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 1980’s 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 2004–2006, 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. 

MDRand 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:

1. Conduct rapid surveys of XDR TB to determine the burden of disease;
2. Enhance laboratory capacity to support surveillance and diagnosis, with emphasis on drug-susceptibility testing;
3. Improve the technical capacity of practitioners to respond to XDR TB outbreaks and manage patients;
4. Implement infection-control precautions; 
5. Increase research support to develop new anti-TB drugs;
6. Increase research support to create rapid diagnostics for TB and for MDR and XDR TB; and
7. 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 WHO’s 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/CDC’s 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.

Gaps

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 1950’s, 60’s, and 70’s.  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 President’s 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. 

Last revised: January 12,2009