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Class Distinction

By Joel Gallant, M.D., M.P.H.

March/April 2012

Class Distinction

All antiretroviral drugs work in essentially the same way -- by preventing the virus from replicating. They're classified based on the stage of the HIV life cycle they target. Most antiretroviral regimens include drugs from at least two of the six classes, because attacking the virus with drugs that work in different ways helps prevent resistance.

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

Nucleoside analogs ("nukes" or NRTIs) prevent reverse transcriptase, a viral enzyme, from turning the virus's RNA into DNA. NRTIs mimic the normal building blocks of DNA, but when they join the growing DNA chain, they keep the process from being completed. The nukes have been around since Retrovir (zidovudine or AZT) was approved in the mid-1980s, and they've been components of just about every drug regimen ever since. Although we sometimes refer to the two NRTIs used in most regimens as the "backbone," they tend to be weaker than the drugs they're combined with, serving mainly to prevent resistance. Some of the earliest nukes -- Zerit (d4T), Retrovir, and Videx (ddI) -- are no longer widely used because of toxicity. The four safer and better tolerated drugs are Viread (tenofovir), Emtriva (emtricitabine or FTC), Ziagen (abacavir), and Epivir (lamivudine or 3TC). Viread and Emtriva are combined together in the form of either Truvada or Atripla, which also contains Sustiva. Ziagen and Epivir are combined together in the form of Epzicom. These drugs are a big improvement over their older cousins, though Viread sometimes causes kidney problems, and Ziagen may increase the risk of heart attacks, especially in people with other cardiac risk factors. Current guidelines recommend Truvada as the preferred nuke backbone, with Epzicom as an alternative. So-called "nuke-sparing regimens" are being studied; they usually consist of a protease inhibitor plus either an NNRTI or an integrase inhibitor.

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

The NNRTIs, or "non-nukes," block the activity of reverse transcriptase so it can't make DNA. NNRTIs are most often used in first-line therapy. Sustiva (efavirenz, also a part of Atripla), is the preferred NNRTI, and Viramune (nevirapine) is an alternative. Intelence (etravirine) is used for people who have resistance to the other NNRTIs. NNRTIs are well tolerated over the long term, but side effects can occur, usually during the first few weeks, including nervous system side effects with Sustiva, liver toxicity with Viramune, and rash with both. Resistance to NNRTIs can occur easily and quickly if the viral load isn't suppressed or if treatment is interrupted. The big event for 2011 is likely to be the approval of rilpivirine, a new NNRTI, as well as a single pill combination of rilpivirine with the components of Truvada. Rilpivirine will be used for initial therapy. It has fewer side effects than Sustiva/Atripla, but may be somewhat less potent, especially in people with high viral loads.


Protease Inhibitors (PIs)

The PIs block protease, an enzyme used by HIV to cleave large proteins into smaller proteins, which are then used to assemble new viral particles. It was the combination of NRTIs plus PIs that revolutionized HIV treatment, allowing us to completely and durably suppress viral replication. Although they saved countless lives, the early PIs were hard to take, requiring lots of pills frequently, and having many side effects and long-term toxicities. That's changed, partly because newer PIs were developed, and partly because of boosting: all recommended PIs are taken with a low dose of Norvir (ritonavir), which boosts drug levels and simplifies dosing. The two preferred PIs for initial therapy, Prezista (darunavir) and Reyataz (atazanavir), are once-daily drugs with few side effects and little toxicity. Still, they can cause diarrhea or elevatated lipid levels. Reyataz sometimes causes jaundice, and Prezista can cause an allergic rash. It's not easy to develop resistance to boosted PIs, which make them good choices for people who are likely to miss doses or interrupt therapy. Non-Norvir boosters are being developed; the one furthest along is cobicistat.

Integrase Inhibitors

Integrase inhibitors block the insertion of HIV DNA into human DNA. There is one approved integrase inhibitor, Isentress (raltegravir), which is now a preferred drug for initial therapy. It's very well tolerated, but has to be taken twice a day. Two more are in advanced stages of development. Elvitegravir, a once-daily drug, will be available in a "quad" pill that also contains the booster cobicistat and the Truvada components. S/GSK1349572 ("572") is another once-daily integrase inhibitor now in clinical trials. There's a lot of cross-resistance among these three drugs, so it's not clear that you can use another if you develop resistance to one.

CCR5 Antagonists

CCR5 inhibitors are a type of entry inhibitor; they block entry of the virus into the CD4 cell by interfering with its binding to the CCR5 co-receptor. Selzentry (maraviroc) is approved for both treatment-experienced patients and for initial therapy. However, Selzentry is not a preferred agent for first-line treatment, in part because you can't use it without first doing a tropism test to make sure you have purely "R5 virus": virus that gets into the cell using the CCR5 co-receptor. If you have any virus that uses CXCR4, Selzentry won't work.

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 (enfuvirtide or T-20). Fuzeon requires subcutaneous injections twice a day, and because we now have so many easier options, it's rarely used. However, it's still a useful option for people with extensive drug resistance.

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