The Centers for Disease Control estimates that between 850,000 to 950,000 people in the United States are infected with the Human Immunodeficiency Virus (HIV) , which can cause Acquired Immune Deficiency Syndrome (AIDS) .
Thanks to the availability of antiretroviral drugs such as ritonavir (Norvir) and tenofovir (Viread), which work by blocking the reproduction and spread of HIV once it has invaded white blood cells, HIV has evolved from a death sentence for all patients to a chronic condition for most. But HIV can mutate (change its genetic structure) in a way that allows it to become resistant to existing drugs, even when they are given in combination. As a result, people with multi-drug resistant HIV may find themselves without an effective treatment option.
Enter enfuvirtide (Fuzeon), which was approved by the US Food and Drug Administration (FDA) on March 13, 2003. Enfuvirtide is the first of a new class of AIDS-fighting drugs, called fusion inhibitors. Rather than blocking the spread of HIV from one white blood cell to the next, fusion inhibitors work by preventing HIV from invading white blood cells in the first place.
In a study to be published in the May 29, 2003 issue of the New England Journal of Medicine , but released early, researchers used enfuvirtide to effectively treat HIV in patients resistant to other AIDS-fighting drugs.
The researchers enrolled 501 HIV-positive patients, aged 16 and older, who had been treated for at least six months with at least three types of antiretroviral drugs, had developed a resistance to these drugs, or both. The participants also had at least 5000 copies per milliliter (ml) of plasma HIV-1 RNA, a measure of viral load , or the amount of virus in a certain amount of blood. The higher the viral load, the more serious the infection.
An optimal antiretroviral treatment was selected for all of the study participants, based on previous treatment and resistance.
The patients were then randomized to receive either a twice-daily injection of 90 milligrams (mg) of enfuvirtide plus their optimal antiretroviral therapy, or to receive only their optimal antiretroviral therapy (control group). No placebo injection was given to the control patients. 332 patients were assigned to the enfuvirtide group, and 169 patients were assigned to the control group.
After 24 weeks, the researchers measured the study participant’s plasma HIV-1 RNA levels. They also measured the levels of CD4+ T-cells, which is the kind of white blood cell that HIV attacks. Low CD4+ T cell levels indicate a weakening immune system. Adverse side effects were also noted.
At 24 weeks, the enfuvirtide group experienced a decrease in plasma HIV-1 RNA levels that was about 8.5 times greater than the decrease experienced by the control group (a decrease of 49.66 copies of HIV-1 RNA per milliliter versus 5.81 copies/ml). This represented a significant difference. Also, at week 24, the increase in CD4+ cell count was significantly greater in the enfuvirtide group than in the control group (76.2 cells/mm3 versus 32.1 cells/mm3).
The most common adverse effect of enfuvirtide was a reaction at the side of injection, which was experienced by 98.2% of the enfuvirtide group. However, only 2.8% of patients in this group discontinued treatment because of injection-site reactions. Bacterial pneumonia was also more common in the enfuvirtide group than in the control group, but the overall incidence of bacterial infection was similar in the two groups.
Enfuvirtide was recently approved by the FDA for use in combination with other anti-HIV medications to treat advanced HIV-1 infection in adults and children aged six years and older. In this study, enfuvirtide significantly decreased plasma HIV-1 RNA levels and significantly increased CD4+ cells levels in patients taking it along with antiretroviral therapy. Even though the study did not assess the ultimate outcome of interest—death from AIDS—enfuvirtide represents a long-awaited new option for AIDS patients with multidrug resistance.
A 48-week study of enfuvirtide is being conducted to see if the positive effects of the drug continue over time, and to gauge any longer-term adverse effects that the drug may have. Because more patients treated with the drug in the present study developed bacterial pneumonia than controls, enfuvirtide will carry an FDA label warning physicians to carefully monitor their patients for signs and symptoms of pneumonia.
Unfortunately, the high cost of Enfuvirtide, expected to be about $20,000 per year, will make the drug inaccessible to many of the people who would benefit most.
RESOURCES:
AIDSinfo
US Department of Health and Human Services
http://www.aidsinfo.nih.gov/
National Institute of Allergy and Infectious Diseases
National Institutes of Health
http://www.niaid.nih.gov
Sources:
FDA approves first drug in new class of HIV treatment for HIV infected adults and children with advanced disease. FDA press release. Available at:
http://www.fda.gov
Accessed March 19, 2003
Lalezari JP et. Al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in north and south america. NEJM . 2003.
Last reviewed Mar 19, 2003 by Richard Glickman-Simon, MD
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