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XDR–TB, MDR–TB emerge as global threats
Clinicians, researchers, health organizations and industry tout urgent need for infection control, awareness and laboratory growth.
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TORONTO – Ten years ago, a microbiologist only a month into her position as vice president of scientific affairs for a leading drug manufacturer received a phone call. The call, and the response to it, would launch a $150 million project — and counting — that would become part of a first step in a global effort to thwart a tuberculosis epidemic.
Two young Harvard physicians at a tuberculosis clinic in Peru needed drugs for their patients, but had run out of money. They had been paying for two of four necessary drugs in the treatment course for multidrug-resistant TB (MDR–TB) with their own money. They called Eli Lilly and Company for assistance.
A decade later, the project and Eli Lilly’s support of Partners in Health is in full swing globally, but TB has spread rapidly in two additional mutated forms, MDR–TB and extensively drug-resistant TB (XDR–TB).
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TB specialists from industry, research institutions, clinics and WHO met here for the American Society for Microbiology 107th General Meeting to discuss MDR–TB and XDR–TB intervention efforts.
MDR–TB is now present in 90 countries. XDR–TB is now emerging as a worldwide threat because strains resistant to more than three of the six classes of second line drugs used to treat MDR–TB have been identified. In one survey, 9.9% of MDR–TB patients met criteria for XDR–TB.
Although the drug industry continues to support research and drug development, the short-term prognosis is not optimistic, partly because TB control was neglected for years in resource-limited countries and because of the nature of the disease.
“Drug development for any disease is challenging, but this is particularly true for TB because the organism is complex and one drug is not enough,” said Gail H. Cassell, PhD, vice president of scientific affairs for Eli Lilly.
“At least four new antibiotics are needed because tuberculosis treatment requires a combination of antibiotics,” she said. Cassell fielded the call for drug help 10 years ago, which she called the highlight of her career, and has been working on follow-up since.
Global effect
WHO estimates that 423,000 new cases of MDR–TB occur each year. Only 5% of those cases are incident cases in which the patient has access to proper diagnostics and care, and only 2% have access to treatment. Someone dies from TB every 20 seconds, according to another estimate.
“This is just the tip of the iceberg,” said Ernesto Jaramillo, MD, leader of the drug resistant team at WHO Geneva. “I would like to make clear that XDR–TB and MDR–TB are not a theoretical threat; this is a fact.”
An important element to curbing XDR–TB and MDR–TB is effective TB control, which has been grossly neglected in previous decades. Barriers include lack of facilities for diagnostics, lack of skilled health care professionals and limited or no drug access.
Partnerships between the Bill and Melinda Gates Foundation, Partners in Health and Eli Lilly have demonstrated that TB control can be feasible and cost-effective in the long run.
Management of TB is not simple or inexpensive, however. Initial estimates by WHO are $900 million this year for a proper response, and $1.2 billion next year.
“If TB control is properly delivered, we are paving the way for prevention of MDR–TB and XDR–TB, as well,” Jaramillo said. “XDR–TB is nothing new. The importance of the threat is just being acknowledged now.”
Jaramillo noted a report to WHO of a person with XDR–TB on a plane traveling from Russia to South Africa.
“What do we do with the 300 contacts, they asked,” Jaramillo said. The report was months before the Andrew Speaker case was reported in the U.S. media.
Two cases of MDR–TB were reported in Denver in the past few months.
“The physician told me that neither of these patients had ever been treated before, meaning they caught it from other people and there was absolutely no hint of where the infection could have come from,” Cassell said.
In similarity to the Speaker case, one Denver patient was a young, male lawyer who was otherwise healthy. The lawyer had visited a TB hospital on a local Rotary Club trip to Southeast Asia.
XDR–TB burdens and barriers
XDR–TB was first defined in a collaborative study conducted by the CDC, WHO and 14 national TB reference laboratories. The findings were published last year in Morbidity and Mortality Weekly Report.
“XDR–TB is a wake-up call and there are serious consequences if we fail to implement effective TB control,” said Sarita Shah, MD, assistant professor at Albert Einstein College of Medicine and author of the first XDR–TB summary.
In a survey of nearly 18,000 isolates, 20% of those were MDR–TB and 10% of those were XDR–TB. Drug susceptible TB is curable in 95% of cases, but mortality rates for XDR–TB are more than 50%. For patients co-infected with HIV, mortality rates are estimated at 90%.
“We must strengthen TB control at the same time as we expand HIV care and treatment in improving health care for patients in parts of the world most affected by this epidemic,” Shah said.
One barrier to controlling the problem is limited lab capability, particularly in HIV–endemic countries. HIV makes a person more susceptible to TB and makes the pathogen more deadly. In South Africa, there are 14 laboratories capable of culture and drug susceptibility, which is more than the rest of Africa combined.
Treatment in low HIV areas
Partners in Health and Brigham and Women’s Hospital have been providing technical assistance to scale up TB treatment in Peru and Russia since 1996. Both areas have low HIV/AIDS burdens and study participants from clinics there had better outcomes attributed to the intervention and the lack of HIV coinfections.
In a retrospective study in Peru, MDR–TB patients (n=670) were treated during the course of three years at the clinics. Seven percent had XDR–TB at treatment initiation. The cure rate among the XDR cohort of 48 patients was 60% compared with 67% of non-XDR patients.
“It was encouraging that our cure rates were not terrible and they were not significantly altered depending on whether you did or did not have XDR–TB,” said Sonya S. Shin, MD, a clinician at Brigham and Women’s Hospital and Partners in Health.
Similarly, death rates were not significantly different. The death rate was 23% in the XDR cohort versus 21% in the MDR cohort.
In Russia, a retrospective analysis of XDR and MDR patients (n=582) from both the civilian and prison sector was conducted from 2000 to 2004. About 5% of the total cohort (n=28) had baseline XDR upon beginning MDR treatment. The cure rate was 54% in the XDR group and 64% in the MDR group.
In the Russian cohort, researchers identified 54 cases (about 10%) that did not have XDR at initiation of MDR treatment but later had some repeat susceptibility that demonstrated XDR during the treatment course. Those patients were found to be more likely to have substance abuse issues and higher baseline drug resistance.
“Even in strong MDR and XDR interventions, XDR should be expected to occur,” Shin said.
The results showed that XDR can be treated in cohorts with low HIV burden as more than 50% patients were cured during the intervention.
“Obviously that is not as high a rate as we want, but it is still meaningful when you talk about individual outcomes,” she said.
HIV endemic areas
Outcomes for people with MDR–TB and XDR–TB in South Africa are worse than in low endemic regions. HIV epidemics have been closely intertwined in South Africa for the past decade. Annual mortality rates among TB and HIV co-infected patients range from 30% to 40%.
“The hope in South Africa was that once antiretrovirals for HIV were available, mortality would decline,” said Neel R. Gandhi, MD, an assistant professor at the Albert Einstein College of Medicine and a researcher with the Tugela Ferry Research Collaboration in South Africa.
“Unfortunately, what we are seeing is even though antiretrovirals are available, TB and HIV co-infected people are continuing to die.”
In a recent study, researchers found that people who were responding well to antiretroviral therapy (ART) died of MDR–and XDR–TB. A large portion of MDR–TB and XDR–TB patients die without a proper diagnosis because of a lack of laboratory capacity and diagnostics. Researchers said patients with HIV vulnerable to MDR–TB and XDR–TB are admitted to hospitals there and are exposed to the pathogens because of poor infection control.
“This scenario results in a cascade of outbreaks similar to those in Europe, which results in a large number of drug resistant patients and a high mortality,” Gandhi said. “If there is a threat of XDR–TB anywhere, it’s really a threat everywhere.”
Industry response
Current medications for TB are 40 years old and require a six- to nine-month regimen. For MDR–TB and XDR–TB, treatment duration can extend to two years. Difficulty in adherence in low resource countries causes drug resistance. Resistance and HIV co-infection make the pandemic more deadly.
“The magnitude of the challenge is so great that no one organization alone has the resources to be successful, so public–private partnerships are the way to go,” Cassell said.
Partners in Health work in Peru for the first time proved that patients with MDR–TB could be effectively treated, and then WHO and the CDC started the DOTS-Plus program for MDR–TB treatment, she said.
At present, there are seven compounds in clinical development for TB treatment, but there is a 50% failure rate even in phase 3 of clinical development.
“Another issue is that we have to treat TB with a cocktail of drugs, we don’t need just one, we need four at a minimum, and urgently,” Cassell said.
“We’ll be lucky if we have one new drug by 2019. Based upon historical data on drug development in general and what is currently in the TB drug development pipeline, there’s only a chance this will happen.”
In a $70 million philanthropic effort announced in 2003, Eli Lilly transferred its manufacturing technology for two of the five candidate drugs for MDR–TB to four of the highest burden countries and provided funding for training of health care workers. It added another $50 million to the project in March, bringing the total commitment to $120 million, which expands health care worker training and drugs provided at lower costs.
“I only tell you this because $120 million sound like a lot, but it’s really just a drop in the bucket compared to what is needed on all our parts to tackle the XDR–TB challenge,” Cassell said. – by Kirsten H. Ellis
For more information:
- Cassell GH. Industry.
- Weyer K. Laboratory infrastructure and infection control: The realities.
- Shin SS. On the ground clinical experiences community health care settings in Russia and other countries.
- Gandhi NR. The South African experience.
- Jaramillo E. A plan for action World Health Organization.
- Special Interest Symposium. Extensively Resistant Tuberculosis (XDR-TB): Pubic Health and Policy Implications. Special Interest Symposium 96. Presented at: The American Society for Microbiology 107th General Meeting; May 21-25, 2007; Toronto.