Prevalence and Factors Associated with Tuberculosis Treatment Success among TB/ HIV Co-Infection in North-East Malaysia

Background : One of the six strategies developed by WHO, in order to stop Tuberculosis (TB) is addressing TB/HIV high-risk groups. This study aimed to determine the prevalence of successful TB treatment and factors associated with TB treatment success among TB/HIV co-infection patients in North-East Malaysia. Methods : A cross-sectional study was carried out in the a-year period from 2003 to 2012 by reviewing TB/HIV records in all hospitals and health clinics. The outcome of interest was treatment success as defined by Ministry of Health (MOH) when the patients was cured or completed TB treatment. Results : Out of 1510 total TB/HIV co-infection cases, 27.9% (95% CI: 25.2, 30.6) of the patients were having treatment success. A majority of TB/HIV co-infection cases were male (91.1%). Fifty-eight percent the patients were drug addicts and 6% were having positive tuberculin tests. The multiple logistic regression revealed that male (OR: 0.39, 95% CI: 0.22, 0.71) and positive tuberculin test result (OR: 2.61, 95% CI: 1.63, 4.19) were significantly associated with the treatment success of TB/HIV co-infection patients. Other factors such as age, comorbid, sputum smear and x-ray findings were not significantly factors in this study. Conclusion : Female patients and those with negative tuberculin test should be emphasised for successful tuberculosis treatment.


Introduction
Tuberculosis (TB) has been recognised as a major global public health issue by the World Health Assembly (WHA) since 1991. Starting that year, global efforts to control TB were reinvigorated. The World Health Organisation (WHO) declared TB as a global emergency in 1993 and in 1995 recommended Directly Observed Treatment Short Course (DOTS) as a cost-effective strategy for TB control worldwide (1). Human immunodeficiency virus (HIV) is the greatest single risk factor for developing tuberculosis and life-threatening (2). effect on the outcome of TB treatment. In Kelantan, HIV-positive, non-intravenous drug users (IVDU) were more likely to become noncompliance compared to HIV patients who were IVDU while HIV-positive patients had higher compliance compared to HIV-negative patients (13). Previous studies were not much discussing on BCG scar, sputum smear, tuberculin test, and x-ray findings of the TB treatment success. However, the factors were found to have insignificant association with the TB treatment outcome in several studies (11,13,14). This study aimed to determine the prevalence of successful TB treatment and its association with socio-demographic and clinical characteristics among TB/HIV co-infection cases in North-East Malaysia.

Methods
A cross-sectional study was conducted by reviewing TB records from the hospitals and health clinics in all ten districts in Kelantan. All cases diagnosed with TB/HIV co-infection and registered to the Kelantan Health Department from 2003 up to 2012 were included in this study. Using PS software, it was estimated 1588 cases needed to achieve the objective of the study (15). The parameter for this estimation included a level of significance at 5%, a power 80%, proportion of unemployed who were success at 14% (16) and a success: failure ratio of 1:3. Simple random sampling was applied to achieve the sample size.
All selected cases were retrieved from the medical records system, known as TB Wallet at chest clinic at hospitals or health clinics. Socio-demographic, clinical characteristics and outcome of the patients were recorded into a data collection form. Treatment success refers to the patients who were cured and have completed TB treatment (4). Completed TB treatment was defined as any patient who had completed a TB regime based on the Clinical Practice Guidelines created by Malaysia Ministry of Health (4). Thus, all patients with cure or completed treatment outcomes were categorised as treatment success, while other outcomes which were treatment default, treatment failure and death were categorised as treatment failure.
Data were analysed using Statistical Package of Social Science (SPSS) version 20. A 95% confidence interval was used to describe the prevalence TB treatment success. Simple Logistic Regression and Multiple Logistic Regression There are two forms of TB: latent TB and TB disease. Latent TB occurs when the mycobacterium infected in the body are not active and do not produce symptom (3). TB/ HIV co-infection occurs when HIV patients were having either latent TB or TB disease or when TB patients are infected with HIV.
There are five TB outcomes: cure, treatment completion, treatment default, death, and treatment failure. The cure outcome refers to a patient who is smear-negative at, or one month prior to, the completion of treatment and on at least one previous occasion (4). In 1990, WHO chose 2015 as the target to cutting TB mortality and prevalence in half (5).
In Malaysia, a higher sex ratio between male to female 10.7:1 was observed in patients with pulmonary tuberculosis (PTB) in Malaysia (6). Hospital Kota Bharu, Kelantan also were having males as the majority patients with TB/HIV co-infection patients (7). Only 14 countries in the WHO European region able to provide agedisaggregated data for Lazarus et al. (2) study and it is found that majority of co-infections were reported in people aged 25-34 followed by 35-44. Most of notified cases in Zambia are also in the range of 25-44 and there is a significant difference in TB prevalence between children (< 15 years) and adult (8).
Gender and age may affect the outcome of TB treatment, where male and a higher age may contribute to failure of the treatment (9). However, as reported by Lazarus et al. (2) there was no significant gender difference in the age distribution of co-infection in the 14 countries. Another major factor that contributes to failure of TB treatment is married patients (9).
In case of sputum smear examination, many persons in late stage of HIV infection with TB are sputum smear negative. HIV-infected persons are more likely to have disseminated and extra pulmonary TB than HIV-negative persons. HIV infection sometimes reduces the skin test response to tuberculin (10). A study by Nissapatorn et al. (6) found that the other characteristics of patients with pulmonary and extrapulmonary tuberculosis were not statistically different from each other. Nik Nor Ronaidi et al. (11) also found that smoker and diabetic patients were contributing to unsuccessful TB treatment.
Regarding clinical characteristics of TB, results of sputum microscopic examinations were more often positive in diabetic patients (12). Thus, diabetes mellitus has a negative  After adjusting for confounding variables using the multiple logistic regression, gender and tuberculin test were found to be significantly associated to TB treatment success among TB/HIV co-infection in Kelantan (Table 3)  IVDU were tended to be more compliant to TB treatment compared to IVDU. It was suggested that this happens due to special attention by clinician, and strong family support or close observation of prisoners or members of drug rehabilitation centres.
In this study, those with a positive tuberculin test had a higher chance of having treatment success compared to those with a negative tuberculin test. Those who had a tuberculin positive tuberculin test were assumed to have developed an immune response to the TB bacterium (18). Indication of an individual having a past or recent TB infection that was demonstrated by a positive tuberculin test, in starting TB preventive treatment early (21). On average, for treatment of latent TB infection for HIV-infected individuals with a positive tuberculin skin test, there was approximately 60 % protection for up to three years (22). Thus, having a positive tuberculin test should lead to treatment success, a conclusion in this study supports.

Conclusion
The findings of this study showed that factors associated with treatment success among TB/HIV co-infection cases in Kelantan North of Malaysia were gender and tuberculin test. Since male and patients with negative result of tuberculin test results have a higher risk of treatment failure among TB/HIV coinfection patients, this group should strictly focus on increased awareness is important for early diagnosis, compliance and successful TB treatment. However, the males that are a part of the unemployment and drug addict groups should also receive focus since they also have a higher chance of treatment failure.

Acknowledgements
We would like to express our special thanks to all the medical staffs in hospitals and health clinics who give full support and cooperation during the data collection. This study was approved by the Human Research Ethics Committee of USM and the Medical Research and Ethics Committee, Ministry of Health Malaysia. This research was funded by Research University grant 1001/PPSP/817064. Our special thanks also goes to the Director General of Health Malaysia for his permission to publish this article.

Discussion
This study has shown that being a male patient, not working and being a drug addict may decrease the chance of having TB treatment success, while having positive tuberculin test increasing the chance of having TB treatment success. However, after adjusting for other potential confounding variables, gender and tuberculin test were the only factors that found to be significantly associated with the TB treatment success among TB/HIV co-infection cases in Kelantan. Male patients were having higher prevalence of tuberculosis in Malaysia, as well as in Kelantan where majority of TB/ HIV co-infection were male patients (6,7). These findings may help explain why this study found male patients to have a lower chance as treatment success than female patients. Another study in Klang Valley, Malaysia also discovered there was a higher prevalence of TB among male patients, but female patients had higher treatment success (17).
A study in Malawi revealed being female patients of TB/HIV co-infection compared with male patients correlated with successful outcomes of TB treatment (18). Nevertheless, other study in Nigeria found that male patients of TB/HIV co-infection either in rural or urban areas, contributed to successful TB treatment compared to female patients (19). Moreover, in the previous studies conducted among TB patients, female patients were found to have higher contribution to the unsuccessful of TB treatment (11,13).
A study conducted in Nepal showed, unemployment leads to a high risk of nonadherence to TB treatment (OR: 9.2). This supports the finding of this study, where those who are not working have a lower chance of treatment success (9). A study conducted in Malaysia was found that there was no significant association of occupation to poor compliance with anti-TB treatment (13). However, based on the results of same cross-sectional study, the unemployed had the highest level of poor compliance compared to those with an occupation.
Many studies reported that drug addicts were also found to contribute to the treatment failure. This finding is plausible since logically, drug addicts usually tend to be homeless, and not take care of their health, leading to late diagnosis and treatment default. However, in a study conducted in Kelantan by Naing et al. (13), non-