Our study demonstrates ART can be safely administered early in the onset of TB treatment and that the urgency of starting ART during the course of TB therapy is dependent on the immune status of the patient. For patients with CD4+ counts below 50 cells/ mm3, AIDS-related illnesses and mortality were reduced by 42% from 26.6% to 15.5% in those who started ART two weeks after start of TB treatment compared to those who started 8 to 12 weeks after initiation of TB therapy. That such a small delay in time to initiate ART for those with low CD4+ T lymphocytes would have such a detrimental effect on AIDS and mortality highlights the vulnerability and suppression of the host immune system to AIDS complications in the setting of TB, and the remarkable capacity for ART to abrogate this effect rapidly.
Our study shows that for those with CD4+ lymphocytes greater than 50 cells/mm3
, waiting 8–12 weeks after the initiation of TB therapy did not confer any increased risk of an AIDS-defining illness or death and was associated with less TB IRIS. For several reasons including TB IRIS, this brief delay in starting ART may simplify TB management, although TB IRIS still occurred in the early treatment arm. Our study should not be interpreted to indicate that there is no urgency to starting ART in this group of patients; indeed, delaying ART until after completion of TB therapy increased mortality in a concurrent randomized study. 2
Results from this trial complement and extend findings from other concurrent randomized studies of ART among HIV-1 infected persons with TB. Mortality in the CAMELIA study (median entry CD4+ lymphocyte counts of 25 cells/mm3
(IQR,10,56) ) and death or AIDS defining illness in the low CD4+ strata (<50 cells/mm3
) of our study and in the SAPIT study were all significantly reduced among patients starting immediate vs early ART. 13, 14
Our study also extends the generalizability of prior studies through its inclusion of these patients from four continents and those with either confirmed or probable TB.
Clinicians are often hesitant to start ART because of potential medication toxicity and laboratory abnormalities that may occur when ART and TB therapy are started in close proximity. Overall, there was no difference in these events between the immediate and early ART strategies; interestingly, there was a higher frequency of neutropenia and thrombocytopenia in the early as compared to the immediate arm. The explanation for the difference is likely multi-factorial, although immediate ART could have exerted a more rapid effect on reversing bone marrow suppression characteristic of untreated HIV disease.
Consistent with earlier studies, there was a higher rate of TB IRIS in the immediate compared to early ART arm of the study. 8
However, the more frequent and earlier occurrence of these events did not lead to worse overall outcomes. Prednisone was used to alleviate symptoms by about half of the subjects with TB IRIS in our study; the optimal use of prednisone in this setting to reduce symptoms without increasing susceptibility to masking other complications is an area of active study. 15
Assessment of optimal ART strategies must take into account rates of plasma HIV-1 RNA suppression and CD4+ lymphocyte response. Starting ART early could potentially jeopardize adherence and lead to higher rates of virologic failure, development of viral resistance and worse immune response. Patients simultaneously treated for both TB and HIV-1 have an extremely high pill burden and side effects of the antimicrobial agents are overlapping with not only each other but also with the clinical manifestations of TB. Thus, it is reassuring that despite the additional burden to adhere to a complex treatment regimen with the immediate start of ART, participants on the immediate arm achieved similar rates of viral suppression at 48 weeks on study compared those who delayed treatment until at least 8 weeks of TB treatment. Similar results were observed in ACTG A5164, an ART strategy study for patients with AIDS conditions other than TB. 16
Patients with known drug-resistant TB were ineligible for our study; thus results here may not be applicable to this population.17
For patients with TB meningitis where TB IRIS can lead to inflammation in the central nervous system, our study does not provide definitive guidance. A recent randomized study of adults exclusively with TB meningitis in Viet Nam reported extraordinary high mortality rates in both arms and no benefit of immediate versus early ART. 18
These exceptions withstanding, our study provides evidence that it is feasible and safe to start ART within 2 weeks of TB treatment start, and that for individuals with CD4+ lymphocytes <50 cells/mm3
, it significantly reduces morbidity and mortality.
Applying the findings of this study to the clinical setting will require a concerted and coordinated effort on behalf of TB and HIV programs worldwide. Prompt HIV testing among TB patients is critical to the application of our findings. 19
Although progress is visible on this front, less than half of patients in sub-Saharan Africa who reported to TB control programs had HIV testing in 2008.5
Implementation of these findings also means that ART services must either be available at the TB clinic or there must be a seamless referral to HIV clinics that can rapidly absorb patients and initiate ART.20, 21
Time requirements for HIV and ART adherence counseling prior to ART initiation will need to be balanced with the substantial risk of morbidity and mortality with treatment delay. Training for TB IRIS identification and treatment may need to be increased. Implementation studies that identify barriers to adaptation of the clinical practice of immediate ART for patients with low CD4 cell counts newly diagnosed with TB are clearly warranted to ensure the benefits of this research are realized.