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Tuberculosis (TB) is often thought of as a disease of the past, but a recent resurgence and the spread of drug-resistant forms makes it very much an issue of the present day and age. Though the global death rate from TB dropped more than 40 percent in the years between 1990 and 2011, there are still crucial gaps in coverage and severe shortcomings when it comes to diagnostics and care options. Furthermore, we are currently seeing an alarming rise in cases of drug-resistant and multidrug-resistant tuberculosis—DR TB and MDR TB—that do not respond to the customary first-line drugs.
One of the three main killer infectious diseases—along with HIV/AIDS and malaria—TB infected nearly nine million people in 2011 and killed 1.4 million, according to the World Health Organization (WHO). One out of every four deaths of people living with HIV/AIDS is caused by TB as well.
In 2011, 22 countries accounted for roughly 80 percent of all new TB cases. Southeast Asia has had the highest numbers of new TB cases in recent years—roughly 60 percent of the global cohort—but sub-Saharan Africa has a higher concentration of new cases. The Western Pacific region has been hit particularly hard as well.
A Killer Disease with Deadlier Forms
TB is caused by a bacterium, Mycobacterium tuberculosis, that the WHO says infects one third of the world’s population. Between five and 10 percent of infected people develop the disease and become contagious at some point in their lives. (For those with HIV or AIDS, the rate is much higher.)
The disease usually develops in the lungs, although there are extra-pulmonary cases where the bacilli infect other parts of the body, usually the lymph nodes, bones, central nervous system, or cardiovascular and gastrointestinal systems. Major symptoms of TB are: prolonged cough, bloody expectorations, chest pain, and changes in a person's general health status. Coughing, sneezing, talking, and spitting can all spread the bacilli into the air, where they can remain viable for several hours—time during which they could we be inhaled by another person.
In 2011, 310,000 cases of MDR-TB were diagnosed, according to the WHO. Barely one in twenty TB patients is even tested for drug resistance, though, so this number likely represents just the tip of the iceberg. And yet the reaction of the global medical community has been slow, vague, and inefficient, particularly when it comes to developing better treatment options for MDR TB patients, including children.
In several countries, including those of the former Soviet bloc, rates of DR TB are high and threaten to overwhelm TB control efforts. The disease is also having a particularly devastating effect in countries that are highly affected by HIV/AIDS, since people with compromised immune systems are much more likely to develop active TB.
Troubles with Diagnoses and Care
The research and development (R&D) of new, more effective diagnostic tools and drugs for TB been severely lacking for decades now. In countries where the disease is most prevalent, diagnosis has depended largely on one archaic test for the last 120 years—smear microscopy, the microscope examination of sputum, or lung fluid for the TB bacilli.
The test is only accurate half of the time, even less so for patients who also have HIV. This means that too many patients start treatment late, if they start it at all. Children, who often cannot produce sputum, urgently need a new diagnostic tool, especially since they are particularly vulnerable to dying if they develop active TB.
A promising new diagnostic test, Xpert MTB/RIF, was introduced in 2010, and MSF has used it in many of its programs since. It’s not applicable to all settings, nor is it effective for diagnosing children or patients with extra-pulmonary TB, so MSF continues to call for further research and development in diagnostics for TB, particularly for a simpler and easier-to-use "point-of-care" test.
At the same time, however, the test clearly represents a significant advance for timely TB and DR TB diagnosis. The Xpert MTD/RIF is much faster than sputum smear microscopy—providing results within two hours—and it did result in an average 50 percent increase in lab-based diagnosis of TB. It also detects resistance to one of the primary TB drugs, rifampcin, so MSF was able to use it to compile data from 25 projects in 14 countries that showed the growing global crisis of DR TB. “This new TB test is helping expose the true size of the drug-resistant TB epidemic and get people on treatment faster,” said Dr. Helen Bygrave, HIV/TB specialist with MSF in South Africa, in December 2012. In an MSF project in Zimbabwe, for instance, preliminary results showed that the introduction of the test resulted in a near quadrupling of DR TB diagnoses. In an MSF project in Swaziland, the delay between collecting a patient’s sample and starting DR TB treatment was reduced by 79 percent, from 65.9 days to 13.9 days.
Another MSF study released in late-2012 reinforced the notion that tests better adapted to children with TB are sorely needed—as is more information on just how many children are suffering from TB. Drawing on data collected over three years from 2,451 children with TB in 13 MSF projects across six countries, it showed that children co-infected with HIV and TB were at a greater risk of dying than children solely with TB, at 12.8 percent compared to 5.2 percent in HIV-negative children. And while more than half the whole cohort (56 percent) had pulmonary TB, only 6.4 percent had tested "positive" for TB with sputum smear microscopy. “When you’re only detecting TB in one out of ten children, you can be sure that many are falling through the cracks simply because they’re not being diagnosed, resulting in unnecessary deaths and the disease spreading to others,” said Dr. Philipp du Cros, head of MSF's medical department in London. “Most revealing of this sad reality is that until just last month, there was little data on the global burden of pediatric TB.”
“What we need to see now is test developers showing that children are a priority, and that will mean developing tests that respond to their needs,” said Dr. Grania Brigden, TB Advisor for MSF’s Access Campaign. “We need to move away from having to put children through excruciating procedures to get lab specimens that in the end don’t provide us with a diagnosis.”
Old, Lengthy Treatment
First-line treatment of TB requires a six- to eight-month regimen of medicines that were introduced more than 50 years ago. It is a grueling process even in the best-case scenario, but if treatment is interrupted, if adherence slips, it can give rise to drug-resistant strains of the disease.
When this happens, as it has happened, the challenges are even greater. MDR TB patients do not respond to the two most powerful first-line drugs, isoniazid and rifampicin. The medicines used to treat MDR TB are of limited efficacy, with a cure rate of just 48 percent. They often produce disabling side-effects, and the treatment course lasts for two years. Extensively drug-resistant TB (XDR TB) is often untreatable and many patients can only receive palliative care.
This is worrisome now that some 4 percent of new TB cases involve DR TB. Pediatric formulations of DR TB drugs are also urgently needed.
After a 40-year virtual R&D standstill, there are now some promising new medicines for drug-sensitive and drug-resistant TB in the drug pipeline. Two new drugs to treat TB—the first to be developed for the disease in almost 50 years—are expected to come to market in 2013 and are both active against drug-resistant forms of the disease. Their introduction represents a critical opportunity to improve DR TB treatment and every effort should be made to ensure they are used in a way that allows treatment to be made more tolerable, affordable, and accessible to patients in developing countries.
“With new medicines for drug-resistant TB at the doorstep for the first time in half a century, the global health community can’t afford not to seize the opportunity of a lifetime by stopping drug-resistant TB from spiraling out of control,” said Dr. Manica Balasegaram, executive director of MSF’s Access Campaign.
MSF and TB Treatment
In 2011, MSF treated nearly 31,000 people for TB in a host of different countries and programs. Often working alongside national health authorities, MSF had projects situated in locations ranging from prisons in Kyrgyzstan to small towns in Cambodia to HIV-endemic settings such as Swaziland and South Africa. Teams also treated more than 1,000 patients with drug-resistant TB.
MSF uses fixed-dose combination drugs (FDCs), which, by combining multiple medicines into a single drug, reduce the number of pills patients must take each day, greatly simplifying treatment. However, patients with MDR TB can be required to take up to 20 pills per day; and the medicines used in fighting drug-resistant strains can cause often intolerable side effects, including nausea, severe vomiting, depression, aggressive behavior, hallucinations, vertigo, hearing loss, and diarrhea.
“It was a nightmare,” one patient said of the treatment. “You can’t even imagine how hard it was to take the medicines. You want to sleep, but you can’t. You’re tired, you have heartburn. You vomit, but you don’t feel better.”
R&D into TB drugs and diagnostics was neglected for decades because the disease primarily affects developing countries and therefore did not represent a lucrative market for the pharmaceutical industry. In 2011, though, the not-for-profit Global Alliance for TB Drug Development, a product development partnership founded in 2000 to accelerate R&D for TB drugs, had ten new or repurposed compounds in the clinical development stage with the intention that in the future some of them will be part of a single treatment regimen against both drug-sensitive TB and all forms of drug-resistant TB.
To treat TB, the WHO recommends the so-called DOTS (Directly Observed Treatment Short-course) strategy, where patients take medication under supervision from health staff. MSF has found that daily supervision of treatment is too demanding for most of our patients and instead implements self-administered therapy with patient education and support to ensure adherence. In many countries affected by conflict, access to health structures is limited for the population. Conflict interrupts travel and makes people fearful of leaving their shelters to seek assistance. It can also lead to the collapse of existing health systems.
For example, in Somalia’s Middle Shabelle Region, MSF implemented a modified strategy that enabled patients diagnosed with TB to receive their first dose under supervision from health staff and then continue their treatment at home until their next scheduled appointment at the health center. Poverty and the inability to access transportation to reach a clinic can also hinder a patient’s adherence to their treatment regimen. MSF’s TB program in Armenia provides coupons for food and fuel in the winter and a transportation allowance for discharged patients. Patients in Cambodia are set up with a local nurse for home-based supervision.
Treating Patients with TB-HIV/AIDS Co-infection
People with compromised immune systems are even more susceptible to developing active TB; in fact, TB is the biggest killer of people with HIV/AIDS worldwide. Treating patients co-infected with HIV and TB is a huge challenge.
“These patients [co-infected with TB and HIV] have to take between 13 and 16 pills a day,” said Dr. Gilles Van Cutsem, coordinator of an MSF program in South Africa. “There are also interactions between HIV and TB treatments which cause side effects like liver problems or allergies.”
In Swaziland in 2010 and 2011, more than 80 percent of TB patients were found to be co-infected with HIV. A few years ago, MSF started a systematic decentralization of care and integration of TB and HIV treatment in Swaziland, so patients can get care for both diseases at the same place, closer to where they live. MSF also implemented task-shifting; given the dire shortage of health professionals, delegating responsibilities to lower cadres of workers—from doctors to nurses, and from nurses to lay community workers—has proved to be an effective model of care delivery and allowed more people to be treated.
Some Success, More Challenges
There has been some good news in the fight against TB, such as the introduction of new and faster tests, as well as, in MSF’s case, the welcome announcement in October 2012 that a 48-year-old Zimbabwean woman had become MSF’s first MDR TB patient in the country to be cured of the disease. But there are still a great many challenges ahead. Too many people are not getting the treatment they need. Too many people are not getting diagnosed properly or soon enough. Too few new products are being developed given the size and scope of the problem.
TB has to be understood as a disease of today, of right now, rather than of some bygone age. A new urgency must attend the search for a safe, effective, oral, short-course of drugs that isn’t as toxic but is affordable and adapted for the remote and rural places MSF works. Furthermore, a great many people in a great many places would benefit immensely from the development of a simple, effective point-of-care test that does not rely on sputum, that can diagnose TB swiftly and accurately, and that can detect drug resistance. And children with DR TB need pediatric formulations of the drugs that might help them outlive their disease. TB has been with us for a long time, but these things need to happen soon if present-day victims are to avoid the fates of those who contracted the disease in days long gone by.