The World's Tuberculosis Crisis: The Need for New Treatments

Transcript of a press teleconference held March 21, 2001, on the occasion of World TB Day 2001

Featured speakers:

• Dr. James Orbinski

  , former president, Doctors Without Borders/Médecins Sans Frontières (MSF) International Council, president of Global TB Alliance Stakeholders Association

• Dr. Giorgio Roscigno

  , Acting CEO of the Global Alliance for TB Drug Development

James Orbinski:

Hello, I'm going to go through a number of issues. First of all, I'm going to give you an overview of the tuberculosis problem and then address two issues that MSF wants to put firmly on the agenda for World TB Day, March 24.

In essence, tuberculosis today is a global public health emergency. It is a curable disease and yet two billion people are infected with mycobacterium tuberculosis. 16 million people around the world live with active tuberculosis, and a very significant percentage of those 16 million people are spreading tuberculosis.

Every year, two to three million people die of tuberculosis and the number of new cases- or the incidence of tuberculosis- is increasing significantly. What we see today is that the incidence in the last year alone has gone up from 8 million new cases last year to 8.3 million new cases this year. This is quite significant. By the year 2020, the rate of spread may increase by up to 40% so that 70 million people could be dead by then and over a billion more people infected with tuberculosis. At the same time, we are seeing the rise and spread of multi drug resistant tuberculosis. In the last few years, MDRTB has been identified in over 100 countries and this is now a major, major global public health emergency in addition to the emergency that primary tuberculosis represents.

This is not a disease of the past but it is a global political problem today. And it is a disease primarily of the poor, with 90% of old and new cases occurring in the developing world.

The key issue that MSF wants to emphasize for World TB Day, is the need for new research and development, for new medications to treat tuberculosis to shorten the duration of TB treatment, to improve the treatment of latent tuberculosis infection, to treat MDRTB, and to simplify the standard therapy for tuberculosis.

The second point that we would like to make involves the standard therapy for tuberculosis today, or what is called DOTS-which is directly observed therapy short course. There is no question that DOTS is good however DOTS must get better in terms of its efficacy, its ability to actually reach and treat people with tuberculosis. DOTS has to improve through better diagnostic tests, through more effective treatment protocols, in its ability to detect and treat MDRTB, and also again for research and development for new TB drugs.

DOTS must also expand. At this point in time, only 25% of people who have tuberculosis are in active treatment programs which means that 75% of people with active tuberculosis are not in active treatment programs. The DOTS program also has to be adapted so that it more clearly addresses the rise of the second epidemic, multi drug resistant tuberculosis.

With that, I'm going to pass you over to Giorgio Roscigno who is the acting CEO for the Global Alliance for TB Drug Development. Before I do that, I just want to say that MSF strongly supports TB drug development and we are actively involved in that alliance and we are offering it our full, full support.

Giorgio Roscigno:

Good morning everybody. I am the acting chief executive officer for The Global Alliance for TB Drug Development. The Global Alliance for TB Drug Development is a new public private partnership that has been established last year and this partnership has three offices, one in New York, one in Brussels and one in Cape Town. It was created by a very specific need that came out of a meeting that we had last year in Cape Town in February 2000 in which the attention has been refocused on the need for new TB drugs. The outcome of that meeting was that we needed to create some sort of structure that would focus the attention of researchers, both in the public and the private sector, to develop new TB drugs.

The new TB drugs that we need today, as James has said, have to address the problem of expanding DOTS. DOTS is quite a good strategy in the sense that it calls for a supervision of treatment for TB patients for up to six or nine months. This is cumbersome for developing countries where follow-up of six to nine months can be quite expensive and quite difficult to implement. As a result, the DOTS strategy, even though it has made some significant achievements and improvements in the last four to five years, it still is only covering 25% of the overall TB patients worldwide. As an outcome of our Cape Town meeting, it was clear that we needed a new drug or a new series of drugs that would shorten the duration of the TB treatment to 2 months because we have data whereby the compliance of treatment up to 2 months is very high even in developing countries, even in operational conditions that are very difficult. The compliance falls after 2 months so if we had a drug that shortened the duration of TB treatment or otherwise facilitated this completion, it would be a dramatic improvement. This priority has also been set and confirmed by all the national tuberculosis program officers in the world that have identified the duration of treatment as an important problem.

The second objective of these new TB drugs is to help with the problem of latent TB infection. Latent TB infection is the infection of micro bacterial tuberculosis for which around 1.8 billion, almost two billion people are infected worldwide. The point is that the chances for someone who is infected to develop the disease is very low in developed countries whereas the chances for developing the disease in countries where the immune system of people can be weakened by concomitant infection but especially by HIV infection is dramatically higher. We can talk about a 20-50% chance for anyone who is co-infected with HIV and TB to develop active tuberculosis within five years. The number of HIV and TB co-infected persons is growing substantially and we are going to disclose some data on that in our press conference on Friday in Brussels.

The current treatment of latent infection still consists of a very long duration of treatment that goes from the three months of short course chemotherapy to up to six months or twelve months. The objective of the Global Alliance is to improve this by shortening it t to a couple of weeks.

The third objective is that we would like a drug that would be effective against multiple drug resistant TB which is an emerging problem especially in Eastern Europe. But it is also becoming a problem even in high TB burden countries outside of Eastern Europe.

That's what we have identified as our needs. The vision and the mission of the Global Alliance which I would like briefly to tell you before I pass to you for your questions is that our vision is that we want to provide new medicines with equitable access for the proven treatment of TB. The important point here is the equitable access; we want to be sure that whatever new projects that Global Alliance invests in, we are going to work just as an R&D, as a virtual R&D company. We are not going to own any laboratories but we're just going to work in a virtual way and we hope to invest money in these new products and we will then leverage our ownership of these products to ensure an equitable access for the improved treatment of TB.

This is basically what our vision is. Our mission is also to accelerate the discovery and the development of new cost effective TB drugs. That's in a nutshell what Global Alliance is.

Question:

What would be the structure of this new corporation, or whatever it is, that you have formed for this research?

Giorgio Roscigno:

This is a public/private partnership. Very similar to the Vaccine for Aids Initiative (IAVI) and for the MMV or Medicine for Malaria Venture. The structure of this is that we have a board of directors which is the governing body of the whole organization. We have a CEO and then a very lean virtual organization which consists of an R&D director, an advocacy director and a business development director. The concept here is to strike partnerships or deals with pharmaceutical industries and/or academia and then move the products and fill those gaps that we have identified for the development of new TB drugs. By investing money in those drugs we hope to push the products towards regulatory approval. Did I answer your questions?

Question:

Yes. Can you tell me more about the government part of it? The public part? How does that work?

Giorgio Roscigno:

So far we have already received some funding, most of this has come from the Bill and Melinda Gates Foundation and from the Rockefeller Foundation. We are already discussing with governments because we believe, as Dr. Orbinski has said, that there is certainly a very strong responsibility of governments to take up this issue about developing new drugs for TB because this is becoming, in fact it already is, a global emergency. We are talking with different governments and we are seeking endorsements from governments in the high burdened countries.

One very important feature is that we have created a coalition of research and development of high burden countries. And this coalition groups all the high burdened countries where the disease is particularly endemic and that's in the South-- in Asia, in Africa and in Latin America, and we are working very actively with the R&D groups in the South to make sure that there is appropriate capacity building in the South and the transfer of the technology to make sure that the equity of the distribution of the drug eventually, when we have developed it, will be assured.

Question: I have a question about how you in the TB world will work with people who are working with HIV/AIDS-especially the Pandemic and Sub-Saharan Africa, whether these are parallel paths or whether there have already been thoughts on how both of you intersect? And is there concern especially that HIV/AIDS could act as the elephant in the room-not only in getting funds but also attention?

James Orbinski:

There is no question that the HIV epidemic has been the major catalyst in the developing world in increasing the number of people with TB and there is no question in terms of appropriate research and development HIV and its interaction with TB, have to be a major part of the R&D equation.

That said, there are a number of initiatives that are starting to look at that. I just had a meeting this morning with the Rockefeller Foundation where we were talking specifically about that issue. There is also a meeting coming up in Uganda in about six weeks that will look at that particular issue as well. MSF is strongly involved in both of those initiatives and will definitely support them as they move along.

That said though, there is no question that tuberculosis itself, regardless of the HIV catalyst that has increased the incidence and prevalence of TB, that tuberculosis itself still requires a clear and specific focus in terms of new R&D for new drugs. And that focus, when it yields results, will not only impact on TB itself but will also show very significant benefits to patients with HIV.

Question:

Dr Orbinski, what do you think about the proposals within the TB community and perhaps within the HIV community as well, to use DOTS as the strategy to dispense the antiretroviral therapy that, with luck as I see it anyway, will soon be more widely available to poor countries?

James Orbinski:

I think that that is an issue that requires a lot of thought and a lot of careful analysis before there is a major initiative to embark on a DOTS oriented strategy for antiretroviral therapy. DOTS is not a perfect strategy. It's good and I want to make that point very clear. It's a good strategy. It's had an enormous impact on at least 25% of people with tuberculosis. However it's got to improve significantly in terms of expanding its scope, in terms of increasing the efficacy of a DOTS program and so on. The other thing to keep in mind is that HIV and TB are two very different diseases. DOTS is a short-term therapy that lasts between six and eight months. When we are talking about treatment for HIV using antiretroviral therapy we're talking about a lifetime treatment. There is no question that a lifetime treatment program will have to be, in the developing world particularly, but also in the developed world, will have to be simplified, will have to be developed according to new clinical protocols, new approaches to laboratory support for therapy, new approaches to fix dose combinations, new approaches to patient monitoring to ensure compliance and to making sure that drug resistance doesn't emerge.. All those issues have to be dealt with. So it's a complicated issue and there are a number of people who are beginning to look at it. It's early days yet for that kind of proposal.

Giorgio Roscigno:

I think that it's a very important question and I understand where you are coming from. I want to make a comment. Certainly the infrastructure that in the successful country has been created for tuberculosis is the one that in infectious diseases resembles most to what might be required for a successful in a DOTS treatment strategy for HAART in HIV patients in Africa. If you look at what is happening in Brazil, where 80,000 patients have been put into treatment for HIV/AIDS every year then one has to be very creative to think how can we be likely be able to put 5 million HIV positive or AIDS patients in Africa by the year 2005 under a scheme of treatment that will have to be somehow, user friendly and, at the same time, will have to ensure compliance by all of these patients. And if I understood your point, what you are saying, is that the TB program could be a vehicle to pass through this. I don't disagree with your thinking in the sense that TB being the longest - it's like leprosy-there are all these possible examples. Another thing that one would have to be very careful is developing practical problems for each of these diseases because if there would be a vertical program for HIV another for TB and another for malaria, already in developing countries, this would be a tremendous investment. So the possibility of integrating part of this progress which is not yet there but as a future guideline, it must be something interesting that certainly must be explored in the future.

James Orbinski:

I'd like to make one more comment about that. The DOTS acronym is directly observed therapy, short course. But the DOTS program has five core elements to it.

The first one is political commitment. The second is microscopy and laboratory support, the third is drug supplies, the fourth is surveillance and monitoring systems and the fifth is efficient and effective clinical protocols or regimens for actually delivering services. Conceptually, each of those five pillars are highly relevant to new thinking around delivery of antiretroviral therapy. But the specifics really need to be worked out in detail. And the specifics of difference between HIV and TB need to be considered carefully in the construction of any new program.

Question:

I'm trying to understand what I've heard here. It sounds to me as though you Dr. Roscigno, feel that the DOTS model with direct observation of therapy is a good way to approach the delivery of heart and antiretroviral therapy on a broad scale in developing countries and that you, Dr. Orbinski, have reservations about whether that system might be too cumbersome-perhaps too cumbersome for TB as well and needs some streamlining.

Giorgio Roscigno:

not to correct you but what I said was that if we have to think about a model for Africa where HIV antiretroviral therapy will have to be delivered to patients where the number might be as high as 5 million in the next five years-then we have to devise some sort of model that might be some how resembling in some part to DOTS because that is the nearest sort of administration under supervision that we have. We will have to improve it a lot. There are a lot of things that will have to be improved within DOTS but I think that that is what I really said.

James Orbinski:

I'm not skeptical. I don't want to give you that impression. But I'm cautious. The reason for the caution is what I said earlier: DOTS is good but it's going to get better. And to use that as a model as it stands now would be a mistake. There are some key issues around DOTS that have to improve in terms of its scope, it's reach to the number of people who have TB. Also in terms of its diagnostic methodology-its testing methodologies, the efficacy of its protocols and also its ability to adapt to the emergence of multi drug resistant tuberculosis. Those are just simple key points that the DOTS strategy has got to now encompass. So when we are talking about a different disease-HIV-with a different pathophysiology, with a different means of transmission, with a different epidemiology and so forth, we have to careful that we don't try to develop a "Mc Medicine Model" of health care delivery that is attractive, but too simplistic. That's all I'm saying.

Question:

How would you tailor the DOTS strategy to fit the widespread? I know that MSF is pushing very hard for improved access to HIV antiretroviral in the Third World. What sort of strategy do you envision that would prevent the upsurge in certain resistant strains of HIV and yet deliver anti HIV meds to where they are needed?

James Orbinski:

At this point, what we're doing is that we started a series of pilot studies in Africa and elsewhere to actually look at what kinds of strategies will work best. It's too early right now to make a comment or give any indication as to what the results are going to look like.

Question:

I would like to hear a little more about some of those projects if you could. Also, on DOTS not working as well as it should, are you concerned that DOTS actually creates MDRTB because it does not have individualized regimens at times, it looks at more of a standard response when a person isn't reacting well to treatment?

James Orbinski:

Poorly implemented DOTS programs where patients do not finish their therapy for all kinds of very good reasons certainly leads to the emergence of drug resistance, there is no question about that. What we need to do, in terms of improving DOTS, is develop appropriate strategies that will stop that from happening.

Giorgio Roscigno:

In my view, one should not make this suggestion that DOTS causes MDRTB. In fact, standardized treatment by definition, does not cause MDRTB. In fact, that's the best public health approach, is to have standardized treatment. On the contrary, when you give the liberty of personalized treatment to doctors and you introduce elements of anarchy into the treatment of TB, that's when there is the likelihood of developing MDRTB is higher. I think the example of Eastern Europe is a very good example in this respect. Wherever doctors implemented it properly and wherever the treatment is given standardized, there is no association so far that indicates more MDRTB. I would be very careful in saying that.

Question:

It seems illogical, although in practice it might not work out that way, if in the retrievement scheme, you add one drug to a failing regimen you might induce resistance to that one drug. Especially if the laboratory facilities are not sophisticated enough and if the implementation of DOTS is calling for standardized treatment as opposed to doing individualized treatment which is what's happening in a lot of countries.

James Orbinski:

One of the things that I'm actually saying in my previous comment is that drug sensitivity testing and culture have to be the key components of the DOTS strategy unit.

That microscopy alone, because of the emergence of MDRTB is not enough. And that's the kind of very practical adaptation in a DOTS strategy that we would like to see emerge.