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10 Convergence of Science and Policy to Create a Call for Action During the final session of the workshop, Salmaan Keshavjee, Gerrit Coetzee, Janet Tobias, Paul Farmer, Carlos Pérez-Vélez, Peter Cegielski, and Mingting Chen summarized the major themes that emerged from the pre- sentations and discussion in the areas of key challenges, infection control, diagnostics, treatment, high-quality care for all, and linkages from science to clinical care. KEY CHALLENGES Keshavjee began by observing that the past decade has seen gains in policy, diagnostics, the extension of treatment to more patients, drug deliv- ery mechanisms, and ambulatory care, but major gaps remain. More than 93 percent of patients do not receive treatment, and fewer than 1 percent are being treated with quality-assured drugs in programs of sufficient qual- ity. The results from the PETTS (see Chapter 6) are particularly disturbing, he said, showing that many patients exhibit resistance to second-line drugs at baseline. In part, this finding reflects the fact that patients often seek care and take drugs periodically while they are awaiting treatment. Data from South Africa and China confirm these high levels of drug resistance. The data from China showing 25 percent resistance to fluoro- quinolones—the backbone of the second-line drug regimen—are startling, said Keshavjee. Coetzee observed that South Africa has been hit by multiple “avalanches,” including the HIV epidemic, drug-resistant TB, and a rapidly migrating population. In response, the country has been deploying line probes to identify MDR TB patients early, but this effort has caused the 101

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102 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA health care system in South Africa to be severely overburdened. In contrast, some of the data from Russia are promising, he said. TB has declined in prisons and in the civilian sector. Still, the total numbers of TB patients in the country are staggering. The situation with respect to the treatment and diagnosis of children also remains stark, said Keshavjee. Representing 10−25 percent of patients, children demonstrate the complexity of the challenge, especially since diag- nostics still cannot identify many cases of pediatric TB. Keshavjee empha- sized the importance of making children a priority in the fight against TB. The addition of MDR TB cases to the current pool of TB cases is cumu- lative, said Keshavjee. Patients are being diagnosed earlier and are being given effective treatment, but for that reason they also are present in the health care system longer. And because MDR TB is much more expensive to treat than drug-susceptible TB, budget pressures are severe. Moreover, the data regarding amplification of resistance are compel- ling, according to Keshavjee. If the right regimen is not initiated from the beginning, resistance is amplified. A one-size-fits-all approach is not advis- able given the existing data. But ensuring that people are receiving the treatment they require through tailored therapy will not be easy. Finally, Keshavjee emphasized that TB is striking particularly hard in socially vulnerable populations, such as people who abuse alcohol (see Chapter 7). Delivering care to these populations is a daunting task, although it can be accomplished through careful planning. Keshavjee cited PEPFAR as a model for what can be accomplished. In the case of PEPFAR, a disease was viewed as an emergency, resources were made available, boots were put on the ground, and outcomes were produced. These outcomes may not be perfect, but people are on treatment. Coetzee stressed that countries need to strengthen their health systems to deal with the TB epidemic, but it is difficult for them to establish com- plex laboratory networks, multiyear treatment programs, monitoring of adverse effects, and so on. In South Africa in particular, for example, it is very difficult to scale up successful approaches with limited resources, espe- cially limited human resources. Coetzee explained that money can usually be found without difficulty through such sources as PEPFAR; the biggest problem is finding and attracting the individuals to carry out the work. Keshavjee suggested that the provision of technical assistance needs to change. Many places in the world require experts who can work with the local system for months to build up a health infrastructure, yet long-term onsite technical assistance is rare. Even New York, with a well-developed health system, required many inputs to counter TB.

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103 CONVERGENCE OF SCIENCE AND POLICY INFECTION CONTROL Keshavjee noted that infection control remains a major problem, as demonstrated by the data from Shanghai (see Chapter 4). Until patients are started on treatment, they are infectious. Information management also remains a problem in many places, with implications for both diagnosis and treatment (see Chapter 5). Systems to manage data and get results back to clinicians are still lacking in many places. Keshavjee pointed to some positive developments with regard to infec- tion control. In China, for example, a country with a complex health system and many patients, the fact that the government is combating TB is grounds for hope (see Chapter 2). DIAGNOSTICS Farmer noted that diagnostic methods are linked to both care and pre- vention. For example, a molecular diagnostic for rifampin resistance would be invaluable, since one mutation describes about 80 percent of rifampin resistance, and rifampin resistance stands as a marker for MDR TB. Yet such a diagnostic is not yet widely available, although Farmer commended the Russian TB community for working hard to improve the quality of diagnostics (see Chapter 3). Current diagnostics are inadequate, said Farmer, and even recently introduced diagnostics have weaknesses. While the EXPAND-TB Program launched by the WHO through the Global Laboratory Initiative is an important step toward ensuring that countries have culture and rapid diagnostic capacity, much more is needed, including point-of-care tests. Some potential rapid diagnostic methods, such as the mass spectrometry approach, are very appealing, but it remains to be seen how practical they will be for TB. Farmer noted that candidates for rapid diagnostics exist (see Chapter 5), but a push is needed to bring these candidates to the mainstream. Vali- dation of tests needs to be transparent so that the international scientific community knows that they work. Regulations also must be established for the use of these tests. A forum for action could push new diagnostics forward so they would not linger from year to year without being ready for deployment, said Farmer. TREATMENT Keshavjee summarized problems in obtaining enough quality second- line drugs (see Chapter 8). Existing mechanisms for making high-quality second-line drugs available, such as the GLC, have many strengths. The

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104 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA GLC system provides drugs at a great discount compared with local markets, especially in Russia, where GLC prices are 5 to 10 times lower. But the market for these drugs is limited in that it is a market for what people can buy, not what they need to buy. Partly as a result, delays are experienced through the Global Drug Facility mechanism. Challenges are experienced as well in individual countries, such as regulations that require buying drugs from domestic manufacturers. An increase in drug prices also has affected the number of patients being treated. For example, when the price of some of the GLC drugs sold through the Global Drug Facility rose by 44 percent, 1,000 patients had to be cut from treatment in Russia. The opposite is happening with HIV drugs, whose prices are declining. Many countries have hundreds of thousands of people to treat. They must be able to buy drugs through their own mechanisms and from their own suppliers, and they must be able to ensure that their manufacturers are making quality products, said Coetzee. Single suppliers and manufactur- ers are not sufficient. Tobias emphasized that strengthening the regulatory authorities in countries with a high burden of MDR TB and in countries that export drugs is important as well. Coetzee noted that in South Africa, the biggest policy debate currently involves treatment of MDR TB in the community. Health care systems are so overwhelmed, with hospitals being full and people being put on lists and sent home, that community treatment is already a reality. The group that has the most say in decisions about community treatment is the community itself, but the community “has not yet spoken,” said Coetzee. TB is more stigmatized now than in the past, with drug-resistant strains circulating in the community. Civil problems need to be managed sensitively. Community-based care cannot happen unless patients and communities are treated as partners in the health care system, said Tobias. Prevention, infection control, and treatment all require partnerships with patients and communities. Tobias noted that the development of partnerships in part requires finding advocates “because that will increase public will and fund- ing.” As the experience in Tomsk showed, even difficult patients can be partners (see Chapter 7). “They may be alcoholic, they may be challenged, but they are becoming our partners. That’s why we are going to be suc- cessful,” said Tobias. HIGH-QUALITY CARE FOR ALL People in affluent countries expect the best available care, while people in less affluent countries, and even children in affluent countries, are expected to be satisfied with lower-quality care. This double standard is based on the false rationale of inadequate resources, said Cegielski. The

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105 CONVERGENCE OF SCIENCE AND POLICY proper response is not to lower the standards but to increase the resources. That such an outcome is possible has been demonstrated repeatedly over the past decade by the Global Fund to Fight AIDS, Tuberculosis, and Malaria, UNITAID, PEPFAR and other U.S. government contributions, the Gates Foundation, the increase in the NIH budget for TB research, and other funding decisions. Similarly, said Cegielski, it is not appropri- ate to accept policy guidelines and recommendations that promote lesser standards for people who live in less affluent circumstances, in middle- income countries, or in lower-income countries. The development of inter- national standards for TB care and new initiatives for the improvement and acceleration of regulatory guidelines and frameworks demonstrate what is possible. Farmer indicated that various dogmas and ideologies have hampered rather than enhanced responses to the epidemic. The main source of tension has been a real or perceived scarcity of resources, often taking the form of competition between people who are working on the same team—for example, on TB and on diabetes. Farmer said this type of competition is seen in all areas of medicine. However, “The more you go down this gradi- ent of social inequality towards so-called resource-poor settings, the more this competition is palpable and, I would say, unhealthy.” The example of AIDS illustrates how this competition can be over- come, said Farmer. Twenty years ago, when he was an intern at Brigham and Women’s Hospital, the wards were full of young adults dying of AIDS. By the time he had finished his training in infectious disease, combina- tion chemotherapy had emptied the hospitals of patients with AIDS, and death rates had dropped dramatically. Another example of cooperation rather than competition involves mother-to-child transmission of HIV. In the early 1990s, a major epidemic of pediatric HIV in the United States was feared because there had been a substantial epidemic of HIV infection among women living in poverty. Yet in 2007, said Farmer, fewer than five American children died of AIDS. Although AIDS remains a leading killer of young adults, a combination of treatment for women in the United States and mandatory testing of women during pregnancy prevented a pediatric epidemic. Yet in South Africa, TB and HIV remain among the leading kill- ers of children. It is not a good idea to talk about diseases as untreatable, said Farmer. The tools may not yet be available for pan-resistant TB—patients cannot currently be cured when their infection is resistant to nine or ten drugs. But real or perceived scarcities can undermine the kinds of collaboration needed for prevention and care. The world is undergoing a transition, said Pérez-Vélez. Many countries, including the former Soviet Union, have experienced changes in their public health systems as a result of overall changes in government. Health care has

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106 DRUG-RESISTANT TUBERCULOSIS IN RUSSIA undergone dramatic changes in South America, for example. Colombia has been moving toward a model of competing, managed-care organizations, which is a familiar model in the United States. Consequences of this change have been that BCG vaccinations have decreased, active case finding and contact investigation have been reduced, cure rates have decreased, and default rates have increased. All this has been the result, said Pérez-Vélez, of transferring TB control to the for-profit managed-care marketplace. “There is no profit to be made in tuberculosis, as we all know too well,” he said. In the United States, the CDC and the states maintain good TB control programs, but the public−private mix has not thrived in many developing countries. Pérez-Vélez concluded by calling attention to the International Stan- érez-Vélez rez-Vélez élez lez Stan- dards for Tuberculosis Care (ISTC), which have been endorsed by more than 50 national and international organizations and are widely used in TB control programs. An independent body’s monitoring of countries’ adherence to the ISTC in both the public and private sectors could counter the lack of political will to uphold international standards of TB care, said Pérez-Vélez. LINKAGES FROM SCIENCE TO CLINICAL CARE According to Farmer, science has not kept pace with the epidemics of HIV and drug-resistant TB. The science is moving forward, but uptake into public health programs is slow everywhere in the world. This gap between knowledge and implementation is the biggest problem facing medicine in the United States, Farmer said, and in most of the places where he has worked. Cegielski echoed this point, saying that many new diagnostics are already commercially available, but they are not universally accessible. The chance that a new compound in the drug development pipeline will make it to final regulatory approval and the commercial market is only about 70 percent. So the question becomes what to do while waiting for necessary breakthroughs. One possibility, said Cegielski, is to accelerate regulatory science, as Margaret Hamburg suggested (see Chapter 9). For example, the Critical Path Initiative is focusing on drugs in combination so that each new drug is not expected to solve the problem, because resistance inevitably will emerge. Also, a great deal of work can be done with available tools, said Cegielski. Many drugs on the market that have been approved by the FDA and other regulatory authorities may have antimycobacterial activity. They could be investigated immediately for their efficacy against TB in general or drug-resistant TB in particular. Such tests also would help build the

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107 CONVERGENCE OF SCIENCE AND POLICY infrastructure for clinical trials, for the evaluation of new drugs, and for the development of new diagnostics. The vital links among clinical care, basic science, clinical research, drug manufacturing, and better policy require the kinds of collaborations forged at the Moscow workshop. “I hope this will be regarded by others as one in a series of potentially historic meetings that push forward the envelope as we contemplate improving our responses to drug-resistant tuberculosis,” said Farmer.

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