Our data demonstrate that, among U.S. patients with HIV, smear-negative TB patients who initiated treatment had significantly lower 2-year mortality than smear-positive patients. This was true even in the pre–HAART era, when mortality from HIV/AIDS was exceedingly high. The strengths of this study include the robustness of this population-based data, which has been estimated as >99% complete for capturing TB cases 
, the routine use of culture in the United States to confirm TB and the use of other diagnostic tests to identify opportunistic pulmonary infections other than TB.
The finding of lower mortality in patients with HIV treated for smear-negative TB in the United States is different from what has been reported in resource-limited settings 
. The significantly decreased hazard for death among smear-negative TB/HIV patients in our analysis suggests that those with smear-negative TB who were alive at the time diagnosis was established, overall, had earlier, less severe disease than patients with smear-positive TB.
Many studies have demonstrated that patients with HIV infection have higher rates of smear-negative TB 
, but it is unclear if this is due to screening, or misdiagnosis, or if immune suppression itself diminishes the bacillary density in sputum. In the United States, incarcerated persons usually undergo aggressive TB screening 
, and the increased prevalence of smear-negative disease among this population supports the effect of screening in identifying early stage disease. This, along with the higher prevalence of smear-negative disease in TB patients who have normal chest radiographs seen in this analysis, suggests that smear-negative disease may indeed be an early stage of TB in the United States, even among patients with HIV.
Smear status may correlate with degree of immune dysfunction, and it has been hypothesized that, because worsening immune suppression impairs pulmonary cavitation 
and cavitation correlates with smear-positivity 
, patients with HIV and TB who are smear-negative have more severe immune suppression 
. There is, however, little consistency among studies that have directly investigated the correlation between immune function, as measured by CD4 count, and smear status. Some studies have shown that sputum bacillary density appears to decrease with falling CD4 count 
, but other studies have demonstrated that the more severely immune compromised patients seem to have higher rates of smear-positive TB disease 
. The discrepant findings suggest that the correlation between immune functioning and sputum bacillary density may not be linear. While we were unable to directly account for immune suppression in our analysis, our findings do not support the hypothesis that among patients with HIV, smear-negative TB disease is associated with greater immune suppression than smear-positive TB disease.
Differences in the study populations themselves may also explain why our findings differ from those previously published from resource-limited settings with higher HIV prevalence. By including only TB cases with microbiologic confirmation of disease, we eliminated non-TB pulmonary diseases (e.g., Pneumocystis jirovecii
pneumonia, fungal diseases, etc.,) that otherwise might be misdiagnosed as TB. In countries that are unable to perform routine sputum cultures, the diagnosis of pulmonary TB in a patient with negative sputum smears is based on clinical and radiologic findings. These findings, however, are often nonspecific in persons with HIV, especially those with smear-negative disease 
. In our results, for example, 1,051 (16%) of 6,481 smear-negative, culture-confirmed pulmonary TB patients with chest radiograph reports had films that were interpreted as normal. In studies that did not use culture as a gold standard, it is likely that a substantial proportion of smear-negative TB patients was misdiagnosed and inappropriately treated, thus leading to higher mortality.
It is probable that patients with smear-negative TB in resource-limited countries have even more considerable diagnostic and treatment delays than smear-negative TB/HIV patients in the United States. Because smear microscopy is frequently the sole diagnostic laboratory test available, sputum examinations are usually repeated multiple times for TB patients whose initial sputum smears are negative for AFB, causing significant delays in diagnosis and treatment 
. Indeed, current international guidelines suggest that, in the absence of mycobacterial culture, a minimum of at least two sputum specimens negative for AFB, radiographic abnormalities consistent with active TB, laboratory confirmation of HIV infection or strong clinical evidence of HIV infection, and a decision by a clinician to treat with anti-TB medications should be documented to categorize a patient as a smear-negative TB case 
. These delays have deleterious consequences for both the individual and public health 
. Delays in TB diagnosis among patients with HIV are particularly dangerous for the individual since HIV infection in patients with TB, regardless of smear status, is associated with high early mortality 
. In our analysis, time to initiation of therapy was significantly longer for surviving patients with smear-negative TB than for patients with smear-positive disease. These diagnostic and treatment delays, and their effect on survival, are likely to be smaller in the United States, where ancillary studies (such as sputum culture and nucleic acid amplification) are often submitted at the same time that smears are collected, than in countries where ancillary tests may not be readily available 
Finally, it is also possible that differences in treatment contributed to the different findings. In some resource-limited countries, patients with smear-negative TB were not always treated with rifampicin throughout their treatment regimens 
. Moreover rifampicin, because of its spectrum of activity, may treat some infections other than TB 
. The RVCT does not collect TB case management details, so we were not able to examine the effect of changes in TB treatment, or adherence to treatment, over time.
This study must be interpreted with the following considerations. Fluorescent microscopy has been increasingly used in the United States over the time period studied, and it is more sensitive for detection than microscopy used in most high TB burden settings 
. Thus, findings from smear-negative TB patients in this study may differ from those among patients designated as sputum smear-negative based on less sensitive microscopy methods. A difference in the sensitivity of diagnostic technique, however, might explain a change in the size of the hazard rate between smear-negative TB and smear-positive TB, but would not account for a reversal. We were not able to examine patient-level effects of HAART since HIV treatment data is not reported on the RVCT; yet ecologic analyses did not suggest differences in the relationship between smear-negative TB disease and mortality in the pre- and post-HAART data. Importantly, we were unable to include patients who died before diagnosis was established, so we cannot make conclusions about all persons with smear-negative TB disease, and these findings are directly relevant only to patients who are alive at diagnosis and initiate therapy.
In the United States, mortality in patients with HIV infection was not higher among patients with smear-negative TB disease, as compared to those with smear-positive disease, and it is reasonable to conclude that smear-negative TB in patients who initiate treatment appears to represent an earlier or less severe form of TB disease. The difference between these findings and those from resource-limited settings is likely because diagnostics are better in this resource-rich setting. Accurate and timely TB diagnosis remains of paramount importance worldwide, especially as the global HIV epidemic confounds clinical presentation and worsens disease outcomes, and the findings of this analysis argue for the need for improved, affordable diagnostic tests in high-burden, resource-limited countries. In addition, greater efforts to identify TB cases early through active screening in high-risk groups are critical and must be combined with improved outreach to persons with limited healthcare access.