Rilpivirine: drug profile of a second-generation non-nucleoside reverse transcriptase HIV-inhibitor

Abstract

Rilpivirine (RPV) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine family. RPV can be given once daily, is well absorbed and should be administered with food. It is eliminated mainly by hepatic metabolism. Two phase III noninferiority trials (ECHO and THRIVE), compared RPV 25mg with efavirenz (EFV) 600 mg, both given once daily, and combined with 2NRTI backbone. At week 48, response rate for pooled data were 84 versus 82% (difference: 2%; 95% CI: -2.0 to 6.0%). EFV arms performed better than RPV arms when at higher baseline HIV RNA, so RPV was approved for treatment-naïve patients with HIV RNA below 100,000 copies/ml. Approximately 90% of viruses phenotypically resistant to RPV showed cross-resistance to ETR. Conversely, phenotypic analysis showed that in EFV arm, none were resistant to the second-generation NNRTIs. CD4 count increases were similar between groups, but RPV showed a lower rate of discontinuation due to adverse events and lower rates of central nervous system effects, rash and lipid abnormalities. Potency, tolerability and co-formulation in a single tablet (Eviplera^®, Complera^®) make this drug a new and attractive option for the treatment of HIV.

Keywords::

• antivirals
• highly active antiretroviral therapy
• HIV infection
• HIV therapy
• non-nucleoside reverse transcriptase inhibitor
• rilpivirine
• TMC278

Financial & competing interests disclosure

D Ripamonti has received speaker fees and advisory board payments from Janssen-Cilag, Bristol-Myers Squibb, Abbott and Boehringer-Ingelheim. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Rilpivirine (RPV) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine (DAPY) family which retains activity against first-generation NNRTIs-resistant HIV. In particular, RPV retains in vitro a full activity against the K103N mutation, a resistance mutation associated with both efavirenz (EFV) and nevirapine (NVP).

• RPV can be given once daily, should be taken with food, is rapidly and well absorbed, it is 99% bound to human plasma proteins, it is a substrate of CYP3A4 enzyme activity and is eliminated mainly by hepatic metabolism. RPV shows a moderate level of drug-to-drug interactions, but not suitable for coadministration with proton pump inhibitors and rifampin.

• In Phase III trials (RPV 25 mg once daily), 96-week data confirmed that RPV had a similar rate of treatment response compared to EFV, it was better tolerated with a lower incidence of adverse events and rash, when compared to EFV. However, when baseline HIV RNA was higher (>100,000 copies), the risk of virological failure was increased compared with EFV-based therapy.

• At virological failure, the three most common resistance mutations in the RPV arm were M184I, E138K and M184V (the first two mostly combined), while K103N was the most common resistance mutation in the EFV arm. Phenotypic analysis showed that in EFV arm none were resistant to RPV or etravirine, whereas 50% of the RPV patients had resistance to ETR. This can limit the NNRTI sequencing.

• A total of four single-tablet regimens will be available over 1–3 years making ‘one pill once-a-day’ the paradigm of HIV treatment in the next future.

Notes