Tuberculosis infection is present in 1.8 billion people worldwide. With the advent of multi-drug therapy in the 1970s, the treatment of tuberculosis with a “short course” of drugs was possible, and tuberculosis became the first disease whose treatment (and not only prevention) was adopted by the public health community. Since that time, tuberculosis treatment has been under the purview of national governments using the recommended “DOTS” strategy (Directly Observed Therapy Short Course)--a course of six to eight months of therapy with multi-drug regimens and observed therapy to prevent the development of resistance. However, as with any infectious disease, resistance to antibiotics develops, and this has been the case for tuberculosis since the first anti-tuberculosis drug, streptomycin, was discovered in 1945.
Multi-drug resistant tuberculosis (MDR-TB) is defined as a strain of tuberculosis that is resistant to the most potent drugs—isoniazid and rifamipin. In addition, some strains of TB have developed resistance to an even broader array of drugs and have been dubbed extensively drug-resistant (XDR), defined as MDR with additional resistance to a fluoroquinolone and an injectable drug. When the tuberculosis organism is replicating in the body in the presence of low levels of drugs due to irregular or inadequate treatment, resistant mutants of tuberculosis are selected. Once an individual has a strain of drug-resistant tuberculosis, he or she may transmit the strain to others.
XDR-TB has already been found in 28 countries on six continents, including all of the G8 countries. There has been great progress made in recent years to address the emergence of MDR-TB, but the existing plan to fight this disease will need to be broadened and strengthened to tackle XDR-TB and HIV co-infection.
What is different now?
Several issues have converged to draw attention to the specter of resistant tuberculosis.
First, people with HIV are exquisitely sensitive to contracting tuberculosis, developing active and progressive tuberculosis infection and dying if the correct anti-tuberculosis drugs are not given promptly. What sparked the current global concern over XDR-TB is that in the South African province of KwaZulu-Natal, where HIV prevalence is high and immunity to tuberculosis is weaker, these highly resistant (XDR) strains were transmitted from person to person. The linkages between TB and HIV programs are critical, and all persons with HIV should be carefully screened for TB. Similarly, all individuals presenting with tuberculosis should be offered an HIV test and the barriers to HIV testing (both logistical and financial) should be minimized.
Second, we know that HIV treatment—with highly active antiretroviral therapy (ART)--improves the immunity of people living with HIV and decreases their likelihood of developing active TB if they are exposed to a TB strain of any kind. This therapy has been terribly delayed in resource-poor countries due to insufficient resources and lack of political will. Redoubling the effort to effectively diagnose HIV and treat and retain those who need ART is needed to impact individual mortality from tuberculosis and the spread of drug-sensitive and drug-resistant tuberculosis.
Third, the spread of XDR-TB is a consequence of a woefully inadequate health care infrastructure, one that is insufficient to prevent the spread of XDR-TB, facilitate its prompt detection, and administer its appropriate treatment. In dilapidated clinics and hospitals, tuberculosis easily spreads in crowded and poorly ventilated wards. The severe shortages of health workers caused by poor pay, immigration to other countries (so-called “brain drain”), and attrition from AIDS sap the manpower needed to address this epidemic. Investments in health workers and health facilities are fundamental to any effort battling TB and HIV/AIDS.
Fourth, diagnostic capacity is needed. Almost nothing has been invested in providing laboratories in resource-poor settings—such facilities were deemed too costly by the conventional public health approach. Yet drug resistance can only be diagnosed by culturing the tuberculosis organism. Safe and modern laboratories must be built and technical staff trained to find XDR and facilitate its treatment and control.
Finally, our world is gripped with two interrelated pandemics—HIV and TB—and the prevention, control and treatment of these diseases require long-term, community-based therapy. Such ambulatory treatment assures adherence to and completion of the prescribed treatment, improving outcomes and preventing the development of resistance. It also decreases the concentration of infectious people in congregate settings. Community health workers are best suited to provide this type of therapy, but this class of health workers does not exist in most places in the world and where they do, they are often asked to serve as volunteers, resulting in high attrition rates and the need for constant retraining. Developing a global cadre of health workers of this type is critical to tackling these pandemics.
Is it treatable?
In southern Africa, death rates among people living with HIV in South Africa who acquire XDR-TB have been estimated at around 85 percent. This is not because XDR-TB is untreatable, but rather because in most places, patients infected with XDR-TB have not been promptly diagnosed and correctly treated. This failure to provide services has led to the myth that XDR-TB is untreatable or a death sentence.
Our organization, Partners In Health, affiliated with the Brigham and Women’s Hospital and Harvard Medical School, has been successfully treating MDR-TB since 1994 in Haiti, Peru, Russia, and most recently in Rwanda and Lesotho. Socios en Salud, our “sister organization” in Peru, arguably has more experience in MDR-TB than any other organization in the world, having treated over 10,000 cases of MDR-TB. As early as 1996, we documented high levels of resistance in some of these cases, which would now by definition be labeled XDR-TB. In Peru, however, the highly resistant nature of many of the strains did not garner the same type of media attention because of the low prevalence of HIV. In such settings, the spread is not as rapid as in southern Africa, where a high proportion of the population has HIV and has not received antiretroviral therapy.
What is needed?
Treatment is possible but it depends on prompt diagnosis and timely administration of appropriate therapy and sustained treatment for 2 years. This requires health care workers who are trained to have a suspicion for drug-resistant TB, HIV testing linked to tuberculosis control efforts, a laboratory that is capable of making the diagnosis, health care workers that can prescribe and follow up the treatment for both XDR-TB and HIV, and a cadre of community health workers that can assure adherence to the drugs in the community. If hospitalization is needed, the treatment and control of XDR-TB require hospital wards with adequate ventilation and staffing.
To combat XDR-TB, the World Health Organization (WHO) is calling for at least $650 million globally in immediate emergency funding for the purchasing of drugs and diagnostics, and some immediate infection control. Experts and global leaders like Archbishop Desmond Tutu of South Africa have been calling on the United States to provide $300 million this year because we simply cannot wait another year to jumpstart these efforts. These figures do not capture all of the broader needs of TB treatment and lab strengthening that is needed to both treat and prevent XDR-TB. In fact, to strengthen basic TB control, the WHO-estimated cost is $5 billion annually, in addition to the immediate funds needed to address XDR-TB.
I would like to offer some optimism in the midst of the pessimism that all of us feel sometimes in thinking about an airborne disease that is very difficult to treat. In Peru, the Socios en Salud and Partners In Health collaboration started in 1996 as a primary health care project. Within one year, much to our surprise, we had diagnosed hundreds of patients with MDR-TB. At that time, MDR-TB was considered “untreatable” in poor countries. Led by Dr. Jaime Bayona in Peru, what began as a pilot project of an NGO with only a handful of patients became a full-scale national program. It is now the largest MDR-TB treatment program in the world and is run by the Peruvian Ministry of Health with close collaboration with Dr. Bayona and his team. Then and now, community health workers play a critical role in providing directly observed therapy and what we call accompaniment—home visits to assist in adherence, but also to provide social support and to serve as a liaison to the health system.
Similarly, in 1998, we were invited into the former Soviet Union to treat tuberculosis inside the penitentiary system in Tomsk Oblast, western Siberia. About a quarter of the people with tuberculosis in the prison systems were dying of MDR-TB. With our partners in the prison, under the leadership of Dr. Sergey Mishustin, the prison introduced infection control and comprehensive TB treatment for all TB, including drug-resistant TB. The death rates inside that prison dropped to zero within 2 years. As this program is “scaled out” into the civilian sector, community health workers are instrumental in the provision of therapy in this remote rural area.
Though extremely difficult, it is possible to treat highly drug-resistant TB. With political will, meaningful partnerships, training of health workers (including at community level) and investments in laboratory and health infrastructure, it can be done. The new twist is that when HIV and TB collide--especially when HIV and drug-resistant TB collide--there is an even more urgent need to intervene effectively because HIV speeds up the process and makes epidemics of TB, especially drug-resistant TB, faster and more lethal.
That is what we are seeing in southern Africa. Some of the data that we have seen from the South African province of KwaZulu-Natal, which borders the landlocked country of Lesotho, show very high death rates from drug-resistant TB among patients with HIV who are on therapy for HIV. This has led to the incorrect perception that drug-resistant TB is untreatable.
The reality is that HIV was being treated effectively with antiretroviral therapy, but TB infection was left untreated. Until we bring effective therapy for both MDR-TB and HIV together, we will not see the results we want. A program to treat XTR-TB that we are launching in Lesotho with the support of the Open Society Institute and the Ministry of Health of Lesotho builds on a decade of experience, but it will also face new challenges because of the high rates of HIV and co-infection.
It is all the more urgent for us to develop strong infection control programs that move therapy, whenever possible, into the community. Good community-based care has many positive aspects, one of which is to avoid having infected patients congregate inside treatment facilities--what we call “nosocomial infection” in public health jargon. To some extent, we need to use hospitals to treat this disease, but we have to make the hospitals safe for our patients so that they do not become infected or re-infected.
XDR-TB does not need to be a death sentence. If we can combine good infection control, good prevention strategies, and good therapy, we know from our past experience that we can curb this epidemic and save thousands of lives.
Joia Mukherjee is Medical Director of PIH, Director of the Institute for Health and Social Justice, and Assistant Professor of Medicine at Harvard Medical School and the Brigham and Women's Hospital in Boston.
[published April 2007]