New Studies Show Which Anti-HIV Drug Combinations Work Better Than Others and Why and How They Do It
Andrey Nailor, M.D.·Published 21 February 2012·12 min read
Key points
Using a mathematical formula that carefully measures the degree to which HIV infection of immune system cells is stalled by antiretroviral therapy, AIDS experts at Johns Hopkins have calculated precisely how well dozens of such anti-HIV drugs work, alone or in any of 857 likely combinations, in suppressing the virus.
Combination therapy makes sense for lots of reasons.
Because nucleosides were the first anti-HIV drugs available, combinations of two nucleosides are the best-studied double therapies for HIV infection.
They found that the curves’ steepness reflects the extent to which small increases in the amount of drugs can further suppress attempts by the virus to bounce back, reproduce and spread.
Using a mathematical formula that carefully measures the degree to which HIV infection of immune system cells is stalled by antiretroviral therapy, AIDS experts at Johns Hopkins have calculated precisely how well dozens of such anti-HIV drugs work, alone or in any of 857 likely combinations, in suppressing the virus. Results of the team’s latest research reveal how some combinations work better than others at impeding viral replication, and keeping the disease in check.
“Our study results should help researchers and clinicians develop simpler treatments, using either existing or new drugs, for people who are just starting therapy or people who have already tried and developed resistance to another combination,” says senior study investigator and infectious disease specialist Robert Siliciano, M.D., Ph.D.
Siliciano, a professor at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator, and colleagues constructed the measurement tool, called the instantaneous inhibitory potential, or IIP, in the laboratory several years ago by analyzing the shape of drug dose-response curves in human immune system cells infected with HIV. They found that the curves’ steepness reflects the extent to which small increases in the amount of drugs can further suppress attempts by the virus to bounce back, reproduce and spread.
Researchers say their latest study findings, to be published in the journal Nature Medicine online Feb. 19, along with other recent studies, provide valuable information to physicians about the potential strength of different combination drug therapies, and can help in streamlining and tailoring so-called highly active antiretroviral therapy, or HAART, to as few possible drugs as needed. Several hundred thousand of the more than 1 million Americans living with HIV disease are currently using HAART to fight the disease.
Among the latest study’s key findings was that the most potent drug combos included the drugs efavirenz (a non-nucleoside reverse transcriptase inhibitor) and darunavir (a protease inhibitor.) According to the Hopkins team’s calculations, the drug mix suppressed viral replication by more than a trillion times, enough to prevent infection of every single lymphocyte, or immune system cell, of which there are a trillion in the body.
Combination therapy is the use of two or more drugs at the same time for the same disease. Doctors have known for a long time that the best way-often the only way-to control some diseases is to combine several drugs. For example, tuberculosis (TB) and some kinds of cancer are best treated with combination therapy.
When drugs were developed to treat infection with HIV-the virus that causes AIDS-they became available one at a time. And most doctors used them one at a time to try to slow down HIV infection and help infected people live longer. As more and more anti-HIV drugs were approved for use, some doctors began giving them together. Studies were planned to see if two drugs worked better than one, then if three drugs worked better than two. Time after time, these studies demonstrated that what works for tuberculosis and cancer also works for HIV infection: Taking a combination of drugs directed against the virus is better than taking only one.
Written and revised by
Andrey Nailor, M.D.
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This article answers some of the basic questions about combination therapy for HIV infection: Why does combination therapy work better than one-drug therapy? What anti-HIV drugs are available? Which ones work best together? Of course, we don't have a final answer to the last question, because many combinations of drugs have not been compared in carefully planned studies. But the studies that have been done have convinced almost all doctors that combination therapy offers the best hope for slowing down HIV infection.
The least-powerful drug was found to be one of the oldest anti-HIV medications, d4T, or stavudine (a nucleoside analogue reverse transcriptase inhibitor), which had the power to suppress viral replication by less than 10 times if used on its own (although, Siliciano points out, it works much better when taken in combination with other drugs.)
Why does combination therapy make sense?
Combination therapy makes sense for lots of reasons. Here are the most important ones:
It takes a lot to stop HIV. HIV makes new copies of itself inside infected cells at a very fast rate. Every day, billions of new copies of HIV are made. Every day, millions of infected cells die. One drug, by itself, can slow down this fast rate of infection. Two drugs can slow it down more. In fact, sometimes two drugs can be more than twice as good as one drug. In other words, when the right two drugs are added together, 1 plus 1 equals more than 2.
Anti-HIV drugs from different drug groups attack the virus in different ways. In section 2, we saw how different anti-HIV drugs attack HIV at different steps in the process it goes through to make copies of itself (Figure 1). Think of the HIV enzymes reverse transcriptase and protease as "targets" that can be shot at with different groups of drugs. Drugs that hit the reverse transcriptase target stop HIV just after it enters a cell, and drugs that hit the protease target stop HIV just before it leaves a cell. Hitting two targets increases the chance of stopping HIV and protecting new cells from infection. That's why nucleosides (which aim at reverse transcriptase) and protease inhibitors (which aim at protease) work so well together.
If non-nucleosides and protease inhibitors are given together, they may raise or lower levels of each other in the body. The first studies to show how these drugs interact have now been completed. See "A non-nucleoside and a protease inhibitor."
Different anti-HIV drugs can attack the virus in different types of cells and in different parts of the body. HIV gets inside several different types of cells in different parts of the body. And the drugs we have to treat HIV differ in how well they attack the virus in these different cells. For example, the nucleosides AZT and d4T and the non-nucleoside nevirapine get inside cells in the spinal cord and the brain better than other drugs. So doctors often like to make one of those drugs part of any combination, because it's important to go after HIV wherever it may be hiding. Laboratory studies also show that the nucleosides AZT and d4T work best in infected cells that are actively producing new copies of HIV, while the nucleosides ddI, ddC, and 3TC work best in cells that are infected but "resting" and not yet actively producing new HIV. But the actual effect this difference may have in people with HIV has not been determined. The table shown above summarizes what's known about how well different drugs work in different cells and parts of the body.
Combinations of anti-HIV drugs may overcome or delay resistance. Resistance is the ability of HIV to change its structure in ways that make drugs less effective. HIV has to make only a single, small change to resist the effects of some drugs. For other drugs, HIV has to make several changes. When one drug is given by itself, sooner or later HIV makes the necessary changes to resist that drug. But if two drugs are given together, it takes longer for HIV to make the changes necessary for resistance. When three drugs are given together, it takes even longer. Some people have taken three-drug combinations for a year or more with no signs of emerging resistance.
If anti-HIV drugs are combined in the right way, their side effects will not be increased. All anti-HIV drugs have side effects-the unwanted (sometimes harmful) effects that almost all drugs produce (see Table). Some different anti-HIV drugs have the same side effects. When doctors plan combination therapy, they try to give drugs that have different side effects. Doing so reduces the chance that any single side effect will be so bad that a person has to stop taking the drug (or drugs) that cause it. The main goal of combination therapy is to find the strongest combination of drugs with the lowest level of side effects.
Siliciano says the most widely used combination, a single pill known as Atripla, consisting of tenofovir disoproxil fumarate (a nucleotide analogue reverse transcriptase inhibitor), emtricitabine (a nucleoside analogue reverse transcriptase inhibitor), and efavirenz, was able to reduce viral replication to as few as one in a billion.
Siliciano points out, however, that any drug combination which suppresses viral replication to the degree that out of every 100,000 lymphocytes exposed to the drugs, only one lymphocyte is likely to be infected (for five tenfold reductions) – is sufficient to keep the disease in check, so long as people take their medication as prescribed.
{pagebreak} “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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