Archive for the ‘CCR5’ Category

April 24, 2007

April 25, 2007

Potential new treatment for HIV

The first truly new treatment for HIV to come along in a while has just passed over another hurdle.  The FDA antiviral advisory panel has backed the approval of Pfizer’s CCR5 inhibitor Maraviroc.  This compound is unique from currently approved HIV-inhibitors since it targets a host-receptor, CCR5, and prevents the virus from using this receptor as a handle with which to gain access to the cell. The discovery of CCR5 as a potential drug target is just as compelling as the discovery of the drug which was developed by Pfizer to exploit this point in the virus’ replication cycle.

Early on in the AIDS crisis it was realized that certain individuals appeared to be resistant to infection with HIV while at the same time another set of patients showed little disease progression after they were infected. The explanation for these phenomena came when it was discovered that the virus needed the host cell receptor CCR5 in addition to the CD4 receptor to bind to and gain entry into the cell. Those individuals who were resistant to infection as well as those who were non-progressors possessed a mutant form of the CCR5 gene which reduced its expression. Resistance to infection occurrs for homozygous individuals while slow disease progression occurs in those who are heterozygous. Moreover, in the general population people who carry this mutation appear to be perfectly healthy which immediately indicated that it might be a useful target. Researchers in the field called this an “experiment of nature” since nature had essentially carried out a gene knock-out experiment.

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Word of the week…Placebo 

In the strictest definition it the measured response to an inactive substance brought about solely by the patient’s belief that it will work in a prescribed manner…ie. the “power of suggestion” and the patient believing they will respond according to the suggestion is all that is needed to elicit a response.

Double-blind, placebo controlled drug trials are now considered the gold standard by which a drug’s safety and effectiveness is measured. In order for a drug to be considered useful and safe it must demonstrate increased efficacy or response rate compared to placebo while at the same time show a reduced incidence or degree of side effects. In recent years there has been some debate on whether the use of placebo provides the fairest comparison of a new drug particularly in areas where a treatment already exists.

However, a more basic question one might ask is whether there really is such a thing as a placebo effect according to the definition above. Granted, responses to placebo treatment have been reported and in certain cases patients treated with an inactive substance how shown response rates up to 30%. But are these true object responses that can measured by unbiased clinical observations or are these so-called responses just artifacts of the subjective determination the outcome? My belief is that there is probably not some special phenomenon behind the placebo response and that people can not effect a physical response to an inactive substance through the power of suggestion.

At the extreme end of the spectrum the existence of a true placebo response is easy to argue against. Clinical trials that lean on the patients self-evaluation of their symptoms to determine their response to a drug will most likely be influenced by the subjective nature of the outcomes measurement. Typically these are clinical trials of drugs such as anti-depressants, anxiolytics and in some cases pain medications and not surprisingly these trails are accompanied by high “response rates” to placebo treatment.

To be fair, there are trials were measurable objective responses have been seen, but the question still remains about whether this true placebo response. It is in cases that the response is the result of some unaccounted for factor inherent in the trial design, for some patients the clinical setting alone might be responsible for the response…patients might be eating better, sleeping better or be more relaxed.

To get at the answer to this question a group in Copenhagen has reviewed a number of clinical trials (New England J. Med. (2001) 344, 1594 (no DOI), J. Internal Med. (2004) 256, 91)  Most importantly, they have looked only at clinical trials which included a “no treatment” arm in addition to the placebo arm with the idea being that this would show whether there was a true placebo response. The result was that they found little evidence that patients treated with placebo faired better than patients who received no treatment, except for trials that looked at medications for pain, but given the subjective element in this type of trial it is not surprising.