Issue: March 2013
March 01, 2013
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Collaboration needed for global MDR-TB threat

Issue: March 2013
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In December, bedaquiline was approved by the FDA for the treatment of multidrug-resistant tuberculosis — one of only two tuberculosis drugs approved since rifampin in 1968. To put that into perspective, there have been 33 antiretroviral drugs approved, either single or combination agents, for the treatment of HIV since 1987.

The backbone of treatment for TB consists of rifampicin and isoniazid. However, MDR-TB, which is resistant to both of those agents, is a growing, global health concern. With a limited number of agents available for the treatment of TB in general, MDR-TB makes treating an already difficult infection even more difficult.

“It’s a serious concern and it’s not an exaggerated concern,” said Joel Ernst, MD, professor in the departments of medicine, microbiology and immunology at NYU Langone Medical Center, and an Infectious Disease News Editorial Board member. “In TB, more so than in any other infections, losing the two first-line drugs [to resistance]is a big loss.”

According to the WHO Global TB report, TB is the second leading cause of death from infectious disease, after HIV. In 2011, there were an estimated 8.9 million new cases of TB, and among those, approximately 3.7% were estimated as having MDR-TB. There are many challenges associated with MDR-TB but those involved with TB, on a national and a global scale, are trying to determine the true extent of the problem, develop new treatments, increase funding and improve diagnostic methods.

Mario Raviglione, MD, director of the Stop TB Department at WHO, said an estimated $2 billion will be required in 2015 for diagnosis and treatment of MDR-TB.

Photo courtesy of International Union Against TB and Lung Diseases/JT Photo

“It’s a big challenge, and there has been only slow progress, so far,” Mario Raviglione, MD, director of the Stop TB Department at WHO, said in an interview with Infectious Disease News. “There are a ton of different obstacles at all levels that have to be addressed together. One needs to have laboratories capable of diagnosis MDR-TB, second-line drugs of quality available, well-defined care approaches, regulations to ensure private practitioners are following international standards, and a quality assured surveillance system so that data in all countries are comparable.”

Infectious Disease News spoke with leading experts in TB to discuss the issues surrounding MDR-TB.

MDR-TB prevalence

MDR-TB made headlines when outbreaks occurred among AIDS patients in four hospitals from 1988 to 1991: three in New York City and one in Miami. When a subsequent outbreak in the New York prison system later led to the death of a prison guard from MDR-TB, the issue rose to international prominence.

“That basically brought the issue to the forefront,” Kenneth G. Castro, MD, director of the CDC’s division of tuberculosis elimination, said in an interview. “It provided an impetus to WHO and other organizations to try to get a handle on how common MDR-TB is in the world. The findings of the first drug resistance survey unveiled that, in some countries, especially the former Soviet Union and countries in Eastern Europe, the rates were quite high.”

According to Raviglione, WHO set up an international network of laboratories in 1994 to determine the extent of MDR-TB in the world. Previously, the data in different countries were not comparable, so it was unknown whether the resistance being seen in one country was the same as the resistance seen in other countries. WHO worked to standardize the reporting methodology, launching the Global Project with other partners as a way to estimate the extent of MDR-TB. In 1998, the first results were published in The New England Journal of Medicine.

The problem was more acute than people realized. All 35 countries and regions surveyed had reported cases of MDR-TB, with the highest prevalence being found in the former Soviet Union, where the prevalence of MDR-TB was 9% to 10%. Later in Asia, where the prevalence was 12% to 15%.

“When these data from the Global Project came out, that’s when we recognized that MDR-TB was, in fact, a true global health problem,” Charles Daley, MD, chief of the division of mycobacterial and respiratory infections at National Jewish Hospital in Denver, told Infectious Disease News.

Today, most cases of MDR-TB — over 60% in 2011 — occur in China, India, the Russian Federation, Pakistan and the Phillipines.

Path to resistance

For many infections, there are a number of antibiotics in the armamentarium that physicians can turn to as alternatives. This is not the case for TB.

“Drug resistance in TB did not exist before the 1960s, when we started using drugs to treat it,” Robert Horsburgh, MD, professor of epidemiology, biostatistics and medicine at Boston University, said in an interview. “When the drugs began to be used more widely, drug resistance started to spread. Unfortunately, there were no other drugs to turn to.”

This means that drug resistance is actually a manmade problem, according to Mel Spigelman, MD, president and CEO of the TB Alliance, a nonprofit global alliance group dedicated to developing new treatments for TB. The current problem of MDR-TB is that TB, in general, has been a fairly neglected disease, but not neglected enough.

“There have been enough resources put behind TB so that patients are treated, but the amount of resources that have been put into treatment have not gone into treatments that are scalable enough to fight the existing problem,” Spigelman said.

Archaic treatment

Drug-susceptible TB is already difficult to treat. With MDR-TB, the already complex treatment becomes more complicated.

“MDR-TB is much more difficult to treat and requires more extensive treatments that are more toxic,” David Cohn, MD, an Editorial Board member of Infectious Disease News, said. “Not only are the treatments more toxic, the treatment time lasts 18 to 24 months, if not more. We clearly need better drugs for second-line TB treatment because the drugs we have are archaic.”

The complex treatment regimen for MDR-TB involves more drugs that are not as potent as the first-line treatment drugs, Ernst said. In addition, the treatment period could potentially be four times as long as the treatment period for drug-susceptible TB.

“Patients need to attend clinic for treatment for four times as long,” Ernst said. “In an oversimplified mathematical way, you have four times as many patients in the clinic, but not as many resources.”

The drugs also are expensive. In the late 1990s, the cost for the treatment course ranged from $5,000 in the poorest countries, up to well over $20,000 in the United States and developed countries, Raviglione said.

By 2000, the Green Light Committee was formed, which was a technical committee advising WHO to evaluate MDR-TB proposals from countries and determine what countries would benefit most from subsidized, quality-assured second-line drugs, ensuring that the treatment of MDR-TB would stay within WHO guidelines.

Detecting resistance

When patients find out they have TB, they still will not know immediately that they have MDR-TB because drug susceptibility testing is not a quick process.

“What we’re dealing with is a slow-growing mycobacterium that in solid media takes several weeks to grow and then needs identification and drug susceptibility testing,” Castro said. “If you are relying exclusively on these methods, we’re talking about a 12-week span to identify the disease and then do drug susceptibility testing. These results are fairly irrelevant in informing clinical decisions on the selection of adequate treatment regimens. Even the liquid media methods still take about 4 weeks to detect drug resistance.”

According to Daley, although these tests are accurate for some drugs, the time needed for the tests hinders the ability to get patients started on appropriate treatment more quickly. Not treating the patients properly poses the risk that the patients will transmit the disease to others, continuing the cycle of the spread of MDR-TB.

There is a molecular test available, the GeneXpert system (Cepheid), that can identify TB and determine whether the TB is resistant to rifampcin within 90 minutes. This test represents a paradigm shift in the detection of TB and drug resistance, Daley said, but the technology, although fast and accurate, is not cheap.

Charles Daley

Charles Daley

“By looking at cost projections, you could probably show, that over time, widespread use of this test will save money by diagnosing people quickly, getting them treatment and preventing transmission to others,” Daley said. “In the long run, this will probably be a cost-effective strategy.”

GeneXpert is not yet licensed by the FDA for use in the United States to detect TB. In the meantime, Castro and colleagues at the CDC are working on other molecular methods to detect resistance, by sequencing DNA to identify the mutations that confer resistance.

“It’s going to take investment in the research that provides proof of principle, and then it will need to withstand vigorous quality assurance methods,” Castro said. “It then needs to be accessible to patients, and it will be necessary to make sure that the results are used to make a difference in patient outcomes.”

New treatments, less time

The accelerated approval of bedaquiline (Sirturo, Janssen Therapeutics) was a major milestone for MDR-TB. Bedaquiline is in a new class of drugs called diarylquinolines, which have a novel mechanism of action against mycobacteria. In clinical trials to date, bedaquiline was highly effective against MDR-TB combined with current second-line therapies.

Another potential player that experts are optimistic about is delamanid (Otsuka). In The New England Journal of Medicine, researchers reported that delamanid, a nitro-dihydro-imidazooxazole derivative, improved the rate of sputum culture conversion when given to patients with MDR-TB with the background regimen.

There are many efforts to develop better treatments for MDR-TB in part because of the efforts of organizations like TB Alliance and RESIST-TB, which is chaired by Horsburgh.

“The only way progress can be made in this field is through partnerships, which is at the core of our existence,” Spigelman said of the TB Alliance. “We currently have [a pipeline of] projects ranging from basic research to phase 3 clinical trials. We have the potential to revolutionize the treatment of TB, if we can mobilize the resources and the partnerships that it will take to bring all of this across the finish line.”

In phase 2b stages right now is a new regimen that could potentially bring treatment time down to 4 months, Spigelman said. In the laboratory, they have identified regimens that cure TB in mice in 6 weeks.

RESIST-TB works with the TB Alliance in research efforts and is currently involved in phase 3 research of delamanid and in testing short TB drug regimens.

“There are some new drugs out there, and the most important thing right now is to take these new drugs, figure out how to use them best and put them out in the places that need them the most,” Horsburgh said. “This is going to require a lot of steps.”

Funding for TB

According to Raviglione, an estimated $8 billion will be required in 2015 for the diagnosis and treatment of TB, of which 2 billion are just for MDR-TB. Costs for second-line drugs alone are about $300 million a year.

“The amount that currently goes into TB control from the Global Fund is about $400 million a year, which is 90% of all external funding,” Raviglione said. “However, the gap remains high, and we estimate that an additional one billion US dollars would be necessary from international financers to help fill such gap. In research and development of new tools, about 2 billion US dollars per year would be necessary but only 630 million were mobilized in 2010. This is a major problem because acceleration of research cannot happen. When you compare HIV and TB, they are similar, globally speaking, in that they kill roughly the same number of people. But if you look at the amount of money committed to HIV research, it is much higher than what is being spent in TB, which is completely disproportionate to the burden of TB.”

The Bill & Melinda Gates Foundation has allocated more than $900 million for TB research during a 6-year period, which results in about $160 million a year. Raviglione said the NIH funds about the same amount. There are some drug companies that have contributed to the investments, including those that are in the network with the TB Alliance, who were key players in the development of bedaquiline.

“It hasn’t been easy, but we’ve been successful,” Spigelman said. “By working together, we can bring a lot more resources to the party and provide a path for companies to maximize the benefit of investing what are, realistically, small sums of resources.”

These advances provide a lot of hope that the detection and treatment of MDR-TB will be easier. But a lot of work still must be done.

Unfortunately, there has been the emergence of extensively drug-resistant TB, which also is resistant to fluoroquinolones and any of the second-line TB injectable drugs: amikacin, kanamycin or capreomycin (Capastat, Akorn). XDR-TB comprised 9% of the MDR-TB cases in 2012 and was reported in 84 countries.

In the meantime, MDR-TB remains a global health problem, and partnerships between WHO, pharmaceutical companies, CDC, TB Alliance, RESIST-TB and others are necessary to change this.

“It’s a solvable and winnable problem, but it’s a problem that will cost a lot of time and money to fix,” Daley said. —by Emily Shafer

References:
CDC. MMWR Morb Mortal Wkly Rep. 1991;40(34):585-591.
Gler MT. N Engl J Med. 2012;366:2151-2160.
Pablos-Méndez A. N Engl J Med. 1998;338:1641-1649.
TB/HIV Working Group. TB/HIV Facts 2012-2013. Available at: www.stoptb.org/wg/tb_hiv/assets/documents/TB-HIV-Fact_Sheet_2012.pdf. Accessed Feb. 20, 2013.
WHO. Global TB Report 2012. Available at: www.who.int/tb/publications/global_report/en/. Accessed Feb. 20, 2013.
WHO. Multidrug-resistant tuberculosis (MDR-TB) 2012 Update. Available at: www.who.int/tb/publications/MDRFactSheet2012.pdf. Accessed Feb. 20, 2013.
For more information:
David Cohn, MD, can be reached at david.cohn@dhha.org.
Charles Daley, MD, can be reached at National Jewish Health, 1400 Jackson Street, Denver, CO 80206; email: daleyc@njhealth.org.
Joel Ernst, MD, did not provide contact information.
Mario Raviglione, MD, can be reached at STD Dept., WHO, 20, Avenue Appia, CH-1211 Geneva; email: raviglionem@who.int.
Mel Spigelman, MD, can be reached 40 Wall Street, 24th Floor; New York, NY 10005.

Disclosures: Daley reports serving as the Chair the Data Monitoring Committee for clinical trials of delaminid. Cohn, Ernst and Raviglione report no relevant financial disclosures.