July 10, 2001
The International AIDS Society-USA -- not to be confused with the International AIDS Society (without the "USA" at the end), the organizer of this meeting (although both organizations share many things) -- organized a symposia Tuesday about some of the most important issues currently in antiretroviral therapy. The format of the symposia involved the presentation of cases and a voting system from the audience, with an end discussion among the panelists about the different possible options and a summary statement from one of the panelists.
The main goal of this exercise was probably educational: to show, by presenting different cases to the audience, the complexities and difficulties of the decisions regarding antiretroviral therapy. The International AIDS Society-USA is the organization which writes one of the two most popular "Guidelines" for the treatment of HIV. They are published in the Journal of the American Medical Association on a yearly basis. This organization also periodically provides updated recommendations about the use of resistance testing.
Several cases were presented, which I won't discuss in detail. The most interesting aspect of the discussion was the shift away from the "hit early hit hard" paradigm that seems definitely dead. Even those who were strong proponents of very aggressive HIV management only a couple of years ago, now defended that in many cases it is reasonable to wait until more significant declines of CD4 cells have occurred before the initiation of antiretroviral therapy. Some British doctors who have always been less aggressive in HIV treatment than their counterparts in the US must feel victorious.
We discussed the arguments in favor of a delayed initiation of antiretroviral therapy. On Sunday, Julio Montaner gave a very good overview of them. During this symposia we again heard that it is unrealistic to expect to eradicate HIV infection with the current antiretroviral drugs, that the preservation of the CTL response against HIV has only been attained with the treatment of seroconverters and that immune reconstitution happens even in very advanced stages of the disease. No new arguments were presented, at least no new arguments based on solid scientific data.
That is one of the things that bothers me about this and other guidelines -- they seem to sanction the prevailing view of the field, and in many occasions are not based on any solid data. They represent the opinion of some opinionated leaders, but their opinions change on a yearly basis without solid support. I think it would be more intellectually honest to state some general principles -- such as, when therapy is chosen, your goal should be to get complete viral suppression, or that you should treat women the same way as you treat men, and that it's best not to change medications often. Beyond that, it should be stated that there is not much data about when to start -- early or late -- and please "do your best and use common sense." That would prevent them from changing the "threshold" every year.
These guidelines, as well as other guidelines, have always been behind what doctors in the field are actually doing. Now, because of the toxicities associated with antiretroviral therapies, the field is more conservative, so the guidelines are more conservative. The pendulum will swing again and they will be more aggressive in the future, or they might even start recommending intermittent therapy before the clinical trials are done.
Different scenarios of patients ready to start therapy were discussed. In general, it is clear that the audience and the panelists tend to use more non-protease-inhibitor-based regimens. Starting with an NNRTI-based regimen was the most frequently selected option, and also there was a lot of interest in triple-nucleoside regimens -- especially for patients with concomitant problems like hepatitis C, or alcoholism. It seems that protease-inhibitor-boosted regimens are still popular for patients with very advanced disease or patients with extremely high viral loads. Although, as Montaner pointed out, only the randomized studies suggest that the potency of a NNRTI regimen is similar in that situation, but who needs data if you have an opinion?
In patients co-infected with hepatitis C, if it is possible, and depending on the clinical situation of the patient, most physicians will treat hepatitis C first, and then treat HIV; although, as with everything in life, there were some opposing voices. In general, there were more agreements in this panel than in others, because the prevailing perception is that NNRTIs are as potent and better tolerated than protease inhibitors.
Unfortunately, there is no clear answer to the question "With what?", as Dr. Hirsch discussed. We will have to wait until studies like ACTG 384 or Initio are presented. I think ACTG 384 data will be available during the next International Conference in AIDS, which will take place in Barcelona next year. Until then, we will have to be patient and use our brains.
In the next discussion, the panelists again discussed different paradigmatic scenarios. As expected, the cases in this discussion became more complex. There was discussion about "blips" (the presence of transient detectable viral loads in patients fully suppressed). Dianne Havlir will publish a paper in the Journal of the American Medical Association about this issue in the next few weeks.
There was also talk of what is the appropriate timing for switches: should you wait until the viral load has gone up to a pre-established level or should you switch immediately. Unfortunately, there is not a lot of data to make a rational decision here, so the panelists (and the audience) are making educated guesses, a method that has proven frequently wrong in HIV management -- but we don't really have a choice here.
There was a long discussion about genotypic testing and therapeutic selection of "rescue" regimens with specific mutations. While they discussed these genotypes I wondered about the utility of the exercise. The audience included a significant proportion of doctors from developing countries; they were obviously less familiar with the issues related to sensitivity testing and some of the responses were off the mark. I guess the exercise serves an educational purpose, but it is difficult to figure out the utility of it when many of the people in the audience do not have access to these tests, nor will they have access to them in the next few years. Dr. Saag also discussed a phenotype and the difficulties establishing adequate "cut-off points" to define sensitivity and resistance in those assays.
The final discussion was definitely the most interesting part of the whole symposia. Fortunately, there was no discussion of cases, because most of the panelists in this group have very limited experience (if any) in the management of patients with HIV in the developing world. Unfortunately, many people were already leaving the conference room because of the late hour.
Dr. Mauro Schechter from Brazil gave a great short discussion about how the use of HAART that is provided for free in Brazil has produced a dramatic effect in mortality associated with HIV. The impact has been similar to the improvements observed in the "first world." The most curious thing is that these improvements started to happen even before the use of "triple" therapy, and they were observed also in patients taking double nucleoside therapy. He talked about the compulsory licensing in Brazil that has reduced dramatically the cost of antiretroviral therapy for the population and finally he said that we should abandon the "dogmas" that have plagued our field, and that we should consider alternative strategies for the management of HIV infection. His short speech justified the stay during the whole symposia (at least for me).
David Kazenstein also gave a nice short talk about Africa and what would be the impact of generic drugs in the management of HIV, and the need to explore new models in which therapeutic decisions are made clinically without the help of the technology to which we are accustomed in the North. And that was it. After ten hours of meetings, we all were ready for a break.
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