Receipt of Prophylaxis and Treatment
During the first 12 weeks after the initiation of ART, patients in the enhanced-prophylaxis group were prescribed isoniazid prophylaxis for 84.4% of person-time and isoniazid treatment for 11.3% of person-time, as compared with 3.6% and 10.7% of person-time, respectively, in the standard-prophylaxis group. Patients in the enhanced-prophylaxis group were prescribed fluconazole prophylaxis for 96.7% of person-time and fluconazole treatment for 1.9% of person-time, as compared with 0.3% and 2.6% of person-time, respectively, in the standard-prophylaxis group (Fig. S1 in the Supplementary Appendix). All the patients in the enhanced-prophylaxis group were prescribed azithromycin and albendazole (Table 1).
At 12 weeks, a substantial proportion of the patients in the standard-prophylaxis group initiated isoniazid preventive therapy (Fig. S2 in the Supplementary Appendix). Thus, from 12 week to 48 weeks, the patients in the enhanced-prophylaxis group were prescribed isoniazid prophylaxis for 46.3% of person-time and isoniazid treatment for 3.2% of person-time, as compared with 54.8% and 3.2% of person-time, respectively, in the standard-prophylaxis group. In contrast, after 12 weeks, patients in the enhanced-prophylaxis group were prescribed fluconazole prophylaxis for 2.3% of person-time and fluconazole treatment for 0.7% of person-time, as compared with 0.5% and 0.8% of person-time, respectively, in the standard-prophylaxis group.
During the first 12 weeks, the patient-reported rate of adherence to prophylaxis was slightly (but significantly) poorer in the enhanced-prophylaxis group than in the standard-prophylaxis group (P=0.004); for example, 7.4% and 5.2% of the patients, respectively, reported that they had missed any doses of prophylaxis drugs (including trimethoprim–sulfamethoxazole) between weeks 8 and 12. However, during weeks 12 to 48, the adherence rates were similar in the two groups (P=0.30), as were rates of patient-reported acceptability of the drugs (Fig. S3B and S3C in the Supplementary Appendix).
Mortality at 24 Weeks and 48 Weeks
Death by 24 weeks (the primary outcome) was reported in 80 patients in the enhanced-prophylaxis group and in 108 in the standard-prophylaxis group (8.9% vs. 12.2% by Kaplan–Meier analysis; hazard ratio in the enhanced-prophylaxis group, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03 by the log-rank test) (Fig. 2A). Thus, at 24 weeks, 30 patients would need to have received enhanced prophylaxis to prevent 1 death. A significant survival benefit was maintained through 48 weeks, with deaths reported in 98 patients in the enhanced-prophylaxis group and in 127 in the standard-prophylaxis group (11.0% vs. 14.4% by Kaplan–Meier analysis; hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04 by the log-rank test) (Fig. 2A). Thus, at 48 weeks, 29 patients would need to have received enhanced prophylaxis to prevent 1 death. There was no evidence that benefits varied over time (P=0.49 for interaction in the comparison of 0 to 24 weeks vs. 24 to 48 weeks) and no evidence of interaction with other factorial randomizations to additional raltegravir or supplementary food (P>0.70).
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The most common primary cause of death was infection in 92 of 225 deaths (40.9%) (Table S2 in the Supplementary Appendix). Causes of death were often multifactorial; many occurred at home, and a clear cause was not determined. As adjudicated by the end-point review committee, deaths from cryptococcus infection and from unascertained causes occurred less frequently in the enhanced-prophylaxis group than in the standard-prophylaxis group (P=0.04 and P=0.03, respectively), but there was no evidence of significant between-group differences in the rates of death from tuberculosis (P=0.72), presumptive bacterial infections (P=0.63), or other causes (P=0.85) (Fig. 2B). There was marginal evidence that IRIS-compatible deaths were less common with enhanced prophylaxis than with standard prophylaxis (P=0.06). (Details are provided in the Results section in the Supplementary Appendix.)
Estimated rates of death were highest on day 18, when the absolute difference between enhanced prophylaxis and standard prophylaxis was greatest; these rates then decreased sharply through week 12. The rate of death from unascertained causes followed a similar pattern to that of known causes (Fig. S4 in the Supplementary Appendix).
There was no evidence that the mortality benefit varied across nine preplanned subgroups, including the other randomizations (P>0.20). In particular, there was no evidence that mortality benefits depended on the CD4+ count at the initiation of ART (P=0.29 for the interaction with categories of CD4+ count; P=0.89 for the interaction with the CD4+ count as a continuous variable). Of nine exploratory subgroup analyses, only one suggested that benefits from enhanced prophylaxis might be greater among male patients than among female patients (P=0.048) (Fig. S5 in the Supplementary Appendix).
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