In yet another setback for the star-crossed CCR5 drug class, Merck has announced it will not seek approval for the drug vicriviroc in treatment experienced patients. Merck acquired Vicriviroc, once known as Schering D, when they merged with Schering-Plough in late 2009. While the company's press release promises continued development of the drug for use in people taking HIV drugs for the first time, it remains to be seen whether this drug, long stalled in development, can gain the sort of traction needed to be approved. 

Vicriviroc is an HIV drug that works by attaching to the CCR5 receptor that HIV can use to gain entry in to CD4 and other immune system cells. Not long ago, this drug class was considered to be the 'next big thing' in anti-HIV drugs, holding the potential for strong activity and few side effects. This promise has largely failed to materialize due to a combination of unexpected toxicities, poor performance and company missteps.

A few short years ago, there were three promising CCR5 drugs bunched closely together in the development pipeline. The first to fall was apliviroc, being developed by GlaxoSmithKline. GSK halted development of apliviroc when rare, but catastrophic liver toxicity occurred. Maraviroc- sold in the US as Selzentry- did gain approval a couple years back, but it has been beset by poor sales and the need for an expensive and slow blood test required for its use.

This announcement was based on vicriviroc's failure in two, phase III trials. While disappointing, this is hardly surprising. It had shown marginal benefit at best, and its development was plagued by delays and the lack of a clear development plan by Schering. When Merck and Schering merged, there was a glimmer of hope that Merck's better track record of drug development would finally move vicriviroc forward. This faint glimmer may prove to be a mirage.

The future of HIV drug development is uncertain and troubling. Pharmaceutical companies are looking elsewhere, to markets that are larger (like heart disease), more profitable (like aging) or less crowded (like HCV). While the need for new HIV drugs is undeniable, the simple truth is that more and more companies do not see HIV as an attractive, or even viable option. The failure of another HIV drug is likely to add to this worrying trend.

The HIV drug development pipeline isn't exactly empty. New drugs are being studied. Good drugs, handled correctly by the company developing them can make their mark on the epidemic. HIV is a very data driven market, one where good drugs win out, at least eventually. Whether or not activists and interested scientists can convince the corporate bean counters to invest the necessary capital and other resources to developing these vital new drugs remains to be seen.

In and of itself the latest setback for vicriviroc isn't huge. While Reuters' coverage claimed that 'some industry analysts' considered vicriviroc to be, 'potentially the best' drug of its type, I certainly don't. This drug has languished in development, making halting progress at best. It is more important for the psychology of the HIV drug development field, than for the drug's merits. 

The New York Times today ran an article detailing the ongoing hurdles that researchers face when trying to study marijuana for medical uses. It got me thinking about both the power of anecdote and the influence of politics on the scientific process.

I have been living with HIV now for 17 years. I went on treatment in the mid '90st. I started with dual nucleosides (d4T and 3TC), and moved on to protease inhibitors as soon as they were available. I had a rough go of it with the early PIs- particularly Crixivan and full dose Norvir.

When I started treatment one of my issues was being underweight. I was also prone to GI side effects, like nausea  in fact my family doctor curses what he calls the 'Dalton Stomach'). My doc prescribed Marinol for me, and said that most of her patients preferred the 'herbal form,' meaning of course marijuana. At the time, it had been years since I smoked any pot, but the medical marijuana movement was starting up and the first such club had opened in San Francisco.

One weekend I went camping with some close friends. On our way home, I was really nauseated. My then-young daughter was on the trip with me, and I tried to avoid using marijuana when I was with her. We stopped along the way to eat lunch, and I was doing all I could not to vomit. Finally, I walked down the road a bit, took out my pipe and smoked a little bit of pot.

Almost instantly I felt better. The people I was with were quite struck with the difference it made- more so than I was. They said my color and affect and energy changed dramatically. They instantly believed in medical marijuana.

Anecdotes like this are powerful and important. Many, perhaps most, medical advances are sparked by anecdotes, or simpe observation. I learned recently that lithium's use to treat bipolar disorder came when researchers studying it for seizures noticed that people's moods seemed to be impacted. Viagra was being studied as a heart medicine when its affects on erectile dysfunction were noticed. These stories are very common.

I used medical marijuana based entirely on anecdotal evidence. Word was it helped with things like nausea and weight gain. I tried it and it worked well for me. I had to make the choice to try it based entirely on what I was hearing from others living with HIV. 

Anecdotes must be followed up by careful research if they are to become part of evidence based medicine. There is a lot of interest among researchers at looking at various medical uses for marijuana, but the roadblocks in their way are enormous. It is a classic catch-22: the government claims that there is not enough evidence of marijuana's medical benefits for it to be used in this way, while at the same time blocking the research that would show whether or not it works.

While I have been fortunate to live in California, where voters semi-legalized medical marijuana, I am reminded of what can happen under other circumstances. I learned a while back that one of my favorite teachers had to buy marijuana for his mother who was being treated for cancer. This was back in the 80s. If he had been arrested buying this medicine for his mom, he would have lost his job- plain and simple.

The government needs to get out of science's way. Take down the barriers to scientific study of marijuana. If it doesn't offer any benefit over currently available options, so be it- the point is to allow the research. There is no compelling public health reason not to allow such research to go forward- it is simply politics and institutional inertia. 

The earthquake in Haiti is one of those events so vast in scope as to be impossible to really comprehend from afar. While no place deserves this kind of devastation, Haiti is perhaps the worst place for such a disaster. If, as it has been said, Afghanistan is where empires go to die, Haiti might be where misery goes to live.

Haiti and AIDS are indelibly linked. Haitians were perhaps the most feared and reviled of the original 'Four H Club' of Haitians, Homosexuals, Heroin users and Hemophiliacs. Extreme poverty, language and cultural barriers served to isolate and demonize people from Haiti- especially those seeking refuge from the western hemisphere's poorest country.

If any place on earth deserves a break it is Haiti. Haiti was the first independent nation built by freed slaves. While Pat Robertson might like to entertain the racist fantasy that Haiti's long suffering is due to a 'deal with the devil' they supposedly struck to win independence, the truth is they shrugged off the all to human evil of slavery and have been suffering its lingering effects along with those colonialism, ineffective governance, a lack of natural resources, an inadequate infrastructure and international neglect ever since.

'Mother Nature,' can be exceptionally cruel, as can be seen by the bodies currently rotting in the streets of Port au Prince. The pictures of collapsed buildings, roads and hillsides tell of both the power of nature and the consequence of a country that just doesn't have what it needs. The lack of building codes has led to untold death and misery- and a bit of condescending recrimination all too reminiscent of the immediate aftermath of Katrina.

It doesn't have to be this way. Yesterday I read somewhere that every day cruise ships throw away more food than the average family in Haiti uses in a year. I don't know if that is accurate, but it at least serves as a good metaphor for the very real consequences of massive economic inequality. There is much that is out of our control in this world, and certainly earthquakes are one of those things. How we allocate and use the world's resources however is very much in our control.

While the 'Teabag Movement' gets its collective panties in a wad over entirely imagined 'creeping socialism'- the greatest threat to the world is on display today in Haiti, just as it was in New Orleans, as it was in Biafra, as it was with the Tsunami of 2004. While we have some influence on what we call 'natural disasters', they will always be a part of life on earth. As long as we tolerate a world where bankers get multi-million dollar bonuses for running their businesses in to the ground, while just a few hundred miles south of the richest country on Earth most people live on less than a dollar a day- those natural disasters will have very unnatural consequences.

I am part way through the book, 'Denialism: How Irrational Thinking Hinders Scientific Progress, Harms the Planet, and Threatens Our Lives,' by Michael Specter. I will review the book properly when I am done reading it. Right now though, I want to talk about one of the important concepts he talks about- one that is of vital importance to people living with HIV/AIDS. The concept is how harm and risk are understood and misunderstood in our society.

It is my experience that people with HIV/AIDS, and those who work with us think about risk and harm quite a bit. We think of it in terms of our meds, of our sex lives and increasingly of things like heat disease, cognitive decline and other consequences of aging. It is also my experience that we often talk about risk and harm in ways that are both inaccurate and unhelpful. While some of this can be chalked up to inadequate math and science education, the important concepts involved are neither highly technical nor particularly complicated.

Most importantly: all risk is relative. In other words if you want to understand how risky something is, you have to compare it to something else. So to say something is 'safer' means nothing if you don't say what it is safer than. For example if you want to understand how risky it is to fly on an airplane you can't just look the likelihood of perishing in a plane crash (the number of plane crash fatalities divided by the number of people taking flights during a defined time), you need to compare it to something appropriate- like driving a car, taking the train, or not traveling at all.

Relative risk is what we need to understand to make good healthcare decisions. As a person living with HIV I have to weigh the risk of taking an HIV drug. I can do this in a few ways. I can look up the list of possible side effects and leave it at that. This will give me important, but incomplete information. It will tell me what to look for, and that is all. A better way to look at the same thing would be to look at how likely any possible side effect is- what percentage of people got the side effect- is it 5% or 25%? This way gives me a better, but still incomplete basis to make a decision. I now know how likely a side effect is, but I need to know one more thing- what is my risk of not taking the drug? This should be though of in two ways- both by comparing that risk to other drugs I might take, and to the risk of not taking any drugs at all?

The foundation of medicine is the concept of 'do no harm.' Sometimes the most harmful thing to do is nothing at all. An easy example would be whether or not to take something like Septra or Bactrim to prevent PCP (pneumocystis jerovici pneumonia) if your CD4 count is below 200. There are known risks to taking these drugs, including the risk of death. If the question is posed as 'is taking Septra more risky than not taking it?' the answer may be different if you only look the risk of a fatal drug reaction than if you compare that risk to the risk of getting PCP if you don't take it. While there is a small risk of a fatal drug reaction from taking Septra, there is a bigger risk of getting PCP if you don't take it.

This is made more difficult because of the power of the anecdote. To most anyone who isn't a statistician or scientist, anecdotal evidence (otherwise known as our real life experience) is much more powerful and compelling than an incidence calculation or risk ratio. Back to flying as an example- as Specter says in the book- we are bound to remember dramatic and compelling events like a plane crash, and just as likely to forget all of the planes that didn't crash. But the risk of flying is demonstrably lower than the risk of driving. Plane crashes are more dramatic and much less common that car accidents- this leads many of us us to be more fearful of flying than driving, even though our chance of dying in a plane crash is a tiny fraction of our risk of dying in a car crash.

I had a discussion about this with a friend recently as I was starting a non-HIV related meds. She was telling me of some online forums she had used when taking the same drug, and warning me of the horror stories people posted. I thanked her for the resource and told her that because of my work in HIV treatment activism, I had a pretty good lens to view those kinds of things.

Whenever I talk about HIV drugs and side effects, I start off by stating that I think that almost everyone with HIV or any close connection to people with HIV is highly likely to have an exaggerated sense of both the frequency (how often) and the severity (how bad) of side effects from any HIV drug. The reason for this is simple- we notice when people have side effects, especially the more severe ones. We don't notice when people don't have them, just like we don't really notice when planes don't crash.

This is not to discount the reality of side effects- they happen and should be paid attention to. It is simply to remember that most every medical decision we make entails risk and the only way to really understand that risk to compare the risk of the alternatives, including the risk of doing nothing at all.

AIDS activism grew out of this understanding- people were willing to fight for the right to take very real risks with their lives by taking drugs that were not well understood or even known to work, because the risk of not trying them was understood to mean almost certain death. A drug like Hivid (ddc) would never stand a chance of being approved (or probably even getting in to human studied) today, because it caused too many side effects and there are safer alternatives. When the drug was approved the risk of side effects was pretty much (but incompletely) understood- but there weren't really safer alternatives. Therefore it made sense for the drug to be approved at that time. It equally makes sense for the drug not to be used now- the relative risk has changed.