The Median Time to Develop Recurrent Tuberculosis at a Tertiary Hospital in Kota Bharu , Kelantan , Malaysia

1 Unit of Biostatistics and Research Methodology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia. 2 Universiti Sultan Zainal Abidin (UniSZA), Faculty of Medicine and Health Sciences (FPSK), Jalan Sultan Mahmud 20400, Kuala Terengganu, Terengganu, Malaysia. 3 Department of Community Medicine, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia. 4 Respiratory Specialist, Chest Clinic, Department of Medicine, Hospital Raja Perempuan Zainab II, 15000 Kota Bharu, Kelantan, Malaysia. 5 Unit of Pharmacology, FPSK, UniSZA, 20400 Kuala Terengganu, Terengganu, Malaysia.


INTRODUCTION
Tuberculosis (TB) remain as a potential killer for mankind killer from the prehistoric time (Daniel, 2006).Evidence suggest that TB has been present for at least 15,000 years.It has been reported that TB affecting humans bones dated back to 2400-3400 BC (Iseman, 2013).TB was epidemics in many countries which includes "Europe and North America in 18 th and 19 th centuries" and then subsided with the invention of streptomycin and isoniazid (Daniel, 2006).Consequently, TB declined slowly in the developed countries.TB has reappeared as a potential killer again with the emergence of HIV and AIDS (Daniel, 2006)."TB is, thus, the leading cause of mortality in people with HIV/AIDS, and HIV contributes to a substantial proportion of tuberculosis deaths" (Chaisson & Churchyard, 2010).Globally, every year more than 8-9 million people are newly infected (Uddin et al., 2006).Therefore, in 1995, the World Health Organization launched the Directly Observed Treatment Short-course (DOTS) strategy for control of TB (WHO, 2006).Recurrence of TB is an important indicator to evaluate the current TB control program.Relapses are the primary cause of TB recurrences (Millet et al., 2013)."True relapse can only occur when TB persists after treatment despite apparent cure" and mainly due to inadequate treatment, either due to irrational combination of medicines and duration of treatment (Lambert et al., 2003).
Recurrences can also occur with a different strain (Lambert et al., 2003;Fine & Small, 1999;Van Rie et al., 1999).Globally, the total number of re-treated cases under DOTS programs in 2008 was 775 403 (WHO, 2010).Multple studies suggest that recurrent TB is significantly related with drugresistance and has lower cure rates.Recurrent TB is a major clinical problem to cure and control (Cox et al., 2006;El Sahly et al., 2004;Mallory et al., 2004;Panjabi et al., 2007).
The recurrent TB are more expensive to treat and consume major portion national budgets.Only 61% of registered recurrent TB successfully treated in Malaysia (WHO, 2013).
According to the Infectious Disease Act, 342, 1988, of Malaysia all diagnosed new case of TB should be within one of diagnosis (The Ministry of Health, 2012).The number of retreated of TB cases in 2009 was 1181 in Malaysia.
Among these 1181 re-treated patients 36% 2%, 16%, and 46% were due to relapse, recurrences after failure, recurrences after default, and others respectively (WHO, 2013).The current study is conducted to determine the median time to develop recurrent TB in patients.
There are only a few studies has been conducted in this regard.Therefore, the findings of the current study will contribute more data about the risk of recurrent TB.

Study Design
The study was conducted by retrospective record review to address the median time to develop recurrent TB patients.

Study Participants
18 years old and above TB patients who must have taken at least one month previous TB therapy.ii.Those who received retreatment therapy for TB disease.TB in these patients was diagnosed and treated by the clinical, radiological and/or bacteriological evidences according to the control and management of TB guidelines of the Ministry of Health, Malaysia (The Ministry of Health, 2012).
Although, the calculated sample size was 120, there was a scantiness of patients.Therefore, no sampling method was applied.114 patients who fulfilled the inclusion and exclusion criteria were incorporated in this study.The patients who are below 18 years and do not receive anti-tubercular treatment and retreatment were excluded.

Study Area
The study was conducted at the Chest Clinic in 920bedded HRPZ II Hospital in Kota Bharu having estimated the population of 577 301 in 2009.

Data Collection
Researchers with the help of the staff retrieved the data of recurrent cases registered at the Chest Clinic of HRPZ II, by using the proforma documents from June to July 2010.

Case Definitions
The case definitions were used according to the Malaysia practice guideline for the control and management of TB except those for defaulter case and recurrent TB case (The Ministry of Health, 2012).A patient who took the previously anti-tubercular therapy for at least one month and then missed more than six doses of daily treatment or more than two doses of biweekly treatment was considered as a defaulter case.A patient who had the previous history of TB disease regardless of pulmonary involvement and .sputum smear results and has developed another episode after complete treatment or treatment failure or after default was defined as a relapse or recurrent or re-treatment case.The survival time was referred to re-take another round of treatment with a TB patient.

Statistical Analysis
Data entry and analysis were performed by using SPSS software version 18.The median survival time with 95% confidence intervals for recurrence the TB incidents was determined by the use of the Kaplan-Meier analysis.Categorical independent variables with two levels.The P value was set at < 0.05.
Regarding variables with more than two levels, pair-wise comparison result.A P value was compared with Bonferronicorrected alpha level.

RESULTS
There were altogether 363 recurrent TB cases at HRPZ II from 01/01/2003-31/12/2009.However, only 114 records were retrieved (Table 1).The remaining cases had inadequate information and official papers were damaged.Among 114 records, 93.86% had only one previous episode, and the other 6.14% had between 2-3 episodes of TB.Those with more than 1 previous TB infection, data of the most recent infection was collected.The survival time was "duration between the last date of previous therapy and the first date of taking treatment for the next infection." All patients received the intensive phase of TB treatment during which some patients took more than one drug regimen.21 patients took SHRZ regimen, 84 patients received EHRZ regimen, and 12 patients took HRZ regimen.The median (IQR) duration to receive the treatment for SHRZ, EHRZ, and HRZ regimens were 2.0 (0.0), 2.0 (1.0), 2 (1.8) months respectively.
Thirty-six patients (31.6%) did not take the treatment for the continuing phase, and during that period, some patients had to take more than one treatment regimen as in the previous stage.
The H 2 R 2 regimen was given to 26 patients, 14 people got S 2 H 2 R 2 regimen, 40 people got HR regimen, and 7 people took the other drug regimens.The (IQR) months to take the treatment for H 2 R 2 , S 2 H 2 R 2 , HR and other drug regimens were 4.5 (2.3), 4.0 (2.3), 5.5 (5.0) and 4.0 (7.0) correspondingly.With regard to treatment compliance, 60 patients (52.6%) defaulted and did not take the complete course of therapy.
The overall median developing time was 6 months [95% CI: 4.58, 7.42] for TB recurrence in patients of the current study (Figure 1).There were statistically significant differences [p= 0.026] found between the recipients and non-recipients of S 2 H 2 R 2 drug regimen, and also between the recipients and non-recipients of daily HR drug regimen [p=0.049]during the continuation phase of Kaplan-Meier analysis.Moreover, there was a considerable time difference (p=0.006) between defaulters and non-defaulters of treatment to get recurrent TB.The time to develop recurrent TB was statistically significant between defaulters and non-defaulters [Table 1, 2, 3 and Figure 2a,  b, c].

DISCUSSION
This study found that the overall median time to develop recurrent TB was 6 months [95% CI: 4.58, 7.42] after the end of the previous disease episode.Various case definitions of recurrence of TB and diverse inclusion and exclusion criteria, as well as different studied variables, exist among various reports.Most of the previous studies were analyzed only on completely cured patients; whereas this study was done on a heterogeneous group constituting cured not only patients but also defaulters and treatment failure cases.One study in Uganda whose inclusion criteria is the same as this study reported that most instances [about 80%] had recurrent TB within 8 months of the previous disease episode (Anyama et al., 2007).The analyses done only on cured patients, recurrent TB was found to occur within 6-9 months from the start of treatment (Driver et al., 2001).Again, multiple studies reported that the majority of the cured cases had recurrences within 6 months after completely healed (Thomas et al., 2005;Dholakia et al, 2000;TRC, 1997 and1983;EABMRC, 1976).Therefore, TB clinicians and health care personnel should be more cautious about the risk of recurrent TB in less than one year after completion of anti-tubercular regimen.Recurrences could be consequences of the inappropriate treatment regimens, inadequate therapy attributable to poor or non-compliance with treatment (Yamagishi & Toyota, 2009;Kopanoff et al., 1998).This study found that defaulters were found to have recurrent TB earlier than non-defaulters.Studies conducted in South Africa and Brazil also elucidated that the defaulters were found to experience higher recurrent TB (Golub et al., 2008;Verver et al., 2005).The patients having a history of default in the preceding episode are more likely to be defaulters in succeeding episodes also (Chandrasekaran et al., 2006).Poor compliance with treatment resulting in unnecessary prolongation treatment duration, elevated risk of treatment failure, emergence of acquired drug resistance TB, and continue as open case, remains an obstacle to the accomplishment of a TB control program (Vijay et al., 2010).Nowadays, TB clinicians recognized the importance of rifampicin in treating TB.Several studies proved that the better treatment outcomes came out with rifampicin containing regimen than   bacteriostatic Thiacetazone (T) (EABMRC, 1972 and1977).The current study found that patients who received S 2 H 2 R 2 drug regimen or daily HR drug therapy during the continuation phase took a longer duration to get recurrent TB.The findings of the present work advocate the use of 2 first line anti-tubercular drugs: Isoniazid, and Rifampicin; in both initial and continuation phase.
Recurrent TB is attributable to reactivation of the previous disease or re-infection with different strains of M. Tuberculosis.The relapse or endogenous reactivation results from low potent regimen or poor compliance even though treatment is completed (Korenromp et al., 2003).On the contrary, exogenous re-infection is related to background TB incidence and HIV prevalence of a country (Cox et al., 2006).One study report suggested that relapse mostly occurred within 6 months following the end of the previous treatment (Jasmer et al., 2004) whereas incidence of exogenous reinfection escalated with the time interval between the end of therapy for the last episode and the start of taking treatment for subsequent one (Shen et al., 2006).There is evidence that there is a relationship between strains of M. Tuberculosis and recurrent TB.Beijing strains are prevalent in Asia and North America, and they are mostly related to relapse of the previous infection (Burman et al., 2009;Sun et al., 2006).One study reported that strains of Beijing family were also widespread in West Malaysia but not in East Malaysia (Dale et al., 1999).Consequently, the recurrent cases in this study could be consequences of relapse of the previous infection.Malaysia holds an intermediate burden of TB with a prevalence of 109 [47-173] cases per 100 000 population (WHO, 2013) and has 10.88 HIV incidence rate in 2009 (Ministry of Health, 2009).Current research has found that the accessibility and availability to use of DNA fingerprinting method is limited.Thus, our study cannot differentiate the underlying causes of recurrent TB in this studied area, and further research is necessary to investigate the epidemiology of recurrent TB.

Fig. 1 :
Fig. 1: Kaplan-Meier Survival Curve of Expressing the Probabilities of Getting Recurrent TB.

Fig. 2a :
Fig. 2a: Kapalan-Meier Survival curve displaying the median time to get recurrent TB of recipients and non-recipients of S2H2R2 drug regimen during the continuation phase.

Fig. 2b :
Fig. 2b: Kapalan-Meier Survival curve showing the median time to get recurrent TB of recipients and non-recipients of daily HR drug regimen during the continuation phase.

Fig. 2c :
Fig. 2c: Kapalan-Meier Survival curve is presenting the median time to get recurrent TB of defaulters and non-defaulters of treatment.

Table 1 :
Median Time to get recurrent TB according to sociodemographic features (n=114).

Table 2 :
Median Time to get recurrent TB according to Laboratory and Radiographic characteristics (n = 114).

Table 3 :
Median Time to recurrent TB according to the treatment regiments and compliance factors (n = 114).