Introduction: Why Do We Need a New Class of HIV Medications?

Source : http://www.thebody.com/fuzeon/intro.html

Fuzeon -- A Review of the First Entry Inhibitor

By Calvin Cohen, M.D., M.S.
2003

Reason #1: Resistance to Current Drugs
Treating HIV infection involves many challenges, including occasionally troublesome side effects and the difficulty of taking once- or twice-daily medications for a long period of time.
But one of the most difficult challenges is what to do when a medication no longer has any effect on HIV. When this happens, we say that HIV is "resistant" to a medication. This means that the amount of HIV in your body is able to grow despite the presence of that medication in your body.

Once resistance develops, it's not the initial return of HIV reproducing inside your body that causes a problem for the immune system; after all, HIV usually doesn't return in very high numbers. The problem is that once HIV is given even a little leeway to grow, it tends to begin mutating -- that is changing its genetic structure -- more and more. Each mutation helps HIV thrive, and as it does, it can cause additional immune damage.
And, of course, the more your immune system is damaged, the more vulnerable you are to a host of other, often dangerous, infections. Researchers continue to look for ways in which you can maintain a healthy immune system despite the low-level presence of HIV. In addition, researchers are always looking for combinations of HIV medications that can contain HIV for long periods of time despite this low-level presence.

One clear goal of HIV treatment is to avoid resistance and to "suppress" HIV, or stop HIV from reproducing itself. When HIV is fully suppressed, it is "undetectable" in your blood, meaning that although HIV is still present in your blood, we cannot see it with the viral load tests currently available. (It should be noted, however, that viral load tests do not measure the presence of HIV in body tissues such as the lymph nodes or the brain, just the presence of HIV in the blood.)

Once HIV is "undetectable," resistance usually does not occur and treatment will be far more reliable, long-lasting and successful.

Reason #2: Cross Resistance
Another challenge in HIV treatment is the occurrence of "cross resistance." Cross resistance occurs when a mutation in HIV allows HIV to "ignore" or resist the effect of more than one medication -- including a medication that someone may never have taken. So, despite the fact that we have about 20 different FDA-approved HIV medications, if your HIV becomes resistant to almost any of these medications, there will be some degree of cross resistance to other medications -- even though you have not yet used them.

Cross resistance is particularly a concern if, when you were first infected with HIV, you were infected with a strain of HIV that already had some resistance mutations. When this is the case, even before your treatment begins, there may be fewer combinations of HIV medications that will work reliably.

It is important to understand that cross resistance occurs within a specific "class" of antivirals. Researchers categorize each HIV medication within a class based on similarities in the way each medication stops the growth of HIV in the body. For the past several years, HIV treatment has been based on a combination of at least three different medications from one or more of three classes: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

So, for example, if you develop resistance to one NNRTI such as nevirapine (Viramune), you're almost guaranteed to have cross resistance with another NNRTI such as efavirenz (Sustiva, Stocrin).

Cross resistance, however, is much more likely to happen with NNRTIs than with NRTIs or PIs. With NRTIs and PIs, another drug within the same class can still be used if you develop resistance to the first one you try. For example, if you are resistant to 3TC (lamivudine, Epivir), which is an NRTI, you will be cross resistant primarily to FTC (emtricitabine, Emtriva), but cross resistant to a much lesser extent with other NRTIs, such as tenofovir (Viread) or d4T (stavudine, Zerit).

It should be noted that even if there is not complete cross resistance between two drugs, it is possible for the mutations that made HIV resistant to one drug give HIV a "head start" in creating additional mutations that can eventually make HIV resistant to other drugs.

These problems explain why so many people with HIV now have treatment-resistant strains of HIV. Many HIV-positive people have a hard time finding treatment combinations that will reliably suppress HIV for years and not cause many side effects. Therefore, if their HIV is not completely suppressed, they develop strains of HIV that have become at least partially resistant to several available medications. Furthermore, there are now many people who have at least some degree of resistance to all three classes of antivirals used in initial therapy.

Fortunately, cross resistance occurs only within a class of drugs, not between classes. In other words, if you've become resistant to NNRTIs, you're still probably going to be fully susceptible to NRTIs and PIs (i.e., your HIV will remain vulnerable and able to be attacked by those classes of drugs). And when HIV is fully susceptible to enough new drugs, it can be fully suppressed.
For several years now, it has been understood that when you switch from one treatment combination to another after resistance has developed, choosing an "anchor" drug from a new class of medications is among the best ways to reliably reestablish HIV suppression. This is particularly true if most of the drugs available are less than fully potent because you have some degree of cross resistance.

The newest class of HIV drugs is the entry inhibitors, also known as fusion inhibitors. The first approved medication in this class is Fuzeon (enfuvirtide, also known as ENF or T-20). This breakthrough HIV medication offers an important option for people dealing with resistance.