Rilpivirine (Edurant), previously known as TMC278) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), developed by Johnson & Johnson/Tibotec. Rilpivirine was submitted for licensing in the United States in November 2010 and received approval for use as first-line treatment in May 2011. European marketing approval followed in November 2011.
It has also been combined in a once-daily tablet (Eviplera) with Gilead’s drugs tenofovir and FTC, which received marketing approval in the EU in November 2011. This combination tablet is marketed as Complera in the US. Researchers are also working on an injectable form of this drug that utilises nanoparticles and would only need to be taken once a month. (Van t’Klooster)
In a 96-week randomised phase II study with over 350 treatment-naive participants, rilpivirine suppressed viral load and increased CD4 counts in similar numbers to efavirenz. This was a dose-ranging study comparing three blinded, once-daily doses of rilpivirine to open-label once-daily efavirenz (600mg), in combination with either AZT/3TC (Combivir; 76%) or tenofovir/FTC (Truvada, 24%).
In a time to loss of virological response (TLOVR) analysis, 73% of patients in all three rilpivirine arms combined achieved viral loads below 50 copies/ml, compared with 71% in the efavirenz arm. Rilpivirine was active against wild-type and NNRTI-resistant virus. Very few participants (6% rilpivirine arms vs 7% efavirenz) experienced virological failure. When NNRTI resistance emerged, rates were broadly similar across all study arms. Most of the virological failures in the rilpivirine arm were related to mutations at 184V and 138K.
The drug also appears to produce a lower incidence of rash, nervous system disorders, psychiatric events, and lipid abnormalities as compared to efavirenz. Adverse event data in the combined rilpivirine arms versus efavirenz at 96 weeks were as follows:
- Rash, 9 vs 21% in the rilpivirine and efavirenz arms respectively.
- Nervous system disorders, 31 vs 48% in the rilpivirine and efavirenz arms respectively.
- Reports of abnormal dreams/nightmares: 3 vs 11% in the rilpivirine and efavirenz arms respectively.
- Total cholesterol, 9mg/dl for combined rilpivirine arms vs 35.4mg/dl for efavirenz.
- LDL cholesterol, 4.5 mg/dl vs 18.2mg/dl for efavirenz.
- HDL cholesterol, 6.2 mg/dl vs 11.3mg/dl for efavirenz.
- Triglycerides, a reduction of 9.9mg/dl vs an increase of 29.2 mg/dl for efavirenz.
However, patients in the rilpivirine combined arms group (all doses) had higher numbers of grade 3 to 4 adverse events (27 vs 21% EFV) and grade 3-4 laboratory abnormalities (27 vs 24% EFV arm). (Santoscoy)
A pooled analysis of 48-week data has been presented from two international phase III studies, ECHO and THRIVE, each of which compared rilpivirine 25mg once daily to efavirenz 600mg once daily, in combination with two nucleoside analogues, in treatment-naive individuals. (Cohen)
The ECHO study randomised 690 patients, and all received a nucleoside analogue backbone of tenofovir and emtricitabine. THRIVE randomised 678 patients, with the nucleoside backbone chosen by the patient’s doctor: around 60% of participants received tenofovir/FTC, 30% received AZT/3TC and 10% received abacavir/3TC.
Participants had relatively low CD4 counts (a median of around 250), and high viral load (median 5 log, or 100,000 copies/ml). After 48 weeks of treatment the proportions with viral load below 50 copies/ml were almost identical (84.3% in the rilpivirine arm, 82.3% in the efavirenz arm), demonstrating non-inferiority.
Virological failures (defined as two viral loads above 50 copies/ml even if viral load was suppressed again at week 48) were more frequent in the rilpivirine arm (9 vs 4.8%), and this difference was largely driven by the higher failure rate in the ECHO study (11 vs 4.4%). The statistical significance of this difference was not reported, but the difference did not vary according to nucleoside backbone, nor by baseline viral load
Patients taking rilpivirine who experienced virological failure tended to develop the E138K mutation that causes resistance to the second-line NNRTI etravirine. Half of those who experienced treatment failure while taking rilpivirine developed resistance to the drug, and of them, 90% developed resistance to etravirine too.
As in the phase II studies, discontinuations due to adverse events were significantly more common in the efavirenz group (6.7 vs 2%), and central nervous system adverse events (such as dizziness and abnormal dreams) were significantly more common, occurring two to three times more often in these patients (overall frequency 38 vs 17%). Rash was also more common in efavirenz-treated patients.
Van t’Klooster G et al. Long-acting TMC278, a parenteral-depot formulation delivering therapeutic NNRTI concentrations in preclinical and clinical settings. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 134, 2008.
Santoscoy M et al. TMC278 (rilpivirine), a next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naïve patients: 96-week results of study C204. XVII International AIDS Conference, Mexico City, abstract TUAB0103, 2008.
Cohen C et al. The single-tablet, fixed-dose regimen of elvitegravir/GS-9350/emtricitabine/tenofovir DF (Quad) achieves a high rate of virologic suppression and GS-9350 is an effective booster. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 58LB, San Francisco, 2010.