Rilpivirine (RPV) IS a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in adult patients not previously treated with antiretroviral therapy. RPV is primarily metabolised by the cytochrome P-450 (CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP 3A inhibitors may lead to increased concentrations of RPV, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric pH may lead to decreased concentrations of RPV, thus promoting virological failure or resistance to RPV.
There are two primary factors that contribute to the emergence of resistance to NNRTIs: (1) HIV-1 RT can tolerate a wide range of sequences in and around the NNRTI binding pocket and (2) there is extensive HIV-1 genetic variation. Although most HIV-infected individuals are initially infected with a single virion, HIV-1 variants arise rapidly due to high viral loads in HIV-1 infected patients, which leads to the infection of large numbers of cells, the rapid turnover of these infected cells, and to errors made during HIV-1 replication. Ultimately, error-prone replication creates the mutations that enable HIV-1 to develop resistance against antiretroviral drugs. Several drug-resistant mutants were selected in HIV-infected individuals by the first generation NNRTIs (NVP, EFV, and DLV).
The second-generation NNRTIs, ETR and RPV, were designed to be less bulky and more flexible, and are better able to adapt to the changes in the NNRTI binding pocket caused by resistance mutations. This allows these newer NNRTIs to effectively inhibit both WT HIV-1 and several drug resistant variants. Using a single-round infection assay, Smith et al (2016) identified several RPV analogues that potently inhibited a broad panel of NNRTI-resistant mutants. Additionally, they determined that several resistant mutants selected by either RPV or doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogues.
CONCLUSIONS
The antiviral data suggested that there are RPV analogues that could be candidates for further development as NNRTIs, and one of the most promising compounds was modelled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants.
RPV’S PLACE IN THERAPY
James et al (2012) reviewed the pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of RPV.
Two phase III, randomised, double-blind, double-dummy, active-controlled trials compared RPV with EFV in HIV-infected adults not previously treated with an antiretroviral. The investigators concluded that RPV, when combined with two nucleoside or nucleotide reverse transcriptase inhibitors, was noninferior to EFV for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/mL) in adults with HIV infection not previously treated with antiretroviral therapy. The most commonly reported adverse effects included depression, insomnia, headache, and rash. RPV is administered as a single 25mg tablet given once daily in combination with other ARV drugs in order to optimise efficacy and reduce resistance.
Conclusion: RPV is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy.
