MEDICATION RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS PATIENTS

1.0 Introduction

The discovery of anti-tuberculosis drugs in the 1940s followed by combination chemotherapy made tuberculosis a curable disease. In the developed countries, effective treatment and surveillance reduced tuberculosis dramatically with high hopes of total eradication (Raviglione et al., 1992; Raviglione et al., 1995). However, in the 1980s, it was realized that tuberculosis had not only ceased to decline in the developed countries, notably the USA, but was actually increasing, particularly in major cities (Raviglione et al., 1995). It was also soon realized that the disease was out of control and increasing at an alarming rate across most of the poorest regions of the world especially Africa due to HIV/AIDS (Raviglione et al., 1992; WHO, 2009).

Despite aggressive international efforts, tuberculosis remains a leading infectious cause of death, with an estimated 8.6 million incident cases per year. In 2012, an estimated 1.3 million people died from the disease. These death rates, however, only partially depict the global TB threat; more than 80% of TB patients are in the economically productive age of 15 to 49 years (WHO, 2013).

Global tuberculosis control efforts have been threatened by the emergence of multidrug resistant tuberculosis (MDR-TB). MDR-TB is defined as strains of Mycobacterium tuberculosis which show high level resistance to both isoniazid and rifampicin, with or without resistance to other anti TB drugs (WHO, 2013). MDR-TB is estimated to cause 4% of new tuberculosis cases in the developing world. Patients infected with MDR strains are not only difficult to cure but also more likely to remain sources of infection for a longer period of time than those with drug susceptible organisms. MDR-TB requires longer duration of treatment (up to 2 years) to achieve cure, in comparison with 6 month treatment for drug susceptible TB, lower cure rates and even higher default rates.

The cost of drugs to treat an MDR-TB case can be up to 100 times more expensive than the cost of treating a drug susceptible TB case (Leimane and Leimans, 2006). Because of its increasing prevalence MDR-TB is now subdivided into basic MDR-TB, with resistance only to rifampicin and isoniazid, and extensively drug resistant TB (XDR-TB), with a similar resistance pattern but with resistance to one or more additional first and/or second line drugs.Various perturbations in the individual drug target genes are responsible for the genesis of anti-TB drugs resistance. Rifampicin resistance has been shown to be caused by a change in the β-subunit of DNA dependent RNA polymerase, which is encoded by the rpoβ gene. More than 95% of rifampicin resistant strains are associated with mutations within an 81-base pair region of the rpoβ gene, which is termed rifampicin resistance determinant region (Telenti et al., 1993; Traore et al., 2000; Sharma and Mohan, 2006).

On the contrary, resistance to isoniazid is due to mutations at one of two main sites, in either the katG or inhA genes (Zhang et al.,1992; Piatek et al., 2000). These mutations are not directly connected, and so separate mutations are required for organisms to change from a drug susceptible isolate to MDR-TB. Furthermore, rifampicin resistance has been considered to be a surrogate marker for checking multidrug resistance in clinical isolates of M. tuberculosis since rifampicin resistance is often accompanied by resistance to isoniazid (Traore et al., 2000; Sharma and Mohan, 2006).

Drug resistance in M. tuberculosis occurs by random, single step, spontaneous mutation at a low but predictable frequency, in large bacterial populations. The accurate diagnosis of MDR-TB requires a positive culture of M. tuberculosis and drug susceptibility testing. Previous drug treatment is the largest single risk factor for the presence of MDR-TB. There is a strong suspicion of drug resistance, including MDR-TB, in persons with a history of prior treatment or in treatment failure cases.

The emergence of drug resistance in M. tuberculosis has been associated with a variety of management, health provider and patient related factors. These include

1. Deficient or deteriorating TB control programmes resulting in inadequate administration of effective treatment;
2. Poor case holding, administration of sub-standard drugs, inadequate or irregular drug supply and lack of supervision;
3. Ignorance of health care workers in epidemiology, treatment and control; (iv) improper prescription of regimens;
4. Interruption of chemotherapy due to side effects; (vi) non-adherence of patients to the prescribed drug therapy;
5. Availability of anti-TB drugs across the counter, without prescription;
6. (viii) massive bacillary load;
7. Illiteracy and low socio economic status of the patients; (x) the epidemic of HIV infection; (xi) laboratory delays in identification and susceptibility testing of M. tuberculosis isolates;
8. Use of nonstandardized laboratory techniques, poor quality drug powders and lack of quality control measures; and
9. Use of anti-TB drugs for indications other than tuberculosis (Paramasivanand Venkataraman, 2004).

In most countries, MDR-TB has increased in incidence and interferes with TB control programs, particularly in developing countries, where prevalence rates are as high as 48% (Iseman and Sbarbaro, 1992; Cohn et al., 1997). The high infection and death rates pose an urgent challenge to rapidly detect cases. The extent of the problem of MDR-TB has been examined by the World Health Organization (WHO) in cross sectional surveys of drug resistance in either clinical series or whole country cohorts (Espinal et al., 2001). Cross sectional surveys almost certainly under estimate the burden and number of cases of MDR-TB because they do not take into account the numerical burden of TB in the high burden countries.

When the exercise is repeated with a mathematical modelling design using drug resistance estimates and the number of cases of TB, a more accurate picture of the global MDR-TB burden is claimed (Dye et al., 2002b). However, even this has been criticized as under estimating the global burden for the following reason. The stated number of cases per year from a country often includes up to 20% of cases which are actually on retreatment (i.e. have had a previous course of first line drugs). The prevalence of MDR-TB in retreatment cases is between 30% and 80% depending on the country.

In Gujerat, India, for example, where there are about 400,000 new cases annually, if it is assumed that 20% are being retreated and there is an MDR-TB rate of 30 − 80% in retreatment cases, this would include 24,000 − 64,000 cases of MDR-TB [i.e. (400,000 × 0.2 × (0.3 − 0.8)]. The estimate of the global burden obtained by modelling could be wrong by a factor of 2 − 4. In the USA, HIV positive MDR-TB cases initially had a 100% mortality (Small et al., 1993), but with greater awareness and early diagnosis an improvement in initial survival rates up to 50% has been reported (Salomon et al., 1995). HIV negative cases in the USA have had better response rates of between 56% (Goble et al., 1993) and 69% (Telzak et al., 1995). Nosocomial outbreaks, often in an HIV setting, are well documented in other countries as well as the USA. An outbreak in Spain between 1991 and 1995 killed 47 of 48 patients infected (Herrera et al., 1996), and in two outbreaks in London (Chelsea and Westminster Hospital and St Thomas”Ÿs Hospital) the mortality was over 50% in HIV positive patients (Breathnach et al., 1998).

Understanding the scientific basis of short course 6 month chemotherapy for tuberculosis helps to explain why the loss of sensitivity to both isoniazid and rifampicin, even without resistance to additional drugs, has such major effects on outcome. Numerous controlled trials have shown that a 6 month regimen of rifampicin and isoniazid, supplemented by pyrazinamide and streptomycin or ethambutol for the first 2 months, will provide a cure in > 95% of cases if the medication is taken correctly. Such a regimen also renders infectious cases non infectious in 2 weeks
(Ormerod, 1997). Each drug varies in its ability to kill tubercle bacilli (bactericidal ability), to deal with persistent organisms which are only occasionally metabolically active (sterilizing ability) and to prevent the emergence of drug resistance (Ormerod, 1997).

Isoniazid is the best bactericidal drug and if mono resistance to this occurs, treatment with rifampicin and ethambutol has to be extended for 9 − 12 months, in addition to 2 months initial pyrazinamide. Rifampicin is the best sterilizing drug, and mono resistance to this drug requires treatment with isoniazid and ethambutol for 18 months, with 2 months initial pyrazinamide. Therefore loss of response to both the main bactericidal drug and the main sterilizing drug means that patients remain infectious for much longer, both in the community and in hospital, that treatment is required for at least 12 and possibly more than 24 months, and that less effective and more toxic second line drugs have to be used (Joint Tuberculosis Committee of the British Thoracic Society, 1998).
Although some individuals who have not had previous TB treatment are infected by MDR-TB, this is not the case for most patients. Many new cases of MDR-TB are created each year by a combination of physician error and poor patient compliance with treatment, which turn fully susceptible organisms, or those with less complex resistance patterns, into MDR-TB.

1.1 Statement of the problem

The global burden of TB remains enormous. In 2012, there were an estimated 8.6 million incident cases of TB and 1.3 million people died from the disease. Among these deaths there were an estimated 170,000 from MDR-TB. General problem of MDR-TB with an estimated 450,000 incidence cases worldwide annually has been recognized since the first World Health Organization (WHO) global survey on drug resistance in the late 1990s (WHO, 2013). MDR-TB has reached alarming levels worldwide with the emergence of strains that are virtually untreatable with the existing drugs. Drug-resistant strains, along with HIV/AIDS, are causing the biggest challenge to efficient management and control of TB. The report of an outbreak of extensively drug resistant TB (XDR-TB) in South Africa (Gandhi et al., 2006), with its extremely high case fatality rate, has drawn wide attention.

It has been indicated that MDR-TB is likely to be more prevalent in Africa than previous reports indicated. The latest WHO global report on anti-tuberculosis drug resistance in the world was produced in 2008 and published in a 2010 WHO report on MDR-TB epidemic. A systematic literature review of evidence about mortality associated with MDR-TB was commissioned by WHO in 2013. The results have been used to produce global estimates of MDR-TB incidence and mortality in 2012. The estimate of mortality due to MDR-TB is slightly higher than before, while the incidence is similar to the previous estimate (WHO, 2013).

1.2 Justification

Five of 13 countries with the highest incidence rates of TB per capita are in Africa. According to the WHO global report on anti-tuberculosis drug resistance in the world, MDR-TB strains have emerged in all regions of the world (WHO, 2013). The overwhelming burden of MDR-TB is in high burden resource poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource rich settings. Lack of comprehensive national DRS data from all countries in Africa is a barrier to understanding the magnitude of prevalence and incidence of MDR-TB.

WHO (2013) reported Nigeria as the thirteenth in the list of the 22 highest incidence countries on the basis of numbers of new cases of TB. Also, Nigeria is considered as having moderate rate of MDR-TB. According to the National drug resistance survey in 2012, the prevalence rate of MDR-TB in Nigeria is about 2.9%. However, MDR-TB in Africa, including in Nigeria, is more prevalent than previously reported. Given the limited health care funding and substantial incidence of HIV in Nigeria, even a relatively low but increasing tide of MDR-TB can lead to disastrous consequences for the country. The availability of drugs on the open market and a private sector that delivers drugs to the population in an unregulated fashion in Nigeria could also be factors that might favour development of MDR-TB. There is very little information on the prevalence of MDR-TB in Nigeria and specifically in Kaduna State.

1.3 Research Questions

The study came up with research questions so as to be able to ascertain the above stated objectives. The specific research questions for the study are stated below as follows:

• Is there MDR-TB in Kaduna State?
• If there is, what is the prevalence of MDR-TB in Kaduna State?
• What socio-demographic factors predispose to MDR-TB in Kaduna State?

1.4 Research Hypothesis

In order to pursue the objective of this study, the following generalized statements have been designed to guide and aids in obtaining the result for the experiment to be conducted. For this work, the null hypothesis will be represented with H0 while the alternative hypothesis will be represented with hypothesis H1.

• Null Hypothesis (H0): MDR-TB is not prevalent in Kaduna State
• Alternative Hypothesis (H1): MDR-TB is prevalent in Kaduna State

1.5 Aim of the Study

The aim of the study is to determine the existence and prevalence of MDR-TB in Kaduna State, Nigeria.

1.6 Objectives of the Study

Specifically, the objectives of the study are:

1. To determine some demographic and risk factors that may be associated with tuberculosis among the study population
2. To screen sputum samples for Acid Fast Bacilli (AFB) using microscopy
3. To isolate and characterize M. tuberculosis from smear positive sputum samples
4. To determine the anti-tuberculosis drug susceptibility of the isolates
5. To determine the patterns of mutations in the resistant isolates