Wednesday, June 18, 2008

A good question

Ironically this was posted by the (of late disruptive) Liam Scheff, although of course it's not his words - they are far too sane.

This was emailed to me by a non-Blogspot member. Consider:

1. Fundamental assumption: accept medicine the way it is. Therefore, your attempts to improve it are unwanted.

Who really knows how long those kids will live? Maybe all of them will die in their 20's due to ARV's? Who knows, there is evidence that ARV's prolong lives that are Th2 imbalanced, with respect to their immune system balance among Th1 and Th2 (helper T-cell inversion). The reason, the drugs depress the production of the cells that make these cytokines by killing them, and thereby abating an autoimmune condition.

But there is much evidence that these are harmful:

It has been about 7 years since it was published in The Journal, AIDS, that children born to ZDV-treated mothers "are more likely to have a rapid course of HIV-1 infection compared with children born to untreated mothers, as disease progression and immunological deterioration are significantly more rapid and the risk of death is actually increased during the first 3 years of life" [12. de Martino et al., Rapid disease progression in HIV-1 perinatally infected children born to mothers receiving zidovudine monotherapy during pregnancy. AIDS. 13 (8):927-933, May 28, 1999.The Italian Register for HIV Infection in Children. AIDS, 13:927-933, 1999].

Therefore, it behooves us to think about at least improving the situation for the children involved, don't you agree?

Discussion is warranted. Can we suppress the Th1-2 population by non-toxic means, or perhaps by interference. Suppose we invent a peptide that interferes with the harmful effects of Th2 cytokine-driven storms on the tissues and especially on other immune cells (since the Payer's patches go first finally, indicating complete disruption of the lymph system).

Are we really expected to believe that there is no room for growth in medicine? Critical analysis, and then discussion regarding weaknesses and strengths in a hypothesis are required.

Whomever this is raises a number of good points. Firstly, the assumption that medicine is good enough is obviously entirely wrong. Medics and scientists in general (or let's broaden the scope to include the entire human race) have been wrong in the past, are probably wrong about some things now, and will be wrong about new things in the future. We cannot accept the status quo and expect that there's no room to improve. In the case of HIV for example, monotherapy led to dual therapy which led to hit-hard-hit-early with triple therapy, and now we're looking at monitoring and waiting until it's worth treating (if at all). Each step appeared to be the "best" approach at the time, but in hindsight they weren't the best way to go. Hindsight of course is 20/20. In another decade or so no doubt we'll look back and wonder how we managed the way we did...

The Th1/Th2 imbalance is also a feature of any chronic viral infection - HIV included. The antivirals don't actually kill off the T cells, but HIV-induced immune activation certainly does, and there is HIV-induced impaired T cell replacement. If anything the meds improve both of these actions, which is why they result in increased T cell counts over time.

The AZT study mentioned was important, although there is a large caveat in that the survival hit was in those who were HIV-infected _despite_ AZT prophylaxis. Obviously there were fewer HIV-infected kids than there would normally be without AZT. The questions that arise are: is this an effect of AZT directly? Is this because "tougher" clones of HIV made it through the AZT and were therefore worse to acquire (this would confound the results and make it appear as if AZT correlated with a worse outcome, even though it wasn't causal)? Does the AZT prophylaxis actually _select_ for more difficult viral clones? I don't think anyone yet has an answer to those questions, but all are potentially valid.

The real issue for me, and which denialists, well, deny, is that untreated HIV infection is so goddam awful in kids. Fully 25% or more will die by age 5 years. In the era of decent therapy and prophylaxis, risks of opportunistic infections and death are much less.

PEDIATRICS Vol. 120 No. 1 July 2007, pp. 100-109 (doi:10.1542/peds.2006-2052)

Could more be done - I certainly hope so, and the idea presented here about some kind of immune modulator sounds intriguing, and not the first time it's been suggested. We know that CCR5-delta32 mutations severely hamper viral replication but don't seem to hurt the human host, so if a way could be found to mimick that without buggering up the normal immune function, they why not? There is strong evidence that somewhere along the way cytokine signaling is wrong in HIV infection, and whether something abnormal needs to be turned off or something normal needs to be turned back on, it's far from a bad idea to look into that.


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