Thursday, January 19, 2006

Uh... What?

Although I'm really not quite a big fan of the argument from authority, there are occasions on which I might read a news article and be forced to conclude that the fact that people are experts on a given topic--and therefore presumably know more about it than I do--is the only reason I have to conclude that they're not deranged.

Today's case in point: the announcement that the NIH has halted a major AIDS study, one titled "Strategies for Management of Anti-Retroviral Therapy." The reason why:

Researchers concluded that those who took their medicine only when their immune systems waned were more than twice as likely to get sicker or die as people who took the drugs every day.


My initial response: uh, duh? But a bit later on in the article is a bit more of an explanation:

Combinations of potent anti-HIV drugs help patients live longer, and slow their progression from HIV infection to full-blown AIDS. But the combinations can cause serious side effects; it's inconvenient to take numerous pills a day, and the drugs are expensive.

While treatment guidelines back continuous therapy, earlier small studies had suggested it might be possible to take medication breaks and still control the virus while reducing side effects and cutting costs. So the NIH funded a bigger study — one of the largest ever done with HIV therapies — to see if those early results were real.


So here's my two cents. HIV is a particularly insidious virus, and one that I personally find morbidly fascinating. Part of the key of the virus' success is that it isn't actually very good at replicating itself (or, to be more precise, at reverse transcribing itself). This makes it a highly mutation-prone virus. Since the drugs prescribed for it are basically very powerful selection mechanisms, the HIV population in a patent's body can quickly become predominately resistant to any one drug. This is the logic underlying the current "drug cocktail" approach, known as Highly Active Anti-Retroviral Therapy, or HAART. Basically, the idea is that a patient can take multiple reverse transcriptase inhibitors (drugs that inhibit HIV's ability to insert itself into the genome by preventing it from reverse transcribing its genetic information--maintained as RNA--into DNA) and a protease inhibitor (a drug which inhibits protease, which IIRC is the enzyme HIV uses to cleave the proteins HIV tricks the cell into producing in order to prepare new virons). By administering them together, one can prevent the virus from becoming resistant to any one of the drugs administered. You see, any one mutation that confers resistance to one drug will probably not be beneficial to the other drugs--even if the mutation confers resistance to a specific reverse transcriptase inhibitors, it will be unlikely to confer resistance to another at the same time. And the odds of simultaneous mutations conferring resistance to a multitude of drugs a the same time or in short order are fairly slim.

However, there's a down side to this. As I'm sure everyone reading this is full aware, the side effects of all these drugs--even the current generation--are notoriously atrocious. AZT, the prototypical antiretroviral, was originally developed for treatment of cancer but was cast aside due to a considerable side effect profile. Its use in HIV treatment was only initially adopted out of sheer desperation--at the time, there was nothing else. Also, these drugs are also notoriously expensive, and most (if not all currently in use) are under patents that will be lasting for the foreseeable future. Since HIV is becoming more and more of an epidemic throughout much of the developing world, this is also problematic. So I do understand the motivations in trying to develop a protocol that reduces a patient's ongoing dependency on these drugs.

But at the same time? Any intro Bio student can tell you that on-and-off use of an antiviral or antibacterial regimen is a recipe for increased drug resistance. And although HAART minimizes occurrence of resistance, I wouldn't think it could eliminate it, especially in such a context. As I said above, I'm forced to assume that these people know more about what they're talking about than I do (and to be honest, they had pilot studies on their side, referenced in the quote above).

But apparently, they not only had an increase in illness and fatalities to deal with, they had another problem on their plate to boot:

Not only did that strategy not control the HIV virus, but there actually was an increase in side effects affecting the heart, kidney and liver in patients taking the drugs only episodically, NIH said.

The side-effect increase was counterintuitive, and researchers so far can't explain it, said Dr. Sandra Lehrman of NIH's AIDS division.


Again, these people hopefully know more on the topic than I do. But I'd guess that the answer to this one could be fairly simple: patients on a continued regiment probably acquire some amount of tolerance to the drugs in the HAART therapy. Of course, this is mostly a shot in the dark since I don't really have any knowledge of what tolerances are built to which effects of any of these drugs.

I will point out, however, that the idea that tolerance is developed to some effects of a drug but not others is not remotely novel. To draw on my own field, tolerance to negative drug effects is such an intrinsic aspect of heroin addiction that I've seen it claimed that first-time users don't even get to really experience the high due to their lack of tolerance to the drug's more harmful effects. I've also seen it claimed that dosages used by addicts are frequently several times the LD50 for drug-naive users. Sorry, I wish I could be more specific on these claims, but it IS two o'clock in the morning.

Anyways: for those who might be inclined to complain that I'm on my fifth post and I still haven't hit anything very neurosciencey, I will point out that a large part of my fascination with HIV was due to long conversations with my girlfriend about the mysteries of HIV-related dementia, a field she intends to go into research in. Which is just one of many reasons why she's incredibly hot. That wasn't TOO morbid a thing to say, was it?

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