1210 children were enrolled (March 15, 2007–Nov 18, 2008). One was randomly assigned twice at different centres (second randomisation was excluded), and three had major eligibility violations, leaving 600 children assigned to routine laboratory and 606 to clinically driven monitoring, and 397 to group A, 404 to group B, and 405 to group C (). Baseline characteristics were similar across randomised groups (). Median follow-up to planned trial closure (March 16, 2012) was 4·0 (IQR 3·7–4·4) years in each monitoring and ART-strategy group (maximum 5·0 years; total 4685 child-years). Only 33 (3%) children (median follow-up 150 [IQR 46–169] weeks) not known to have died were not seen after trial closure (). Completeness of nurse visits every 4–6 weeks and doctor visits every 12 weeks was more than 95% (46 531/48 461 nurse, 19 088/19 765 doctor visits) and was similar in all groups.
Characteristics at randomisation
For children assigned to clinically driven monitoring, clinicians could request individual laboratory toxicity results from routine haematology or biochemistry panels for clinical reasons. Panel tests could also be requested in both groups at extra patient-initiated visits. However, most were done at routine visits (10 805 [92%] haematology and 10 778 [94%] biochemistry; appendix
). In clinically driven monitoring, apart from week 8 haemoglobin (returned per protocol), very few results were released (from 486 [4%] panels); most commonly requested results were haemoglobin (2%, n=265) and neutrophils (3%, n=323; appendix
). More additional haematology tests were requested during nurse visits or extra visits in routine laboratory than in clinically driven monitoring (p<0·0001); there were no significant differences in requests for additional biochemistry tests (p=0·17) or other non-routine (eg, electrolytes) tests (p=0·97).
At trial end, 578 (95%) children on clinically driven monitoring versus 565 (94%) on routine laboratory monitoring were still on first-line ART (); 330 (83%) children in group A, 356 (88%) in group B, and 367 (91%) in group C were still on their original randomised regimen. Among 151 first-line drug changes, equal numbers were due to adverse events and antituberculosis therapy (both 59 changes [39%]; ). Changes to first-line therapy occurred at rates of 3·3 per 100 child-years in routine laboratory monitoring versus 3·2 per 100 child-years in clinically driven monitoring (p=0·94); and 3·5, 3·7, and 2·6 per 100 child-years in groups A, B, and C, respectively (p=0·25).
30 children in group A, 20 in group B, and nine in group C stopped nevirapine because of starting antituberculosis treatment. Whereas in group A nevirapine was mainly substituted with zidovudine (<3 years) or efavirenz (>3 years), in the four-drug groups, about a third (five children in group B and six in C) simply dropped nevirapine during four-drug induction to continue on three NRTIs. Adverse events resulted in a drug being substituted or dropped in five children in group A, 28 in group B, and 26 in group C; most changes were zidovudine-related (16 in B, 20 in C; ).
Adherence by self-reported questionnaire was similar in both monitoring groups: mean 6·7% (1813/26 917) of children on clinically driven monitoring reported missing doses in the past 28 days versus 6·5% (1683/25 935) on routine laboratory monitoring (p=0·26). There were small but significant differences by ART strategy, with fewer reporting missing doses in the past 28 days in group A through week 36 (induction period; 7·9% [253/2966] in group A, 9·8% [326/3014] in group B, 9·0% [295/2999] in group C; p=0·02) and overall (6·1% [1059/16345], 7·3% [1302/16640], 6·5% [1135/16371], respectively; p<0·0001).
No child switched to second-line treatment during their first year on ART. Overall, 28 (5%) children on clinically driven monitoring versus 35 (6%) on routine laboratory monitoring switched to second-line treatment (hazard ratio [HR] 0·78, 95% CI 0·48–1·29, p=0·22; ; ), after median 2·8 (IQR 1·8–3·3) years versus 2·2 (1·5–3·0) years, respectively. All children on routine laboratory monitoring meeting CD4 switch criteria actually switched. At switch, median CD4 percentage was 8·5% (IQR 1·5–22·5) in the clinically driven monitoring group and 7% (3–13) in the routine laboratory monitoring group; 11 children (39%) versus 14 (40%) had CD4 percentage less than 5% and six children (21%) versus none had CD4 percentage greater than 25%, respectively. 2% of follow-up (40/2373 child-years) was spent on second-line treatment in children on clinically driven monitoring versus 3% (67/2311 child-years) in those on routine laboratory monitoring. 26 [7%] children in group A switched to second-line treatment versus 17 [4%] in group B and 20 (5%) in group C; these differences were not significant (p=0·25; ).
Figure 2 Substitution in first-line ART (any reason) and switch to second-line ART (A) By monitoring strategy. (B) By ART strategy. Lines show cumulative incidence of switch to second-line treatment before death on first-line, and of substitution in first-line (more ...)
There was no evidence of interaction between monitoring and induction-maintenance ART strategies in primary or secondary outcomes (heterogeneity p>0·1) except for WHO stage 4 events or death in the first year on ART, for which the relative difference between clinically driven and routine laboratory monitoring varied by first-line ART strategy (appendix
). Since most variation was between groups B and C, who received identical ART for the first 36 weeks, this year 1 interaction appeared attributable to chance in children initiating ART with severe immunodeficiency.
47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (2·0 vs 1·7 per 100 child-years, respectively). The absolute difference of 0·32 per 100 child-years (95% CI −0·47 to 1·12) translated into a relative HR of 1·13 (95% CI 0·73–1·73, p=0·59; ). The upper 95% confidence limit for the absolute difference was below the non-inferiority margin of 1·6.
New WHO 4 stage event or death (A), CD4 (B), viral load (C), and adverse events (D), by monitoring strategy
Although overall progression was similar, a prespecified subgroup analysis showed children on routine laboratory monitoring had higher event rates during the first 3 months on ART and lower rates from the second year on ART compared with those on clinically driven monitoring (heterogeneity p=0·045; appendix
). After year 1, 23 (4%) children on clinically driven monitoring versus six (1%) on routine laboratory monitoring had a first WHO stage 4 event or died (difference 0·
99 per 100 child-years, 95% CI 0·
002). The most common WHO stage 4 events were oesophageal candidiasis (eight on clinically driven and five on routine laboratory monitoring) and severe unexplained failure-to-thrive (nine on clinically driven and three on routine laboratory monitoring).
25 (4%) children died in the clinically driven monitoring group versus 29 (5%) in the routine laboratory monitoring group (1·1 vs
1·3 per 100 child-years, respectively; difference −0·2 per 100 child-years, 95% CI −0·82 to 0·41; HR 0·84, 95% CI 0·49–1·44; p=0·45; appendix
). Most deaths (19 clinically driven and 20 routine laboratory monitoring) were primarily HIV-related; only one was drug-related (chemotherapy plus zidovudine). Similar variation over time (heterogeneity p=0·
) was observed for deaths alone as for the combined endpoint of WHO stage 4 or death (13 deaths on clinically driven and 27 on routine laboratory monitoring in first year, 12 vs
two subsequently; difference 0·56 per 100 child-years, 95% CI 0·15–0·97, with 12 of the 14 deaths after 1 year in children aged >8 years). Progression to new WHO stage 3 or 4 events or death gave similar results (HR [clinically driven:routine laboratory monitoring] 1·00, 0·73–1·38; p=0·98; appendix
). Pulmonary tuberculosis was the commonest WHO stage 3 event (25 clinically driven monitoring, 28 routine laboratory monitoring). Among 45 WHO stage 3 or 4 events reported on clinically driven monitoring and 21 on routine laboratory monitoring from the second year onwards, 14 versus one were failure-to-thrive and 15 versus 15 were extrapulmonary or pulmonary tuberculosis, highlighting the potential of weight monitoring to identify first-line CD4 failure clinically.
CD4 percentage increased throughout the first 3 years on ART before plateauing in both groups (; p=0·23). Only 11 (2%) children on clinically driven monitoring versus two (<1%) on routine laboratory monitoring had CD4 less than 5% at their last visit (exact p=0·01; appendix
). Viral load suppression was similar in both monitoring groups (; global p>0·7). At the latest test, median 3·7 (IQR 3·0–4·1) years after ART initiation, 351 (77%) of 458 children on clinically driven monitoring versus 345 (78%) of 443 on routine laboratory monitoring had viral load less than 400 copies per mL (p=0·66), similar across ages (heterogeneity p=0·25); 329 (72%) on clinically driven monitoring versus 313 (71%) on routine laboratory monitoring had viral load less than 80 copies per mL (p=0·70).
Weight for age and height for age did not differ significantly between groups (p=0·71, p=0·07; appendix
). 49 (9%) children on clinically driven monitoring versus 29 (5%) on routine laboratory monitoring had weight-for-age Z
score less than −3 (approximate one thousandth percentile of normal UK weight) at last visit (global p=0·12).
One or more grade 3 or 4 adverse events (co-primary endpoint) occurred in 283 (47%) children on clinically driven monitoring versus 282 (47%) on routine laboratory monitoring (HR 0·98, 95% CI 0·83–1·16, p=0·83; ). Of 1170 adverse events (621 clinically driven monitoring, 549 routine laboratory monitoring), 810 (69%) were asymptomatic laboratory results, most commonly grade 3 neutropenia (171 clinically driven monitoring, 167 routine laboratory monitoring; appendix
); only 87 (7%) were definitely, probably, or uncertainly ART-related (41 clinically driven monitoring, 46 routine laboratory monitoring). 111 (18%) children on clinically driven monitoring versus 109 (18%) on routine laboratory monitoring had one or more grade 4 adverse events (HR 0·99, 0·76–1·29, p=0·94). Although there was no difference in grade 4 adverse events, 147 (24%) children on clinically driven monitoring versus 117 (20%) on routine laboratory monitoring had one or more serious adverse events (any grade; HR 1·30, 1·02–1·66, p=0·04). Most of the 362 serious adverse events (217 clinically driven, 145 routine laboratory monitoring) were malaria (113 clinically driven, 65 routine laboratory monitoring), and most (179 clinically driven, 117 routine laboratory monitoring) were admissions to hospital. The excess malaria serious adverse events in the clinically driven monitoring group were mostly in children with parasite counts less than 500 per 200 white blood cells, or were not diagnostically confirmed (). Differences in time to first hospital admission were smaller (HR 1·18, 0·99–1·41, p=0·07), with no difference in duration of admission (median 5 [IQR 3–6] days in clinically driven and routine laboratory monitoring; rank-sum p=0·54). ART-modifying adverse events occurred in 31 (5%) children on clinically driven monitoring versus 32 (5%) on routine laboratory monitoring (HR 0·95, 0·58–1·56, p=0·84). The most common modification (14 clinically driven, 13 routine laboratory monitoring) was to stop (on four-drug regimen) or substitute zidovudine.
There was no significant difference between the three ART strategy randomisation groups in mean CD4 percentage change at week 72 (p=0·33) or 144 (p=0·69; ). However, at week 36 (when all children moved to three drugs), CD4 percentage responses were significantly greater in the four-drug induction groups (p<0·0001; ; appendix
New WHO 4 stage event or death (A), CD4 (B), viral load (C), and adverse events (D), by ART strategy
Viral load suppression less than 400 copies per mL was similar in the three ART strategy groups at weeks 4, 36, and 48 (p>0·4), but differed significantly at weeks 24 (p=0·009) and 144 (p=0·009; ). At week 24, suppression was significantly greater in induction groups receiving four drugs (285 [88%] of 324 children in groups B and C vs
114 [77%] of 148 in group A). By contrast, similarly to week 144, at the latest test suppression was significantly greater in children receiving two NRTIs plus an NNRTI (496 [84%] of 591 in groups A and B vs
200 [65%] of 310 in group C). No significant difference was seen in suppression less than 80 copies per mL at week 24 (p=0·41); however, suppression less than 80 copies per mL was significantly greater in groups A and B at week 144 and latest test (466 [79%] in groups A and B vs
176 [57%] in group C; p<0·0001). Results were similar when restricted to children younger than 5 years (not shown) or 3 years (appendix
There was no evidence of differences between ART-strategy groups in progression to new WHO stage 4 event or death (HR [B:A] 0·89, 95% CI 0·53–1·48; HR [C:A] 0·91, 0·54–1·52; global p=0·89), WHO stage 3 or 4 event or death (HR [B:A] 0·82, 0·55–1·20; HR [C:A] 0·80, 0·54–1·17; global p=0·44), or mortality overall (HR [B:A] 0·66, 0·33–1·31; HR [C:A] 0·97, 0·52–1·81; global p=0·43; ; appendix
). In particular, there was no evidence that greater initial CD4 increases in groups B or C significantly reduced disease progression risks in the first year (13 deaths in group A vs
nine in group B vs
18 in group C; 22 vs
24 WHO stage 4 events or deaths; 36 vs
37 WHO stage 3 or 4 events or deaths). However, there was also no suggestion of higher event rates in group C receiving long-term three-NRTI maintenance, despite lower long-term viral load suppression; if anything, fewer events occurred after 1 year (seven deaths in group A vs
five in group B vs
two in group C; 18 vs
eight WHO stage 4 events or deaths; 37 vs
17 WHO stage 3 or 4 events or deaths). There was no evidence of differences in weight for age (p=0·58) or height for age (p=0·90) across ART strategies (appendix
157 (40%) children in group A, 190 (47%) in group B, and 218 (54%) in group C had one or more grade 3 or 4 adverse events (co-primary endpoint; HR [B:A] 1·32, 95% CI 1·07–1·63; HR [C:A] 1·58, 1·29–1·94; global p=0·0001; ). The difference was almost exclusively driven by excess asymptomatic neutropenia (86 vs
184 events; appendix
). There were 15 versus 41 versus 31 definitely, probably, or uncertainly ART-related grade 3 or 4 adverse events, respectively. There were no significant differences in grade 3 or 4 anaemia or grade 4 only anaemia (with or without clinical symptoms; grade 3 or 4: 38 vs
44, respectively; grade 4: 21 vs
25, respectively). There were also no significant differences in the numbers of children with one or more grade 4 adverse events (63 [16%] vs
81 [20%] vs
76 [19%]; HR [B:A] 1·27, 0·91–1·76; HR [C:A] 1·20, 0·86–1·68; global p=0·34) or serious adverse events (87 [22%] vs
82 [20%] vs
95 [23%]; HR [B:A] 0·92, 0·68–1·25; HR [C:A] 1·09, 0·81–1·46; global p=0·53).
ART-modifying adverse events occurred in eight (2%) children in group A versus 30 (7%) in group B and 25 (6%) in group C (HR [B:A] 3·80, 95% CI 1·74–8·29; HR (C:A) 3·09, 1·39–6·85; global p=0·002; ). The most common modification (13 children in group B, 14 in C) was to stop (on four-drug regimen) or substitute zidovudine because of anaemia, even though grade 3 and 4 anaemias occurred similarly across all three groups. Despite substantial numbers of grade 3 neutropenias, only six children (two in group B, four in group C) modified ART (zidovudine) for this reason. Three children substituted zidovudine because of lipoatrophy in group C; two children in group A and three in group B substituted efavirenz because of lipodystrophy or gynaecomastia.