The Need for Global Action Against Multidrug-Resistant Tuberculosis

Imagine a new disease. It spreads by droplet nuclei. Humans carry it from one country to another. The disease infects both healthy persons and those with compromised immune systems. For every person evidently ill, 10 to 20 are infected silently, and as many as 10% per year of those who are immunocompromised will develop active disease and spread the infection. The disease is curable with drugs that are available in industrialized countries but considered too expensive for developing countries. Left untreated, the disease is likely to affect tens of millions worldwide and kill at least half of those who develop active disease. It seems clear that the global health community would make an urgent commitment to fight such a disease, if there were an opportunity to stop it early in its spread.

There is a real disease that fits this profile: multidrug-resistant tuberculosis (MDRTB). Yet many leading public health organizations and funding agencies are doing little to fight it. These groups need to recognize the new, significant threat to human health that MDRTB presents. Global surveillance of tuberculosis (TB) drug resistance shows that MDRTB now exists in every country examined except Kenya with an overall mean prevalence of 4.3% of all TB cases, including both new and retreatment cases.¹ In extreme situations, eg, in Estonia and Latvia, the rate of multidrug resistance in patients who have not been previously treated for TB, or primary resistance, is 10.2% to 14.4%.¹ The prevalence of multidrug resistance among patients previously treated for TB, or acquired resistance, is 54.4% in Latvia, 19.7% in the Dominican Republic, 15.7% in Peru, and 7.1% in the United States.^{1 - 2}

For TB, the World Health Organization (WHO) advocates the use of a standardized regimen called directly observed treatment, short-course (DOTS).^{3 - 4} By adopting DOTS, WHO has argued that it is possible to control TB worldwide. Some DOTS programs have demonstrated improved cure rates compared with programs that were in place before DOTS. These programs also have shown a decline in the development of drug resistance among patients treated for TB.^{5 - 6} Despite these important advances, DOTS alone will not control MDRTB. The DOTS treatment failure rate for patients with MDRTB ranges from 15% to 77%.^{6 - 7}

Today there is no coordinated global effort to treat MDRTB. While preventing new cases of MDRTB by using effective treatment strategies for patients with drug-sensitive TB is essential,³ this approach does nothing to control MDRTB where it already exists. For instance, in Korea⁶ and Algeria,⁸ where effective DOTS programs have been in place and drug resistance rates have been measured repeatedly, the prevalence of MDRTB has remained unchanged or increased. Multidrug-resistant tuberculosis is treatable. The most successful hospital and community-based treatment programs based on culture and drug susceptibility results have shown cure rates of 85% and greater.^{9 - 10}

The hesitation in taking on MDRTB reflects the current high costs per patient treated. The treatment of MDRTB requires expertise and medications that are significantly more expensive than first-line drugs used for drug-sensitive TB. Treating a case of MDRTB in a developing country can range in cost from $800 to $10,000 (P. Farmer, MD, PhD, personal communication, 1999). WHO refers to MDRTB treatment as "an expensive luxury which is only affordable where national resources are moderate or good."¹¹ The tragedy is that many countries where MDRTB exists and is increasing do not have the resources to add to their current programs. In most of the countries with the necessary resources, TB and MDRTB case rates are already low and declining.

In addition to humanitarian reasons, why should the United States, the countries of western Europe, and other industrialized countries invest in TB treatment, including MDRTB treatment, worldwide? It is expensive to treat MDRTB; it is even more expensive to fail to treat it. Tuberculosis control in low-incidence countries increasingly depends on TB control in high-incidence countries. Tuberculosis does not respect borders. The proportion of US TB cases occurring in foreign-born individuals has increased annually since 1986,¹² and reached 36.1% in 1996.¹³ In some low-incidence areas, such as Canada¹⁴ and New South Wales, Australia,¹⁵ the majority of TB cases occur in foreign-born persons. In addition, rates of drug resistance and multidrug resistance are higher among foreign-born persons.¹⁶ Furthermore, it is neither desirable nor possible to close borders. It has been estimated that 500 million people cross international borders every year by commercial air travel alone.¹⁷

The future costs are high if the global health community fails to confront MDRTB. The human immunodeficiency virus (HIV) pandemic provides an important illustration of this concept. Ten thousand dollars per infected person would be an impossible sum for a developing country to spend to prevent a case. Yet, had it been possible to treat HIV and stop its spread when there were fewer than 1 million cases worldwide, the price would have been affordable for resource-rich countries. In 1993, care for patients with acquired immunodeficiency syndrome and HIV in North America alone cost US $5.5 billion.¹⁸

The recent US TB epidemic demonstrates the importance of considering future costs in deciding on the worth of present control measures. In the mid-1980s, then-director of the Centers for Disease Control and Prevention James Mason, MD, testified before Congress that $36 million per year was needed to eliminate TB in the United States.¹⁹ However, TB was not considered serious enough to justify the cost, and the funds were not provided. In 1991 alone, direct medical expenditures for TB in the United States exceeded an estimated $700 million.²⁰ Between 1992 and 1995, more than $1 billion was spent to reverse increasing TB rates in New York City.²¹ The cost of treating MDRTB, in lives and dollars, is far less today than it will be if the global health community continues to delay.

WHO, the Centers for Disease Control and Prevention, and other organizations agree that an essential aspect of TB control and, ideally, of TB elimination is the effective treatment of all individuals with active TB.^{3 ,22} Although important tools for the prevention of TB exist, they have limitations. BCG vaccination provides important but imperfect protection.²³ Chemoprophylaxis is operationally difficult to implement in many populations and is not 100% effective.^{24 - 25} Control of MDRTB requires effective treatment of patients with MDRTB. If ignored, MDRTB will increase. This is clear from the epidemiology of TB, which is the cause of 25% of preventable mortality among adults in the developing world. An estimated 1.7 billion persons worldwide are already infected. An estimated 2.5 million people die each year of TB.²⁶

By inadequately treating MDRTB, the global community is not only acceding to the current burden of disease in infected individuals but to the seeding of successive generations with infections that will lead to illness, disease transmission, and premature death.

What is necessary to control TB and move toward elimination? Effective treatment must be provided for all patients with active TB. For patients with MDRTB, effective treatment requires individualized treatment regimens based on culture, drug susceptibility testing, and supervision by physicians and health care workers experienced in the management of this disease.

WHO has developed a network of international reference laboratories for TB drug susceptibility testing.²⁷ The technology for getting samples from around the world to these laboratories and getting the results back to sites at which they are needed in a timely fashion already exists. There are recognized TB treatment centers that are capable of supplying expert advice and training in MDRTB treatment.

What has been lacking is the global commitment to effectively treat all patients with TB, including MDRTB, and economic support for programs to accomplish this goal. Infectious diseases that spread, threaten health, and cause significant morbidity and mortality worldwide can only be effectively treated on a global scale. Countries with few resources and high rates of MDRTB and other infectious diseases cannot afford alone to treat the other serious infections within their borders. The lessons of epidemiology, infectious disease modeling, and history all point in the same direction. The incidence of MDRTB will increase if the disease is left untreated, and its occurrence will spread across borders. International organizations that can call on significant economic resources to address fiscal and security issues around the world already exist. While WHO, as well as numerous nongovernmental organizations, brings invaluable expertise to global health problems, none currently has the financial resources to take on the prevention and treatment of infectious diseases worldwide. Resource-rich countries need to play a larger role in footing the bill for decreasing the global spread of life-threatening infectious diseases. These funds could either be allocated to individual countries through existing international health organizations or through a new global health fund. The humanitarian reasons are clear, as are the reasons stemming from "enlightened self-interest."

The expertise for combating MDRTB already exists. The global community can afford to treat all cases of TB—both drug susceptible and multidrug resistant. Clearly, it cannot afford not to.