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New Drug Regimens Prevent HIV Transmission, Yet Model Highlights Growing Resistance

An easy-to-manage, intermittent dosing schedule of antiretroviral medication may work just as well as daily doses to prevent transmission of human immunodeficiency virus or HIV, new research on monkeys published in Science Translational Medicine suggests. HIV currently affects about 33 million people worldwide, according to the World Health Organization.

Antiretroviral drugs have transformed the lives of HIV-infected people by preventing progression to full-blown AIDS. These drugs also dramatically reduce HIV transmission from mothers to infants during pregnancy and breastfeeding, and previous studies in monkeys suggest that daily doses can also reduce transmission from unprotected sex.

But preventative treatment with antiretroviral drugs is costly and impractical—even if confined to a high-risk population. If ongoing clinical trials in healthy people confirm that daily doses of antiretroviral drugs diminish the chances of acquiring HIV after exposure to the virus, a reasonable next step may be to evaluate more practical, less costly drug schedules in humans.

For three months, Gerardo Garcia-Lerma and colleagues at the U.S. Centers for Disease Control and Prevention (CDC) exposed macaque monkeys to weekly doses of a primate version of HIV engineered to resemble the human virus. They showed that intermittent doses of antiretroviral drugs could prevent infection in the monkeys.

The best protection—equivalent to that provided by daily antiviral medication—occurred when drugs were given one, three, or seven days before virus exposure followed by a second dose two hours after exposure. Less effective, yet still better than no treatment at all, was a schedule in which the drug was given two hours before or after exposure and then again 24 hours later. Drugs given only one to two full days after exposure did not safeguard against infection.

However, increasing resistance to many of these antiretroviral treatments is a serious problem, especially in developed areas of the world where such treatments are widespread. Because people who are infected with drug-resistant strains of HIV can potentially infect more than one other person, researchers are now recognizing the possibility of an emerging epidemic of HIV—resistant to traditional antiretroviral treatments—in these developed countries.

This week in Science, Robert Smith? (sic) from the University of California-Los Angeles and colleagues explain how they created a theoretical model based on data from San Francisco, where over the past 20 years, HIV resistance to antiretroviral treatments has steadily risen. Their model takes into account the transmission of single-, double-, and triple-resistant strains of the virus, and it accurately reproduces the documented evolution of transmitted resistance in that city over the past couple of decades. The researchers used it to identify the key immunologic, virologic, and treatment factors that drive HIV resistance to antiretroviral treatment in that city.

Their model also reveals that, while effective treatment has kept the transmission of resistant HIV under 15% in San Francisco, a full 60% of the resistant HIV strains in the city are capable of causing self-sustaining epidemics. For this reason, Smith? and his colleagues warn that a new wave of HIV, resistant to antiretroviral treatment, could emerge to pose a significant threat to public health.

“We predict a wave of Non-Nucleoside Reverse Transcriptase Inhibitor-resistant strains will emerge over the next five years in San Francisco due to transmission from untreated individuals,” Smith? writes in his report.

The researchers say that their model can be recalibrated to assess the dynamics of HIV resistance anywhere that antiretroviral treatments have been used.

Their research was published online by the journal Science, at the Science Express website, on 14 January. The findings are timely since the World Health Organization is currently rolling out its strategy for universal HIV testing and treatment.

Science Translational Medicine, the newest journal from Science, focuses on outstanding science with promise to improve human health and quality-of-life. Under the direction of Chief Scientific Advisor and former director of the National Institutes of Health Elias Zerhouni and Editor Katrina Kelner, the journal aims to publish groundbreaking research from basic biology that will help make significant advances in medical care, along with commentary on the latest issues in translational medicine.

Nadia Ramlagan and Brandon Bryn

14 January 2010