An update on clinical utility of rilpivirine in the management of HIV infection in treatment-naïve patients

Figures & data

Figure 1 Proportion of responders to rilpivirine (A) and efavirenz (B) in the THRIVE and ECHO studies. Response rate in subjects in the rilpivirine group was reduced when baseline viral load was >100,000 copies/mL.^26,27

Abbreviations: THRIVE, TMC278 against HIV, in a once daily RegImen Versus Efavirenz; ECHO, Early Capture HIV Cohort Study.

Figure 2 Lipid changes (mg/dL) in TDF/FTC/RPV versus continued ritonavir-boosted plus two NRTIs at week 24 after switching.

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; NRTIs, nucleoside analog reverse transcriptase inhibitors; TC, total cholesterol; TDF/FTC/RPV, tenofovir/emtricitabine/rilpivirine; TG, triglyceride; RTV, ritronavir.

Table 1 Comparison of characteristics of non-nucleoside analog reverse transcriptase inhibitors that are recommended for treatment-naïve patients

Initial US approval	Efavirenz 1998	Nevirapine 1996	Rilpivirine 2011
Action	Noncompetitive inhibition of HIV-1 RT	Noncompetitive inhibition of HIV-1 RT	Noncompetitive inhibition of HIV-1 RT
Dose	Tablet 600, 200, 50 mg	Tablet 200 mg, 400 mg (od tablet with XR tablet formulation, Nevirapine XR) Oral suspension	Tablet 25 mg
Dose in adult and frequency of dosing	600 mg od	200 mg bid or 400 mg od (NVP XR) Require 14-day lead-in period	25 mg od
T1/2	40–55 hours	25–30 hours	50 hours
Protein binding	99.5%	60%	99.7%
Elimination	Metabolized by CYP2B6 and CYP3A4; CYP3A4 mixed inducer/inhibitor (more an inducer than an inhibitor)	Metabolized by CYP substrate, inducer of 3A4 and 2B6	Metabolized by CYP3A4
Major drug and food interactions
Use with rifamycin (rifampicin or rifabutin)	Increase dose of efavirenz to 800 mg od when used with rifampicin	Rifampicin should not be used*	Contraindicated
Use with antifungal agents	Decrease to 300 mg od, increase voriconazole to 400 mg every 12 hours	Significant drug interaction with itraconazole and ketoconazole	No significant change in voriconazole
Hormonal contraceptives	No significant interaction levonorgestrel (decrease AUC 83%), norelgestromin (decrease AUC 64%) (Consider alternative or additional method)	Significant interaction with ethinyl estradiol, norethindrone (Consider alternative or additional method)	No significant interaction with ethinyl estradiol, levonorgestrel, norelgestromin
Other major drug interactions			Contraindicated when used with PPI Contraindicated when used with systemic steroid Contraindicated when co-administered with carbamazepine, phenobarbital, phenytoin
Food interaction	High-fat and high-calorie meal increases AUC by 22% and 17%	No food effect	Food requirement
Adverse events
Rash	Any type of rash occurs 8%–26%, discontinue efavirenz due to rash 1.7%	All rash 15% Higher incidence of rash, including fatal hypersensitivity reactions	All rash l%–3%
Hepatotoxicity	4.5% had any hepatic event	10% had hepatotoxicity	3.6% had any hepatic event
	Rate of elevated liver enzymes 25% in patients with HBV or HCV co-infection	Higher incidence of hepatoxicity than other NNRTIs Contraindicated in moderate or severe hepatic impairment Restriction of use in females with CD4 >250 and males with CD4 >400 cells/mm^3	Rate of elevated liver enzymes 27.8% in patients with HBV or HCV co-infection
Lipids	Increase in concentration of total cholesterol, triglyceride	Increase in HDL-C and decreases in TC: HDL-C ratio than an EFV-containing regimen	Minimal increase in TC and TG
Neuropsychiatric side effects	35% of patients had any grade of CNS side effects Dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams Serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms	None	Dizziness, abnormal dreams and nightmare but significantly lower than with EFV
Use in specific populations
Use in pregnancy	Pregnancy category D (teratogenic in nonhuman primate)	Pregnancy category B; however, risk of severe hepatic event in CD4 >250 cells/mm^3	Pregnancy category B; lacking data for teratogenicity in animals
Use in renal impairment	No dosage adjustment	No contraindication in renal impairment. Adjust dosage in CLCR <20 cc/mL	No dosage adjustment
Use in liver impairment	Contraindicated in Child-Pugh B or C (moderate to severe hepatic impairment)	Contraindicated in Child-Pugh B or C (moderate to severe hepatic impairment)	No dose adjustment in mild hepatic impairment but (Child-Pugh A and B) Limited data in severe hepatic impairment
Fixed-dose combination	Co-formulated with TDF/FTC/EFV (Atripla®)	AZT/3TC/NVP (200 mg of NVP) D4T/3TC/NVP Available in some countries	Co-formulated with TDF/FTC/RPV (Complera®)
Pricing	Sustiva® $US785.90/month Atripla® $US2,253.88/month	Viramune® $US723.08/month Viramune XR® $US670.63/month	Edurant® $US804.38/month Complera® $US2,195.83/month
Patterns of resistance	K103N/S P225H K1O1E/Q/R V1081 M230I/L G190S/T/A L1001	Y181C K101E G190A/S K103N V106A/M V108I T188C/L A97G F227L M230L	• More likely to develop virologic failure due to resistance than EFV and more likely to have resistance to 3TC or FTC • 14% of patients in THRIVE and ECHO had virologie failure with novel NNRTI-associated mutations E138K/G K101E/P/T V901 Y181C/I V1891 H221Y V1791/D/L Emergent NRTI mutations in patients who failed rilpivirine M1841/V 53% K65R 9%

Notes: Pricing of antiretroviral agents was from DHHS guidelines version dated February 12, 2013¹⁰

* NVP with rifampicin may be co-administered in patients who cannot tolerate EFV.⁴⁵

Abbreviations: AUC, area under the concentration-time curve; AZT/3TC/NVP, zidovudine/lamivudine/nevirapine; bid, twice daily; CL_CR, creatinine clearance; CNS, central nervous system; CYP, cytochrome P450; D4T/3TC/NVP, stavudine/lamivudine/nevirapine; EFV, efavirenz; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL-C, high-density lipoprotein cholesterol; NRTI, nucleoside analog reverse transcriptase inhibitor; NNRTI, non-nucleoside analog reverse transcriptase inhibitor; od, once daily; PPI, proton-pump inhibitor; RT, reverse transcriptase; T_1/2, elimination half-life; TC, total cholesterol; TDF/FTC/EFV, tenofovir/emtricitabine/efavirenz; TDF/FTC/RPV, tenofovir/emtricitabine/rilpivirine; TG, triglyceride; XR, extended release; THRIVE, TMC278 against HIV, in a once daily Regimen Versus Efavirenz; ECHO, Early Capture HIV Cohort Study.

Table 2 Summary characteristics of rilpivirine (Edurant®)

Class	NNRTI
Action	Rilpivirine acts at hydrophobic position near NNRTI-binding site and causes inactivation of reverse transcriptase enzyme
Dose	25 mg once daily, with food
Formulation	Tablet, fixed-dose combination with TDF/FTC
Time to maximal plasma concentration	4–5 hours
Elimination half-life	Approximately 50 hours
Dose in hepatic impairment	• No dose adjustment in mild and moderate hepatic impairment (Child-Pugh class A and B)
	• No clinical information in Child-Pugh class A
Dose in renal impairment	• No dose adjustment is required in mild to moderate renal impairment
	• Require monitoring in severe or end-stage renal disease
	• Rilpivirine is highly protein-bound and may not be significantly removed by hemodialysis or peritoneal dialysis
	• Higher risk of hepatitis in patients co-infected with HBV or HCV
Use in pregnancy	Pregnancy category B
Use in patients with tuberculosis	Contraindicated if co-administered with rifampicin and rifabutin, rifapentine
Adverse effects	Rash, depression, insomnia, headache
	Use with caution when co-administered with drugs that prolong QTc
Major drug interactions	Acid-lowering agents such as antacid and H-receptor antagonists. RPV is contraindicated when co-administered with PPI
	Contraindicated when co-administered with • Anticonvulsants: carbamazepine, oxcarbamazepine, Phenobarbital, and phenytoin • Glucocorticoid (>one dose) systemic dexamethasone • St John’s wort • Rifabutin
Conditions in which it should be used with caution	Patients with baseline HIV-1 viral load >100,000 copies/mL due to possible suboptimal response
Resistance pattern	• E138K/G, K101E/P/T, V90l, Y181C/I, V189I, H221Y, V179I/D/L • M184I/V (emergent NRTI mutations in patients who failed rilpivirine) • 90% of patients who failed rilpivirine had cross-resistance to etravirine and efavirenz
Price in the USA	Edurant® (rilpivirine) 30 tabs $804.38
	Complera® (TDF/FTC/RPV) 30 tabs $2,195.83

Note: Data from.¹⁰

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; NNRTI, non-nucleoside analog reverse transcriptase inhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; PPI, proton-pump inhibitor; QTc, corrected QT interval; TDF/FTC/RPV, tenofovir/emtricitabine/rilpivirine.

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