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School of Medicine
New Index Explains Why Some Drugs Work Better than Others Against HIV - 06/15/2008
New Index Explains Why Some Drugs Work Better than Others Against HIV
Release Date: June 15, 2008
A team of AIDS experts at Johns Hopkins has found a simple mathematical equation that accurately explains how well each of 25 anti-HIV drugs in five commonly used drug groups suppresses the virus and keeps the disease in check.
They say this new numbered index offers the first explanation for why only certain drug combinations are effective, because they include at least one higher-scoring drug.
Scientists constructed the new scale, dubbed the instantaneous inhibitory potential, or IIP, by measuring and recalculating the changes in the downward-sloping dose-response curve. The bending line reflects the extent to which small increases in blood levels of drugs can further suppress attempts by the virus to bounce back, reproduce and spread.
With any treatment falling far short of 100 percent, they say, the virus can quickly mutate, desensitizing it to whatever drug combination is being used.
The team’s findings are set to appear online June 15 in the journal Nature Medicine.
Using a lab test developed at Johns Hopkins in 2006, the researchers analyzed varying concentrations of each drug to count how many human immune system cells, from among many millions, were infected in a single round of HIV replication.
The Johns Hopkins team then calculated the mathematical slope or steepness in the dose-response curves for each drug, finding different slopes for each drug class, with some much steeper than expected. When the numbers were reconfigured, based on how many tenfold reductions in the infection levels each drug could produce at its normal blood levels, the scientists created an index that they showed was superior to the standard measure of drug potency, the so-called IC50, which is the precise dose at which the drug works at half its maximal potential.
“It has become clear that after more than a decade of using drug combinations to fight HIV, we need a better tool than the IC50 to let us compare drugs in a way that reflects their ability to suppress the virus,” says senior study investigator and infectious disease specialist Robert Siliciano, M.D., Ph.D.
“People infected with HIV need as much assurance as possible that they are using a powerful enough drug combination to achieve 100 percent viral suppression because any shortfalls, even 1 percent less suppression, could lead to drug resistance,” says Siliciano, a professor at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator.
According to Siliciano, researchers have long known that the steepness of the dose-response curve, which can be calculated in the lab during a drug’s initial investigation and before widespread use in patients, is part of mathematical formulas used to describe how well a drug works. But until now, he says, “physicians were unaware of the clinical significance of curve steepness and the value of combining this with IC50 measures of how tightly a drug molecule chemically bonds to a virus. Using both gives us a much better gauge of how well a drug blocks the virus’s ability to reproduce and infect other cells.”
The IIP calculation is scaled from less than 1 to 10 or greater, corresponding to logarithmic multiples of 10, where a 1 indicates a moderate level of drug suppression, at 90 percent, and 10 translates to 99.99999999 percent (eight 9s after the decimal point), meaning near total suppression.
Study results showed IIP ranges from around 1 to 4 for seven commonly used nucleoside reverse transcriptase inhibitors (NRTIs) and five integrase inhibitors (IIs); between 2 and 6 for five non-nucleoside reverse transcriptase inhibitors (NNRTIs) and for two fusion inhibitors (FIs); and between 2 and 10 for eight protease inhibitors (PIs) studied.
The Hopkins team says the IIP index will also guide future drug and vaccine development because it can be used to calculate which agents have the best potential for depressing levels of HIV in the body.
Moreover, says lead study investigator Lin Shen, M.D., a doctoral candidate in pharmacology at Johns Hopkins, the IIP could be measured for drugs slated for development, labeling them early on as potential failures if the values are too low.
Shen points out that drugs with lower indices, close to 1, such as the nucleoside reverse transcriptase inhibitor AZT (at 1.23), are known to work when matched with more powerful drugs, such as the non-nucleoside reverse transcriptase inhibitor efavirenz, at 5.72.
She cautions that patients and their physicians should not use this new index or IC50 values to determine their drug combination in highly active antiretroviral therapy, or HAART for short. She says clinical trials are first required to set optimal treatments, because the IIP index, though a useful comparison tool, does not take into account other key features of drug effectiveness, such as toxicity and side effects, which for some patients are overriding determinants in drug selection.
“It may turn out that integrase inhibitors, for example, could penetrate more deeply into tissues, making them a better option than other drugs with higher IIP values,” she says.
Shen began the study after noticing that antiviral drugs with very different clinical success rates had similar IC50 profiles, leading her to believe there must be another mathematical means of comparing drugs that better assesses their ability to suppress HIV. She also noticed that the dose-response curve’s steepness, a part of the standard equation used to evaluate how well a drug works, was being overlooked.
She says the next steps in the research are to use the index in analyzing drug resistance and to determine if changes in treatment need to be made.
Hundreds of thousands of the more than 1 million Americans infected with HIV are currently using HAART.
Funding for this study, conducted solely at Johns Hopkins, was provided by the National Institute of Allergy and Infectious Diseases, a member of the National Institutes of Health (NIH), and the Doris Duke Charitable Foundation. Pharmaceutical manufacturer Merck & Co. Inc., and the NIH’s AIDS reagent program donated supplies of drugs involved in the study.
Besides Siliciano and Shen, other Hopkins researchers who took part in this study were Susan Petersen; Ahmad Sedaghat; Moira McMahon; Marc Callender, M.D.; Haili Zhang, Ph.D.; Yan Zhou, Ph.D.; and Eleanor Pitt, M.D.
Additional assistance was provided by Karen Anderson, Ph.D., at Yale University’s School of Medicine, in New Haven, Conn.; and by Edward Acosta, Pharm.D., at the University of Alabama at Birmingham School of Medicine.
Currently, there are more than 33 million people in the world living with HIV, including an estimated 950,000 in the United States and 23,000 in the state of Maryland. Nearly half of all HIV-infected patients in the United States develop resistance to one or more classes of treatment medications.
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