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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
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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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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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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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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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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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