Jaundice and Hepatocellular Damage AssociatedWith Nevirapine TherapyManish Prakash, M.D., Vijayrama Poreddy, M.D., Lakshma Tiyyagura, M.D., and Maurizio Bonacini, M.D.Divisions of Infectious Diseases and Gastrointestinal and Liver Diseases, Keck School of Medicine, LosAngeles; and Keck School of Medicine Liver Unit, Downey, California

OBJECTIVE: Nevirapine is a nonnucleoside reverse transcrip-tion inhibitor that is used as part of highly active antiretro-viral therapeutic combinations. Nevirapine has been associ-ated with a skin rash in 32 to 48% of patients. Recent reportsindicate that hepatic toxicity also occurs.

METHODS: We describe four instances of reversible hepa-tocellular damage associated with the use of nevirapine inpatients with HIV infection. Two of the four patients werealso coinfected with the hepatitis C virus.

RESULTS: Evidence of malaise, skin rash, and icteric hepa-titis with pruritus occurred 4–6 wk after the beginning ofnevirapine therapy. No evidence of metabolic acidosis waspresent in any of our patients. In all cases, liver test resultsdeclined to normal or near normal levels, and pruritus dis-appeared 4–6 wk after discontinuation of the medication.No patient was rechallenged with the drug.

CONCLUSION: Nevirapine can be associated with icterichepatitis, which appears to be reversible after withdrawal ofthe drug. (Am J Gastroenterol 2001;96:1571–1574. © 2001by Am. Coll. of Gastroenterology)

INTRODUCTION

Nevirapine is a nonnucleoside reverse transcription inhibitor(NNRTI) that is used as part of highly active antiretroviraltherapeutic combinations. This drug has been associatedwith a cutaneous rash in 32 to 48% of patients (1, 2). Of 245patients who received nevirapine in published clinical trials,about 8% developed severe (grades 3 and 4) rashes, and 1%developed the Stevens-Johnson syndrome (3). Rashes wereoften accompanied by fever, starting within 4 wk of therapyand typically resolved after discontinuation of the drug (1,3). For this reason, it is recommended that nevirapine bestarted at a dosage of 200 mg daily. Recent reports indicatethat hepatic toxicity may also occur. In particular, recentcases of icteric hepatitis potentially attributable to nevirap-ine have been reported (4–7).

In this article, we describe four instances of reversiblehepatocellular damage associated with nevirapine therapy inpatients with HIV infection.

MATERIALS AND METHODS

Patients were selected from a cohort of patients with HIVinfection referred to the HIV/Hepatitis Clinic of the Uni-versity of Southern California. Patients who were takingnevirapine and who experienced an increase in total bilirubinand/or an increase in serum ALAT (ALT) or AST greater thantwice the upper limit of normal or greater than twice thebaseline values were considered to be possible cases. We thenused a published clinical score to assess the likelihood ofcause–effect relationship with the drug (8). This score is com-prised of the following elements: 1) temporal relationship(score range,22 to 1 9); 2) exclusion of alternative causes(score range,23 to1 3); 3) extrahepatic manifestations (scorerange, 0 to1 3); 4) reexposure (score range, 0 to1 3); and 5)previous literature reports (score range,23 to 1 3).

The probability of an association may be definite (score of.17), probable (score of 14–17), possible (score of 10–13),or unlikely (score,#9) (8). We report cases with scores$10, in other words, with at least a possible association. Nopatient received a rechallenge with nevirapine as it wasdeemed unethical.

CASE REPORTS

Case 1A 47-yr-old man with a history of HIV/HCV coinfectionpresented with a 3-wk history of myalgias, skin rash, fever,and jaundice (Table 1). Four weeks before the beginning ofsymptoms, nevirapine had been added to ongoing AZT andddI therapy, which the patient had been taking for 7 months.

Physical examination showed icterus and a generalizedskin rash. There was no hepatosplenomegaly or ascites.

The hepatitis B surface antigen and the hepatitis A anti-body, IgM type, were both negative. The anion gap was 9.The CBC showed 20% eosinophils. An ultrasound of theabdomen showed a liver of normal size with a smoothsurface. There were no masses and no gallstones, and thecommon bile duct (CBD) measured 2 mm in diameter.Serum ALT, ALP, and total bilirubin levels are summarizedin Table 2. The peak ALT was 288 IU/L (baseline, 36 IU/L),and peak bilirubin was 17.8 mg% (baseline, 0.7 mg%). Theprothrombin time and serum creatinine were normal. Nevi-rapine was discontinued immediately. Serum transaminases,

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alkaline phosphatase, and total bilirubin returned to normalwithin 5 wk of discontinuing the medication.

Case 2A 27-yr-old Latino man with a history of HIV infectiondiagnosed in 1994 presented to the hospital with a cutaneousrash, malaise, fever, jaundice, and vomiting (Table 1). Healso had generalized itching and diffuse arthralgias. Thepatient had been on Lamivudine and AZT for 2 yr, whichwas changed to Combivir (AZT and 3TC) and nevirapine 4wk before the beginning of symptoms. The patient had beena heavy drinker before the last 3 yr.

On physical examination, the blood pressure was normal.There was a generalized skin rash and jaundice but nohepatosplenomegaly. Tests for A, B, and autoimmune typesof hepatitis were negative. The anion gap was normal, andthere was no peripheral eosinophilia. Ultrasound of theabdomen showed a liver with a smooth surface, no masses,and echographic features consistent with steatosis. The CBDmeasured 4.1 mm in diameter. Serum ALT and bilirubinlevels are summarized in Table 2. Peak ALT and bilirubinwere 3493 IU/L and 12.3 mg%, respectively. The prothrom-bin time was 1.6 INR, and the creatinine level was normal.The patient had stopped taking his medications 2 wk earlierbecause of his symptoms. The serum transaminases, ALP,and bilirubin levels all returned to baseline within 6 wk.Prothrombin time was also normalized.

Case 3A 41-yr-old male with a history of HIV infection presentedwith a 4-wk history of fever, rash, and jaundice. He alsocomplained of itching and malaise (Table 1). Nevirapinewas added to the ongoing antiretroviral regimen (AZT andnelfinavir) 4 wk before the onset of symptoms. All hismedications were discontinued 1 wk before his admission tothe hospital because of persistent symptoms. Alcohol con-sumption was less than three drinks per week.

Physical examination revealed a generalized pruritic rash,icterus, and splenomegaly. There were no ascites.

The hepatitis B surface antigen and the anti-HCV anti-body were negative. An HAV-IgM was not performed. Theanion gap was 12. An ultrasound of the abdomen showed asmooth liver surface with no mass and no nodules or spleno-megaly. The CBD was 5.2 cm in diameter and the gallblad-der had a thickened wall. The peak serum ALT, ALP, andbilirubin were 312 IU/L, 426 IU/L, and 14.8 mg%, respec-tively. The prothrombin time, eosinophil count, and serumcreatinine were normal. All liver tests returned to normalwithin 10 wk after withdrawal of all medications.

Case 4A 49-yr-old Latino male was seen in clinic with complaintsof oral blisters, a mildly pruritic rash over both lower ex-tremities, arthralgias, and abdominal pain (Table 1). Thepatient had a history of HIV/HCV coinfection and was on3TC, AZT, and ddI. Nevirapine had been added 4 wk beforethe onset of symptoms. There was no history of fever.

Physical examination revealed normal vital signs. Therewas a maculopapular rash on both lower extremities andsome epigastric tenderness. The liver was palpable and offirm consistency. There were no ascites, splenomegaly, orasterixis.

The anion gap was 12, and the eosinophil count wasnormal. An abdominal ultrasound revealed gallstones withgallbladder wall thickening but no intrahepatic duct or CBDdilation. A computed tomography scan revealed liver sur-face nodularity consistent with cirrhosis. A liver biopsy wasattempted but yielded no evaluable tissue.

The main laboratory values are shown in Table 2. Thehepatitis B surface antigen was negative. Peak ALT, AST,ALP, and total bilirubin levels were 348 IU/L, 510 IU/L,258 IU/L, and 8.2 mg% at wk 16, although nevirapine hadbeen discontinued at wk 8. The patient developed transientascites, which was treated with diuretics. As laboratoryvalues improved, he no longer needed diuretics. Liver testvalues returned to baseline 7 wk after the enzymes’ peak,and the patient became completely asymptomatic.

DISCUSSION

The advent of newer antiretroviral medications in the pastdecade has resulted in major improvements in the well-

Table 1. Clinical Features of Patients With Possible Nevirapine Toxicity

PatientAge(yr) HCV or HBV

Time toPeak ALT

(wk)

Peak ALT toResolution

(wk) Rash Arthralgias Pruritus AlcoholClinicalScore*

1 47 HCV 2 5 Yes Yes Yes No 142 27 Negative 2 6 Yes Yes Yes H/O 133 41 Negative 12 10 Yes No Yes Social 134 49 HCV 16 7 Yes Yes Yes No 13

H/O 5 history of heavy ethanol use.* Score, 10–135 possible hepatotoxicity; score, 14–155 probable hepatotoxicity (Ref 8).

Table 2. Peak Laboratory Values From Patients With PossibleNevirapine Toxicity

PatientsALT

(IU/L)AST

(IU/L)Bilirubin(mg%)

ALP(IU/L)

1 288 150 17.8 8512 3493 2365 12.3 2663 312 192 14.8 4264 348 510 8.2 258

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being and prognosis of patients with HIV infection (9).However, a number of drugs in the nucleoside analog andthe protease inhibitor class have been found to be potentiallyhepatotoxic (10). So far, the class of medications termedNNRTIs has been infrequently associated with elevatedliver enzymes (10). In the case of nevirapine, the PhysiciansDesk Reference reports elevated liver tests in 7%, as com-pared with 4% in the control group (11). Only three poten-tial cases of hepatic failure related to nevirapine have beenreported so far (4, 5, 7). One of these cases (7) described apatient coinfected with hepatitis C, like our patients 1 and 4,who had peripheral eosinophilia similar to our patient 1 andwho displayed peak liver tests and bilirubin several daysafter stopping the medications, like our patient 4 (7). Thispatient was successfully treated with corticosteroids (7).

In the absence of a positive rechallenge, drug hepatotox-icity is usually diagnosed by exclusion and is often based ontemporal evidence of association (8). In patients with HIVinfection, there are two additional difficulties. First, thesepatients almost always are treated with a cocktail of drugs,including several classes of potentially hepatotoxic drugs(10, 12). Second, coinfection with chronic viral hepatitis Bor C, as we found in two of our patients, often complicatesthe evaluation (10). Indeed, it is difficult to confidentlydifferentiate drug-induced hepatotoxicity from exacerbationof viral hepatitis. In cases of HIV/HCV coinfection, suddenincreases in liver enzyme levels have been attributed to a“reconstituted” immune system (peripheral CD4 lympho-cyte counts), and these seem to mediate liver damage inHIV/HCV-coinfected patients (13, 14). Hepatitis C has in-deed been deemed a risk factor associated with an increasedlikelihood of drug-induced hepatotoxicity in patients takingnucleoside analogs (10). Other factors include glutathionedeficiency (15), either because of alcohol use or because ofdecreased synthesis associated with HIV infection (16), orthe use of concomitant complementary medicines (17).

Despite the above-mentioned shortcomings, we believethat it is possible to estimate the likelihood that a drug isinvolved in the development of liver injury. A recentlypublished article detailed a clinical scale assessing thecause–effect relationship between a medication and thedevelopment of liver injury (8). The latter depends heavilyon the temporal association between start and discontinua-tion of the drug in question and associated changes in serumliver enzymes and bilirubin (8). In addition, this scale addspoints for the elimination of obstruction, acute viral injury,and alcoholic liver disease (8). An assessment of extrahe-patic manifestations such as fever, rashes, arthralgias, eo-sinophilia, or cytopenia is also part of the scale, as is theexistence of published association between the drug in ques-tion and liver injury (8).

Our cases illustrate a number of important clinical fea-tures. First, all four cases were reversible upon drug with-drawal, without specific therapy. This includes case 4, inwhich the patient had cirrhosis with transient ascitic decom-pensation. Second, all four cases involved an associated rash

that, in the case of nevirapine, would weigh for the diagnosisof an allergic type of drug hepatotoxicity and against apossible HCV reactivation (1, 2, 6, 7). Third, all but onepatient had ALT elevations greater than AST, and of amagnitude that virtually eliminates alcoholic liver disease.The only exception was patient 4, who had cirrhosis, and inwhom AST elevation predominated. In addition, two pa-tients (1 and 3) had elevations in alkaline phosphatasegreater than three times the upper limit of normal, pointingto a mixed hepatocellular–cholestatic pattern of liver injury.Fourth, all four patients had a normal anion gap, a featurethat would make lactic acidosis and nucleoside analog tox-icity less likely. Finally, three of our four patients had eitherchronic hepatitis C or a history of heavy ethanol intake.Although the permissive nature of viral infection or alcoholabuse in terms of nevirapine-associated hepatotoxicity isspeculative, both have been viewed as risk factors for hep-atotoxicity in general (10, 15).

In conclusion, we found that nevirapine may be associ-ated with cases of an allergic type of hepatotoxicity, whichare hepatocellular with ALT predominance or are mixedhepatocellular–cholestatic in pattern. We found no evidenceof metabolic acidosis, and this finding pleads against mito-chondrial toxicity. Three of our four cases occurred inpatients with either chronic hepatitis C or alcohol abuse. Allfour were reversible after withdrawal of the drug. We sug-gest that coinfected patients or patients with heavy alcoholintake should be carefully monitored for signs and symp-toms of liver disease and that nevirapine should be stoppedat the earliest sign of hepatotoxicity.

Reprint requests and correspondence:Maurizio Bonacini,M.D., Keck School of Medicine of the University of SouthernCalifornia, HMR 101, 2011 Zonal Avenue, Los Angeles, CA90033.

Received Aug. 24, 2000; accepted Jan. 9, 2001.

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