Predictors of loss to follow-up among children in the first and second years of antiretroviral treatment in Johannesburg, South Africa

Figures & data

Fig. 1.  Flow chart of HIV-infected children initiating ART at HSCC between 01 April 2004 and 30 April 2012.

Table 1. Overall cohort characteristics at baseline (N=4,266) and at 12 months on treatment (N=3,640)

	Baseline		12-month characteristics
Characteristic	N	%	N	%
Sex
Male	2188	51.3	1760	50.9
Female	2078	48.7	1700	49.1
Age
< 1 year	823	19.3
1 to <3 years	949	22.3	998	28.8
3 to <5 years	634	14.9	587	17.0
5 to 12 years	1860	43.6	1875	54.2
Median age, years (IQR)	4.2 (1.4–7.4)		5.2 (2.4–8.5)
Year of starting ART
2004–05	969	22.7	865	25.0
2006–08	1742	40.8	1548	44.7
2009–11	1555	36.5	1047	30.3
Primary caregiver
Mother	2226	52.2	1800	52.0
Grandmother	641	15.0	594	17.2
Other family	827	19.4	741	21.4
Foster/institution/neighbour/guardian	301	7.1	256	7.4
Data missing	271	6.4	69	2.0
Weight-for-age Z score
> −2 (not underweight)	3112	73.0	2430	70.2
−2 to −3 (moderately underweight)	461	10.8	543	15.7
< −3 (severely underweight)	369	8.7	426	12.3
Data missing	324	7.6	61	1.8
Mean WAZ (standard deviation)	−0.1 (2.6)		−0.8 (2.1)
Height-for-age Z score
> −2 (no stunting)	2911	68.2	2850	82.4
−2 to −3 (moderate stunting)	90	2.1	126	3.6
< −3 (severe stunting)	39	0.9	46	1.3
Data missing	1226	28.7	438	12.6
Mean HAZ (standard deviation)	2.7 (3.2)		1.9(2.8)
Weight-for-height Z score
> −2 (no wasting)	1273	29.8	1145	33.1
−2 to −3 (moderate wasting)	421	9.9	406	11.7
< −3 (severe wasting)	832	19.5	841	24.3
Data missing	1740	40.8	1068	30.9
Mean (standard deviation)	−2.2 (2.2)		−2.2(2.1)
Immune suppression^§
Mild	263	6.2	1639	47.4
Advanced/severe	2927	68.6	1663	48.1
Data missing	1076	25.2	158	4.6
WHO clinical stage
½	621	14.6	558	16.1
¾	3144	73.7	2815	81.4
Data missing	501	11.7	87	2.5
CD4 cell percentage
≥ 15%	1327	31.11	2701	78.1
< 15%	1883	44.14	617	17.8
Data missing	1056	24.75	142	4.1
Mean (standard deviation)	14.5 (9.3)		23.6(9.5)
Log10 of plasma viral load (copies/mL)
Data missing	1158	27.1	177	5.1
Mean (standard deviation)	11.4 (2.6)		5.8 (3.6)
Initial regimen
NNRTI-based	1884	44.2	1251	36.2
PI-based	2024	47.4	1405	40.6
Data missing	350	8.4	804	23.2

^§ Definitions of immune suppression according to the 2006 WHO classification of HIV-associated immunodeficiency in children by age and CD4%: (children <1 year: mild=CD4% of 30–35%, advanced=CD4% of 25–29%, severe=CD4% <25%; children 1 to <3 years: mild=CD4% of 25–30%, advanced=CD4% of 20–25%, severe=CD4% <20%; children 3 to <5 years: mild=CD4% of 20–25%, advanced=CD4% of 15–19%, severe=CD4% <15%; children >5 years: mild=CD4 cell count 350–499 cells/mm³, advanced=CD4 cell count 200–349 cells/mm³, severe=CD4 cell count <200 cells/mm³ or CD4% <15%) (14).

WHO: World Health Organization; NNRTI: non-nucleoside reverse transcriptase inhibitor (efavirenz or niverapine); PI: protease inhibitor (lopinavir/ritonavir).

Fig. 2.  Kaplan–Meier estimates of cumulative probability of LTFU by caregiver relationship during the first year and second year on ART.

Table 2. Baseline characteristics associated with LTFU in the first year on ART

Characteristic	Unadjusted HR (95% CI)	p	Adjusted HR* (95% CI)	p
Sex
Male	1		–
Female	0.94 (0.76–1.17)	0.580
Age at ART initiation
< 1 year	1		1
1 to 3 years	0.79 (0.61–1.04)	<0.093	1.15 (0.79–1.69)	0.458
3 to <5 years	0.30 (0.19–0.45)	<0.001	0.47 (0.27–0.83)	0.009
5 to 12 years	0.31 (0.24–0.42)	<0.001	0.61 (0.41–0.93)	0.020
Year of starting ART
2004–05	1		1
2006–08	2.48 (1.56–3.93)	<0.001	2.05 (1.21–3.49)	0.008
2009–11	6.28 (4.05–9.75)	<0.001	4.90(2.92–8.20)	<0.001
Primary caregiver
Mother	1		1
Grandmother	0.13 (0.07–0.26)	<0.001	0.12 (0.04–0.31)	<0.001
Other family	0.45 (0.32–0.63)	<0.001	0.57 (0.37–0.88)	0.011
Foster/institution/neighbour/guardian	0.43 (0.25–0.76)	0.003	0.38 (0.18–0.82)	0.013
Weight-for-age Z score
> −2 (not underweight)	1		1
−2 to −3 (moderately underweight)	3.38 (2.52–4.53)	<0.001	2.71 (1.90–3.88)	<0.001
< −3 (severely underweight)	4.83 (3.61–6.49)	<0.001	3.64 (2.51–5.27)	<0.001
Height-for-age Z score
> −2 (no stunting)	1		-
−2 to −3 (moderate stunting)	11.10 (7.28–16.93)	<0.001
< −3 (severe stunting)	15.17 (8.52–27.02)	<0.001
Weight-for-height Z score
> −2 (no wasting)	1		-
−2 to −3 (moderate wasting)	0.89 (0.58–1.37)	0.592
< −3 (severe wasting)	0.43 (0.28–0.67)	<0.001
Immune suppression^§
Mild	1		-
Advanced/severe	0.49 (0.33–0.71)	<0.001
WHO clinical stage
1/2	1		-
3/4	1.37 (0.95–1.98)	0.090
CD4 cell percentage	1.04 (1.02–1.05)	<0.001	1.01 (0.99–1.02)	0.212
Log10 of plasma viral load (copies/mL)	1.10 (1.04–1.16)	<0.001
Initial regimen
NNRTI-based	1		-
PI-based	2.45 (1.88–3.21)	<0.001

*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 <1 year: mild=CD4% of 30–35%, advanced=CD4% of 25–29%, severe=CD4% <25%; children 1 to <3 years: mild=CD4% of 25–30%, advanced=CD4% of 20–25%, severe=CD4% <20%; children 3 to <5 years: mild=CD4% of 20–25%, advanced=CD4% of 15–19%, severe=CD4% <15%; children >5 years: mild=CD4 cell count 350–499 cells/mm³, advanced=CD4 cell count 200–349 cells/mm³, severe=CD4 cell count <200 cells/mm³ or CD4% <15%) (14).

WHO: World Health Organization; NNRTI: non-nucleoside reverse transcriptase inhibitor (efavirenz or niverapine); PI: protease inhibitor (lopinavir/ritonavir).

Table 3. The effect of 12-month characteristics on LTFU in the second year on ART

Characteristic	Unadjusted HR (95% CI)	p	Adjusted HR* (95% CI)	p
Sex
Male	1		–
Female	1.15 (0.83–1.8)	0.399
Age at 12 months on ART
1 to <3 years	1		1
3 to <5 years	0.82 (0.53–1.29)	0.397	1.19 (0.74–1.91)	0.471
5 to 12 years	0.58 (0.41–0.83)	0.003	0.88 (0.58–1.35)	0.566
Year of starting ART
2004–05	1		1
2006–08	1.91 (1.19–3.08)	0.007	1.85 (1.12–3.07)	0.017
2009–11	2.84 (1.73–4.66)	<0.001	2.68 (1.58–4.55)	<0.001
Primary caregiver
Mother	1		1
Grandmother	0.23 (0.12–0.46)	<0.001	0.30 (0.15–0.59)	0.001
Other family	0.41 (0.26–0.67)	<0.001	0.49 (0.30–0.82)	0.006
Foster/institution/neighbour/guardian	0.63 (0.33–1.20)	0.155	0.59 (0.28–1.21)	0.150
Weight-for-age Z score
> −2 (not underweight)	1		1
−2 to −3 (moderately underweight)	2.09 (1.37–3.18)	0.001	1.97 (1.28–3.04)	0.004
< −3 (severely underweight)	3.51 (2.38–5.18)	<0.001	2.93 (1.91–4.47)	<0.001
Height-for-age Z score
> −2 (no stunting)	1		–
−2 to −3 (moderate stunting)	5.05 (2.60–9.81)	<0.001
< −3 (severe stunting)	13.52 (6.19–29.55)	<0.001
Weight-for-height Z score
> −2 (no wasting)	1		–
−2 to −3 (moderate wasting)	0.55 (0.28–1.09)	0.081
< −3 (severe wasting)	0.64 (0.39–1.03)	0.068
Immune suppression^§
Mild	1		–
Advanced/Severe	1.74 (1.23–2.46)	0.002
WHO clinical stage
½	1		–
¾	1.46 (0.88–2.43)	0.140
CD4 cell percentage	0.98 (0.96–0.99)	0.007	0.97 (0.96–0.99)	0.004
Log10 of plasma viral load (copies/mL)	1.17 (1.12–1.21)	<0.001	–
Regimen at 12 months
NNRTI-based	1		–
PI-based	1.43(0.93–2.20)	0.099

* N=3,283 in adjusted model.

^§ Definitions of immune suppression according to the WHO classification of HIV-associated immunodeficiency in children by age and CD4%: (children <1 year: mild=CD4% of 30–35%, advanced=CD4% of 25–29%, severe=CD4% <25%; children 1 to <3 years: mild=CD4% of 25–30%, advanced=CD4% of 20–25%, severe=CD4% <20%; children 3 to <5 years: mild=CD4% of 20–25%, advanced=CD4% of 15–19%, severe=CD4% <15%; children >5 years: mild=CD4 cell count 350–499 cells/mm³, advanced=CD4 cell count 200–349 cells/mm³, severe=CD4 cell count <200 cells/mm³ or CD4% <15%) (14).

WHO: World Health Organization; NNRTI: non-nucleoside reverse transcriptase inhibitor (efavirenz or niverapine); PI: protease inhibitor (lopinavir/ritonavir).

Table 4. Sensitivity analyses: LTFU in the first year

	Model A (original)		Model B (imputed CD4% missing values)		Model C (age and year of start as continuous)
Characteristic	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p
Age at HAART initiation
< 1 year	1		1
1 to <3 years	1.15 (0.79–1.69)	0.458	0.89 (0.66–1.21)	0.452
3 to <5 years	0.47 (0.27–0.83)	0.009	0.39 (0.24–0.63)	<0.001
5 to 12 years	0.61 (0.41–0.93)	0.020	0.49 (0.35–0.69)	<0.001
Age (as continuous variable)					0.93 (0.88–0.97)	0.002
Year of starting ART
2004–05	1		1
2006–08	2.05 (1.21–3.49)	0.008	2.08 (1.27–3.39)	0.003
2009–11	4.90(2.92–8.20)	<0.001	4.67(2.90–7.50)	<0.001
Year of starting ART (as a continuous variable)					1.36 (1.26–1.47)	<0.001
Primary caregiver
Mother	1		1		1
Grandmother	0.12 (0.04–0.31)	<0.001	0.18(0.09–0.37)	<0.001	0.12(0.04–0.31)	<0.001
Other family	0.57 (0.37–0.88)	0.011	0.64(0.45–0.93)	0.018	0.57(0.37–0.87)	0.010
Non-family	0.38 (0.18–0.82)	0.013	0.49(0.27–0.87)	0.015	0.40 (0.19–0.86)	0.019
Weight-for-age Z score
> −2	1		1		1
−2 to −3	2.71 (1.90–3.88)	<0.001	2.96(2.19–4.00)	<0.001	2.75 (1.92–3.93)	<0.001
< −3	3.64 (2.51–5.27)	<0.001	4.06(3.01–5.49)	<0.001	3.57 (2.48–5.18)	<0.001
CD4 cell percentage	1.01 (0.99–1.02)	0.212	1.01(0.99–1.02)	0.443	1.01 (0.99–1.02)	0.383

Likelihood ratio test between Model A and Model C showed that there was no difference between the model (p=0.449).

Tests for linear trend for age group were significant (p<0.001) and so were tests for departure from linear trend (p<0.001) 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 (p<0.001) and those for departure from linear trend were not significant (p=0.935), hence there was a linear relationship between year of ART start and LTFU.

Table 5. Sensitivity analyses: LTFU in the second year

Characteristic	Model D (original)		Model E (age and year of start as continuous)
	HR (95% CI)	p	HR (95% CI)p	p
Age at 12 months
1 to <3 years	1
3 to <5 years	1.19 (0.74–1.91)	0.471
5 to 12 years	0.88 (0.58–1.35)	0.566
Age (as continuous variable)			0.94 (0.89–0.99)	0.047
Year of Starting ART
2004–2005	1
2006–2008	1.85 (1.12–3.07)	0.017
2009–2011	2.68 (1.58–4.55)	<0.001
Year of starting ART (as a continuous variable)			1.21 (1.10–1.34)	<0.001
Primary caregiver
Mother	1		1
Grandmother	0.30 (0.15–0.59)	0.001	0.32(0.16–0.64)	0.001
Other family	0.49 (0.30–0.82)	0.006	0.54(0.32–0.89)	0.017
Foster/Institution/Neighbour/Guardian	0.59 (0.28–1.21)	0.150	0.63(0.30–1.29)	0.206
Weight-for-age Z score
> −2 (Not underweight)	1		1
−2 to −3 (Moderately underweight)	1.97 (1.28–3.04)	0.004	1.97 (1.29–3.04)	0.002
< −3 (Severely underweight)	2.93 (1.91–4.47)	<0.001	2.65(1.74–4.04)	<0.001
CD4 cell percentage	0.97 (0.96–0.99)	0.004	0.97 (0.95–0.99)	0.001

Likelihood ratio test between Model D and Model E showed that there was no difference between the model (p=1.000). 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 (p=0.003) and those for departure from linear trend were not significant (p=0.525), 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 (p<0.001) and those for departure from linear trend were not significant (p=0.559), hence there was a linear relationship between year of ART start and LTFU in the second year.

National Department of Health South Africa. Guidelines for the management of HIV in children. 2nd ed. Pretoria: National Department of Health South Africa. 2010, p. 30. Available from: http://www.sahivsoc.org/upload/documents/Guidelines_for_Management_of_HIV_in_Children_2010.pdf [cited 20 September 2012].

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