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.
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.