§ Corresponding author: José-Esteban Peris, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Valencia, Avda. V. Andrés Estellés, s/n, 46100-Burjassot, Valencia, Spain. Tel: +34 963543353. Fax: +34 963544911. (se.vu@sirep.e.esoj)
Received 2013 Feb 4; Revised 2013 Jun 21; Accepted 2013 Jul 29. Copyright © 2013 Usach I et al; licensee International AIDS SocietyThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection.
First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186.
This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.
Keywords: human immunodeficiency virus, non-nucleoside reverse transcriptase inhibitors, nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, next-generation non-nucleoside reverse transcriptase inhibitors
Infections with the human immunodeficiency virus (HIV) are typically treated with drug combinations consisting of at least three different antiretroviral drugs. Essential components of this highly active antiretroviral therapy (HAART) are HIV protease inhibitors (PIs), non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs and NRTIs), fusion inhibitors (FIs), CCR5 antagonists and integrase strand transfer inhibitors (INSTIs). Currently, preferred regimens use combinations of two NRTIs and either an NNRTI, a ritonavir-boosted PI or an INSTI, which have all resulted in decreased HIV RNA levels (
Recent data suggest that virologic failure on first-line regimens mostly occurs due to either pre-existing (transmitted) drug resistance or suboptimal adherence [1]. Therefore, genotypic resistance testing and adherence to the treatment are fundamental criteria when selecting the most optimal initial antiretroviral regimen. Although the prevalence of NNRTI resistance is higher than PI resistance in antiretroviral naïve patients, it has been reported that patients receiving NNRTIs show a higher rate of adherence than patients receiving PIs [2]. Furthermore, some authors do not recommend the widespread use of PI-based first-line therapy, in spite of more favourable resistance implications of PI- versus NNRTI-based first-line therapy, due to resource limitations in some countries and lack of second-line regimens (for patients with failure of an initial antiretroviral therapy) based on other antiretroviral classes [3]. A disadvantage of PI-based regimens is the large number of drug-drug interactions, which may make their use in patients taking other medications more difficult. Regimens containing raltegravir, the most commonly used INSTI, have fewer drug-drug interactions than PI-based regimens. However, raltegravir, like NNRTIs, has a low genetic barrier to resistance, with the additional disadvantage (related to treatment adherence) of requiring twice-daily dosing. A newer INSTI, elvitegravir, can be administrated once daily combined with cobicistat (an inhibitor of elvitegravir metabolism) and two NRTIs [1].
NNRTIs are usually not recommended as components of second-line regimens because of an increased risk of resistance-related failures [3, 4].
There are two types of HIV, HIV-1 and HIV-2, and both can cause acquired immune deficiency syndrome (AIDS). Most AIDS infections are due to HIV type 1 (HIV-1) strains, while HIV-2 represents a significant minority of all HIV infections in some countries, such as Guinea-Bissau and Portugal [5]. There are important differences between HIV-1 and HIV-2 that provide insights into virus evolution, tropism and pathogenesis. In particular, HIV-2 is less readily transmitted and is generally less pathogenic than HIV-1 [6].
Five NNRTIs (nevirapine, NVP; delavirdine, DLV; efavirenz, EFV; etravirine, ETR; and rilpivirine, RPV) are currently US Food and Drug Administration (FDA) approved. Moreover, all of them except for DLV have been approved by the European Union. Their chemical structures and main characteristics are described in Figure 1 and Table 1 , respectively. To improve adherence and reduce the risk of treatment errors, EFV (Atripla ® ) and RPV (Complera ® /Eviplera ® ) have been co-formulated with two NRTIs (emtricitabine and tenofovir) as a single-tablet, once-daily regimen ( Table 2 ). Atripla ® and Complera ® / Eviplera ® are recommended for treatment of HIV-1 infection when the agents included in the co-formulation are drugs of choice. However, they are not recommended in patients with creatinine clearance lower than 50 mL/min. In these patients, it is recommended to use the individual drugs of the fixed-dose combination and adjust tenofovir and emtricitabine doses according to creatinine clearance [1].