Secondary Outcomes at 48 Weeks
Enhanced prophylaxis was associated with significantly lower rates of WHO stage 3 or 4 events or death than was standard prophylaxis (in 179 patients [19.8%] vs. 224 [24.9%], P=0.008), along with lower rates of a new diagnosis of tuberculosis (in 64 patients [7.1%] vs. 92 [10.2%], P=0.02), cryptococcal infection (9 [1.0%] vs. 23 [2.6%], P=0.01), candidiasis (10 [1.1%] vs. 23 [2.6%], P=0.02), and new hospitalization (154 [17.0%] vs. 186 [20.7%], P=0.03) (Fig. 3, and Table S3 in the Supplementary Appendix).
Discussion
Among HIV-infected adults and older children with advanced immunosuppression who initiated ART, the relative rate of death at 24 weeks was 27% lower among those who received an enhanced antimicrobial prophylaxis package than among those who received trimethoprim–sulfamethoxazole alone (standard prophylaxis) for 12 weeks. Benefits were maintained through 48 weeks (24% lower rate), with a number-needed-to-treat of 29 to prevent one death. Patients who received enhanced prophylaxis also had a significantly lower rate of hospitalization, WHO stage 3 or 4 events, IRIS-compatible events, tuberculosis, and cryptococcal and candida infections; the rate of presumptive bacterial infection was similar in the two groups. There was no evidence of increased toxicity, poorer HIV viral-load suppression, or worse adherence to the ART regimen with enhanced prophylaxis; rather, there were nonsignificantly fewer serious adverse events and grade 4 adverse events.
Two trials have shown a lack of efficacy of an alternative approach to reducing early tuberculosis-related mortality through the initiation of preemptive tuberculosis treatment with four drugs at the time of ART initiation in all adults with severe immunosuppression.16,17 A third trial was terminated early because of low enrollment22; a fourth is ongoing.23 Isoniazid prophylaxis is effective and is now recommended in WHO guidelines after the exclusion of active disease,15 but when our trial started, such treatment was not standard care in any of the recruiting countries. At that time, it had been implemented in only 28% of African countries.24 The timing of the initiation of isoniazid prophylaxis is unspecified in the WHO guidelines. Barriers to uptake include poor availability of individual isoniazid–pyridoxine formulations and concern about toxicity, pill burden, and isoniazid resistance. During the first 12 weeks after the administration of single-dose albendazole and azithromycin (one pill once daily for 5 days), the enhanced-prophylaxis regimen in our trial required only one more pill per day than was required for standard prophylaxis; in addition, enhanced prophylaxis was associated with good rates of acceptability and adherence.25 Unfortunately, we could not assess isoniazid resistance in new tuberculosis cases, since these investigations were not routinely performed at the trial centers. Previously, low rates of isoniazid resistance have been reported with isoniazid preventive therapy.26
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To prevent cryptococcal disease, the WHO recommends testing for cryptococcal antigen in patients with a CD4+ count of fewer than 100 cells per cubic millimeter.1 Such screening and preemptive treatment reduced early mortality in one trial,27 but screening tests may not be available at lower-level health facilities. We therefore evaluated a lower-cost dose of fluconazole (100 mg) once daily for all patients with immunosuppression, administered during the first 12 weeks of ART, when CD4+ counts remain lowest. This dose was extrapolated from an effective dose of 200 mg three times weekly among patients who tested negative for cryptococcal antigen and who had initiated ART with a CD4+ count of fewer than 200 cells per cubic millimeter.28 The rate of death associated with cryptococcal infection remained significantly elevated for at least 12 weeks in the standard-prophylaxis group, a finding that supports this approach.
One of the limitations of our trial is that we tested an antimicrobial prophylaxis package, which made it difficult to quantify the effect of each component. In the enhanced-prophylaxis group, the rates of death and complications from cryptococcal infection were significantly lower than those in the standard-prophylaxis group, as was the rate of new tuberculosis infection but not the rate of death from tuberculosis. Another limitation of our trial is that although there was no significant between-group difference in the rate of severe bacterial infections, most of the diagnoses were presumptive because many centers lacked facilities for performing microbiologic analyses, and causes of death were frequently not ascertained because the patients died at home soon after randomization. However, the patients who received enhanced prophylaxis had a lower rate of early death from unknown causes. Given the diagnostic challenges posed by severe bacterial infections and their major contribution to HIV-related mortality,3,9 it is likely that such infections contributed to deaths of unknown cause. Thus, azithromycin may provide additional protection over trimethoprim–sulfamethoxazole, given its broad antimicrobial activity, longer half-life, antiinflammatory properties, and activity against nontuberculous mycobacteria.29 Concern regarding antimicrobial resistance30 should be balanced against the potential for a substantial short-term mortality benefit in this high-risk population. Further mechanistic studies will be needed to determine the contribution of each drug to the efficacy of enhanced prophylaxis and to assess whether omitting any component of the package could reduce its efficacy.
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The cost of enhanced prophylaxis ranged from $8 to $34 across trial countries (Table S6 in the Supplementary Appendix). However, drug costs varied by a factor of 10, which highlights the importance of ensuring that all countries can access drugs at the lowest prices. At the minimum price, the cost per quality-adjusted life-year falls within recently published cost-effectiveness thresholds for even the lowest-income countries.31 This analysis does not capture the longer-term benefits associated with reduced mortality beyond 48 weeks, and the inclusion of such benefits would further increase the value-for-money of enhanced prophylaxis.
We enrolled both adults and older children or adolescents because the rates and causes of death are similar regardless of age.7 We expected that 300 children over the age of 5 years would be enrolled, but we identified only 72 who had a CD4+ count of fewer than 100 cells per cubic millimeter. This finding may be due to improved coverage of ART to prevent mother-to-child HIV transmission.32 Although the numbers were lower than expected, there is no reason why the enhanced-prophylaxis package would not benefit older children who are vulnerable to tuberculosis, cryptococcal infection, candidiasis, and helminths. In contrast, the trial recruited adults faster than expected, which suggests that large numbers of patients could benefit from enhanced prophylaxis. Nearly half of the patients had minimal symptoms despite having a median CD4+ count of 37 cells per cubic millimeter, which shows the continued importance of obtaining CD4+ counts for the assessment of patients before ART initiation.33 Whether patients who initiate ART with a CD4+ count of 100 to 200 cells per cubic millimeter would also benefit from enhanced prophylaxis is unclear. However, two other groups with potentially low CD4+ counts may benefit from enhanced prophylaxis: those in whom ART has failed, especially if the pre-ART CD4+ count was low,34 and those returning to care after they had been lost to follow-up.
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Another limitation of our trial is its openlabel design, as necessitated by the multiple randomizations, weight-based pediatric dosing, and importance of comparing adherence and acceptability in the two groups. However, the primary mortality end point was objective. The pragmatic design meant that the patients who received standard prophylaxis also spent time receiving treatments or secondary prophylaxis as necessary, which probably reduced the differences between the groups. However, any dilution bias would lead to an underestimation of the benefits of enhanced prophylaxis.
In conclusion, we found a survival benefit for multicomponent enhanced antimicrobial prophylaxis in adults and older children with advanced HIV infection who were initiating ART with a CD4+ count of fewer than 100 cells per cubic millimeter — a group that represents a substantial proportion of those starting treatment who are at increased risk for early death.4 The enhanced prophylaxis is relatively inexpensive, has a low pill burden and an acceptable side-effect profile, and would be easy to implement at primary health centers since it relies only on screening for clinical symptoms and testing of CD4+ counts to identify asymptomatic patients with advanced HIV infection.
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