Standard 6 months of rifampicin containing treatment is considered curative for new drug sensitive pulmonary TB, and the sputum smear conversion is considered as a reliable marker for successful treatment. In this study, we show that sterilizing cure was not achieved in all cured patients after standard treatment, and viable cultivable bacilli were detected in 6% of patients despite successful sputum smear conversion. Earlier studies have shown that MTB may persist in lung tissue for months to years even after bacterial sterilization is achieved at the end of treatment [12-15]. A study has shown the presence of MTB mRNA in the context of non-resolving and intensifying lesions on positron emission tomography-computed tomography (PET–CT ) images after treatment completion and bacterial sterilization suggesting that even apparently sterilizing curative treatment for TB may not eradicate all of the MTB bacteria in most patients . The persisting bacilli could lead to relapse as shown in a study from Uganda where 10% of successfully treated patients with standard 6 months regimen patients got recurrence of TB within one year, and 81% of these recurrent TB cases were due to relapse . The relapse rates ranges from 2.6% to 9.7% after successful standard treatment and sterilization cure [13, 16-18]. Based on these findings it can be speculated that relapse rate after non-sterilizing cure might be even higher. A study from Japan reported complete resolution of all active pulmonary TB lesions on PET-CT scan after 12 months of treatment, and no relapse at 1 year of follow-up . These findings raise questions whether the presence of viable bacilli after treatment and relapse is related to the duration of treatment. The higher relapse rates in patient groups with impaired immunity support the concept that a competent immune response has an important complementary role in the ultimate control of residual bacteria after completion of antibiotic treatment [18, 20, 21].
Previous studies have shown that presence of lung cavities on chest X-ray at baseline is inversely proportional to sterilization at the end of treatment . In our study no association was seen with cavities at start of treatment and sputum sterilization at 6 month of treatment. Culture positivity of sputum at 2 month has been shown to be associated with culture positivity at 6 month implying high bacterial load at the start of treatment could lead to unfavorable outcome . We did not apply culture at 2 months but smear positivity at 2 months was not associated with culture positivity at 6 month, and neither was higher bacillary load at the start of treatment associated with sputum culture positivity at the end of treatment. However lack of these associations could be due to small number of patients with unfavorable outcome in our study.
In this study 5/12 culture positive cases had recent history of TB in family, implying the possibility of reinfection from the home environment rather than treatment failure as the source of culture positivity. Different studies in past have shown that exogenous reinfection could be a major cause of post primary TB after achieving cure especially in TB endemic areas . People who had TB once are at an increased risk of developing TB when re-infected. Reinfection rate after successful treatment could be as high as four times that of new TB . These findings emphasize the importance of achieving sterilizing cures and preventing transmission.
In our cohort, the proportion (5%) of diabetics among the TB patients was much lower than the prevalence of diabetes mellitus in general population in Pakistan, which is shown to be 26.3% . This, and lack of association of diabetes with culture positivity at the end of treatment does not confirm the earlier studies indicating diabetes as a risk factor for active pulmonary TB and unfavorable treatment outcomes [20, 27, 28]. The prevalence of diabetes in our study could have been been underestimated as prevlance was based on patient history and serum glucose levels were not measured, leaving the possibility that some patients might had undiagnosed diabetes. A cross sectional study from Lahore, Pakistan found 14.8 % diabetics among TB patients by measuring serum glucose and HbA1C levels . This prevalence is higher than our cohort but still lower than the prevalence in general population. A Malaysian study reviewed 1267 active TB patients at a tertiary hospital, and did not find diabetes as a risk factor for treatment failure . Thus diabetes may not be a substantial risk factor for all pulmonary TB and unfavorable treatment response.
Inadequate chemotherapy causing exposure of bacilli to a single effective drug can lead to selection of resistant subpopulations, and unfavorable treatment outcomes [31-33]. The national prevalence of 7% INH resistance among rifampicin sensitive cases in Pakistan implies that a substantial number of TB patients receive only one effective drug in the continuation phase . However in our study, addition of ethambutol in the continuation phase had no effect on sterilization of sputum. Ethambutol is a bacteriostatic drug while INH is bactericidal. Despite WHO recommendation, the evidence to quantify the ability of ethambutol to achieve better outcomes when used in combination to “protect rifampicin” in patients with pretreatment INH resistance, is insufficient, and further research is needed.
There are some shortcomings of the study. It is a relatively small study, with a small number of unfavorable outcomes. Culture was not performed on many cases due to logistic reasons, and Chest X-ray results could not be retrieved for several patients. This could have added bias in the study. Patients were not followed- up after treatment to determine the recurrence of TB. Despite these shortcomings, the study gives useful information about the treatment outcomes in the routine TB control program settings, and could contribute towards evidence for improving the routine TB care.