Clinical trials of HIV antiretroviral therapy: Non-nucleoside reverse transcriptase inhibitors
- Paul E Sax, MD
Paul E Sax, MD
- Section Editor — HIV
- Clinical Director, Division of Infectious Diseases
- Brigham and Women's Hospital
- Professor of Medicine
- Harvard Medical School
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of potent oral antiretroviral (ARV) drugs. One member of this class, efavirenz, is currently a preferred first-line agent for antiretroviral-naïve patients according to several treatment guidelines [1,2].
There are currently five approved NNRTIs (efavirenz, nevirapine, rilpivirine, etravirine, and delavirdine). Efavirenz, rilpivirine and nevirapine are predominantly used in treatment-naïve patients, while etravirine is indicated for treatment-experienced patients. Due to its less favorable pill burden, dosing frequency, and adverse event profile, delavirdine is rarely used. This topic will summarize the comparative clinical trial data in both treatment-naive and treatment-experienced patients supporting the use of these agents in various patient populations.
Information regarding selecting antiretroviral regimens, toxicity, and dosing is found elsewhere. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient".)
Antiretroviral treatment (ART) regimens should have at least three active antiretroviral medications. In treatment-naïve patients, recommended therapy will have two nucleoside reverse transcriptase inhibitors (NRTIs) (one of them lamivudine or emtricitabine) and a third active drug consisting of either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI). (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient".)
The major advantages of the NNRTIs are their relative potency and low pill burden, the latter especially notable with efavirenz, which can be given co-formulated with the NRTIs tenofovir and emtricitabine as one pill daily. A major disadvantage for nevirapine, delavirdine, and efavirenz is that a single resistance mutation can lead to complete loss of antiviral activity; this property is sometimes referred to as a "low genetic barrier" to resistance. (See "Primer on interpretation of HIV drug resistance testing".)
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- Vingerhoets J, Peeters M, Corbett C, et al. Presented at the 13th annual Conference on Retroviruses and Opportunistic Infections, Denver, CO, February 5-8th, 2006; abstract #154.
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- Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet 2011; 378:229.
- Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet 2011; 378:238.
- Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS 2013; 27:939.
- Molina JM, Clumeck N, Redant K, et al. Rilpivirine vs. efavirenz in HIV-1 patients with baseline viral load 100,000 copies/ml or less: week 48 phase III analysis. AIDS 2013; 27:889.
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- Woodfall B, Vingerhoets M, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in Study TMC125-C227. The Eighth International Congress on Drug Therapy in HIV infection. November 12-16, 2006. Glasgow, UK. Abstract #PL5.6.
- Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:29.
- Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:39.
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- Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS 2009; 23:2289.
- GENERAL PRINCIPLES
- Abbreviations used
- TREATMENT-NAIVE PATIENTS
- Efavirenz and nevirapine (2NN study)
- Efavirenz versus rilpivirine
- TREATMENT-EXPERIENCED PATIENTS
- Switch strategies (NEFA study)
- Etravirine versus PI-based ART (TMC125-227 trial)
- Etravirine in patients with drug resistance (DUET trials)
- SUMMARY AND RECOMMENDATIONS