Drug Resistant TB: CDCs Public Health Response
United States House of Representatives Foreign Affairs Subcommittee on Africa and Global Health
Wednesday, February 27, 2008
Julie L. Gerberding, M.D., M.P.H.
Centers for Disease Control and Prevention
U.S. Department of Health and Human Services
Good afternoon, I am Dr. Julie Louise Gerberding, Director of the Centers for Disease Control and Prevention within the Department of Health and Human Services (HHS). It is my pleasure to be here to discuss with you CDCs role in the response to drug resistant TB, globally and in the United States.
Tuberculosis (TB) is an airborne infectious disease that is spread from person to person, usually through coughing. In the late 19th and early 20th centuries, until the introduction of streptomycin in the 1940s, TB was one of the leading causes of death in the United States. Currently, the World Health Organization (WHO) reports that one in three people in the world is infected with dormant TB bacteria (latent TB infection). Only when the bacteria become active do people become ill with TB. Bacteria become active as a result of anything that can reduce the persons immunity, such as HIV, advancing age, or some underlying medical conditions such as cancer or diabetes. Currently TB that is not resistant to drugs can be treated with six to nine months of first-line drugs (the most effective), including isoniazid and rifampin; this treatment cures over 95 percent of patients. Nearly nine million people in the world develop TB disease each year, and since people in many resource-poor countries lack access to appropriate treatment, about 1.6 million die.
TB that is resistant to at least isoniazid and rifampin is called multidrug-resistant (MDR) TB. MDR TB requires treatment for 18-24 months with second-line drugs that are much less effective, usually poorly tolerated by the patient, and far more costly. There are currently only six categories of second-line drugs, of which twofluoroquinolones and injectable aminoglycosidesare the most important. The cure rate is 70-80 percent under optimal conditions and, in most settings, is closer to 50 percent. Many countries with a high TB burden find it impossible to treat MDR TB patients because of the cost of drugs, and the more sophisticated laboratory services, technical expertise, and intensive programmatic support activities that are required. Extensively drug-resistant TB (XDR TB) is a subset of MDR TB caused by strains of bacteria that are resistant to the most effective first- and second-line drugs.
Drug resistance develops when patients receive incomplete or inadequate treatment. Treatment of drug-resistant TB requires at least six months of treatment with four different antibiotics. If this complex regimen is interrupted, drug susceptible bacilli are killed, but more resistant strains persist and form larger colonies. Persons with these resistant strains in their lungs can then pass these resistant bacteria to other susceptible individuals through coughing. We have also learned that weaknesses in a TB program create opportunities for drug resistance to develop: either through the interruption of drug supply, the inappropriate prescription of treatment regimens administered by medical providers, the failure to support patients on therapy, the non-adherence to treatment by patients, and the lack of implementation of infection-control precautions.
Scope of the problem
In response to anecdotal reports from physicians who were finding cases of TB that were unresponsive to the first-line and second-line TB drugs, in 2005 CDC and WHO jointly conducted the first survey, with support from the U.S. Agency for International Development, for resistance to both first and second line TB drugs. The survey examined almost 18,000 patient sputum samples, or isolates, collected during 2000 to 2004 by WHOs network of Supranational Reference Laboratories. Researchers examined the drug-resistant isolates, and found that, of those isolates meeting the definition of MDR TB, 10 percent met the definition for XDR TB. XDR TB was identified in 17 countries from all regions of the world, most frequently in the former Soviet Union and Asia. Data from sub-Saharan Africa were very limited. Most laboratories in this region use culture methods for diagnosis, which are unable to detect drug resistant organisms. This report, published in CDCs Morbidity and Mortality Weekly Report in March 2006, was the first widely circulated publication to use the term extensively drug resistant TB. WHO is releasing the fourth global drug susceptibility test data today, which show worrisome trends in several countries. Dr. Raviglione will describe these in more detail in his testimony.
Because many countries do not routinely test all isolates for resistance to second line drugs, the precise global incidence of XDR TB remains uncertain. However, because of the ease with which drug resistance can occur (because of the use of second-line drugs in suboptimal conditions, funding shortages, changes in program focus away from TB case management, interruptions in drug availability, high HIV prevalence), XDR TB could be much more widespread than the WHO survey shows.
Morbidity and Mortality from XDR TB
Reported mortality rates among persons with XDR-TB are extremely high. In the U.S., 25% of XDR-TB patients die within 1 year and 32% die during treatment (compared with 19% and 23%, respectively, for MDR-TB). Only 38% of XDR-TB patients complete treatment successfully compared to 53% of MDR-TB patients. Among HIV-infected persons, illness is more severe, mortality rates are higher, and death occurs within a shorter time, either because the disease itself is more severe, or whether at presentation, the patient is suffering with more advanced disease and more severe comorbidities, or a combination of factors. As Dr. Raviglione explained in his testimony, the world saw evidence of this in the alarmingly high mortality rates resulting from the 2006 outbreak of XDR-TB in an HIV-positive population in KwaZulu-Natal in South Africa. Of the 53 XDR-TB patients, 52 died and they died within an average of 25 days, including those benefiting from antiretroviral drugs.
What is the threat in the United States?
The TB resurgence that occurred from 1985 to 1992 in our country provides a poignant example of how outbreaks of drug-resistant TB can develop. From 1953 (the establishment of national U.S. surveillance) through the mid 1980s, TB cases in the United States declined steadily, from approximately 83,000 to 22,000 new cases per year. But in 1985, CDC began documenting increases in TB incidence. A key factor associated with this increase was the dismantling of TB programs, which occurred when health departments stopped receiving TB categorical funds, and shifted resources to other public-health activities. Other factors included the burgeoning HIV epidemic, increased immigration from countries with high TB incidence rates, lack of infection-control precautions in healthcare settings, and the widespread occurrence of MDR TB at a time when the laboratory capacity to readily identify these strains was inadequate. The Congress then appropriated an increase in funds, and the situation was remedied after programs were again able to prescribe appropriate drug regimens for patients, have adequate laboratory capacity to diagnose and manage patients, provide appropriate programmatic support for patients, assure adherence with prescribed regimens, and conduct effective contact investigations.
These intensive control efforts also resulted in a decrease in MDR TB cases in the United States, which fell from 483 reported cases in 1993 to 111 in 2006. However, the epidemiology of these cases also changed. In 1993, 31 percent of MDR TB cases in the United States occurred in foreign-born persons; whereas in 2005, 81 percent of MDR TB cases occurred in foreign-born persons. Between 1993 and 2006, a retrospective analysis of 47 cases of XDR TB were reported in the United States to CDC. As with MDR TB, the epidemiology for XDR has changed. In the years 1993-1999, 62 percent of XDR TB cases occurred in U.S.-born persons and most of these cases occurred in persons with HIV infection. While from 2000-2006, 73 percent of XDR TB cases occurred in foreign-born persons, and only 18 percent of the U.S. XDR TB cases occurred in HIV-infected persons.
While the total number of MDR and XDR TB cases in the U.S. is relatively small, their impact on U.S. TB control programs can be significant in terms of human capital and financial resources. One patient with MDR or XDR TB requires a minimum of 18-24 months of treatment. Recently collected data from California show that in-patient costs alone for someone with XDR TB may exceed $600,000 per case.¹ The treatment of some individual cases has cost as much as $1 million. The cost of a potential resurgence, however, is far higher. In New York City alone, the estimated cost to control the MDR TB epidemic of the late 1980s exceeded one billion dollars (in 1991 dollars).²
CDC also works to prevent the introduction of TB cases into the United States and the movement of infected individuals between states. The required overseas medical screening of immigrants and refugees is an important activity to prevent importation of TB into the United States. In 2007, CDC updated its Technical Instructions for Tuberculosis Screening and Treatment, which are used by the physicians who perform overseas medical examinations, to be consistent with modern diagnostic technologies and international standards for treatment. With the cooperation of the U.S. Department of State and international partners, HHS/CDC is in the process of implementing these improved screening procedures. These procedures include routine screening procedures for children; cultures for persons whose x-ray suggests TB, and drug susceptibility testing if cultures are positive. Patients are required to complete treatment overseas before embarking for the United States, under directly observed therapy and using established drug regimens. According to preliminary studies, these revised procedures are three times as sensitive at detecting TB. We have clear evidence of the new procedures efficacy. For example, during 20042006, CDC responded to an outbreak of MDR TB in a refugee group in Thailand that was resulting in cases being imported into the United States. CDC and international partners implemented comprehensive measures in Thailand that allowed the Hmong refugees to receive treatment according to international standards, and TB importations to the U.S. were greatly reduced. Evaluation and monitoring of this activity are ongoing.
When necessary, CDC can use isolation and quarantine strategies to restrict the movement of individuals who are traveling with TB. It should be noted that state and local governments have primary responsibility for isolation and quarantine within their borders and conduct these activities in accordance with their respective laws and policies. However, CDC maintains a close partnership with DHS and its agencies, and coordinates with DHS when asked by states for assistance to restrict travel. CDC has worked hard over the past months to strengthen the link between public health and homeland security. The partnership between Customs and Border Protection and CDC is particularly vital, as CBP provides situational awareness that allows for an effective response to public health threats.MDR and XDR in HIV high-prevalence areas
In areas such as sub-Saharan Africa, TB rates have substantially increased over the past decade, which parallels the rising number of HIV/AIDS patients. HIV coinfection makes it more difficult to diagnose and treat TB. More than 50 percent of persons with TB in sub-Saharan Africa are HIV-infected. In countries with a high HIV burden, weak and underfunded TB control programs become strained by the influx of new HIV-TB patients. In most of these countries, the government does not regulate second-line TB drugs and they are not widely available. In Botswana, for example, TB incidence was declining until about 1987, when it began to rise sharply as HIV prevalence increased, tripling by 2002. A significant increase in the prevalence of overall drug resistance among the TB cases followed this jump in the burden of TB patients. The WHO and its partners anticipate that drug resistance will continue to increase because of weaknesses in national TB programs in many countries.
MDR and XDR TB in countries with low HIV prevalence
XDR TB is also a potentially dangerous problem for countries with low HIV prevalence if they lack adequate national TB programs. One of the conditions that contribute to the development of drug-resistant TB is when physicians prescribe drug regimens without the benefit of timely drug-susceptibility testing. Available data indicate the highest MDR TB and XDR TB prevalence rates occur in the former Soviet Union and Asia in low-HIV-prevalence populations. Persons in these countries who are treated effectively are cured of non-resistant TB. However, if conditions exist in which second line drugs prescribed for MDR TB are misused, development of XDR TB will result.
Response to XDR TB Globally
CDC works closely with other agencies to prevent TB globally, including the National Institutes of Health (NIH), the U.S. Agency for International Development (USAID), WHO and non-governmental agencies through a variety of programs, including the Emergency Plan and the Global Fund for AIDS, TB and Malaria. In September 2006, HHS/CDC, WHO, and other partners from the Stop TB partnership developed an action plan to address XDR TB. This includes taking the first, all-important step of addressing TB program deficiencies as quickly as possible to turn off the faucet of drug resistance. The action plan recommended the following:
- Conduct rapid surveys of XDR TB to determine the burden of disease;
- Enhance laboratory capacity to support surveillance and diagnosis, with emphasis on drug-susceptibility testing;
- Improve the technical capacity of practitioners to respond to XDR TB outbreaks and manage patients;
- Implement infection-control precautions;
- Increase research support to develop new anti-TB drugs;
- Increase research support to create rapid diagnostics for TB and for MDR and XDR TB; and
- Promote universal access to antiretrovirals under joint TB/HIV activities.
The U.S. Federal TB Task Force, which was established in 1991 by then CDC Director Dr. William Roper to coordinate federal efforts to address TB, has written a domestic and international response plan to address XDR TB for U.S. Government agencies. The U.S. Government also participated in the development of WHOs Global MDR/XDR TB Plan.
HHS/CDC also supports WHO and the Stop TB Partnership on a number of important activities, including providing technical assistance to the Global Drug Facility, which works to supply quality medications for TB programs. HHS/CDC also is a member of the Green Light Committee, which supports efforts to procure high-quality, low-cost medications linked to appropriate, managed treatment for MDR TB. During the period 2000-2007, the Green Light Committee evaluated 126 applications for access to reduced-cost TB drugs, and approved 93 applications for access to drugs for drug-resistant TB treatment project sites in 51 countries.
In addition, HHS/CDCs TB Trials Consortium has a leading role in clinical tuberculosis research that forms the basis for the Treatment Guidelines developed by HHS/CDC with the American Thoracic Society and the Infectious Diseases Society of America, and in updating TB treatment regimens for both HIV and non-HIV infected patients. The complementary research efforts of CDC and NIH play a key role in the development of new drugs and new regimens for drug-resistant TB. In FY 2007, CDC funded the consortium to initiate a pilot study to identify a treatment regimen for patients with drug-resistant strains of TB.
In collaboration with USAID and others, CDC technical experts are also working directly with host country governments and partners to implement improved infection control, rapid case detection, effective treatment, surveillance for drug resistance, and expanded program capacity, on an urgent basis. For example, currently CDC staff is assisting with an XDR TB outbreak in Botswana. CDC has also assembled teams of experts, including epidemiologists, microbiologists, and infection control specialists who are prepared for rapid deployment to respond to XDR TB outbreaks throughout the world.
Response to XDR in People Living with HIV/AIDS
With the support of the Office of the Global AIDS Coordinator (OGAC) and PEPFAR funding, CDC has been providing technical assistance to host governments in PEPFAR-supported countries. This funding has been used to strengthen collaboration between National TB and AIDS Control Programs and to work with National Public Health Laboratories to strengthen TB diagnostic services. This technical assistance supports a variety of activities, including (1) decreasing the pool of severely immunocompromised patients through ARV treatment, (2) reducing TB morbidity and mortality through early identification of TB suspects and patients in HIV prevention and care settings, (3) integrating TB and HIV services to assure uninterrupted treatment of HIV-infected TB patients, and (4) providing isoniazid preventive therapy as part of a package of care for HIV-infected patients. In addition, CDC is helping to strengthen TB laboratory capacity, especially at points of service to promote rapid diagnosis of TB; conduct TB drug resistance surveillance; and strengthen TB infection control practices in HIV care settings. In FY 2007, a portion of PEPFAR funds were used to address prevention and control of XDR TB in HIV-infected persons. In FY 2008, this funding will be continued.
Globally, HHS/CDC, WHO, and USAID have taken critical steps toward characterizing and controlling the threat of XDR TB. The importance of the role of infection control in high-burden HIV settings is becoming increasingly apparent. In the FY 2008 Conference on Retroviruses and Opportunistic Infections, data were presented that suggest a large proportion of persons with HIV in South Africa recently became infected with these highly resistant strains. We know that considerable improvement in TB infection-control practices in healthcare settings, achieved through relatively simple and inexpensive practices (for example, having waiting rooms outside in covered but open areas, installing fans, separating coughing patients, etc.), can achieve considerable improvements in TB infection-control practices in healthcare settings. To provide guidance on TB infection control, CDC, in collaboration with the WHO, OGAC, and the International Union Against TB and Lung Disease recently published a guidance document titled TB Infection Control in the Era of Expanding HIV Care and Treatment.
There is room for improvement in other areas, especially diagnostic services, treatment, and program management. Research on new tools for prevention, treatment, and diagnosis is needed both domestically and internationally to modernize and accelerate TB elimination. Importantly, the international community lacks new, effective drug regimens to replace drugs that have become ineffective against TB, or that interact unfavorably with anti-retrovirals and other HIV medications. According to the Advisory Council for the Elimination of Tuberculosis, TB drug development is at an unprecedented point. For the first time in 50 years at least four new anti-TB compounds entered human clinical trials, and several others are ready for advanced pre-clinical testing. These new compounds represent new drug classes that are not cross-resistant with existing agents, and can offer promise for resistant cases. CDC is working with WHO and other partners to develop the laboratory capacities and services required to meet the goals of the Global Plan for Tuberculosis Control and the Millennium Development goals, as well as to build integrated sustainable laboratory networks capable of providing the laboratory services needed to combat TB, HIV, and malaria.
New diagnostic tests in TB control are beginning to appear on the horizon and could provide beneficial results. Currently diagnosis of TB disease relies on the sputum smear examination, which has been in use for 125 years and is poorly sensitive and imperfect, especially in HIV infected persons. New blood tests have entered the market recently, and appear to offer improved performance, although they are more costly and have yet to undergo extensive field testing. Field evaluation of optimal, efficient diagnostic tests, as well as rapid tests for the detection of TB drug resistance, is critical. CDC is working with WHO and other partners to determine how best to integrate the use of these tests into routine TB diagnostic and control activities. For example, in Peru, CDC decentralized drug susceptibility testing to two district laboratories including a rapid low-cost test for MDR TB. In this project, the turn-around-time for testing for drug susceptibility was cut from nearly 3 months to 1 month at $5 per patient. In Latvia, CDC helped implement molecular screening for rifapentine resistance with about a 2-day turn-around-time. In Russia, Nepal, and the Philippines and Uzbekistan, CDC is implementing a modern laboratory standard for rapid culture and drug susceptibility testing. All of these projects include cost-effectiveness evaluations.
The presence of XDR TB globally has highlighted the need for laboratories to make services for TB, MDR TB and XDR TB more rapid and reliable. TB patients in developing countries frequently lack access to reliable, quality-assured, and prompt TB laboratory services. As a result, clinicians are unable to make timely, correct patient management decisions. Many laboratory techniques used in these countries to confirm a diagnosis of TB and to identify drug resistance were developed in the 1950s, 60s, and 70s. To combat resistance to anti-TB drugs, clinicians must have the most current methods, applied to their fullest capacity. Increasing the availability of genotyping also would allow programs to identify links between patients.
Given that TB is still a major threat to HIV-infected persons, partners such as the Presidents Emergency Plan, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, national governments, and others must ensure programs to prevent and control TB work closely together to protect vulnerable populations from acquiring this virtually untreatable form of TB.
In addition, given the increasing proportion of the burden of TB in the United States among foreign-born persons, there is a strong need to improve the quality of overseas medical screening of U.S. bound immigrants, including the ability to detect and treat XDR TB in this population.
Equally important will be the strengthening of program infrastructures, both domestically and abroad, through training and sustained support. While we are working to improve methods to diagnose and treat TB, we should continue to work to assist countries in improving their detection of new cases of TB and of successfully treating those that are detected. Strong program infrastructure, utilizing proven effective methods, such as Directly Observed Therapy Short-Course (DOTS), capable of meeting targets for detection of new cases and successful treatment, will prevent new agents from becoming drug-resistant in the first place.
Thank you for the opportunity to present CDCs findings and activities on drug resistant TB to date. I would be happy to answer any questions.
¹Inpatient care has been estimated for California XDR TB patients from 1993-2006 at an average of approximately $600,000 per patient. These estimates do not include outpatient costs or productivity losses, which are likely to be substantial for those treated for many years, or for the 25 percent of whom died from XDR TB. Jenny Flood, MD, TB Controller, State of California, personal communication.
²(Tuberculosis in New York City Turning the Tide. Thomas R. Frieden, M.D., M.P.H., Paula I. Fujiwara, M.D., M.P.H., Rita M. Washko, M.D., and Margaret A. Hamburg, M.D. New England Journal of Medicine, July 27, 1995).
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