Rilpivirine is a nonnucleoside reverse transcriptase inhibitor used in combination with other antiretroviral agents in the therapy of human immunodeficiency virus (HIV) infection. Rilpivirine is associated with a low rate of transient serum aminotransferase elevations during therapy and has been implicated in rare cases of clinically apparent acute liver injury.
Rilpivirine (ril" pi vir' een) is an antiretroviral agent that acts by noncompetitive binding to, and inhibition of the HIV reverse transcriptase. Rilpivirine is a nonnucleoside reverse transcriptase inhibitor similar in action to nevirapine, efavirenz, delavirdine and etavirine. In several randomized controlled trials, rilpivirine was found to have similar efficacy to efavirenz when combined with at least two nucleoside analogues (typically tenofovir and emtricitabine). Rilpivirine was the fifth nonnucleoside reverse transcriptase inhibitor approved by the FDA , and current indications are for the treatment of HIV infection in combination with other HIV medications. Rilpivirine is available under the brand name Edurant in tablets of 25 mg. The recommended dose is 25 mg orally once daily with a meal. Rilpivirine is also available in a fixed dose combination (25 mg) once a day tablet with emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) under the brand name Complera  and a similar combination with tenofovir alafenamide fumarate (25 mg) under the brand name Odefsey . Antiviral resistance can occur and resistance patterns are similar to, and cross react with those due to other nonnucleoside reverse transcription inhibitors. Common side effects include fatigue, dizziness, headache, insomnia, depression and skin rashes.
Serum aminotransferase elevations occur in 25% or more of patients on rilpivirine therapy, but elevations above 5 times the upper limit of normal are uncommon, occurring in 1% to 4% of patients. The rate of serum aminotransferase elevations during rilpivirine therapy is higher in patients who are coinfected with hepatitis B or C [~10% have values greater than 5 times ULN]. The product label for rilpivirine induces a warning about hepatotoxicity particularly in patients with HBV or HCV coinfection and recommends monitoring for liver test abnormalities. During the first several years of wide spread clinical use of rilpivirine, a single case report of liver injury was published. The case was marked by prominent elevations in serum ALT and AST without jaundice arising within days of starting therapy and resolving rapidly upon stopping (Case 1). There was no rash, eosinophilia or other prominent immunoallergic features which are typical of the liver injury associated with nevirapine and efavirenz. Thus, clinically apparent hepatotoxicity due to rilpivirine may occur but is rare.
Liklihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
While hepatotoxicity from rilpivirine may be rare, it is likely due to hypersensitivity. Rilpivirine is extensively metabolized in the liver via the cytochrome P450 system (predominantly CYP 3A4) and production of a toxic or immunogenic intermediate may trigger liver injury.
Outcome and Management
The severity of the liver injury linked to rilpivirine therapy has been mild and self-limited and characterized by serum aminotransferase elevations with no or minimal symptoms and no rash. Recovery has been prompt upon drug discontinuation. Rilpivirine has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between rilpivirine and other nonnucleoside reverse transcriptase inhibitors, although there may be cross reactivity in occurrence of rash.
Drug Class: Antiviral Agents,
Other Drugs in the Subclass, Nonnucleoside Reverse Transcriptase Inhibitors: Delavirdine, Efavirenz, Etravirine, Nevirapine
Case 1. Mild hepatitis arising within a few days of starting rilpivirine.
[Modified from: Ahmed Y, Siddiqui W, Enoch CB, Albrecht H, Bookstaver PB. Rare case of rilpivirine-induced severe allergic hepatitis. J Antimicrob Chemother 2012 Oct 12. [Epub ahead of print] PubMed Citation]
A 28 year old man with HIV and mycobacterium avium intracellulare complex (MAC) infection on long term antiretroviral therapy developed fatigue, nausea and fever within days of changing his antiviral regimen to include rilpivirine. He had a long history of HIV infection for which he had received various antiretroviral regimens that most recently had included tenofovir, emtricitabine, raltegravir and zidovudine. To simplify his regimen, he was switched to a once daily combination of rilpivirine, tenofovir and emtricitabine. His other medications included azithromycin and ethambutol for MAC infection, atovaquone for Pneumocystis jiroveci prophylaxis, and amlodipine and carvedilol for hypertension, all of which he had taken for more than a year. Within a few days of starting the new regimen, he developed progressive weakness, fatigue, nausea and fever. He had no recent exposures to viral hepatitis and had had normal routine liver tests in the past. He denied excessive alcohol intake. On examination, he was febrile (39.2 oC) and had tachycardia (102 beats/min), but was not jaundiced and had no rash or signs of chronic liver disease. Laboratory testing showed marked elevations in serum aminotransferase levels (ALT 1516 U/L, AST 5931) with mild increases in alkaline phosphatase (239 U/L), normal bilirubin (1.0 mg/dL), mild renal impairment (creatinine 2.5 mg/dL), and no eosinophils (Table). Tests for hepatitis A, B and C were negative as were blood alcohol and acetaminophen levels and a urine toxicology screen. All medications were stopped and he received supportive care and hydration. His liver test abnormalities improved rapidly and were almost normal by hospital day 16. His medications were then restarted, but the antiretroviral regimen was changed to tenofovir, emtricitabine, atazanavir, low dose ritonavir and raltegravir without rilpivirine. In follow up, his liver enzymes were normal.
||Rilpivirine (25 mg daily)
|Pattern:||Hepatocellular (R=9.1) |
|Severity:||1+ (no jaundice)|
||Complete in 4 weeks
|Other medications:||Tenofovir, emtricitabine, atovaquone, ethambutol, azithromycin, carvedilol and amlodipine (all were later restarted without recurrence)|
|Time After Starting
||Days After Stopping
||Alk P (U/L)
|4 days ||0||1516||293||1.0||Admission|
|6 days||2 days||775||110|
|8 days||4 days||614||195|
|13 days||9 days||170||178|
|19 days||15 days||107||157||Drugs restarted|
|5 weeks||1 month||24||134||Outpatient clinic|
A young man with HIV infection and MAC infection developed fever, fatigue and marked serum aminotransferase elevations within 4 days of starting rilpivirine. He was taking several other medications with a potential for hepatotoxicity, but rilpivirine was the only agent that was recently started. The mode of onset and clinical course resembled acute hepatic necrosis with sudden marked increases in ALT and AST, but minimal or no increase in alkaline phosphatase and bilirubin followed by a rapid decline upon stopping the drug. The INR and either LDH or CPK levels would have been helpful, but were not reported. The differential diagnosis for this clinical pattern includes acetaminophen overdose and acute cocaine toxicity, but toxicology screening ruled out these possibilities. Another possible diagnosis was shock, hypoxia or ischemia, but the history did not suggest such an episode (although the patient was clearly dehydrated upon presentation). The published case was described as "severe", but without jaundice or coagulation abnormalities it is more accurate to describe the case as mild or at most moderate in severity. Furthermore, the hepatitis was described as "allergic", but besides fever there were no other allergic features such as rash, facial edema, lymphadenopathy, lymphocytosis or eosinophilia. Immunoallergic hepatitis is typical of the hepatotoxicity of nevirapine and efavirenz, two first generation nonnucleoside reverse transcriptase inhibitors.
REPRESENTATIVE TRADE NAMES
Rilpivirine – Edurant®
Rilpivirine, Emtricitabine, Tenofovir – Complera®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
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