[5][6] It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.

[9] In the European Union, rilpivirine is approved in combination with cabotegravir for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current antiretroviral treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).

Such drugs can accelerate the breaking down of rilpivirine, substantially decreasing its plasma concentrations and potentially resulting in loss of effectiveness and possible resistance.

[9] Some of these drugs also induce the enzyme UGT1A1 and thus reduce blood plasma concentrations of cabotegravir, further compromising the effectiveness of this combination therapy.

[12] It is also contraindicated in combination with proton pump inhibitors because the increased gastric pH causes decreased rilpivirine absorption from the gut, with similar consequences as with CYP3A4 inducers.

[17][18] A fixed-dose medication combining rilpivirine with emtricitabine and tenofovir alafenamide (TAF) was approved for use in the US in March 2016 with the brand name Odefsey.

[11] Rilpivirine entered phase III clinical trials in April 2008,[22][23] and was approved for use in the United States in May 2011 under the brand name Edurant.

[24][25] On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for rilpivirine under the trade name Rekambys, intended for the treatment of human immunodeficiency virus type-1 (HIV-1) infection in combination with cabotegravir injection.