Dr. Lange: "Well, we have a press conference regarding a supplement of AIDS (Vol. 18, Supplement 3, June 2004) that's based on a consultation that was convened by the World Bank last year, to address the issue of resistance with the scale up of antiretrovirals in developing countries. Dan Kuritzkes was one of the co-editors of the supplement and the keynote speaker, I believe."
P4P: "And so this was a concern about the scale up of antiretrovirals in developing countries ..."
Dr. Kuritzkes: "Concerns have been raised in some quarters that resistance will become rampant with the scale up of antiretroviral therapy in resource poor settings and that this might be a reason to either slow down the scale up, or to rethink the way in which the scale up was being conducted. So the consultation was to examine the issues surrounding drug resistance, it's relationship to adherence, and approaches optimizing adherence and to provide a realistic assessment to the World Bank about the expectations for drug resistance and whether this was or wasn't a sufficient concern to cause any delay. I think that what was pointed out over the course of the day and a half long meeting, was that we couldn't take the experience in the developed world where treatment had been rolled out over a period of fifteen years, with single drug, then two drug, then three drug regimens, leading to high prevalence of drug resistance, as a model for what would occur in resource poor settings where, for the most part, triple-drug therapy was going to be introduced all at once. So that they would be starting with patients who are essentially treatment naive and would have an expectation of much higher success rates than were initially experienced with HAART in the West."
"Our second point was that in many of the pilot programs that have been undertaken to date; in Khayelitsha (South Africa), in Haiti, and in Brazil, which is not a pilot but a national program, and in other places in the world; adherence has really been outstanding and often much better than what we see in the developed world with correspondingly high success rates and low resistance rates. So I think ... we also had input from the people at the WHO, who are involved in surveillance programs to do resistance testing, and the overall conclusions of the meeting were that, number one; while the introduction of antiretroviral therapy may lead to some drug resistance occurring, it's unlikely to cause a global epidemic of resistance. There's no evidence that resistance would be any more of a problem in a resource poor setting than it already has been in the West. Although we need to be alert to the concerns about drug resistance and have appropriate approaches for monitoring, but that overall, we thought this was clearly not a reason to delay the urgent introduction of antiretroviral therapy into resource poor countries."
P4P: "I sort of got the same feeling just from listening to folks at the conference. Anything that you would add to that?"
Dr. Lange: "No. That was very comprehensive." [Laughter]
P4P: "Well, let me ask you this. In terms of nevirapine and MTCT programs with mothers developing some resistance, kids developing resistance, and with the lack of really being able to do the kinds of resistance testing, genotyping and phenotyping that we're doing in the states; how's that going to play into this? Because a lot of the generic combinations that we're going to be introducing here, may very well contain nevirapine?"
Dr. Lange: "Yes, the nevirapine resistance issue is related to prevention, mother-to-child transmission use of single dose nevirapene. That's what's being debated here heavily, because the South African government decided to advise against single dose nevirapine for prevention of mother-to-child transmission. I think that both Dan and I think it is an inadequate prevention. The tragedy, however, is that still in many places in sub-Saharan Africa, it's the only thing people can get. And you have to balance the benefit of having a 50 percent reduction in mother-to-child transmission, in a setting where therapy's not available at the moment, against the development of resistance against nevirapine. And we also don't know for certain whether ... I think there is some tantalizing data from northern Thailand suggesting that it will have a negative impact on the subsequent response to triple-drug therapy. However, what was also interesting in the Thai studies was the longer the period between the user's single use nevirapine and the actual start of HAART, the less impact there was. So it may be since you're not dealing with the majority population, that there might be years between, it might not have that much an impact. But my own guess is that it will have an impact and it will continue to have an impact. The question is should you now stop an intervention that's the only thing people have got in certain regions. That has nothing to do with the nevirapine resistance issue in treatment, where basically if you give a nevirapine containing regimen, a HAART regimen, if people really take their drugs, the occurrence of resistance is not all that great."
P4P: "So the bottom line here is for those moms who may have taken that single dose nevirapine, and who may have some resistance, if they're starting to get ARVs now, you're saying the impact is not going to be that great?"
Dr. Lange: "There is an impact. The data already show there is an impact. But what I'm saying is you have to balance that against not having ... where you don't have the treatment, and the only thing that's available is single dose nevirapine. Obviously we need to move beyond single dose nevirapine. Even if we use single dose triple-therapy, including a non-nuke, you still have the issue of different half lives. So we should be working very hard to find better interventions for prevention of mother-to-child transmission. But we shouldn't stop what has already been built up."
P4P: "Certainly it will be a consideration then for screening women that are going to be starting therapy to see if they have done the single dose of nevirapine, and making an alternative choice ..."
Dr. Kuritzkes: "I think the dilemma currently is for most countries there is no alternative. I think the issue is that, today the most effective, most widely used approach for preventing mother-to-child transmission is the use of peri-partum nevirapine, either alone or in combination with AZT as they're doing here in Thailand. Most of those women will not need immediate antiretroviral therapy after they deliver, and given the pace of change that we've seen in the rollout of antiretroviral therapy and scaling up, it's hard to know what will and won't be available in a year's time, or two year's time. And so to stop programs today that are effective in reducing the rate of mother-to-child transmission, because of this possibility that women will develop drug resistance and have less effective therapy in the future, is a short-sighted approach. Resistance will be a problem. It may be a bigger problem than we currently anticipate, but we really don't know, because the real issue is the longevity of these resistant viruses. Even as they disappear from the plasma, from the blood stream, do we still have undetected reservoirs or minor variants that persist and may compromise the activity of future regimens."
Dr. Lange: "I do think however that it's shameful that the researchers who did the original studies, because this was foreseen with the long half-life of this drug, didn't address that issue and we've lost years and years, and could have devised better strategies."
Dr. Kuritzkes: "I think when these strategies were first envisioned, nobody had the real vision to think that antiretroviral therapy would one day be a reality in this setting. So people were assuming that one could use single dose nevirapine without concern for consequences, because these were never drugs that would be used for treatment, and now they are. And it's becoming an important issue. There's a randomized clinical trial that the AIDS Clinical Trials Group in the US, NIH, are going to be conducting primarily in Africa, looking at comparison of nevirapene, well actually an efavirenz based versus a protease inhibitor based regimen, in women who have had exposure to single dose nevirapine, to determine whether there's a difference and whether that difference is related to the emergence of nevirapine resistance."
Dr. Kuritzkes: "Right. It will be something comparable along those lines. It may be a combivir or tenofovir, FTC regimen. The main comparison in the study is going to be whether it's a non-nucleoside, RT inhibitor or protease inhibitor regimen. Those are the kind of data that we really need, because it will, first of all, help to solidify what's been observed in the pilot studies to date, and I think if we're going to make broad policy changes in terms of how we approach antiretroviral therapy, we need the data. I think once the data are available, the data will not only drive policy, it will drive pricing, because then there's solid data to show the need for a continent or the need for a large country that this is the right thing to do, then we can begin to worry about how to make the drug available."
Dr. Lange: "Obviously if you have no other choice, like now, if you're giving triple-therapy in Africa, it's these fixed dose combinations, D4T, 3TC, and efavirenz, or nevirapine. We should really be planning for the future, and stimulating innovation into making treatment combinations that are going to be more effective and safe. And then, as Dan says, the price will come down. We need to plan for the long term. ..."
P4P: "Let me switch tracks here real quick. As conference organizer this year, how have things been going? What's been good for you? What's been bad for you?"
Dr. Lange: "I think the good thing about the conference is the enormous outreach it has in the region. It's going to have a large impact on the countries here in the realization that they need to scale up prevention efforts. That's a very important outcome. I think the attention for prevention technologies is a very good thing.
I must say I'm becoming quite tired of unconstructive activism and I really think we should to start to deal with that issue in another sense, because this is nothing to do with inclusiveness. ... I mean, if you don't like what Randall Tobias has to say, you don't have to listen to him. If there's other people in the room who want to listen, let them listen. Probably 9 out of 10 of those people are not a friend of Randall Tobias, but they came there to listen to him. ... I find it horrible when Hank McKinnell, the CEO of Pfizer, came here, which I think is very courageous, he stands at the podium to have a discussion on intellectual property, and they throw body bags on the podium.
It's not helping the response against the epidemic. You know, you have to engage ... it comes back to the issue of making the pills that we need. We're now going for the cheap solutions, and everybody's shouting for cheap solutions, but we should again be planning for the long term. If you plan for the long term you're going to need the support of the Hank McKinnells. You need to engage those people and make sure that those people are going to sell pills for a dollar a day and make the right pills."
P4P: "You know, having some activist background, and, Joep, you know I've participated in things before. I mean, I got tossed out of Paris when Chirac was talking. I wasn't at these sessions you're discussing now, but I participated here in the Opening Day Protest and in the protest where international warrants for citizen's arrest of the G-8 leaders were issued."
Dr. Lange: "Well that's fine. We need the protests. We need the protests at the meeting. I'm not saying we shouldn't have the protests. It's just that we need to find more constructive ways of protesting than just preventing or almost preventing people from speaking. If Tobias is saying the wrong things, counter him with arguments, and there's plenty of opportunity for that. And it is being done. This morning at the plenary, [inaudible] the abstinence message, and that's how it should be."
P4P: "I have to agree with you to some extent on some of those things. But I guess the history of this has been ... you know, people haven't had a voice, and sometimes you had to make that noise."
Dr. Lange: "I fully recognize that. I absolutely fully recognize that and I think the activist community has played a tremendously important role in getting us where we are now, because we would still would not have as many active drugs on the market if you hadn't been fighting for too much. But we're now entering a different stage of the epidemic. We now need to engage these leaders. What we need to do is to make sure that we're going to implement. And if we want to implement, we need everybody."
P4P: "I heard somebody say at a press conference earlier regarding the leadership track, that it was an effort to compliment on the one hand, and challenge leaders on the other hand. What kinds of challenges are being presented to leaders here? How are those folks going to be engaged? Those leaders who haven't been doing as much as perhaps they should have been doing or, I shouldn't say perhaps, who just haven't been doing as much ..."
Dr. Lange: "Well the problem with that is that the leaders that come are usually the ones who have. On the other hand, having someone like Hank McKinnell here at least it offers the opportunity to criticize what they haven't been doing or have been doing wrong, and the same is true for national leaders, but again you get the ones that actually have done ... You get a mix. So I think we have to turn it around a little bit and we have to move the conference to those places. For instance Russia, Putin isn't paying any attention to HIV, so let's have the conference in Moscow."
P4P: "And put the pressure on him."
Dr. Lange: "Yes, because here you see what has happened. I mean, we have to see what comes out of it, but what has happened is that Thaksin (Shinawatra, Thai Prime Minister) who shot 2,500 drug users last year, now has said he's all for harm reduction. And then I thought it was so ..., I understood Paisan's anger, because they had walked out, which was disgraceful. (This was a reference to the Opening Ceremony where Paisan Suwannawong was abandoned on the podium by other speakers, including PM Shinawatra.) But at the same time, Paisan could say, 'Wow what a pledge. We're going to hold you to your words. We'll make you accountable.' I thought it was terrific. The whole concept of harm reduction has been introduced to that clique because of the conference here."
P4P: "Well, like you say, folks will be looking to hold them to their promises I'm sure."
Dr. Lange: "Yes, yes. But I guess you have more chance of holding them to their promise in a culture like this if you're actually not criticizing them for past mistakes, because you're creating shame. You need to say, 'It's fantastic that we get to work on this together.' If Thaksin would be proud of doing that, it will happen."
P4P: "Any profound or prominent take home message coming out this, out of these days here in Bangkok?"
Dr. Lange: "... now I'm talking again about the global picture, we need really coordination of donors, and coordination of implementers. With the whole scale up, we really need coordination ... which is, I think, happening to some extent. We need coordination of prevention research, which may happen through Global Enterprise. We need better coordination of the treatment, access to treatment campaign. We still are missing real leadership."
P4P: "Dan, anything?"
Dr. Kuritzkes: "Well, I think the whole debate about the mother-child prevention approaches is a healthy debate to be having here and it's going to stimulate people re-examining how to do this better and what the optimum approaches might be. I think the focus on that, I think that was some of the most exciting and pervasive messages in terms of treatment. There was a session here this morning, the session on resistance, the session that dealt with it in the late breakers today, the fact there's so many different studies now being looked at. People are trying to understand the consequences. I think it's also important to view this as a bridge to providing appropriate triple-therapy to pregnant women, which again is a long term goal. People talk about now that it's unaffordable, that it's impractical. But five years ago even single dose nevirapene would have been considered unaffordable and impractical."
P4P: "Well listen, I'm sorry there wasn't any turn out other than me here, but at least I got the story ..."
Dr. Lange: [Laughter] "No, it was great, much more relaxing actually." [More Laughter]
Back to the Summer 2004 issue of Positives for Positives.