**9. Programmatic management of drug resistant TB**

Policies, strategies, protocols and guidelines for TB management are well explained and articulated on the paper. However, their implementation in resource-limited sittings remains challenging due to weak case finding strategies, unclear patient tracing mechanisms (espe‐ cially defaulters), a lack of MDR-TB rapid diagnostic tools, absence of childhood TB case finding approaches and inadequate patient support services. Furthermore, specialized drug resistant TB services are limited to locations that often exclude many patients living in remote areas from receiving adequate health care. Recording systems, mainly paper-based, are time consuming for health care providers, and therefore reduces time for quality care. Addressing these many challenges requires collaboration from different components of national TB control programmes. These components include case detection, treatment, prevention, surveillance, and adequate monitoring/evaluation of the programme's performance. Such objectives are the backbone of DOTS-Plus management programme introduced by the WHO in 1998 [48]. Many DOTS-plus pilot projects provided evidence base for this strategy in the management of drug resistant TB [59,89,90]. Based on the success of pilot projects, the WHO issued in 2006 guide‐ lines for what is now called programmatic management of drug-resistant TB (PMDT), which were recently updated with extra focus on the detection and treatment of drug-resistant TB in resources limited settings [91]. Priority topics identified in the new WHO document are:


PMDT is currently highly supported by funding for MDR-TB treatment, which has dramati‐ cally increased in the past few years. Multi-billion dollar funds are now available through governments and donors, including the Global Fund to Fight AIDS, Tuberculosis and Malaria, UNITAID and the GLC committee [90]. Such fund was essential to demonstrate the feasibility and effectiveness of PMDT in many resource-limited settings, where it is needed most [92]. The current status of MDR-TB epidemic requires urgent moving of PMDT beyond this pilot project stage in order to respond to the call of Stop TB for the treatment of 1.6 million MDR-TB patients in the near future [93].

Although the last WHO document on TB control provides comprehensive guidelines for good PMDT, The WHO recognizes that many crucial management issues remain to be addressed. Thus, during the development of the recent PMDT document, a review published in 2008 [92] revealed some important gaps in knowledge that need to be addressed in order to optimize PMDT:


Itisalsoimportanttonotethatsocialstigmaanddiscriminationarestillmajorobstaclesforaccess to TB care services in many countries [94,95]. Similarly, financial issues and geographical accessibility is also a barrier for the continuation of treatment [96,97]. Misconceptions about TB are highly prevalent, which discourages seeking help in time or encourage those with TB to seek help from traditional healers [98]. Therefore national TB programmes must also include specific strategies to combat these issues in order to optimize the implementation of good PMDT.

Diversity in the epidemiology of MDR-TB poses a challenge for its management in various settings [99]. Ideally, TB management approaches need to be adapted to each particular setting. However it is possible to build a minimal package that could be adapted to specific countries wishing to implement proper TB management approaches. Accordingly, in 2003 a Stop TB Working Group on DOTS-Plus for MDR-TB identified key research questions to be answered in order to scale up the management of all forms of drug-resistant TB and to maximize its public health impact [99]. The working group felt that evidence is needed to address the following questions:

	- **◦** laboratory and treatment provision

disease by definition. Therefore, special effort should be made to explain the nature of the

**•** Healthcare expenditures are a very important factor that affects compliance. TB patients often feel that the cost of long-term treatment would be a financial burden, which definitely threatens therapy compliance. Therefore, health care personnel should discuss the patient's resources and help identifying sources that might provide financial assistance to low-

Overall providing care centered on patient needs and expectations is a key component for the

Policies, strategies, protocols and guidelines for TB management are well explained and articulated on the paper. However, their implementation in resource-limited sittings remains challenging due to weak case finding strategies, unclear patient tracing mechanisms (espe‐ cially defaulters), a lack of MDR-TB rapid diagnostic tools, absence of childhood TB case finding approaches and inadequate patient support services. Furthermore, specialized drug resistant TB services are limited to locations that often exclude many patients living in remote areas from receiving adequate health care. Recording systems, mainly paper-based, are time consuming for health care providers, and therefore reduces time for quality care. Addressing these many challenges requires collaboration from different components of national TB control programmes. These components include case detection, treatment, prevention, surveillance, and adequate monitoring/evaluation of the programme's performance. Such objectives are the backbone of DOTS-Plus management programme introduced by the WHO in 1998 [48]. Many DOTS-plus pilot projects provided evidence base for this strategy in the management of drug resistant TB [59,89,90]. Based on the success of pilot projects, the WHO issued in 2006 guide‐ lines for what is now called programmatic management of drug-resistant TB (PMDT), which were recently updated with extra focus on the detection and treatment of drug-resistant TB in resources limited settings [91]. Priority topics identified in the new WHO document are:

**•** Case-finding through use of rapid molecular tests; investigation of contacts and other high-

PMDT is currently highly supported by funding for MDR-TB treatment, which has dramati‐ cally increased in the past few years. Multi-billion dollar funds are now available through governments and donors, including the Global Fund to Fight AIDS, Tuberculosis and Malaria, UNITAID and the GLC committee [90]. Such fund was essential to demonstrate the feasibility and effectiveness of PMDT in many resource-limited settings, where it is needed most [92].

**•** Regimens for MDR-TB and their duration in HIV-positive and HIV-negative patients;

disease with a particular focus on the asymptomatic stage of TB.

**9. Programmatic management of drug resistant TB**

income patients.

risk groups;

**•** Models of care.

**•** Monitoring during treatment;

success of TB control programmes.

218 Tuberculosis - Current Issues in Diagnosis and Management


**•** How should infected contacts of DR-TB patients be managed?

Ensuring that these research questions are addressed is the responsibility of all parties involved in the management of MDR-TB. If adequately addressed, they will generate a solid evidencebase to support existing WHO guidelines.

prevention and communication [102]. Therefore, many countries will continue to experience

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 221

A systematic review of factors that contribute to non-adherence [103] indicate that many social and economic barriers prevent patients from successfully completing their treatment. A wide range of interacting factors impact on the patient behavior, which is subject to changes during the course of treatment. According to Doctor Without Borders [104], one of the major chal‐ lenges faced by drug resistant TB patients is the long and arduous treatment period, which can involve large numbers of tablets each day, as well as injectables, both expensive and not always easily available or accessible. Low-income patients living in remote area often struggle to reach specialized TB clinics, in particular when the harsh winter weather affect severely the country's road network and compromises the transportation system. Therefore, in the absence of efficient patient-centered approaches, it is almost impossible to convince patients to continue

In the Russian Federation, the proportion of MDR-TB patients defaulting from treatment has increased from 12% in 2001 to almost 30% in 2004 [105], despite the expansion of the DOTS programme to include the treatment of drug resistant TB in 2000. This failure to control drug resistant TB was mainly attributed to the absence of patient-centered strategies adapted to many risk factors for non-adherence such as poverty, unemployment, homelessness, alcohol‐ ism, drug abuse and mental illness, to name a few [105]. In response to the alarming proportion of defaulters, a novel patient-centered TB treatment delivery programme (Sputnik) was introduced in Tomsk City [106]. Sputnik care providers accompanied patients through treatment by remaining responsible for patients from the time of enrollment in the programme until the end of treatment (Box 4). The programme paid a particular attention to care giving. In addition to clinical preparation, nurses received a comprehensive training on how to care for patients facing a myriad of biosocial challenges. Indeed, a review of the emotional support that nurses provide to patients living with MTR-TB [107] concluded that nursing of TB patients could be improved with an integrated approach where the nurses are responsible for treating not only the patient, but also ambient factors that affect health, such as family and community.

substantial difficulties in treating drug resistant TB patients at high risk of defaulting.

this forceful effort every day for up to two years.

A high nurse-to patient ratio (2:15),

Easier access to specialists

**Box 4.** Sputnik programme package

improving TB patient adherence.

More staff time per patient to facilitate bonding and defaulter searching Provision of portable phones to nurses, which increases flexibility

procuring documentation required to access social services

Expanded social and psychological support, which included clothing and assistance with

The application of the Sputnik programme led to a mean adherence of 79.0% and a cure rate of 71.1%, indicating that adapted patient-centered approaches contributed significantly to

The integration of PMDT into existing TB control programmes beyond the limited pilot project phase has become a critical emergency in order to respond to the increasing spread of MDR/ XDR-TB worldwide. However, analysis of current WHO strategies by many experts in the field of TB management [100] suggest that successful PMDT will still require:


#### **10. Patient centered care approach**

Acquiring adequate care for TB is becoming increasingly complex and costly when patients are infected with drug resistant Mtb. This problem is further amplified when patient access to health care centers is limited and adequate patient-clinician relationships are absent. To address this issue Stop TB included patient centered approach as one of its important under‐ lying principles. It insists on respect for patients right as individuals and as partners in TB care and control. Therefore what are usually characterized as 'patient problems' need to be reconfigured into solidarity with patients and programmatic challenges. Patient-centeredness can be traced back to the adoption of the right to health as part of the International Human right declaration in 1948 [101], but it is only in the 1990s, as result of the community reaction to the AIDS epidemic, that its importance has been perceived. Since then, the rise in prevalence of all forms of TB in HIV individuals has become one of the major stimulating factors for implementation of patient-centered approaches in TB care.

Promoting patient-centered case management involves assessing each TB patient's needs and identifying a treatment plan that ensures the completion of therapy. Policies and guidelines for patient-centered approaches are currently widely distributed. Unfortunately, their application in the field is progressing very slowly. Applying a patient-centered approach takes time and requires effort at many levels. It is a new way of thinking, teaching, providing care, prevention and communication [102]. Therefore, many countries will continue to experience substantial difficulties in treating drug resistant TB patients at high risk of defaulting.

A systematic review of factors that contribute to non-adherence [103] indicate that many social and economic barriers prevent patients from successfully completing their treatment. A wide range of interacting factors impact on the patient behavior, which is subject to changes during the course of treatment. According to Doctor Without Borders [104], one of the major chal‐ lenges faced by drug resistant TB patients is the long and arduous treatment period, which can involve large numbers of tablets each day, as well as injectables, both expensive and not always easily available or accessible. Low-income patients living in remote area often struggle to reach specialized TB clinics, in particular when the harsh winter weather affect severely the country's road network and compromises the transportation system. Therefore, in the absence of efficient patient-centered approaches, it is almost impossible to convince patients to continue this forceful effort every day for up to two years.

In the Russian Federation, the proportion of MDR-TB patients defaulting from treatment has increased from 12% in 2001 to almost 30% in 2004 [105], despite the expansion of the DOTS programme to include the treatment of drug resistant TB in 2000. This failure to control drug resistant TB was mainly attributed to the absence of patient-centered strategies adapted to many risk factors for non-adherence such as poverty, unemployment, homelessness, alcohol‐ ism, drug abuse and mental illness, to name a few [105]. In response to the alarming proportion of defaulters, a novel patient-centered TB treatment delivery programme (Sputnik) was introduced in Tomsk City [106]. Sputnik care providers accompanied patients through treatment by remaining responsible for patients from the time of enrollment in the programme until the end of treatment (Box 4). The programme paid a particular attention to care giving. In addition to clinical preparation, nurses received a comprehensive training on how to care for patients facing a myriad of biosocial challenges. Indeed, a review of the emotional support that nurses provide to patients living with MTR-TB [107] concluded that nursing of TB patients could be improved with an integrated approach where the nurses are responsible for treating not only the patient, but also ambient factors that affect health, such as family and community.


**Box 4.** Sputnik programme package

**•** How should infected contacts of DR-TB patients be managed?

of TB management [100] suggest that successful PMDT will still require:

treatment regimens as well as of candidate second-line drugs;

ing treatment adherence, and improving infection control;

**•** New and improved tools for drug resistance testing;

treatment of contacts of patients with DR-TB.

implementation of patient-centered approaches in TB care.

**10. Patient centered care approach**

base to support existing WHO guidelines.

220 Tuberculosis - Current Issues in Diagnosis and Management

settings;

Ensuring that these research questions are addressed is the responsibility of all parties involved in the management of MDR-TB. If adequately addressed, they will generate a solid evidence-

The integration of PMDT into existing TB control programmes beyond the limited pilot project phase has become a critical emergency in order to respond to the increasing spread of MDR/ XDR-TB worldwide. However, analysis of current WHO strategies by many experts in the field

**•** Clinical trials to test the efficacy and effectiveness of simplified and shorter second-line

**•** New and improved strategies for identifying patients with drug-resistant disease, promot‐

**•** Better epidemiological data to explain geographic variations in occurrence of drug resist‐ ance and to identify the greatest contributors to development of drug resistance in specific

**•** Clinical trials to test the efficacy and effectiveness of new regimens for prophylactic

Acquiring adequate care for TB is becoming increasingly complex and costly when patients are infected with drug resistant Mtb. This problem is further amplified when patient access to health care centers is limited and adequate patient-clinician relationships are absent. To address this issue Stop TB included patient centered approach as one of its important under‐ lying principles. It insists on respect for patients right as individuals and as partners in TB care and control. Therefore what are usually characterized as 'patient problems' need to be reconfigured into solidarity with patients and programmatic challenges. Patient-centeredness can be traced back to the adoption of the right to health as part of the International Human right declaration in 1948 [101], but it is only in the 1990s, as result of the community reaction to the AIDS epidemic, that its importance has been perceived. Since then, the rise in prevalence of all forms of TB in HIV individuals has become one of the major stimulating factors for

Promoting patient-centered case management involves assessing each TB patient's needs and identifying a treatment plan that ensures the completion of therapy. Policies and guidelines for patient-centered approaches are currently widely distributed. Unfortunately, their application in the field is progressing very slowly. Applying a patient-centered approach takes time and requires effort at many levels. It is a new way of thinking, teaching, providing care,

The application of the Sputnik programme led to a mean adherence of 79.0% and a cure rate of 71.1%, indicating that adapted patient-centered approaches contributed significantly to improving TB patient adherence.

In 1998, the Centers for Disease Control and Prevention (CDC) and the Institute of Medicine of the National Academy of Sciences conducted a study to determine if TB eradication in the United State was feasible. The resulting report "*Ending Neglect: The Elimination of Tuberculosis in the United States*" concluded that TB elimination would require "aggressive and decisive action beyond what was in effect." One of the top objectives of the new CDC plan is to ensure that patient-centered case management and monitoring of treatment outcomes are the standard of care for all TB patients [108]. In particular, the CDC guidelines recommend all patients with active TB must be tested for HIV infection and that all patients double infected with Mtb and HIV infection must be appropriately and adequately treated. To ensure adher‐ ence to treatment, the CDC recommend the inclusion of multiple enablers (e.g., transportation vouchers and housing for the homeless) and incentives that will motivate the patient (e.g., food coupons), and other treatment enhancers such as alternative treatment delivery sites, and strategies to overcome social and cultural barriers.

**11. Drug resistant TB infection (tansmission) in the community and**

population is already infected with TB, a situation that appear to be stationary [111].

Because MDR strains carry mutations in major metabolic activities, in particular INH resistant strains lacking catalase activity [112], some researchers have suggested that they may be less virulent and less transmissible [113]. Contrasting with this hypothesis, the epidemic that occurred in New York City in the 1990s [114,115], which affected mainly HIV-infected persons, proved that MDR strains are highly virulent and transmissible. Current data on MDR TB prevalence in Africa, Eastern Europe and Asia [116] provides further evidence of this phe‐ nomenon. Drug resistant TB can be transmitted in virtually any setting but healthcare settings, correctional institutions and homeless shelters have an increased risk of transmission. The level of drug resistance TB in hospital settings varies according to local TB prevalence. For instance an university hospitals in Paris (France), reported MDR rates of respectively 1.2% among TB cases [117], while in university hospitals in Manila (Philippine), this figure was an alarming

It is generally thought that the emergence of drug-resistant TB (usually termed acquired) occurs in settings where patients fail to adhere to proper treatment regimens or receive inadequate treatment. It is difficult to assign the current magnitude of the epidemic to acquired resistance alone. Another mechanism for the perpetuation of resistance, which has largely been neglected in the development of TB control programmes, is the direct transmission of drugresistant strains (called primary or transmitted resistance) [119]. In the 2006 XDR-TB outbreak in KwaZulu-Natal (South Africa), 52 of 53 people who contracted the disease (all of them HIV infected) died within weeks [120]. This outbreak received international attention because 85 percent of infected patients had genetically similar XDR strain, indicating that resistance was likely transmitted rather than acquired. Consistent with these findings, a study conducted in Tomsk (Siberia) –a setting where HIV infection is not widespread and effective TB treatment is available– to identify factors leading to increases in MDR-TB cases [121], revealed that a patient was six times more likely to develop MDR-TB if hospitalized for drug-susceptible TB than if not hospitalized. These results strongly suggest that nosocomial transmission of TB rather than resistance (acquired predominantly by nonadherence) is increasingly responsible

for the rising MDR TB case rates in Russia and probably in many other places.

TB is a highly contagious disease, acquired mainly through inhalation of airborne aerosols. Infection can occur by inhaling as few as 5-10 living bacteria. People with active TB infection spread the bacterium not only by coughing and sneezing but also by spitting, speaking, singing or laughing. The infectiousness of a TB patient is directly related to the number of droplet nuclei carrying Mtb that are expelled into the air. These droplets rapidly evaporated to form tiny particle nuclei, which could remain airborne for several days [110]. Given this mode of propagation, a person with active TB can spread the germs to up to 15 people in a year, if left untreated [4]. Therefore the process of TB spread also needs to be controlled in order to successfully combat the TB epidemic. In this regards, Nardell recommend the term "trans‐ mission control of TB" instead of "infection control of TB", since a third of the world's

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 223

**hospitals**

53.5% [118].

Addressing social and economic barriers definitely increases patient access to adequate TB care. However, health education would also strengthen patient-centered approaches. Under‐ standing an illness and how it affects ones life, as well as available treatment options, are necessary for a patient and community to take an active role in TB management. With input from community health professionals from several countries, a literacy tool kit "Within Our Reach: A TB Literacy Toolkit" was developed in 2009 for health educators, outreach workers, counselors, and supervisors who provide services to TB patients [109] and (Box 5).


#### **Box 5.** Supporting objectives of the TB Literacy Toolkit

The tools are designed to educate TB and HIV patients, their caregivers, and their communities about TB and what it takes to complete a full course of TB treatment. The kit developers suggest that individual sessions should be conducted with flipcharts between the health provider and patient, and videos should be played in a waiting area or during community education events.

Patient-centeredness has become a central approach towards realizing universal access for all patients to efficient TB care. However scaling up this approach is progressing slowly in high TB-burden countries and is mainly challenged by the socio-economic determinants of knowl‐ edge and attitudes about TB among health care providers and the general population. Therefore optimal patient-centeredness approach requires collaborative efforts between all organizations serving TB patients to ensure that health care providers, policy makers, com‐ munity leaders and the public are knowledgeable about TB disease.
