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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.]
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.
PRODUCT INFORMATION
Efavirenz
REPRESENTATIVE TRADE NAMES
Efavirenz – Sustiva®
DRUG CLASS
Antiviral Agents
Product labeling at DailyMed, National Library of Medicine, NIH
DRUG |
CAS REGISTRY NUMBER |
MOLECULAR FORMULA |
STRUCTURE |
Efavirenz |
154598-52-4 |
C14-H9-Cl-F3-N-O2 |
![Efavirenz Chemical Structure](images/Efavirenz_Structure.png) |
References Last Updated: 05 December 2011
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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).
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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).
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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).
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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).
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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).
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).
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).
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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).
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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]).
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).
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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]).
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]).
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).
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).
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).
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).
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]).
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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).
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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).
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).
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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).
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).
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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).
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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).
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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).
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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).
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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]).
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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).
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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).
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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).
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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).
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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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