To hear some drug companies, doctors, researchers and publications tell it, deciding on the best strategy for choosing among the 15 approved anti-HIV drugs and their thousands of possible combinations is simply a matter of good science and clear thinking. In reality, picking an effective, long-lasting combo is more like playing the one-armed bandits in Las Vegas. And, on top of choosing a first-time combo, HIVers must face the added complexity that each choice made upfront affects the options available later on if the combo fails. This issue has recently been dubbed "sequencing" -- mapping out which drug combo to use first, which to switch to for No. 2 and which to save for No. 3, 4 or more.
The sad fact is that although logical-sounding theories of sequencing strategies are easy to come by, none is based on evidence proved by clinical trials. Each of the players offering advice comes with a mixed bag of motives, ranging from pure greed to sincere belief. Drug-company marketers try to persuade consumers that their own product is the best choice: More potent! Easier to take! A resistance profile ideal for first-time users! Researchers, for a variety of reasons -- from personal but inconclusive observations to their consulting contracts with pharma -- sometimes take a position and get stuck there. Doctors' preferences are also affected by multiple influences -- at best, guided by their own clinical experience; at worst, unduly influenced by drug-company marketers bearing gifts. Even we treatment advocates are not above personal bias, sometimes favoring our own theories whether or not there is strong evidence to support them.
While waiting for perfect answers that may never come, we must remember that no advice can substitute for scientific evidence. A compelling case can be made for many approaches, but when it comes to cold, hard proof, the sequencing ship is fresh out of torpedoes. Still, we must make the best of what we've got by making sure that we pursue strategies that offer a reasonable chance of working.
A good first rule in sequencing, as in life in general, is to learn to recognize bullshit when it's staring you in the face -- especially in the form of a drug ad. To chose only one of many pharma examples: in early PR, Hoffman-LaRoche trumpeted that its new protease inhibitor (PI), saquinavir (the old hard-gel version), didn't lead to cross-resistance to other PIs. So if your virus developed the necessary mutations to become resistant to its product, you could easily change to another drug in the same class -- and be golden. The data, however, showed that the drug was so poorly retained in the body that its effect was minimal -- weak activity against the virus translated into fewer mutations during therapy. In other words, Roche's spinners had found a clever way of presenting a drawback as a benefit.
The no-bullshit approach leaves today's HIVer choosing from three general strategies:
Protease-Based Regimen: This typically means a combination of a single PI plus two drugs from the older class of nucleoside reverse transcriptase inhibitors, or NRTIs (for a complete list of anti-HIV drugs, see "La Vida Lingo" below). This strategy evolved in 1996 largely because most HIVers on treatment were on NRTIs, and when a PI was used with the standard two-drug combinations, it yielded the best results recorded in clinical studies up to that time.
Protease-Sparing Regimen: Today, PI combos are seen as far from perfect. Although PI potency is respected and proven, the benefits often extract a high price with their long list of side effects. As a result, many physicians have shifted gears, withholding the PI punch for treatment-experienced people with more advanced disease. The most popular PI-sparing regimen uses one of the three NNRTIs in place of the PI -- which, on a good day, can be every bit as potent as a PI (but they also feature their own list of side effects). Typically, as with a PI-based combo, one NNRTI is joined with two NRTIs. The advantage of this regimen, in theory, is to reduce toxicity and save the PIs for later illness. When protease-sparing vs. protease-using data from clinical trials are compared, they generally come out even. But no data show that one helps you live longer than the other.
"Spare Everything" Regimen: Recently a third type of regimen has emerged as an option. It uses three drugs of the same class all at the same time. The most common example is Glaxo's new Trizivir, which, by combining its own three NRTIs (AZT/3TC/abacavir) in a single pill taken twice daily, certainly offers adherence simplicity. But how well does a "spare everything" regimen compare with a PI-based or a PI-sparing regimen? With so little data, all we can say for sure is that this combination apparently performs adequately for a year or more, especially when you have a relatively low viral load at the start. How you will fare over the long haul is anybody's guess.
Each of these three regimens can, in theory, be applied as regimen No. 1, 2, 3 or salvage, the last resort. But it is impossible to take a position on these three types of regimen -- at any stage of treatment -- without getting argument. Patient A, still sailing happily three years into her first regimen, says, "Start with a PI-based regimen -- it's tried and true." Casting about for salvage therapy, B says, "Don't make my mistake. Save the protease for later when you'll really need it." With two new classes to choose from for his second regimen, C says, "Why waste either a PI or an NNRTI up front if three NRTIs will do the trick?" Different points of view, yes, but having friends who will lead you through their own successes and failures can help to personalize what's at stake.
And four more questions to ask anybody offering you sequencing advice:
1. If an NNRTI isn't used in a first-line therapy, when should it be?
2. If one PI is potent and durable, would using two PIs plus a single NRTI or NNRTI be more so?
3. To "boost" or not? While the concept of using small doses of ritonavir (what's known as "pharmacokinetic," or "PK," boosting) to up the activity and durability of the other PIs (as Abbott does in Kaletra) is convincing, the jury's still out on whether such a combo should be used every time you use a PI.
4. What about mixing all three classes of drugs at once? From the perspective of drug potency alone, this would seem the most logical choice. And plenty of HIVers swear by it. This has long been the standard approach in cancer chemotherapy: multiple drugs with multiple independent mechanisms of action. The trouble with HIV is that treatment never ends, unlike cancer, and there's a fear of "using up" all three classes at once.
So what's a good HIVer to do? Join a denialist cult or the Republican party? Hey, don't panic! Use these guidelines when making a drug-combo decision:
First shot, best shot: People almost always have their best response to their first regimen, so look for one that has proven potency, side effects you can manage and a dosing schedule you can stick to. No. 1's success or failure will help determine future options. The initial regimen is likely the most important treatment step you'll take and, fortunately, many choices will produce reasonably good results. Think through each of the three drugs in the combo, their potency, side effects, dosing schedule and other adherence issues, and decide which best suits your lifestyle.
Genetic diversity: We're not talking quotas here -- rather, differing patterns of resistance. Taking three drugs would be futile if each can be crippled by your HIV developing the same mutations. Genetic diversity can be achieved even by using the right drugs in a single class as long as their "resistance profiles" are different.
PI Boosting: Although most PIs are very potent in a lab dish, they are quickly broken down and excreted from a human body. As a result, many researchers are now routinely combining the PIs (except nelfinavir) with a small dose of ritonavir, which not only makes them work better and last longer by suppressing the production of certain liver enzymes, but often reduces the frequency and number of pills taken. A good PI combo will have a "forgiving" nature, which means that the Mutation Monster won't get you if you fail to take the drug exactly on time every time. "Boosting" is not particularly relevant to NRTIs or NNRTIs.
Multiple mutations: The NNRTIs can be easily crippled if your virus picks up a single specific mutation, so this class should always be combined with drugs that are genetically diverse. Most PIs require that your virus make several mutations before it can get around them; most NRTIs -- except 3TC -- also require multiple mutations to lose efficacy -- plus they combine effectively with other drugs.
Ease of use: This is key to drug adherence -- your consistency in taking the combination as prescribed. Look at an entire day's schedule and the specific requirements of each drug: how many pills, how many times, what dietary or other restrictions. Often, these considerations conflict with the equally important issues listed above. Only you can decide which is the priority for you.
Second-case scenario: Consider what you will do for No. 2, if and when the first regimen fails. Do you want to get into the PI class early or late? When do you want to cash in your NNRTI option? The time for using the NNRTI drugs is critical because resistance to one usually conveys resistance to all. You only have one shot with NNRTIs.
Options open: When a regimen "fails" (see "Demand Results"), not every drug has necessarily become resistant. First-line failure is a good time to use resistance testing to determine which drug is the culprit. By replacing only the one drug to which HIV is resistant, you will do a better job of preserving options for future use. Also, it is sometimes possible to "intensify" a regimen that is beginning to fail by adding a new drug or "PK boosting." Go over all your options and their various benefits and drawbacks with your doctor. Ask doc's opinion, and be sure to speak up about your own.
Regimen vs. resistance: With the info from your resistance test, select a combo based on a drug(s) that you know your virus will be sensitive, or vulnerable, to. If you spared the PIs your first time around, now may be the time to use them. Or if your viral resistance is only "partial" (information that only a "phenotypic," not a "genotypic," test will give), make sure the new drug is potent enough to overcome it at a dose you can tolerate.
Debriefing: Ask yourself why the first regimen failed. Could you have done anything differently to prevent it? How was your adherence, and why? What could you do to maximize chances that your next regimen will go the distance?
THIRD-LINE OR SALVAGE THERAPY
Nice and easy: Don't rush into any rash decisions. Treatment failure does not signify clinical failure: You might feel great (whether or not your CD4s and viral load remain stable) long after your last combo bites the dust.
Pen and paper: If you haven't done so already, write down a plan, including your current combo, your past combos and the options available to you if No. 3, 4 or more goes bad. Update and revise your strategy, adding new information reported by doctors, newsletters, educational forums and the like (see "Resources"). Note any experimental drugs and how to access them. Seeing in print that there are indeed options can turn down the panic volume.
Fight, don't switch: Switching regimens isn't always the answer, especially if you are running out of options. Increasing data suggest that HIVers continue to thrive while sticking with a "failing" third or fourth regimen, though the reasons are unclear. If you don't have a good combo to turn to, consider staying where you are and waiting for a pair of new drugs to become available. If your virus is sensitive to only one or two drugs, jumping to a new regimen or just adding a drug you know will fail (due to cross-resistance) might waste your last two options. How long you can hold out without a new regimen is unpredictable, but it's fairly clear you won't gain anything by switching to an inadequate regimen.
Quick access: Ask a local treatment specialist about new drugs, expanded access programs or clinical trials.
In the end, the choice of a first, last or in-between regimen is never easy. But what about living with HIV ever has been? The good news, though, is that several approaches, and even some salvage regimens, do work reasonably well. Making a decision only gets mind-numbing when you feel you must pick "the best" approach, as there is no hard data to help you, and, of course, plenty of people will be happy to shoot theories. But opinions, like that multitalented bodily orifice, are a dime a dozen, and everybody's got one. Your job, if you choose to accept it, is to cut through the B.S., ask the right questions, and think through which strategy and which drugs fits best in your own private Idaho. If that seems too much to ask, make sure you have an experienced and open-minded AIDS doctor and share the info burden. In another two or three decades, all the current options may have been studied and ranked. But our real hope is that by then something far better will have arrived.
For more information on drug-sequencing resources, further readings and different perspectives, visit www.poz.com/sequencing
LA VIDA LINGO
Come to terms with sequencing
Drug level: The amount of drug in your bloodstream after it is taken; high levels increase the risk of side effects, while low levels can diminish potency.
Durability: How long a drug remains effective before your virus develops resistance.
Multiple class-sparing: A three-drug regimen, either all of the same class or excluding PIs or NNRTIs.
Mutation: Minor changes in the genetic structure of HIV created when it "makes a mistake" reproducing itself.
Potency: How effectively a drug suppresses HIV either in your body or in lab cultures.
Protease inhibitors (PIs): A class of six powerful antivirals that attack HIV just before it produces new copies of itself: amprenavir (Agenerase), nelfinavir (Viracept), indinavir (Crixivan), lopinavir-ritonavir (Kaletra), ritonavir (Norvir), saquinavir (Fortovase).
Protease-based: A regimen of three or more drugs that includes one or more PIs.
Protease-sparing: A regimen of three or more drugs that excludes PIs, usually by substituting an NNRTI.
Resistance: The ability of your virus to overcome the suppressive action of the drug(s) used to treat it. The likelihood increases when a regimen is weak or doses are frequently missed.
Resistance test: It analyzes your virus in order to help you decide which drugs will work best to suppress it. There are two types: Genotypic identifies specific mutations that correspond to resistance to specific drugs. Phenotypic grows your virus in a lab dish with each drug and measures the degree to which it is effective.
Reverse transcriptase inhibitor: Two classes of powerful antivirals that attack HIV just after it enters a cell: NRTIs, or Nucleoside Analogue Reverse Transcriptase Inhibitors, the oldest class of six anti-HIV drugs: 3TC (Epivir); abacavir (Ziagen), AZT (Retrovir),d4T (Zerit), ddC (Hivid), ddI (Videx); plus three new easier-to-use formulations: Combivir (AZT-3TC); Trizivir (AZT-3TC-abacavir) and VidexEC (delayed-release ddI). NNRTIs, or Non-Nucleoside Analogue Reverse Transcriptase Inhibitors: delavirdine (Rescriptor), efavirenz (Sustiva), nevirapine (Viramune).
Salvage therapy: A regimen used when a person no longer responds to most available drugs.
Tolerability: How free a drug is from side effects or other unpleasant outcomes. A drug might be well tolerated in one way (few side effects), but poorly in another (difficult adherence).
Treatment failure: The inability of a regimen to suppress viral load below the limit of detection.