• The biomedical approaches and delivery systems used to attack TB are not being optimized.
• Moving from a minimalist approach to an “optimalist” approach, in which TB cases are identified rapidly, active case finding is performed, infection control is implemented to reduce transmission, and patients are treated based on the results of rapid DST, could yield dramatic progress.
• The BRICS countries have a unique opportunity to take a leadership role and scale up diagnosis and treatment of TB and MDR TB, in addition to the socioeconomic interventions that reduce poverty and enhance TB control efforts.
• The intentions of BRICS country health ministers, as reflected in the Delhi Ministerial Communiqué (see Box 1-4 in Chapter 1), reveal promise in the potential future leadership of the BRICS to combat MDR TB.
a Identified by Salmaan Keshavjee, Director, Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School.
1 This chapter is based on the presentation by Salmaan Keshavjee, Director, Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School.
In the final session of the workshop, Salmaan Keshavjee, Harvard Medical School, presented his views on what will be required to achieve zero deaths from TB. His talk revisited many of the topics discussed during the workshop and provides a useful look back on the meeting.
Rates of HIV infection and deaths from AIDS have dropped markedly in recent years, as have deaths from malaria. During this same period, however, death rates for TB have been nearly static, declining only about 1 percent per year. The only reason TB mortality may appear to be declining is that HIV-infected patients dying from TB are sometimes classified as “non-TB deaths.” This is a classification artifact and does not represent the true impact of the disease or the unmet need for treatment, said Keshavjee, who noted that, although effective treatment regimens for TB have been available since the early 1950s, 1.5 million to 2 million people still die annually from the disease. “Overall, we have not been successful with the tools that we have been using,” said Keshavjee.
The reason for this lack of success is that optimal biomedical approaches and delivery systems have not been used to attack the disease. The DOTS approach, for example, is a minimalist, not an optimized strategy. Although it has saved millions of lives by standardizing treatment for TB, it was never designed to address drug resistance, a phenomenon that has existed since the use of the first anti-TB drugs. According to Keshavjee, “years of advocating an approach that overlooked resistant strains was a mistake.” DOTS, which requires having a regular supply of high-quality drugs, has had great benefits, but the program also has several limitations:
• It lacks integration with country procurement systems.
• It includes neither SLDs nor drugs for adverse events.
• The DOTS strategy does not include active case detection and relies on patients appearing when they are sick.
• The program has no strategy for latent disease, despite research showing that treatment of latent disease yields mortality and transmission benefits.
• A sole focus on short-course chemotherapy as a panacea has curtailed the development of appropriate adjunct therapies, such as surgery, for patients with advanced disease.
Diagnosis with sputum smear microscopy also has been suboptimal for patients with smear-negative or extrapulmonary TB. It has low sensitivity in patients with paucibacillary disease, such as pediatric populations or people infected with HIV, and is incapable of identifying resistant strains.
Although sputum microscopy is low cost and can be performed in remote areas, it is not well suited to addressing some of the principal drivers of the TB epidemic over the past two decades, Keshavjee said.
Keshavjee noted further that standardized recording and reporting have led to much greater accountability in TB control worldwide. However, the systems used have been unable to capture complex data, such as those related to MDR TB, coinfection with HIV, and diabetes as a comorbidity.
Finally, Keshavjee suggested that a minimalist approach has led to a lack of focus on transmission and infection control and thus a lack of emphasis on the appropriate design of facilities and systems to prevent transmission. Particularly with MDR TB, strains of which have mistakenly been thought to be too weak for transmission, the lack of infection control has contributed to the spread of the disease. A minimalist approach also has led to limited engagement with the private sector, not only for drug delivery but also for drug R&D. Clinical and delivery systems have been separate from other health services, so that TB screening has not been conducted as a routine part of health care.
“The paradigm we have been working within has been very inflexible,” Keshavjee said. “It has not been able to respond to change in light of new evidence.” The paradigm now needs to be revised, he asserted.
Keshavjee urged moving from a minimalist approach to an “optimalist” approach. He invoked the acronym FAST used earlier in the workshop by Edward A. Nardell, Brigham and Women’s Hospital, Harvard Medical School, which stands for
• Find TB cases through rapid diagnosis.
• Perform Active case finding by focusing on cough surveillance.
• Separate safely and reduce exposure through infection control.
• Treat effectively based on rapid DST.
Keshavjee noted that, in general, the case detection rate for all TB patients has been improving in recent years. Yet, an estimated one-third of all TB cases—more than 3 million people—are not detected each year. Addressing the first of the above steps, Keshavjee added that HIV and TB have been driving each other’s epidemics for years. Yet, the percentage of HIV positive people screened for TB remains low on a global level. Although some countries do perform universal screening of those infected with HIV for TB, “on a global level, every person with HIV should be screened,” Keshavjee said. Similarly, children make up somewhere between 10 and 30 percent of TB patients, but diagnostics for children are poor and
often are not employed. More appropriate diagnostics and case-finding strategies for children remain “a dire need,” said Keshavjee.
The workshop clearly demonstrated potential solutions to these problems, Keshavjee said. One solution is to develop true point-of-care tests for TB and DR TB. The perfect test is not essential, said Keshavjee. For example, the rapid strep test is accurate just 75 percent of the time, but it has a crucial benefit: It can be performed at the point of care. When people must walk hours to a clinic or spend precious resources on transportation, they need to be diagnosed quickly and started on treatment.
The performance of TB programs also can be improved. The percentage of newly diagnosed TB patients who receive DST remains below 10 percent worldwide and is only about 30 percent even in Europe. Even the percentage of retreatment cases receiving DST is below 10 percent, despite the greater likelihood of drug resistance in these cases.
Improvement also can be achieved by realizing that with molecular drug susceptibility tests, one size does not fit all. Tests to determine SLD resistance reliably therefore need to take variation into account. Within countries there exist pockets of resistance that are different, which means that diagnostics need to be applied in a calculated way.
A further area for improvement is integration of TB programs with other parts of the public and private health systems. For example, Keshavjee described a project funded by the Stop TB Partnership’s TB Reach initiative in which Pakistani health care workers at private general practitioner clinics screened patients for TB and referred them for sputum smear microscopy and X-rays. During the course of just 1 year, the case notification rate for all forms of TB almost quadrupled. Many of the patients were smear-negative but proved to have cavities when X-rayed.
With respect to treatment, Keshavjee stressed that when patients are started on an effective treatment regimen, they become less infectious. The optimal way forward is therefore to give people the right treatment so that high resistance does not develop. Data from South Africa indicate that standardized therapy has drawbacks because of the variation that exists even on a local scale.
MDR TB is still TB, Keshavjee emphasized. It is transmitted through the air, which is why it spreads. Universal access to care may be extremely difficult to achieve, but it must be a priority. Keshavjee suggested that the way to achieve universal access to care is through community-based care. “Patients have lives, they have kids, they can’t be locked up for 2 years,” he said. “It’s unreasonable for us to expect that from people, and we don’t have the beds or capacity to do that anyway.” Ambulatory care and community-based approaches provide a way to treat large numbers of patients rapidly, safely, and outside of congregate settings. Community-based care that works takes the needs of patients into account. It provides
wraparound services such as provision of food and other enablers that help patients complete treatment successfully.
For patients to be placed on an effective regimen, a reliable, affordable supply of quality-assured drugs is essential. Improved supplies of SLDs would be a major achievement, said Keshavjee, but the drugs need to be part of a comprehensive package that includes ancillary drugs for adverse events, equipment required to deliver the drugs, and other delivery mechanisms. Today, this system is centrally run, which has some benefits, but there also are benefits to having a variety of nodes in a supply chain system, which can improve efficiency and effectiveness. In this way, the demand for and supply of drugs can be more evenly matched so that all the drugs that are made are used.
Keshavjee next turned to preventive therapy for TB, which he acknowledged can be a contentious subject. But given the challenge of dealing with active cases, preventive efforts can produce benefits, especially in areas with high rates of latent disease. Studies conducted in the 1960s showed that isoniazid therapy can have a protective effect that persists over two decades, and possibly for a lifetime. Such therapy also has been shown to be highly effective in preventing mortality among people living with HIV. In addition, prophylaxis for contacts of MDR TB patients—an area of inquiry that remains to be sufficiently explored—can be important, especially for children, for people infected with HIV, or for contacts. Keshavjee suggested that preventive therapy should begin by focusing on those at highest risk of developing active TB, such as individuals exposed to silica dust, patients treated with immune modulators such as steroids, diabetics, and smokers.
Addressing adjunct therapies, Keshavjee cited the need for further research to determine their effectiveness. Potential approaches include the use of autologous mesenchymal stromal cells, other immunomodulators or anti-inflammatories, or therapeutic vaccines. Mortality rates are very high among people with XDR TB and those who have failed treatment, which argues for considering other therapies.
Keshavjee next noted that effective treatment requires not only having the right drugs but also optimizing care delivery systems or platforms. Even when the right drugs are available, they may not be used enough or appropriately for patients to be cured. In many places, an implementation gap hinders treatment delivery, and this is an area requiring much greater focus, particularly for drugs that need to be delivered for extended periods. Keshavjee acknowledged that the delivery of treatments can be daunting. Many of the countries with the highest burden of MDR TB have relatively weak health care systems. In such cases, mechanisms to fill the implementation gap are a priority.
Taking a broader view, Keshavjee emphasized that TB is a disease of poverty, and ameliorating poverty can have an enormous effect on its
control. In addition to biological factors, food security and consumption patterns, health-seeking behaviors, housing quality, ventilation, and many other factors contribute to infection and active disease. Socioeconomic interventions can reduce the exposure to these risk factors, lower the burden of disease, improve screening, and boost treatment success. Even eliminating fees for patients can increase the use of public and private health care. “TB is a biological phenomenon, but it’s also a social phenomenon,” said Keshavjee. As an example, he briefly described a study of cash transfers and microfinance interventions for TB control (Boccia et al., 2011).
Similarly, investments in national TB programs in the public sector, while not a complete solution, can produce higher case detection rates and lower TB incidence, prevalence, and mortality (Akachi et al., 2012). Strengthening the public sector also can improve private-sector care through increased monitoring and engagement.
Reflecting on a white paper developed to support the first workshop in the IOM series, Keshavjee indicated that the system for providing international technical assistance is currently inadequate. The system needs to be transformed to do better at drawing on the experience of successful regional MDR TB treatment programs; to include the provision of onsite, long-term technical assistance; and where necessary, to involve onsite implementation teams (Keshavjee and Seung, 2008). The underlying message is that countries need strong support, such as was provided by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), if their TB programs are to succeed, asserted Keshavjee.
Keshavjee reported that at a recent meeting in Cambridge, Massachusetts, a group of researchers, administrators, policy makers, and advocates discussed how to move forward with TB control. The group decided that it needed an orienting principle at the dawn of the 21st century, when people are still dying of a treatable disease. The group decided that the world needs to strive for “zero deaths from TB.” It signed a document called the Cambridge Declaration calling for zero deaths, zero new infections, and zero suffering. “I think that the FAST method and what we have discussed today is a way forward for achieving zero TB deaths,” Keshavjee said.
Continuing with the theme of the role of socioeconomic factors in TB, Keshavjee noted that the BRICS countries still have a great deal of poverty. Reflecting on the link between poverty and rates of TB, he cited the example of Brazil, where the number of people living in extreme poverty has fallen dramatically during the past 20 years. Over the same period, Brazil’s TB rate has declined by 50 percent, while the global rate has declined by only 15 percent. “I’m not suggesting that we shift our focus away com-
pletely from biomedicine to the business of economic development,” said Keshavjee. “[But] this shows us that if you have people coming out of poverty you probably get less disease, you’re able to fight disease better, and you have better outcomes if you have disease. This should convince us that we have to think about having some component that invests in the social aspects of TB for our patients as an integral part of every program.”
The BRICS countries could provide leadership for TB treatment and control, Keshavjee said, echoing comments made throughout the workshop. He reiterated the commitments made in the Delhi Ministerial Communiqué, in which the BRICS health ministers recognized that MDR TB is a major public health problem for their countries. The ministers resolved to
• collaborate and cooperate for the development of capacity and infrastructure;
• reduce the prevalence and incidence of TB through innovation in drugs/vaccines and diagnostics and the promotion of consortia of TB researchers; and
• collaborate on clinical trials of drugs and vaccines, strengthening access to affordable medicines and the delivery of high-quality care.
The ministers also recognized the need to cooperate in adopting and improving systems for
• notification of TB patients;
• availability of anti-TB drugs at treatment facilities through improved supplier performance; and
• procurement and the logistics and management of HIV-associated TB in the primary health care system.
In conclusion, Keshavjee said:
Everything we have been talking about they seem to want to do. Is there some scenario where we can imagine that the BRICS countries will take a leadership role moving forward? The BRICS countries have a high proportion of the global burden of disease. They also have growing economies…. These countries are well poised to commit to scaling up the treatment of MDR TB and the treatment of regular TB…. We need to think big coming out of this meeting about what we expect from our host and the other BRICS countries.
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