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 the 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 the MTB bacteria in most of the patients [7]. 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 [16]. The relapse rates range 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 the relapse rate after non-sterilizing cure might be even higher, which would have a significant impact on the global control of TB. 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 [19]. These findings raise questions on the presence of viable bacilli after treatment and whether 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]. The findings of the study highlights the need for improvement in monitoring treatment response by developing a sensitive, specific and inexpensive surrogate marker for quantifying TB other than the gold standard of culture, as it is not feasible to perform culture in routine for monitoring treatment response in the low-resource high TB endemic setting. Previous studies have shown that presence of the lung cavities on chest X-ray at the start of treatment is inversely proportional to sterilization at the end of treatment [22]. However, in our study, no association was seen with cavities at the start of treatment and sputum sterilization at 6 months of treatment. Culture positivity of sputum at 2 months is thought to be associated with culture positivity at 6 months implying high bacterial load at the start of treatment could lead to unfavorable outcomes [23]. We did not apply culture at 2 months but higher bacillary load at the start of treatment, or smear positivity at 2 months was not associated with culture positivity at the end of treatment. Lack of these associations could be due to a small number of patients with unfavorable outcome in our study.
In this study 5/12 culture-positive cases had a recent history of TB in their family, implying the possibility of reinfection from the home environment rather than treatment failure as the source of culture positivity. Different studies in the past have shown that exogenous reinfection could be a major cause of recurrent TB after achieving cure especially in TB endemic areas [24]. Patients who have had TB once are at an increased risk of developing TB when re-infected. Relapse is shown to occur early after treatment completion, whereas reinfection dominates after one year and shown to account for at least half of recurrent disease [25]. 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 the general population in Pakistan, which is shown to be 26.3% [26]. Additionally the 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 underestimated as prevlance was based on patient history and serum glucose levels were not measured, leaving the possibility that some patients might have undiagnosed diabetes. A cross-sectional study from Lahore, Pakistan found 14.8 % diabetics among TB patients by measuring serum glucose and HbA1C levels [29]. This prevalence is higher than our cohort but still lower than the prevalence in the 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 [30]. Thus diabetes may not be a substantial risk factor for all pulmonary TB and unfavorable treatment responses.
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 [8]. However, in our study, addition of ethambutol in the continuation phase did not affect 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 in the study. It is a relatively small study, with a small number of unfavorable outcomes. Culture was not performed in all smear-negative cases due to resource constrains. Chest X-ray results could not be retrieved for several patients, and data on the recurrence of TB was not available. This could have added bias in the study. Despite these shortcomings, the study provides useful information about the treatment outcomes in the routine TB control program settings and could contribute towards evidence for improving routine TB care.