ORIGINAL ARTICLE Year : 2021  |  Volume : 70  |  Issue : 1  |  Page : 26-30

Treatment outcome in smear-positive pulmonary tuberculosis patients treated with a fixed-dose drug combination regimen in comparison with a separate regimen: a randomized clinical trial

Seyed Saeed Hashemi Nazari1, Saeid Fallah2, Vahideh Raeisi2
1 Department of Epidemiology, School of Allied Medical Sciences, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Health Management and Social Development Research Center, Golestan University of Medical Sciences, Gorgan, Iran

Date of Submission17-May-2019Date of Decision15-Jul-2019Date of Acceptance30-Jul-2019Date of Web Publication27-Mar-2021

Correspondence Address:
PHD Student of Epidemiology Saeid Fallah
Health Management and Social Development Research Center, Golestan University of Medical Sciences, Shahid Beheshti Street, Kordkuy City, 4881113178
Iran

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejcdt.ejcdt_110_19

Context The number of tuberculosis (TB) patients and multidrug-resistant species of Mycobacterium tuberculosis are increasing worldwide. Effective treatment is still the key factor to control TB in the society.
Aims The aim of the study was to compare the efficacy of fixed-dose combination (FDC) and separate drug (SD) in the treatment of TB.
Settings and design The study was a randomized, clinical trial carried out on 331 smear-positive TB patients in the Golestan province, Iran.
Patients and methods Diagnosis and monitoring method was direct observation of sputum smears under a light microscope, which was used at the end of the second, third, fourth, fifth, or sixth months during the treatment.
Statistical analysis used Sputum smear conversion rate at the end of second months and therapy outcome at the end of the treatment period were compared in both groups of the study by using the Poisson regression model and calculation incidence rate ratio.
Results Sputum smear conversion rate at the end of the second month of the treatment had no significant difference between two groups. Success rate at the end of the treatment period was 89.36% in the intervention group and 95.65% in the nonintervention group which had significant difference (P=0.03). Adverse event incidence rate was 5.44% in all studied cases during the period of treatment. It had significant difference between the group who received FDC (8.93%) and the other who received SD (1.86%).
Conclusion SD had better efficacy than FDC drugs in the treatment of TB patients.

Keywords: efficacy, fixed-dose combination, separate drug, tuberculosis

How to cite this article:
Nazari SH, Fallah S, Raeisi V. Treatment outcome in smear-positive pulmonary tuberculosis patients treated with a fixed-dose drug combination regimen in comparison with a separate regimen: a randomized clinical trial. Egypt J Chest Dis Tuberc 2021;70:26-30
How to cite this URL:
Nazari SH, Fallah S, Raeisi V. Treatment outcome in smear-positive pulmonary tuberculosis patients treated with a fixed-dose drug combination regimen in comparison with a separate regimen: a randomized clinical trial. Egypt J Chest Dis Tuberc [serial online] 2021 [cited 2021 Dec 5];70:26-30. Available from: http://www.ejcdt.eg.net/text.asp?2021/70/1/26/312127   Introduction 

Tuberculosis (TB) is an acute necrotizing infectious disease which involves different organs in the body and causes clinical, radiographic, and bacteriologic changes in patients. The number of TB patients is increasing and this rising pattern still continues [1].

Studies on the treatment of TB showed a lower success rate of therapies of smear-positive patients in Iran in comparison with the average rates of regional countries which was 87% in Iran versus 91% in the East Mediterranean region in 2015 [2]. Increasing the number of TB patients and reduction in treatment success rates on the other hand leads to a rise in death numbers due to TB in Iran in contrast with other regional countries and other parts of the world [3]. TB control is only possible by early detection and effective treatment of the disease as soon as possible [4]. Ineffective treatment of TB patients results in longer period of infectivity, drug resistance, resistant TB, and higher risk of transmission of drug-resistant species of Mycobacterium [5].

There are two different drug regimens for treatment of TB patients: fixed-dose combination (FDC) and separate drugs (SD). Both of these regimens have proponents and opponents. Proponent specialists of FDC put them prior to SD regimen because they express that these drugs have better compliance of patients and simplicity of prescription, easier management to prepare the drugs, planned reduction of costs, and lower chance of drug resistance. On the other hand, opponent specialists convey that FDC increases the possibility of drug resistance as in the acidic environment of stomach, chemical interactions between Rifampin and Isoniazid reduces the bioavailability of Rifampin in FDC. Besides, Pyrazinamide and Ethambutol expedites this process [6],[7],[8]. Moreover, these specialists doubt to prescribe FDC because of the possibility of receiving higher doses than needed in younger children, omitting or adjusting all drug components due to complications of a specific drug in the combination and being more expensive than SD [6]. Furthermore, different results of various studies contributed to this disagreement. For example, Zhang et al. [9] showed FDC had better therapeutic effects than SD in TB patients. In contrast, results of the study of Aseffa et al. [10] and Limaa et al. [11] showed no significant difference between the efficacies of the wo above-mentioned regimens. Study of Pramudita et al. [12] showed higher risk of recurrence when patients receive FDC. Therefore, considering that there was no study done in Iran to compare the efficacy of these two drug regimens and Golestan province became the study pilot to use FDC for TB patients, the study was designed as a randomized clinical trial to help the authorities to make better decisions in TB control.

  Patients and methods 

This study was a randomized clinical trial (IRCT2014051917764N1) done after approbation in Deputy of Research and Technology and Ethics Committee in Urmia University of Medical Sciences (Thesis number: 92-01-32-142, Ethics Committee code: UMSU.REC.1393.55).

The duration of the study was 11 months from 05/31/2014 to 04/26/2015 and it was studied on 331 smear-positive TB patients from all 13 cities of Golestan province, Iran. Diagnosis and monitoring method was direct observation of sputum smears under a light microscope which was used at the end of second, third, fourth, fifth, or sixth months during the treatment by TB laboratory experts in each 13 cities of Golestan province. All positive results were confirmed by experts of TB referral laboratory in the central health facility of the province.

Informed consent, positive sputum smear, being a new case, weight more than 30 kg, age more than 13 years old, possibility of short-course treatment under observation of a health emissary, absence of diabetes and immune deficiency or any liver and kidney disease were the inclusion criteria. Occurrence of health-threatening complications during the treatment and patients’ renunciation of continuing the study were the exclusion criteria.

Treatment was done based on DOTS (Directly Observed Treatment, Short-course) according to the National TB Control Protocol [13] by a physician in charge in each city. Intervention group received FDC and the nonintervention group received SD. Drug dosing for each group is followed in [Table 1].

Random allocation of patients to intervention and nonintervention groups was done in a study coordinating center in the central health facility of the province by using the table of random numbers following one to one ratio. A physician in charge for TB plan in each city called the study coordinating center as he/she recognized a new TB patient with the needed inclusion criteria. Then the patient would be categorized to study groups according to a random number table and the result of categorization would be told to the physician. Finally, the physician would start treatment based on DOTS strategy according to the National TB Control Protocol.

Data collection tool was a checklist adjusted by the researcher based on goals, hypotheses, and the needed data for testing hypotheses to reach the goals of the study. A checklist was filled out by a TB educated personnel for each patient in cities of the province. Gathering information was done by referring to patients’ files and interviewing the cases or their families with the adjusted checklist. After all, data was analyzed by stat software version 14 (StataCrop LP, Ver: 14, Texas, USA).

Sputum smear conversion rate at the end of the second month (i.e. end of intensive phase of treatment) and therapy outcome at the end of fifth or sixth months of treatment were compared in both groups of the study by using the Poisson regression model with robust error variance and calculation incidence rate ratio. Level of significance was assumed at P value less than 0.05.

  Results 

In all, 331 smear-positive new cases of TB were studied in this clinical trial. The intervention group had 168 patients and the nonintervention group had 163 cases. Of these, 141 cases from the intervention group and 138 cases from the nonintervention group stayed until the end of the study; 55.89% of all the cases were men and 44.1% were women. At the beginning of the study, the average age was 48.5±21.4 and the average weight was 57.5±13.6.

Distribution of variable of sex had significant difference in intervention and nonintervention groups, but other variables were distributed equally between two groups. Details are followed in [Table 2].

Sputum smear conversion rate at the end of the second month of treatment had no significant difference between two groups as it was 86.31% in the intervention group and 89.61% in the nonintervention group. As it is shown in [Table 3], adjusted incidence rate ratio (AIRR) of remaining Bacillus in the smears was 1.41 more in the intervention group 2 months after starting the treatment which had no significant difference between study groups (P=0.3).

As shown in [Table 4], success rate at the end of treatment period was 89.36% in the intervention group and 95.65% in the nonintervention group which had significant difference (P=0.03). AIRR of failure of treatment was 3.9 in the intervention group in comparison to the nonintervention group.

Adverse event incidence rate was 5.44% in all studied cases during the period of treatment. It had significant difference between the group that received FDC (8.93%) and the other that received SD (1.86%). AIRR of adverse event was 3.39 in the intervention group in comparison to the nonintervention group ([Table 5]).

  Discussion 

This study was the first study on the efficacy of FDC drugs in an Iranian population and it seemed that success rate in both groups of intervention and nonintervention was apparently higher than the expected rates of National TB control protocol which was 85%. Adverse event incidence rate was 8.93% in the intervention group and 1.86% in the nonintervention group which was in good level in comparison with other studies [14],[15].

Sputum conversion rate 2 months after starting the treatment, like studies in other countries, showed no significant difference between intervention and nonintervention groups. Conversion rates in the FDC group (86.31%) and in the SD group (89.61%) were similar to the results of the above-mentioned studies [14],[15],[16],[17].

Results of the study at the end of the treatment period revealed that there was significant difference between two groups of the intervention and nonintervention in their therapeutic response rate as it was 89.36% in the intervention group while it was 95.65% in the SD group.

This result was in contrast to the study of Ferreira et al. [18] which was done on 40 patients aged more than 18 years in a metropolis in Brazil as a prospective descriptive study. It also opposed the study of Gravendeel et al. [16] which compared the efficacy of National TB Control Protocol of Indonesia with FDC and showed no significant difference in therapeutic success rate between two groups.

Furthermore, the study of Zhang et al. [19] in China and the study of Bartacek et al. [15] in 26 centers in five countries showed no significant difference between FDC and SD in treatment success rate. A systematic review by Mathew [6] revealed no significant difference in both groups as well. The different result of our study may be due to differences in study population, design of study and interventions, methods of therapy and drug dosing, outcome definition, inclusion and diagnostic criteria. In addition, similar results to our study were seen in the study of Zhu et al. [17] in China, although it was not significant either.

During the treatment, the chance of complications was three times more in patients who received FDC than the ones who received SD. Studies of Su and Perng [20], Gravendeel et al. [16], and Chaulet and Boulahbal [21] showed lower incidence rate of complications in patients treated by FDC while the studies of Zhang et al. [19], Lienhardt et al. [14] and Albanna et al. [22] revealed no significant difference between two groups of FDC and SD in the incidence rate of complications. In contrast to the above studies, a study by Bartacek et al. [15] showed that complications such as weakness and lethargy, fever, and headache were more common in the group who received FDC. A study by Majdoub et al. [23] revealed that hematologic complications were more common in patients treated with FDC due to significant difference in the doses of Isoniazid and Rifampin between the study groups. These contradictory outcomes may be the result of various accuracies and difference specificity of diagnostic tools for complications which leads to increased observer error in detecting them.Finally, it seemed that sputum smear conversion rate was same in both groups of FDC and SD in the intensive phase of treatment but the success rate of the 6-month period treatment which is the ultimate goal of treating TB patients was higher in the group who received SD. This is probably due to instability and decreased bioavailability of Rifampin [24],[25],[26],[27] which is the main and a very effective component of first-line drugs in sterilizing the body from Mycobacterium bacilli. Furthermore, incidence rate of complications was higher in patients who received FDC. Therefore, it is recommended to use SD in the treatment of TB if it is possible or perform an appropriate intervention in the drug combination of FDC based on scientific studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References 
1.Hatami H, Razavi S, Ardabili H, Majlesi F, Nozadi M, Parizadeh S. Epidemiology and Control of Tuberculosis. The Textbook of Public Health. 2, Tehran: Arjmand; 2006. p. 1120–1139.  
    2.World Health Organization. Data by WHO region 2018 [updated 2018-10-10; cited 2019]. Treatment success, Data by country. Available from: http://apps.who.int/gho/data/node.main.602?lang=e.  
    3.World Health Organization. Data by WHO region 2018 [updated 2019-01-14; cited 2019]. Deaths due to tuberculosis, Data by country. Available from: http://apps.who.int/gho/data/view.main.57020ALL?lang=en.  
    4.Fauci AS, Harrison TR. Harrison’s principles of internal medicine. 17th ed. New York: McGraw-Hill Medical; 2008. 1 v:1006–1020.  
    5.Bonnet M, Pardini M, Meacci F, Orrù G, Yesilkaya H, Jarosz T et al. Treatment of tuberculosis in a region with high drug resistance: outcomes, drug resistance amplification and re-infection. PLoS ONE 2011; 6:8.  
    6.Mathew JL. Fixed-dose drug combination for treatment of tuberculosis. Indian Pediatrics 2009; 46:877–880.  
    7.Bhutani H, Mariappan TT, Singh S. The physical andchemical stability of anti-tuberculosis fixed-dosecombination products under accelerated climatic conditions. Int J Tuberc Lung Dis 2004; 8:1073–1080.  
    8.Milán-Segovia RC, Domínguez-Ramírez AM, Jung-Cook H, Magaña-Aquino M, Romero-Méndez MC, Medellin-Garibay SE et al. Relative bioavailability of rifampicin in a three-drug fixed-dose combination formulation. Int J Tuberc Lung Dis 2010; 14:1454–1460.  
    9.Zhang HQ, Xi XE, Wang YL, Han W, Zhang CX, Jiao JH. Side effects of tuberculosis treatment with fixed-dose combinations. J Biol Reg Homeos Ag 2015; 29:379–388.  
    10.Aseffa A, Chukwu JN, Vahedi M, Aguwa EN, Bedru A, Mebrahtu T et al. Efficacy and safety of ‘fixed dose’ versus ‘loose’ drug regimens for treatment of pulmonary tuberculosis in two high TB-burden African countries: a randomized controlled trial. Plos One 2016; 11:6.  
    11.Limaa GC, Silvab EV, Magalhães PdeO, Naves JS. Efficacy and safety of a four-drug fixed-dose combination regimen versus separate drugs for treatment of pulmonary tuberculosis: a systematic review and meta-analysis. Braz J Microbiol 2017; 48:198–207.  
    12.Pramudita A, Rumende CM, Findyartini A. Fixed-dose combination antituberculosis therapy as a risk factor for tuberculosis recurrence: an evidence-based case report. Acta Med Indones 2017; 49:175–182.  
    13.Nasehi M, Mirhaghghani L. Tuberculosis national guideline. 2, editor. Tehran: Andishmand 2010.  
    14.Lienhardt C, Cook SV, Burgos M, Yorke-Edwards V, Rigouts L, Anyo G et al. Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis:the study c randomized controlled trial. JAMA 2011; 305:1415–1423.  
    15.Bartacek A, Schütt D, Panosch B, Borek M. Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis. Int J Tuberc Lung Dis 2009; 13:760–766.  
    16.Gravendeel JMT, Asapa AS, Becx-Bleumink M, Vrakking HA. Preliminary results of an operational field study to compare side-effects, complaints and treatment results of a single-drug short-course regimen with a four-drug fixed-dose combination (4FDC) regimen in South Sulawesi, Republic of Indonesia. Tuberculosis 2003; 83:183–186.  
    17.Zhu L, Yan B, Ma W. Controlled clinical study on efficacy of fixed-dose compounds rifater/rifinah in antituberculous chemotherapy. Zhonghua Jie He He Hu Xi Za Zhi 1998; 21:645–647.  
    18.Ferreira ACG, Júnior JLRdS, Conde MB, Rabahi MF. Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil. J Bras Pneumol 2013; 39:76–83.  
    19.Zhang LX, Kan GQ, Tu DH, Wan LY, Faruqi AR. Fixed-dose combination chemotherapy versus multiple, single-drug chemotherapy for tuberculosis. Curr Therap Res 1996; 57:849–856.  
    20.Su W-J., Perng R-P. Fixed-dose combination chemotherapy (Rifater®/Rifinah®) for active pulmonary tuberculosis in Taiwan: a two-year follow-up. Int J Tuberc Lung Dis 2002; 6:1029–1032.  
    21.Chaulet P, Boulahbal F. Clinical trial of a combination of three drugs in fixed proportions in the treatment of tuberculosis. Tuberc Lung Dis 1995; 76:407–412.  
    22.Albanna AS, Smith BM, Cowan D, Menzies D. Fixed-dose combination antituberculosis therapy: a systematic review and meta-analysis. Eur Respir J 2013; 42:721–732.  
    23.Majdoub S, Daghfouss H, Ben Saad S, Ben Tkhayat A, Tritar F. Antituberculosis fixed multi-dose combination and single drug therapy in active tuberculosis: What is about drug hypersensitivity reactions? Eur Respir J 2016; 48:PA1112.  
    24.Xu J, Jin H, Zhu H, Zheng M, Wang B, Liu C et al. Oral bioavailability of rifampicin, isoniazid, ethambutol, and pyrazinamide in a 4-drug fixed-dose combination compared with the separate formulations in healthy Chinese male volunteers. Clin Therap 2013; 35:161–168.  
    25.Nyazema NZ, Rabvukwa P, Gumbo J, Ndudzo P, Chitemerere C. Bioavailability of rifampicin in a separate formulation and fixed dose combination with isoniazid NIH: a case for a fixed dose combination (FDC) for the treatment of tuberculosis. Cent Afr J Med 1999; 45:141–144.  
    26.Shishoo CJ, Shah SA, Rathod IS, Savale SS, Vora MJ. Impaired bioavailability of rifampicin in presence of isoniazid from fixed dose combination (FDC) formulation. Int J Pharm 2001; 228:53–67.  
    27.Pillai G, Fourie PB, Padayatchi N, Onyebujoh PC, McIlleron H, Smith PJ et al. Recent bioequivalence studies on fixed-dose combination anti-tuberculosis drug formulations available on the global market. Int J Tuberc Lung Dis 1999; 3:309–316.  
    

 
 

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]