Persistent sputum smear positivity among new cases of pulmonary tuberculosis after 2 months of self-administered outpatient treatment in Yaounde, Cameroon

INTRODUCTION

One of the important ways used to monitor the effectiveness of treatment in patients with sputum smear-positive pulmonary tuberculosis (SSPPTB) is to examine their sputum smears for acid-fast bacilli (AFB) at specific periods of their treatment. In new cases with SSPPTB, these examinations are carried out at the end of the 2-month intensive phase of treatment and the end of the 5^th and 6^th months of treatment.^[1] The results of the follow-up examination of sputum smears at the end of the 2-month intensive phase are crucial, for it is known that persistent sputum positivity at the end of this phase of treatment predicts adverse outcomes in terms of treatment failure and relapse as well as default from treatment.^[2-7] The persistence of sputum smear positivity at the end of this phase of treatment is all the more problematic from a public health perspective, as a significant proportion of these patients can still spread the disease.^[8]

In Cameroon, before 2015 and in accordance with the guidelines of the National Tuberculosis Control Program (NTCP), all SSPPTB cases were systematically hospitalized during the intensive phase of treatment to ensure that they received directly observed therapy (DOT). The incidence of non-conversion of sputum smears in new cases of pulmonary tuberculosis (TB) at the end of the intensive phase of treatment at the TB diagnostic and treatment center (TBDTC) of the Jamot Hospital in Yaounde (JHY) was reported to be 13.4% and 10.2%, respectively, in 2009 and 2014.^[9,10]

Since 2015 and in accordance with the new guidelines of the NTCP,^[11] SSPPTB patients, except for severe and complicated cases, are no longer hospitalized but rather receive self-administered treatment on an outpatient basis throughout the entire treatment course. Since the treatment of patients is no longer administered under direct observation and supervision by the health personnel as was previously the case, the impact of this change in policy on the non-conversion of patients’ sputum smears at the end of the intensive phase of treatment is not known. This study aimed to determine the incidence of persistent positive sputum smears at the end of the 2-month intensive phase of anti-TB treatment in new cases of patients with SSPPTB and to identify some factors associated with it in the TB-DTC of the JHY.

MATERIALS AND METHODS

RESULTS

During the study period, a total of 4042 new patients with SSPPTB were enrolled in treatment at the TB-DTC of the JHY. Of these 4042 patients, 906 were excluded from the study. Figure 1 presents the flow chart showing the selection of patients retained for the study. There was, however, no statistical difference with respect to age and sex between those excluded and the 3136 patients aged 15 years and above who were retained for the analysis.

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Figure 1:

Flow chart showing the selection of study participants. JHY: Jamot Hospital in Yaounde, SSPPTB: Sputum smear-positive pulmonary tuberculosis, TB-DTC: Tuberculosis diagnostic and treatment center.

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DISCUSSION

Sputum smear microscopy continues to be the main tool used in most low-income countries for monitoring the effectiveness of treatment in patients diagnosed with sputum smear-positive pulmonary TB despite the controversies surrounding its usefulness. Several studies have shown, however, that persistent positive sputum smears at the end of the 2-month intensive phase of anti-TB treatment in new cases of smear-positive pulmonary TB are one of the strongest predictors of treatment failure.^[2-5] Meanwhile, the controversy raised by the persistence of sputum smear positivity at the end of the 2-month intensive phase of treatment arises from the fact that the predictive value of a smear result at the end of the 2^nd month is rather high when the result is negative but considerably less so when it is positive.^[13] Indeed, a positive sputum smear for AFB does not permit one to know whether these are still viable bacilli or not after 2 months of anti-TB treatment. To assess sputum sterilization correctly, it is ideal to study sputum cultures for mycobacterial growth at the end of 2 months of treatment, as microscopy may also show non-viable or dead bacilli. Under program conditions, however, particularly in most low-income countries like Cameroon, cultures for mycobacteria are not usually available under field conditions. Meanwhile, the possible role of a smear-positive status by the end of the 2^nd month of treatment can presently be used as a surrogate to warrant the susceptibility testing of sputum specimens of these patients for at least rifampicin resistance given the availability now of the Xpert Mycobacterium tuberculosis/Rifampicin (MTB/RIF) assay (Cepheid GeneXpert^® System, USA), which not only detects MTB in specimens but also its resistance to rifampicin, a surrogate marker for multidrug-resistant TB.

The incidence of persistent sputum smear positivity (PSSP) in new cases of smear-positive pulmonary TB in this study was 10.59%. This is lower than the rate of 13.4% reported by Kuaban et al.^[9] but almost similar to the rate of 10.2% reported by Pefura-Yone et al.^[10] in similar studies in the same TB-DTC of the JHY, respectively, in 2009 and 2014. The result of this study suggests, therefore, that the magnitude of sputum smear non-conversion has remained stable and has not been affected negatively by the abolition of the policy of hospitalization of patients during the intensive phase of treatment meant to ensure that the health personnel directly observed the treatment of patients. This stability of the incidence of sputum smear non-conversion can probably be explained by the health education given to the patients with insistence on adherence to treatment as prescribed by the health staff of the DTC of the hospital at the start of their treatment and during their weekly return for their drug refill.

In this study, we assessed some factors in new cases with sputum smear-positive pulmonary TB in a bid to identify those that could be associated with persistent positive sputum smears at the end of the 2-month intensive phase of treatment. Bivariate analysis of these factors showed that an HIV seropositive status was not significantly associated with non-conversion of positive sputum smears. Of the factors that showed a significant association with PSSP at the end of the 2-month intensive phase of anti-TB therapy on bivariate analysis, age ≥35 years, the male sex, and a pre-treatment sputum smear bacillary load ≥2+ remained as independent significant factors of non-conversion of sputum smears on multivariable analysis.

HIV-positive status was not associated with the persistence of positive smears at the end of the 2-month intensive phase of treatment in our study. Our results are in agreement with those of several studies that have shown that there is no association between HIV status and delay in bacteriological conversion.^[9,14-16] However, several factors exist that could potentially cause patients with an HIV-positive status to have delayed bacteriological conversion of sputum smears. Firstly, it has been reported that TB and HIV coinfection enhances the risk of harboring and acquiring drug-resistant strains, particularly in high TB burden settings,^[17] a situation that can lead to delayed conversion of sputum smears. Second, adherence to treatment is a major challenge for this group of patients, given the higher pill burden that they must take, overlapping or additive adverse reactions, and drug-to-drug interactions^[17,18] that may expose this group of patients to a delay in the bacteriological conversion of sputum smears. In addition, some biological mechanisms have been reported to contribute to drug resistance in HIV-infected individuals, and impaired drug absorption is one of the reasons for the ineffectiveness of TB treatment in this group of patients, particularly with such drugs as rifampicin and ethambutol.^[19,20]

In this study, age ≥35 years was an independent predictor of persistent positive sputum smears at the end of the 2-month intensive phase of treatment. Our results are similar to those reported by several authors^[6,9,21] who observed that age ≥40 years is associated with PSSP at the end of the intensive phase of treatment. The precise reason for this association is not known. However, this could probably be explained by the fact that patients at this age, due to socioeconomic challenges, such as losing hours from their jobs to attend health facilities for treatment, may not adhere properly to the taking of their medications.^[22] In addition, age-related impairment of the immune system in these patients may lead to poor clearance of mycobacteria from the lungs.^[21]

Men were less likely than women in this study to have sputum smears converted at the end of the 2-month intensive phase of treatment. Our result is in line with the findings reported by other authors.^[4,23,24] This finding probably reflects the behavioral differences between men and women with respect to the taking of medications. Indeed, male patients have been reported to have treatment failure due to irregular taking of medicines as compared to women.^[23] Our result, however, differs from those of a similar study carried out in the same TB-DTC of the JHY in 2009, in which no difference between the two sexes with respect to sputum smear non-conversion was observed.^[9] This may be explained by the fact that at that period, patients were all hospitalized during the intensive phase of treatment, with medications being administered under direct observation and supervision by the health personnel.

In this study, a pre-treatment bacillary load in sputum smears of ≥2+ was also an independent predictor of persistent positive sputum smears at the end of the intensive phase of treatment. Many authors have reported on the influence a pre-treatment bacillary load has on sputum smear conversion at the end of the intensive phase of treatment.^{[4,6,9,14,15]} For example, Singla et al.^[6] reported that patients with numerous bacilli on pre-treatment sputum smears had an almost six-fold greater risk of sputum smear non-conversion than patients with few bacilli. Meanwhile, in a study from the Gambia, Lienhardt et al.^[4] observed that sputum smear conversion at the end of the intensive phase of treatment in patients with sputum smear of 1+, 2+, and 3+ was 96.2%, 85.3%, and 81.8%, respectively. Our result agrees with the findings of these authors. PSSP in patients with a pre-treatment bacillary load in sputum smears of ≥2+ could be due to a clinical failure because of poor adherence to anti-TB treatment. This will suggest the need for DOT under the supervision of health personnel targeting such patients. It could also possibly arise from the resistance of their TB disease to anti-TB drugs. This will support the notion that patients with a pre-treatment bacillary load of 2+ or more may constitute a high-risk group for drug resistance, especially multidrug or rifampicin resistance (MDR/RR). As such, this group of patients could be included in the high-risk group of patients for MDR/RR-TB so that they could benefit from drug susceptibility testing. A rapid molecular test such as MTB/RIF (Cepheid Sunnyvale CA, USA), which not only detects MTB in sputum but also its resistance to rifampicin, could be adopted for this purpose. Patient’s consent not required as patients identity is not disclosed or compromised. Cost-effectiveness studies may, however, be needed to judge the appropriateness of this strategy in resource-limited settings such as Cameroon.

Our study was limited by its retrospective design and the operational nature of the study, which relied solely on information routinely collected and maintained in the TBDTC of the JHY. As such, we were unable to assess some other potential risk factors for sputum smear non-conversion at the end of the 2-month intensive phase of treatment in our study population. We, however, think that the retrospective nature of our study is likely to have only a minimal impact on our results because the regular supervision and monitoring activities of the center by the NTCP are quite robust. Second, as the study was conducted only in one of the DTCs of Cameroon, our results may not be easily generalized to all the new SSPPTB patients treated in other centers of the country. This notwithstanding, the strength of our study lies in the large sample size of the patients studied, with a relatively large number of patients with persistent positive sputum smears at the end of their intensive phase of treatment.

CONCLUSION

The rate of PSSP in new SSPPTB patients after 2 months of self-administered outpatient treatment is similar to rates observed before 2015. Age ≥35 years, the male gender, and a pre-treatment sputum smear bacillary load ≥2+ were the most significant factors associated with PSSP. It is, therefore, recommended that patients with these features be given the 2-month intensive phase treatment under direct observation and supervision by health personnel. In addition, patients who, despite this measure, remain sputum smear positive should benefit from an Xpert MTB/RIF assay to determine if their disease is rifampicin-resistant or not and be treated accordingly if this is the case.