Non-nucleoside Reverse Transcriptase Inhibitors  (NNRTIs)

Agents: efavirenz (EFV), nevirapine (NVP), etravirine (ETR), delavirdine (DLV)

Combinations: efavirenz/tenofovir/emtricitabine (Atripla)

The non-nucleoside reverse transcriptase inhibitors  (NNRTIs) inhibit the same enzyme as the NRTIs but work through a different mechanism and have greatly different pharmacologic properties. That extra N makes a big difference: it’s very important to keep the two drug classes straight.

Spectrum

Only current clinical use is for HIV.

Adverse Effects

CNS:  Efavirenz can cause a broad spectrum of CNS effects; common effects include dizziness,  drowsiness (or sometimes insomnia), and abnormal (and especially vivid) dreams. Less common effects include depression, psychosis,  and suicidal ideation. The onset of effects is usually very rapid (with the first few doses) and often subsides after several weeks of therapy.  These effects may be minimized by taking the drug on an empty stomach and by taking at bedtime or 2–3 hours prior. A history of mental illness or depression is a relative contraindication to the use of efavirenz.

Dermatologic: Rashes can occur with all NNRTIs, although the nevirapine appears to be the biggest offender. Though some mild forms can be treated with antihistamines, any lesions involving the mucous membranes (suggesting Stevens-Johnson syndrome or similar eruptions) must be managed urgently and represent an absolute contraindication to rechallenge.

Hepatotoxicity: All NNRTIs can cause a spectrum of hepatotoxicity, from asymptomatic transaminase elevations, to clinical hepatitis, to fulminant hepatic failure. Nevirapine-induced hepatotoxicity may occur in the context of a hypersensitivity reaction. Monitoring of signs and symptoms of hepatitis and liver enzymes is important for all these agents.

Hypersensitivity: Nevirapine can cause a hypersensitivity reaction characterized by flulike symptoms, fever, jaundice, and abdominal pain,  with or without a rash. Fulminant hepatic failure and severe rash (e.g., toxic epidermal necrolysis) are the most feared manifestations of nevirapine hypersensitivity reactions. Interestingly, this syndrome appears to be more frequent in patients who are less immuno-compromised (have higher CD4 counts) when     starting nevirapine. The risk of nevirapine hypersensitivity syndrome may be reduced by using a “reverse taper” upon drug initiation:  start with a lower dose and escalate to full dose over 2 weeks, when the risk is highest.

Metabolic: Lipohypertrophy, manifesting as a gradual accumulation of fat in the abdomen,  chest, and neck (as a “buffalo hump”), may occur with the NNRTIs. Efavirenz and nevirapine have also been linked to hyperlipidemia.

Pregnancy/Lactation: Efavirenz is a pregnancy category D agent and should not be offered to pregnant women or those trying to conceive or not using effective birth control. Other NNRTIs are pregnancy category C.

Important Facts

• A key limitation of NNRTIs has been the low  “genetic barrier” to resistance. A single point mutation can lead to high-level resistance to the entire class of drugs. Thus, even stricter adherence may be necessary to NNRTI-based regimens to prevent the emergence of resistance.  The advanced-generation agent etravirine possesses activity against viruses with the most common NNRTI mutations, and it may have a role for patients who have failed other NNRTIs.

• NNRTIs have a much broader drug interaction profile than the NRTIs (remember, one  N makes a lot of difference!). Generally, nevirapine and etravirine are inducers of drug metabolism, delavirdine is an inhibitor, and efavirenz shows mixed inducing and inhibitory proper-ties. Thus, careful screening of these drugs against all other agents in a patient’s regimen is warranted.

What They’re Good For

A combination regimen of efavirenz with the NRTIs tenofovir and emtricitabine is one of the preferred regimens for treatment-naive patients with HIV. Co-formulated as Atripla, this regimen represents the long-sought one-pill, once-daily antiretroviral regimen. Of course, this doesn’t mean it is necessarily the best choice for any individual patient.  The other NNRTIs tend to be used as second-line therapy in treatment-experienced patients.

Don’t Forget!

When initiating an NNRTI, the first few weeks are key. Patients must be counseled carefully about recognizing adverse effects, especially skin reactions and symptoms of hepatotoxicity. The need for strict adherence to prevent resistance, the dose titration schedule for nevirapine, and the CNS effects of efavirenz need to be fully explained to patients. There’s really only one shot to get it right with these very valuable drugs!

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.