How do they work against the virus?

The non-nucleoside reverse transcriptase inhibitors (NNRTIs, also known as "non-nukes") are drugs that attach to the reverse transcriptase enzyme. They bind in a site that is somewhat different than the "nukes", but essentially do the same thing. Although they bind on the same enzyme as the nukes, because they bind on a different site, they are safely (and recommended to be) combined with the nukes. Once bound, the virus can no longer convert its genetic makeup into your T-cells, thus preventing the virus from replicating.

There are three drugs in this class: Sustiva (efavirenz, EFV), Viramune (nevirapine, NVP) and less used Rescriptor (delavirdine, DLV). These drugs have differences but also similarities. Table 1 shows some unique factors. The similarities of the NNRTI class will also be reviewed.

Do They Play Well Together?

This part of the article will focus more on Sustiva and Viramune since they are prescribed more often than Rescriptor. The following are drug interactions between the NNRTIs and PIs and NRTIs, indicating the various PK changes and what should be done with dosing.

NNRTIs AND PIs

Sustiva

Remember: Sustiva is an inducer, mostly of CYP3A4, so it generally tends to decrease the concentration of the other drug!

Sustiva and Reyataz -- Because Sustiva may decrease the AUC of Reyataz by 74% and C_min by 93% (see ABCs of Pharmacokinetics), it is recommended that 100 mg of Norvir is given once daily with the Reyataz and Sustiva combination. Also, Reyataz will need to be decreased from the usual 400 mg daily to 300 mg daily when Norvir is added (see Protease Inhibitors). Because you need to take Reyataz with food, you may want to separate your dose of Reyataz/Norvir and Sustiva. If you cannot or you simply want to take them all together, make sure you don't have a high fat snack when you take these medicines, as this may increase the concentrations of Sustiva in your body and the chance for side effects (see Table No. 1).

Sustiva and Lexiva -- Sustiva will decrease Lexiva's C_min by 36%. If you are taking Lexiva once daily, it is recommended to take 300 mg (3 capsules) of Norvir with the Lexiva (2 tablets). This is more Norvir than is recommended to be taken with Lexiva without Sustiva (see Protease Inhibitors). Total dose will be Lexiva 1400 mg + Norvir 300 mg once daily with or without food. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack. This only applies to once-daily dosing of this combination. No additional Norvir dosing is needed if you are taking boosted Lexiva twice daily (see Protease Inhibitors).

Sustiva and Kaletra -- Sustiva will lower the C_min of Kaletra by 39%. Thus you need to add an extra capsule of Kaletra for a total of 4 pills twice daily with food. Since Sustiva should be taken on an empty stomach, it is best to separate these medications by at least 2 hours. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack.

Sustiva and Crixivan -- Sustiva lowers the AUC of Crixivan ranging from 33-46%, and C_min ranging from 39-57%. You have to either increase the Crixivan dose to 1,000 mg every 8 hours or, more recommended, use 100 mg?200 mg of Norvir twice daily (Crixivan 800 mg + Norvir 100 mg?200 mg twice daily). The latter regimen allows you to go from three times daily to twice daily dosing (by adding Norvir). Your doctor will let you know if you should take the 100 mg or 200 mg dose. If you take Crixivan/Norvir and Sustiva at the same time, make sure you take it on an empty stomach, to avoid high Sustiva concentrations. If you want to take your Crixivan/Norvir with some food, it is best to separate it from the Sustiva by at least 2 hours. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack.

Sustiva and Invirase and Fortovase -- When you take Sustiva with this drug, it will decrease the AUC by 62%, thus you cannot use this without boosting it! For both Invirase and Fortovase, there are two dosing regimens: Invirase/Fortovase 400 mg + Norvir 400 mg given twice daily with food or Invirase/Fortovase 1,000 mg + Norvir 100 mg given twice daily with food. Your doctor may have you take more Norvir to make sure you have adequate Invirase/ Fortovase in your body. Since Sustiva should be taken on an empty stomach, it is best to separate the Invirase or Fortovase with Norvir from Sustiva by at least 2 hours. Remember that if you decide to eat when taking this combination, eat a low-fat or no-fat snack.

Viramune

Remember: Viramune is an inducer of CYP3A4, so it may decrease the concentration of the other drug!

Viramune and Reyataz -- There are no conclusive data with this combination, but the drug concentration of Reyataz is expected to decrease due to the inducing effects of Viramune. Thus, at this time, it is recommended to boost 300 mg of Reyataz with 100 mg of Norvir (see Protease Inhibitors).

Viramune and Lexiva -- There are no data with this combination, but the drug concentration of Lexiva is expected to decrease due to the inducing effects of Viramune. Thus you will likely need to use a boosted regimen. While 700 mg Lexiva + 100 mg Norvir is commonly used, it is unknown if this will be sufficient to offset the interaction. This may be one of the times where TDM would be useful (see Protease Inhibitors).

Viramune and Kaletra -- Like the interaction with Sustiva, if you take Viramune and Kaletra, we can see a decrease in the Kaletra AUC by 27% and C_min by 51-55%. Thus, you need more Kaletra! For this interaction, you should be taking Kaletra 4 capsules twice daily with food (533 mg/133 mg).

Viramune and Crixivan -- When you take these two drugs together, the C_min of Crixivan is decreased by 44%, so you need a different dose. You either have to increase Crixivan to 1000 mg every 8 hours or add 100 mg?200 mg of Norvir twice daily (Crixivan 800 mg + Norvir 100 mg?200 mg twice daily). If you add Norvir, this interaction allows you to go from three times daily to twice-daily dosing, taken with or without food. Your doctor will decide which dose of Norvir you should be taking.

Viramune and Invirase or Fortovase -- With this interaction, the AUC of Invirase/Fortovase is decreased by 38%, thus boosting is needed with Norvir. The amount of Norvir depends on the drug (Invirase or Fortovase) and amount of drug used as listed below.

• Invirase 1,000 mg + Norvir 100 mg given twice daily with food
• Fortovase 400 mg + Norvir 400 mg given twice daily with food
• Fortovase 1,000 mg + Norvir 100 mg given twice daily with food

Your doctor may have you take more Invirase, Fortovase and/or Norvir to make sure you have adequate Invirase/ Fortovase in your body. Your doctor may also decide to use TDM to make sure you are getting adequate drug in your body.

Rescriptor and PIs

Concentrations of PIs may be increased due to the inhibitory effect of Rescriptor. A PI dose reduction may be required. Talk to your pharmacist or doctor about these interactions.

NNRTIs and RTIs

No clinically significant interactions with either Sustiva, Viramune or Rescriptor.

Stopping or Switching Medications

Stopping medications: Because Sustiva and Viramune have a long half-life, it will take longer for it to clear from your body. If you were to stop all your antiretrovirals at the same time, some of the nukes with shorter half-lives will be cleared sooner than the non-nukes (See Figure 1: Theoretical Pharmacokinetics of Sustiva + Combivir). For a period of time, you may only have the non-nukes in your blood. Conversely, if you have a nuke backbone that has longer half-lives (See Figure 2: Theoretical Pharmacokinetics of Truvada + Sustiva) extension of nucleoside dosing may not be necessary. Depending on the nuke backbone, there is some information that if you stop the non-nuke, you might need to continue the nukes to avoid the development of mutations -- but you should discuss this with your doctor first. There may also be drug interactions if you quickly switch from a non-nuke regimen to a PI regimen. For example, if you switch from Sustiva to Kaletra, you need to make sure there isn't any Sustiva around to interact and lower Kaletra levels. Ask your clinical pharmacist or physician on how to plan your switch!

Switching Between Non-Nukes

Switching from Sustiva to Viramune: Some recent information may change how you take your Viramune if you are switching to it from taking Sustiva. You may be able to take the full dose of Viramune from day one (200 mg twice daily). This would mean you may not have to go through the lead-in dosing of 200 mg once daily for 2 weeks. You might be able do this because the remaining Sustiva in the body may lower concentration of Viramune in the body. By taking the full dose of Viramune from day 1 on, drug levels may be higher and closer to normal. This is very different than what you find in the package insert for either drug, so be sure to talk to your doctor or pharmacist about this first! Taking too much Viramune too soon may increase the risk for side effects (liver problems for example).

Switching from Viramune to Sustiva: Take the full dose of Sustiva on the first day of the switch.

Again, talk to your clinical pharmacist or doctor on how to plan this switch.

The metabolism of NNRTIs makes it very important when it comes to the potential drug interactions. The last thing you'd want is to lower the concentration of your HIV meds and risk developing resistance. Always check with your doctor or pharmacist whenever you are prescribed a new medication.

Jean Lee, Pharm.D. is an HIV Clinical Pharmacist working at the McAuley Health Center, Saint Mary's Health Care in Grand Rapids, MI.

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