Re: Rumor About Gilead Sciences
Nov 11, 2003
Happy Halloween (and thanks for the great web site), I too heard the rumor about Gilead Sciences' Viread pro-drug getting into lymph nodes - supposedly where no anti-HIV drug has gone before.
First, is there up-to-date and accurate information on which drugs get behind the blood-eye, blood-brain, blood-testes, blood-whatever barriers? If so, where can I find it?
At least one top HIV doctor/researcher has told me, "All the drugs pretty much get into all the areas of the body." But the professional and lay press regularly print articles about "new" HIV sanctuaries (hiding sites for HIV) being discovered that apparently are impervious to anti-HIV drugs. I get the impression that either nobody really knows what areas of the body the different anti-HIV drugs get into OR that there is so much diversity in how people absorb (adsorb?), metabolize and eliminate drugs from individual cells AND the blood stream, that only individual testing, with a specific drug combination, will be of value.
The most obvious case in point is Viread/tenofovir's association with two recently failed clinical trials.
Viread/tenofovir + Ziagen/abacavir failed to lower my viral load AND failed to prevent a CD4+ T cell drop in me - and I usually have more than 900 CD4+ T cells and viral loads under 2,000 copies/mml off-drug for three months.
Note: I had a CD4+ T cell nadir of 490 cells/mml about fifteen years ago, two years into ACTG019.
When a drug combination doesn't work in someone with either very strong anti-HIV immunity or replicative-deficient HIV (or a combination of both) you know that the drugs are most likely to blame.
To make this issue more complicated, I understand that our bodies have complex cellular mechanisms for eliminating toxins, and that specific anti-HIV drugs may get pumped-out of some people's cells and blood faster than others. I wonder whether this could account for the big differences in how people respond to various drugs.
About seven years ago we learned that drinking a glass of grapefruit juice could raise the level of several anti-HIV drugs in the blood stream due to interactions with liver enzymes. Type "HIV Grapefruit Juice" into GOOGLE and you'll get hundreds of links to reports on this subject.
What's been proven (peer-reviewed) regarding the effectiveness of various anti-HIV drugs in entering and working in various areas of the body that blocks or greatly restricts immune system cells from entering?
Do we know anything more about Viread/tenofovir's association with two recently failed clinical trials?
Response from Dr. Pierone
Lots of questions here, where to begin?
Let's start with sanctuary sites. I would agree with the top HIV researcher that felt "that all drugs pretty much get into all areas of the body". Although it may not have been formally tested for all drugs and all parts of the body, the use of combination therapy for HIV seems to compensate for the lack of dispersion of any one particular agent. Many antiretroviral agents have been tested for in various body sites and mostly you can find decent levels. We could look everywhere, but remember that when you ask permission from a patient to stick a very long pointy needle into one of their organs to measure drug levels you better have a pretty good explanation of what you hope to prove.
You are right in that we see vastly different response to medications among individuals depending on multiple complex reasons that may range from citrus consumption to cellular efflux mechanisms. Really, any of the dozens of discrete steps from drug acquisition to toilet flushing are not the same in any two people. It's remarkable that a "one size fits all approach" has any usefulness in drug treatment (but it does in many studies).
The recent failure of triple nuke regimens containing tenofovir (Viread) was surprising and disturbing. We expected that since tenofovir is more potent that AZT (and less toxic) it would make sense to substitute it and try tenofovir (Viread), abacavir (Ziagen) and lamivudine (Epivir). This triple nuke combination had a much higher than expected failure rate. See this link for additional reporting on this study from ICAAC. We don't know understand the basic science underlying this unexpected result, so stay tuned.
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