The contribution of disease and drug related factors to non-compliance with directly observed treatment short-course among tuberculosis patients

Non-compliance with anti-tuberculosis therapy has been cited as a major barrier to the control of TB. There are different factors responsible for the non-compliance of TB. The cross sectional prospective participants in the study were interviewed by using a set of questionnaire. TB patients were enrolled at DOTS Centre of LRS Institute of Tuberculosis and Respiratory Disease, New Delhi, India. Patients who discontinued and interrupted the treatment for more than 2 months were categorized as noncompliance cases. T-test was used for comparing the means of control and case groups. The default rate of Delhi LRS-RNTCP defined area was 3.53%. 60% of non-compliance occurred in category II patients. Maximum patients had 3+ initial bacillary load (42.5%). 27.5% patients had positive influence on non-compliance in response to problem created by TB. Patients who suffered from adverse drug reaction and toxicity of drug contributed the highest rate (40%); and 22.5% had no role in noncompliance of tuberculosis patients. Drug related factors were major factors involved in noncompliance with tuberculosis treatment. Thus, we recommend that ADR monitoring and least ADR active drug be used.


INTRODUCTION
Tuberculosis (TB) affects nearly 1/3 rd of the world's population, which is more than any other infectious diseases.Among infected individuals, approximately eight million develop active TB and almost two million of these die from this disease.The incidence of tuberculosis has steadily increased and is responsible for 26% of all avoidable deaths of adults in the developing world (Tripathi et al., 2004;Erhabor et al., 2000;The Global Tuberculosis Epidemic, 2010).Many tuberculosis epidemiologists regard obtaining high compliance levels in the population under treatment as even more important to a community's welfare as finding new cases.Poor compliance with treatment leads to a major impediment to effective tuberculosis chemotherapy worldwide, and is one of the major causes of prolonged infectivity, poor outcomes, treatment failure and drug resistance (Amoran et al., 2011).Drug resistance and obstacles to successful directly observed therapy short-course (DOTS) impede disease control.Among patients being re-treated for TB because of initial treat-ment failure, default from initial treatment, or relapse following initial treatment, drug resistance is common and re-treatment outcome is inferior (Dooley et al., 2011).
Several risk factors are identified as the cause of drug resistant tuberculosis, of which the three most important are: previous treatment with anti-tubercular drugs which may be inappropriate, incomplete or erratic, high prevalence of drug resistant tuberculosis in the community and contact with a patient known to have drug resistant TB.In patients with previous treatment or disease, the odds of resistant to tuberculosis were 4 to 7 times higher than for persons with no history of past treatment (Prasad, 2005).Poor case management, often because of non-adherence to treatment, has emerged as the most important factor in the resurgence of tuberculosis and the appearance of multiple drug resistance (MDR).The prolonged duration of treatment, the need for multiple drugs, socio-economic factors and drug toxicity are the main reasons for non-adherence to treatment.The currently recommended minimum duration of treatment is 6 months; even though it is much shorter than the previously recommended 12 to 24 months, it is still very long.According to World Health Organization (WHO), directly observed therapy ensures successful treatment of patients with tuberculosis (M Chan- Yeung et al., 2003).Although drug resistance could contribute to the poor response to anti-TB medications, it is unlikely to be the main factor that leads to treatment failure in our study (Samman et al., 2003).
In 2010, there was an estimated prevalence of 650,000 cases of MDR-TB and in 2008 it was estimated that there were 150,000 MDR-TB deaths annually.The number of patients enrolled for MDR-TB treatment increased to 46,000 in 2010.While more people are being treated for MDR-TB in 2010, it is just 16% of the estimated number of MDR-TB patients that needed treatment, that is, MDR-TB patients that would be identified if all newly-notified TB patients were tested for drug resistance (World Health Organization, 2011, 2012).MDR-TB is a man-made phenomenon, almost always due to inadequate therapy.Although patients' non-adherence is often thought to be the most common cause of drug resistance, many studies have shown that organizational failure of TB control programmers, lack of available drugs and clinical error are responsible for much of the MDR-TB problem existing today.Human error resulting in inadequate therapy includes incorrect drug prescription, lack of patients' education and supervision and patients' non-adherence to treatment.Common clinical errors include addition of a single drug to a failing regimen, inadequate primary regimens, failure to recognize existing drug resistance, failure to provide directly observed therapy and failure to manage non-adherence (Weyer, 2005).Non-compliance is defined as missing more than 25% of treatment in a month.It means to miss injection (daily/ intermittent) for more than one week or not collecting drugs for more than one week, which is known as defaulters; while defaulting for more than one month is known as abandoned treatment.The non-compliance group also includes patients who defaulted treatment and later retrieved it through any means such as home visits, letter, returning in own accord etc; which is known as defaulter retrieval.It also includes patients who abandoned treatment but retrieved it by bringing it back on their own accord for resumption of treatment.This is known as retrieval of abandoned treatment.Non-compliance was identified by a registry, which was regularly updated and medical records were also checked for confirmation of non-compliance.Besides well-known risk factors, the most important unresolved challenge in TB control is the treatment completion.Treatment will only be effective if the patient completes the regimen which includes a combination of drugs recommended by the physicians.Poor compliance contributes to the worsening of the TB situation by increasing incidence and initiating drug resistance.Resistance to anti-TB drugs has also emerged as an important obstacle to the control of the disease.Worldwide patients' compliance with anti-TB therapy (with an estimate as low as 40%) in developing countries remains the principal cause of treatment failure.The critical aspect of management is ensuring compliance with a full course of chemotherapy.The World Health Organization recommends at least 85% cure rate of all diagnosed TB cases.In order to achieve this cure rate, compliance needs to be in the order of 85 to 90% (Naing et al., 2001).DOTS strategy was employed for national program of tuberculosis control.Both smear positive and smear negative pulmonary tuberculosis (SPPTB, SNPTB) patients are routinely treated by six month therapeutic regimen according to NPT.Subsidizing the initial signs and symptoms of SNPTB and conversion of sputum from positive acid-fast bacillus (AFB) to negative (SPPTB) are the criteria for improvement.Lack of change in/ or worse clinical findings as well as conversion of sputum from negative to positive reflects treatment failure.Six month therapeutic regimen is a treatment of choice for smear positive patients, but for various reasons such as economic, drug toxicity, patients' compliance and availability of drugs, shorter and fewer drug combination can be employed, when resistance is not connected to antituberculosis therapy like smear negative pulmonary tuberculosis (Alavi, 2009).Adverse effects diminish treatment effectiveness, because they significantly contribute to non-adherence, eventually contributing to treatment failure, relapse or the emergence of drugresistance.Adherence to the prescribed treatment is crucial for curing patients with active TB.Because of the long treatment period, the patient should be motivated to continue treatment even when he is feeling better.Additionally, the interruption of TB treatment and the switch to anti-tuberculosis drugs, which is required in patients who do not tolerate drugs, result in a suboptimal treatment response (Tostmann et al., 2008).Monitoring the outcome of treatment is essential in order to evaluate the effectiveness of the intervention.Recommendations on how to evaluate treatment outcomes using standardized in all patients should be routinely monitored by the epidemiological surveillance system.This would make it possible to recognize and amend system failures before the incidence and proportion of resistant isolates rise (Bao et al., 2007).

MATERIALS AND METHODS
The study was conducted between 10 th February, 2008 to 20 July, 2009 on patients who were enrolled for TB treatment at the DOTS Centre of LRS-RNTCP defined area.This study focused on finding out the contributing factors to non-compliance with the treatment of TB.The definition of non-compliance was based on the results satisfying one or more of the following criteria: (1) ≥ 2 consecutive weeks of therapy were missed; (2) Treatment was prolonged >30 days against plan owing to missed doses; (3) Incarceration by the tuberculosis control program for presenting an immediate threat to public health.Patients who missed more than 2 consecutive months of DOT were defined as having defaulted from therapy.For each case of non-compliance controls were randomly selected (using computer-generated random numbers) from cases of completed treatment.
Total patients enrolled in LRS-RNTCP defined area for treatment were 566, out of which 80 were enrolled to find out the contribution of disease and drug related factors to non-compliance with ongoing tuberculosis treatment.Out of 80 enrolled patients, 40 patients served as control (i.e. group I) & 40 patients as cases (i.e. group II).
Group I received short course chemotherapy according to standard guidelines of RNTCP and was categorized as compliance under DOTS.Group II received short course chemotherapy according to RNTCP guidelines, but due to some reasons or factors, the short course chemotherapy was interrupted and patients fell under noncompliance.
The inclusion criteria for the study include: the TB patients recommended for DOTS regimen, at various DOTS centres of defined LRS-RNTCP area will be included irrespective of age and sex and patients who are treated with combination of antituberculosis therapy.The exclusion criteria are mentally retarded and unconscious patients, patients who are not treated with combination of anti-tuberculosis therapy, patients who are not willing to participate and have any active or chronic disease and patients who are unable to comply.Data were collected on patient's demographic profile (age, gender, weight, height, address, marital status etc), family, social and socio-economic status, individual personality, knowledge about TB, drug toxicity, side effects etc.The questionnaires used in this study were designed to find out the role of disease and drug related factors in non-compliance with directly observed short course among tuberculosis patients.It was classified into three categories as shown in Appendix 1.
The sources of data were patients' treatment card, patients' I.D. card and individual interview from patients.Statistical analysis for finding out the factors contributing to non-compliance of DOTS amongst TB patient in cases (group II) was compared with that of the control (group I).T-test was used for comparing the means of the two groups.The number and proportions were compared with P-value.

RESULTS
During the specified period of time in different DOTS centres of LRS-RNTCP defined area, five hundred and sixty six tuberculosis patients were enrolled for treatment.The study finds out that the default rate was 3.53% among them (Table 1).
There was 27% of non compliance in category I patients, 60% in category II patients and 13% in category III patients (Figure 1).
The distribution of non-compliance according to initial bacillary load was found in this manner: the highest case of non-compliance was observed in patients with 3+ initial bacillary load (42.5%) and lowest was found in patients with 1+ initial bacillary load (17.5%) (Figure 2).Prevalence of non-compliance in patients with 2+ initial bacillary load was 22.5% and in negative patients, 17.5%.
Patients' behavior caused by TB problem was noted and it was found that 27.5% patients had positive influence on non-compliance in response to problem created by TB; 62.5% had intermediate influence on the problem created by TB as factors responsible for noncompliance with TB treatment and 10% had negative influence on the problem created by TB as factors responsible for non-compliance (Figure 3).
According to the question-and-answer session with patients, it was observed that disease related factors and drug related factors had major role in the contribution of non-compliance with TB treatments (Figure 4).Based on our finding, the disease related factors were the majority of patients who have negative influence on noncompliance with TB treatments (40%), while 35% patients had intermediate influence on disease related factors responsible for non-compliance with TB treatment and 25% patient had positive influence on non-compliance.
Drug related factors were observed as the highest contributor to non-compliance with TB treatment (Figure 5).The patients who suffered from adverse drug reaction and toxicity of drug contributed the highest rate and it was 40%.Although, 37.5% of non-compliant patients have intermediate influence on the contribution to noncompliance while 22.5% had no role in non-compliance of TB patients.

DISCUSSION AND CONCLUSION
The present study revealed that the disease and drugs related factors had strong association with adherence to tuberculosis treatment.It was found that the default rate was 3.53%.Similar findings were found in RNTCP status report in 2008 where 4 to 6% were the national default rate reported.The category of non-compliant patients was studied and found that majority of non-compliant patients where from category II, which was also described by Jaggarajamma et al. (2007).The types of patients according to initial bacillary load were noted and found that non-compliance is found more in 3+ initial bacillary load patients.Similar observation was observed by Ducati et al. (2006).The study shows that the majority of patients have neither positive nor negative influence on problem created by TB; rather they have intermediate influence on problem created by TB, which is responsible for non-compliance with tuberculosis treatment; this was also observed by Naing et al. (2001).Also, we observed that the disease related factors do not have much influence on non-compliance with tuberculosis treatment; majority of patients had negative influence on the role of the disease related factors; Lertmaharit et al. (2005) had almost similar finding.Drug related factors like adverse drug reaction and toxicity contributed the highest role in non-compliance of tuberculosis.It was found that severe adverse drug reaction and toxicity have direct impact on compliance with the treatment, and that the ADR susceptible TB patients were more prone to non-adherence; this is similar to that found in the research of Jaggarajamma et al. (2007).
The treatment of TB under DOTS-RNTCP program was good and that is why the default rate of South Delhi Region, India was similar to India scenario.Although, the category of patients, initial bacillary load, problem created by TB, disease related factors did not have much influence on non-compliance to tuberculosis treatment.And the main reasons for non-compliance were drug related factors.The common problem created by anti-TB drugs are nausea, vomiting, giddiness, headache, skin rashes, tightness in chest and cough.staff of all DOTS centre of LRS institute for their full cooperation and support.The study would not have been successfully completed without the help of our study patients and their families.Also, we thank the Dean of College of Applied Medical Science, Al-Quawayyah, Dr. Mohammad Al-Ghanaem for his encouragement and support in writing this paper.Last but not the least, we thank Dr. Ansari Mukhtar Aleem for his co-operation and support in writing this paper.
Appendix 1. Questionnaires on the role of disease and drug related factors in non-compliance of directly observed short course among tuberculosis patients (1).Problem created by TB (Knowledge about problem created by TB, the requirement of treatment and effect of non-compliance).

Table 1 .
Default rate of TB patients.
The assessment of non-compliance based on above question.A higher score on the scale 0f 0 to +10 indicates negative influence to noncompliance and lower scale indicates to positive influence to non compliance.The assessment is based on following chart: 3).Drug related factors It consists of 10 questions to determine whether the drug causing side effects or adverse drug reaction.That's force the patient towards the non-compliance).Did you experience Musculoskeletal (Arthralgia, long bones pain, localized joint pain, phlebitis, edema of the legs). (