Clinicopathological Conference: Hepatitis C in a Patient With Human Immunodeficiency Virus Infection

Transcription

1 Hepatology at the Millennium Clinicopathological Conference: Hepatitis C in a Patient With Human Immunodeficiency Virus Infection LORNA M. DOVE, JUDY ALONZO, AND TERESA L. WRIGHT Liver disease is common in patients infected with the human immunodeficiency virus (HIV). The use of multiple potentially hepatotoxic medications, coinfection with hepatitis viruses, and opportunistic infections that involve the liver make liver test abnormalities a common occurrence in these patients. Frequently, a patient can have more than one possible explanation for such abnormalities, evaluation of which often requires a stepwise approach and careful reasoning. Here we present a patient with multiple risk factors for liver disease and obvious abnormalities in laboratory tests but in whom clinical symptoms were lacking. The appropriate evaluation and care of this patient required a multidisciplinary approach involving both specialists in infectious diseases as well as in hepatology. PRESENTATION OF CASE A 50-year-old man was referred to a liver clinic with increasing alanine transaminase (ALT) activity that had developed in the setting of hepatitis C virus (HCV) and HIV coinfection. The patient was found initially to have HIV and HCV in He was completely asymptomatic and on presentation had a CD4 T lymphocyte count of 489/cm 3 and HIV RNA of ,000 copies/ml (Roche Amplicor, Branchburg NJ). In July 1997, treatment with AZT, 3TC, and nelfinavir were initiated. The patient tolerated the medications well without obvious side effects. Three months later, his CD4 lymphocyte count was 583 and his HIV viral load undetectable. Following written informed consent, he was enrolled in a study of the natural history of HIV/HCV coinfection. He was doing well without complaints. His physical examination was normal. His total serum bilirubin was 0.6 mg/dl (normal 1.0 mg/dl), alkaline phosphatase was 65 U/L (normal U/L), ALT was 30 U/L (normal 7-56 U/L), and his aspartate transaminase (AST) was minimally elevated at 47 U/L (normal 5-35 U/L). HCV RNA at enrollment was Meq/mL (branched DNA; Chiron Corporation, Emeryville, CA). Enrollment in the natural history study required follow-up every Abbreviations: HIV, human immunodeficiency virus; ALT, alanine transaminase; HCV, hepatitis C virus; AST, aspartate transaminase; HAART, highly active antiretroviral therapy. From the Departments of Medicine and Pathology, Department of Veterans Affairs Medical Center, University of California, San Francisco, CA. Received December 15, 1999; accepted April 4, Address reprint requests to: Lorna M. Dove, M.D., M.P.H., Department of Medicine and Pathology, Department of Veterans Affairs Medical Center, University of California, San Francisco, CA evo@itsa.ucsf.edu; fax: Copyright 2000 by the American Association for the Study of Liver Diseases /00/ $3.00/0 doi: /jhep months, and on subsequent visits, it was noted that his AST and ALT levels began to rise (Table 1). He specifically denied abdominal pain, fevers, chills, night sweats, cough, shortness of breath, anorexia, weight loss, or new rashes. Medications at this visit included nelfinavir, AZT, 3TC, lansoprazole, wellbutrin intermittently for smoking cessation, and prazosin, which was discontinued before any change in liver function tests. He denied use of any over-thecounter preparations, herbs, or alternative therapies. The past medical history was notable for hepatitis B in the 1960s, esophageal stricture, and urinary frequency. The patient denied coronary artery disease, seizure disorder, or uncontrolled depression. He had used injection drugs from 1968 until 1986; he received a tapering course of methadone that was completed in He used tobacco but not alcohol. The family history was negative for autoimmune illnesses, liver disease, or tuberculosis. Physical Examination. The vital signs were stable with a heart rate of 70 beats/min, blood pressure 116/78, and oxygen saturation of 95% on room air. He was anicteric without spider angiomata or palmar erythema. His oropharynx was normal with no evidence of thrush; his neck was supple without lymphadenopathy. His lungs were clear and cardiac examination was unremarkable. His abdomen was soft; liver span was 9 cm, and no splenomegaly was appreciated. There was no evidence of ascites, tenderness, rebound, or guarding. The patient was alert and appropriate with no evidence of focal deficits and no encephalopathy. Laboratory Tests. The patient s white blood cell count was 6.3 k/cmm, hemoglobin was 15.2 g/dl, hematocrit was 43.6%, platelet count was 174 k/cmm, AST was 110, ALT was 181, albumin was 4.0 g/dl, prothrombin time was 10.9 seconds, international normalized ratio was 1.0, and HCV RNA was meq/ml (Chiron Corporation). The patient had HCV genotype-1a and was hepatitis B surface antigen negative, hepatitis B core antibody positive, and hepatitis B surface antibody positive. In November 1998, the patient underwent liver biopsy for evaluation of rising ALT levels. He continued to feel well without complaints. Pathology. A percutaneous needle biopsy from the right lobe of the liver was performed and the specimen processed for routine light microscopic examination. The hematoxylin and eosin stained slide showed hepatic parenchyma with intact architecture without evidence of cirrhosis. The portal tracts were mildly expanded by nodular aggregates of inflammatory cells, which consisted predominantly of small, round lymphocytes with a few admixed plasma cells and eosinophils, inflammatory grade 2/4 (nodular portal lymphoid infiltrates, mild piecemeal necrosis), and fibrosis stage 2/4

2 148 DOVE, ALONZO, AND WRIGHT HEPATOLOGY July 2000 TABLE 1. Laboratory Data Laboratory Test Date ALT (U/I) AST (U/I) TBIL (mg/dl) ALKP (U/I) CD4 (No./cmm) HIV RNA ( 1,000/mL) HCV RNA (meq/ml) April 1997* July September August November April May June September Abbreviations: TBIL, total bilirubin; ALKP, alkaline phosphatase. *Initial visit. HIV medications (AZT, 3TC, and nelfinavir) initiated. Enrolled in HIV/HCV natural history study. Liver biopsy. HAART discontinued. HAART reinstituted. (enlarged fibrotic portal tracts, portal-portal septae). 1 Refractile polarizable crystalline material was present within portal macrophages. Mild piecemeal necrosis and occasional lobular acidophil bodies were also present. A single, pericentral noncaseating granuloma composed of epithelioid histiocytes with a peripheral rim of lymphocytes and plasma cells was identified. No polarizable material was seen in association with the granuloma. Acid fast and Gomori methenamine silver stains were negative for acid fast bacilli and fungi, respectively. A Prussian blue iron stain was negative in the hepatic parenchyma but showed staining within the granuloma. A trichrome stain showed portal tract enlargement and portal-portal septae with intact architecture. There was minimal microvesicular steatosis. No cholestasis, Mallory hyaline, or viropathic changes were identified (Figs. 1-3). DISCUSSION Background. During 1996, AIDS-related opportunistic infections were diagnosed in an estimated 56,730 persons, a decline of 6% when compared with Deaths among persons reported with AIDS declined 23% in 1996 compared with This improvement in morbidity and mortality probably comes as the result of improved identification and care of infected patients as well as the success of new treatment modalities such as protease inhibitors. Because of this improvement in HIV-associated morbidity, there appears to be an increased amount of liver disease in HIV-infected patients. Patients previously dying from infectious complications of HIV disease may now live long enough to manifest complications of their hepatitis infection. Whether this noted increase in liver-related morbidity and mortality represents a true change in incidence or only in the recognition of the disease is still a matter of debate. Nevertheless, there is a renewed interest in coinfection, which is likely to intensify over the next decade. HIV and HCV: Epidemiology and Natural History. Given the common modes of transmission of HIV and HCV, coinfection with these viruses is frequent, ranging anywhere from 11% to 94% 3 depending on the population studied. In injection drug users, HCV infection alone occurs in greater than 80% of FIG. 1. Chronic portal inflammatory infiltrate.

3 HEPATOLOGY Vol. 32, No. 1, 2000 DOVE, ALONZO, AND WRIGHT 149 titer in the progression of liver disease has not been clarified in any population, with or without immune compromise. A CD8 cytotoxic lymphocyte response that is increased because of underlying HIV infection may accelerate liver injury and progression of disease. Conversely, a depressed class I restricted cellular immune response to HCV in HIV-infected patients may contribute to elevated HCV-RNA levels and hepatic fibrosis. Although the pathophysiology is not clear, recent data have shown that in coinfected patients, low CD4 count, as well as alcohol consumption and young age at the time of HCV infection, are related to the rate of fibrosis progression. 9 The association of progression with a low CD4 count further supports the importance of immune function in containing liver injury. HIV Drugs and Potential Hepatotoxicity. The problem of druginduced hepatotoxicity is prominent in HIV-infected patients probably because of multidrug regimes as well as underlying liver disease, which may predispose to medication-induced injury. The list of potential hepatotoxins used in the treatment of HIV is extensive (Table 2). With regard to drugs taken by the patient under discussion, both AZT and nelfinavir have been associated with hepatotoxicity. With the frequent use of protease inhibitors such as nelfinavir in HIV disease, special attention to this drug class is warranted. HIV protease inhibitors prevent cleavage of gag and gag-pol protein precursors in acutely and chronically infected cells, arresting maturation and thereby blocking the infectiv- FIG. 2. Portal inflammatory infiltrate with refractile and polarizable foreign material. patients 4 ; in injectors with HIV infection, HCV infection is almost universal. 5 Cross-sectional descriptions of coinfected patients show that the development of symptomatic liver disease is more common than in patients infected with HCV alone. 6,7 In fact, in one study the risk of hepatic decompensation was estimated to be approximately 10.8% 20 years after exposure. 6 These clinical findings have been supported by histological data that have revealed that the rate of fibrosis progression and cirrhosis development appears to be accelerated in coinfected patients. 8,9 The underlying reason for this increased risk is unknown. The progression of HCV likely is dependent both on viral and host factors. The immune response to HCV, or lack thereof, is believed to play a major role in the development of persistent disease and may affect progression. Both CD4 and CD8 T cells are involved in the response to HCV. 10,11 CD8 lymphocytes may be responsible for not only viral clearance but also hepatocyte injury. 12 Many have postulated that the more rapid progression of liver disease in patients with immune deficiency is secondary to enhanced HCV replication. Indeed HCV RNA levels are increased in patients coinfected with HIV, although the role of increased viral FIG. 3. Pericentral noncaseating granuloma.

4 150 DOVE, ALONZO, AND WRIGHT HEPATOLOGY July 2000 TABLE 2. Common Drugs Associated With Liver Abnormalities Used in the Treatment of HIV and HIV Complications Predominantly Hepatocellular Disease Clarithromycin Delaviridine Didanosine (ddi) Dideoxycytidine (ddc) Efavirenz Indinavir Isoniazid Ketoconazole Nelfinavir Nevirapine Pentamidine Ritonavir Saquinavir Stavudine (d4t) Trimethoprim-sulfamethoxazole Zidovudine Data from Flexner 16 and Service HATI. 43 Predominantly Cholestatic Disease Rifampin Ketoconazole Trimethoprim-sulfamethoxazole ity of new virions. 16 The use of these drugs in combination with nucleoside analogues is believed to improve morbidity and mortality in patients with HIV infection. In fact, it is recommended that all patients receive a protease inhibitor as part of their initial therapy. 17 The protease inhibitors are metabolized by the cytochrome P450 system. Therefore, they can interact with drugs that either inhibit or induce P-450 metabolizing enzymes. An additional concern is that drug metabolism may be decreased in patients with chronic liver disease. 16 Severe hepatitis as a complication of protease inhibitor therapy is believed to be rare, 16 but there exist multiple case reports of patients developing severe hepatitis B and even fulminant hepatic failure while receiving protease inhibitor therapy. 18 Mild elevation of AST and ALT levels has been reported with indinavir, nelfinavir, ritonavir, and saquinavir. Reversible unconjugated hyperbilirubinemia is seen frequently in patients taking indinavir, without elevation of serum transaminase. 16 Also of concern is the effect of immune reconstitution in patients with underlying chronic viral hepatitis. If hepatic inflammation is dependent on an intact immune response to HCV, one could postulate that improvements in immunity resulting from highly active antiretroviral therapy (HAART) regimes may precipitate acute inflammation and alter the natural history of hepatitis C. Recent small studies show that, in patients with underlying HCV, treatment regimens including protease inhibitors caused an elevation in transaminase activity as well as in HCV viral RNA. 19,20 These elevations were seen within the first month, and the median time for a return to baseline was 9 months. The largest trial to date that has evaluated the impact of protease inhibitor therapy on patients with chronic hepatitis revealed that, while hepatotoxicity was seen more frequently in coinfected patients on protease inhibitors, severe hepatotoxicity was noted in only 12.2% of coinfected patients. This compares with 10.4% of patients with HIV alone. 21 More large studies are needed before the true impact of protease inhibitor therapy on patients with HIV hepatitis coinfection can be determined. Evaluation of Abnormal Liver Enzymes in HIV-Infected Patients. Hepatic biochemical abnormalities have been noted in as many as 80% of HIV-infected patients at some point during their clinical course and often prompt further evaluation. Of 501 liver biopsy specimens reviewed in two urban hospitals, abnormal liver test was the indication for more than 85%. 25 The evaluation of a patient with HIV disease and elevated AST and ALT levels is not unlike that for the immunocompetent patient. Careful attention must be given to exposures, risk factors for viral hepatitis, and medications. Serological tests for viral hepatitis should include anti-hcv, hepatitis B surface antigen, and anti hepatitis B core, followed by chemistries for other diagnoses and finally biopsy if the diagnosis is not apparent. 26 In HIV-infected patients with HCV coinfection, the sensitivity and specificity of first, second, and third generation enzyme immunosorbent assays have been challenged Difficulties with both false positive and false negative results have been identified. Also, a fall in seroreactivity to certain viral antigens has been linked to more frequent indeterminate responses of the RIBA Given the above information, qualitative HCV-RNA assays may be necessary for establishing the diagnosis of HCV infection in an HIV-infected patient. Additional recommendations include early consideration of an imaging study as well as early timing of a liver biopsy in patients with significant immunocompromise (defined as a CD4 lymphocyte count less than 200). The latter is justified by the poor specificity of radiographic tests for liver disease in immunocompromised patients as well as the frequent finding of multiple histological abnormalities. 31 Clinical Differential Diagnosis. In this patient, the differential diagnosis includes chronic HCV, drug hepatotoxicity, and infiltrative disease. Increased AST and ALT activities are the most frequent indicators of hepatocellular dysfunction and represent markers of hepatocyte necrosis. Although liver disease is common in patients with HIV infection, particularly in those who have developed clinical manifestations of AIDS, it generally is associated with only mild elevation of serum transaminases. Drug induced hepatotoxicity is a likely contributor in many instances. Among infectious entities involving the liver, viral hepatitis is probably the most common. Although many opportunistic infections may involve the liver, markedly elevated ALT and AST levels are rare. Pathology Differential. The liver biopsy findings were those of chronic HCV infection. The finding of polarizable material within portal macrophages is commonly seen in patients with a history of injection drug use. In addition, a single noncaseating epithelioid granuloma was identified. Granulomata can be found in a variety of infectious and noninfectious conditions 32 (Table 3). Infectious Fungus Histoplasma capsulatum Aspergillus Mucor Mycobacteria Brucella Listeria Epstein Barr virus Cytomegalovirus Coxiella burnetii TABLE 3. Etiologies of Granulomatous Hepatitis Noninfectious Primary biliary cirrhosis Inflammatory bowel disease Drug reaction Hodgkin s disease Foreign material Sarcoidosis

5 HEPATOLOGY Vol. 32, No. 1, 2000 DOVE, ALONZO, AND WRIGHT 151 CLINICAL COURSE After the biopsy results returned, additional evaluations included a chest radiograph, which showed no focal abnormalities, a negative purified protein derivative (PPD) (but with negative controls, indicating anergy), a calcium level, and an angiotensin converting enzyme, all of which were within normal limits. In April 1999 after consultation with the patient s primary provider, all medications were discontinued, and laboratory tests were followed (Table 1). The options considered at the time included (1) to discontinue all medications, (2) to institute HCV therapy, (3) to change HIV therapy, or (4) to make no changes and continue to follow the patient. We chose option 1 in an effort to minimize confusion in the long term. If we changed the HIV antiviral therapy, we could not be sure that persistent elevation represented HCV; rather it could be caused by continued reaction to a different regime. If we simply initiated HCV therapy in addition to his current medication regime, persistent elevation of ALT could reflect a poor response to interferon or persistent drug hepatotoxicity. Complete simultaneous discontinuation of HAART therapy is considered to be safer than a sequential discontinuation for avoiding HIV resistance, and thus we chose this approach. The case illustrates the difficulty in differentiating drug toxicity from fluctuations in transaminase activity seen in patients with chronic HCV. With discontinuation of therapy we noted initial improvement but not normalization of serum ALT levels. The CD4 count was unchanged. After 3 months on no therapy, the ALT level again began to rise, suggesting that HCV was the primary problem. It remains an open question which, if any, medication in this patient s regime contributed to the transaminase elevation. The prompt response on discontinuation of medications initially suggested drug-related hepatotoxicity, but the subsequent rise in ALT in the absence of medications made this less likely. The presence of HCV RNA in this patient convinces us that he has chronic infection. It is possible that immune reconstitution and immune response to HCV explain the fluctuating levels of transaminase. This seems unlikely given his well-preserved immune status at the initiation of HIV therapy and maintenance of a good CD4 count after HIV therapy had been discontinued. We had the luxury of monitoring this patient s natural history on no treatment. This was largely because of travel plans of the patient, which precluded early reintroduction of HIV antivirals or initiation of HCV therapy. This 3-month window changed our perspective and presumed diagnosis. If his therapy plan had been dictated by laboratory data in June 1999, we would have assumed that the liver abnormalities were HAART related and would have changed his regime accordingly. The rising ALT levels in September 1999 convinced us to resume his previously effective HAART and to institute HCV therapy with interferon alfa 2b (3 MU subcutaneous three times a week) plus ribavirin (1,000 mg/d orally) (Schering Plough Research Institute, Kenilworth, NJ). The presence of a granuloma on biopsy raised the issue of diagnoses other than HCV, although this is a nonspecific finding and often not associated with disease. The patient clearly had no evidence of tuberculosis, sarcoid, or lymphoma. Granulomas have also been noted in drug-induced hepatitis but are not typical of HCV. In this case, the liver biopsy provided a basis on which to broaden the diagnostic evaluation. In HIV, especially in patients with advanced immunocompromise, multiple simultaneous problems are not unusual. Given this information, biopsy before definitive diagnosis and treatment is valuable and perhaps crucial. HCV TREATMENT IN HIV-INFECTED PATIENTS Early in the HIV epidemic, there was little enthusiasm for treating HCV infection in dually infected patients. Underlying this lack of interest were data suggesting that HIV mortality was independent of HCV infection; enthusiasm was dampened also by the lackluster performance of interferon monotherapy in all patient populations. 3,33 Although interferon alone has little demonstrable efficacy, there appears to be no difference in the response of dually infected patients compared with patients infected with HCV alone, with respect to improvement in ALT. 34,35 Reports have shown ALT normalization as well as clearance of HCV RNA in 22.5% of patients 12 months after therapy was discontinued. 36 With regard to the combination of interferon and ribavirin, randomized trials in immunocompetent patients show an improved sustained virological response in patients receiving combination therapy relative to interferon monotherapy (36% vs. 18%). 37,38 The effectiveness of combination therapy in patients with HIV disease has yet to be determined. Although the safety of ribavirin alone in HIV-infected patients has been shown, 39,40 the potential negative interaction of ribavirin with other HIV-related therapy is a concern. Drug antagonism has been shown between azidothymidine and ribavirin in vitro. 41 No major complications have been noted in preliminary data from the largest trial of combination therapy in coinfected patients. 42 A significant decrease in CD4 count was noted in the patients receiving interferon and ribavirin therapy, but there was not an increase in HIV viral load. 42 Thus far, the numbers evaluated in trials are small, and more patients need to be followed long term before we can accurately determine the safety and efficacy of combination therapy. FINAL DIAGNOSIS The patient was diagnosed with HCV disease in the setting of HIV. FOLLOW-UP At the end of 3 months, the patient was tolerating therapy without major side effects. Response to treatment is unclear at this time. REFERENCES 1. Tsui WM. New classification of chronic hepatitis and more. Adv Anatomic Pathol 1996;3: Update: trends in aids incidence, deaths, and prevalence United States, MMWR Morb Mortal Wkly Rep 1997;4446: Dorrucci M, Pezzotti P, Phillips A, Lepri AC, Rezza G, ISS (Italian Seroconversion Study). Coinfection of hepatitis C virus with human immunodeficiency virus and progression to AIDS. J Infect Dis 1995;172: Thomas D, Vlahov D, Solomon L, Cohn S, Taylor E, Garfein N. Correlates of hepatitis C virus infections among injecting drug users. Medicine 1995;74: Thomas D, Shih J, Alter H, Vlahov D, Cohn S, Hoover D, Cheung L, Nelson K. Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users. J Infect Dis 1996;174: Telfer P, Savin C, Devereux H, Scott F, Sucheiko G, Lee C. The progression of HCV-associated liver disease in a cohort of haemophilic patients. Br J Haematol 1994;87:

6 152 DOVE, ALONZO, AND WRIGHT HEPATOLOGY July Eyster ME, Diamonds LS, Lien JM, Ehmann WC, Quan S, Goedert JJ. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J AIDS 1993;6: Soto B, Sanchez-Quijano A, Rodrigo L, del Olmo J, Garcia-Bengoechea M, Hernandez-Quero J, Rey C, et al. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 1997;26: Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, Vidaud M, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. HEPATOLOGY 1999;30: Koziel M. The role of immune responses in the pathogenesis of hepatitis C virus infection. J Viral Hepatol 1997;4: Naoumov N. Hepatitis C virus-specific CD4 T cells: do they help or damage? Gastroenterology 1999;117: Chisari F. Cytotoxic T cells and viral hepatitis. J Clin Invest 1997;99: Telfer P, Brown D, Devereux H, Lee C, DuSheiko G. HCV RNA levels and HIV infection: evidence for a viral interaction in haemophilic patients. Br J Haematol 1994;88: Eyster E, Gried M, Di Bisceglie A, Goedert J, Study TMHC. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Blood 1994;84: Beld M, Penning M, Lukashov V, McMorrow M, Roos M, Pakker N, van den Hoek A, Goudsmit J. Evidence that both HIV and HIV-induced immunodeficiency enhance HCV replication among seroconverters. Virology 1998;244: Flexner C. HIV-protease inhibitors. N Engl J Med 1998;338: Carpenter C, Fischl M, Hamer S. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society USA Panel. JAMA 1997;277: Carr A, Cooper D. Restoration of immunity to chronic hepatitis B infection in a HIV-infected patient on protease inhibitors. Lancet 1997;349: Rutschmann O, Negro F, Hirschel B, Hadengue A, Anwar D, Perrin L. Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients coinfected with HIV. J Infect Dis 1998;177: Vento S, Garofano T, Renzini C, Casali F, Ferraro T, Concia E. Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy. AIDS 1998;12: Sulkowski M, Thomas D, Chaisson R, Moore R. 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: Lefkowitch J. Pathology of AIDS-related liver disease. Dig Dis 1994;12: Dworkin B, Stajl R, Giardina M, Wormser G, Weiss L, Jankowski R, Rosenthal W. The liver in acquired immune deficiency syndrome: emphasis on patients with intravenous drug abuse. Am J Gastroenterol 1987;82: Schneiderman D, Arenson D, Cello J, Margaretten W, Weber T. Hepatic disease in patients with the acquired immune deficiency syndrome. HEPATOLOGY 1987;7: Poles M, Dieterich D, Schwarz E, Weinshel E, Lew E, Lew R, Scholes J. Liver biopsy findings in 501 patients infected with human immunodeficiency virus (HIV). J Acquir Immune Defic Syndr Hum Retrovirol 1996;11: Friedman L, Martin P, Munoz S. Liver function test and the objective evaluation of patients with liver disease. In: Zakim D, Boyer T, eds. Hepatology: A Textbook of Liver Disease. Vol. 1. Philadelphia: Saunders, 1996: Marcellin P, Colin J, Martinot-Peignoux M, Pham B-N, Lefort V, Picault A-B, Degott C, et al. Hepatitis C virus infection in anti-hiv positive and negative French homosexual men with chronic hepatitis: comparison of second and third-generation anti-hcv testing. Liver 1993;13: Chamot E, Hirschel B, Wintsch J, Claude-Francois R, Gabriel V, Deglon J-J, Yerly S, et al. Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users. AIDS 1990;4: Ragni M, Ndimbie O, Rice E, Bontempo G, Nedjar S. The presence of hepatitis C virus (HCV) antibody in human immunodeficiency viruspositive hemophiliac men undergoing HCV seroreversion. Blood 1993;82: Marcellin P, Martinot-Peignoux M, Elias A, Branger M, Courtois F, Level R, Erlinger S, et al. Hepatitis C virus (HCV) viremia in human immunodeficiency virus-seronegative and seropositive patients with indeterminate HCV recombinant immunoblot assay. J Infect Dis 1994; 170: Beale T, Wetton C, Crofton M. A sonographic-pathological correlation of liver biopsies in patients with the acquired immune deficiency syndrome (AIDS). Clin Radiol 1995;50: Ferrell L. Hepatic granulomas: a morphologic approach to diagnosis. Surg Pathol 1990;3: Wright T, Hollander H, Pu X, Held M, Lipson P, Quan S, Polito A, et al. Hepatitis C in HIV-infected patients with and without AIDS: prevalence and relationship to patient survival. HEPATOLOGY 1994;20: Boyer N, Marcellin P, Degott C, Degos F, Saimot A, Erlinger S, Benhamou J. Recombinant interferon-alpha for chronic hepatitis C in patients positive for antibody to human immunodeficiency virus. J Infect Dis 1992;165: Marriott E, Navas S, del Romero J, Soledad G, Castillo I, Quiroga JA, Carreno V. Treatment with recombinant alpha-interferon of chronic hepatitis C in anti-hiv-positive patients. J Med Virol 1993;40: Soriano V, Garcia-Samaniego J, Bravo R, Gonzalez J, Castro A, Castilla J, Martinez-Odriozola P, et al. Interferon alfa for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;23: Reichard O, Gunnar N, Aril F, Jean-Henrik B, Sonnerborg A, Weiland O. Randomized, double-blind, placebo-controlled trial of interferon alfa-2b with and without ribavirin for chronic hepatitis C. Lancet 1998;351: McHutchinson J, Gordon S, Schiff E. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339: Berner R, Tremblay N, Tsoukas C, Bergeun N. Drug sensitivity of human immunodeficiency virus type 1 isolated after ribavirin therapy. J Infect Dis 1997;175: Japour A, Lestoria J, Meehov P, Conor J, Griffith B, Clax P, Holden-Wittre J, et al. A phase I study of the safety, pharmokinetics and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. J Acquir Immune Defic Syndr Hum Retrovirol 1996;13: Vogt M, Hartshorn K, Furman P, Chou T-C, Fyfe J, Coleman L, Crumpacker C, et al. Ribavirin antagonizes the effect of azidothymidine on HIV replication. Science 1987;235: Dietrich D, Weisz K, Goldman D, Malicdem M. Combination treatment with interferon (IFN) and ribavirin (RBV) for hepatitis C (HCV) in HIV co-infection patients [Abstract]. HEPATOLOGY 1999;30(Suppl):266A. 43. Service HATI. Drug Therapy. Vol. 1999: CDC, 1999.