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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 38  |  Issue : 6  |  Page : 252-257

New combination for patients with latent tuberculosis infection: A pilot study


1 Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

Date of Submission15-Apr-2018
Date of Decision14-May-2018
Date of Acceptance27-May-2018
Date of Web Publication22-Oct-2018

Correspondence Address:
Dr. Te-Yu Lin
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_46_18

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  Abstract 

Background: Latent tuberculosis infection (LTBI) is characterized by the presence of immune responses to Mycobacterium tuberculosis without clinical evidence of active TB. LTBI treatment among persons at risk for progression to active disease is an important strategy for TB control and elimination. This prospective observational study aimed to compare the incidences of hepatitis and side effects between a new 2-month combination regimen of isoniazid, rifampin and pyrazinamid (2HRZ) plus excipient and the standard 3-month regimen of isoniazid and rifapentine (3HP) for LTBI treatment in Taiwan. Materials and Methods: Between January 1, 2017, and December 31, 2017, all patients aged ≥20 years diagnosed LTBI were included in the study. Demographic and baseline laboratory assessment of the patients at diagnosis was collected. Eligible individuals were allocated to the 2-month regimen comprising HUEXC030, isoniazid, rifampin, and pyrazinamide (2HRZ) or 3-month regimen with isoniazid and rifapentine (HP). All symptoms and side effects during treatment were recorded. Results: Nineteen patients received the 2-month regimen with HRZ plus HUEXC030, while 23 received the 3-month regimen with HP. The treatment completion rates were 73.7% and 82.6% in the 2- and 3-month regimen groups, respectively. The most common side effects during treatment were fatigue/myalgia/weakness, loss of appetite, and rash. The aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels were similar in both groups after 4 weeks of treatment. Conclusions: This study demonstrates that LTBI patients receiving the 2-month regimen with HRZ plus HUEXC030 experienced similar side effects including hepatitis as patients on the 3-month regimen with HP. This new combination treatment regimen may be an alternative for the treatment of LTBI.

Keywords: Latent tuberculosis infection, isoniazid, pyrazinamide and HUEXC030, isoniazid and rifapentine, rifampin


How to cite this article:
Lin TY, Liu FC. New combination for patients with latent tuberculosis infection: A pilot study. J Med Sci 2018;38:252-7

How to cite this URL:
Lin TY, Liu FC. New combination for patients with latent tuberculosis infection: A pilot study. J Med Sci [serial online] 2018 [cited 2018 Nov 14];38:252-7. Available from: http://www.jmedscindmc.com/text.asp?2018/38/6/252/239023


  Introduction Top


Tuberculosis (TB) poses a global public health threat and remains one of the major causes of death among infectious diseases.[1],[2] Approximately 10,000–15,000 newly diagnosed TB cases are reported annually in Taiwan. Latent TB infection (LTBI) is characterized by the presence of immune responses to Mycobacterium tuberculosis infection without clinical evidence of active TB.[3] It is estimated that one-third of the human population harbors TB in its latent form, and from this reservoir, active TB will develop in the coming decades. The likelihood of progression of LTBI to active TB depends on bacterial, host, and environmental factors.[4] The reactivation of TB can be averted by preventive treatment. Treatment of LTBI among persons at risk for progression to active disease is an important strategy for TB control and elimination.[5],[6]

There are three major treatment regimens of LTBI according to the treatment guideline in Taiwan. The first regimen comprises 9 months of isoniazid treatment. This treatment duration is longer and results in poor compliance with medication, which directly affects the effectiveness of prophylactic treatment.[7] Besides, isoniazid therapy also has a high rate of resistance; about 10% of TB cases were resistant to isoniazid in 2000–2010 in Taiwan. Another preventive regimen, comprising 3 months of treatment with isoniazid and rifapentine (HP), has an equivalent efficacy to 9 months of isoniazid and fewer side effects but is more expensive.[8] The Taiwan Centers for Disease Control (CDC) recommends 4 months of rifampin treatment if the index case had multidrug-resistant TB.[9]

A 2-month regimen of isoniazid, rifampin, and pyrazinamide (2HRZ) has been used for LTBI treatment in Portugal for over 20 years. The rationale for the use of HRZ for LTBI treatment is that rifampin and pyrazinamide have good sterilizing capacity and activity against intermittently metabolically active and intracellular organisms. The efficacy of this treatment is equivalent to 9 months of treatment with isoniazid. There is no patient developed disease after completion. However, hepatotoxicity as a side effect is still a major concern.[10] Durate et al. found that approximately 1.5% of LTBI patients presented with hepatitis during the 2-month treatment, similar to isoniazid therapy. Adverse events other than hepatotoxicity are similar to isoniazid treatment.

The side effect of hepatitis during 2HRZ treatment is attributed to isoniazid, rifampin, and pyrazinamide. Isoniazid is acetylated by N-acetyltransferase in the liver [Figure 1]. The intermediate by-product of the above process, acetylisoniazid, rapidly hydrolyzes to acetylhydrazine, and is further acetylated by N-acetyltransferase to nontoxic diacetylhydrazine or oxidized to a toxic reactive metabolite by the cytochrome P450 2E1 (CYP2E1) enzyme. This toxic metabolite could be eliminated through glutathione catalysis by glutathione S-transferase. Besides, isoniazid is also hydrolyzed by amidase to toxic hydrazine. Pyrazinamide is metabolized to pyrazinoic acid (PA) by pyrazinamidase in the liver [Figure 2]. Pyrazinamide and PA are further metabolized to 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid, respectively, by xanthine oxidase. The excipient, HUEXC030 is both a CYP2E1 and amidase inhibitor, and so prevents the metabolism of isoniazid and pyrazinamide to toxic metabolites in the liver, thereby preventing the side effect of hepatitis. Series animal, pharmacokinetic and pharmacodynamic studies have revealed evidence that this excipient could lessen the incidence of hepatitis resulting from isoniazid and pyrazinamide.[11],[12],[13]
Figure 1: Metabolic pathway of isoniazid in humans

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Figure 2: Metabolic pathway of pyrazinamide in humans

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Most treatment regimens for LTBI have hepatitis as a side effect and involve longer treatment durations. This prospective observational study aimed to compare the incidences of hepatitis and side effects between the new 2-month combination regimen (2HRZ plus excipient) and the standard 3-month regimen comprising isoniazid and rifapentine for LTBI treatment in Taiwan.


  Materials and Methods Top


This prospective observational study was conducted at Tri-Service General Hospital, a 1700-bed tertiary care center in Taiwan. Patients ≥20 years old, who satisfied the inclusion criteria for the diagnosis of LTBI between January 1, 2017, and December 31, 2017, were included in the study. Criteria for participation in the trial included an age of at least 20 years, close contact with TB patients with positive or indeterminate interferon-gamma release assay results without typical TB symptoms, a normal chest radiograph, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than the upper limits of normal. Exclusion criteria were as follows: participants with a history of hepatitis B and C or other uncontrollable medical illness; pregnancy; history of allergy to isoniazid, rifampin, and pyrazinamide; history of an acute infectious disease 4 weeks before treatment; and liver function test results higher than the upper limit of normal.

Eligible individuals were allocated to the 2-month regimen with HUEXC030, isoniazid, rifampin, and pyrazinamide or the 3-month regimen with isoniazid and rifapentine. Baseline laboratory assessment before treatment included hemogram, serologic markers of hepatitis B and C viruses, and serum biochemistry, including AST, ALT, and total bilirubin and renal function. The study was approved by the Research Ethics Committee of Tri-Service General Hospital (IRB: 2-106-01-008). Individuals in the 2-month regimen group were given isoniazid 5 mg/kg qd, rifampin 10 mg/kg qd, pyrazinamide 20–25 mg/kg qd, and HUEXC030 600 mg qd. Participants in the 3-month regimen group were given isoniazid 15 mg/kg (maximum 900 mg) qw and rifapentine 900 mg qw. The directly observed treatment, short-course strategy was applied to both groups.

A case record form was used to collect information on the demographic and clinical characteristics of the patients at diagnosis. All symptoms and side effects suggestive of drug toxicity (fatigue/myalgia/weakness, headache, nausea/vomiting, fever/chills, rash/itching, and loss of appetite) during the course of treatment were recorded. Serum biochemistry, including AST, ALT, total bilirubin, and renal function were measured after entry and 4 weeks after treatment. Individuals were withdrawn if they experienced intolerable drug side effects (fever, nausea/vomiting, malaise, or hepatotoxicity). Hepatotoxicity was defined as AST or ALT levels five times higher than the upper limit of normal, with or without hepatic symptoms; three times higher than the upper limit of normal with hepatic symptoms; or total bilirubin level higher than 3 mg/dl.

Statistical analysis

Categorical variables were analyzed using Chi-square tests, while continuous variables were compared using the Student's t-test. P < 0.05 was considered statistically significant. All statistical analyses were performed with the SPSS software version (SPSS Inc., Chicago, IL, USA).


  Results Top


A total of 42 patients who satisfied the diagnostic criteria for LTBI were included in our study. Comparison of baseline demographic and clinical characteristics of latent TB patients is shown in [Table 1]. Among them, 19 patients received the 2-month regimen comprising HRZ plus HUEXC030, whereas 23 patients received the 3-month regimen with HP. The mean age of the 2-month treatment group was 51.58 ± 5.14 years, whereas that of the 3-month treatment group was 53.17 ± 3.896 years. The proportion of male individuals in each group was 26.3% and 39.1%, respectively. Hypertensive cardiovascular disease and diabetes were the most common comorbid conditions (19.0%), followed by end-stage renal disease (7.1%). Individuals in the two-month regimen group were given isoniazid 5 mg/kg qd, rifampin 10 mg/kg qd, pyrazinamide 20-25 mg/kg qd, and HUEXC030 600 mg qd. Participants in the 3-month regimen group were given isoniazid 15 mg/kg (maximum 900 mg) qw and rifapentine 900 mg qw.
Table 1: Comparison of demographic and clinical characteristics of latent tuberculosis patients receiving 2HRZ plus HUEXC030 and 3HP regimens

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Comparison of side effects among LTBI patients receiving 2HRZ plus HUEXC030 and 3HP regimens is shown in [Table 2]. The treatment completion rate was 73.7% in the 2-month regimen group and 82.6% in the 3-month regimen group. The adverse symptoms of fatigue/myalgia/weakness were experienced by six patients (31.6%) in the 2-month regimen group and six patients (26.1%) in the 3-month regimen group. Rash/itching symptoms were reported by 2 patients (10.5%) in the 2-month regimen group and 2 patients (8.7%) in the 3-month regimen group. Nausea/vomiting symptom was experienced by one patient (5.3%) in the 2-month regimen group and two patients in the 3-month regimen group. The symptom of loss of appetite was observed in three patients (7.1%) in the 2-month regimen group.
Table 2: Comparison of side effects between patients with latent tuberculosis infection receiving 2HRZ plus HUEXC030 and 3HP regimens

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Laboratory values of patients with LTBI receiving 2HRZ plus HUEXC030 and 3HP regimens are shown in [Table 3]. The mean value of creatinine was lower among patients receiving the 2-month regimen compared to those receiving the 3-month regimen (0.80 ± 0.043 vs. 3.2 ± 0.085 mg/dl, P = 0.0485). The values of AST, ALT, and total bilirubin before treatment were similar in both groups (19.05 ± 1.66 vs. 24.42 ± 3.30 U/L, P = 0.1547; 19.00 ± 2.61 vs. 23.30 ± 5.21 U/L, P = 0.4724; and 0.64 ± 0.07 vs. 0.72 ± 0.15 mg/dl, P = 0.6383 for the 2-month regimen group vs. 3-month regimen group, respectively). The values of AST, ALT, and total bilirubin 4 weeks after treatment were similar in both groups (20.25 ± 3.591 vs. 23.63 ± 1.972 U/L, P = 0.3881; 14.80 ± 3.056 vs. 20.63 ± 3.676 U/L, P = 0.4080; and 0.54 ± 0.07 vs. 0.63 ± 0.07 mg/dl, P = 0.3985, for the 2-month regimen group vs. 3-month regimen group, respectively). Two patients and one patient developed hepatotoxicity in the 2-month regimen and 3-month regimen groups, respectively (10.5% vs. 4.3%).
Table 3: Comparison of laboratory values of patients with latent tuberculosis infection receiving 2HRZ plus HUEXC030 and 3HP regimens

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  Discussion Top


The present study demonstrates that LTBI patients receiving the 2-month regimen with HRZ plus HUEXC030 experience similar side effects, including hepatitis, as patients on the 3-month regimen with isoniazid and rifapentine. The treatment completion rate was similar in both treatment groups. This new combination treatment regimen may be an alternative in the treatment of LTBI.

Treatment of LTBI is an essential component of the TB elimination strategy.[14] The traditional regimen comprises a 9-month-long treatment with isoniazid.[15] Hepatotoxicity and decreased compliance are major concerns with the daily use of isoniazid for 9 months. Hasely et al. found that a 2-month regimen of daily rifampin and pyrazinamide is effective and resulted in similar hepatotoxicity levels compared to the 9-month regimen of isoniazid among HIV patients.[16],[17] The US CDC previously adopted the short pyrazinamide/rifampin regimen as an alternative therapy but no longer recommends it on account of severe hepatotoxicity.[18],[19] Sterling et al. found that another short-course 3-month regimen with isoniazid plus rifapentine had equivalent efficacy as the 9-month regimen with isoniazid and was an acceptable regimen on account of equivalent prophylaxis, similar side effects, and short-course treatment.

The 2-month regimen with isoniazid, rifampin, and pyrazinamide has been widely used in Portugal. This regimen had good intracellular activity, but the risk of hepatitis is still a concern. If overcome side effects of liver toxicity with isonizaid, rifampin and pyrazinamide, the two-month preventive administration can not only shorten treatment period but also improve safety treatment of LTBI. The side effect of hepatitis due to HRZ treatment is attributed to the accumulation of toxic metabolites of isoniazid, rifampin, and pyrazinamide in the liver. CYP2E1 and amidase play important roles in the metabolic pathways of isoniazid and pyrazinamide. HUEXC030 is both an inhibitor of CYP2E1 and amidase and was able to alleviate hepatitis in animal and human studies. The incidence of hepatotoxicity in this regimen group was also similar to the 3-month regimen group, implying that HUEXC030 may play a protective role against hepatitis during treatment with isoniazid and pyrazinamide.

The completion rate with the daily use of isoniazid for 9 months is 50%–80%.[20] Sterling et al. found about a 90% completion rate for the 3-month regimen. Evidence of the efficacy of interventions aimed at improving treatment adherence and completion showed that shorter treatment duration was significantly associated with increased adherence.[21] We propose a 2-month regimen with isoniazid, rifampin, and pyrazinamide plus HUEXC030, with a shorter treatment duration than the 3-month regimen, thereby improving treatment adherence and completion rate.

The incidence of hepatotoxicity during various treatments of LTBI is around 1%–5%.[5],[6],[8] The incidence of hepatotoxicity in our study was 10.5% and 4.3% in the 2- and 3-month regimens, respectively. The possible explanations for the higher incidence of hepatotoxicity in the 2-month regimen group are as follows. First, the sample size was small and may have influenced the results during the observation period. Second, although HUEXC030 in the 2-month regimen with isoniazid, rifampin, and pyrazinamide could alleviate hepatitis caused by isoniazid and pyrazinamide, rifampin-associated hepatotoxicity could not be prevented by HUEXC030.

There are several limitations in our study. First, our study is a pilot study and the sample size in each group was small. Further randomized controlled clinical trials are warranted to compare these two LTBI treatment regimens. Second, the study observation period was short; thus, the treatment efficacy could not be addressed in our study. Third, the excipient HUEXC030 is not available in every hospital, and the combination with isoniazid, rifampin, and pyrazinamide is not recommended in the current national treatment guidelines for LTBI, resulting in difficulty in extrapolation of our study results.


  Conclusions Top


Our preliminary study showed that combination of isoniazid, rifampin, and pyrazinamide plus HUEXC030 was an acceptable regimen for treatment of LTBI. The course of treatment is shorter than other three major treatment regimens of LTBI. Further randomized controlled trials are recommended to extrapolate our study findings.

Acknowledgment

This study was supported by grants from the Centers for Disease Control, Taiwan (MOHW-106-CDC-C-114-000104). The funding sources had no role in study design and conduct; data collection, analysis, or interpretation; or in the writing of the manuscript or the decision to submit it for publication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, et al. LTBI: Latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 2009;33:956-73.  Back to cited text no. 3
    
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McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin vs. isoniazid for the treatment of latent tuberculosis: Improved completion rates but more hepatotoxicity. Chest 2003;123:102-6.  Back to cited text no. 19
    
20.
Lines G, Hunter P, Bleything S. Improving treatment completion rates for latent tuberculosis infection: A review of two treatment regimens at a community health center. J Health Care Poor Underserved 2015;26:1428-39.  Back to cited text no. 20
    
21.
Horsburgh CR Jr., Goldberg S, Bethel J, Chen S, Colson PW, Hirsch-Moverman Y, et al. Latent TB infection treatment acceptance and completion in the United States and Canada. Chest 2010;137:401-9.  Back to cited text no. 21
    


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