by Chael Needle

LifeGuide [Treatment Horizons]

Challenging the saying that “no news is good news,” recent research has been buzzing with studies about resistance. To clarify: The first item covers resistance to HIV, while the others refer to drug resistance:

In the Journal of Medical Genetics, biologists Christopher Duncan and Susan Scott of Liverpool University’s School of Biological Sciences in the U.K. published the results of a study that revises earlier research about the types of medieval plague in Europe that conferred genetic resistance to HIV. Researchers dismissed theories which claim that resistance can be attributed to smallpox or bubonic plague, and have suggested instead that epidemics of viral hemorrhagic fever are responsible.

The researchers created a mathematical model of genetic mutation in response to plague, which included an outbreak from the Black Death in 1347 to the Great Plague of London (1665–66) and the Plague of Copenhagen more than half a century later. Around ten percent of Europeans enjoy protection against AIDS thanks to the CCR5-delta32 mutation, particularly those living in Scandinavia (fourteen to fifteen percent), which prevents HIV from entering the cells of the immune system. The mutation is rarer around the Mediterranean and absent from sub-Saharan Africa and Asia. Duncan and Scott show how the pressure of natural selection increases the number of those carrying the resistance from around one in 20,000 at the time when plague devastated Europe, particularly France, during the mid-fourteenth century to one in ten three centuries later. Researchers did not believe any practical benefit would come from the theory as it’s unlikely that the genetic mutation could be reproduced artificially to create protection.

At the recent Conference on Retroviruses and Opportunistic Infections, data culled from an analysis of two large-scale Phase III studies showed that nearly twice as many HIV-positive patients with drug- resistant virus who took tipranavir achieved a treatment response compared to patients taking the most commonly prescribed protease inhibitor on the market, Kaletra (39.6 percent versus 21.4 percent). (Kaletra, from Abbott Laboratories, bundles up lopinavir and ritonavir.)

Tipranavir, a non-peptidic protease inhibitor, is an investigational drug currently under FDA review (though it is available through that bureau’s Expanded Access Program); it is being developed by Boehringer-Ingelheim. The drug’s potency is increased when dosed with Norvir (ritonavir).

The study also reported that 34.1 percent of patients taking tipranavir versus 18.3 percent of patients taking Kaletra achieved a viral load below the limit of quantification. Patients taking tipranavir consistently achieved a greater treatment response than those taking another protease inhibitor being used as a point of reference, regardless of the number and type of baseline protease mutations. 

ViroLogic, Inc., announced the publication in the Journal of Acquired Immune Deficiency Syndromes of the results of an independently conducted study that compared the precision and sensitivity of its HIV drug-resistance assay PhenoSense HIV with Antivirogram, developed by Virco BVBA. Results from the study, conducted by investigators at Stanford University, showed that PhenoSense HIV is more precise than Antivirogram and is superior in detecting resistance to currently approved NRTIs. The lead investigator, Robert Shafer, MD, noted that the ability to “precisely measure low level changes in susceptibility to NRTIs is critical, as small changes are known to be clinically significant for these drugs.”

In the study, the precision and sensitivity of each assay was assessed by examining drug resistance in wild-type viruses (those lacking drug-resistance mutations) and in viruses with commonly found mutations. PhenoSense HIV was found to be more likely than Antivirogram to detect resistance to the nukes abacavir (ABC), didanosine (ddI) and stavudine (d4T) in viruses with common drug-resistance mutations. The study found no significant differences between the two assays in detecting resistance to PIs and nukes.

Visit www.aumag.org to read a more in-depth report on tipranavir’s study trial results or refer to December 2004’s Treatment Horizons in the print version.

Chael Needle wrote about viral load spikes and resistance in the March issue.

April 2005