**5. Challenges in MDR TB therapy**

This approach greatly reduces the workload for laboratories and decreases the cost of national surveys. It may also result in the detection of cases that would otherwise have been missed by culture and conventional DST, particularly in settings with delays in transporting sputum samples to laboratories for testing. Although not a complete surrogate for MDR-TB, particu‐ larly in settings where levels of drug resistance are low, rifampicin resistance is the most important indicator of MDR-TB and has serious clinical implications for affected patients.

It is noteworthy that the supply of these technologically advanced diagnostics though now in more countries cannot serve the total at-risk populations, because these machines are kept strategically in reference laboratories. There is a critical need to develop within each country a framework that would address the accessibility to reference centers. In the Western Pacific and Eastern Mediterranean regions, it is reported that there was less than one reference center per 100,000 population. In Nigeria, a high TB burden country and the fourth highest African country with MDR TB, there are only 9 reference centers which are inadequate for the whole

There is therefore need in the high TB burden areas to still supplement the recent high-tech diagnostic tools with sputum smear microscopy as an initial screening tool and as such be placed in such a way that these can be accessible to all. Improvements in microscopy using fluorescent light emitting diode microscopy, which is more sensitive than light microscopy, has been proposed and adopted in South Africa, and less so in Mozambique, Bangladesh, and

The other aspect that needs careful attention in laboratory diagnosis is the need for regular quality assurance of the machines. Likewise, regular capacity training for laboratory personnel to ensure optimal standards of diagnosis and DST Xpert MT/RIF Newer areas of research for improved diagnostics is the research for correlates of protective immunity and host biomarkers

Pediatric TB diagnosis has also been largely based on clinical criteria due to the pauci bacillary nature of their disease [3, 34-36]. In the cases of TB HIV coinfection, the diagnosis of TB disease is usually more difficult because the symptom specificity is reduced due to similarity with chronic HIV-related symptoms, and chest radiograph interpretation is complicated by HIVrelated comorbidity and atypical disease presentation. In this case, diagnosis involves linking the child with an adult with confirmed pulmonary TB [37]. However, older children producing sputum can have bacteriological confirmation and where facilities are accessible DST is performed [8]. To date, there is still widespread under-diagnosis of MDR TB in younger children. Children are less likely than adults to acquire MDR TB during treatment due to the lower bacillary load and less-frequent cavity formation [38]. Acquisition of strains of MDR TB through primary transmission has been shown to be same for children as for adults [39].

of TB that could help determine the potential for susceptibility or protection [33].

at-risk population of 170 million.

8 An Overview of Tropical Diseases

**4. Unrecognised MDR TB populations**

Nigeria [1].

**4.1. Pediatric MDR TB**

The Global target of MDR TB treatment is to achieve 75% treatment success by 2015. To achieve success in treatment programs, WHO has published a document which contains the guide to Programmatic Management of Drug-resistant TB (PMDT) which covers all key policies in MDR TB care and control. The numbers of cases treated are usually reported in cohorts that commence therapy within a certain year. In this way it is hoped that treatment outcomes would be clearly understood and modifications where necessary would be implemented. WHO [1] reports increasing numbers of cases enrolled into treatment programs for MDR TB and XDR TB of 47% from 2010 to 2013. In specific terms, however, this increase has been achieved mainly in low TB burden countries. The issue of inadequate notification from weak reporting systems in most high-burden countries is also thought to contribute to only a modest increase despite all efforts made at increasing treatment coverage. Notification still plays a crucial part in the monitoring of treatment outcomes. This depends on systematic record collection, storage, and retrieval by electronic means. All these processes are not uniformly accessible in all parts of the same country and also differ significantly from country to country. Adequately trained personnel to manage this process is crucial and a vital gap.

The treatment target of 75% success outcome has only been reached by 29 out of 126 countries that have reported outcome. Only five of the 27 MDR TB high-burden countries have reached 70% treatment successes (Figure 3). The success recorded in high-burden countries is closely related to the implementation of EXPAND TB project and the scale-up of PMDT in these countries. The identified gaps to achieving treatment include unavailability of second-line TB drugs whose costs are prohibitive in many high-burden countries. This requires substantial financial and health care resources [42]. To ameliorate this, the Global Fund facility which procures TB drugs for the public sector of many countries has increased supply and dropped prices of some MDR TB drugs by 2009 [43].

#### **5.1. Clinical and laboratory monitoring**

Drugs used in the treatment of MDR TB are less effective, more toxic (90% experience side effects), used for longer duration (usually more than 2 years' duration), and are more costly than drugs used in susceptible TB (10-100 times more costly) [44]. In the 27 high-burden countries, the expenditure for MDR-TB treatment has increased cost of TB care from an

estimated 1.3 billion USD in 2010 to 4.4 billion USD by 2015 [45]. Some of the common adverse effects might also require monitoring such as ototoxicity and renal failure. There is also the need to document improvement by follow-up of bacteriologic cultures. In addition to these, cases need to be monitored because some MDR TB cases are in advanced stages of disease with other end-stage organ failures. MDR TB therapy is often characterized by low treatment completion rates due to death (15%), default (14-23%), and treatment failure (8-9%) [46]. To

<sup>(</sup>Adapted from WHO Global TB Report, 2014)

**Figure 3.** Treatment outcomes for patients diagnosed with MDR TB by WHO region, 2007-2011 cohorts.

achieve increased access, compliance, effective therapy, and retention in care, there is a need for close monitoring. This is traditionally done by hospital-based care at MDR TB referral centers for the initial therapy through health care providers. The model of care involves an initial hospitalization until sputum culture conversion followed by ambulatory phase of treatment in the nearest DOTS facility. However, hospital-based care may serve as an obstacle to access. Ambulatory-based care and community-based care have been proposed in manage‐ ment of MDR TB cases [47]. There have been some successful experiences in some countries using these methods [1]. There would be need for collaboration between these models of care especially when dealing with patients with advanced disease who may benefit for some periods from hospital-based care but would need community- or home-based care for terminal stages. Community and Ambulatory care also serve to ensure adequate contact tracing for cases of MDR and XDR TB, which is of great importance given the role of transmission of disease in spreading the MDR TB epidemic.

When contacts are traced, there is need for DST to identify appropriate second-line drugs. Currently, the diagnostic tools recommended are molecular-based testings: Line probe Assays and Xpert MTB/RIF. There is need, however, to establish quality control measures for these tests to avoid false positives and false negatives. Such tools as would ensure international standards for reference laboratories and other peripheral centers have been developed in some countries. Laboratory monitoring also includes structured assessment tools for TB microscopy, which is shared among laboratory networks.
