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Drug adherence and efficacy of smear microscopy in the diagnosis of pulmonary tuberculosis after 2 months of medication in North-western Tanzania

Open AccessPublished:August 03, 2017DOI:https://doi.org/10.1016/j.ijid.2017.07.025

      Highlights

      • Over two thirds of smear positive patients are wrongly put into extension of intensive phase treatment, this may cause increased costs and drug toxicity.
      • Culture should be advocated to confirm smear positivity at 2 months.
      • Drug adherence to TB treatment in North-western Tanzania is good as per WHO guidelines and is associated with successful cure.
      • No MDR-TB was observed in North-western Tanzania.
      • Continued surveillance and emphasizing of drug adherence to TB medications should be kept upbeat in order to control tuberculosis in developing countries.

      Abstract

      Objectives

      The study aimed at assessing the Tuberculosis (TB) medication adherence level and the efficacy of smear microscopy in the diagnosing pulmonary TB at month 2.

      Methods

      A prospective study was conducted at the four sites located in the Northern-western Tanzania. New smear positive, pulmonary TB patients were followed up and their adherence to TB medication assessed after 2 months of the treatment. In addition, the acid fast bacilli (AFB) smear microscopy was performed after 2 and 5 months of the treatment. All smear positive samples were subjected to geneXpert (MTB/RIF) assay and culture on the Lowenstein Jensen (LJ) media.

      Results

      A total of 331 smear positive, newly diagnosed patients with pulmonary TB were enrolled. The median age was 36 [Interquartile range (IQR): 28–45] years and males formed the slightly majority, 187 (56.5%) of the participants. A total of 105 (31.7%) patients were infected with HIV. Out of 331 patients, 36 (10.9%) were still AFB smear positive at the end of two month. Of these 19 (52.8%) were positive on GeneXpert MTB RIF and none was Rifampicin resistant. Of note, only 13 (31.1%) were culture positive (viable). None of the patients was positive at month 5. Poor adherence to TB medications in the first 2 months of treatment was observed in 56/331 (16.9%) [95% CI = 12.9–21.0] of the patients.

      Conclusion

      Over two thirds of smear positive patients are wrongly put in one month extension of the intensive phase treatment; this may cause increased costs and drug toxicity. Culture should be advocated to confirm smear positivity after 2 months of medications. TB treatment drug adherence in our setting is good and is associated with successful cure. No multidrug resistant tuberculosis (MDR-TB) was observed. Continued surveillance and emphasizing of TB drug adherence should be kept upbeat in order to control tuberculosis in developing countries.

      Keywords

      Introduction

      Tuberculosis (TB) is a major public health problem. The number of TB cases with poor outcome (failure, relapse, death) following first line TB treatment is increasing in the sub-Saharan Africa (
      • Dye C.
      • Bassili A.
      • Bierrenbach A.L.
      • Broekmans J.F.
      • Chadha V.K.
      • Glaziou P.
      • et al.
      Measuring tuberculosis burden, trends, and the impact of control programmes.
      ,
      • World Health Organization
      Global tuberculosis report.
      ). The MDR-TB globally is reported to be 3.9% and 21.0% among newly diagnosed and previously treated cases respectively (
      • World Health Organization
      Global tuberculosis report.
      ). In Tanzania 1.1% of all new TB cases are MDR-TB (
      • Chonde T.M.
      • Basra D.
      • Mfinanga S.G.
      • Range N.
      • Lwilla F.
      • Shirima R.P.
      • et al.
      National anti-tuberculosis drug resistance study in Tanzania.
      ). Furthermore, unfavourable treatment outcomes as high as 14.2% has been reported in TB re-treatment cases (
      • Ministry of Health and Social Welfare
      National tuberculosis and leprosy programme, annnual report.
      ) and the treatment success rate for new and relapse cases TB was 90% (
      • World Health Organization
      Global tuberculosis report.
      ).
      Optimal adherence to TB treatment is a key to successful outcome. Several factors such as the patient’s related and health care related factors have been found to contribute to MDR-TB. There is paucity of data regarding drug adherence and factors associated with poor adherence to TB medications in North-western Tanzania. Most studies have documented that poor adherence is a key parameter that can predict poor treatment outcome (
      • Hirpa S.
      • Medhin G.
      • Girma B.
      • Melese M.
      • Mekonen A.
      • Suarez P.
      • et al.
      Determinants of multidrug-resistant tuberculosis in patients who underwent first-line treatment in Addis Ababa: a case control study.
      ) and there is a clear link between poor adherence and MDR-TB. Therefore it is important to follow up patients taking anti-tuberculosis medication to ensure optimal adherence in order to control TB. To achieve this, the WHO recommends all countries to practice direct observed therapy strategy (DOTS). The current study determined the efficacy of smear microscopy in the detection of pulmonary TB after 2 months of treatment and assess the level of TB drug adherence and associated factors. These findings are useful for designing interventions to promote optimal adherence to anti-TB treatment so as to reduce the magnitude of MDR-TB in this setting. Furthermore, findings from this study provide proper explanation for acid fast bacilli (AFB) positive follow up regarding their viability.

      Patients, materials and methods

      Study site and population

      The study was conducted in the city of Mwanza, North-western Tanzania. The city has a population of >0.7 million and TB and HIV prevalence of 9.8% and 7.2% respectively (
      • National Bureau of Statistics (NBS)
      • Office of Chief Government Statistician (OCGS) Zanzibar
      2012 population and housing census: population distribution by administrative units; key findings.
      ,
      • Tanzania Commission for AIDS (TACAIDS)
      • Zanzibar AIDS Commission (ZAC)
      • National Bureau of Statistics (NBS)
      • Office of the Chief Government Statistician (OCGS)
      • ICF International
      Tanzania HIV/AIDS and malaria indicator survey 2011–2012.
      ,

      Ministry of Health and Social Welfare. Manual of the national tuberculosis and leprosy programme in Tanzania. Dar es Salaam: 2013 [cited 30 November 2014]. Sixth: Available from: ntlp.go.tz/index.php?option=com_phocadownload&view.

      ). The target population was newly pulmonary TB patients who were about to start anti-TB. The target population was sampled from presumptive TB patients attending four clinics, namely the Bugando Medical Centre, Sekou-Toure Regional Hospital, Nyamagana District Hospital and Buzuruga.

      Study design and duration

      This was a prospective cohort study that was conducted among smear positive pulmonary tuberculosis patients. Study was conducted from February 2015 to March 2016. Patients starting TB treatment were assessed for overall drug adherence after 2 months of medication (intensive phase treatment). The TB drug adherence was assessed using TB adherence chart from the TB clinic. For the intensive phase treatment, patients had to take 56 doses, and the patients who missed less than 5 doses during the intensive phase treatment were categorized to have the overall TB drug adherence of >90% (good). Patients with the adherence ≤90% (poor) missed 5 or more doses during the intensive phase treatment (
      • Awofeso N.
      Anti-tuberculosis medication side-effects constitute major factor for poor adherence to tuberculosis treatment.
      ,
      • Woimo T.T.
      • Yimer W.K.
      • Bati T.
      • Gesesew H.A.
      The prevalence and factors associated for anti-tuberculosis treatment non-adherence among pulmonary tuberculosis patients in public health care facilities in South Ethiopia: a cross-sectional study.
      ).

      Recruitment procedure

      We recruited consecutively all newly diagnosed smear positive TB patients attending TB clinics at four different sites in the city of Mwanza. We recruited and followed up for 5 months patients aged ≥18 years and residence of Mwanza city.

      Data collection

      A structured questionnaire was administered; socio-demographic data and clinical characteristics were collected. Information collected included age, gender, socio-economic status, HIV status, past medical, co-morbid conditions, weight and height. Adherence to TB medications was verified through TB clinic cards.

      Specimen collection and Laboratory analyses

      Sputum for acid fast bacilli testing was collected at baseline and after 2, and 5 months. Patients who were still positive after 2 months of the treatment had to continue with the initial phase treatment for one month and thereafter another sputum sample was collected for additional smear microscopy. The sputum samples were processed and interpreted in accordance with the NTLP and WHO guidelines and then subjected to geneXpert (MTB/RIF) assay. Additional sputum samples were processed and cultured on the Lowenstein Jensen (LJ) media as described previously (
      • Kidenya B.R.
      • Kabangila R.
      • Peck R.N.
      • Mshana S.E.
      • Webster L.E.
      • Koenig S.P.
      • et al.
      Early and efficient detection of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures.
      ). Blood samples were collected for determining HIV status using two rapid tests done serially as per National AIDS Control Programme Guidelines (). The Bugando Medical Centre TB laboratory was used to run all laboratory procedures. At regular intervals, all specimens collected were packed with ice and at each end of the working hours they were transported to the Bugando Medical Centre TB laboratory for further laboratory analyses.

      Data management and analysis

      Data collected were double entered in EpiData software and then transferred to the STATA for cleaning, completeness and analysis. The outcomes of interest were level of TB medication adherence after 2 months of medication. Descriptive statistics were analyzed to describe the distribution of poor TB medication adherence across relevant strata. Univariate followed by multivariate logistic regression analyses were done to determine potential predictors of poor TB medication adherence. Potential predictors included age, gender, employment status, education level, marital status, being positive at month 2 and HIV status. A final model of multivariate logistic regression analysis was performed with all the predictors with a p-value <0.2 in the univariate analysis controlled for age and sex. Odds ratios with 95% confidence interval (CI) were computed. Factors with a p-value of <0.05 were considered to be of statistical significance.

      Quality assurance

      Standard operating procedures (SOPs) were developed and strictly followed in all study sites. Prior to data collection, research assistants from the participating sites were trained on the SOPs to promote accuracy and consistency of the study procedures. This was strengthened by regular supportive supervision during the course of the study. Filled forms were examined for completeness and correctness.

      Ethical considerations

      The ethical approval was sought from the Joint Bugando Medical Centre/Catholic University of Health and Allied Sciences Ethics Review Board. Permission to conduct the study was sought from local authorities where the study was implemented. Information about the purpose of the study, confidentiality, willingness to participate and decision to withdraw was provided to all invitees. Written or thumbprint informed consent was obtained before enrolment.

      Results

      A total of 331 newly diagnosed pulmonary TB patients were enrolled from 4 sites in the city of Mwanza. The median age was 36 [IQR: 28–45] years and number of males was 187 (56.5%). There were 105 (31.7%) patients who were infected with HIV. Of 331 patients, 158 (47.7%) were from Sekou-Toure Regional hospital. Table 1 summarizes the baseline characteristics.
      Table 1Baseline characteristics of 331 patients.
      Participants characteristicsNumber (n)

      Median
      Applied for age.
      Percent (%)

      IQR
      Applied for age.
      Age (years)3628–45
      Hospital
       Bugando Medical Center278.2
       Buzuruga Health Center5316.0
       Nyamagana9328.1
       Sekotoure Regional hospital15847.7
      Sex
       Male18756.5
       Female14443.5
      Marital status
       Single9629.0
       Married18255.0
       Divorced3711.2
       Widowed164.8
      Employment
       Peasant3711.2
       Business9929.9
       Unemployed13942.0
       Employed5616.9
      Education level
       No formal education3911.8
       Primary18054.4
       Secondary9929.9
       Tertiary133.9
      HIV infection
       Yes10531.7
       No22668.3
      a Applied for age.

      Prevalence of MDR-TB and viability of Mycobacterium tuberculosis on smear positive sputa

      At the end of two months, of the 331 patients enrolled, 36 (10.9%) were still AFB smear positive comprising 20 (55.6%) males and 16 (44.4%) females. Of these, 19 (52.8%) were positive on GeneXpert MTB RIF and none was rifampicin resistant, hence none had MDR-TB. Of the 36 smear positive patients after 2 months of medication, 13 (36.1%) were culture positive on LJ media, hence had viable Mycobacterium tuberculosis. The remaining 8 (22.2%) patients were positive on GeneXpert MTB RIF but negative on culture, while 15 (41.7%) patients were negative on both culture and GeneXpert. All sputum samples from 36 patients were negative after one month extension of the intensive phase. Furthermore, all sputum samples from participants were negative both on smear and culture after 5 months of medications. Table 2 summarizes the distribution of smear positivity rate after 2 and 5 months of medications among TB patients.
      Table 2Smear positivity rate after 2 and 5 months of medications among 331 patient.
      Number (n)Percent (%)
      Smear positivity at month 2
       Yes3610.9
       No29589.1
      Smear positivity rate at month 5
       Yes00.0
       No331100

      Drug adherence to TB medications

      For the intensive phase treatment, there were 275 (83.1%) [95% CI = 79.0–87.1] patients with overall drug adherence of >90% (good). Of note, there were 56 (16.9%) [95% CI = 12.9–21.0] patients with the adherence ≤90% (poor). Table 3 summarizes the distribution of drug adherence level among TB patients.
      Table 3Drug adherence at second month for 331 patients.
      Drug adherenceNumber (n)Percent (%)
       >90% (good)27583.1
       ≤90% (poor)5616.9

      Factors associated with poor (≤90%) drug adherence to TB medications

      On multivariate analysis, factors associated with poor drug adherence were being infected with HIV (OR = 2.6; 95% CI 1.3–5.3; p-value = 0.005), being AFB positive at 2 months (OR 9.0; 95% CI 3.9–20.8; p-value <0.001), being married (OR 2.6; 95% CI 1.1–6.3; p-value = 0.030), and being divorced (OR 4.2; 95% CI 1.3–13.7; p-value = 0.018). Table 4 summarizes factors associated with poor adherence to TB medications.
      Table 4Factors associated poor (≤90%) drug adherence to ant-tuberculosis for 331 patients.
      Patient factorDrug adherenceUnivariate analysisMultivariate analysis
      PoorGoodOR [95% CI]p-valueOR [95% CI]p-value
      n (%)n (%)
      Age
      Age is median (IQR).
      37 (27–43)35 (28–45)0.99 [0.96–1.01]0.3080.97 [0.94–1.01]0.136
      Sex
       Male35 (18.7)152 (81.3)1.0
       Female21 (14.6)123 (85.4)0.7 [0.4–1.3]0.3210.5 [0.3–1.1]0.074
      Marital status
       Single11 (11.5)85 (88.5)1.0
       Married34 (18.7)148 (81.3)1.8 [0.9–3.7]0.1242.6 [1.1–6.3]0.030
       Divorced9 (24.3)28 (76.7)2.5 [0.9–6.6]0.0694.2 [1.3–13.7]0.018
       Widowed2 (12.5)14 (87.5)1.1 [0.2–5.5]0.9042.0 [0.2–16.4]0.509
      Employment
       Peasant3 (8.1)34 (91.9)1.0
       Business14 (14.1)85 (85.9)1.9 [0.5–6.9]0.3500.9 [0.2–3.7]0.875
       Unemployed32 (23.0)107 (77.0)3.4 [0.9–11.8]0.0552.4 [0.6–8.8]0.195
       Employed7 (12.5)49 (87.5)1.6 [0.4–6.7]0.5061.2 [0.3–5.3]0.839
      Education level
       No formal education3 (7.7)36 (92.3)1.0
       Primary30 (16.7)150 (83.3)2.4 [0.7–8.3]0.1672.3 [0.6–10.0]0.248
       Secondary21 (21.2)78 (78.8)3.2 [0.9–11.5]0.0713.6 [0.8–16.4]0.096
       Tertiary2 (15.4)11 (84.6)2.2 [0.3–14.7]0.4243.7 [0.4–31.7]0.239
      HIV infection
       No29 (12.8)197 (87.2)1.0
       Yes27 (25.7)78 (74.3)2.4 [1.3–4.2]0.0042.6 [1.3–5.3]0.005
      Positive at 2 months
       No37 (12.5)258 (87.5)1.0
       Yes19 (52.8)17 (47.2)7.8 [3.7–16.3]<0.0019.0 [3.9–20.8]<0.001
      a Age is median (IQR).

      Discussion

      In this study there were no MDR-TB cases observed among patients who were still smear positive after 2 months of TB medication. However; there are several reports showing MDR-TB is becoming a significant public health problem in East Africa (
      • Ministry of Health and Social Welfare
      National tuberculosis and leprosy programme, annnual report.
      ,
      • Kidenya B.R.
      • Webster L.E.
      • Behan S.
      • Kabangila R.
      • Peck R.N.
      • Mshana S.E.
      • et al.
      Epidemiology and genetic diversity of multidrug-resistant tuberculosis in East Africa.
      ). This finding could be attributed to an effective TB program in this setting which needs to be sustained to ensure the incidence of MDR TB is maintained at a low rate or eliminated.
      We found the smear-positivity rate of 10.9% after 2 months of treatment among the 331 TB cases, with only one third of them being viable. This is due to the fact that TB patients on medications continue to expectorate dead Mycobacterium tuberculosis on their sputum for some time (
      • National Bureau of Statistics (NBS)
      • Office of Chief Government Statistician (OCGS) Zanzibar
      2012 population and housing census: population distribution by administrative units; key findings.
      ). Despite a high chance of having dead Mycobacterium tuberculosis on smear results after 2 months of treatment, a smear microscope has been used to predict the treatment outcome at this juncture (
      • Tanzania Commission for AIDS (TACAIDS)
      • Zanzibar AIDS Commission (ZAC)
      • National Bureau of Statistics (NBS)
      • Office of the Chief Government Statistician (OCGS)
      • ICF International
      Tanzania HIV/AIDS and malaria indicator survey 2011–2012.
      ). In our case two thirds of patients who were positive at 2 months continued with extension of the initial phase of the TB medications without having viable Mycobacterium tuberculosis. Therefore, they were wrongly subjected to extension of the initial phase. This may increase unnecessary costs of treatment and exposes the patients to drug toxicity. However, none had positive smear after a one-month extension of the TB treatment, this practice underscores the utility of smear microscopy and it should be adhered to in order to control TB in our setting.
      TB Treatment practises in Tanzania are performed according to the WHO guidelines in which, for non-MDR pulmonary Tuberculosis patients, the guidelines recommend that patients should be monitored by follow-up sputum smear microscopy at the time of completion of the initial (intensive) phase of treatment. If the sputum smear is still positive at completion of the intensive phase, patients should continue with intensive phase medications and sputum microscopy and culture should be performed again at month 3 (
      • World Health Organization
      Treatment of tuberculosis guidelines.
      ). Whereas, for MDR-TB (
      • World Health Organization
      Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis.
      ) the use of sputum smear microscopy and culture rather than sputum smear alone is recommended. To the best of our knowledge, only a few studies have addressed implications of only using smear for treatment monitoring and not culture after 2 months of medications.
      Poor adherence to treatment of chronic diseases including TB is a worldwide problem (
      • Chonde T.M.
      • Basra D.
      • Mfinanga S.G.
      • Range N.
      • Lwilla F.
      • Shirima R.P.
      • et al.
      National anti-tuberculosis drug resistance study in Tanzania.
      ). However, patients with TB are expected to have adherence levels greater than 90% in order to facilitate cure (
      • Ministry of Health and Social Welfare
      National tuberculosis and leprosy programme, annnual report.
      ,
      • Hirpa S.
      • Medhin G.
      • Girma B.
      • Melese M.
      • Mekonen A.
      • Suarez P.
      • et al.
      Determinants of multidrug-resistant tuberculosis in patients who underwent first-line treatment in Addis Ababa: a case control study.
      ). In the current study the prevalence of poor adherence was 16.9% which is comparable to what was observed by Adane et al in Ethiopia (
      • Adane A.A.
      • Alene K.A.
      • Koye D.N.
      • Zeleke B.M.
      Non-adherence to anti-tuberculosis treatment and determinant factors among patients with tuberculosis in Northwest Ethiopia.
      ). The prevalence of poor adherence in our study was significantly lower than the previous reports from Southern Ethiopia (20.8%) and Uganda (28%) (
      • Adane A.A.
      • Alene K.A.
      • Koye D.N.
      • Zeleke B.M.
      Non-adherence to anti-tuberculosis treatment and determinant factors among patients with tuberculosis in Northwest Ethiopia.
      ,
      • Kisambu J.
      • Nuwaha F.
      • Sekandi J.N.
      Adherence to treatment and supervision for tuberculosis in a DOTS programme among pastoralists in Uganda.
      ). The directly observed treatment, short-course (DOTS) programme that is implemented in Tanzania should continue as it has shown good practice in drug adherence, therefore encouraging more counselling to minimize the non-adherence to less than 5%.
      It should be noted that 17 people out of 100 in the current study had poor adherence, hence are at risk of TB treatment failure and MDR TB development (
      • World Health Organization
      Global tuberculosis report.
      ). Our findings were further supported by the fact that patients with positive smear at month 2 were significantly more likely to have poor adherence. Non-adherence to anti tuberculosis treatment is one of the crucial challenges in improving tuberculosis cure rates and reducing further healthcare costs (
      • Chonde T.M.
      • Basra D.
      • Mfinanga S.G.
      • Range N.
      • Lwilla F.
      • Shirima R.P.
      • et al.
      National anti-tuberculosis drug resistance study in Tanzania.
      ). Since poor adherence may result in treatment failure which is a potential risk for MDR-TB (
      • Chonde T.M.
      • Basra D.
      • Mfinanga S.G.
      • Range N.
      • Lwilla F.
      • Shirima R.P.
      • et al.
      National anti-tuberculosis drug resistance study in Tanzania.
      ), it is imperative to encourage patients to have adherence of >90%.
      As previously documented, factors associated with poor drug adherence were being infected with HIV (
      • Awofeso N.
      Anti-tuberculosis medication side-effects constitute major factor for poor adherence to tuberculosis treatment.
      ,
      • Govender S.
      What are the reasons for patients not adhering to their anti-TB treatment in a South African district hospital?.
      ), being AFB positive at month 2, being married and being divorced. Patients with HIV might have low drug adherence due to the fact that they have a lot of medications to take.

      Study limitations

      A limitation of this study was the objective way of assessing adherence due to the fact that an INH urine test was not done.

      Conclusion

      Over two thirds of smear positive patients are wrongly put in one-month extension of the intensive phase treatment; this may cause increased costs and drug toxicity. Drug adherence to TB treatment in our setting is good as per WHO guidelines. Factors associated with poor drug adherence were being married, being divorced, having HIV infection and being AFB positive at month 2. No MDR-TB was observed among patients who were still smear positive after 2 months of medication. Continued surveillance and emphasizing of drug adherence to TB medications should be kept upbeat in order to control TB by minimizing the transmission. Furthermore we recommend the use of culture before subjecting patients to extension of intensive phase.

      Acknowledgements

      We would like to express our sincere gratefulness to the Germany Leprosy and Tuberculosis Relief Association (DAHW) and NIMR-Global Fund Round 8 for sponsoring this project. We thank also the Catholic University of Health and Allied Sciences for administrative support that has contributed to the success of this study. We are indebted to the TB clinic coordinators for Bugando Medical Hospital, Sekou-Toure Regional Hospital, Nyamagana District Hospital and Buzuruga Health Centre for the cooperation towards completion of this work. Lastly we acknowledge the contribution of study participants for their acceptance to be part of this work.

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