NLM NIDDK Livertox Database

Livertox

DRUG RECORD

 

EFAVIRENZ

 

Introduction

Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection. Efavirenz is associated with a low rate of serum enzyme elevations during therapy and is a rare cause of clinically apparent acute liver injury.

 

Background

Efavirenz is an antiretroviral agent that acts by non-competitive binding to and inhibiting the HIV reverse transcriptase. Efavirenz is a non-nucleoside reverse transcriptase inhibitor and is similar to nevirapine in its mechanism of action but has little or no structural similarity. Efavirenz was approved by the FDA in 1998 and currently used in many antiretroviral regimens.  Efavirenz is indicated for the treatment of HIV infection in combination with other antiretroviral agents. Efavirenz is available under the brand name Sustiva in capsules of 50 and 200 mg and in tablets of 600 mg. Efavirenz is also available in fixed combination with emtricitabine and tenofovir under the brand name Atripla. The recommended dose of efavirenz is 600 mg orally once daily. Common side effects include headache, dizziness, insomnia, fatigue and skin rashes (~25%).

 

Hepatotoxicity

Serum aminotransferase elevations above 5 times the upper limit of normal occur in 1% to 8% of patients on efavirenz; and this rate is higher in patients who have HCV co-infection. Clinically apparent hepatotoxicity due to efavirenz is rare, but many convincing cases have been published. The liver injury is usually immunoallergic in pattern and arises within 1 to 8 weeks of starting therapy. Signs of hypersensitivity are common including rash, fever, and eosinophilia and sometimes facial edema, lymphadenoapthy and lymphocytosis. Autoantibody formation is rare.  The serum enzyme pattern is typically cholestatic or mixed. Recovery is rapid upon stopping therapy.

 

Mechanism of Injury

The cause of the clinically apparent hepatotoxicity from efavirenz appears to be hypersensitivity. Features such as eosinophilia, skin rash and biopsy findings suggest that the injury is due to an immunoallergic reaction.

 

Outcome and Management

The severity of the liver injury ranges from mild and transient enzyme elevations to acute hepatocellular jaundice and even fulminant liver failure and death.  Typically, improvements start within a few days of stopping efavirenz and full recovery is expected within 2 to 8 weeks.  Corticosteroids are often used and appear to help reverse fever and rash, but their role in ameliorating the liver disease is uncertain.  Rechallenge may lead to recurrence and should be avoided.  Despite the similarity in causing immunoallergic hepatitis, there does not seem to be cross-sensitivity to the hepatic injury between efavirenz and nevirapine or other nonnucleoside reverse transcriptase inhibitors, although there may be cross reactivity in occurrence of rash.

[The non-nucleoside reverse transcriptase inhibitors in current use include delavirdine, efavirenz, etravine and nevirapine.]

 

Drug Class:  Antiviral Agents

 

Other drugs in the Subclass, Nonnucleoside Reverse Transcriptase Inhibitors:  Delavirdine, Etravirine, Nevirapine, Rilpivirine

 

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Case 1. Efavirenz-induced hypersensitivity reaction manifesting in rash and hepatitis.
[Modified from: Leung JM, O'Brien JG, Wong HK, Winslow DL. Efavirenz-induced hypersensitivity reaction manifesting in rash and hepatitis in a Latino male. Ann Pharmacother 2008; 42: 425-9. PubMed Citation]

A 30 year old man newly diagnosed with HIV infection [CD4: 20 cells/mm3; HIV-1 RNA: 32,388 copies/mL] developed skin rash and fever 11 days after starting the combination of efavirenz (600 mg), tenofovir (300 mg), and emtricitabine (200 mg) once daily. He was also being treated with pyrimethamine (75 mg/day) and sulfadiazine (6 g/day) for toxoplasmosis and azithromycin and fluconazole for prophylaxis against opportunistic infections, all of which had been started four weeks before the antiretrovirals. He denied alcohol use or exposures to viral hepatitis. Physical examination showed a generalized erythematous rash. Therapy was continued. One week later he complained of abdominal pain, nausea and fever and blood tests showed marked elevations in serum aminotransferase levels (Table). All medications were stopped. Serum enzyme elevations peaked 5 days after stopping antiretroviral therapy and he recovered slowly but completely. Serum lactate levels were normal, and tests for viral hepatitis A, B and C and autoantibodies were negative. He was subsequently treated with tenofovir, emtricitabine and atazanavir without recurrence of the liver abnormalities.

 

Key Points

 

Medication:	Efavirenz (600 mg daily)
Pattern:	Cholestatic (R=1.9)
Severity:	4+ (Jaundice, hospitalization, and coagulopathy)
Latency:	11  Days to onset of rash, 18 days to onset of jaundice
Recovery:	Yes
Other medications:	Pyrimethamine, sulfadiazine, azithromycin, fluconazole, tenofovir, emtricitabine

 

Laboratory Values

 

Time After Starting	Time After Stopping	ALT* (U/L)	Alk P* (U/L)	Bilirubin* (mg/dL)	Other
18 days		699	1073	3.0
3 weeks	0	1181	1362	4.2	Temperature 39.5o C
	5 days	2132	760	10.0	Ammonia 119; INR 2.6
4 weeks	1 week	488	840	7.5
Normal Values		<40	<117	<1.2

* Values estimated from Figure 1.

Comment

The sudden onset of rash followed by fever and a cholestatic hepatitis within 2-3 weeks of starting efavirenz suggests an immunoallergic form of drug-induced liver disease.  A similar type of liver injury can occur with sulfadiazine, but the timing was better for efavirenz.  A possible role for tenofovir and emtricitabine appeared unlikely because of the lack of recurrence with rechallenge.

 

Case 2. Efavirenz-induced acute eosinophilic hepatitis.
[Modified from: Verdon R, Six M, Rousselot P, Bazin C. Efavirenz-induced acute eosinophilic hepatitis. J Hepatol 2001; 34: 783-5. PubMed Citation]

A patient on long-term antiretroviral therapy developed skin rash, fever and abdominal pain 4 weeks after switching from indinavir to efavirenz on top of a chronic regimen of zidovudine and lamivudine. Serum bilirubin was normal but aminotransferase and alkaline phosphatase levels were elevated (Table). The patient was known to have had antibody to hepatitis C, but serum aminotransferase levels were normal when efavirenz was started and HCV RNA was not detected in serum on multiple occasions. He had no history of liver disease and did not drink alcohol. Tests for hepatitis A and B and for autoantibodies were normal or negative. An ultrasound of the abdominal showed no evidence of obstruction. Liver biopsy showed hepatocellular injury with frequent eosinophils. Improvement began within days of stopping efavirenz, and tests were normal 5 weeks later.

 

Key Points

 

Medication:	Efavirenz (600-1200 mg daily)
Pattern:	Mixed (R=2.9), later cholestatic
Severity:	1+ (Symptomatic, no frank jaundice)
Latency:	4 Weeks
Recovery:	Yes, complete in 4-5 weeks
Other medications:	Zidovudine, lamivudine, indinavir

 

Laboratory Values

 

Time After Starting	Time After Stopping	ALT (U/L)	Alk P (U/L)	Bilirubin (mg/dL)	Other
Pre		16	65	1.5	Efavirenz started
4 weeks	0	718	684	1.1	Efavirenz stopped
5 weeks	1 week	141	928	0.7	Eosinophils: 1110/µL
6 weeks	2 weeks	25	246	0.6
2 months	5 weeks	19	156	0.8
Normal Values		<38	<105	<1.2

Comment

The onset of rash and liver injury within 4 weeks of starting efavirenz in a patient on long-term zidovudine and lamivudine is highly suggestive of a hypersensitivity reaction with an accompanying anicteric hepatitis due to efavirenz. This case also had biopsy findings which suggested an allergic nature of the toxicity of this drug. The role of hepatitis C was ruled out by the absence of detectable HCV RNA before, during and after the onset of injury. Recovery was rapid upon stopping therapy and corticosteroids were not used.

 

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REPRESENTATIVE TRADE NAMES
Efavirenz – Sustiva®

DRUG CLASS
Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Efavirenz	154598-52-4	C14-H9-Cl-F3-N-O2

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References Last Updated: 05 December 2011

1. Spengler U. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 567-91.  (Review of hepatotoxicity of antiviral agents including the nonnucleoside reverse transcriptase inhibitors published in 2007).

2. Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 1273-1314.  (Textbook of pharmacology and therapeutics). 

3. Division of AIDS, National Institute of Allergy and Infectious Diseases. Table for grading severity of adult adverse experiences. Version 1.0, Clarification August 2009.  Website accessed November 2011: http://www.docstoc.com/docs/42821660/DAIDS-Toxicity-Table. (Tables for grading ALT, AST, Alk P and bilirubin elevations for the AIDS Clinical Trials Group, all expressed as upper limits of normal [ULN]; for ALT, AST, Alk P and GGT: grade 1 [mild]=1.25-2.5; grade 2 [moderate]=2.6-5.0; grade 3 [severe]=5.1-10.0; and grade 4 [potentially life-threatening]=>10.0 times ULN).

4. Adkins JC, Noble S. Efavirenz. Drugs 1998; 56: 1055-64. PubMed Citation  (Review of structure, pharmacology, antiviral resistance, efficacy and safety of efavirenz; no discussion of hepatotoxicity).

5. Havlir DV, Lange JM. New antiretrovirals and new combinations. AIDS 1998; 12 Suppl A: S165-74. PubMed Citation  (Review of new agents, including nelfinavir, nevirapine, delaviridine, efavirenz and abacavir; most significant toxicities discussed include diarrhea for nelfinavir, rash and hepatitis for nevirapine, rash for delavirdine; little information available on toxicities of other agents).

6. Moyle G. Efavirenz; shifting the HAART paradigm in adult HIV-1 infection. Expert Opinion on Investigational Drugs 1999; 8: 473-86. PubMed Citation  (Review of structure, activity, pharmacology, efficacy and safety of efavirenz; ALT elevations occur in 2-3% of both efavirenz and control groups using comparative agents).

7. Clarke S, Harrington P, Barry M, Mulcahy F. The tolerability of efavirenz after nevirapine-related adverse events. Clin Infect Dis 2000; 31: 806-7. PubMed Citation  (Among 8 patients stopping nevirapine because of toxicity including 3 with ALT elevations [>5 times ULN], none developed liver toxicity and only one had any symptoms [facial edema] after switching to efavirenz).

8. Bossi P, Colin D, Dricaire F, Caumes E. Hypersensitivity syndrome associated with efavirenz therapy. Clin Infect Dis 2000; 30: 227-8. PubMed Citation  (44 year old woman developed rash 20 days after starting efavirenz, lamivudine and stavudine, followed by fever and jaundice [bilirubin 16.5 mg/dL, ALT 458 U/L, 9% eosinophils], resolving rapidly with corticosteroid therapy).

9. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000; 283: 74-80. PubMed Citation  (Among 298 patients with HIV infection, ALT elevations above 5 times ULN occurred in 10.4% per year during antiretroviral treatment; factors associated with ALT elevations included ritonavir [27.3%] and coinfection with either HCV or HBV; ALT with bilirubin elevations occurred in 3 patients; 2 on indinavir and all 3 with co-infection).

10. Velasco M, Guijarro C. Elevated liver enzymes following initiation of antiretroviral therapy. JAMA 2000; 283: 2526-7. PubMed Citation  (Letter in response to Sulkowski et al. [JAMA 2000] pointing out that antiretroviral therapy can cause immune reconstitution and flares of hepatitis B or C which may be misdiagnosed as hepatotoxicity).

11. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Elevated liver enzymes following initiation of antiretroviral therapy JAMA 2000; 283: 2526-7. PubMed Citation  (Reply to Velasco and Guijarro pointing at that the majority of the ALT elevations described could not be attributed to immune reconstitution).

12. Soriano V, Dona C, Barreiro P, Gonzalez-Lahoz J. Is there cross-toxicity between nevirapine and efavirenz in subjects developing rash. AIDS 2000; 14: 1672-3. PubMed Citation  (Retrospective review, only 1 of 8 patients with rash on nevirapine developed rash on efavirenz; no mention of hepatic cross-reactions).

13. Verdon R, Six M, Rousselot P, Bazin C. Efavirenz-induced acute eosinophilic hepatitis. J Hepatol. 2001; 34: 783-5. PubMed Citation  (45 year old man developed rash and abdominal pain 4 weeks after starting efavirenz [ bilirubin 18.0 mg/dL, ALT 141 U/L, Alk P 684 U/L], resolving within 4 weeks of stopping: Case 2).

14. Hill JB, Sheffield JS, Zeeman GG, Wendel GD Jr. Hepatotoxicity with antiretroviral treatment of pregnant women. Obstet Gynecol 2001; 98: 909-11. PubMed Citation  (Two cases, 28 year old on zidovudine, lamivudine and efavirenz developed jaundice at 18 weeks gestation with ALT 421 U/L, bilirubin 20.3 mg/dL remaining jaundiced until delivered at 27 weeks, resolving in 5 months after delivery; 22 year old started on lamivudine, zidovudine and nelfinavir at 14 weeks gestation and developed jaundice 10 weeks later with ALT 1598 U/L, bilirubin 8.9 mg/dL progressing to acute liver failure and death).

15. Clark S, Creighton S, Portmann B, Taylor C, Wendon J, Cramp M. Acute liver failure associated with antiretroviral treatment for HIV: a report of six cases. J Hepatol 2002; 36: 295-301. PubMed Citation  (6 patients with HIV infection who developed acute liver failure on stavudine [n=5], lamivudine [n=3], didanosine [n=2], saquinavir [n=2], efavirenz [n=2], nevirapine [n=2], or nelfinavir, delaviridine or zidovudine [n=1] for 1-3 months [peak bilirubin 2.7-32 mg/dL, AST 240-8650 U/L, Alk P 122-191 U/L]; 2 had signs of hypersensitivity, two had hepatitis B and 5 died; autopsies showed massive necrosis and one had massive steatosis).

16. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK; Panel on Clinical Practices for the Treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm Rep 2002; 51(RR-7): 1-55. PubMed Citation  (Recommendations on use of antiretroviral agents for HIV infection including indications, efficacy, need for monitoring and side effects including hepatotoxicity).

17. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: 182-9. PubMed Citation  (Prospective analysis of 568 patients, ALT levels >5 ULN occurred in 16% on nevirapine and 8% on efavirenz, only 1/3rd in first 12 weeks, usually associated with HBV or HCV co-infection [69%] or concurrent protease inhibitor therapy [82%]; no recurrence on switching from one to the other).

18. Abrescia N, D'Abbraccio M, Figoni M, Busto A, Butrico E, De Marco M, Viglietti R. Fulminant hepatic failure after the start of an efavirenz-based HAART regimen in a treatment-naive female AIDS patient without hepatitis virus co-infection. J Antimicrob Chemother 2002; 50: 763-5. PubMed Citation  (30 year old woman developed rash after 7 and jaundice after 10 days of combination antiretroviral therapy with stavudine, zidovudine, lamivudine and efavirenz [ bilirubin 12.6 mg/dL, ALT 6 times ULN], subsequently worsening and dying 1 week later despite stopping therapy promptly).

19. Pulido F, Torralba M. NNRTI hepatotoxicity: efavirenz versus nevirapine. J HIV Ther 2002; Suppl 2: S3-16. PubMed Citation  (Review of hepatotoxicity of all antiretrovirals with focus on non-nucleoside reverse transcriptase inhibitors).

20. Law WP, Dore GJ, Duncombe CJ, Mahanontharit A, Boyd MA, Ruxrungtham K, Lange JM, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996-2001. AIDS 2003; 17: 2191-9. PubMed Citation  (Among 692 patients in 8 controlled trials in Thailand, rate of ALT elevations above 5 times ULN was 6.1/100 patient-years overall; in multivariate analysis, risk factors were HBV [RR=3.9], HCV [3.0], and use of nonnucleoside reverse transcriptase inhibitors [6.8], rate with nevirapine [18.6/100 person-years] higher than efavirenz [2.4]).

21. Ena J, Amador C, Benito C, Fenoll V, Pasquau F. Risk and determinants of developing severe liver toxicity during therapy with nevirapine-and efavirenz-containing regimens in HIV-infected patients. Int J STD AIDS 2003; 14: 776-81. PubMed Citation  (Retrospective review of 136 patients treated with nonnucleoside reverse transcriptase inhibitor combinations, 48% had ALT elevations which were >5 times ULN in 20%: risk factors were alcohol use, HCV infection and 4-drug regimens; 3 of 17 patients with ALT elevations on nevirapine redeveloped ALT elevations on restarting; 2 patients with jaundice but both had HCV infection and were exposed to other hepatotoxins).

22. Kontorinis N, Dieterich D. Hepatotoxicity of antiretroviral therapy. AIDS Rev 2003; 5: 36-43. PubMed Citation  (Review of definition of hepatotoxicity in antiretroviral studies; grade 1=1.5-3, grade 2=3-5, grade 3=5-10 and grade 4=>10 times ULN or baseline ALT values).

23. Ogedegbe AO, Sulkowski MS. Antiretroviral-associated liver injury. Clin Liver Dis 2003; 7: 475-99. PubMed Citation  (Review of hepatotoxicity of antiretrovirals; ALT elevations above 5 times ULN reported in 7% with zidovudine, 16% didanosine, 9-13% stavudine, <1% lamivudine, tenofovir and abacavir, 3-10% protease inhibitors, 10% nevirapine and 8% efavirenz; recommends monitoring at 4 weeks and then every 12 weeks, stopping if ALT levels are >10 times ULN or if symptoms of liver injury are present, monitoring more closely if ALT levels are elevated).

24. Ofotokun I, Pomeroy C. Sex differences in adverse reactions to antiretroviral drugs. Top HIV Med 2003; 11: 55-9. PubMed Citation  (Review of sex differences in adverse events; higher frequency of mitochondrial toxicity and hypersensitivity in women than men).

25. Martín-Carbonero L, Núñez M, González-Lahoz J, Soriano V. Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clin Trials 2003; 4: 115-20. PubMed Citation  (Retrospective analysis of 298 patients, ALT elevations >5 times ULN occurred in 12% of nevirapine vs 4% of efavirenz treated patients, more frequent with HCV co-infection, in women and in alcohol drinkers).

26. Manfredi R, Calza L, Chiodo F. Efavirenz versus nevirapine in current clinical practice: a prospective, open-label observational study. J Acquir Immune Defic Syndr 2004; 35: 492-502. PubMed Citation  (Comparison of 287 patients on efavirenz vs 258 on nevirapine in practice situation; similar efficacy but higher rate of ALT abnormalities with nevirapine [52% vs 18%]) and discontinuation because of liver toxicity [3.5% vs 0]).

27. Dieterich DT, Robinson PA, Love J, Stern JO. Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004; 38 Suppl 2: S80-9. PubMed Citation  (Review of hepatotoxicity of nonnucleoside reverse transcriptase inhibitors: in 17 controlled trials of nevirapine, 10% of patients developed ALT or AST elevations >5 times ULN and 5% had a symptomatic hepatic event).

28. Te HS. Cholestasis in HIV-infected patients. Clin Liver Dis 2004; 8: 213-28, viii-ix. PubMed Citation  (Review of causes of cholestasis in HIV-infected patients including antiretrovirals).

29. Abrescia N, D’Abbraccio M, Figoni M, Busto A, Maddaloni A, De Marco M. Hepatotoxicity of antiretroviral drugs. Curr Pharm Des 2005; 11: 3697-710. PubMed Citation  (Review of hepatotoxicity of antiretrovirals; major syndrome with nonnucleoside reverse transcriptase inhibitors is hypersensitivity).

30. Núñez M, Soriano V. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. Drug Saf 2005; 28: 53-66. PubMed Citation  (Review of liver toxicity of antiretrovirals).

31. Aranzabal L, Casado JL, Moya J, Quereda C, Diz S, Moreno A, Moreno L, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2005; 40: 588-93. PubMed Citation  (Among 107 patients with HIV-HCV co-infection and pre-treatment liver biopsy; ALT elevations of >5 times ULN [or 3.5 times baseline] occurred in 38% with advanced fibrosis and 15% without. Higher rates of ALT elevations with nevirapine and efavirenz [13%] found only in those with advanced fibrosis).

32. Verma S, Bhakta H, Nowain A, Pais S, Kanel G, Squires K, Squires K. Severe cholestatic liver injury days after initiating antiretroviral therapy in a patient with AIDS: drug toxicity or immune reconstitution inflammatory syndrome? Dig Dis Sci 2005; 50: 1813-7. PubMed Citation  (37 year old man with AIDS developed rash and fever one week after starting efavirenz and lopinavir/ritonavir and one day after restarting azithromycin, trimethoprim/sulfamethoxazole(TMP/SMS), one week later becoming jaundiced [bilirubin 0.4 rising to 9.9 mg/dL, ALT 20 to 103 U/L, Alk P 70 to 700 U/L], values normalizing within a few weeks of stopping, but recurring with jaundice after 2 re-challenges using same antiretroviral regimen without TMP/SMS).

33. Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, Keiser O, et al.; Swiss HIV Cohort Study. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 2005; 15: 1-5. PubMed Citation  (Analysis of an allele of CYP 2B6, the major hepatic enzyme responsible for efavirenz and nevirapine metabolism; G516T was associated with higher drug levels for both agents and higher tissue levels correlated with greater neuropsychiatric side effects).

34. Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, Wakeford C, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005; 191: 825-9. PubMed Citation  (In a prospective study, ALT elevations >5 times normal occurred in 17% [66/385] of nevirapine vs 0% [0/83] of efavirenz-treated patients, usually in first 12 weeks, most had symptoms including rash, nausea and jaundice; two cases of acute liver failure and death on nevirapine).

35. Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F, Uip DE, et al.; 2NN Study Group. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005; 10: 489-98. PubMed Citation  (Among 1077 patients, no association found between adverse events and plasma levels or pharmacokinetics of nevirapine and efavirenz, except for a slight correlation of higher efavirenz levels and ALT elevations).

36. Torti C, Lapadula G, Casari S, Puoti M, Nelson M, Quiros-Roldan E, Bella D, et al.; EPOKA-MASTER Study Group. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort. BMC Infect Dis 2005; 5: 58. PubMed Citation  (Among 1038 HIV-HCV co-infected patients starting antiretroviral therapy, the risk of ALT elevations above 5 times ULN was 17.1/100 patient years in treatment naïve and 8.2 in treatment- experienced group; risk factors being baseline ALT levels and nonnucleoside reverse transcriptase inhibitor use).

37. Zhou J, Phanupak P, Kiertiburanakul S, Ditangco R, Kamarulzaman A, Pujary S; TREAT Asia HIV Observational Database. Highly active antiretroviral treatment containing efavirenz or nevirapine and related toxicity in the TREAT Asia HIV Observational Database. J Acquir Immune Defic Syndr 2006; 43: 501-3. PubMed Citation  (Analysis of 735 HIV-positive patients started on efavirenz- and 813 on nevirapine-containing regimens; 12 patients in both groups developed ALT >5 times normal but monitoring was irregular; no deaths from liver disease; no racial differences in rates of ALT elevations, HCV coinfection was a risk factor).

38. Buyse S, Vibert E, Sebagh M, Antonini T, Ichai P, Castaing D, Samuel D, et al. Liver transplantation for fulminant hepatitis related to nevirapine therapy. Liver Transpl 2006; 12: 1880-2. PubMed Citation  (38 year old woman with HIV infection developed acute liver failure 6 weeks after starting nevirapine plus zidovudine and lamivudine [bilirubin 11.2 mg/dL, ALT 12578 U/L, GGT 340 U/L], undergoing liver transplantation and tolerating efavirenz in follow up after transplant).

39. Ritchie MD, Haas DW, Motsinger AA, Donahue JP, Erdem H, Raffanti S, Rebeiro P, et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity. Clin Infect Dis 2006; 43: 779-82. PubMed Citation  (Case control study of 9 nevirapine and 4 efavirenz recipients who developed ALT >5 times ULN on therapy vs 49 controls; found weak association with a MDR1 [p-glycoprotein: ABC B1] polymorphism).

40. Servoss JC, Kitch DW, Andersen JW, Reisler RB, Chung RT, Robbins GK. Predictors of antiretroviral-related hepatotoxicity in the adult AIDS Clinical Trial Group(1989-1999). J Acquir Immune Defic Syndr 2006; 43: 320-3. PubMed Citation  (Analysis of factors that predict “serious hepatotoxicity” in 9% of cohort of 8851 patients with HIV infection enrolled in trials of antiretroviral therapy; factors identified included baseline liver test abnormalities, HCV infection, and in subgroups, didanosine, nevirapine and stavudine).

41. Hofman P, Nelson AM. The pathology induced by highly active antiretroviral therapy against human immunodeficiency virus: an update. Curr Med Chem 2006; 13: 3121-32. PubMed Citation  (Review of pathology of adverse effects of antiretroviral agents with examples of mitochondrial liver injury and cholestasis).

42. Núñez M. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. J Hepatol 2006; 44(1 Suppl): S132-9. PubMed Citation  (Review of hepatotoxicity of antiretrovirals; elevations in ALT or AST above 5 times ULN occur in 2% to 18% of HIV-positive patients starting therapy, more frequent with HCV or HBV co-infection; combination of protease inhibitors with low-dose ritonavir does not seem to increase risk; agents with highest risk are nevirapine and the non-nucleoside reverse transcriptase inhibitors).

43. Hoffmann C, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL, Churchyard GJ, et al. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21: 1301-08. PubMed Citation  (Among 868 Africans with HIV infection, ALT elevations >5 times ULN occurred in 7.7 per 100 person-years with lamivudine, zidovudine and efavirenz; risk was increased by anti-tuberculosis therapy [8.5 fold], HBsAg [3 fold] and low CD4 counts [1.9 fold]).

44. Bourlière M, Duclos-Vallée JC, Pol S. [Liver and antiretrovirals: hepatotoxicity, steatosis and monitoring of patients with liver disease] Gastroenterol Clin Biol 2007; 31: 895-905. French. PubMed Citation  (Review of hepatotoxicity of antiretrovirals in French discussing patterns of toxic idiosyncrasy, hypersensitivity [nevirapine and abacavir], mitochondrial toxicity [zalcitabine, didanosine, stavudine and zidovudine], steatohepatitis [protease inhibitors with lipodystrophy], immune restoration [in patients with HIV-HBV or -HCV coinfection]; recommendations for management focusing on prevention and monitoring).

45. Jain MK. Drug-induced liver injury associated with HIV medications. Clin Liver Dis 2007; 11: 615-39, vii-viii. PubMed Citation  (Review of hepatotoxicity of antiretroviral medications; ALT elevations occur in 2% to 18% of patients, but often resolve spontaneously even without dose modification; classes of injury include hypersensitivity [nevirapine, efavirenz, abacavir], mitochondrial damage [stavudine, didanosine, zidovudine], flares of hepatitis B [lamivudine, emtricitabine, tenofovir], flares of hepatitis C [any potent regimen], idiosyncratic injury [ritonavir, nevirapine, efavirenz], and cholestatic hepatitis [many agents]).

46. Esser S, Helbig D, Hillen U, Dissemond J, Grabbe S. Side effects of HIV therapy. J Dtsch Dermatol Ges 2007; 5: 745-54. PubMed Citation  (Review of side effects of antiretroviral agents focusing on immune reconstitution syndrome, lipodystrophy, cutaneous skin reactions, hypersensitivity reactions [abacavir, nevirapine], hyperbilirubinemia [indinavir, atazanavir], local reactions [enfuvirtide] and hyperpigmentation [zidovudine, emtricitabine]).

47. Mussi-Pinhata MM, Rego MA, Freimanis L, Kakehasi FM, Machado DM, Cardoso EM, Read JS; NISDI Perinatal Protocol Study Group. Maternal antiretrovirals and hepatic enzyme, hematologic abnormalities among human immunodeficiency virus type 1-uninfected infants: the NISDI perinatal study. Pediatr Infect Dis J 2007; 26: 1032-7. PubMed Citation  (Liver enzyme elevations in newborns of HIV infected mothers on various antiretroviral regimens; infants whose mothers received protease inhibitors were more likely to have ALT elevations [odds ratio 1.9] similarly for non-nucleoside reverse transcriptase inhibitors [odds ratio 2.4] most elevations were mild and self-limited).

48. Mehta U, Maartens G. Is it safe to switch between efavirenz and nevirapine in the event of toxicity? Lancet Infect Dis 2007; 7: 733-8. PubMed Citation  (Review: some evidence of cross-sensitivity between nevirapine and efavirenz to skin rash, but none to hepatotoxicity: 11 patients in literature switched and no recurrence).

49. Rivero A, Mira JA, Pineda JA. Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 2007; 59: 342-6. PubMed Citation  (Review of liver toxicity of nevirapine and efavirenz, ALT elevations >5 times ULN reported in 1-8% of efavirenz compared to 4-16% of nevirapine recipients).

50. Lattuada E, Lanzafame M, Carolo G, Gottardi M, Concia E, Vento S. Does tenofovir increase efavirenz hepatotoxicity? AIDS 2008; 22: 995-6. PubMed Citation  (Three patients with HIV infection without hepatitis B or C on efavirenz therapy who developed ALT elevations 4-6 weeks after starting tenofovir; ALT 144, 186 and 392 U/L [previously normal] resolving with stopping tenofovir).

51. Medrano J, Barreiro P, Tuma P, Vispo E, Labarga P, Blanco F, Soriano V. Risk for immune-mediated liver reactions by nevirapine revisited. AIDS Rev 2008; 10: 110-5. PubMed Citation  (Review: Symptomatic hepatic events occur in ~5% of patients taking nevirapine, early hypersensitivity reactions occurring especially in women with CD4 counts >250 and with HBV or HCV infection. Late onset hepatotoxicity may be class effect [with efavirenz]).

52. Bae WH, Wester C, Smeaton LM, Shapiro RL, Lockman S, Onyait K, Thior I, et al. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. AIDS 2008; 22: 1633-40. PubMed Citation  (Prospective monitoring found that only 1 of 69 infants born to antiretroviral-treated mothers and none of 109 infants born to drug-therapy unexposed mothers with HIV infection developed ALT elevations > 5 times ULN during the first 7 months of life).

53. Sathia L, Obiorah I, Taylor G, Kon O, O’Donoghue M, Gibbins S, Walsh J, et al. Concomitant use of nonnucleoside analogue reverse transcriptase inhibitors and rifampicin in TB/HIV type 1-coinfected patients. AIDS Res Hum Retroviruses 2008; 24: 897-901. PubMed Citation  (Among 103 HIV positive patients with tuberculosis receiving rifampin, including 17 on nevirapine and 26 efavirenz, transient elevations in ALT occurred in 17%, but only 2 patients stopped therapy for ALT elevations >5 times ULN, and both safely restarted anti-tuberculous therapy after ALT abnormalities resolved).

54. Brück S, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, Rump JA, et al. Hepatotoxicity in patients prescribed efavirenz or nevirapine. Eur J Med Res 2008; 13: 343-8. PubMed Citation  (Among 151 patients starting efavirenz and 145 nevirapine, rates of ALT elevations were similar in the two groups; 6% vs 3.4% had ALT levels >2.5 times ULN and 1.2% vs 2.1% had ALT >5 times ULN; only predictive factor identified was HBsAg; no fatal cases).

55. Leung JM, O'Brien JG, Wong HK, Winslow DL. Efavirenz-induced hypersensitivity reaction manifesting in rash and hepatitis in a Latino male. Ann Pharmacother 2008; 42: 425-9. PubMed Citation  (30 year old man developed rash 11 days after starting tenofovir, emtricitabine and efavirenz for HIV infection, and jaundice and fever arose by day 18 [bilirubin 3.0 mg/dL, ALT 699 U/L, Alk P 1073 U/L], values peaking 5 days after stopping and ultimately resolving).

56. Soriano V, Puoti M, Garcia-Gascó P, Rockstroh JK, Benhamou Y, Barreiro P, McGovern B. Antiretroviral drugs and liver injury. AIDS 2008; 22: 1-13. PubMed Citation  (Review of hepatotoxicity of antiretroviral drugs with recommendations on management, stopping therapy if symptoms arise, with overt jaundice [direct bilirubin], evidence of mitochondrial toxicity, ALT >10 times ULN, ALT at lower levels if newly marketed agent; important to rule out other causes: problematic agents include didanosine, stavudine and zidovudine; nevirapine and efavirenz, full dose ritonavir and tipranavir).

57. Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, Cahn P, et al.; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008; 300: 555-70. PubMed Citation  (Recent recommendations on use of antiviral therapy in adults with HIV infection including use of recently approved agents: raltegravir, maraviroc and etravirine).

58. Vitezica ZG, Milpied B, Lonjou C, Borot N, Ledger TN, Lefebvre A, Hovnanian A. HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. AIDS 2008; 22: 540-1. PubMed Citation  (Among 21 patients with HIV infection treated with nevirapine [n=14] or efavirenz [n=7], 6 developed a hypersensitivity rash, 5 of whom had DRB1*01 compared to 1 [7%] control).

59. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, et al.; Drug Induced Liver Injury Network(DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34.PubMed Citation (Among 300 cases of drug-induced liver disease in the US collected between 2004 and 2008; 7 were attributed to antiretroviral agents, 2 nevirapine, 1 efavirez and 4 miscellaneous combinations). 

60. Ingiliz P, Benhamou Y. Elevated liver enzymes in HIV monoinfected patients on HIV therapy: what are the implications? J HIV Ther 2009; 14: 3-7. PubMed Citation.  (Review of the causes of serum enzyme elevations during antiretroviral therapy; non-nucleoside reverse transcriptase inhibitors are capable of causing a hypersensitivity reaction with liver injury arising during the first 6 weeks of therapy as well as an immunologically mediated injury that arises 6 to 12 months after starting treatment).

61. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC.  Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation. (World wide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, 3 antiretroviral agents were among the top 40 cases, including zidovudine [8th, 106 cases], lamivudine [26th, 45 cases] and nevirapine [36th, 37 cases]).  

62. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation. (Among 1198 patients with acute liver failure enrolled in a U.S. prospective study between 1998 and 2007, 133 were attributed to drug-induced liver injury and 4 to antiretroviral agents, including 3 to combinations with stavudine and 1 to abacavir).  

63. Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N: Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. PubMed Citation. (Among 30 children with suspected drug-induced liver injury, none were attributed to an antiretroviral agent). 

64. Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C, Godfrey C, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med 2011; 154: 445-56. PubMed Citation.  (Among 1848 patients treated with either efavirenz or atazanavir/ritonavir in combination with nucleoside analogues, ALT elevations occurred in 2% and at a similar rate in both groups).  

65. Yimer G, Amogne W, Habtewold A, Makonnen E, Ueda N, Suda A, Worku A, et al. High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J 2011 [in press]. PubMed Citation  (Among 261 patients with HIV infection and low CD4 counts started on 1 of 3 efavirenz-based regimens, 41 [16%] developed liver injury, usually within 8 weeks, 11 cases considered severe, but only 2 required change in regimen; statistical association found with CYP 2B6 polymorphisms).

66. Mankhatitham W, Lueangniyomkul A, Manosuthi W. Hepatotoxicity in patients co-infected with tuberculosis and HIV-1 while receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and rifampicin-containing anti-tuberculosis regimen. Southeast Asian J Trop Med Public Health 2011; 42: 651-8. PubMed Citation.  (Among 134 patients with HIV infection and tuberculosis treated with rifampin, ALT elevations > 5 times ULN occurred in 3 patients on nevirapine [4.6%] and 1 [1.4%] on efavirenz).

      

 

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