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Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Therapy

Key Management Information



Direct Links to NNRTI Info
Key Points
Generic Brand
delavirdine Rescriptor
nevirapine Viramune
efavirenz Sustiva
etravirine Intelence
rilpivirine Edurant
NNRTI Summary Information


Key Points About NNRTIs



1 NNRTIs as currently formulated and understood all share the issue of cross-resistance resulting from a single or very few mutations in the HIV reverse transcriptase genome.  This is referred to as a "low barrier to resistance."  When subjected to uncontrolled viremia for whatever reason, these drugs as well as this class of drugs may become inactive due to the development of resistance.  Therefore, in patients with the highest levels of viremia, uncertain acquired resistance, poor options for background therapy, and/or the most profound immunoincompetence, protease inhibitors may be preferred over NNRTIs.  In all patients use NNRTIs ONLY in POTENT 3 or 4 drug combinations. 
2 Rash is a fairly frequent adverse effect especially with nevirapine. Close follow-up is warranted when these drugs are used. Mild rash may be observed in up to 33% of patients while on NNRTI therapy; moderate or progressive rash necessitates discontinuation.  Hypersensitivity is cross-reactive between nevirapine and delavirdine and to a lesser extent with efavirenz.  Stevens-Johnson syndrome due to nevirapine is probably seen at a frequency equal to or higher than most other medications.  A once-a-day formulation of nevirapine (Viramune XR) was approved in 2011.  Unfortunately because there are safer and more effective NNRTIs available since the introduction of efavirenz, nevirapine is not recommended unless other alternatives are contraindicated.
3 The side effect profile of efavirenz is characterized by a 50% or more incidence of CNS disturbance, usually of a stimulatory nature.  The spectrum of this side effect varies from minimal sleep disturbance and vivid dreams to aggravation of other psychiatric disturbances and psychosis.  Mood disturbance and anxiety are quite common.  Persons who require a high degree of mental focus for their living (e.g., airline pilot, air traffic controller, etc.) or those who have underlying mental health disorders may be better served by options other than efavirenz.  If insomnia, depression, or issues involving interpersonal relationships develop or increase while on efavirenz, consider other antiretroviral options.  In most cases, nevirapine would be a reasonable substitution.  Rilpirivine, approved in May 2011, is also a once-daily dosed NNRTI, but the incidence of CNS side effects is significantly lower.
4 Many studies point to the NNRTIs (especially efavirenz) as extremely potent, durable, pharmacokinetically-well-suited, easier to adhere to, and possibly less toxic alternatives to protease inhibitors.  Efavirenz may be the gold standard of antiretroviral therapy especially when combined with zidovudine and lamivudine in patients na´ve to therapy.  Recent strides in protease inhibitor development (atazanavir, fosamprenavir) may eliminate some of these advantages currently held by NNRTIs.
5 Delavirdine increases serum levels of protease inhibitors.  If the patient can accept the higher pill-burden associated with delavirdine, this drug may be a prudent component of a protease inhibitor-containing regimen.  Frequent dosing of delavirdine limits its usefulness.  Delavirdine is seldom used anymore.
6 Efavirenz and nevirapine significantly reduce protease inhibitor serum levels.  Dosing of nelfinavir, indinavir, lopinavir/ritonavir, saquinavir, and amprenavir must be increased by 25-33% to compensate for this effect or boosting with ritonavir should be employed.  Atazanavir must be boosted with ritonavir when it is used with efavirenz.  However, the interaction of nevirapine and atazanavir is uncertain at this time (May 2004), and this combination should be avoided until specific interaction data is available.  The same uncertainty exists for the interaction of nevirapine with fosamprenavir.
7 There are multiple drug interactions associated with use of the NNRTIs.  When prescribing, check for interactions carefully via drug reference book, PDA, computer, this site, or your pharmacist.
8 Certain resistance mutations confer in vitro hypersensitivity to NNRTIs.  The clinical significance of this is not fully understood, but it is probably of a minimal nature (May 2004)
9 Hepatotoxicity is fairly frequent with the NNRTIs, especially nevirapine and single daily dosing of nevirapine.  Liver enzymes should be checked at 2 and 4 weeks after initiation of therapy and monthly until stability is assured. Hepatotoxicity appears to much more frequent (12x) in persons who initiate nevirapine with relatively intact immunity.  Therefore according to the manufacturer it should be used very cautiously if at all in women with CD4 lymphocyte counts greater than 250 (and in men with CD4 lymphocyte counts greater than 400)  This leads to the important necessity to educate the patient regarding signs and symptoms of hepatotoxicity.  The hepatotoxicity usually occurs in the first 6 weeks of therapy, but patients should be monitored carefully for at least the first 18 weeks of therapy.  Hepatotoxicity is generally considered tolerable if mild (<4-5 times the upper limit of normal of AST and ALT) and if nonprogressive.
10 Efavirenz should not be used in women who desire to become pregnant, women who are using inadequate birth control, or women who are pregnant.   Severe birth defects were noted in 3 of 31 monkeys who were given efavirenz during pregnancy. Click here for more info. 
11 New Information and Recommendations on Discontinuation of NNRTIs with prolonged half-lives:
Due to the long serum and/or intracellular half-lives of nevirapine and efavirenz, sudden discontinuation of these drugs without substitution of other potent antiretrovirals may result in prolonged subtherapeutic drug levels for several weeks leading ultimately to possible resistance to this entire class of drugs.
 It is therefore recommended that when antiretrovirals are discontinued that include nevirapine or efavirenz, a potent and active protease inhibitor should be substituted first for the NNRTI.  This protease inhibitor substitution therapy should then be continued for 2 weeks.  At that point when NNRTI levels are essentially zero, the PI-based substitute antiretroviral therapy may be stopped.  An alternative to this strategy may be to stop the long-acting NNRTI 5 days prior to discontinuing the NRTI backbone.  Although the strategies above seem reasonable, they remain untested.
12 Etravirine is a second-generation NNRTI that was approved in late 2007.  It's resistance profile is distinct from that of the the first-generation NNRTIs.  In particular it maintains full susceptibility to the K103N mutation, and unlike the first generation NNRTIs it loses its activity only after 3 or more mutations that include the following: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S.  Although not approved for once daily dosing, the pharmacokinetics of etravirine would support it.
13 A sustained-release, once-daily preparation of nevirapine was FDA-approved in April 2011.  Unfortunately, the toxicity profile is unchanged.
14 Rilpivirine (approved in May 2011), a second generation NNRTI like etravirine, may be dosed once-a-day.  It appears to have a much lower incidence of CNS side effects and skin rash than efavirenz.  However, rilpivirine does not appear to work as well as efavirenz against baseline HIV RNA of >100,000 copies/mcL.  Additionally rilpivirine must have an acid milieu in the stomach for absorption; therefore the concomitant use of proton pump inhibitors (PPIs) is contraindicated (and the use of histamine-2 blockers such as famotidine, cimetidine, etc., is discouraged.)



NNRTI Summary Information



Pill Burden
per day
per day
Rash PI Drug
Other Resistance Mutations
2 1-2 33%  ↓ 25-33% hepatitis risk 12x higher
for women CD4>250
K103N, Y181C/I, Y188C/L/H, G190A/S, M230L
12 3 33% ↑↑ hepatitis K103N, Y181C/I, Y188C/L/H, G190A/S, M230L, P236L
1 1 5%  ↓ 25-33% %50 CNS

pregnancy contraindication

K103N, Y181C/I, Y188C/L/H, M230L
4 2 <0.1% used only with


multiple drug interactions V90I, A98G, L100I, K101E, K101P, V106I,
V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S
1 1 <0.1% ? ? ?


For detailed NNRTI Mutation information, please consult with or check the HIV Resistance Test section of this site. 


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Links to Antiretroviral Sections (click on anything)
Nucleoside & Nucleotide Reverse Transcriptase Inhibitors (NRTI)
AZT  |  ddI  |  d4T  |  3TC  |  ABC  |  FTC  |  TDF  |  Combivir  |  Trizivir  |  Epzicom  |  Truvada
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI)
efavirenz  |  nevirapine  |  delavirdine  |  etravirine  |  rilpivirine
Protease Inhibitors (PI)  |  Boosted Protease Inhibitors
saquinavir  indinavir  |  ritonavir  |  nelfinavir  |  lopinavir + ritonavir  |  atazanavir  |  fosamprenavir  | tipranavir
Fusion Inhibitors
Atripla (efavirenz/tenofovir/emtricitabine)  |  Complera (rilpivirine/tenofovir/emtricitabine)  | Stribild (elvitegravir/cobicistat/tenofovir/emtricitabine)


Quick Menu / Table of Contents
Introduction Principles Management NRTI Info NNRTI Info
PI Info Fusion Inhibitors Drug Summary Investigational Adherence
Lab Evaluation Resistance Tests PEP Antiretroviral Tables OI Prevention
Vaccinations TB Therapy Hepatitis Therapy OI Diagnosis OI Therapy
Bibliography Links Palliative Therapy


Updated 1.7.2013