (0.320.89)
0.63 (0.301.29)
0.017
0.206
2 (Not underweight)
2 to 3 (Moderately underweight)
1.97 (1.283.04)
0.004
1.97 (1.293.04)
0.002
B3 (Severely underweight)
2.93 (1.914.47)
B0.001
2.65 (1.744.04)
B0.001
0.97 (0.960.99)
0.004
0.97 (0.950.99)
0.001
CD4 cell percentage
Likelihood ratio test between Model D and Model E showed that there was no difference between the model (p1.000). No
imputation of missing CD4% was done for the LTFU in the second year model since only 4.1% had missing CD4% at
12 months.
Tests for linear trend for age group at 12 months were significant (p0.003) and those for departure from linear trend were not
significant (p0.525), hence there was a linear relationship between age group at 12 months and LTFU in the second year.
Tests for linear trend for year of ART initiation were significant (pB0.001) and those for departure from linear trend were not
significant (p0.559), hence there was a linear relationship between year of ART start and LTFU in the second year.
not have been updated promptly on the HSCC database. A recent study of paediatric ART adherence in
Gugulethu, Cape Town, showed that children cared
for by their mothers were more adherent than those
cared for by other relatives or foster parents, contradictory findings to those in our study (24).
This study draws its strength from a large sample
size of children accessing care at the same site. The
data was prospectively collected in an electronic format
and includes social factors such as caregiver relationship
which other cohorts elsewhere may not be able to collect
adequately. Sensitivity analyses yielded similar results
with the main analyses.
Our study had some limitations. The study was
observational and key variables at baseline such as
CD4 cell percentage, and log10 viral load had high
proportions of missing data. Additionally, the quality
of care at a referral academic hospital such the HSCC
178
is likely to differ from that of lower levels of care or in

rural areas. We used data from only one non-randomly
selected urban site; therefore, these results cannot be
generalised to children accessing care in non-urban
settings.
Conclusion
Increased roll-out of ART for HIV-infected children,
particularly in recent years, has led to an increase in
LTFU, especially in infants and strategies to retain
infants and children in care need investigation. There
are similarities between predictors of LTFU and known
predictors of death. Unreported mortality possibly inflates LTFU in the first and second year of ART. Familybased care models improving maternal access to ART
and reducing mortality need further exploration. The
holistic care of HIV-positive children should emphasise
linkage of caregivers to adult HIV care programmes.
There is need to investigate the effect of differential

access to ART between mothers and their children in
South Africa and its impact on ART outcomes in
children. There is need to strengthen ART roll-out
programmes with resources to cope with rapid increases
in enrolled patients.
10.
11.
Acknowledgements
This study was initially carried out and submitted as a research
report by Mazvita Sengayi in partial fulfilment of the requirements
of the MSc (Med) in the field of Epidemiology and Biostatistics
at the University of the Witwatersrand School of Public Health.
The authors wish to acknowledge the teaching staff at the Wits
School of Public Health Epidemiology Division, WRHI colleagues
who maintain the HSCC databases, HSCC clinical staff and children
enrolled at the HSCC.
12.
13.
Conflict of interest and funding

Authors declare that they have no competing interests.
The Harriet Shezi Childrens Clinic is supported by the
Gauteng Provincial Government and the USAID (Grant
number 674-CA-674-A-00-08-0000).
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*Mazvita Sengayi
National Cancer Registry
National Health Laboratory Service
47 de Korte Street
Braamfontein
Johannesburg, 2001
South Africa
Email: [email protected]

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BUILDING NEW KNOWLEDGE SUPPLEMENT

Predictors of loss to follow-up among

ub-Saharan Africa is home to 90% of the worlds

In the same period, paediatric ART programmes in

Mazvita Sengayi et al.

higher retention than adults, a rise in LTFU has been

All children B12 years of age who started ART at

Citation: Glob Health Action 2013, 6: 19248 - http://dx.doi.org/10.3402/gha.v6i0.19248

Loss to follow-up in children

and scaled Schoenfeld residuals) were used to test for

7.18.8). There were 113 reported deaths and 202 known

LTFU in the second year on ART

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(page number not for citation purpose)

Mazvita Sengayi et al.

5118 children started

113 reported deaths

3460 In care at the end

2643 on ART at the end

had a linear relationship with LTFU in the second year

Citation: Glob Health Action 2013, 6: 19248 - http://dx.doi.org/10.3402/gha.v6i0.19248

Loss to follow-up in children

Median age, years (IQR)

Year of starting ART

2 (not underweight)

B3 (severely underweight)

Mean WAZ (standard deviation)

B3 (severe stunting)

Mean HAZ (standard deviation)

B3 (severe wasting)

Mean (standard deviation)

CD4 cell percentage

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(page number not for citation purpose)

Mazvita Sengayi et al.

Mean (standard deviation)

Log10 of plasma viral load (copies/mL)

Mean (standard deviation)

90 days on ART (18) and may be partly attributable to

Fig. 2. KaplanMeier estimates of cumulative probability

in successive enrolment calendar periods with those

Citation: Glob Health Action 2013, 6: 19248 - http://dx.doi.org/10.3402/gha.v6i0.19248

Loss to follow-up in children

Unadjusted HR (95% CI)

Adjusted HR* (95% CI)

Age at ART initiation

Year of starting ART

B3 (severely underweight)

2 (no stunting)

B3 (severe stunting)

2 (no wasting)

B3 (severe wasting)

WHO clinical stage

CD4 cell percentage

Log10 of plasma viral load (copies/mL)

*N 3078 for adjusted model.

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(page number not for citation purpose)