**8. Compliance issues from patients and health care providers**

The treatment for MDR-TB is long and complex and relies on a handful of antibiotics with uncertain efficacy. The WHO has launched an 8-point plan to ensure optimal management of XDR-TB patients with currently available drugs (Box 2). However, guidelines do not always translateeasilyintorealworldpractice.Inadditiontodirectlyobservedtreatment,what support can be offered to convince a patient to continue painful treatment? And how should patients who have exhausted all treatment options with existing second-line drugs be cared for?


#### **Box 2.** WHO 8-point plan

Given the lack of clear evidence in support of preventive therapy, the WHO does not recom‐ mend universal use of second-line drugs for chemoprophylaxis in MDR-TB contacts. Current guidance for the management of drug resistant TB contacts are largely based on expert opinions, which do not reject nor support provision of preventive therapy with the currently available drugs. In this context a guidance document presenting the most up-to-date evidence and expert opinion regarding the management of contacts of MDR- and XDR-TB patients has been recently proposed (March 2012) by the European Centre for Disease Prevention and Control (ECDC) [76]. Box 1 summarizes key recommendations provided by ECDC document.

**Which factors should be evaluated to decide whether to provide preventive therapy to MDR TB contacts**

the source case of infection; and the contact's risk for adverse drug events if initiating preventive therapy.

**Are there any specific risk groups to whom special attention should be paid?**

the drug susceptibility pattern of the source case's likely infecting strain;

ensure that the treatment costs for the patient are covered.

preferable, given the currently available drugs and evidence.

**Which arrangements should be in place if preventive therapy is considered?**

not given preventive therapy should be followed-up by careful clinical observation. Follow-ups should be performed according to existing national guidelines.

When evaluating an MDR TB contact and deciding between the two options (to provide preventive therapy and/or careful clinical observation and information), an overall individual risk assessment should be conducted, taking into consideration the following: the MDR TB contact's risk for progression to TB disease; the drug susceptibility pattern of

Children below the age of five years and immunocompromised persons in close contact with MDR TB patients and considered to have LTBI are at particular risk of progressing to TB disease. These risk groups might benefit from preventive therapy. The preventive therapy may be interrupted if, based on further examination, infection is found to

Persons over five years of age in close contact with MDR TB patients and considered to have LTBI could also be

If the decision is made to put an individual on preventive therapy, the selection of the drugs should be based on:

the selection of single or multiple drugs and the duration of treatment will depend on the availability of drugs with bactericidal activity for the particular infecting strain; alternatively, the decision can follow national guidelines.

If preventive therapy is considered by the expert physician or other healthcare provider, national legislation should

If preventive therapy is considered to be relevant for a particular individual, careful clinical monitoring and follow-up is essential for the detection of drug-adverse events and signs of TB disease if the preventive therapy is not effective.

As the currently available treatment options are very limited for XDR TB, it is likely that the risks of preventive therapy outweigh the benefits for contacts of XDR TB patients. Thus, the option to inform and observe the contacts will be

**How should health authorities conduct follow-ups for MDR TB and XDR TB contacts suspected to have LTBI?** All MDR TB and XDR TB contacts considered to have LTBI who, after a comprehensive individual risk assessment, are

All persons in contact with MDR TB or XDR TB (after exclusion of TB disease) should be informed about the risks and symptoms, carefully observed, and provided with easy access to a specialized TB clinic in case of symptoms between

considered for preventive therapy if the individual risk assessment indicates this course of action.

the potential adverse events in individual patients, taking into account age and other risk factors;

**considered to have LTBI?**

214 Tuberculosis - Current Issues in Diagnosis and Management

local patterns of drug resistance;

**Specific opinions for XDR TB contacts**

be unlikely.

In many cases, MDR-TB treatment results in poor compliance with subsequent development of further drug resistance (i.e. XDR-TB), which leaves infected patients, namely HIV positive individuals, virtually untreatable using currently available drugs. The WHO defines a

<sup>1.</sup> Strengthen quality of basic TB and HIV/AIDS control

<sup>2.</sup> Scale up programmatic management of MDR-TB and XDR-TB

defaulter as being off drugs for more than 8 weeks after completing at least one month of treatment [81]. It is an operational definition to guide physicians in the decision of using a retreatment or second line regimen if the patient comes back to the health facility after defaulting. However it is imperative that health providers understand predictive factors for treatment default so that they can implement additional measures to target the population at risk. In this context, a recent review (2010) assessed TB treatment compliance and the factors predictive for poor adherence based on the analysis of 4 studies performed in Sub-Saharan Africa in the last 10 years [82]. The review revealed a high proportion of patients defaulting, which varied between 11.3% and 29.6%. Defaulting appears to be associated with many factors such as distance from the hospital, not being on the first course of TB medications, lack of repeated smears, drug-associated side effects, transportation difficulties, absence of family support and poor knowledge about TB disease and its treatment. Thus it is unfortunate that health care institutions continue to blame vulnerable and powerless patients who are unable, for this multitude of reasons, to comply with the treatment. Since distance from health care centers is a major factor, national programmes should at least consider making drugs more widely available, by either providing TB treatment in smaller health centers, or organizing mobile TB clinics, especially in rural areas.

with TB cases. They prescribe too few drugs or the wrong drugs, give inadequate doses of drugs, or prescribe an inadequate duration of treatment [86]. The standardized method of determining cure is based on bacteriologic laboratory testing for the growth of Mtb on culture media. However many health care providers rely on clinical observation to determine treatment outcome [87], either because of shortages in equipment and adequate infrastructure or because they trust their own observation above test results. Such mismanagement is a major cause of acquired drug resistance and treatment failure. On the other hand, on many occasions lung cancer was misdiagnosed and treated as sputum negative TB, a medical error due to high

4. Enhancing public health response while addressing the social determinants of health

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 217

It is therefore important that healthcare personnel at the forefront in the fight against TB acquire appropriate and state-of-the art training on TB management. In this regards, the WMA launched in its website a new online refresher course for care providers in many languages. The course provides basic clinical care information for TB including the latest diagnostics, treatment and information about multidrug-resistant TB. It also provides information on how to ensure patient adherence and infection control and includes many aspects of TB care and management. Dr. Julia Seyer, medical adviser at the WMA, said: 'When we started an online MDR-TB training course in 2006, we discovered that many physicians were missing the most

In summary, both the lack of patient adherence to treatment and deficiencies in programme managements are compromising the effectiveness of MDR TB treatment and the interaction of these two issues raises further the barrier to achieving efficient TB control. From the various

**•** Addressing therapy-related adverse events should contribute positively in improving patient's compliance. Therefore, potential adverse effects must be carefully evaluated when designing the therapy plan. Alternative plans should be discussed with the patients to

**•** Healthcare system quality is significantly related to compliance. Long waiting times and unhappy experiences during clinic visits are frequent complains from TB patients. A healthcare system that considers patient satisfaction would enhance patient adherence to

**•** Compliance is also affected by the characteristics of TB disease. While non-adherence is not a major issue when treating short duration infections, this is not the case for TB, a chronic

opinions on the issue of non-compliance it can be concluded that:

minimize the possibility of therapeutic barriers.

TB prevalence and radiological similarities [88].

1. Adherence research

3. Supporting communities

5. Embracing palliative care 6. Advocacy for research

**Box 3.** Additional considerations to the WHO 8-point plan

2. Building the evidence-base for infection control practices

basic knowledge about normal TB'.

TB treatment.

It is time to admit that TB disease is not a 'patient problem' by default but rather a social and community responsibility that requires close cooperation and collaboration at all levels of the health care system. Forcing a patient to continue an ineffective, toxic regimen that results in uncertain outcome also raises an ethical issue yet to be resolved. Ereqat and colleagues report‐ ed a recent case of a MDR-TB patient who withdrew from treatment after 2 years while still sputum-positive [83]. Due to persistent efforts to force compliance, the patient disappeared carryingwithhimthepotentialtoinfectallpeoplewithwhomhehascontact.Theauthorssuggest consulting with legal practitioners about the legality of enforced treatment and how patients who refuse or interrupt treatment can be managed to protect them and their potential con‐ tacts. It is obvious that in the absence of alternative treatment, this approach might end up with a response to TB without medication (i.e incarceration). For this type of recalcitrant patients, other TB specialists [84,85] propose directing efforts towards exploring possible regimens with better chances of cure and securing an appropriate living environment. Indeed, the threat of incarceration will just encourage patients to disappear and propagate the disease. Providing supportiveaccommodationwithaccesstocounselingandpalliativecare,whenrequired,should reduce the risk of transmission to others [84]. Overall, until newer drugs become available, management that balances the risk of disease spread with individual human rights is likely to be more humane and less costly to health services compared with involuntary detention [85]. In this context, Upshur and Colleagues propose a list of additional considerations to the manage‐ ment of drug resistant TB as moral correlates to the current WHO 8-point plan (Box 3).

A paramount issue in TB management is that in many countries with limited resources most of the healthcare is provided by the private sector where the number of qualified medical personnel to prevent and treat drug resistant TB remains very limited. In this regard, the World Medical Association (WMA, http://www.wma.net) revealed that many doctors are no longer being taught to diagnose and treat TB. Thus, private physicians make frequent errors in dealing 1. Adherence research

defaulter as being off drugs for more than 8 weeks after completing at least one month of treatment [81]. It is an operational definition to guide physicians in the decision of using a retreatment or second line regimen if the patient comes back to the health facility after defaulting. However it is imperative that health providers understand predictive factors for treatment default so that they can implement additional measures to target the population at risk. In this context, a recent review (2010) assessed TB treatment compliance and the factors predictive for poor adherence based on the analysis of 4 studies performed in Sub-Saharan Africa in the last 10 years [82]. The review revealed a high proportion of patients defaulting, which varied between 11.3% and 29.6%. Defaulting appears to be associated with many factors such as distance from the hospital, not being on the first course of TB medications, lack of repeated smears, drug-associated side effects, transportation difficulties, absence of family support and poor knowledge about TB disease and its treatment. Thus it is unfortunate that health care institutions continue to blame vulnerable and powerless patients who are unable, for this multitude of reasons, to comply with the treatment. Since distance from health care centers is a major factor, national programmes should at least consider making drugs more widely available, by either providing TB treatment in smaller health centers, or organizing

It is time to admit that TB disease is not a 'patient problem' by default but rather a social and community responsibility that requires close cooperation and collaboration at all levels of the health care system. Forcing a patient to continue an ineffective, toxic regimen that results in uncertain outcome also raises an ethical issue yet to be resolved. Ereqat and colleagues report‐ ed a recent case of a MDR-TB patient who withdrew from treatment after 2 years while still sputum-positive [83]. Due to persistent efforts to force compliance, the patient disappeared carryingwithhimthepotentialtoinfectallpeoplewithwhomhehascontact.Theauthorssuggest consulting with legal practitioners about the legality of enforced treatment and how patients who refuse or interrupt treatment can be managed to protect them and their potential con‐ tacts. It is obvious that in the absence of alternative treatment, this approach might end up with a response to TB without medication (i.e incarceration). For this type of recalcitrant patients, other TB specialists [84,85] propose directing efforts towards exploring possible regimens with better chances of cure and securing an appropriate living environment. Indeed, the threat of incarceration will just encourage patients to disappear and propagate the disease. Providing supportiveaccommodationwithaccesstocounselingandpalliativecare,whenrequired,should reduce the risk of transmission to others [84]. Overall, until newer drugs become available, management that balances the risk of disease spread with individual human rights is likely to be more humane and less costly to health services compared with involuntary detention [85]. In this context, Upshur and Colleagues propose a list of additional considerations to the manage‐

ment of drug resistant TB as moral correlates to the current WHO 8-point plan (Box 3).

A paramount issue in TB management is that in many countries with limited resources most of the healthcare is provided by the private sector where the number of qualified medical personnel to prevent and treat drug resistant TB remains very limited. In this regard, the World Medical Association (WMA, http://www.wma.net) revealed that many doctors are no longer being taught to diagnose and treat TB. Thus, private physicians make frequent errors in dealing

mobile TB clinics, especially in rural areas.

216 Tuberculosis - Current Issues in Diagnosis and Management


with TB cases. They prescribe too few drugs or the wrong drugs, give inadequate doses of drugs, or prescribe an inadequate duration of treatment [86]. The standardized method of determining cure is based on bacteriologic laboratory testing for the growth of Mtb on culture media. However many health care providers rely on clinical observation to determine treatment outcome [87], either because of shortages in equipment and adequate infrastructure or because they trust their own observation above test results. Such mismanagement is a major cause of acquired drug resistance and treatment failure. On the other hand, on many occasions lung cancer was misdiagnosed and treated as sputum negative TB, a medical error due to high TB prevalence and radiological similarities [88].

It is therefore important that healthcare personnel at the forefront in the fight against TB acquire appropriate and state-of-the art training on TB management. In this regards, the WMA launched in its website a new online refresher course for care providers in many languages. The course provides basic clinical care information for TB including the latest diagnostics, treatment and information about multidrug-resistant TB. It also provides information on how to ensure patient adherence and infection control and includes many aspects of TB care and management. Dr. Julia Seyer, medical adviser at the WMA, said: 'When we started an online MDR-TB training course in 2006, we discovered that many physicians were missing the most basic knowledge about normal TB'.

In summary, both the lack of patient adherence to treatment and deficiencies in programme managements are compromising the effectiveness of MDR TB treatment and the interaction of these two issues raises further the barrier to achieving efficient TB control. From the various opinions on the issue of non-compliance it can be concluded that:


disease by definition. Therefore, special effort should be made to explain the nature of the disease with a particular focus on the asymptomatic stage of TB.

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-

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 219

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

**•** Lack of high quality evidence from randomized controlled trials for optimizing treatment regimens in patients with MDR-TB, including the best combination of drugs and treatment

**•** The therapy for symptomatic relief from adverse reactions linked to second-line TB drugs. 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

**•** How can regimens be selected (either at the programme or at the individual patient level) based on standardized and reproducible DST that adequately reflects *in vivo* responsiveness

**•** How can setting specific treatment strategies be optimized with respect to effectiveness, complexity (dosing, eligibility, duration, and monitoring of outcome and side effects),

**•** What is the minimum infrastructure needed to scale-up PMDT, in terms of:

**◦** prevention of transmission to other patients and health care workers

**•** Very limited information about treatment and management of pediatric MDR-TB; **•** Identification of the most effective chemoprophylaxis for contacts of MDR-TB cases;

TB patients in the near future [93].

PMDT:

duration;

following questions:

to treatment?

safety, adherence, and affordability?

**◦** laboratory and treatment provision

**◦** efficient and equitable patient selection

**•** 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 lowincome patients.

Overall providing care centered on patient needs and expectations is a key component for the success of TB control programmes.
