Reichman: “TB has always been ignored and forgotten”

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In advance of World TB Day (Saturday, March 24) Science Speaks sat down with tuberculosis (TB) expert Lee B. Reichman, MD, MPH, founding executive director of the New Jersey Medical School Global Tuberculosis Institute, to discuss the spread of drug-resistant TB and what he thinks are the most promising advances coming down the scientific pipeline.  Dr. Reichman has published more than 200 articles, scientific reviews and book chapters focusing on the diagnosis, treatment, prevention, control, regimen adherence and epidemiology of and advocacy for TB. He also co-authored the book Timebomb: The Global Epidemic of Multidrug-Resistant Tuberculosis with Janice Hopkins Tanne in 2002.

Lee B. Reichman, MD, MPH, founding executive director of the New Jersey Medical School Global Tuberculosis Institute.

There was an article in the European Respiratory Journal released recently about the rise of drug-resistant cases of TB in the European Union as a reflection of poor TB case management. Can you tell me a bit about what is going on there?
If you get TB and you don’t treat it properly the TB becomes resistant to the commonly used antibiotics – so where a drug-sensitive or “easy” case of TB is treated with a six to nine month course of antibiotics, a drug-resistant case of TB turns into two years of therapy with drugs that make you sick as a dog. If you treat a person with a lot of organisms with not enough drugs, they get resistant to those drugs, and it is entirely predictable. We know how to deal with drug resistant TB, but dealing with it requires resources.

People with drug resistant TB also don’t die right away – they might infect other people. Several years ago the World Health Organization (WHO) didn’t believe in treating multidrug-resistant TB (MDR-TB) because it was expensive and difficult to treat. They honestly thought people with MDR-TB wouldn’t infect other people. And then it was pointed out to them – by Dr. Paul Farmer and others at Partners in Health – that that’s not true.  That led to the practical management of drug-resistant TB and looking for new drugs, looking for strategies to make sure patients take their meds, and treating these difficult patients. There are about half a million of these cases, and about 10 percent are accurately treated, under the standards for treatment that have been promulgated.

I have found in dealing with European physicians that they are more attuned to dealing with TB than most American doctors are.

Is this a reflection of a lack of adequate public health funding?
I can’t speak to that at all. It’s like a two-edged sword. We have about 600,000 physicians in the U.S. – and we now have 12,000 cases of TB per year. Most doctors have to wait a long time to see one case of TB. So how much training can you do on this one person for the one case of TB they might see? When they come in and say they are making cuts to public health funding– training physicians to deal with this one case of TB is one of the first things to go. And then when it isn’t treated properly it will become drug resistant and infect other people. In the U.S. we only have 100 cases of MDR-TB per year because we have a good MDR-TB control program.

I’m sure you have heard about the reports of the “extra extensively” or “totally” drug-resistant TB strain in Mumbai, India recently. What are your thoughts on what’s going on there?
The WHO has yet to accept any definition of this. I’m a member of the Green Light Committee which makes these determinations. How good is the lab that made the diagnosis? Some of these labs, if you’ll excuse me, suck. What quality control has been going on there? Is it really untreatable? Or is it just extensively drug resistant TB (XDR-TB) or MDR-TB?

When Andrew Speaker was first diagnosed with TB in the U.S. they did cultures and said he had XDR-TB and put him on a “No-Fly” list because his was transmissible and extremely hard to treat. But he was getting married in Greece, and he hopped on the plane anyway. They did a culture in another lab in Colorado, and that lab diagnosed it as MDR-TB. The difference between XDR and MDR is resistance to one more antibiotic. Labs disagree all the time. It’s not a conspiracy. MDR has a 50 percent cure rate, XDR has a 30 percent cure rate, drug susceptible TB has a 95 percent plus cure rate. Would you like to sit next to one of these folks on a plane? I think that’s the point – you don’t want to sit next to someone who has the flu even.

The definition is not what matters – it is entirely predictable that if you treat XDR poorly, it’s going to become resistant to the next drug that comes along, too.

I think the WHO has a responsibility not to wear their advocacy hat. What they should do is alarm everyone enough to get everyone on directly observed therapy, short course (DOTS), and make sure the drug supply is good, and these drugs have to be bioavailable drugs (not counterfeit drugs or drugs made by unscrupulous manufacturers). To determine what this is they are dealing with in India, the WHO has to be rational, direct and objective.

Do you think a similar situation could unfold in Europe if appropriate action isn’t taken?
Probably not to the degree of India because India has hundreds of millions of people, they’re all close together, and India has a huge untrained, unregulated private medical sector. And a lot of these screw-ups in the care of people with TB take place in the private sector. The public health sector does a pretty good job.

The cause of this increased amount of drug resistance is that a patient isn’t treated properly or doesn’t take his medication as directed, or he’s infected by someone that was not treated properly. Drug resistance doesn’t occur in nature. If you see this in India, sooner or later some guy is going to get on a plane and head to Italy or the United States and expose people there.

Why is 70 percent of the TB in the U.S. found in foreign-born individuals? Because they reflect the TB found in their country of origin.

It would seem that we are finally seeing some movement in the development of new tools—finally some new drugs in development, a vaccine in trials and a new diagnostic.  What do you make of this? Do you feel like we might be on the verge of a transformative moment?  Is the pipeline rich enough? What in your view are the R&D urgent priorities?
I certainly am hopeful. I think the fact that people are studying TB, looking for cures, looking for new diagnostics like GeneXpert (which has been a really seminal discovery), is very important. But the answer isn’t just rolling out GeneXpert all over the place. Is the capability there to properly treat the disease it diagnoses? In some cases yes, but in some cases no.

Suppose we have movement in these new drug areas, remember what brought us MDR in the first place – poor drug management, poor prescriptions, poor DOTS. So you invest all this money, finally invent the “holy grail” drug, and you roll it out under great fanfare in the same places that developed drug resistance to the last drugs… what’s going to be different this time? Not a lot, I think.

If nothing is different in managing how these patients are treated, the new drugs will immediately lose their effectiveness just like the old ones did. Take for instance fluoroquinolones. They aren’t even approved for use in TB, but they are excellent. Then in places like the Philippines they’re already 50 percent resistant to floroquinolones. So this is another wake up call.

It’s really exciting stuff – these new drugs they work well, and they aren’t toxic. But, if they’re brought out and no one is concerned with who is treating these patients or how they’re treating these patients, then they’re going to become resistant to those drugs too, and we’re in danger of history repeating itself.

What in your view are the R&D urgent priorities?
They have this clinical path for new TB drugs and the idea is if they introduce a new regimen, put the whole thing in one pill so you can’t take one without taking the other. This idea was introduced by Dr. Mel Spigelman of the TB Alliance. I think that’s the kind of thing that has real potential – if those drugs are given only in combination, then you can’t take one without the other, and you won’t get drug resistance.

The Critical Path to TB Drug Regimens initiative is a consortium of the TB Alliance, The Gates Foundation, the Critical Path Institute, and all of these big hitters. What Spigelman suggested and they adopted is that rather than wait 20 years for a new TB drug to be tested and approved – why not take four new drugs, put them together, and get them all approved for treating the different spectrums of disease and get the regimen approved? Since you’re going to have to use a multiple drug regimen for TB anyway, that makes much more sense and would speed things through the pipeline much quicker.

Thinking like that from the beginning, or only taking TB treatment through DOTS, that’s the way to go.

Let’s talk a little bit about your book – Timebomb: the global epidemic of multi-drug-resistant tuberculosis, co-authored with Janice Hopkins Tanne. The first chapter of your book is called “Ebola with Wings,” why do you make that comparison?
The book came out on Sept. 11, 2001 – not a great day to release a book. And it turned out the publisher McGraw Hill said, “We don’t promote books,” when the whole purpose was to draw attention to the TB problem.

Everybody got excited about Ebola. Ebola was a very transmissible virus. Richard Bumgarner at the Stop TB department at the World Health Organization called TB “Ebola with wings,” which it really was because TB is so ubiquitously spread, and prominent in enclaves of Africa where Ebola was also prominent.

You mention in your book the TB epidemic that arose in New York City in the early 80s. Can you give me a little history lesson on that – what led to that outbreak? Was it a lack of public health funding? A lack of awareness?
It was sort of a perfect storm. They started counting TB rates in the U.S. and reporting them in 1953. A graph would show perpetual decline of TB rates at around five or six percent, with little deviation. If you look before they started counting them, the rates have probably been falling way before then. Drugs for TB were only invented in the early 1950s but the downward trend had been happening even before then. Then, in the mid ‘80s, the rates actually leveled off, and then they began to rise. And it rose 20 percent in adults, 35 percent in children. That’s the largest rise in TB ever in an industrialized nation.

And then of course the U.S. government in their wisdom decided to no longer fund TB programs with categorical grants – with specific money for TB that cannot be diverted to other political priorities. It was during the Nixon administration I believe, they said, “Hey we think that the local jurisdictions, the states should be able to use the money how they want to use it.” These block grants could be used for TB or Alzheimer’s, or really whatever had the more vocal constituent lobby. People stopped using money for TB and used it for other priorities. They stopped doing directly observed therapy, limited open clinic hours, anything to save money. Some of the cases in New York City were drug resistant. I think they had 400 deaths in the early ‘90s attributable to drug-resistant TB.

I say perfect storm because this happened just as AIDS surfaced in early 1980s. The realization hit five years later that people with AIDS get the diseases that infect their population. The first AIDS victims were gay males. They didn’t get TB because that wasn’t big in their population – they got things like Kaposi’s Sarcoma [a cancer commonly developed by people with AIDS]. The TB crept up when AIDS started occurring in populations that had lots of TB – for example New Jersey’s injection drug user population at that time, the homeless, alcoholics, etcetera.

“The squeaky wheel principal” came into effect – which essentially means poor people and minority groups got TB and no one ever noticed. But a white guy gets TB, and it’s on the front page of The New York Times. And that’s exactly what happened. A prison guard is infected with TB as a result of the epidemic spreading in prisons, and in November of 1992 or so it immediately gets all sorts of attention. That led to a five part series in The New York Times, a cover story in Newsweek – attention that TB never had seen before. They started appropriating lots of money to reverse the man-made epidemic that had previously occurred, and that did the trick. But it cost them $1 billion in excess expenditures to do so.

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