At enrolment (), the 214 patients in the early integrated-therapy group and the 215 patients in the late integrated-therapy group had similar demographic and clinical characteristics (). Median CD4+ count was 150 cells/mm3
and viral load was 161000 copies/ml at baseline; similar between both groups. Median duration of follow-up in the trial was 17.7 months (interquartile range (IQR), 14.0 to 17.8). At study completion, the retention rates were 76.9% and 71.5% in the early and late integrated-therapy groups respectively (Information on retention and causes of death is provided in the online material
Baseline characteristics of the patients in the SAPIT trial*
Initiation of antiretroviral therapy
Among patients who completed tuberculosis therapy, the median treatment duration was 210 days (207 participants) and 203 days (210 participants) in the early and late integrated-therapy groups respectively. A total of 92.5% (198/214) of the patients in the early integrated-therapy group and 76.3% (164/215) in the late integrated-therapy group started antiretroviral therapy during the study (P<0.001). The longer period from randomization to antiretroviral therapy initiation resulted in more patients being lost to follow-up, withdrawing or dying prior to antiretroviral therapy initiation in the late integrated therapy group (). However, there are no significant differences in the overall rates of lost-to-follow-up (12.1% vs 15.8%, P=0.33) and withdrawals (9.3% vs 10.7%, P=0.75) between the early and late integrated-therapy groups.
The 198 patients in the early integrated-therapy group, who started antiretroviral therapy, did so at a median of 21 days (IQR 15 to 29) after tuberculosis therapy initiation. Reasons for 33 of these patients initiating antiretroviral therapy after the four-week window were; missed their antiretroviral therapy initiation visit (n=9), abnormal liver function (n=8), other laboratory abnormalities (n=2), refused antiretroviral therapy initiation (n=4), or clinical conditions precluding antiretroviral therapy initiation (n=10).
The 164 patients in the late integrated-therapy group, who started antiretroviral therapy, did so at a median of 97 days (IQR: 77 to 126.5) after the initiation of tuberculosis therapy. One patient started antiretroviral therapy during the intensive phase of tuberculosis treatment. Reasons for 47 of these patients starting antiretroviral therapy more than four weeks after completion of the intensive phase of tuberculosis treatment were: missed their antiretroviral therapy initiation visit (n=29), abnormal liver function (n=1), refused antiretroviral therapy initiation (n=6), or clinical conditions precluding antiretroviral therapy initiation (n=11).
Incidence rates of AIDS or death
Incidence rates of AIDS or death were 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late integrated-therapy groups respectively (Incidence Rate Ratio (IRR), 0.89; 95%Confidence Interval (95%CI), 0.44 to 1.79; P=0.73). After adjustment for baseline WHO disease stage (stage 4 vs. stage 3), age, sex, history of tuberculosis, extrapulmonary tuberculosis, and baseline CD4+ cell count and HIV RNA level, the hazard ratio was 0.86 (95% CI, 0.42 to 1.85). The probability of observing 18 of AIDS or death cases in the early ART group and 19 cases in the late ART group was 5.6%, 1.9%, and 0.4% if the true difference in AIDS or death between the arms was 40%, 50% and 60% respectively. In a sensitivity analysis, where all participants lost to follow-up were regarded as having died, the incidence was 17.0 (95% CI 12.3 to 22.8) and 21.7 per 100 person years (95% CI 16.3 to 28.4) in the early and late integrated arms respectively, (IRR: 0.78, 95% CI: 0.51 to 1.19, P=0.227).
Incidence rates of AIDS or death by CD4+ count
A statistically significant (P = 0.027) interaction between therapy group and CD4+ count for AIDS or death, indicating heterogeneity across the two CD4 strata in the effect of time to ART initiation on AIDS or death. The incidence rates of AIDS or death in the subset of patients with CD4+ counts <50 cells/mm3 (n=72) were 8.5 per 100 person-years (95%CI, 2.3 to 21.9) in the early integrated-therapy group compared to 26.3 per 100 person-years (95%CI, 12.6 to 48.4) in the late integrated-therapy group (IRR 0.32, 95% CI, 0.07 to 1.13, P=0.06) (). In patients enrolled with CD4+ counts ≥50 cells/mm3 (n=357), the incidence rates of AIDS or death were 6.6 (95%CI, 3.6 to 11.0) and 4.4 (95%CI, 2.0 to 8.3) per 100 person-years in the early and late integrated-therapy groups respectively (IRR, 1.51, 95% CI 0.61 to 3.95, P=0.34) ().
Kaplan Meier survival curves for combined AIDS and mortality by early and late integrated therapy groups for tuberculosis-HIV co-infected patients with a) CD4+ count <50 cells/mm3 and b) CD4+ counts ≥50 cells/mm3.
Mortality, AIDS defining illness and mortality combined and immune reconstitution inflammatory syndrome rates, stratified according to baseline CD4+ cell count.
In the early integrated-therapy group, IRIS occurred 4.7 times (P=0.01) more frequently in patients with CD4+ count below 50 cells/mm3 and 2.2 times (P=0.02) more frequently in patients with CD4+ counts ≥50 cells/mm3 (). No statistically significant interaction indicating a lack of heterogeneity across the two CD4 strata in the effect of time to ART initiation on IRIS. The median time from antiretroviral therapy initiation to development of IRIS was 15.0 (IQR, 7 – 30) days in the early integrated-therapy group and 15.5 (IQR, 14 – 28) days in the late integrated-therapy group. Steroid treatment was required by 7 (9.1%) patients with IRIS; 5 of them had CD4+ counts below 50 cells/mm3.
Adherence and drug switches
Nineteen patients in each of the two study groups are known to have defaulted tuberculosis therapy (8.9% and 8.8% in the early and late integrated-therapy groups respectively), either by choosing to interrupt therapy or by not attending the clinic for any further scheduled study visits before treatment completion.
Based on monthly pill counts, patients in the early integrated-therapy group and the late integrated-therapy group took 98.0% and 98.8% of their assigned antiretroviral tablets, respectively, during the trial.
Antiretroviral drug switches due to toxicity were required for 10 patients in the early integrated-therapy group and for one patient in the late integrated-therapy group (P=0.006). In patients with CD4+ counts ≥ 50 cells/mm3, antiretroviral therapy switches occurred in seven patients in the early therapy group and in one patient in the late therapy group (P=0.04).
A total of 15 patients changed their antiretroviral regimens due to virological failure; 6 in the early integrated-therapy group and 9 in the late integrated therapy-group. The antiretroviral drug switches occurred on average 9.0 (95%CI: 5.9 to 12.2) and 11.9 (9.1 to 14.6) months after antiretroviral therapy initiation in the early and late integrated-therapy groups respectively (P=0.18).
Tuberculosis and HIV treatment outcomes
There is no statistically significant difference in tuberculosis drug resistance () at baseline between the study groups. Tuberculosis treatment outcomes did not differ between the groups (); this did not change after adjustment for presence of multi-drug resistance. At 6 and 12 months after randomization, the proportion of participants with a suppressed HIV RNA level did not differ between the integrated-therapy groups. However, the mean CD4+ count increase from baseline to 12 and 18 months post randomization was significantly higher in the early integrated-therapy group compared to the late integrated-therapy group ().
Clinical Outcomes of Tuberculosis and Antiretroviral Therapy in the SAPIT trial.
There were 112 and 107 patients with grade 3/4 non-IRIS adverse events in the early (42.8 per 100 person-years) and late (42.6 per 100 person-years) integrated-therapy groups, respectively (P=0.98). There were 56 and 50 patients with serious adverse events in the early and late integrated-treatment groups respectively.