It's hard to believe, but it has been more than five years since the protease inhibitors (PIs) made their therapeutic debut and forever changed our approach to managing HIV. Perhaps the most impressive aspect of this milestone is that researchers and healthcare providers are continuously finding new and improved ways to use this powerful class of anti-HIV drugs. For evidence of this, one doesn't need to look much further than the current trend of dual-protease inhibitor therapy -- the combination of two PIs with two nucleoside analogues.
There's nothing really new about taking two PIs at the same time. Soon after the first PIs were approved -- or, more precisely, after people began experiencing viral load rebounds while taking regimens containing only one PI -- people figured out that doubling up on PIs seemed to be an effective way to maintain control over drug-resistant virus. What is new is the fact that more people who are just starting anti-HIV therapy are now using dual-PI regimens. Surely they're not doing this to double their pleasure or double their fun. Then what, exactly, is so fascinating about dual-PI therapy?
To appreciate the reasoning behind dual-PI therapy, it's important to understand the drawbacks of regimens that contain only one PI. All too often, PIs fail because of the difficulties many HIV-positive people have in maintaining adequate levels of these drugs in their blood. For example, indinavir (Crixivan) must be taken every eight hours with either no or minimal amounts of food to ensure proper drug levels. And there's very little room for slippage -- not following the strict three-times-daily regimen or taking the medication while there's still fatty food in your stomach can cause Crixivan levels to fall below the minimum needed to suppress HIV. This can cause viral load levels to fluctuate and, ultimately, the development of irreversible drug resistance.
There are also the side effects associated with "full-dose" PI therapy to consider. Standard ritonavir (Norvir) therapy, for example, requires that six pills be taken twice a day. Even for people with stomachs of steel and a high tolerance for toxicities, Norvir can be an extremely harsh drug to take. Diarrhea, nausea, vomiting, numbness or tingling around the mouth, and general discomfort are quite common when using a standard Norvir regimen. Yet it's an extremely powerful and useful PI option for HIV-positive people. So finding ways to use it safely and effectively has always remained a priority.
Given the drawbacks of individual PIs, it's hard to believe that taking two of these drugs at the same time can actually make things easier. After all, this would mean more pills, taken more times a day, greater dietary restrictions, and a risk of more side effects, right? Not necessarily.
The magic behind dual-PI regimens can be found in the effect that some protease inhibitors, especially Norvir, have on other PIs. All PIs are broken down (metabolized) in the body by the cytochrome P450 system of enzymes found in the liver, gut, and other tissues. More than any other PI, Norvir blocks these enzymes and, as a result, slows down the rate by which other drugs are metabolized and forced out of the body. In other words, Norvir dramatically increases the amount of many other drugs in the body and increases the length of time these drugs remain in the bloodstream.
Because it has such a profound impact on the P450 enzyme system, Norvir can spell trouble for people who combine this PI with other prescription and over-the-counter drugs. For example, people who take Norvir should either avoid or greatly reduce their dosage of certain sedatives, antihistamines, lipid-lowering drugs, and even Viagra. Yet behind these sinister details are a number of potential advantages. For example, when Norvir is combined with Crixivan, the amount of Crixivan in the blood is increased by approximately 480%! This allows people to take lower doses of both drugs (one or two Norvir capsules plus two Crixivan capsules) twice a day. In other words, the increased amount of Crixivan in the blood allows people to do away with the pesky mid-day dose. What's more, combining both drugs does away with dietary restrictions -- even if Crixivan is taken with food, enough of it is available in the bloodstream to combat HIV.
Crixivan is hardly the only PI that has been paired with Norvir. In fact, Norvir has a long history with saquinavir (both the old hard-gel Invirase version and the newer soft-gel Fortovase version). When Norvir and Fortovase are combined, researchers have determined that the safest dose for both drugs is 400mg taken twice a day. It might also be possible that combinations of Norvir/Fortovase and Norvir/Crixivan can be taken once a day -- a few clinical trials are currently looking at this possibility.
And the list goes on. Norvir significantly increases the amount of amprenavir (Agenerase) in the blood. The same holds true for nelfinavir (Viracept). Combined with Norvir, the amount of Viracept in the blood is increased more than 15 times. It's also true that when Viracept is combined with Fortovase -- without the addition of Norvir -- the levels of both drugs are increased significantly. This allows both drugs (five Viracept tablets and six Fortovase capsules) to be taken twice a day. There are also dual-PI regimens to watch out for: combinations of Crixivan/Fortovase don't appear to be any more beneficial than each drug taken separately, and Agenerase, when combined with Fortovase, actually reduces the amounts of both drugs in the blood.
More PI = More Power?
For people starting PI therapy, numerous studies have determined that one protease inhibitor is usually enough to reduce viral load and keep it undetectable for a prolonged period of time. It's still not clear if dual-PI therapy is any more (or less) effective than single-PI therapy in treatment-naive patients. But the fact that low doses of Norvir can simplify a regimen may be reason enough to start therapy using two PIs. After all, a regimen that is easier to take is much more likely to be taken correctly.
For HIV-positive folks who have tried and failed regimens containing single PIs, using two PIs together is not so much about simplification -- although this never hurts -- as it is about intensification and improved effectiveness. Intensification is a relatively new concept in the struggle to deal with drug-resistant virus. When HIV begins to show signs of drug resistance, such as an increasing viral load while taking a regimen containing a single PI and two nucleoside analogues, the usual approach is to switch to another regimen. Unfortunately, switching from a regimen containing one PI to another regimen containing yet another single PI is rarely successful in returning viral load to undetectable levels or in keeping it there. The reason for this is cross-resistance -- HIV mutations associated with resistance to one PI almost guarantees that all of the other currently available PIs will be of limited use.
What's now being studied in clinical trials -- and practiced by many healthcare providers and patients -- is the use of Norvir to intensify a failing regimen. When HIV mutations start accumulating during PI therapy, what's really changing is the sensitivity of the virus to the drugs being used. With each additional mutation in HIV's structure, the virus's sensitivity to the drug or combination of drugs dwindles further. The way to overcome HIV's decreasing sensitivity is to either use drugs with a different resistance profile or to increase -- intensify -- the amount of the drug to which HIV has become resistant.
Picture it like this: drug resistance is like a brick wall. To keep viral load undetectable, you'll either need to go around the wall by finding new drugs or you can go over the wall by increasing the amount of drug in your bloodstream to keep HIV in check. The best way to do this -- without doubling the dose (and the risk of side effects) of your current PI -- is to add a P450-blocking PI to the mix.
There are two variations on this theme. The first is to simply add Norvir to a combination that shows early signs of resistance. For example, if you have experienced a low-level rebound in your viral load while taking a Crixivan-based regimen and a drug-resistance test shows that you only have a few mutations associated with Crixivan resistance, adding Norvir to "boost" the effectiveness of Crixivan might do the trick. In this case, a low dose of Norvir (usually two 100mg capsules twice a day) is added to the Crixivan (reduced from two pills three times a day to two pills twice a day), a minor change that has been shown to help people with low-level Crixivan resistance regain control over their viral load.
Another option is to switch from one PI to another PI in combination with Norvir. For example, switching from a Viracept-based regimen to a Crixivan/Norvir-based regimen not only introduces a new PI into the mix, but also uses Norvir to boost the activity of the second PI against whatever cross-resistance mutations are present. In fact, this is the concept behind Kaletra, Abbott's newest PI, which contains lopinavir and a low dose of Norvir. By itself, lopinavir is only moderately effective against strains of HIV resistant to other protease inhibitors. With the addition of Norvir, however, lopinavir is usually active against HIV harboring as many as six key PI-resistance mutation.
It's not at all clear when intensification is most likely to succeed. While some studies have demonstrated that HIV with only a few mutations is likely to respond nicely to Norvir intensification, it's difficult to say how effective it is against strains with several key PI mutations. And while it's true that Norvir can be used to radically increase the amount of other PIs in the blood -- to the point that they will overcome highly-resistant virus -- the risk of side effects must be considered.
Downsides to Consider
Unfortunately, as with any anti-HIV treatment strategy that is potentially good, there is always a list of potentially negative problems waiting somewhere in the wings. With dual-PIs, one potential downside revolves around side effects. Some researchers argue that the risk of side effects is lower with dual-PI therapy because the doses of each PI used are usually lower than the standard doses. Alternatively, other researchers are concerned that toxicity may, in fact, be greater when two PIs are used. For example, taking two PIs might increase the risk of liver damage, especially in HIV-positive patients who are co-infected with either hepatitis B or hepatitis C. There is also the possibility that people taking two PIs may be at greater risk for the body-fat changes associated with lipodystrophy, along with increased lipid and/or glucose levels in the blood.
Another fear is that patients who fail a dual-PI regimen will develop a wider range of HIV drug-resistance mutations, more extensive cross resistance, and have fewer future PI options than those failing single-PI regimens. This may be less of a concern with some dual-PI regimens, such as Crixivan combined with low doses of Norvir. Both of these drugs share almost identical resistance mutations. But what about patients -- particularly those who are new to anti-HIV drug therapy -- who start treatment with Kaletra, a drug containing two protease inhibitors with somewhat unique resistance patterns? Oddly, none of the patients who experienced a viral load rebound while taking this drug in clinical trials so far produced any signs of drug-resistance mutations. So it's difficult to tell which PIs can be used after Kaletra has stopped working correctly. While some research suggests that Fortovase and Agenerase are possible options, nothing has been conclusively stated (see "What Role, Kaletra?" in this issue).
In the grand scheme of things, it's clear that new protease inhibitors are very much needed -- drugs that are easier to take, associated with fewer side effects, and active against virus resistant to current options. Luckily, the pipeline has a few promising PIs in development. In the meantime, however, it's good to see that we've got some new tricks to teach these old dogs.
Tim Horn is executive editor of The PRN Notebook_, published by Physicians' Research Network in New York._