Treatment in vaccine trials and AIDS in Brazil

Mauro Schechter MD, Ph.D is one of the leading figures in the field of AIDS in Brazil, and his renown now spreads beyond his home country to the international sphere.

He is Head of the AIDS Research Laboratory at the Universidade Federal do Rio de Janeiro, and was one of the first Brazilian scientists to commit to setting up a preventive AIDS vaccine clinical trial site, as well as being instrumental in setting up the first Community Advisory Board in the country. Schechter also plays a continuing key role in developing and updating the treatment guidelines for Brazilian AIDS patients and is seen as one of the leading AIDS physicians practicing medicine in Brazil today. His international standing has led to his inclusion on a number of influential global health panels, including the International AIDS Society’s Consensus Panel on Antiretroviral Therapy and the Scientific Advisory Committee of IAVI. Recently Schechter spoke to IAVI Report editor Simon Noble about healthcare implications around AIDS vaccine trials and the current situation in Brazil.

 

The AIDS vaccine field is currently tackling the question of the level of health care that should be provided to vaccine trial participants who become incidentally infected. Do you consider that there is a moral imperative to provide a certain level of health care to these participants, or is there a lesser qualification on the issue? Is it more a case of simply the right thing to do?

Well, there is a moral imperative to provide to trial participants care for whatever happens to them that's trial-related. And I think no one would argue about that. What I think is more difficult is what to do with regards to treatment of incidental infections, which are not trial-related damages, what do you have to do for these persons? Is there a moral imperative to provide treatment for them in an environment where there’s no treatment, or providing treatment is just a nice thing to do? And once you provide treatment to these persons, how far do you go? Is it OK that these persons are getting treatment for the virus while their next-door neighbors who did not join the trial are not? So the short answer is that I don't know. I have no doubts that it’s a very nice thing to do, but it might be that I’m doing some harm. From this perspective you may argue that although you thought that you were doing good, that you had the best intentions, you may actually be doing harm. I don't feel I’m really qualified to say what’s right and wrong there. I have no doubts that we have to do everything that’s directly trial-related, to ensure responsibility. But then after that sort of general broad statement, one has to decide what is really trial-related.

In the past it hasn't been incumbent upon vaccine researchers in other disease settings to provide such care. Why do you think that AIDS vaccine research is now being held to a different standard?

If you look back at the whole history of HIV treatment, the standards of care that HIV researchers were held accountable to have always, arguably, been different from what other areas were. Basically, I think, because it hit originally the gay community in the US. So the whole activism changed the way society deals with medical research, which I think is good. When I started in the 1980’s working with HIV, there was no community input, non-medical individuals participating in the design of trials and criticizing trials. And then HIV came about, with the whole idea of having a Community Advisory Board (CAB). You didn’t have a CAB for a diabetes trial or a trial for hair loss. Until there was HIV. And it rightly became the standard. And holding HIV research to higher standards was a good thing. I think HIV research is not the higher ground, just the beacon that tells everyone that eventually you have to do things as you do with HIV research.

Do you think there is a fear that diverting funding towards surrounding healthcare, which can mushroom to community-wide rather than just trial participants, that that will impact upon the speed of scientific discovery, and then ultimately impact on the speed with which an effective preventive vaccine is available to the community?

That's again a situation in which one is trying to do good and may end up doing harm, even though, again, one had the best intentions. I think it comes down to determining what’s the difference, if any, between your responsibilities as a researcher and your responsibilities as a citizen. And it’s always very difficult to decide where one ends and the other one starts. So we have to find ways of equipoise, and at the same time not divert efforts and funds from the trial itself.

One concern about the health care provisions is that this will impact adversely on other avenues of prevention research. And these fields, especially microbicides, have relied on doing short-term research trials without surrounding costs. Do you think that will impact upon microbicide research?

Well, yes, we cannot have double standards. But on the other hand, we’re trying to do this off futurology. By the time most of these trials are ongoing, with the ‘3 by 5’ WHO initiative, hopefully in two or three years time we’ll have millions of people on treatment, then the situation will be totally different from today, where very few are on treatment. It will be a different equation.

What do you think of the idea of getting independent funding for the health care provision and that, in some respects, being independent of the vaccine trials? Essentially you will create ‘seed’ populations at the vaccine trials site but which will be treating the wider community. Do you think that’s a valuable concept?

I think that’s a valuable concept, and that might be a more efficient way of doing two things at the same time. Considering that you will not be able to scale up treatment for everyone at the same time, you have to at some point or another decide you have enough capacity to, say, treat a million people next year. So then you have to decide whether these people will be in North, South, East or West Kenya, for example. Then you could tie that up to where the trials are happening. So, you answer more than one question, probably being much more efficient. In a way the NIH is going through the same discussions now, they have several networks that do different things, and they are discussing how to do them more efficiently, because these networks need to be complimentary. At the moment they aren’t, sometimes they appear to be working in a vacuum. On a global scale, for example, we have the “Enterprise” initiative for the vaccine, which should somehow tie up with the Global Fund and with ‘3 by 5’, and so make the process more efficient.

In the past you’ve advocated for treatment of opportunistic infections and other risk factors that impact on HIV disease, and that this is equally important as antiretrovirals. Could you expand on that a little?

I think a lot of thought goes into antiretroviral therapy, because that was a major success story and people like novelties and sophisticated treatment. On the other hand there’s plenty of data to indicate that mortality was already going down before we had these drugs, and there is also plenty of data to show that this decline is probably due to adequate prophylaxis for opportunistic infections, which are generally very cheap, and have an enormous impact not only on the incidence of these infections but also on overall HIV-related mortality. The other side of the story is that people tend to think that providing antiretroviral therapy needs a very sophisticated infrastructure. It doesn’t. Basically, if people take the drugs, they work. The doctors on the ground don’t have to all be PhDs from Johns Hopkins. Someone can tell patients, “You take these drugs when the sun rises. You take these drugs again when the sun goes down. You’ll be OK. And if you don’t feel good, just come to me, otherwise you’ll be OK”.

What do you think are the first practical steps that can be taken to roll out access to antiretrovirals?

What you need to begin with, and the WHO has done it, is to have simple ‘cookbook’ guidelines – and we can learn from tuberculosis - which tell people how to treat, in very simple ways. Simple guidelines that you get everyone to follow, in which you say “if someone is HIV infected and presents X, Y, Z conditions, which are simple to evaluate, than you give drugs A, B, C.”

Is there still a ‘clade question’ in Brazil? Or is there the attitude that perhaps is becoming dominant, that clades shouldn’t be seen as important because we need to know about protection across clades?

From the scientific point of view in Brazil, the discussion of clades is everywhere. You can argue forever whether clades matter or clades don’t matter. From a practical point of view, because Brazil is mainly a clade B country the issue does not arise to the same extent as, for example, in East Africa where you have lots of clade A or southern Africa with clade C. Since most of the vaccines being developed at the moment are actually clade B vaccines, in a way they are perceived as matching Brazil, although they may not be, because in some areas up to a third of infected Brazilians may have subtype C. Early in the epidemic there were a lot of vocal people saying that we needed a vaccine tailored for Brazil. Now we don’t hear that as much.

In the past, there have been suggestions that the ‘clade question’ is related to people’s fears that they’re going to be used as a testing ground for somebody else’s vaccine. Do you think that attitude has waned?

I think there was an attitude in the early 90’s that you could only test a vaccine in a developing country if you had done the Phase I in the US, but I think that has changed. At least the scientific community really wants to be part of Phase I trials. And you have countries now that really want to be part of a mismatched trial. They should be commended for this.

I think it all goes back to the guinea-pig issue. I feel that this will never die out. On the other hand I think that in the last few years AIDS has produced a working relationship between community activists and scientists, in Brazil at least. I think there is an unprecedented degree of understanding, of mutual trust. But that has only changed in the last several years. In the community, maybe 10 years ago, there was a lot of mistrust.... And now both sides can say, “Well, we disagree on several things, but the fundamental thing is that I think you’re trying to do good. We might have different opinions but you’re not intrinsically a bad person.” I think that has changed a lot.

The Brazilian example is being adapted by the WHO as the model for expanding access to ARVs and other forms of HIV-related care. What do you think are the most important lessons you’ve learned from your experiences in Brazil that might come into play in other communities?

There is always this tension - do you need to build the infrastructure before you supply the drugs, or do you supply the drugs and then build the infrastructure? And Brazil showed that we could do both at the same time. And it worked. That is the basic lesson. There are those who say “Well, if we cannot do CD4 counts and viral loads everywhere we shouldn’t even think about giving treatment”. So, these people think that we can only treat patients if they live in Manhattan. And what Brazil proved was that even if you live in rural Brazil, wherever you are, provided you take your drugs, they will work. Obviously it would be better if we had very sophisticated monitoring systems and very sophisticated doctors everywhere. One would obviously prefer to save the lives of 99% of the people, but, on a population basis, if you save the lives of 95% of the people, you’re doing extremely well.

Is there a lesson there for the AIDS vaccine effort?

There’s a difference because one knew that the drugs worked. It’s not a matter of you have a vaccine that you know works and now you’re trying to see how you will vaccinate people in the world. We don’t have a vaccine. Antiretrovirals in Brazil was a different thing. You had the drugs, you knew they worked, and you had to decide how to make these drugs available to everyone. If one day, hopefully, we have a vaccine then we will have to decide how to make it available to everyone. What Brazil showed is that if you have efficacious drugs, to scale up is not that difficult; it’s a matter of political will. All you need is to commit the resources and have the willpower to do it.

What about the fears expressed that because of lower adherence levels in developing nations we’re going to see resistant viruses emerging?

That’s complete nonsense, and for two reasons. First, there is the misconception that in developed countries adherence rates are very high and failure rates are very low. It has been shown time and again that if you go anywhere, in the US, in France, a large proportion of patients will have “failed”, because the definition of failure many use is “if your viral load is detectable, you’ve failed”, which I think is a bad definition. But if you use that definition, you get about 50% failure rates everywhere. Second, there are several small studies done in developing countries that show that adherence rates are at least as good as, if not better than, in developed countries. Basically I think one of the reasons is that people in developing countries value and treasure what they get much more than the average person living on the Upper West Side. What’s a thousand dollars to these Upper West Siders? You can’t even buy a new Armani coat. But to someone whose annual income is far less than a thousand dollars...

And they’re seeing their family members die.

Yes.

To finish, what is the mood in Brazil these days, regarding the national response to AIDS?

I think there’s a general sense of pride in the Brazilian AIDS program. And rightly, I think, that people look at it not as the work of a particular party or a particular government. They look at it as an AIDS program, developed by several governments and mostly by the same group of people; it’s not because party A, B, or C was in power that the program worked. So there’s a sense of pride, of national achievement, not a party achievement, a demonstration that Brazilians can accomplish important things.