3316 eligible participants were enrolled in DART15
between Jan 15, 2003, and Oct 24, 2004. We excluded 137 (4%) participants who entered a non-randomised pilot study of structured treatment interruptions 28 weeks after ART initiation. Characteristics of the 3179 participants included are representative of participants in ART programmes in Africa (); all participants had CD4 counts lower than 200 cells per μL before starting therapy. Length of follow-up was median 4·9 years (IQR 4·5–5·3) with only 198 (6%) of 3179 participants last seen alive more than 4 months before Dec 31, 2008 (end of follow-up). Completeness of 4-week nurse (98%) and 12-week doctor (99%) visits was very high.
Characteristics of included participants at ART initiation
Participants had variable exposure to co-trimoxazole; prophylaxis was never prescribed during follow-up for 324 (10%) participants, 1959 (62%) were taking it at ART initiation, and 896 (28%) started while on ART, with median 3·5 years (0·9–4·5) total use post-ART in those ever starting. Use at ART initiation varied with centre, year of randomisation, and initial combination treatment. Of 368 participants who died before end of follow-up, only 25 (7%) did not have complete co-trimoxazole history before death and were censored at their last clinic visit. 8128 (57%) person-years of follow-up were spent on co-trimoxazole. Use of prophylaxis differed substantially between the four centres (15%, 72%, 72%, 79%). Only 105 (<1%) person-years of follow-up were spent off ART. Reported ART adherence was high both in participants currently on and off co-trimoxazole, with no missed doses in the past 4 weeks reported at 5234 (83%) and 2426 (78%) visits, respectively, in the first 12 weeks, at 19 688 (93%) and 19 415 (87%) visits in weeks 12–72, and at 65 669 (93%) and 39 965 (91%) visits at more than 72 weeks of ART, excluding visits after randomisation to structured treatment interruptions.
Exclusion of follow-up after randomisation to structured treatment interruptions and upweighting of follow-up after continuous treatment gave 326 deaths (including eight upweighted) in 14 214 total person-years (2·3 per 100 person-years) included in analyses. 85 (26%) deaths occurred within 12 weeks of ART initiation (11·8 per 100 person-years). Present co-trimoxazole prophylaxis halved mortality in the first 12 weeks on ART, with no variation between participants on prophylaxis before screening (odds ratio [OR] 0·52, 95% CI 0·30–0·92, adjusted for baseline factors; p=0·02) versus those starting prophylaxis at the same time as ART (0·46, 0·25–0·84; p=0·01; heterogeneity p=0·69) or of variation between centres (heterogeneity p=0·35). Overall, using unweighted logistic regression and adjusting for baseline factors, but not controlling for time-dependent confounders, we showed that present co-trimoxazole use was associated with a 27% mortality reduction (0·73, 0·56–0·96; p=0·02; between-centre heterogeneity p=0·07).
As expected, mortality was higher in participants with low current CD4 cell count, haemoglobin concentration, or BMI, or with a WHO stage 3 or 4 event in the previous 4 weeks or any stage 3 or 4 event since randomisation (data not shown). These factors were also associated with increased probability of co-trimoxazole use, although extent of association varied between centres (data not shown). When we adjusted for these time-dependent predictors and randomisation to continuous treatment as factors within a regression model for mortality, the estimated OR for co-trimoxazole use was 0·62 (0·48–0·80; p=0·0002; between-centre heterogeneity p=0·50).
In a marginal structural model with inverse-probability treatment weights to control for time-dependent confounders, present prophylaxis reduced overall mortality risk by 35% (OR vs
no present use 0·65, 0·50–0·85, p=0·001; , figure
). Benefit did not differ with randomised monitoring group (heterogeneity p=0·24). Furthermore, mortality risks did not differ between participants who had stopped prophylaxis and never users, and benefit did not vary with increasing time on co-trimoxazole in present users on ART (, ).
Effect of co-trimoxazole prophylaxis on death, new WHO stage 4 events, new or recurrent WHO stage 3 or 4 events, and malaria
Effect of co-trimoxazole prophylaxis with ART from weighted models
Benefit of present co-trimoxazole prophylaxis did, however, vary significantly with time on ART (heterogeneity p=0·04 in a flexible model for time on ART with cubic splines20
), falling from a 58% reduction in the first 4 weeks on ART to a 5% reduction in weeks 68–72 (every additional 4 weeks on ART to 72 weeks increased estimated OR by 1·05 [1·01–1·09]; p=0·03), with no effect subsequently (p=0·67). When we categorised time on ART to show this variation, mortality reduction was greatest in the first 12 weeks of treatment, sustained from 12–72 weeks, but not evident subsequently (heterogeneity p=0·02; ). Adjustment for time on ART and time on co-trimoxazole simultaneously in present users showed that effect of time on ART was not confounded by duration of prophylaxis; similar mortality risk reductions were reported in the first 72 weeks on ART in participants on co-trimoxazole for fewer than 24 consecutive weeks (OR 0·50, 0·34–0·73) and more than 24 consecutive weeks (0·48, 0·28–0·83), and we noted no reduction in mortality after 72 weeks on ART in either group (0·91 [0·47–1·77], heterogeneity before vs
after 72 weeks, p=0·12; OR 0·96 [0·63–1·47], heterogeneity before vs after 72 weeks, p=0·05 respectively). Estimated average 5-year survival in DART participants starting ART with CD4 counts of 15 or 150 cells per μL increased by 5% and 2%, respectively, with co-trimoxazole prophylaxis ().
We estimated effects of prophylaxis on mortality from primary, secondary, or tertiary causes regarded as potentially preventable by co-trimoxazole (92 deaths: septicaemia , pneumonia , severe brain syndrome as defined by the endpoint review committee [generally representing undiagnosed toxoplasmosis; 13], non-cryptococcal meningitis , diarrhoea , malaria , P jirovecii pneumonia , acute febrile event , toxoplasmosis , chronic pulmonary disease , or visceral abscess ), versus other causes (179 deaths: cryptococcus , tuberculosis , lymphoma or Kaposi's sarcoma , other ) versus unknown cause (55), separately. Present prophylaxis reduced risk of deaths from causes regarded as potentially preventable by co-trimoxazole by 21% (OR 0·79, 0·49–1·27), other deaths by 35% (0·65, 0·45–0·93), and unknown deaths by 48% (0·52, 0·27–1·00). In the first 72 weeks on ART, 66 (35%) deaths were from causes potentially preventable by co-trimoxazole compared with 92 (49%) due to other causes and 30 (16%) unknown; with similar mortality risk reductions associated with co-trimoxazole prophylaxis (OR 0·64 [0·37–1·10], 0·48 [0·30–0·77], and 0·29 [0·12–0·73] respectively). After 72 weeks, 26 (19%) deaths were from causes potentially preventable by co-trimoxazole, 87 (63%) were due to other causes, and 25 (18%) were of unknown cause; again, we found no difference in co-trimoxazole effect (OR 1·56 [0·59–4·14], 0·89 [0·53–1·50], and 0·93 [0·38–2·27], respectively).
All participants began ART with a CD4 count lower than 200 cells per μL; 2576 (62%) person-years of follow-up in the first 72 weeks and 2678 (27%) subsequently were spent with most recent CD4 count lower than 200 cells per μL. In the first 72 weeks on ART, we estimated similar mortality reductions in participants with current CD4 counts lower than 200 cells per μL and 200 cells per μL or more on co-trimoxazole prophylaxis (). After 72 weeks on ART we noted no benefit of present co-trimoxazole prophylaxis in participants with current CD4 counts lower than 200 cells per μL or 200 cells per μL or more (). Results were similar for deaths from causes regarded as potentially preventable by co-trimoxazole and for deaths from other causes. Alternative models including an additional CD4 count category of lower than 100 cells per μL (), more than 350 cells per μL, or allowing for a non-linear effect of CD4 cell count also provided no evidence for variation in effect of co-trimoxazole prophylaxis with current CD4 cell count.
Effect of co-trimoxazole prophylaxis on death by time on ART and current CD4 cell count†
Oesophageal candidosis, cryptococcosis, and extrapulmonary tuberculosis were the most common WHO stage 4 events, contributing 159 (31%), 115 (22%), and 108 (21%) first events, respectively. Other diagnoses were individually less common. Only 22 (4%) stage 4 events were P jirovecii pneumonia (21 presumptive), of which 13 of 22 were on co-trimoxazole prophylaxis. We noted little evidence for a reduction in first new WHO stage 4 events after ART initiation with co-trimoxazole (). The marginal benefit seen in past users is probably due to chance or incomplete adjustment for confounders in those stopping co-trimoxazole, and results of sensitivity analyses did not suggest that we had missed any benefit in present users. Results did not differ when oesophageal candidosis was excluded (data not shown). The effect of present prophylaxis on WHO stage 3 and 4 events, including recurrences of previous events as outcomes, was significant, but this small effect did not vary with time on ART (). Heterogeneity existed between centres (p=0·02), and we were unable to obtain consistent estimates of the effect of co-trimoxazole on pneumonia alone (which accounted for 280 [22%] first WHO stage 3 or 4 events) across all four centres, suggesting variable diagnostic criteria or remaining unadjusted confounders.
In the first 12 weeks on ART, CD4 cell count increased by a median 73 cells per μL (32–128) and BMI by 0·76 kg/m2 (0·00–1·60). Participants taking co-trimoxazole did not have greater CD4 cell count or BMI increases than did non-users in the first 12 weeks or subsequently (); estimated CD4 increases were slightly reduced with co-trimoxazole, probably because of some residual confounding (difference vs non-users −3 cells per μL [−12 to 6]; p=0·50). We showed no effect of co-trimoxazole on haemoglobin or platelet counts, and observed a small significant reduction in neutrophil count in participants currently on co-trimoxazole after 72 weeks on ART (). Only 22 (3%) of 650 serious adverse events during the trial were judged to be related to co-trimoxazole (ten definite or probable, 12 uncertain relation, all haematological, rash, or hypersensitivity).
Effect of co-trimoxazole prophylaxis on CD4 cell count, body-mass index, and markers of haematological toxic effects
Harare has low malaria transmission. In Uganda, 1170 (53%) of 2200 participants had at least one malaria event, with 2362 events in total (260 upweighted; 27 per 100 person-years, 1119 [47%] diagnosed by microscopy, 1243 [53%] clinical). Present prophylaxis was associated with a 26% reduction in risk of first new malaria episode in present users (), with similar estimates if more than one episode per person was included (data not shown) and a weakened effect when restricted to parasite-positive diagnoses (0·85 [0·65–1·11]; p=0·23). The reduction in malaria risk associated with co-trimoxazole was maintained throughout follow-up.