HIV Drug Guide Introduction: Mix and Match

Antiretroviral drugs are classified based on the stage of the HIV life cycle they target. In the end, they all do the same thing -- prevent the virus from replicating -- but they do it in different ways. There are now six classes of drugs from which to choose. With few exceptions, most antiretroviral regimens include drugs from at least two classes, because attacking the virus with drugs that work in different ways is thought to help prevent resistance. The traditional combinations, especially for initial therapy, have been combinations of nucleoside analog reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI), but integrase inhibitor-based combinations were recently added to the list of recommended starting regimens, a CCR5 antagonist was recently approved for first-line therapy, and there are ongoing studies looking at novel combinations, including regimens that don't include NRTIs.

Nucleoside Analog Reverse Transcriptase Inhibitors (NRTIs) or "Nukes"

Nucleoside analogs, or "nukes," work by preventing reverse transcriptase, a viral enzyme, from turning HIV RNA into DNA. The nukes mimic the normal building blocks of DNA, but when they get pulled into the growing DNA chain, they screw up the process and keep the chain from being completed. The nukes were the only drugs we had until 1996, and they've been components of just about every drug regimen since the approval of Retrovir (AZT) in the mid-80s. Most ART combinations today consist of at least two nucleosides (the "backbone") plus one or more drugs from a different class. The popularity of nukes took a hit when we learned they caused lipoatrophy, which we'd been blaming on protease inhibitors. But it turned out that lipoatrophy (and other related toxicities) were caused primarily by the thymidine analogs (Zerit and Retrovir) but not by Epivir, Emtriva, Ziagen, or Viread. As a result, we're not as afraid of nukes as we used to be. Still, even the newer agents can have their problems. Viread (a component of Truvada and Atripla) sometimes causes kidney problems, and there is some evidence suggesting that Ziagen (a component of Epzicom and Trizivir) may increase the risk of heart attacks, especially in people who already have cardiac risk factors.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) or "Non-Nukes"

The NNRTIs, or "non-nukes," are powerful, convenient drugs with little long-term toxicity. NNRTIs block reverse transcriptase by binding to a different site compared to nukes. Rather than getting incorporated into the virus' DNA, they interfere with the function of reverse transcriptase so it can't make DNA. Side effects occur early on, usually in the first few weeks, and include nervous system side effects with Sustiva, liver toxicity with Viramune, and rash with both. In contrast to boosted PIs, resistance to NNRTIs can occur easily and quickly if the viral load isn't suppressed. These are great drugs for people who are good at taking meds and want a simple combination, but they're not the best choice for those who start and stop meds frequently. The newest drug in this class, Intelence, is used for people who have developed resistance to the other NNRTIs.

Protease Inhibitors (PIs)

The PIs inhibit the activity of protease, an enzyme used by HIV to cleave large proteins into smaller proteins, which are then used to assemble new viral particles. The PIs are the drugs that changed everything. It was the combination of NRTIs plus PIs that first allowed us to completely suppress HIV viral load. Suddenly, we could do more than just temporarily boost the CD4 count for a year or two. HIV infection quickly went from being a progressive fatal disease to one that was chronic and manageable. Management wasn't easy, though. The early PIs were hard drugs to take: lots of pills, lots of doses, and lots of side effects and long-term toxicity. That's changed, in part because of ritonavir "boosting." Almost all PIs are now taken with a low dose of ritonavir (Norvir), which boosts drug levels and simplifies dosing (see "Norvir"). New PIs and new formulations of old PIs have also expanded options and have made PIs a lot easier to take than they used to be. Still, it's important to be aware of PI toxicity. To varying degrees, the PIs can raise lipids (cholesterol and triglycerides), can cause insulin resistance (which can lead to diabetes), and have been linked to body shape changes, especially fat accumulation. However, these problems seem to occur less frequently with the newer agents. PIs can sometimes cause diarrhea or loose stools that typically disappear with fiber supplements like Metamucil, Fibercon, or Citrucel. Don't be put off by the word "laxative" on the bottle -- fiber helps whether you've got diarrhea or constipation.

Integrase Inhibitor

Integrase inhibitors, the newest class of drugs, block the insertion of HIV DNA into human DNA. There is one approved integrase inhibitor, Isentress, and several more in development. Isentress is now approved for both initial therapy and treatment of drug-resistant virus.

CCR5 Antagonists

Entry inhibitors block entry of the virus into the CD4 cell. There are several stages of viral entry. The first is attachment of the virus to the CD4 receptor. There aren't any attachment inhibitors available yet, but this is a potential target for drug development. The next step is binding of the virus to a co-receptor (either CCR5 or CXCR4). In 2007, the first CCR5 antagonist, Selzentry, was approved by the FDA. It was initially approved for use in treatment-experienced patients, but the FDA recently expanded its indication to include initial therapy. Tropism testing is necessary before using a CCR5 antagonist, since it won't suppress virus that can get into the cell using the CXCR4 co-receptor.

Fusion Inhibitors

The final step of viral entry involves fusion of the envelope of the virus with the membrane of the CD4 cell, a step blocked by Fuzeon. Fuzeon requires twice-daily subcutaneous injection, so it's not often used these days. However, it's still a useful option for people with extensive drug resistance.

Joel Gallant, MD, MPH, is Professor of Medicine and Epidemiology at the Johns Hopkins University School of Medicine's Division of Infectious Diseases, and Associate Director of the Johns Hopkins AIDS Service, and author of the book, 100 Questions & Answers About HIV and AIDS.

To view table of contents for The 14th Annual HIV Drug Guide, click here.

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