1. INTRODUCTION

At no time in recent history has tuberculosis become of great concern as today. Despite highly effective drugs, disease and deaths due to Mycobacterium tuberculosis are increasing in South Africa, fuelled by the HIV epidemic. The most serious aspect of the TB epidemic has been the emergence of DR-TB in the country. DR-TB is a man-made problem, largely due to human error in any or all of the following:

• Management of drug supply
• Patient management
• Prescription of chemotherapy
• Patient adherence

Anti-TB drugs constitute a two-edged sword – while they kill the mycobacteria; they also select for naturally resistant mycobacteria. In this way, strains can become sequentially resistant to several agents and patients may also acquire further drug-resistant strains through re-infection or super- infection.

1.1. Definitions

DR-TB is a disease (usually pulmonary) caused by M. tuberculosis strains resistant to one or more anti-TB drugs.

• MDR-TB is defined as resistance to rifampicin and isoniazid, with or without resistance to other first-line anti-TB drugs.
• XDR-TB is defined as resistance to rifampicin, isoniazid, any fluoroquinolone and resistance to one or more of the following injectable anti-TB drugs: kanamycin,amikacin, and capreomycin.

Drug resistance is further classified according to the history of previous TB treatment:

• Resistance in new patients (previously called ‘primary resistance’) is resistance in the cultures from patients with no history of previous TB treatment or patients who have received TB treatment for less than one month previously. Resistance in new patients provides a measure of the degree of transmission of M. tuberculosis strains.
• Resistance in previously treated patients (previously called ‘acquired resistance’) refers to resistance in cultures from patients with one or more previous TB treatment episodes, of more than one month each. Previously treated patients are also often referred to as re-treatment cases.
• Resistance levels in re-treatment are always higher than in new patients, and provide an indication of the extent to which patients were appropriately treated.

The terms ‘primary’ and ‘acquired’ have been discontinued as epidemiological terminology, as the exact causative nature of drug resistance in a patient is not always possible to assess. Patients may be erroneously labelled as having primary resistance if they do not disclose previous treatment for TB, while patients who fail treatment (and are therefore labelled to have acquired resistance) may have been infected with a resistant strain from the beginning or acquired resistance during treatment.

MDR-TB differs from non-tuberculosis mycobacteria (NTM). NTMs are commonly resistant to both isoniazid and rifampicin but should not be confused with MDR-TB. These Policy Guidelines are relevant for the management of DR-TB only and not for disease caused by NTM.

1.2 Development of Drug-Resistant TB

M. tuberculosis has the ability to undergo spontaneous, slow but constant mutation, resulting in resistant mutant organisms. This natural phenomenon is genetically determined and varies from drug to drug. The probability of spontaneous resistance to individual first-line anti-TB drugs is as follows:

• Isoniazid: 1 in every 10⁶ cell divisions
• Rifampicin: 1 in every 10⁹ cell divisions
• Streptomycin: 1 in every 10⁶ cell divisions
• Ethambutol: 1 in every 10⁵ cell divisions
• Pyrazinamide: 1 in every 10⁵ cell divisions

Usually, the chromosomal location of resistance to different drugs is not linked. Therefore, spontaneously occurring multidrug resistance is extremely rare. For example, the probability of mutation resulting in resistance to isoniazid is 10-6 and for rifampicin it is 10-9. The likelihood of spontaneous resistance to both isoniazid and rifampicin is the product of the two probabilities (i.e.,

10-15). Since the probability of naturally occurring resistant mutants is very low, a large bacterial load (e.g., in lung cavities) is needed for MDR-TB strains to emerge.

Drug resistance is the result of selection of resistant mutants in the bacterial population, due to killing of susceptible bacilli by anti-TB drugs. The problem is greatly exacerbated by inadequate treatment such as direct or indirect monotherapy, resulting from intake of a single anti-TB drug or from intake of several drugs with suboptimal concentrations. Susceptible bacilli are killed rapidly and resistant mutants are then able to multiply.

Erratic  TB treatment with first-line  drugs, either  through clinical error  (i.e., prescription  of inadequate drugs, adding one drug to a failing regimen or programme failure with high treatment non-compliance and default) can result in the emergence of resistance, including MDR-TB. Erratic treatment with second-line drugs can result in XDR-TB a virtually untreatable disease.

1.3. Situational Analysis

South Africa is the world’s third highest burden TB country, only lagging behind countries with significantly larger populations, such as China and India. South Africa is also ranked the fifth highest DR-TB high burden country. In addition, the numbers of MDR-TB and XDR-TB patients have increased due to the concurrent HIV epidemic and inadequate management of TB.  There has been a steady increase in cases since 2006, possibly due to increased case detection (Tables I and II). In 2010, the NHLS diagnosed 7 386 MDR-TB and 741 XDR-TB cases. The reason for the decrease in the number of cases between 2009 and 2010 is not clear.

As shown in Tables I and II, KwaZulu-Natal and Western Cape notified the highest number of cases followed by Eastern Cape and Gauteng.

As shown in Table III, there is a wide gap between the number of MDR- and XDR-TB patients diagnosed, registered and started on treatment. In 2009, the programme did not start DR-TB treatment in approximately 50% of all diagnosed MDR-TB patients. The numbers diagnosed and started on treatment depend on the prevalence of drug-resistance and accessibility and efficiency of diagnostic and treatment services in the provinces.

1.4. Framework for Managing Drug-Resistant TB

Management of DR-TB is organised around five components like the DOTS strategy, because the underlying principles are the same, namely:

• Sustained government commitment;
• Accurate, timely diagnosis through quality assured culture and drug susceptibility testing;
• Appropriate treatment utilising second-line drugs under strict supervision;
• Uninterrupted supply of quality assured second-line drugs; and
• Standardised recording and reporting system.

1.5. Prevention of Drug-Resistant TB

Standardised First-line Regimens for New and Re-Treatment Patients

Ensuring cure of new smear-positive patients the first time will prevent significant development and subsequent spread of drug-resistant TB. This is only possible on a national scale by the use of standardised regimens. Every effort should be made to ensure that patients on regimen 2 (re- treatment) complete their treatment, as they are at a higher risk of developing drug-resistant TB.

Compliance to Treatment Protocols

Compliance with management guidelines as recommended by the National Department of Health ensures that adequate drugs, in the correct combinations and dosages, are prescribed for the correct period of time. Use of fixed combination drugs eliminates the likelihood of selection of drugs and inadequate dosing due to human error.

Patient Adherence and Supervision of Therapy

Adherence refers to how well patients complete the full course of prescribed medication. This often depends on adequate counselling, ongoing support, and access to the facility and attitudes of heath care staff. Directly observed therapy (DOT) during (at the very least) the intensive phase of treatment is the national policy. Excellent adherence during the intensive phase of treatment, during which time the total bacterial load in the patient is being reduced, is crucial to the prevention of drug-resistant TB. This is especially true for sputum smear-positive patients who have a high bacterial load. DOT in the follow-up phase is also important to help prevent relapse.

Drug Supply

The uninterrupted supply of anti-TB drugs to treatment points is crucial in preventing drug resistance.