3.1 Demographic and Clinical Characteristics
Out of a total of 822 CLHIV, were screened for eligibility and 724(88%) fulfilled the inclusion criteria. (Fig. 1). Those eligible, with at least 24 weeks of follow-up, were followed for a total of 3913 person-years. In this period, 34/724 (4.7%) died, 105(14.5%) were lost to follow-up, and 403 (55.7%) were transferred out. The median age at enrollment to the clinic was 78 months (IQR, 38.5-114.5 months). Females comprise 47.2% of the population. Half of the children (50.1%) initiated cART before 2010, whereas 34.7% initiated between 2011 and 2015, and 15.2% in 2016 and onwards. More than half of the children (52%) had advanced HIV disease (WHO clinical stage 3 and 4). The median duration of follow-up was 79 months (IQR, 49–112 months). Those eligible were more likely to be from the Maekel zone (P < 0.03), in an advanced WHO clinical stage (P < 0.004), and on zidovudine (AZT) + lamivudine (3TC) backbone. Furthermore, the majority of the study participants were wasted (weight for height, Z<-2) (P = 0.02), acutely malnourished (weight for age Z <-3) (P-value < 0.001), and severely immunosuppressed (P = 0.037) (Table 1).
Table 1. Baseline characteristics of children included and excluded
Characteristics†
|
Included (n=724)
|
Excluded (n=97)
|
p-Value‡ (χ2)
|
Total n (%)
|
Gender
|
Male
|
376 (85.6)
|
63 (14.4)
|
0.32
|
439 (53.4)
|
Female
|
337 (88)
|
46 (12)
|
383 (46.6)
|
Year of birth
|
2003 (1999 – 2005)
|
2002 (1999 - 2006)
|
0.95
|
|
Address
|
Maekel
|
523 (88.3)
|
69 (11.7)
|
0.03
|
592 (72)
|
Outside Maekel
|
190 (82.6)
|
40 (17.4)
|
230 (28)
|
cART initiation year
|
2011 (2008- 2014)
|
2010 (2007 - 2014)
|
0.57
|
|
2005-2009
|
274 (86.7)
|
42 (13.3)
|
0.75
|
316 (38.6)
|
2010-2014
|
275 (86.2)
|
44 (13.8)
|
319 (62.2)
|
2015-2019
|
162 (88.5)
|
21 (11.5)
|
183 (22.4)
|
Age at cART initiation
|
105 (59 - 142)
|
101 (68 - 135)
|
0.89
|
|
< 67 months
|
174 (84.9)
|
31 (15.1)
|
0.23
|
205 (25.1)
|
67 – 102 months
|
189 (90.9)
|
19 (9.1)
|
205 (25.1)
|
103 - 136 months
|
176 (85.4)
|
30 (14.6)
|
207 (25.3)
|
> 136 months
|
172 (85.6)
|
29 (14.4)
|
201 (24.6)
|
Clinical stage§
|
Early Stage
|
291 (92.1)
|
25 (7.9)
|
<0.001
|
316 (38.9)
|
Advanced Stage
|
413 (83.3)
|
83 (16.7)
|
496 (61.1)
|
TB Status
|
|
Not Symptomatic
|
636 (86.2)
|
88 (13.8)
|
0.893
|
724 (97.6)
|
Symptomatic
|
16 (89)
|
2 (11)
|
18 (2.4)
|
cART backbone
|
AZT + 3TC
|
539 (93.1)
|
41 (6.9)
|
<0.001
|
580 (70.7)
|
ABC + 3TC
|
89 (84)
|
17 (16)
|
106 (12.9)
|
D4T + 3TC
|
49 (52.1)
|
45 (47.9)
|
94 (11.5)
|
TDF + FTC
|
34 (87.4)
|
5 (12.8)
|
39 (4.8)
|
NNRTI/PI
|
NVP
|
360 (85.1)
|
63 (14.9)
|
0.25
|
423 (51.7)
|
EFV
|
349 (88.8)
|
44 (11.2)
|
393 (48)
|
Height for age, z-score
|
Z < -2
|
470 (87.7)
|
66 (12.3)
|
0.2
|
536 (68.3)
|
Z > -2
|
226 (90.8)
|
23 (9.2)
|
249 (31.7)
|
Weight for height, z-score
|
Z < -2
|
40 (75.5)
|
13 (24.5)
|
0.002
|
53 (29.6)
|
Z > -2
|
116 (92.1)
|
10 (7.9)
|
126 (70.4)
|
Weight for age, z-score
|
Z < -2
|
309 (86.6)
|
48 (13.4)
|
<0.005
|
357 (69.6)
|
Z > -2
|
148 (94.9)
|
8 (5.1)
|
156 (30.4)
|
cART changes
|
Yes
|
580 (96.5)
|
21 (3.5)
|
<0.001
|
601 (73.1)
|
No
|
124 (63.3)
|
72 (36.7)
|
196 (23.8)
|
Unknown
|
9 (36)
|
16 (64)
|
25 (3)
|
Immunosuppression
|
Mild
|
87 (90.6)
|
9 (9.4)
|
0.037
|
96 (13.9)
|
Advanced
|
201 (92.4)
|
17 (7.6)
|
224 (32.4)
|
Severe
|
319 (85.8)
|
53 (14.2)
|
372 (53.8)
|
Abbreviations: ABC, abacavir; AZT, zidovudine, cART, combined antiretroviral therapy, CI, confidence interval; d4T, Stavudine; EFV, Efavirenz; IQR, interquartile range; LPV/r; NVP, nevirapine; TB, tuberculosis; 3TC, lamivudine; Z-score, NCHS standard deviation. P values refer to differences between included and excluded patients on baseline characteristics; †Presented as n (%) for categorical data and median (interquartile range) for continuous data; ‡ The comparisons were performed using Pearson’s Chi-square test or Fisher’s exact test, as appropriate, for categorical data, and Wilcoxon rank sum/Mann Whitney U-test for continuous data; §WHO clinical early and advanced refer to stage 1 & 2 and stages 3 &4, respectively
3.2 Prevalence and crude-incidence of cART failure
A total of 279 TF events occurred. The prevalence of failure was 38.5% (95% CI 35-42.2). The crude incidence of TF was 6.5 events per 100-PYFU (95% CI 5.8-7.3). The median time to TF was 4 years (IQR 2-7). Virologic failure occurred alone in 167/279 (23.1% [95% CI 20-26.3]) patients, immunologic failure alone was found in 19 (2.6% [95% CI 1.6-4.1]) cases, 82 (11.3% [95% CI 9.1-13.9]) had only clinical failure and 11 (1.5% [95% CI 0.8-2.7]) children had concomitant virologic, clinical and immunologic failures. Among all the children with TF, only 88 (31.5%) were switched to second-line treatments with the median time to cART switch being 19 months (IQR 11.3-49.7) (Table 2).
Table 2. Crude-incidence rate of cART failure
Characteristics†
|
Person time (years)
|
Events
|
Crude Incidence Rate (95% CI)
|
Rate Ratio
(95% CI)
|
p-Value‡
|
Gender
|
Male
|
2203.3
|
156
|
7.1 (6.1-8.3)
|
0.84 (0.65-1.1)
|
0.07
|
Female
|
2051.41
|
120
|
5.8 (4.9-7)
|
Year of birth
|
<= 2003
|
2602.8
|
175
|
6.7 (5.8-7.8)
|
0.91 (0.7-1.2)
|
0.24
|
2004+
|
1628.8
|
100
|
6.1 (5-7.5)
|
Address
|
Maekel
|
3270.3
|
197
|
6 (5.2-6.9)
|
1.3 (1-1.8)
|
0.01
|
Outside Maekel
|
984.4
|
79
|
8 (6.4-10)
|
Cohort Year
|
<= 2010
|
2685
|
144
|
5.4 (4.5-6.3)
|
1.6 (1.2-2)
|
< 0.001
|
2011+
|
1546.6
|
131
|
8.4 (7.1-10)
|
Clinical stage§
|
Early
|
1615.6
|
92
|
5.6 (4.6-7)
|
1.2 (1-1.6)
|
0.05
|
Late
|
2592.4
|
180
|
6.9 (6-8)
|
Immunosuppression
|
Mild/Advanced
|
1708.5
|
99
|
5.8 (4.7-7)
|
1.2 (0.9-1.5)
|
0.1
|
Severe
|
2007.3
|
136
|
6.8 (5.7-8)
|
Weight for age
|
z > -2
|
1405.9
|
70
|
5 (3.9-6.3)
|
1.5 (1.1-1.9)
|
0.003
|
z <= -2
|
2848.8
|
206
|
7.2 (6.3-8.3)
|
Height for age
|
z > -2
|
1514.8
|
82
|
5.4 (4.4-6.7)
|
1.3 (1-1.7)
|
0.02
|
z <= -2
|
2739.8
|
194
|
7.1 (6.2-8.2)
|
Weight for height
|
z > -2
|
3473.2
|
218
|
6.3 (5.5-7.2)
|
1.2 (0.9-1.6)
|
0.13
|
z <= -2
|
781.5
|
58
|
7.4 (5.7-9.6)
|
cART Backbone
|
AZT + 3TC
|
3615
|
216
|
6 (5.2-6.8)
|
1.5 (1.1-2.1)
|
0.002
|
AZT+3TC, ELSE¶
|
639.7
|
60
|
9.4 (7.3-12.1)
|
NNRTI
|
EFV
|
1819
|
128
|
7 (5.9-8.4)
|
0.9 (0.7-1.1)
|
0.1
|
NVP
|
2424.3
|
145
|
6 (5.1-7)
|
Sub-optimal adherence record
|
Yes
|
549.7
|
201
|
13.6 (10.9-17.1)
|
2.5 (1.9-3.2)
|
< 0.001
|
No
|
3705
|
75
|
5.4 (4.7-6.2)
|
Abbreviations: AZT, zidovudine; 3TC, lamivudine; cART, combined antiretroviral therapy; CI, confidence interval; EFV, efavirenz; LPV/r, lopinavir/ritonavir; NNRTI, Non-nucleoside Reverse Transcriptase Inhibitors; NVP, nevirapine; TB, tuberculosis; Z-score, NCHS standard deviation; †Characteristics were evaluated at baseline, unless otherwise specified; ‡Compares the difference of crude incidence of failure per patients’ characteristics , §WHO clinical early and advanced refer to stage 1 & 2 and stages 3 &4, respectively; ¶abacavir + lamivudine, stavudine + lamivudine or tenofovir + emtricitabine.
3.3 Factors associated with TF
The children who failed on a first-line cART as compared to those who didn’t were more likely to be in advanced WHO clinical stage (p=0.005), have lower baseline CD4+ lymphocyte count (p=0.004), be stunted (P=0.01), have had a longer duration of follow up (p=0.003), have suboptimal adherence (p<0.001), have cART change (p=0.002) and have a higher frequency of change (p =0.001) (Table 3).
Table 3. factors associated with therapy failure.
Characteristics†
|
Therapy failure cases n=279
|
No Therapy failure n=445
|
p-Value‡
|
Total n (%)
|
Gender
|
Males
|
157 (41.1)
|
225 (58.9)
|
0.134
|
382 (52.8)
|
Females
|
122 (35.7)
|
220 (64.4)
|
342 (47.2)
|
Year of birth
|
2002 (1999-2005)
|
2003 (1999-2006)
|
0.114
|
|
Address
|
Maekel
|
199 (37.5)
|
332 (62.5)
|
0.27
|
531 (73.3)
|
Outside Maekel
|
80 (41.5)
|
113 (58.5)
|
193 (26.7)
|
Age at cART initiation (months)
|
103.9 (98.4-109.5)
|
99.3 (94.8-103.7)
|
0.59
|
|
Duration enrollment to cART initiation (months)
|
6 (1 - 33)
|
7 (1 - 36)
|
0.77
|
cART initiation year
|
2010 (2008-2014)
|
2011 (2008-2014)
|
0.71
|
2005 – 2009
|
109 (38.4)
|
175 (61.6)
|
0.87
|
284 (39.3)
|
2010 – 2014
|
110 (39.7)
|
167 (60.3)
|
277 (38.4)
|
2015 – 2019
|
60 (39.3)
|
101 (62.7)
|
161 (22.3)
|
Clinical stage§
|
Stage 1 and 2
|
94 (32.2)
|
198 (67.8)
|
0.005
|
290 (40.6)
|
Stage 3 and 4
|
181 (42.7)
|
243 (57.3)
|
425 (59.4)
|
TB status
|
|
Not symptomatic
|
242 (38.1)
|
393 (61.9)
|
0.28
|
634 (97.5)
|
Symptomatic
|
4 (25)
|
12 (75)
|
16 (2.5)
|
Immunosuppression
|
|
Mild
|
30 (34.5)
|
57 (65.5)
|
0.06
|
87 (14.2)
|
Advanced
|
70 (33.8)
|
137 (66.2)
|
207 (33.8)
|
Severe
|
138 (43.1)
|
181 (56.9)
|
319 (52)
|
Weight for age, z-score
|
Z<= -2
|
117 (37.9)
|
192 (62.1)
|
0.07
|
309 (67.8)
|
Z > -2
|
43 (29.3)
|
104 (70.7)
|
147 (32.2)
|
Height for age, z-score
|
|
Z <=-2
|
193 (41.2)
|
276 (58.8)
|
0.043
|
469 (67.5)
|
Z > -2
|
75 (33.2)
|
151 (66.8)
|
226 (32.5)
|
Weight for height, z-score
|
Z <= -2
|
17 (42.5)
|
23 (57.5)
|
0.16
|
40 (25.8)
|
Z > -2
|
35 (30.4)
|
80 (69.6)
|
115 (74.2)
|
cART Backbone
|
AZT + 3TC
|
217 (40)
|
326 (60)
|
0.14
|
543 (75.1)
|
AZT + 3TC, ELSE¶
|
61 (33.9)
|
119 (66.1)
|
180 (24.9)
|
NNRTI/PI
|
NVP
|
146 (39.9)
|
220 (60.1)
|
0.126
|
366 (50.6)
|
EFV
|
130 (36.6)
|
225 (63.4)
|
355 (49.1)
|
LPV/r
|
2 (100)
|
0
|
2 (0.3)
|
Suboptimal adherence
|
Yes
|
76 (70.7)
|
30 (28.3)
|
<0.001
|
106 (14.6)
|
No
|
203 (32.8)
|
415 (67.2)
|
618 (85.4)
|
cART Substitution
|
Yes
|
243 (41.4)
|
344 (58.6)
|
0.002
|
586 (80.9)
|
No
|
32 (24.8)
|
97 (75.2)
|
129 (17.8)
|
Unknown
|
4 (44.4)
|
5 (55.6)
|
9 (1.2)
|
Frequency of cART change
|
2 (2-3)
|
1 (1-3)
|
< 0.001
|
|
Abbreviations: ABC, abacavir; AZT, zidovudine, cART, combined antiretroviral therapy, CI, confidence interval; d4T, Stavudine; EFV, Efavirenz; IQR, interquartile range; LPV/r; NVP, nevirapine; TB, tuberculosis; 3TC, lamivudine; Z-score, NCHS standard deviation. P values refer to differences between included and excluded patients on baseline characteristics; †Presented as n (%) for categorical data and median (interquartile range) for continuous data; ‡ The comparisons were performed using Pearson’s Chi-square test or Fisher’s exact test, as appropriate, for categorical data, and Wilcoxon rank sum/Mann Whitney U-test for continuous data; §WHO clinical early and advanced refer to stage 1 & 2 and stages 3 &4, respectively. ¶abacavir + lamivudine, stavudine + lamivudine or tenofovir + emtricitabine.
3.4 Relationship between number viral load tests performed and detection of TF
A strong relationship was observed between the number of VL tests performed and TF. A steep drop in the recruitment of infected children into the cART program and an increase in VL testing were also observed in the later years (Figure 2).
3.5 Kaplan-Meier analysis for TF incidence
Figure 3 shows the Kaplan-Meier estimates of failure incidence comparing TF for the following factors; adherence, age at treatment initiation, cohort year, and cART backbone. Sub-optimal adherence was associated with a reduced median time to TF (75.8 (95% CI, 65.7-85.96) months vs 117.2(95% CI, 111.6–122.8) months) (figure 3a). A significant difference in failure rates was also observed between adolescents and children: children, median = 120.7 (95% CI, 115-126.7) months; and adolescents, median = 78 (95% CI, 71.3-85) months (figure 3b). Late initiation year were also associated with shorter median time to TF (2005-2009, mean=124.85 (95% CI, 118.03–131.7) months; 2010-2014, median = 93.24 (95% CI, 88.3-98.1); 2015-2019, mean 51.02 (95% CI, 47.1-54.95) (figure 3c). The average time to TF for AZT+3TC was 114.5 (95%CI, 109.1–119.8) months vs 92.1 (95%CI, 79.7-104.4) months for alternative backbones (Figure 3d).
3.6 Multivariate analysis of independent predictors of TF
In the adjusted Cox proportional hazards model independent predictors of TF were suboptimal adherence (AHR=2.9, 95%CI 2.2–3.9, p<0.001), cART backbone other than AZT and 3TC (AHR=1.6, 95% CI 1.1–2.2, p=0.01), severe immunosuppression (AHR=1.5, 95%CI 1–2.4, p=0.04), wasting or weight for height z <-2 (AHR=1.5, 95% CI 1.1–2.1, p=0.02), late cART initiation calendar years (Adjusted Hazard Ratio (AHR)=1.15, 95%CI 1.1-1.3, p < 0.001), and older age at cART initiation (AHR =1.01, 95%CI 1-1.02, p<0.001) (Table 4).
Table 4: Cox-proportional Hazards of cART failure among children following in NPRH
Characteristics†
|
Crude HR (95% CI)
|
p
|
Adjusted HR (95% CI)
|
p
|
Gender
|
Male
|
1.0 (Reference)
|
|
|
|
Female
|
0.97 (0.7-1.3)
|
0.8
|
|
|
Address
|
Maekel
|
1.0 (Reference)
|
|
1.0 (Reference)
|
|
Outside Maekel
|
1.3 (0.9-1.6)
|
0.15
|
1.3 (0.9-1.7)
|
0.09
|
Age at cART initiation
|
1.01 (1-1.02)
|
<0.001
|
1.01 (1-1.02)
|
<0.001
|
cART started calendar year
|
1.16(1.1-1.2)
|
<0.001
|
1.15(1.1-1.3)
|
<0.001
|
Clinical Stage
|
Early
|
1.0 (Reference)
|
|
|
|
Advanced
|
1.13
|
0.4
|
|
|
Immunosuppression
|
Mild
|
1.0 (Reference)
|
|
1.0 (Reference)
|
|
Advanced
|
1.01 (0.64-1.6)
|
0.9
|
1.02 (0.6-1.6)
|
0.9
|
Severe
|
1.4(0.95-2.3)
|
0.08
|
1.5 (1.02-2.4)
|
0.04
|
Height for age, z score
|
Z >-2
|
1.0 (Reference)
|
|
|
|
Z <-2
|
1.14 (0.8-1.1.5)
|
0.4
|
|
|
Weight for height, z score
|
Z >-2
|
1.0 (Reference)
|
|
1.0 (Reference)
|
|
Z <-2
|
1.5(1.05-2.1)
|
0.02
|
1.5(1.1-2.1)
|
0.02
|
cART Backbone
|
AZT + 3TC
|
1.0 (Reference)
|
|
1.0 (Reference)
|
|
AZT+3TC, Else¶
|
1.6 (1.1-2.4)
|
0.008
|
1.6 (1.1-2.2)
|
0.01
|
NNRTI/PI
|
EFV
|
1.0 (Reference)
|
|
|
|
NVP
|
1.16 (0.9-1.6)
|
0.3
|
|
|
cART change frequency
|
0.9(0.67-1.19)
|
0.46
|
|
|
Suboptimal adherence
|
2.9 (2.1-3.9)
|
<0.001
|
2.9 (2.2-3.9)
|
<0.001
|
Abbreviations: AZT, zidovudine; 3TC, lamivudine; CI, confidence interval; cART, combined antiretroviral therapy; EFV, efavirenz; NVP, nevirapine; d4T, Stavudine; EFV, Efavirenz; z-scores NCHS standard deviations; † Characteristics were evaluated at baseline, unless otherwise specified ‡ The analyses were performed using Cox proportional hazards model; § WHO clinical early and advanced refer to stage 1 & 2 and stages 3 &4; ¶abacavir + lamivudine, stavudine + lamivudine or Tenofovir+emtricitabine.