The expanding numbers of available antiviral therapies REVIEWS. Hyperbilirubinemia in the Setting of Antiviral Therapy

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: REVIEWS Hyperbilirubinemia in the Setting of Antiviral Therapy KEVIN M. KORENBLAT* and PAUL D. BERK*, *Division of Liver Disease, Department of Medicine, and Department of Molecular, Cell, and Developmental Biology, Mount Sinai School of Medicine, New York, New York Hyperbilirubinemia is a common side effect of antiviral medications. The mechanisms underlying its development are multiple and unique to each therapy. During administration of antiviral medications, the hyperbilirubinemia observed in the absence of liver injury is most frequently manifested by isolated increases in the indirect-reacting fraction. Relevant mechanisms leading to indirect hyperbilirubinemia in this setting include hemolysis, decreased hepatic bilirubin clearance as a result of impairment of bilirubin conjugation, or circumstances in which both processes occur simultaneously. Underlying genetic susceptibilities may potentiate these side effects of antiviral therapy. Conjugated (direct-reacting) hyperbilirubinemia can be a consequence of generalized hepatocellular injury, selective cholestatic defects, biliary obstruction, or, rarely, genetic disorders of bilirubin transport. In the specific setting of antiviral therapy, preexisting liver disease or antiviral hepatotoxicity, such as is encountered with the use of the nucleoside and non-nucleoside human immunodeficiency virus reverse transcriptase inhibitors, are the most frequent causes of direct-reacting or mixed direct- and indirect-reacting hyperbilirubinemia. Modification in antiviral drug choice or dose may be required in cases of liver injury or of brisk hemolysis leading to significant anemia. The mild indirect hyperbilirubinemia associated with impairment in conjugation tends to be well tolerated and of little consequence. The decision to continue or discontinue antiviral therapy in the face of hyperbilirubinemia should be made after an assessment of the cause of the elevated bilirubin level and a thorough assessment of the risks and benefits of antiviral therapy. The expanding numbers of available antiviral therapies have dramatically altered the management of viral diseases. The potential benefits of these medications seem mitigated only by issues of viral resistance and side effects. The development of hyperbilirubinemia, with or without concomitant liver injury, is an increasingly recognized side effect of antiviral medications, particularly those associated with the treatment of infections caused by herpes virus, cytomegalovirus (CMV), hepatitis C, and human immunodeficiency virus (HIV). This review focuses on the mechanisms of bilirubin production and excretion and how alterations in these processes result in hyperbilirubinemia. An approach to the evaluation of hyperbilirubinemia in the patient with viral infection is provided. Emphasis is placed on distinguishing between causes of hyperbilirubinemia that may require modification in therapy and those that are of negligible clinical significance. Mechanisms and Physiology of Bilirubin Production and Excretion Bilirubin Production Bilirubin is the end product of the catabolism of heme, the prosthetic moiety of hemoglobin, myoglobin, and other hemoproteins. 1 The major sites of bilirubin production are the spleen and other reticuloendothelial compartments. In normal humans, bilirubin production averages 4 mg kg body weight 1 day 1 (6 M kg body weight 1 day 1 ), 2 and hemoglobin from erythrocyte turnover is the source of 80% 85% of the heme that is eventually catabolized to bilirubin. Bilirubin in Plasma Internal hydrogen bonding between polar moieties within bilirubin constrains the molecule in a rigid, non-polar, and therefore highly insoluble conformation. 1,3 As an otherwise insoluble molecule, bilirubin formed in the periphery is transported to the liver tightly bound to high affinity binding sites on albumin, at concentrations that far exceed its solubility in proteinfree aqueous solutions. If the molar ratio of bilirubin to Abbreviations used in this paper: AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; HIV, human immunodeficiency virus; MRP2, multidrug resistance-associated protein 2; NIAID, National Institute of Allergy and Infectious Diseases; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 304 KORENBLAT AND BERK CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 4 Figure 1. Efficient transfer of bilirubin from blood to bile is dependent on normal sinusoidal architecture, plasma membrane transport processes, and intracellular binding and conjugation. Albumin-bound bilirubin in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both facilitated and simple diffusional processes. Within the cell it is bound to glutathionione-s-transferases and conjugated by UGT1A1 to monoglucuronides and diglucuronides, which are actively transported across the canalicular membrane into the bile. Modified and reprinted with permission from Berk et al. 3 albumin exceeds 1:1 (a bilirubin concentration of approximately 35 mg/dl), the additional bilirubin binds to lower affinity sites, and the unbound bilirubin concentration increases rapidly with further increases in total bilirubin. Hepatic Disposition of Bilirubin Because bilirubin is a potentially toxic waste product, its hepatic disposition is designed to eliminate it from the body via the biliary tract. Transfer of bilirubin from blood to bile involves 4 distinct but interrelated steps (Figure 1). Bilirubin uptake. Bilirubin bound to albumin comes in contact with the microvilli lining the sinusoidal surface of the hepatocytes by passage through the fenestrated endothelium of the hepatic sinusoids into the extrasinusoidal space of Disse. Bilirubin dissociates from albumin and is widely believed to be transported across the hepatocyte plasma membrane into the cell by a protein-mediated, facilitated uptake process, although the exact identity of the bilirubin transporter remains obscure. Recent studies have identified a purely passive, nonsaturable bilirubin uptake component, but its magnitude relative to the saturable process remains to be determined. 4 Intracellular binding. Within the cell, bilirubin partitions between the cytosol and the lipid bilayer of various intracellular membranes. As with bilirubin binding to albumin in plasma, its cytosolic fraction is kept in solution at concentrations that far exceed its aqueous solubility by binding as a non-substrate ligand to a number of proteins, of which the most abundant and best characterized are members of the glutathione-s-transferase superfamily designated ligandins. 1,3 Bilirubin glucuronidation. Making bilirubin soluble, which is essential for biliary excretion, requires disruption of its internal hydrogen bonds. This is achieved by conjugation with glucuronic acid. The resulting monoglucuronide and diglucuronide conjugates are highly soluble in aqueous solutions. The enzyme responsible for bilirubin glucuronidation is the UDPglucuronosyltransferase isoform UGT1A1, which is encoded by the UGT1 gene on chromosome 2. 5 This complex gene consists of 13 alternative first exons (designated A1 A13), each of which encodes a distinct N- terminal region, with a substrate-specific binding site, for one of the multiple protein isoforms produced by this single gene locus. Initiation of RNA transcription at each of these 13 exons is controlled by a separate promoter element immediately upstream of its unique exon. Alternative splicing fuses 1 of these upstream exons with the 4 exons (exons 2 5) common to all UGT1 protein isoforms (Figure 2). Exon A1 and the 4 common exons encode the UGT1A1 protein responsible for bilirubin glucuronidation. 6 Canalicular excretion of bilirubin. The ATP-dependent transport of bilirubin glucuronides across the apical plasma membrane into the canaliculus is mediated by a membrane protein, multidrug resistance-associated protein 2 (MRP2). 7 In mouse models, effective MRP2 function requires the presence of at least one additional protein, radixin, which localizes to the canalicular membrane and directly binds the carboxy-terminal cytoplas- Figure 2. Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 contains at least 13 substratespecific first exons (A1, A2,...), each with its own promoter, that encode the N-terminal substrate-specific 286 amino acids of the various UGT1-encoded isoforms and common exons 2 5 that encode the 245 carboxyl-terminal amino acids common to all of the isoforms. mrnas for specific isoforms are assembled by splicing a particular first exon such as the bilirubin-specific exon A1 to exons 2 5. The resulting message encodes a complete enzyme, in this particular case UGT1A1. Mutations in a first exon affect only a single isoform. Those in exons 2 4 affect all enzymes encoded by the UGT1 gene complex. Modified and reprinted with permission from Berk et al. 3

3 April 2005 HYPERBILIRUBINEMIA DURING ANTIVIRAL THERAPY 305 mic domain of MRP2. 8 Mutations in MRP2 result in conjugated hyperbilirubinemia (Dubin-Johnson syndrome). 9 Extrahepatic fate of excreted bilirubin. Bilirubin excreted into the bile canaliculi passes via the biliary tree into the proximal duodenum. Although some bilirubin reaches the distal ileum/proximal colon unaltered, an appreciable fraction is deconjugated and converted by enteric bacteria into urobilinogens, which then undergo an enterohepatic circulation. Clinical Physiology of Bilirubin The quantity of unconjugated bilirubin in plasma, and hence the plasma unconjugated bilirubin concentration, reflects a balance between bilirubin production and hepatic bilirubin clearance. The plasma unconjugated bilirubin concentration is directly proportional to the rate of bilirubin turnover and inversely proportional to hepatic bilirubin clearance in a manner analogous to the relationship between glomerular filtration rate and serum creatinine (Figure 3). 3,10 Depending on the initial absolute rate of bilirubin clearance, at any given level of bilirubin production equal fractional changes in hepatic bilirubin clearance can have very different effects on absolute plasma bilirubin concentrations. Causes and Consequences of Hyperbilirubinemia Unconjugated Hyperbilirubinemia Unconjugated hyperbilirubinemia is the result of any process that increases bilirubin production, decreases bilirubin clearance, or results in both processes acting in concert. 1,3,10 Hemolysis and increased ineffective erythropoiesis are the most common causes of increased bilirubin production. Chronic unconjugated hyperbilirubinemia due solely to increased bilirubin production rarely exceeds 4 mg/dl, even in the face of brisk hemolysis. It is generally well tolerated, although symptomatic anemia may ensue if hemolysis is severe, and subjects are at increased risk for development of pigmented gallstones. Reduced hepatic bilirubin clearance may result from portosystemic shunting, by which blood bypasses the hepatocytes. Although this is most commonly thought of as occurring through venous channels such as varices, it may also result from capillarization of the hepatic sinusoids, that is, the loss of sinusoidal endothelial fenestrae and increased perisinusoidal matrix deposition, that occurs in cirrhosis. It is also a consequence of an absolute reduction in hepatic blood flow or from abnormalities in Figure 3. Relationship between bilirubin production, as approximated by measurements of plasma bilirubin turnover (BRT), hepatic bilirubin clearance (C BR ), and the plasma concentration of unconjugated bilirubin (BR). Stippled area represents the normal range for bilirubin production; bar on the horizontal axis is the normal range (mean 2 standard deviations) for hepatic bilirubin clearance. A 100% increase in bilirubin production or a 50% decrease in bilirubin clearance will each result in a doubling of the plasma unconjugated bilirubin concentration. However, the absolute magnitude of the increase in bilirubin concentration depends on the initial value for bilirubin clearance. It will be appreciably greater in patients whose initial value for bilirubin clearance is reduced (eg, patients with Gilbert syndrome) than in those whose initial clearance value is normal. mg% mg/dl. Reprinted with permission from Berk et al. 10 the net extraction of bilirubin from the circulation by hepatocytes. Although the precise mechanisms by which bilirubin is taken up by hepatocytes remain unclear, several drugs (for example, rifampin, flavispidic acid, novobiocin, and various cholecystographic contrast agents) are reported to competitively inhibit bilirubin uptake. Delayed expression of UGT1A1 in neonates is primarily responsible for the physiologic jaundice of otherwise normal newborns. Heritable disorders of bilirubin conjugation are well recognized and can also result in unconjugated hyperbilirubinemia. 11 These disorders include Crigler-Najjar syndrome types I and II and Gilbert syndrome Although considered until recently as distinct disorders, these conditions are now all known to result from mutations of different functional severity in the bilirubinconjugating enzyme UGT1A1. 1,3,11 14

4 306 KORENBLAT AND BERK CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 4 Of the hereditary disorders, Gilbert syndrome is the most common and has a phenotypic prevalence of approximately 8% in the general population. It is characterized by a mild, unconjugated hyperbilirubinemia to levels that rarely exceed 4 mg/dl, otherwise normal liver function, and hepatic histology that is also normal other than a modest increase in lipofuscin pigment in some cases. Bilirubin clearance is reduced to approximately one third of normal. 13 The most common recognized molecular defect is the addition of an extra TA dinucleotide sequence to the normal A(TA) 6 TAA transcription initiation sequence (TATAA box) of the A1 exon promoter. 1,14 Homozygosity for the A(TA) 7 TAA promoter mutation appears to be necessary but apparently not always sufficient for clinical expression of Gilbert syndrome, because population studies suggest that only about half of A(TA) 7 TAA homozygotes have hyperbilirubinemia. It has been suggested that additional variables, such as mild hemolysis (reported in up to 50% of patients with Gilbert syndrome) or a separate defect in bilirubin uptake, may be among the factors enhancing phenotypic expression. 1,11 14 Mixed or Conjugated Hyperbilirubinemia Purely conjugated or mixed hyperbilirubinemias often reflect abnormalities in hepatic excretion of conjugated bilirubin. Dubin-Johnson and Rotor s syndromes are uncommon, heritable disorders of conjugated bilirubin excretion. 1,3,11 In Dubin-Johnson syndrome, mutations in MRP2 result in deficient canalicular transport of bilirubin conjugates. 9 The molecular defect in Rotor s syndrome remains unknown but produces a phenotype similar in many respects to that of Dubin-Johnson. In both disorders, general hepatocellular function is preserved, and liver chemistries other than the bilirubin concentration are typically normal. Far more common is the defective bilirubin excretion that occurs with a broad spectrum of hepatobiliary diseases. 11 In these conditions, elevations in bilirubin concentration typically occur in association with abnormalities of other hepatic biochemical tests. 11 This broad category of diseases includes hepatocellular and cholestatic liver diseases, benign postoperative jaundice, mechanical intrahepatic or extrahepatic bile duct obstruction, and a rare group of disorders classified under the rubric of familial intrahepatic cholestasis. 15 Hyperbilirubinemia in the Setting of Antiviral Therapy The highly active antiretroviral treatment regimens that are currently the mainstay of treatment for HIV infection consist of 3 or more antiretroviral drugs from 2 or 3 different antiretroviral drug classes: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside analog reverse transcriptase inhibitors. Members of each class have been associated with the development of nonhemolytic hyperbilirubinemia. The incidence of elevations in hepatic transaminases and/or hyperbilirubinemia with antiretroviral therapy is drug-specific, with the general incidence ranging from 3% 12%. Assessment of potential drug hepatotoxicity in patients with HIV/acquired immunodeficiency syndrome (AIDS) is complicated by the fact that as many as 90% of HIV-infected patients can have abnormal liver function tests at presentation, often as a result of hepatitis C co-infection. 16 Hyperbilirubinemia developing in association with the administration of antiviral medications requires thoughtful scrutiny. Hyperbilirubinemia as a consequence of drug hepatotoxicity typically presents with a pattern of conjugated or mixed elevations in bilirubin. 17 Elevations in serum aminotransferases and alkaline phosphatase also are almost universally present but may be of varying severity. 11,17 In some settings, notably in HIV/ AIDS but also on occasion in hepatitis B and C, the antiviral medication may be important for the very survival of the patient, and the consequences of stopping an effective medication must be carefully weighed against the risks of potential hepatotoxicity. 18,19 Before antiviral therapy is instituted, serum chemistries should be reviewed for elevations in direct and total bilirubin, aminotransferases, and alkaline phosphatase. Establishing whether liver test abnormalities observed during treatment were preexisting or developed in association with the initiation of treatment is an important first step in assessing their significance for continuation of therapy. 19 Preexisting mild, isolated indirect hyperbilirubinemia should raise the possibility of Gilbert syndrome, hemolysis, or, less commonly, disorders of ineffective erythropoiesis. Elevated serum aminotransferases imply hepatocellular injury. Although normal serum aminotransferase levels argue against significant hepatic inflammation, they do not entirely exclude liver disease. Even in the presence of advanced cirrhosis, these enzymes are occasionally normal, and the only biochemical indication of liver disease may be hypoalbuminemia and/or prolongation of clotting times associated with hepatic synthetic dysfunction. 17 An assessment of liver function and the pattern of bilirubin elevation are equally critical to the evaluation of hyperbilirubinemia that follows initiation of antiviral therapy. In particular, new onset or more marked uncon-

5 April 2005 HYPERBILIRUBINEMIA DURING ANTIVIRAL THERAPY 307 jugated hyperbilirubinemia is often an indication of either an extrahepatic side effect of a drug (that is, hemolysis) or its interference with a specific aspect of hepatic bilirubin disposition. In either case, the implications are rarely acutely dangerous. By contrast, elevations in serum aminotransferase levels and/or direct-reacting hyperbilirubinemia with bilirubinuria should raise a concern for hepatotoxicity, which may itself become serious or, occasionally, life-threatening. Critical considerations include distinguishing hyperbilirubinemia and transaminase elevations that are drug-related side effects from those reflecting direct hepatic damage from the diseases for which these therapies are used. Drugs Used Primarily for Treatment of HIV/AIDS Nucleoside/nucleotide reverse transcriptase inhibitors. This class of agents includes zidovudine (AZT), didanosine (ddi), zalcitabine (ddc), stavudine (d4t), lamivudine (3TC), abacavir, and tenofovir (TDF). Hyperbilirubinemia associated with the use of these agents is uncommon. When it occurs, it is typically mixed and accompanied by elevations in serum enzymes typical of hepatic inflammation or injury. Indeed, drug-related hepatotoxicity is a well-recognized effect of the NRTI of HIV, the severity of which can be classified by using the National Institute of Allergy and Infectious Diseases (NIAID) grading scale. 20 Severe hepatotoxicity (NIAID grades 3 and 4) is estimated to occur in about 10% of patients in prospective cohort studies, with patients coinfected with hepatitis B and C at particular risk. 18 The overall rate of hepatotoxicity from regimens that include NRTI, however, does not appear appreciably different than regimens that avoid them. 21 NRTI toxicity is thought to result from inhibition of mitochondrial DNA polymerase, the enzyme required for replication and repair of mitochondrial DNA. This leads to accumulation of mutations in mitochondrial DNA and, in consequence, impairs mitochondrial oxygen-dependent, enzymatic processes. 22,23 Liver injury typically develops after 6 months of therapy and is recognized by abnormalities in liver chemistries and histologic findings of megamitochondria and microvesicular steatosis. The consequences of such hepatotoxicity may be severe and include refractory lactic acidosis and liver failure. 24 Non-nucleoside analogue reverse transcriptase inhibitors. Three drugs, nevirapine (NVP), efavirenz (EFV), and delavirdine (DLV), currently comprise this class of agents. Nevirapine has been reported to cause 3 patterns of hepatotoxicity: asymptomatic serum transaminase elevations, an early-onset hypersensitivity reaction, and a delayed, dose-related hepatitis. Hypersensitivity reactions are typically observed in the beginning weeks of therapy and are associated with fever, rash, leukocytosis with eosinophilia, and elevations in serum IgE. 25 Although the liver chemistry abnormalities associated with the hypersensitivity reaction appear to respond to withdrawal of the drug, cases of acute liver failure have been reported, including one instance in which nevirapine was taken for postexposure prophylaxis. 26 The association of nevirapine hypersensitivity with higher CD4 counts (CD4 250, females; CD4 400, males) may explain the latter observation. The role of coinfection with hepatitis B and C in potentiating nevirapine hepatotoxicity remains unsettled. 27,28 Severe hepatotoxicity has also been observed with the NNRTIs delavirdine and efavirenz, with reported rates of grade 3 or 4 abnormalities of 3.6% and 10.8%, respectively. In randomized prospective trials, the frequency of hepatic transaminase elevations associated with nevirapine treatment is greater, and coinfected patients may be particularly at risk. 29 HIV protease inhibitors. The HIV PI class of medications includes amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, and a fixed combination of lopinavir/ritonavir. As a class, these agents have been associated with a modest incidence (1% 10%) of elevated transaminase levels indicative of hepatotoxicity. In addition to typical hepatotoxicity, clinical trials have reported that up to 12% of subjects receiving indinavir develop asymptomatic unconjugated hyperbilirubinemia, with only occasional concomitant aminotransferase elevations in that patient subset. 30,31 This effect appears to be dose related, because symptomatic hyperbilirubinemia has also been reported when indinavir blood concentrations are increased by the co-administration of ritonavir. 32 The indirect hyperbilirubinemia observed in indinavir-treated patients results from the drug s ability to act as a competitive inhibitor of UGT1A1, in effect producing a Gilbert syndrome like picture. 33 Exaggeration of the hyperbilirubinemia may occur in those with underlying Gilbert syndrome undergoing treatment with indinavir, a finding readily explained by the hyperbolic shape of the serum bilirubin bilirubin clearance curve (Figure 3). 3,10,13 Unconjugated hyperbilirubinemia has also been observed in clinical trials with atazanavir. 34,35 Although elevations in aminotransferases may also occur in this setting, data from trials of atazanavir indicate that there is no relationship between the development of transaminase abnormalities and elevations in bilirubin (O Mara E et al. 40th Interscience Conference on Antimicrobial

6 308 KORENBLAT AND BERK CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 4 Table 1. Hyperbilirubinemia With Antiviral Medications Class Example(s) Pattern of hyperbilirubinemia Mechanism Ref(s) Herpes virus inhibitor Ganciclovir Mixed Hepatotoxicity 36 HIV NRTI AZT, ddi, ddc Mixed Hepatotoxicity: mitochondrial injury with steatosis 21 and lactic acidosis HIV NNRTI Nevirapine, efavirenz, Mixed Hepatotoxicity: hypersensitivity reaction and 29 delavirdine dose-related drug toxicity HIV PI Ritonavir Mixed Hepatotoxicity 31 Indinavir Pure indirect Gilbert s-like syndrome (UGT1A1 inhibition 33 without hepatotoxicity) HCV antiviral Ribavirin Usually indirect Hemolysis; rare hepatotoxicity 38,39 Agents and Chemotherapy, Toronto, Ontario, Canada, Abstract #1645 and # 34727, ASM Press, 2000). These and other data suggest that the unconjugated hyperbilirubinemia seen with atazanavir treatment develops by an effect on UGT1A1 analogous to that of indinavir, ie, by competitive inhibition of UGT1A1. In both cases, the hyperbilirubinemia that may develop is benign and reversible. Drugs Used Principally to Treat Non HIV-1 Viral Infections Ganciclovir and acyclovir. Ganciclovir, a synthetic guanine derivative, is used for prophylaxis against and treatment of CMV infection. Direct-reacting hyperbilirubinemia was observed in 34% of infants treated with ganciclovir for congenital CMV infection. 36 The degree of hyperbilirubinemia was generally modest, but it was quite significant (8 12 mg/dl) in 7% of treated patients. Seventy-five percent and 83% of these infants experienced increased levels of AST and ALT, respectively. AST values that increased by more than 250 IU/L from baseline and ALTs that increased by 150 IU/L were each noted in 36% of cases. The data presentation did not permit a possible correlation of hyperbilirubinemia with elevated serum transaminase levels to be explored in detail, but the overall numbers suggest considerable overlap. Hence, although the exact mechanism of ganciclovir-induced hyperbilirubinemia is unknown, the combined finding of conjugated hyperbilirubinemia and elevations in aminotransferase levels suggest that ganciclovir is hepatotoxic in these patients. However, because all infants in this study were treated, a role of CMV infection per se in producing these abnormalities cannot be excluded. In contrast, in a study of the efficacy of prophylactic ganciclovir in bone marrow transplantation patients, the appearance of hyperbilirubinemia was interpreted as reflecting development of veno-occlusive disease of the liver, a recognized complication of transplantation, rather than a direct effect of the drug. 37 Ribavirin. Ribavirin is a nucleoside analog currently used in combination with interferon- for the treatment of chronic hepatitis C infection. Its principal side effect is hemolytic anemia, which, by causing increased bilirubin production, can result in isolated indirect hyperbilirubinemia. Clinical trials with combination therapy consisting of ribavirin plus one of several interferon preparations for treatment of chronic hepatitis C infection have reported a frequent 2 3 g/dl decrease in hemoglobin levels, with approximately 10% of participants developing a hemoglobin 10 g/dl, in association with unconjugated hyperbilirubinemia. 38 The hyperbilirubinemia tends to be mild, with only 9% developing a total bilirubin greater than 2 mg/dl. 39 Ribavirin-induced hemolysis tends to be maximal in the first 4 weeks of therapy. Dose reduction or subcutaneous administration of erythropoietin is usually adequate treatment in cases in which significant anemia develops. 40 As noted above, NRTIs are recognized as being hepatotoxic and are associated with hepatic steatosis and lactic acidosis. In hepatitis C HIV coinfected subjects, an increased risk for development of lactic acidosis and pancreatitis has been seen with the co-administration of ribavirin and the NRTI didanosine. This is believed to be a consequence of ribavirin s inhibition of the enzyme inosine monophosphate dehydrogenase, resulting in an increased intracellular inosine monophosphate pool, which acts as a phosphate donor in the conversion of didanosine to deoxy inosine monophosphate. For this reason co-administration of didanosine and ribavirin should be avoided. Summary Antiviral therapy can produce hyperbilirubinemia, the seriousness of which depends on the nature and cause of the elevated bilirubin concentration (Table 1).). In the treatment of hepatitis C, the mild indirect hyperbilirubinemia resulting from the increased biliru-

7 April 2005 HYPERBILIRUBINEMIA DURING ANTIVIRAL THERAPY 309 bin production that occurs with the use of ribavirin is generally well tolerated, provided the associated anemia is mild or can be effectively managed. Medications such as the PI indinavir, which impair glucuronidation of bilirubin, also result in an indirect hyperbilirubinemia that is generally well tolerated. In both of these situations, hyperbilirubinemia is readily reversed with discontinuation of the offending drug. The degree of druginduced hyperbilirubinemia will be significantly enhanced if it occurs in patients with underlying Gilbert syndrome. By contrast, the concomitant development of conjugated or mixed hyperbilirubinemia and serum aminotransferase abnormalities, observed with ganciclovir and with both NRTIs and non-nucleoside analog reverse transcriptase inhibitors, appears to reflect potentially significant hepatotoxicity and may be less well tolerated. Underlying conditions such as chronic liver disease or Gilbert syndrome may potentiate the hyperbilirubinemia of antiviral therapies. Because antiviral therapies may be lifesaving, but frank hepatotoxicity associated with their use may be life-threatening, an appreciation of the different forms of hyperbilirubinemia and their underlying pathophysiology is helpful in making appropriate decisions concerning continuation or cessation of therapies. Hyperbilirubinemia that develops during antiviral therapy should prompt an assessment of both hematologic and hepatic function. Isolated indirect-reacting hyperbilirubinemia generally does not need prompt discontinuation of therapy unless it is accompanied by clinically significant hemolysis-induced anemia. Hyperbilirubinemia (especially direct-reacting or mixed) associated with new onset of abnormalities in hepatocellular enzymes or the development of symptoms such as malaise, nausea, vomiting, abdominal pain, and weight loss may indicate significant hepatotoxicity and requires thorough evaluation and possible cessation of antiviral therapy. The decision to continue or discontinue antiviral drug therapy requires a thorough assessment of both the risks and potential benefits of the therapy. References 1. Roy Chowdhury N, Arias IM, Wolkoff AW, et al. Disorders of bilirubin metabolism. In: Arias IM, Boyer JL, Chisari FV, et al, eds. The liver: biology and pathobiology. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2001: Berk P, Howe R, Bloomer J, et al. Studies of bilirubin kinetics in normal adults. J Clin Invest 1969;48: Berk PD, Wolkoff AW. Bilirubin metabolism and the hyperbilirubinemias. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison s principles of internal medicine. 15th ed. New York: McGraw-Hill, 2001: Zucker S, Goessling W, Hoppin A. Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers and native hepatocyte membranes. J Biol Chem 1999;274: Ritter JK, Chen F, Sheen YY, et al. A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem 1992;267: Bosma PJ, Seppen J, Goldhoorn B, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994;269: Gatmaitan ZC, Arias IM. ATP-dependent transport systems in the canalicular membrane of the hepatocyte. Physiol Rev 1995;75: Kikuchi S, Hata M, Fukumoto K, et al. Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nat Genet 2002;31: Kartenbeck J, Leuschner U, Mayer R, et al. 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