Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment

ABSTRACT

Introduction: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy against HIV-1 infections. Here, we provide a comprehensive overview of approved and emerging NNRTIs.

Areas covered: This review covers the latest trend of NNRTIs regarding their pharmacodynamics, pharmacokinetics, mechanisms of drug action, drug resistance as well as new applications such as two-drug regimens and long-acting formulations.

Expert opinion: Since the first NNRTI, nevirapine, was approved in 1996, antiviral drug discovery led to the approval of seven NNRTIs, including nevirapine, delavirdine (discontinued), etravirine, elsulfavirine, efavirenz, rilpivirine, and doravirine. The latter three compounds with favorable pharmacodynamic profiles and minimal adverse effects are often combined with one integrase inhibitor or two NRTIs in once-daily fixed-dose tablets. NNRTI-anchored regimens have been approved as initial therapies in treatment-naïve patients (efficacy: 72% to 86%) or maintaining therapies in virologically-suppressed patients (efficacy: 91% to 95%). Future development of NNRTIs includes: (i) better resistance and cross-resistance profiles; (ii) reduction of drug burden by optimizing two-drug or three-drug combinations; and (iii) improvement of patient adherence by novel long-acting formulations with weekly or monthly administration. Overall, NNRTIs play an important role in the management of HIV-1 infections, especially in resource-limited countries.

KEYWORDS:

• HIV-1
• long-acting therapy
• pharmacodynamics
• pharmacokinetics
• HIV-1 reverse transcriptase

Article highlights

• As of September 2019, seven NNRTIs have been approved for clinical use. NNRTIs are essential components of highly active antiretroviral therapy and NNRTIs-anchored regimens offer >70% of virologic responses in clinical practice.

• The binding of NNRTIs to the drug-binding pocket of HIV-1 reverse transcriptase (RT) would lead to a reposition of the template-primer, therefore preventing the polymerization activity of HIV-1 RT.

• In order to reduce pill burden and improve patient adherence, the current paradigm of triple-drug regimens as the standard of HIV care could be enriched by new switching strategies of two-drug therapies and long-acting drug formulations.

• Despite the availability of 7 NNRTIs approved for clinical use, many challenges lie ahead to develop next-generation NNRTIs with higher virologic responses, better drug resistance profiles, and fewer adverse events, especially for difficult-to-treat patients.

• The advancement of NNRTIs in the combination therapies contributes to better virologic outcomes and minimal adverse events.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 31571368, 31871324, 81730064), the National Science and Technology Major Project of the Ministry of Science and Technology of China (grant number 2018ZX10715004), the Natural Science Foundation of Hunan Province (grant number 2018JJ3713), and the Hunan Youth Elite Project (grant number 2018RS3006).