New Studies Show Which Anti-HIV Drug Combinations Work Better Than Others and Why and How They Do It
“This means that overall access to anti-HIV medications could also improve as we develop simpler combinations of fewer drugs to achieve near total suppression,” says Siliciano. Less than 7 million of the 34 million people worldwide infected with HIV are taking antiretroviral therapy, he notes.
The Johns Hopkins team based its new calculations on five years of analyzing just how antiretroviral drugs hinder key steps in HIV’s life cycle, preventing it from replicating and infecting other immune system cells.
Scientists have for decades focused on multiple drugs targeting different enzymes that are key to the viral life cycle, thinking that multiple barriers along the chain could best halt replication.
What drug combinations work well together?
Nucleoside-nucleoside combinations. Because nucleosides were the first anti-HIV drugs available, combinations of two nucleosides are the best-studied double therapies for HIV infection. Large studies in the United States, Europe, and Australia showed that AZT + ddI or AZT + ddC work better than AZT alone. These studies showed this difference both by counting clinically significant signs of HIV disease and by measuring CD4 counts and amounts of virus in the blood. Another large study in Canada, Europe, Australia, and South Africa showed that adding 3TC to AZT, to AZT + ddI, or to AZT + ddC lowered the chance that HIV disease would get worse. Smaller studies showed that AZT + 3TC, ddI + d4T, and d4T + 3TC are effective in lowering amounts of virus in the blood and helping raise CD4 counts. It’s likely that double-nucleoside combinations will be a part of anti-HIV therapy for a long time.
A protease inhibitor plus two nucleosides. An important question is whether a nucleoside-nucleoside combination is a good way to begin treating a person with HIV infection, or whether therapy should start with an even stronger combination: two nucleosides plus a protease inhibitor. So far, every study that has compared two nucleosides plus a protease inhibitor with a double-nucleoside combination showed that three drugs given together result in a larger and longer-lasting reduction in the amount of virus in the blood when compared with double-nucleoside combinations or with protease inhibitors used as single agents. Indinavir + AZT + 3TC is stronger and lasts longer than AZT + 3TC. Indinavir + AZT + ddI is stronger than AZT + ddI. Saquinavir + AZT + ddC is stronger than AZT + ddC. Because these trials all had the same result, it makes sense when starting treatment to begin with a strong three-drug combination whenever possible. Combination therapy offers the best chance to control HIV infection over a long period of time.
A non-nucleoside and two nucleosides. The best results with the non-nucleoside nevirapine were in a study combining it with two nucleosides: AZT and ddI. As with protease inhibitors (see previous paragraph), the three-drug combination is stronger than the double-nucleoside combination. When combined with only one nucleoside, nevirapine did not work as well.
A non-nucleoside and a protease inhibitor. The first studies of possible interactions between non-nucleosides and protease inhibitors are now finished. Although these interactions can vary from person to person, nevirapine generally lowers levels of indinavir and saquinavir in the blood and delavirdine raises blood levels of these two drugs. Nevirapine has little effect on levels of ritonavir. More study of delavirdine and ritonavir is needed, but results so far suggest that neither drug greatly affects levels of the other drug. Doctors are advised to combine non-nucleosides and protease inhibitors with caution until there are specific recommendations for doing so.
Important notes about three-drug combinations. People who are about to start therapy with a combination containing a protease inhibitor or a non-nucleoside should remember two things:
- If you’re already taking one or more nucleosides and not doing well, it’s best to start taking a protease inhibitor or a non-nucleoside with a different nucleoside combination-either one that you have never taken before or at least one that you have not taken in a long time. Just adding a protease inhibitor or a non-nucleoside to nucleosides that are failing is not a good idea, because it’s likely that virus resistant to all the drugs will emerge rapidly.
- Combinations that include a protease inhibitor or a non-nucleoside must be taken exactly as recommended by the drug manufacturer. Skipping doses or cutting back on how many pills you take every day will give HIV a good opportunity to become resistant to a drug. And sometimes HIV that has become resistant to one drug will also be resistant to other drugs that you have never taken before.
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Martin Markowitz, MD
From International Association of Physicians in AIDS Care
Although the strategy worked, scientists had, until now, no theory to explain why some drug combinations worked well and others did not. Indeed, they point out, one of the newest classes of anti-HIV medications, so-called integrase inhibitors, did not work well as single drug treatments in laboratory experiments, but were highly effective in people when combined with other drugs.
Siliciano says that as a result of the Hopkins team’s latest research and another of their recent findings, published in Science Translational Medicine in July, experts can finally demonstrate how different drug combinations disrupt and halt viral replication.
Researchers found that the steepest curves occurred when the drug targeted a stage in HIV’s life cycle, in which many copies of viral enzymes, were needed. Citing protease inhibitors as an example, Siliciano says several copies of protease enzyme are needed to cleave the virus into hundreds of working parts before HIV can infect a new immune system cell. He goes on to say that “a level of inter-enzyme cooperation” is happening, specific to each stage of HIV replication.
“Our research shows that drugs like protease inhibitors really work like an on-off switch,” says Siliciano. “Above a certain concentration, these drugs completely turn off viral replication. When you have only one copy of a viral enzyme needed in any key part of HIV’s life cycle, a little more drug won’t give you a lot more suppression; but, when you have more than one copy of enzyme needed for viral replication, then the dose-response curve for the drug will be a lot steeper, and a little more drug will completely shut off viral replication, which is what we want.
“It’s gratifying to finally have a consistent metric for evaluating HAART medications that offers reliable information on how well they work in stopping HIV replication, and which also gives us a baseline target for suppression at less than one in 100,000 immune cells becoming infected in the presence of any drug combination,” he adds.
The Johns Hopkins inhibition index was first developed to compare the level of viral inhibition from different drugs in different classes and to show how they could be graded.
Having measured the different potencies of many drugs, Siliciano conducted his next set of lab experiments to focus on the explanation behind different strengths of viral inhibition. The scientists measured the changes in the dose-response curves, plotting the results on graphs and comparing the sloping curves for each drug or combination of drugs.
Funding for this study, conducted solely at Johns Hopkins, was provided by the Howard Hughes Medical Institute and the National Institute of Allergy and Infectious Diseases, a member of the National Institutes of Health (NIH).
Besides Siliciano, other Hopkins researchers who took part in this study were lead investigator Benjamin Jilek, Ph.D.; Melissa Zarr, B.Sc.; Maame Sampah, B.Sc.; Alireza Rabi, B.Sc.; Cynthia Bullen, B.Sc.; Jun Lai, B.Sc.; and Lin Shen, M.D., Ph.D.
Currently, there are more than 34 million people in the world living with HIV, including an estimated 1,178,000 in the United States and 23,000 in the state of Maryland.
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Source: Johns Hopkins Medicine