The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions: Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa (2011)

In the final session of the workshop, Enriqueta Bond and Salim Abdool Karim summarized the major conclusions and recommendations offered by the speakers. A panel consisting of Gail Cassell; Norbert Ndjeka, Department of Health, South Africa; Sidney Parsons,¹ Council for Scientific and Industrial Research (CSIR); Janet Tobias, Ikana Media; and Martie van der Walt, then raised additional issues and responded to questions from workshop participants. This chapter synthesizes the points made, as well as a number of individual suggestions for actions to address urgent needs related to drug-resistant TB, in the areas of epidemiology, infection control, diagnostics, treatment, pediatric TB, research needs, and the need for partnerships. It should be noted that this synthesis is offered as part of the factual summary of the workshop, and should not be construed as reflecting consensus or endorsement by the workshop, the Drug Forum, or the National Academies.

Bond stated that the alarming epidemiology of MDR and XDR TB creates a new urgency for action. Drug-resistant TB is a difficult-to-treat disease that is spreading in the community and is exacerbated by HIV infection. Growing evidence that drug-resistant TB is being transmitted from person to person supports the conclusion that the number of cases seen in southern Africa are only the visible portion of a much larger phenomenon.

Abdool Karim remarked that, as Friedland’s presentation highlighted, when patients are placed on antibiotics, pressure to select resistance grows. The experience in Tugela Ferry (Chapter 2) illustrates the person-to-person spread of drug-resistant TB and the fact that fatalities can occur quickly following infection with XDR TB, particularly among patients with HIV coinfection. Abdool Karim added that a steady increase in resistance eventually will make TDR TB a serious and common problem. Cassell commented that another disturbing observation is the 60 percent rise in XDR TB incidence rates in the Eastern Cape.

As Chaisson noted, a good definition of TDR TB in terms of either the molecular detection of resistant genes or clinical failures does not yet exist. According to Abdool Karim, given the variability in drug susceptibility testing among patients in the region, susceptibility testing on second-line drugs is not necessarily a good way to define TDR TB. Instead, the definition of TDR TB could be based on a clinical diagnosis after failure of treatment for MDR/XDR TB. A workshop participant stressed the importance of accurately measuring the magnitude and distribution of the spread of TDR TB as part of efforts to confront and reverse the epidemic.

Improved infection control and contact tracing could lower morbidity and mortality from drug-resistant TB and lead to the treatment of many more cases. In addition, the creation of a culture of safety through infection control policies could provide greatly increased protection for patients and health care workers. Abdool Karim stated that infection control should be a part of every TB intervention and needs to begin when a patient is identified, diagnosed, and hospitalized. To support infection control, there is a need for further investigation of the mechanisms and sites of the spread of TB within communities, said Abdool Karim, and once infection control measures have been implemented, it will be important to evaluate their effectiveness and make them more broadly available. Improvement in the safety of existing health care facilities is warranted, as is incorporation of infection control in the design and construction of new health care facilities.

An important problem is the lack of district nurses to visit schools and homes. Part of the solution, Cassell suggested, could be to train community workers to become specialists in infection control, with a certificate program that could offer practical training and raise the profile of the role of the community worker. When community health workers are paid, trained, and qualified, they can help ensure that everyone becomes an active participant in health care. Abdool Karim highlighted Lawn’s remarks that contact tracing should be part of all TB programs and should include TB education as a component of the intervention.

Abdool Karim added that, as noted in Thotolo’s presentation, better systems are also needed for the prevention, diagnosis, and treatment of TB and HIV for special populations, including mine workers, ex-miners, and their families; incarcerated populations; and others in difficult-to-reach congregate settings. In addition to health care interventions, it is essential to address the legal, human rights, and socioeconomic issues affecting TB and HIV control among these populations.

Abdool Karim noted that, in the discussions about diagnostics, it became clear that additional screening mechanisms and new assays, including point-of-care TB diagnostics, could transform the ability to deal with drug-resistant TB. Developing these tools will require a greatly expanded research effort. At the same time, current diagnostic approaches require safe laboratory infrastructure to protect against drug-resistant TB. Bond added that meeting the pressing need for laboratory and health care infrastructure will require ongoing, long-term capacity building.

Parsons added that unsuspected cases are a danger. These cases are causing great concern and putting health care workers, communities, and households at risk. Parsons suggested that a process for making interim diagnoses while awaiting the results of more detailed yet time-consuming diagnostics is needed to identify potential TB cases and the strains involved so health care workers can assist with managing patients in the community.

Although the cure rate of MDR TB in South Africa and surrounding countries remains uncertain, drug-resistant TB clearly is not being managed well enough, suggested Ndjeka. Abdool Karim highlighted the growing prevalence of resistance to multiple agents and the especially dire observation that increasing numbers of isolates are resistant to ten key anti-TB drugs. A workshop participant noted that the field of therapeutics for drug-resistant TB has been neglected, and there is a lack of adequate evidence to guide best practices in treatment. Thus, there is a critical need for basic, translational, clinical, and operational research in this area. As Barry suggested, the available evidence must be carefully weighed to determine the sequence in which various antibiotics should be used to avoid resistance while taking into account that cost is also an issue in the choice of drugs. In addition, Abdool Karim remarked, Friedland’s presentation highlighted that the default rate must be addressed if a reasonably high cure rate is to be achieved. Good adherence to treatment and prevention of person-to-person spread of drug-resistant TB are essential to controlling the disease.

Cassell remarked that existing drugs need to be used to maximum effect through the application of available evidence and the results of micro biological and pharmacokinetic studies. In the discussion of Schaaf’s experience in treating children with TB (Chapter 7), it was suggested that pediatric MDR and XDR TB cases should be treated for 12 months, not 24 months as stipulated by the World Health Organization (WHO). A participant observed that, given the adverse effects of second-line drugs, this is an important suggestion, but it needs to be confirmed by rigorous studies. Another suggestion was that drugs used for cross-resistance be reserved for later in treatment regimens. One workshop participant recommended that a group of experts be convened in South Africa to study side effects and cross-resistance.

Van der Walt noted that individualized regimens based on drug sensitivity testing and drug toxicity have become necessary, but in reality, management of MDR TB must be both simplified and decentralized to clinics and other sites, and treatments for TB and HIV need to be integrated. This is a challenge for clinics, one that requires translating policies into practice and applying research evidence in the field. Health care workers will also need training in the diagnosis and treatment of coinfection with HIV, according to van der Walt.

Parsons remarked that funding of $13–$15 million was recently received to increase bed capacity in South Africa. Models are being developed for treatment facilities, most of which will be built to have seven units, each with 40 beds. A minimum of 280 additional beds will be available by December 2010. These beds should be used specifically for intensive-phase treatment and for initial management of patients. However, even these new facilities will not be adequate for the hospitalization of MDR and XDR TB patients, according to Parsons. Van der Walt added that, according to South Africa’s current policy, MDR TB patients must be hospitalized until culture conversion. Hospitalization provides the patient and the family with treatment management and aids their well-being, and the additional beds will be extremely beneficial. With the increasing numbers of MDR TB cases, however, there will continue to be a shortage of beds.

A related problem is that the success rate of MDR TB treatment within 6 months at a facility is extremely low. Gandhi commented that documenting a negative culture means that 10 weeks must pass before results are returned, which doubles the duration of a typical hospital stay. Defaulters are often stigmatized, but in reality the structure makes it very difficult for them to adhere to treatment.

Parsons added that being a patient in a typical facility for 10 months or more is difficult to imagine. While the treatment is good, the hospital environment is not the best place for healing the patient. The process

needs to be humanized, with attention to patients’ dignity and comfort, good meals, and the like, and for most patients, particularly from rural areas, closer proximity to their families and loved ones. A comprehensive approach, including outpatient and community-based treatment and care management, is warranted.

Coetzee commented that patients can be treated effectively and humanely within the community. However, discharging TB patients into the community poses a risk. Patients should not be discharged until appropriate structures are in place to provide adequate treatment and care, especially since DOTS supporters are already overburdened. Gandhi stated that parts of KwaZulu-Natal Province have made the necessary transition to community-based care over the last few years. In 2007, as a result of the overwhelming burden of MDR TB, many people were receiving outpatient treatment in an informal way. Since then, care has been decentralized to centers, to communities, and to homes. When this is done in a structured way, as has been the case in Tugela Ferry, outcomes are very good. In Tugela Ferry, an intensive monitoring system is in place, with teams that visit patients’ homes. Community health workers who are doing the monitoring are paid, which has made a difference.

Parsons noted that one problem with community-based care is that many different types of communities exist in southern Africa. For example, although more study is warranted, community-based care programs appear more likely to succeed in rural communities than in informal settlements. As another example, work in the Eastern Cape to understand the dynamics of rural communities has uncovered a network of traditional leaders and healers who will need to be included in community- and home-based care. Because of the diversity of communities, Parsons said, a multidisciplinary, community-appropriate approach is needed to combat the disease.

Ndjeka remarked that the first draft of a policy to decentralize MDR TB treatment in South Africa has been circulated, but more input and consultation are needed. Because of the diversity of South Africa, each province will have different needs in implementing the policy, with a standard package of requirements being made available across all programs. More generally, said Ndjeka, the actions necessary to control the epidemic need to be clearly articulated, and a plan for moving forward, including costs, needs to be formulated at the highest levels of government.

XDR TB cases will continue to pose great therapeutic challenges. The burden of untreatable cases needs to be assessed based on the available scientific and medical evidence, as do the reasons for these cases being potentially untreatable. Van der Walt noted that new policies could raise human rights concerns and foster public panic; nevertheless, the extent of the problem needs to be communicated, and policy makers will need assistance with the ethical issues associated with untreatable cases.

Abdool Karim noted that the presentations highlighted the challenge of managing TB–HIV coinfection. He suggested that both diseases should be treated concomitantly, and systems of care for each should be better integrated. Separation of TB and HIV treatment reduces the likelihood of therapeutic success and survival of patients. As Lawn suggested, antiretro-viral therapy should be initiated immediately in all HIV-positive individuals irrespective of CD4 count to lessen vulnerability to TB infection. Studies are under way to test this hypothesis.

Finally, Ndjeka noted that WHO’s review of the South Africa TB program in 2009 found that the management of MDR TB in the country does not comply with WHO guidelines. Indeed, it does not comply with the guidelines of the country’s own Department of Health. Monitoring and evaluation are not being performed efficiently, the time required for injectable drug treatments contributes to defaulting, and patients and communities need more information about MDR TB.

According to Bond, a key problem identified during the workshop was that an increasing number of children in southern Africa are contracting drug-resistant TB, mainly through transmission. Children serve as sentinels of the burden of disease, but knowledge of the sources of transmission and of what drug regimens are best for children, as well as pregnant women, is still lacking. Policies and strategies need to accommodate specific situations and scenarios, suggested Bond.

Abdool Karim remarked that as treatment is decentralized not just into district-level facilities but into community-based care, special populations such as children and pregnant women may be easier to reach. One way to improve identification of TB in children is to take a full history of all adult TB cases, including screening for TB in child contacts. Counseling of patients, parents, and family members at every visit would provide support and information about adverse events and the importance of adherence to treatment and follow-up. TB in children could be treated according to the results of drug susceptibility tests of the adult source case until the results of the child’s own culture and drug susceptibility tests were available. Improved pediatric diagnosis is a priority, as most cases are treated empirically without microbiological confirmation and thereby go unrecognized.

Over the course of the workshop, individual participants suggested a number of research questions that, in their judgment, need to be pursued, such as the following:

• How many cases of drug-resistant TB are occurring in southern Africa that are not being diagnosed? How can diagnosis be improved?

• What is the current extent of MDR, XDR, and TDR TB? How can cases be identified more rapidly?

• What is the benefit of intensive case finding in health care facilities and community settings in terms of earlier detection, improved outcomes, and reduced transmission of drug-resistant TB?

• How should information systems be developed and implemented for the management of laboratory and surveillance data?

• What are the best available and future treatment regimens? How can clinical trials be designed and executed to test existing drugs, new drugs, and drug combinations to optimize treatment of MDR and XDR TB?

• How can TB programs be strengthened and suboptimal adherence to treatment regimens be addressed?

• What are the cure rates for MDR and XDR TB?

• What proportion of cases can be attributed to health care facilities, transmission in the community, or evolution of the organism?

• How can preventive, diagnostic, and therapeutic operations in health care facilities, including infection control, be changed and improved? How can steps to that end be taken in lower-level hospitals, and how can households be reached?

• How can the protection of health care workers be enhanced?

Bond and Abdool Karim offered closing remarks addressing the need for partnerships and multidisciplinary approaches to the problem of drug-resistant TB. Bond stated that TB is not just a medical problem. Many of the challenges involve social issues such as poverty, migrant labor, overcrowding, poor nutrition, and inadequate ventilation. Solutions entail not just new diagnostics, vaccines, and treatments but also behaviors of patients

and health care workers, health systems, political commitments, and social mobilization. Ultimately, as has been the case in developed nations, addressing issues of health disparities and social inequities that lie at the root of TB, drug-resistant TB, and HIV will be necessary to combat these convergent epidemics successfully. Actions taken today can help prevent the crisis from worsening. A sense of urgency needs to be communicated to the public and policy makers to mobilize efforts against MDR and XDR TB, said Bond. Central to fostering this agenda is the creation of a strong patient advocacy culture to champion the need for increased resources, help educate the public and policy makers, and raise awareness of human rights issues.

Abdool Karim remarked that the patient, the community, and the family must be regarded as partners if information about TB is to be communicated successfully. This information often needs to be provided proactively, with the proper balance of fear and awareness. Different advocacy partners are needed at different levels. Members of the scientific and medical communities must communicate the realities of drug-resistant TB to the public and to policy makers, and they must translate data into policies commensurate with the magnitude of the problem, said Abdool Karim.

Bond concluded that the collaboration of the IOM and ASSAf at this workshop demonstrates the need for as well as the potential benefit of engaging neutral bodies to assess the evidence; build and share expertise; and prepare medical and educational institutions to play roles in prevention, diagnosis, treatment, training, and research. Bond noted that ASSAf is in an excellent position to continue to convene groups to address the issues surrounding MDR and XDR TB and to solicit the input of a broad array of groups that include patients; health care workers; public health officials; policy makers; the academic community; and groups from the sectors of industry, government, academia, and advocacy.