A Pivotal Treatment Breakthrough

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Early amfAR research paves way for potent new anti-HIV drug
 
March 26, 2007 - In what researchers have called a pivotal moment in HIV treatment, two new drugs have been shown to be highly effective against resistant strains of HIV, a development that offers new hope for tens of thousands of patients whose treatment is failing due to resistance. One of the drugs—maraviroc—blocks the CCR5 co-receptor, a protein the virus uses to gain entry into the cell, whose function was first described by an amfAR grantee in 1995.
Maraviroc and the second drug, raltegravir, developed by Pfizer and Merck respectively, each fight HIV in different ways, and are unlike any of the other classes of antiretrovirals. Both have shown marked efficacy against HIV that is resistant to all other anti-HIV drugs, which is why they are so critical to patients who may be running out of treatment options. The findings were presented at the Conference on Retroviruses and Opportunistic Infections in Los Angeles, February 25–28.

Maraviroc has been in development for more than a decade, with amfAR funding some of the first and most important research demonstrating the feasibility of designing drugs that block CCR5 to treat HIV.

In 1995, amfAR grantee Dr. Nathaniel (Ned) Landau, who had received amfAR funding to conduct research on another aspect of HIV, stumbled upon exciting results pertaining to CCR5 and was promptly given the go-ahead to pursue this new avenue. He and his colleagues published their findings in the prestigious journal Nature, describing the activity of CCR5 as a co-receptor for HIV infection.

Until 1996, researchers had been puzzled as to why HIV could not infect all CD4 cells (i.e., immune cells with the protein CD4 on their surface). Dr. Landau’s findings resolved part of the mystery—CD4 cells must also have a co-receptor on their surface to allow the virus to slip inside the cell. (In most cases HIV uses the CCR5 co-receptor to gain access to human cells, but it can also use another co-receptor called CXCR4.)

Dr. Landau a couple of months later published further results describing a small number of people who have a genetic mutation that results in a total lack of CCR5 in their bodies. These people suffer no ill effects from this lack of CCR5 and are also almost entirely immune from HIV infection.

Dr. Landau’s two findings together spelled out a clear track for drug development. Drugs that could block CCR5 would be likely to impair the ability of HIV to infect cells and unlikely to do any harm.

Results from clinical trials analyzed at 24 weeks showed that approximately twice as many patients receiving maraviroc in combination with an optimized background regimen reached undetectable levels of virus in their blood compared with those who were not on maraviroc. The outcomes of clinical trials indicate the drug is very effective at suppressing even drug-resistant HIV, and it does so with very few, and minor, side effects.

Raltegravir, the other drug making headlines because of its proven efficacy against resistant strains of HIV, blocks an HIV enzyme called integrase. If approved, it will be the first drug that prevents the virus’ genetic material from becoming part of the host cell’s DNA. The main drugs used in therapy today block the other two enzymes of HIV—reverse transcriptase and protease.

In two ongoing Phase III studies of the drug, patients taking raltegravir in combination with an optimized background drug regimen demonstrated significantly greater declines in viral load versus patients who were on an optimized regimen alone.

Both drugs have received “fast track” status from the FDA, meaning they will be reviewed within six months, and Pfizer has already applied to the FDA for permission to sell maraviroc.