Rilpivirine

Rilpivirine is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase with IC50 value of 0.73 nM [1].

Since the existed anti-HIV compound efavirenz showed a serious of side effects including low genetic barrier to resistance and causing CNS disturbance, the alternative NNRTIs (non-nucleoside reverse transcriptase inhibitors) with the advantages (potent, well-tolerated and long plasma half-lives) of efavirenz and without these side effects have been developed. Rilpivirine is one of these new candidate compounds [2].

Rilpivirine showed inhibitory activities to both wild-type HIV (with EC50 value of 0.51 nM) and NNRTI-resistant strains. The conformational flexibility of rilpivirine allowed it to adjust different mutations of the reverse transcriptase. For the singly mutant HIV strains such as L100I, G190S, G190A and V106A, rilpivirine showed higher retained potency than efavirenz and low EC50 values blow 1 nM. In MT-4 cells infected with the K103N isolates, rilpivirine exerted the EC50 value of 0.35 nM. Besides that, rilpivirine showed EC50 values of 2.7 nM and 0.8-1.7 nM for the double-mutant strains K103N/L100I and K103N/ Y181C, respectively. Besides that, rilpivirine was found to significantly inhibit the expression or function of some drug transporters including OATP1B1, CYP3A4 and ABCB1 [2 and 3].

The long elimination half-life and high oral bioavailability of rilpivirine allowed it to be administrated in once-daily oral dose. It showed good oral absorption at dose up to 200 mg in the in vivo evaluation assay. Since rilpivirine has a poor water- and oil- solubility, a nanosuspension injectable formulation has been developed [2 and 4].

References:
[1] Moss D M, Liptrott N J, Curley P, et al.  Rilpivirine inhibits drug transporters ABCB1, SLC22A1, and SLC22A2 in vitro. Antimicrobial agents and chemotherapy, 2013, 57(11): 5612-5618.
[2] Garvey L, Winston A.  Rilpivirine: a novel non-nucleoside reverse transcriptase inhibitor. 2009.
[3] Weiss J, Haefeli W E.  Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. International journal of antimicrobial agents, 2013, 41(5): 484-487.
[4] Baert L, van’t Klooster G, Dries W, et al.  Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. European Journal of Pharmaceutics and Biopharmaceutics, 2009, 72(3): 502-508.

Prevalence of rilpivirine resistance in people starting antiretroviral treatment in Argentina.[Pubmed:28234630]

Antivir Ther. 2017;22(7):625-629.

BACKGROUND: Rilpivirine-based regimens are now preferred or alternative first-line regimens according to many HIV treatment guidelines. Recently, a surveillance study conducted in Argentina determined that prevalence of pretreatment resistance to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) was 10%. The aim of this study was to analyse the prevalence of resistance mutations to newer generation NNRTIs in the population starting ART in Argentina. METHODS: We analysed the prevalence of resistance mutations to Rilpivirine and etravirine (according to the IAS list), obtained through a nationally representative pretreatment HIV-drug resistance (PDR) surveillance study performed in Argentina in 2014-2015. Briefly, 25 ART-dispensing sites throughout the country were randomly chosen to enrol 330 adults starting ART. Samples were processed with Trugene (Siemens)((R)) and analysed using the Stanford algorithm. RESULTS: All 270 samples corresponding to participants with no prior exposure to antiretroviral drugs were included in this analysis. Median (IQR) age was 35 years (28-43); 66.7% were male; median (IQR) CD4(+) T-cell count was 284 cells/mm(3) (112-489). The prevalence of resistance to any antiretroviral was 16% (+/-5%) and prevalence of NNRTI RAMs was 13% (+/-4%). The prevalence of resistance to Rilpivirine was 8% (+/-3%). Prevalence of resistance to etravirine was 4% (+/-3%). The most frequent mutations conferring resistance to Rilpivirine were: E138A (n=6) and G190A (n=4). CONCLUSIONS: This PDR surveillance study showed concerning levels of HIV drug resistance (HIVDR) in Argentina, not only for first-generation NNRTIs but also to Rilpivirine. In our setting, performing resistance testing would be necessary before prescription of ART even if a second-generation NNRTI-based regimen was used as first-line therapy.

UPLC-MS/MS method for the simultaneous quantification of three new antiretroviral drugs, dolutegravir, elvitegravir and rilpivirine, and other thirteen antiretroviral agents plus cobicistat and ritonavir boosters in human plasma.[Pubmed:28219799]

J Pharm Biomed Anal. 2017 May 10;138:223-230.

Rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) are the latest antiretroviral drugs approved for treatment of HIV infection. Currently, poor information is currently available concerning their pharmacokinetic and pharmacodynamic properties, thus making the use of therapeutic drug monitoring for these drugs not useful. This lack of information is partially due to the absence of an high-throughput method for their simultaneous quantification together with other antiretroviral drugs. In this work, we describe the development and validation of a new UPLC-MS/MS method to quantify these drugs, together with other fourteen antiretroviral agents, in human plasma. One hundred microliters of plasma samples were added with internal standard (6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline), underwent a simple protein precipitation with methanol:acetonitrile (50:50v/v) followed by sample dilution with water. Chromatographic separation was performed on a Acquity((R)) UPLC HSS T3 column (150mm x 2.1mm I.D) with a particle size of 1.8mum and compounds were detected with a tandem mass detector, monitoring two ion transitions for each drugs. The mean recovery of RPV, DTG and EVG were 101%, 87% and 112.3% respectively. Accuracy and precision inter/intra-day were below 15% for all drugs, in accordance to Food and Drug Administration guidelines requirements. The UPLC-MS/MS method reported here could be used routinely to monitor plasma concentrations of antiviral drugs, including RPV, DTG and EVG.

Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.[Pubmed:28259776]

Lancet HIV. 2017 May;4(5):e205-e213.

BACKGROUND: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of Rilpivirine, emtricitabine, and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate. METHODS: In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of Rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226. FINDINGS: Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with Rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2.0%, 95.001% CI -5.9 to 1.8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the Rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. INTERPRETATION: Switching to Rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with Rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. FUNDING: Gilead Sciences.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.[Pubmed:28259777]

Lancet HIV. 2017 May;4(5):e195-e204.

BACKGROUND: Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing Rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on Rilpivirine, emtricitabine, and tenofovir disoproxil fumarate. METHODS: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on Rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of either Rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of Rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per mL of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference -0.3%, 95.001% CI -4.2 to 3.7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious. INTERPRETATION: Switching to Rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing Rilpivirine, emtricitabine, tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with Rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. FUNDING: Gilead Sciences.