Hepatic and Pancreatic Dysfunction

in HIV Patients

Chinese Version

Updated July, 2009

Jack T. Stapleton, M.D.   

INTRODUCTION

               Hepatic dysfunction in HIV-infected people is often insidious, with no clinical or laboratory evidence of disease present until late in the course of illness. When clinical illness occurs, presenting signs and symptoms are non-specific, and require laboratory investigation to identify the etiology. Hepatic dysfunction in HIV-infected people is common, with studies early in the epidemic reporting intrahepatic opportunistic infections and malignancies in up to 78% of patients diagnosed with AIDS (1-4). With the advent of effective antiretroviral therapy, opportunistic infections involving the liver have dramatically decreased in frequency (5). However, as HIV-infected people live longer, morbidity and mortality related to chronic active viral hepatitis and drug-related hepatotoxicity have risen. The percentage of deaths due to non-alcoholic liver disease in HIV-infected people increased three-fold between 1987 and 1997 (6,7), and liver disease was the major cause of mortality in HIV-infected patients in one report (8). Thus hepatic dysfunction continues to be a serious and growing problem among HIV-infected people in the HAART era. Hepatic and pancreatic dysfunction in HIV-positive people may be caused by several different pathological processes including infections, toxicity from the ingestion of toxic medications and substances, malignancy, and from underlying hepatic disease unrelated to HIV. In addition to liver disease per se, specific processes involving the biliary tract and pancreas may also occur in HIV-infected individuals.

EPIDEMIOLOGY

               Liver disease is extremely common in the HIV-infected population. Biochemical evidence of hepatic inflammation, as manifested by elevations in liver associated enzymes (LAEs, alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [AP] and total bilirubin) is found in 90% of HIV-infected people, usually when the CD4 count is below 200 cells/mm³ (9,10). However, in one study, only 2% to 3.8% of minimally symptomatic HIV-infected individuals were found to have elevated hepatic transaminase levels (11). The finding of Grade 3 or 4 hepatotoxicity, defined by the AIDS clinical trials group (ACTG) as elevations in LAE's greater than 5 times the upper limit of normal, was retrospectively identified in more than 10% of study participants (12). In addition, hepatomegaly was present in up to 73% of these patients (11,13). The rate of concurrent viral hepatitis is related to the mode of acquisition of HIV. For example, intravenous drug users have a high rate of concurrent hepatitis C virus (HCV) infection relative to non-intravenous drug users, and thus are at increased risk of hepatic dysfunction. Active intravenous drug users and HCV seropositivity were independently associated with an increased likelihood of progression to a new AIDS-defining clinical event or death in a group of 3,100 HIV-infected patients in Switzerland (12).

               The risk of complications from hepatic dysfunction, and the progression of liver disease to cirrhosis or hepatocellular carcinoma depends upon the underlying etiologic agent and/or process. For instance, HIV-therapy related hepatotoxicity was found in 52% of HIV-HCV co-infected patients, compared to 39% among those infected with HIV alone (7,14). Thus, although hepatic dysfunction is extremely common among HIV-infected people, an understanding of both the pathologic process involved and the etiology is necessary to determine the specific risk of progression and the potential for therapeutic intervention.

               Pancreatic disease is also frequent in HIV-positive individuals, occurring in up to 50% of people with advanced HIV disease or AIDS (15-17). Pancreatic disease is generally related to medications (16-20), opportunistic infections (16,17,21), gallstones or neoplasms. The most frequent cause of pancreatic disease in HIV-infected people is related to toxins, either medication use or alcohol. On rare occasion, acute pancreatitis may be the presenting illness during primary HIV-1 infection (22).

DIFFERENTIAL DIAGNOSIS

               There are many different causes of liver and pancreatic disease in HIV-infected people, including infections, malignancy, toxicity from the ingestion of hepatotoxic medications and substances, and underlying hepatic disease unrelated to HIV. Identifying the specific etiology of liver disease in this population requires a systematic and thorough evaluation of the individual patient, taking into account the immunological status, history of injection drug use, prior viral hepatitis, medications, prior and concurrent opportunistic infections, malnutrition, substance use, and travel history.

Infectious Causes of Hepatic Disease

               Among infectious etiologies of hepatic dysfunction, viral hepatitis is the most common cause of hepatitis among HIV-infected people. Several viruses whose main clinical manifestation is hepatitis have been identified and are classified as hepatitis A, B, C, D, and E, although other viruses are also associated with hepatocellular injury. Infections involving the liver can also be manifest by granulomatous inflammation, vascular lesions and abscess formation. A summary of the infectious etiologies of liver dysfunction is shown in Table 1.

Viral Hepatitis: Hepatitis A virus (HAV) is an RNA virus within the Picornavirus family (23,24). Although HAV is transmitted by the fecal-oral route and has been shown to be sexually transmitted (25-31), the prevalence of HAV infection is not increased in HIV-infected individuals relative to controls (27).

               Hepatitis B virus is a DNA virus within the Hepadnaviridae (32). Due to shared modes of transmission (sexual contact and intravenous drug use, evidence of past or active hepatitis B virus (HBV) infection has been found in up to 95% of patients with AIDS, including 35% to 80% in gay men, 60% to 80% for injection drug users, 60% to 80% in people with hemophilia, 5% to 20% for heterosexuals with multiple partners, and 3% to 14% for the general population (33-35). In several studies, 10% to 15% of HIV-positive individuals are chronic carriers of HBV (33-36). If HIV infection precedes HBV, it is less likely that HBV infection will be symptomatic or icteric, yet the rate of development of chronic hepatitis B infection (with persistent HBV surface antigen, HbsAg) is increased (37,38). The severity of HBV infection appears to be related to the immunological status of the HIV-infected person, reflecting the presumed immunopathogenesis of HBV infection (39,40). With low CD4 counts, there appears to be less hepatocyte destruction by host cytotoxic T cells, and both the likelihood of developing persistent infection and an increase in HBV replication are observed (37-39). Before the era of effective antiretroviral therapy, co-infection with HBV did not result in an increased mortality rate (41), although more recently there has been a suggestion that mortality may be increased in HIV-HBV co-infected individuals (36).

Review Article:Hoffman, C., Thio, C. Clinical Implications of HIV and Hepatitis B Co-infection in Asia and Africa. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 402-409.

               Hepatitis C virus (HCV) is an RNA virus classified in the Flaviviridae (42). The rate of HCV antibody positivity among HIV infected people depends largely upon the mode of HIV transmission. Because HCV is efficiently transmitted by parenteral exposure to blood, HCV infection is commonly found in HIV-infected intravenous drug users. The rate of HIV-HCV co-infection ranges from 23% to 75% in the intravenous drug use population (14,43,44). HCV is not as efficiently transmitted through sexual or vertical exposure as it is by percutaneous means, thus the rate of HCV infection in people infected with HIV through non-parenteral exposure tends to be much lower (approximately 4% to 15%) (45). However, recent studies suggest that current antibody testing for HCV is not as sensitive in HIV-infected people as in HIV-negative individuals (46-48). Consequently, more people infected with HIV by sexual transmission may be co-infected with HCV than previously recognized. These studies found that in HIV-infected patients, 5% to 14% of those testing negative for HCV antibody are actually infected when evaluated by HCV RNA testing (46-48). The rate of male to female transmission of HCV is low, but reportedly is increased five-fold in HIV-infection (45). Similarly, vertical transmission of HCV is enhanced when the mother is HIV-positive (49,50).

               Approximately 20% of HIV-negative individuals with HCV infection spontaneously clear their infection, although the rate of clearance may be lower among HIV-positive people (47,48,51,52). Of those persistently infected with HCV, more than half develop chronic hepatitis and approximately 20% develop cirrhosis, on average 20 years following HCV infection (53). A significant number (approximately 5%) of individuals developing cirrhosis ultimately develop hepatocellular carcinoma (53,54). The rate at which HCV disease progresses among HIV-infected people is not yet clear, but before effective antiretroviral therapy, the mortality rate of HIV-HCV co-infected people was not increased compared to HIV only populations (7,55-60). This may reflect the slow pace of disease associated with HCV, and the previously poor prognosis among HIV-infected people. With the advent of effective antiretroviral therapy, HCV-related liver disease and mortality appear to be increasing (7,55,61-64). This may reflect an immune reconstitution syndrome, with increased immunologic destruction of HCV-infected hepatocytes by HCV-specific cytolytic T cells, additive or synergistic effects of hepatotoxic antiviral medications and/or alcohol with HCV, or prolonged survival of individuals with HIV, allowing the HCV-related liver disease time to develop. It appears that HCV infection progresses more rapidly in people with HIV-HCV co-infection (7,55,65), although the effect of antiretroviral therapy on HCV-related liver disease progression is incompletely understood (66). Because HCV appears to be increased in severity with HIV infection, it has increasingly been considered as an opportunistic infection (7,14).

               It is important to remember that extrahepatic manifestations of HCV, and to a lesser extent HBV, may be the presenting clinical finding in co-infected patients. A variety of clinical findings including arthritis, vasculitis, cryoglobulinemia, lichen planus, porphyria cutanea tarda, and polyarteritis nodosa are associated with HCV or HBV, and should prompt evaluation for HCV and HBV, even in the absence of evidence of liver disease (53,67).

               Hepatitis delta virus (HDV) is a defective RNA virus that can only replicate in the presence of active HBV infection (68,69). HDV can infect people simultaneously with HBV or can superinfect HbsAg carriers (68). HDV is thought to be more directly cytotoxic to hepatocytes than is HBV. Consistent with this, 70% to 80% of HIV-infected people with HBV-HDV co-infection progress to cirrhosis (69).

               Like hepatitis A virus, hepatitis E virus (HEV) is transmitted by the fecal-oral route (70). Although there have been reports of increased seroprevalence of HEV in HIV-infected populations (71,72), there have not been any cases or outbreaks of this infection identified. This virus has only rarely been identified in the United States, generally in people returning from developing countries (70,73).

               Hepatitis G virus is also called GB virus type C (GBV-C), and is a member of the Flaviviridae (74,75). GBV-C is closely related to HCV, and was originally identified in people with non-A, non-B, non-C hepatitis. Subsequent studies have shown that GBV-C does not appear to cause hepatitis, or for that matter, any other disease (76-79). GBV-C is transmitted both parenterally and sexually, and is an extremely common infection (80-82). GBV-C viremia is found in approximately 1.8% of healthy blood donors, and in up to 39% of HIV-infected individuals (81). Although GBV-C is closely related to HCV, it does not appear to replicate primarily in the liver (83). Recent studies suggest that it replicates in lymphocytes, and in an in vitro infection model, it was found to replicate in the CD4+ subset of T cells (83). Several studies have found that survival is prolonged among HIV-GBV-C co-infected people compared with HIV-only infected controls, suggesting that GBV-C is one factor in long-term non-progression of HIV disease (81,84-89). Since GBV-C does not appear to cause hepatitis, it will not be discussed further.

Other Viruses Causing Hepatitis: Several DNA viruses including adenovirus and several members of the Herpesvirus family have been associated with clinical hepatitis (90,91). In the pre-HAART era, cytomegalovirus (CMV) was the most common viral opportunistic infection in the liver, and in autopsy studies was found in up to 44% of patients (1,3,92). CMV hepatitis presents as part of a systemic infection, and is usually found in people with evidence of active CMV infection in other sites such as the retina, colon, lungs or biliary tree (93,94). Disseminated herpes simplex virus (HSV) infection can involve the liver, occasionally leading to fulminant hepatocellular necrosis (95). Other members of the herpesviridae associated with liver involvement include Epstein-Barr virus (EBV), varicella-zoster virus (VZV), human herpesvirus-6 (HHV-6), and human herpesvirus-8 (HHV8) (96,97,98).

               It is unclear if there is a direct relationship between HIV and the liver. In vitro data indicate that HIV is able to replicate in hepatoma cell lines, even in the absence of surface expression of CD4 (99). Approximately 80% of liver biopsy specimens obtained from patients with an AIDS clinical diagnosis demonstrate HIV antigens, yet the endothelial cells and Kupffer cells form a barrier which prevents infection of hepatocytes. Since HIV infects macrophages, and the liver contains the largest number of tissue macrophages, the Kupffer cells, it is not surprising that most HIV antigens are found in the Kupffer cells (100,101).

Granulomatous Infections: A variety of fungal, mycobacterial and protozoal infections may cause granulomatous inflammation of the liver. Most of the pathogens associated with granulomatous inflammation do not cause clinically significant disease until the HIV infection has led to severely impaired cellular immunity. As a result, granuloma are frequently poorly formed with minimal inflammatory response. Most of the etiological agents leading to granulomatous hepatitis are not usually identified in people with CD4 counts of more than 100 cells/mm³. Consequently, the frequency of granulomatous liver disease has fallen since the advent of effective ART.

               Liver involvement during systemic fungal infections is not uncommon in people living with HIV. For example, 16% of patients with histoplasmosis have evidence of dissemination to the liver (102), and granulomas have been reported in cryptococcal disease and coccidioidomycosis. Granulomatous hepatitis has been described with Candida albicans, aspergillus species and Sporothrix schenckii, although these findings are uncommon. Extrapulmonary infection with Pneumocystis carinii in people receiving aerosolized pentamidine can occur, and in one autopsy series, hepatic involvement was documented in 39% of cases (102).

               Prior to effective antiretroviral therapy, Mycobacterium avium-intracellulare complex (MAC) was the most frequent cause of hepatic granulomas in people with AIDS (9,33,34,45,103-105). MAI was identified in up to 30% of liver biopsy specimens from AIDS patients (9,33,34,45,103-105). Because disseminated MAC, with or without hepatic involvement, is seldom diagnosed in individuals with more than 50 CD4 cells/mm³, a history of prior and/or concurrent opportunistic infections is common. Mycobacterium tuberculosis (Mtb) infection can occur at any CD4 count, however, in people with early HIV infection (and CD4 counts > 300), the presentation of Mtb is similar to people without HIV infection and usually does not involve the liver. However, in individuals with more advanced HIV disease, atypical presentations of Mtb are more common, and disseminated disease and extrapulmonary involvement of the liver and other organs are more frequent (106-108). Additional non-tuberculous mycobacteria have also been found to cause granulomatous hepatitis. M. xenopi and M. genavense infections are very similar to MAC in their presentation and high association with advanced immune deficiency, whereas M. kansasii may be more similar in clinical findings with M. tb. (109).

               Another type of pathogen that may cause hepatic granuloma formation are protozoa. Toxoplasmosis gondii, Leishmania donovani and Schistosoma species disseminate to the liver by hematogenous spread, and may cause granulomas or hepatitis (110,111).

Vascular Infection: Peliosis hepatitis is caused by infection with Bartonella henselae or Bartonella quintana, the etiologic agents of cat scratch disease or bacillary angiomatosis (14,112,113). Liver disease may occur in the absence of cutaneous manifestations of bacillary angiomatosis, and the onset of lesions may be extremely rapid. In the absence of diagnosing bartonellosis elsewhere, liver biopsy is required for definitive diagnosis, however, there may be an increased risk of hemorrhage from liver biopsy of these vascular lesions (114).

Hepatic Abscess Formation: Although hepatic abscess formation may occur in HIV-infected people, these lesions are relatively rare, and do not appear to occur at an increased frequency than in HIV-negative people. The most common source of infection leading to hepatic abscesses includes cholecystitis, appendicitis, diverticulitis, and peritonitis. In addition, bacterial liver abscesses may follow liver transplantation or biliary tract surgery, and are increased in frequency among people with chronic granulomatous disease. In the United States, bacterial abscesses are more common than amoebic liver abscesses (115-118). Finally, bacterial pathogens other than mycobacteria may cause hepatitis with or without space occupying lesions.

Hepatotoxic Medications and Substances: The use of hepatotoxic medications in HIV-infected people is extremely common, with as many as 90% of people with an AIDS diagnosis receiving at least one drug associated with hepatotoxicity (10). Alcoholic hepatitis complicates this, as up to 80% of HIV-positive people consume alcohol and there is an increased incidence of alcoholism in HIV-infected cohorts compared to the general HIV-negative population (119-124). In addition, the high incidence of HBV and HCV co-infection among HIV-positive people makes interpretation of drug-related hepatotoxicity difficult, as most studies do not address the interactions between medication use, ethanol consumption and viral hepatitis. Liver enzyme abnormalities resulting from medication side effects may present as cholestatic, hepatocellular or a mixed reaction. Table 2 lists several drugs other than antiretroviral agents that are commonly prescribed for HIV-infected people, and notes the pattern of hepatic related enzyme abnormalities observed in clinical trials (125,126).

               Table 3 lists currently licensed anti-retroviral medications prescribed for HIV-infected people, and notes the frequency of hepatotoxicity observed in clinical trials with each agent (127). Of these licensed anti-HIV medications, nucleoside reverse transcriptase inhibitors (NRTI's) have all been associated with mitochondrial toxicity. This toxicity is thought to relate to the NRTI inhibiting DNA polymerases responsible for mitochondrial DNA replication, similar to the mitochondrial myopathy induced by zidovudine (128,129). The defect in mitochondrial function may result in altered oxidative phosphorylation with accumulation of hepatic fat and ultimately, lactic acidosis (11,13,128,130-137). The reactions appear to be dose related, and usually occur after long term (greater than 6 months) of dosing with the NRTI (11). Hepatitis due to mitochondrial toxicity is frequently severe, with mortality rates of 50% in some studies (131-134). Among the NRTI's, zidovudine (138), zalcitabine (128,135,139), and abacavir (Ziagen®) (140) have been associated with a hypersensitivity reaction that may include elevated transaminases.

               Anti-HIV medications in the non-nucleoside reverse transcriptase inhibitor class (NNRTI's) have been associated with severe, life-threatening hepatotoxicity, although the mechanism of this interaction is not understood. Nevirapine and efavirenz induce the cytochrome P-450 enzyme system, leading to an elevation in gamma-glutamyltransferase (GGT), leading to elevations in GGT in as many as 28% of recipients (141-144). Grade 3 or 4 elevation of transaminase levels have been found in up to 15% of nevirapine recipients and in 2% to 3% of efavirenz recipients (141,145). Among HCV or HBV infected patients receiving efavirenz, 13% had grade 3 or 4 elevations in transaminases (145). Twelve cases of hepatotoxicity were reported to the U.S. Food and Drug Administration (FDA) in healthy people who received nevirapine as part of a post-exposure prophylaxis regimen following occupational exposure to HIV (146,147). One of these reactions resulted in liver failure requiring liver transplantation. Delavirdine is an inhibitor of the cytochrome P-450 isoenzyme 3A4, and thus does not cause elevated GGT (126). It has been associated with grade 3 or 4 transaminase elevation in up to 6% recipients (148) in one study. No cases of fulminant hepatitis associated with delavirdine have been reported to date.

               HIV protease inhibitors are metabolized by the cytochrome P-450 system, and interact by either inhibiting or inducing enzyme activity. All of the protease inhibitors have been associated with hepatotoxicity (126), although the risk of severe toxicity appears to vary considerably between agents. For example, indinavir commonly causes asymptomatic elevation of serum indirect bilirubin similar to Gilbert's syndrome (149), and approximately 10% of indinavir recipients develop a total bilirubin of > 2.5 mg/dl (150-152). This cholestasis is not observed with any of the other protease inhibitors. Similarly, in one study ritonavir was associated with a 5-fold higher risk for severe hepatotoxicity than the other protease inhibitors when compared with NRTI's alone (14). In this study, 30% of ritonavir recipients developed transaminase elevations > 3.5 times the upper limits of normal (14). However, other studies have noted only up to 9.1% severe hepatotoxicity with ritonavir, similar to that observed with the other protease inhibitors (153-158). Because ritonavir inhibits the metabolism of other protease inhibitors resulting in more favorable dosing intervals and pill burden, it is commonly used in combination protease inhibitor therapy (159). These combination regimens have also been associated with up to 10% grade 3 or 4 hepatotoxicity (125,160,161). It appears that the risk of hepatotoxicity with protease inhibitors is increased when there is concomitant HCV or HBV infection (162), yet it remains to be determined if this interaction is due to synergistic toxicity of the drug and viral replication, or due to immune reconstitution produced by HIV therapy resulting in increased destruction of viral-infected hepatocytes (9,162-166).

Malignancy: Kaposi's sarcoma is the most common hepatic neoplasm seen in AIDS, with approximately one third of individuals with cutaneous Kaposi's sarcoma also having liver involvement (2,167-169). Although uncommon, Kaposi's sarcoma may present with only liver involvement. Biopsy reveals irregular nodules within the hepatic parenchyma. Occasionally, vascular endothelial cell proliferation in a spindle-cell pattern will be found, similar to the pathologic pattern observed in cutaneous lesions. The liver is the most common abdominal organ involved with high-grade, non-Hodgkin's lymphoma (NHL) in HIV-infected patients, occurring in approximately 15% of patients with lymphoma diagnosed elsewhere (170). NHL lesions in the liver may have a thin enhancing ring on CT scan, and ultrasound will often reveal low-attenuated and hypoechoic cystic masses with septations (171-173). Although most malignant hepatic mass lesions will be due to Kaposi's sarcoma or NHL, infectious etiologies such as fungi, CMV, mycobacteria, bacteria, or abscesses may present as space occupying lesions within the liver.

Underlying Liver Disease: In the evaluation of HIV-infected patients with evidence of hepatic dysfunction, it is important to consider other pathological processes that are not related to HIV infection. Alcoholic liver disease, hemachromatosis, autoimmune hepatitis, Wilson's Disease, primary biliary cirrhosis, alpha1-antitrypsin deficiency, primary or metastatic malignancy, biliary tract disease, and/or pancreatic disease may all present in HIV-infected patients, and these entities should not be overlooked.

Biliary Tract and Pancreatic Disease: Improvements in therapy for HIV antiretroviral therapy have decreased the frequency of AIDS-related cholangitis. However, cryptosporidiosis was the most common cause of cholangitis in AIDS patients in the pre-antiretroviral therapy era (174,175), and should be considered in people with advanced HIV disease and findings of cholangitis. Cryptosporidiosis was found in 29% of HIV-infected individuals with intestinal cryptosporidia (176). CMV (177), Enterocytozoon bineneusi (178), and less commonly MAC, NHL, and Kaposi's sarcoma may all be identified as the cause of cholangitis (179,180). It has been suggested that HIV may lead to cholangitis, although the mechanism by which HIV would do this in not clear. Cryptosporidium, Isospora belli (181) and CMV have been associated with acalculous cholecystitis. Non-infectious causes of biliary tract disease include cholecystitis, cholelithiasis, and cholestatic reactions to hepatotoxic medications.

               Infectious causes of pancreatitis included Pneumocystis carinii, Mycobacterium avium intracellulare, and Mycobacterium tuberculosis, cytomegalovirus, cryptococcus neoformans, cryptosporidiosis, and Toxoplasma gondii (17,21,182). Non-infectious causes of pancreatitis predominate, specifically medication side effects. Among drugs commonly used in HIV-infected individuals, didanosine (Videx®,Bristol Myers Squibb) stavudine (Zerit®, Bristol Myers Squibb) trimethoprim-sulfamethoxazole, pentamidine, dapsone, and ethanol have all been associated with pancreatitis (16,182). Severe hypertriglyceridemia, which may accompany protease inhibitor therapy, may also result in pancreatitis. Other non-infectious causes include gallstone-related pancreatitis, tumor, intravenous drug use (16).

RISK FACTORS

               Virtually all HIV-infected individuals are at risk of developing hepatic dysfunction. As noted above, 80% of HIV-infected individuals drink alcohol, 90% are prescribed drugs with known risk of hepatoxicity, and a high percentage of patients are co-infected with HCV or HBV due to their prior or ongoing exposure to blood and sexually transmitted diseases. As in other organ systems, the immunological status of the individual is key to narrowing the differential diagnosis of hepatic dysfunction. In people with preserved CD4 counts (> 300 cells/mm³), non-infectious causes such as alcohol or hepatotoxic drugs and viral hepatitis are the most likely causes of liver enzyme abnormalities. With the exception of Mtb and the viral hepatitides, opportunistic infections involving the liver usually occur when the CD4 count falls below 50 to 100 cells/mm³. Since approximately 90% of HIV-infected patients with CD4 counts in this range have abnormal transaminase levels (9,10), other clinical findings are required to justify an extensive evaluation for biochemical evidence of hepatitis. The risk of pancreatitis is increased among people with alcohol abuse, a prior history of pancreatitis, hypertriglyceridemia, and gallstones (17).

CLINICAL MANIFESTATIONS

Signs and Symptoms

               Patients with liver disease may complain of fever, right upper quadrant or epigastric pain, anorexia, nausea, vomiting, weight loss, and changes in bowel movements. Symptoms of pruritus, when associated with liver disease, may suggest chronic cholestasis. Clinical signs frequently include hepatomegaly, jaundice, dark urine, and clay colored stool. When there is cirrhosis of the liver, signs of portal hypertension may be present, including palmar erythema, spider angiomata, gynecomastia, testicular atrophy, Dupuytren's contractures, splenomegaly, ascites, caput medusae, and hemorrhoids. Hepatic decompensation may manifest as hepatic encephalopathy, with mental status changes and asterixis. Xanthomata, bronze skin and Kayser-Fleischer rings suggest underlying liver disease (primary biliary cirrhosis, hemachromatosis and Wilson's disease respectively). Depending upon the etiology, a variety of extrahepatic manifestations of specific viral infections may accompany viral hepatitis, for example, arthralgia or vasculitis may accompany hepatic disease (183).

               Most HIV-infected patients with abnormal liver associated enzyme levels will have no symptoms or abnormalities on physical examination. Thus, diagnosis of liver disease must be made on the basis of laboratory abnormalities (see section VI). The presence of clinical signs of portal hypertension should prompt a thorough laboratory evaluation of hepatic function (see below).

               Symptoms suggesting pancreatic disease include epigastric, left upper quadrant, or periumbilical abdominal pain that may radiate through the abdomen to the back, chest, flanks, or lower abdomen. The pain is steady, dull, and boring in character. It is usually more intense when the patient is supine, and may lessen in the sitting position with the trunk flexed forward and the knees drawn up. Additional symptoms of pancreatitis include nausea, vomiting, and abdominal distention secondary to ileus. Symptoms are generally exacerbated by the ingestion of food (183). Patients with pancreatitis initially may present with fever, tachycardia and hypotension. Shock is common in severe instances due to hypovolemia secondary to third-space fluid sequestration with increased vascular permeability and vasodilatation and other systemic signs of inflammation due to the effects of proteolytic and lipolytic enzymes released into the circulation (184). Abdominal tenderness and rigidity may be present, and bowel sounds are diminished or absent.

               Complications of severe pancreatitis include phlegmon, abscess, pseudocyst formation, and localized, non-pancreatic problems including obstructive jaundice, ascites, intraperitoneal hemorrhage, splenic vein thrombosis, bowel infarction and gastrointestinal bleeding. In addition, a variety of metabolic, cardiovascular, pulmonary, renal, and hematological complications are possible. Related to these complications, additional findings such as pleural effusion, pneumonitis, subcutaneous fat necrosis resembling erythema nodosum may be present. Jaundice may occur due to obstructive cholelithiasis or compression of the intrapancreatic portion of the common bile duct due to edema in the head of the pancreas. Cullen's sign and Turner's sign (the presence of a bluish discoloration around the umbilicus or flanks respectively) suggest hemoperitoneum resulting from hemorrhagic necrotizing pancreatitis. Tetany secondary to hypocalcemia may rarely occur. Pancreatic tumors may result in a palpable mass, or Courvoisier's sign (a palpably enlarged gall bladder in a jaundiced patient), jaundice and pruritis may be the presenting sign and symptom of pancreatic disease (183).

RADIOGRAPHIC MANIFESTATIONS

               It is highly unlikely that plain films of the abdomen will identify the presence or etiology of hepatic or pancreatic disease. Pancreatic calcifications may be demonstrated on plain films suggesting chronic pancreatitis, but usually there are no abnormalities present in pancreatitis or biliary tract disease. Imaging studies of the right upper quadrant and abdomen are generally undertaken after hepatic or pancreatic disease has already been diagnosed by laboratory studies, primarily to identify biliary tract obstruction, mass lesions, ascites or other signs of portal hypertension (see below).

DIAGNOSIS

               The initial evaluation of all HIV positive individuals should include a careful and thorough history and physical examination. The history should characterize the use of hepatotoxic medications (including prescription, over-the-counter medications, nutritional supplements, alcohol, and illicit or recreational medications), and determine if there is a past history of viral or other types of hepatitis. The HAV and HBV vaccination status, prior or concurrent opportunistic infection, nutritional status, recent travel, and current and former substance abuse history should be determined. Substance abuse history should determine the type and extent of current or past alcohol, injection and non-injection drug use.

               A careful physical exam will determine if there is hepatomegaly or splenomegaly, abdominal tenderness, jaundice, signs of portal hypertension (see section V, clinical signs and symptoms) or hepatic encephalopathy. The CD4 count of the patient should be determined, as most opportunistic liver diseases do not occur until very low CD4 counts (< 100 cells/mm³). LAE's (ALT, AST, GGT, alkaline phosphatase, and bilirubin) should be determined on all HIV-positive patients on their initial evaluation. These should be repeated on an annual basis, or more frequently if they are abnormal, or if the patient is receiving hepatotoxic medications. Hepatitis B and hepatitis C serologic evaluation should also be done on the initial clinic evaluation (159) to determine the need for further evaluation for liver disease or for treatment, and to refine recommendations for vaccination (Table 4). Figure 1 describes the use of serological tests for the diagnosis of hepatitis B, and figure 2 shows an approach to evaluation of hepatitis C. Information concerning hepatic synthetic function can be gleaned from the serum albumin level and measurement of the prothrombin time. In addition, the total protein level provides insight into chronic hepatitis, as hypergammaglobulinemia is common in chronic hepatitis, however, HIV is also associated with a polyclonal gammopathy.

The Asymptomatic Patient

Hepatocellular Disease: The diagnostic approach to the HIV-positive patient with liver disease depends upon the status of the patient. In asymptomatic individuals with persistent LAE elevations (at least 2 to 5 times the upper limit of normal) and no identifiable cause, the approach will vary depending upon the pattern of LAE abnormality. If the predominant abnormality is in the transaminases (ALT and AST), the initial serologic results for HBV and HCV should be reviewed. If not available, or if the individual was initially susceptible to either virus, these studies should be repeated (see Figures 1 and 2). Patients with HBV or HCV should be further evaluated and managed as outlined below. Hemachromatosis is a very common hereditary disease in Caucasians, occurring in approximately 1 in 200 Caucasians (185-187). Consequently, testing iron, TIBC, and ferritin levels is reasonable in asymptomatic individuals with persistent elevation in transaminases. The finding of a fasting transferrin saturation of > 60% in men and > 50% in women will detect about 90% of patients with homozygous hereditary hemachromatosis (185-187). To avoid missing some of the 10% remaining, some advocate using a "cutoff" of > 45% for directing genetic testing. A serum ferritin of > 300 ng/mL in men and 200 ng/mL in women provides further support for the diagnosis of iron overload, although this is considerably less sensitive than the transferrin saturation. Any person who has evidence for liver disease and iron overload should undergo prompt genetic testing to identify the genetic defect of hemochromatosis (187,188). Measurement of serum alpha-fetoprotein should also be considered, and if elevated the patient should be evaluated for hepatocellular carcinoma by imaging methods (described in more detail below). Individuals with predominantly transaminase elevation are said to have hepatocellular disease.

               In general, withdrawing potential hepatotoxic medications is not warranted in the asymptomatic patient, unless the LAE elevations are severe (greater than 5 to 10 times the upper limits of normal), and there is either a temporal relationship to initiation of a medication, or the patient becomes symptomatic. In asymptomatic individuals, a trial of medication withdrawal is appropriate if feasible, given the need for the medication in question. If it is not feasible to withdraw medications, substitution of an appropriate alternative drug(s) should be considered. If the abnormality persists for several weeks following discontinuation of the potential hepatotoxic drugs, additional evaluation for autoimmune hepatitis (measure ANA, AMA, anti-smooth muscle antibody), Wilson's disease (ceruloplasmin), alpha1-antitrypsin deficiency (1-antitrypsin level) is warranted.

               Asymptomatic HIV-positive patients with HCV infection will require consideration of liver biopsy (see below) to determine the severity of disease and need for treatment (189). Patients with hemachromatosis and Wilson's disease require biopsy to determine an estimation of iron and copper deposition (189). Among patients with other forms of chronic liver disease, there should be serious consideration of a liver biopsy to both confirm the suspected diagnosis (and rule out alternative diagnoses), and to determine the extent of liver damage, specifically to identify early, compensated cirrhosis. In individuals found to have cirrhosis on liver biopsy, additional studies are warranted, such as upper endoscopy to rule out esophageal varices, and screening for hepatocellular carcinoma with serial determinations of serum alpha-fetoprotein and ultrasonography.

               In individuals with asymptomatic elevation of LAEs for greater than 6 to 12 months and in whom no etiology is identified using the studies outlined above, consideration should be given for imaging studies (CT or ultrasound) to exclude a focal lesion or biliary tract disease. Figure 3 illustrates an algorithm for the diagnostic approach for the asymptomatic patient with elevated transaminases.

Cholestatic Disease: Patients with predominantly elevated alkaline phosphatase, bilirubin and GGT levels have cholestatic disease. In patients with elevated levels of total bilirubin, it is important to determine whether it is predominantly due to unconjugated or conjugated (direct) hyperbilirubinemia, as the etiologic considerations differ. In general, if the increase in bilirubin is primarily conjugated (direct), there is impaired hepatic excretion of bilirubin (frequently present in viral or drug related hepatitis, including alcoholic liver disease) or extrahepatic biliary obstruction. If the increase in bilirubin is predominantly unconjugated, there is either overproduction of bilirubin (e.g. hemolysis), decreased hepatic uptake or decreased conjugation of bilirubin (which occurs with some drugs and several hereditary disorders). Sepsis may be associated with both decreased hepatic uptake of bilirubin and decreased bilirubin conjugation, thus is associated with unconjugated hyperbilirubinemia. In severe hepatitis and cirrhosis, there is usually interference in the uptake, conjugation and excretion of bilirubin, however, since excretion is the rate-limiting step of bilirubin metabolism and is usually impaired to the greatest extent in hepatitis and cirrhosis, viral hepatitis and cirrhosis are associated with conjugated hyperbilirubinemia (190).

               As noted above, cholestasis can result form drug hepatotoxicity, malignancy, biliary tract disorders, and a variety of opportunistic infections including mycobacterium avium, mycobacterium tuberculosis, cytomegalovirus, fungal infections, peliosis hepatitis (Bartonella), and protozoal infections. In the asymptomatic patient, cholestasis is most commonly due to drug toxicity. Asymptomatic patients with cholestasis should be counseled to withdraw medications if feasible. If the laboratory studies return to normal, no further studies are required. However, if the LAE's are severe (> 5 x upper limits of normal) or do not promptly improve with discontinuation of medications, imaging studies are indicated to investigate for possible biliary tract disease or focal lesions.

               The two major modalities of hepatic imaging include ultrasound and computerized tomography (CT). Both modalities detect more than 90% of dilated extrahepatic biliary ducts, and along with magnetic resonance imaging (MRI) are sensitive means of identifying intrahepatic, portal, and pancreatic masses (52). Ultrasound has the advantage over CT in that it is more sensitive for detecting stones in the gallbladder. Neither CT nor ultrasound is sensitive for the detection of choledocholithiasis, with a sensitivity of only about 60% for identifying intraductal stones, however, CT appears to be somewhat better than ultrasound for detecting stones within non-dilated bile ducts (46,52). If there is evidence of dilated intra- or extrahepatic ducts, invasive diagnostic procedures are indicated (see below), and the diagnosis of AIDS cholangiopathy should be considered. If no abnormality is identified by the imaging studies, and the symptoms persist, a liver biopsy should be considered. If no focal lesions or dilated intra- or extrahepatic ducts are found, observation is warranted. An algorithm outlining an approach to cholestasis in the asymptomatic patient is shown in Figure 4.

Symptomatic Patient

               The evaluation of abnormalities in liver associated enzymes is similar in the symptomatic patient, although the urgency is increased, and additional studies for causes of acute hepatitis are warranted. In obtaining the patients history, the specific medications being used (including "alternative" or "natural" medications and acetaminophen – containing drugs), and the temporal relationship of these medications to the development of abnormal LAE's should be determined. In the symptomatic patient, if the etiology is potentially related to a medication, a trial of medication withdrawal should be immediately instituted if possible, and if not possible, a therapeutic substitution should be attempted. If the LAEs normalize, the offending medication(s) should be held if possible, or reinstituted under careful monitoring.

               If the parameters do not improve with medication withdrawal, the evaluation is similar to that described in Figures 3 and 4. For patients with hepatocellular disease (with predominantly elevated transaminases), hepatitis A should also be considered, as should hepatitis E if the travel history is compatible. These viruses are diagnosed by measuring HAV- or HEV-specific IgM antibody in the setting of acute hepatitis. In people with chronic hepatitis B virus infection who did not have evidence of severe or active liver disease previously, hepatitis D virus super-infection could be considered, however, this is not common, and diagnosis of this infection would not lead to any changes in management.

               For patients with cholestases, the algorithm is the same as in Figure 4, except that serologic testing for acute viral hepatitis with HAV and HBV should be performed, and in the proper setting, HCV, HDV and HEV should be considered. In symptomatic patients with a cholestatic pattern of LAE abnormality, hepatic imaging studies (reviewed above) are crucial to rule out biliary obstruction or focal lesions.

Pancreatitis: The most common study for determining the presence of pancreatic disease is the serum amylase, however, hyperamylasemia may be present for many conditions not related to the pancreas (intestinal perforation, infarction or ischemia, peritonitis, ectopic pregnancy, ruptured or dissecting aortic aneurysm, splenic rupture, renal insufficiency, diabetic ketoacidosis, burns, carcinoma, macroamylasemia). Especially common in HIV-infected individuals is hyperamylasemia related to salivary gland disease. Hyperamylasemia is present in approximately 75% of patients with acute pancreatitis, although serum amylase may be normal in patients with hypertriglyceridemia and in patients with recurrent alcoholic pancreatitis. Serum lipase levels are elevated in approximately 70% of patients, and one or both enzymes (amylase and lipase) are elevated in 85% of patients with acute pancreatitis. The urine amylase level may remain elevated for 7 to 10 days after the serum amylase level has returned to normal. Leukocytosis is common, and hyperglycemia, hypocalcemia, and elevated liver associated enzymes (ALT, AST), bilirubin and alkaline phosphatase may occur. Plain films of the abdomen are useful in excluding alternative diagnoses, and ultrasound or CT scan are helpful in determining the size and appearance of the pancreas, presence and extent of peripancreatic spread of inflammation and phlegmon, and the condition of the biliary tree.

Invasive Diagnostic Tests

               Liver biopsy is usually the most specific test to determine both the specific etiology and severity of liver diseases (189). Hepatic tissue is indicated for the diagnosis of alcoholic liver disease, nonalcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis (index patients and relatives), and Wilson's disease. Hepatic tissue may also useful in the evaluation of fever of unknown origin, the status of the liver following liver transplantation, evaluation of primary biliary cirrhosis, primary sclerosing cholangitis, or in the evaluation of abnormal results of LAEs with a negative or inconclusive serological evaluation. In addition, liver biopsy is required for the grading and staging of alcoholic liver disease, nonalcoholic steatohepatitis, autoimmune hepatitis, hepatitis C, hepatitis B, and for quantitative estimation of iron or copper levels in individuals with hemachromatosis or Wilson's disease, respectively (189). Among people with unexplained abnormalities of LAE's, the liver biopsy provides an accurate diagnosis in approximately 90% (189,191).

               Since most of the liver diseases evaluated by liver biopsy are diffuse processes, a single biopsy of adequate size is sufficient for diagnostic purposes. A specimen of at least 1.5 cm in length is required for diagnostic purposes (189). A 1.5 cm specimen should contain the 6 to 8 portal triads necessary to adequately determine the extent of liver injury present (189). Liver biopsy is contraindicated in uncooperative patients, patients in whom it is impossible to obtain blood for transfusion, or in whom a vascular tumor is expected (for example, Kaposi's Sarcoma or Cat-Scratch Disease involving the liver), or in people with suspected echinococcal cysts of the liver. Bleeding disorders are a relative contraindication for liver biopsy, unless it is impossible to correct the abnormality, in which case they are an absolute contraindication. Other relative contraindications include morbid obesity, ascites, and infection in the right plural cavity or below the right diaphragm. The main serious complication of liver biopsy is hemorrhage, which usually becomes apparent with in the first 3 hours following the procedure (192,193). Thus it is important to monitor blood pressure and hemoglobin patients following liver biopsy, and to require patients to be able to return to the hospital in which the procedure was performed within 30 minutes after the onset of any adverse symptoms. There are practice guidelines published (by the American Gastroenterological Association) for patients receiving an outpatient liver biopsy (194).

               There are several methods available for obtaining liver tissue, including percutaneous biopsy, transjugular biopsy, laparoscopic biopsy, or fine-needle aspiration guided by ultrasound or CT. In general, percutaneous liver biopsy provides the most rapid and practical approach to obtaining liver tissue. Ultrasonography is recommended prior to percutaneous liver biopsy to identify mass lesions that are clinically silent, define the anatomy of the liver and the relative position of the gallbladder and surrounding organs. However, it is debatable if routine ultrasound evaluation reduces the rate of complications, increases diagnostic yield or is cost effective (189). Fine-needle aspiration biopsy of the liver is performed under ultrasound or CT guidance, and is useful for identifying the etiology of focal hepatic lesions (189). The diagnostic accuracy of fine-needle aspiration approaches 95%, however, non-diagnostic studies require additional studies to exclude a diagnosis of malignancy or infection (195). Fine-needle aspiration has more been shown useful in the evaluation of diffuse liver diseases, and may serve as an alternative to percutaneous liver biopsy (196). Transjugular liver biopsy is indicated if liver biopsy is required in a patient with bleeding disorders, massive ascites, massive obesity or suspected vascular tumors, as it appears to reduce the risk of complications in these individuals (189). Laparoscopic liver biopsy is usually considered among patients requiring liver biopsy and who have ascites of unclear etiology or peritoneal infections.

               There are two scoring systems widely used to interpret liver biopsy findings. The Knodell system (197) is used predominantly in the United States, and the METAVIR scoring system is more widely used in Europe (198). The METAVIR scoring system grades the stage of fibrosis on a 5 point scale (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = few septa, 3 = numerous septa without cirrhosis, 4 = cirrhosis). In addition, METAVIR grades histologic activity (inflammation) on a four point scale (A0 = no inflammation, A1 = mild activity, A2 = moderate activity, and A3 = severe activity). The Knodell scoring system is much more complicated than the METAVIR, and includes grading of periportal bridging hepatocellular necrosis, intralobular degeneration and hepatocellular necrosis, portal inflammation and fibrosis. A numeric score is assigned to each liver biopsy specimen, and the combined score of the four categories form the histology activity index score for the specimen.

               As with all invasive procedures, liver biopsy should only be considered if the results will alter (or potentially alter) the management approach. In addition, liver biopsy decisions should take into account the overall status of the HIV-positive individual. Among patients with hepatitis C for example, the liver biopsy is an important factor in the decision to consider therapy with alpha-interferon (see below). However, if therapy is not considered an option due to advanced HIV disease that has not responded to treatment, liver biopsy for the purpose of grading and staging HCV is not warranted.

               Among patients with evidence of biliary obstruction or cholangitis, further definition and therapy of extrahepatic biliary obstruction can frequently be accomplished by percutaneous cholangiography or endoscopic retrograde cholangiopancreatography (ERCP), and up to 90% of dilated biliary ducts and 70% of non-dilated ducts can be accessed percutaneously (199). From a diagnostic standpoint, cholangiography allows radiographic visualization of the biliary tract, biopsies and cytological evaluation of biliary epithelium may be performed. In addition, bile can be aspirated for microbiological evaluation (including ova and parasite evaluation). Therapy of obstruction can also be considered, including sphincterotomy and the placement of stents. In HIV-infected people with low CD4 counts, diagnosis of specific infection (CMV, MAC, cryptosporidia, etc.) by biopsy of the duodenum, ampulla, or liver provides indirect evidence of the etiology of the biliary obstruction (200). Nevertheless, complications of AIDS-related cholangiopathy occurred as a result of ERCP in up to 10% of individuals undergoing sphincterotomy, with 0.4% of these fatal (201). In addition, pancreatitis occurred in 5.4% of the patients undergoing ERCP in one study (201), and ascending cholangitis can also complicate ERCP (179,202). Thus, ERCP and percutaneous cholangiography should be reserved for symptomatic patients having clear indications for evaluation and/or treatment of biliary obstruction.

               In patients with acute pancreatitis, ERCP is generally contraindicated except when an impacted common bile duct stone may be the cause of the pancreatitis. Endoscopic sphincterotomy in these patients may be therapeutic. In addition, ERCP may be useful in establishing the diagnosis of pancreas divisum, annular pancreas, pancreatic cancer, pancreatic duct abnormalities, however, these studies are generally delayed until the acute pancreatitis has stabilized.

MANAGEMENT

               Once it is apparent that an HIV-positive patient has hepatic or pancreatic disease, it is important to withdraw hepatotoxic (Tables 2 and 3) or pancreatotoxic medications and counsel the individual to avoid acetaminophen and alcohol. The diverse number of infections and neoplastic processes that may involve the liver preclude empiric anti-infective therapy, and specific recommendations for treating bacterial, fungal, protozoal, and viruses (other than the viral hepatitides) are described elsewhere in this book. There is no specific therapy for HAV or HEV. Treatment of HDV relates solely to the treatment and prevention of HBV. Thus, this chapter will only address the approach to treating HCV and HBV. In addition, prevention of viral hepatitis relies upon both behavioral changes preventing exposure to the pathogens, primarily avoidance of unsafe sexual practices, exposure to the blood or secretions of other individuals, good hygienic practices, and immunization. Table 4 outlines recommendations for HAV and HBV immunization in HIV-positive individuals.

Hepatitis C Treatment

               Because HCV has become an increasingly important cause of morbidity and mortality among HIV-positive people, consideration of therapy for HIV – HCV co-infected individuals is required in all HCV co-infected individuals. Unfortunately, there are as yet no large controlled studies of HCV therapy in the HIV co-infected population. Prospective studies are currently underway to address this issue, however, small studies of interferon (IFN) monotherapy found that HIV-HCV co-infected people with preserved CD4 counts responded to IFN approximately at the same rate as HIV-negative patients (44,61,203-206), and thus the treatment of HCV in HIV positive patients is generally based on the standard recommendations for the HIV negative individual.

               Current treatment options for HCV are limited to IFN-based regimens combined with ribavirin, however, these are increasingly effective. Prior to consideration of therapy, it is important to first determine if the patient is a candidate for HCV therapy. Two important questions need to be addressed. First, does the patient have contraindications to IFN therapy? Secondly, does the prognosis of the patient's HIV infection preclude the use of a potentially toxic, expensive, and prolonged (minimum of 6 month, up to 18 month) therapy requiring subcutaneous injections. This consideration must take into account that the predicted median time for the development of cirrhosis to develop in a large study of HCV infected individuals was 30 years (207), and 31% of patients were predicted to never progress, or not progress for 50 years. Since therapy is not without significant toxicity, it is important to clearly determine both the presence of active infection, and the extent of current liver disease before recommending therapy.

               To determine if the HCV antibody positive person has active viremia, plasma should be tested for the presence of HCV RNA. Performance of a quantitative assay is the approach used at some institutions, and specification should be made that the absolute value of HCV RNA needs to be determined. Since the dynamic range of many HCV RNA testing methods is limited, many laboratories report HCV RNA values only up to the upper limits of normal for their method, which is often 1 million genome equivalents per ml (or IU/ml). While this appears high to practitioners used to HIV RNA values, HCV RNA levels are generally 10- to 100-fold higher than that seen for HIV. If the quantitative HCV RNA test is negative, it should be repeated using the most sensitive qualitative test available. However, since more than 80% of HCV antibody positive people have HCV RNA in plasma, and HCV RNA levels are generally quite high, very few people who have a negative quantitative HCV RNA will have a positive HCV qualitative RNA test result. If the patient does not have detectable HCV RNA (expected to occur in approximately 15% to 20% of individuals), no further evaluation for HCV therapy is indicated. However, if HCV RNA is present, a number of additional studies are required.

               Unlike HIV, where the plasma RNA concentration and CD4 count provide useful prognostic information regarding the likelihood of progression of HIV disease, HCV RNA level and serum transaminase levels do not allow prediction of who has, or will develop progressive liver disease. A number of clinical findings and studies can identify portal hypertension (see above); however, there are no non-invasive tests that accurately predict the extent of liver disease in people who do not have advanced liver disease with portal hypertension. Furthermore, non-invasive tests do not provide information predicting the likelihood that an individual with HCV infection will progress to cirrhosis. Among HIV-negative individuals without cirrhosis on liver biopsy, the degree of fibrosis present predicts the likelihood of developing cirrhosis during prospective follow up (208,209). Consequently, liver biopsy is required as part of the evaluation of individuals who have HCV viremia in order to determine the extent of active inflammation and fibrosis. One study found that the rate of progression of fibrosis was more rapid rate among HIV-positive HCV infected people compared to an HIV-negative, HCV positive control (65), however, more information is needed to verify these findings. It appears that HCV related liver disease occurs more frequently in HIV-positive people (58,59,62,64,205,210), and this should be taken into account when evaluating a patient for consideration of HCV treatment. It is also important to remember that the key finding on liver biopsy predicting future progression of liver disease is the extent of fibrosis (see above for description of METAVIR and Knodell scoring systems).

               Additional factors besides the degree of fibrosis on biopsy that appear to increase the rate of progression of liver disease include male gender, alcohol consumption and older age at the time of infection (198), and as noted previously, HIV infection (65). All of these factors need to be considered when considering antiviral therapy for HCV infection, however, the extent of fibrosis on liver biopsy is the prime finding that should lead to a recommendation of therapy. A recent study found that 18% of HCV-infected people with normal serum ALT levels who underwent liver biopsy had evidence for advanced histologic damage of the liver (211). The population studied was biased, as 60% of those biopsied with abnormal ALT values had similar histologic findings, nevertheless, these data support the role of liver biopsy in all people with active HCV infection (211).

Specific Treatment Approach for Hepatitis C: HCV therapy is evaluated by measuring the response in ALT (biochemical response), HCV viral load (virologic response) and histology response. Typically, it is crucial to monitor response to therapy at three time points. If the viral load has not been lowered to nondetectable levels within 3 months of initiation of therapy, it is unlikely that the standard combination therapy regimen will be effective. In this case, therapy should either be discontinued, or changed to an experimental protocol. If the HCV viral load is nondetectable at 3 months, therapy should be continued. If the ALT has normalized on therapy, but the HCV RNA remains detectable, it is less clear whether to stop therapy or not, however, the likelihood of relapse is high in this group of patients, and experimental protocols should be considered. The HCV viral load should be checked at the end of treatment, and again 6 months following completion of treatment. Individuals who have non-detectable HCV RNA 6 months following discontinuation of therapy are said to be "sustained responders". Sustained responders are felt to be cured of HCV, as more than 95% of individuals with an SR remain free of HCV RNA in plasma and liver biopsy specimens 5 years after discontinuing HCV therapy (212,213). Unfortunately, a high percentage of people who become HCV RNA negative at the end of treatment will relapse 6 months after discontinuing therapy, especially among those with genotype 1. These individuals are considered to be responders who relapse.

               Considerable data on therapy of HCV in HIV-negative people has accumulated, and current therapy now consists of administration of a combination of interferon and ribavirin (214-216) (see below). Although there are limited data using this combination in HIV-positive individuals, this is rapidly becoming the standard of HCV treatment care in the HIV-positive population as well. The duration of therapy depends upon the HCV genotype, as genotypes 2 and 3 respond much more favorably to IFN than does genotype 1, and shorter courses of therapy are required for these favorable genotypes. Unfortunately, genotype 1 predominates in the United States, and approximately 75% of U.S. HCV infections are due to genotype 1 (217). Additional factors associated with a favorable response include a "low" HCV RNA concentration (< 2,000,000 genome equivalents per ml plasma, female gender, lesser degree of fibrosis on liver biopsy, higher LDL cholesterol levels, and age < 40 years (214,218,219).

               In 1997 the National Institutes of Health convened an international panel of experts to develop guidelines for treating HCV infection (212). The NIH Consensus development committee, based on available evidence at the time, recommended that IFN therapy is indicated for chronic HCV infection in people between 18 and 60 years of age who have persistently elevated ALT (for more than 6 months), positive HCV RNA tests, a liver biopsy with portal or bridging fibrosis (at least moderate fibrosis) and a moderate degree of inflammation and necrosis. The consensus panel felt that IFN therapy was not indicated for patients with decompensated cirrhosis, mild disease, or people with persistently normal ALT levels. For individuals younger than 18, older than 60, or those with compensated cirrhosis, mild histologic disease or acute hepatitis, the panel felt that the indication for IFN was not clear. The dose recommended was IFN, 3 million units (MU) three times weekly (TIW) for 12 months (212).

               Since the consensus panel recommendations were published, considerable data have surfaced describing improved rates of SR in individuals receiving combination therapy with IFN and ribavirin (RBV). Approximately twice as many individuals had an end-of-treatment response and sustained response with combination therapy for 48 weeks when compared to IFN monotherapy (214,218,220,221). There are many different commercially available preparations of interferons that have been evaluated in HCV studies, including IFN alpha-2b (Intron A, Schering-Plough), INF alpha-2a (Roferon-A, Hoffmann-LaRoche), IFN alpha-n1 (Wellferon, Glaxo Wellcome), consensus interferon (Infergen, Amgen). The NIH consensus panel felt that all forms of interferon appear to have similar efficacy in chronic hepatitis C (212). Currently, ribavirin is only FDA approved and packaged in combination with IFN alpha-2b, however, this will probably not be an issue in the future. Finally, newer formulations of interferon have been developed, and pegylated interferon at high doses and combined with ribavirin appear to have higher rates of sustained response than standard doses of IFN plus ribavivin (215). Another advantage of pegylated interferon is that the polyethylene glycol modification of IFN leads to more constant blood levels, and reduces the number of injections required to one per week (215). Table 5 illustrates data on treatment response rates for IFN monotherapy, IFN plus ribavirin, and pegylated IFN plus ribavirin.

               As mentioned, IFN has significant side effects, with more than 60% of recipients reporting at least one adverse event. One of the most serious side effects of IFN therapy is depression and neuropyschiatric symptoms including irritability, anxiety and lability. Depression occurs in up to 37% of IFN recipients, and anxiety in up to 34% (222-224). In addition, IFN causes patients to fell as though they have the "flu", with nasal congestion, sore throat, cough, rigors, myalgias, headaches, and fatigue. Up to 46% of recipients complain of "flu-like" illness during receipt of IFN (215). Additional side effects include anorexia, insomnia, difficulty concentrating, thrombocytopenia, neutropenia, pruritus, skin rash shortness of breath, and alopecia (225). IFN has also been associated with the development of hypothyroidism, and a baseline TSH should be obtained, and periodically followed. Ribavirin is also associated with depression, and may cause psychosis, disorientation, or suicidal ideation and attempts (222). Additional side effects include hemolytic anemia, pruritus, shortness of breath, skin rash, autoimmune disease, vision or hearing loss, tinnitus, seizures, and acute renal or heart failure. Ribavirin has been associated with fetal loss and fetal abnormalities, and thus it is imperative that recipients (male and female) should use adequate birth control while receiving ribavirin and for 6 months afterwards. Most of these side effects can be managed with counseling, dose reduction, and support therapies (G-CSF for neutropenia and erythropoetin for anemia).

               Absolute contraindications to IFN include present or past psychosis or severe depression, severe neutropenia not responding to supportive G-CSF, severe thrombocytopenia, organ transplantation (except liver transplantation), symptomatic heart disease, decompensated cirrhosis and uncontrolled seizures. Poorly controlled diabetes and autoimmune disorders are relative contraindications for IFN therapy. Patients with end-stage renal disease should not receive ribavirin, nor should people with severe heart disease, pregnancy, or those who cannot use a reliable method of contraception. People with anemia or hemoglobinopathies must be carefully monitored and supported.

               Current dosing schedules for IFN, pegylated IFN, and ribavirin are shown in Table 5. An algorithm for the treatment of patients with chronic HCV is shown in figure 5. A variety of questions remain regarding treating HCV in HIV positive patients. For example: Do people with lower CD4 counts respond to HCV therapy? What is the optimal dosing schedule and duration of therapy in HIV-HCV co-infected individuals? How should nonresponders or people who relapse after a good end of treatment response be managed? Are there different response rates between different racial or ethnic groups? Should people with acute HCV infection receive therapy? Should people with HCV infection and normal ALT values receive therapy? While there are some data to provide some guidance to these questions in the HIV-negative patient, these issues have not been addressed in patients with HIV and HCV infection.

               One additional question that remains unanswered, but is relevant to the HIV-HCV co-infected patient, is when to start anti-HIV therapy in relationship to starting anti-HCV therapy? The NIH consensus guidelines recommend treating the HIV infection first (212), however, the change in approach to HIV therapy has resulted in the identification of HCV infection in increasing numbers of people for whom HIV therapy is not normally recommended. Because HCV tends to be a more slowly progressive disease than HIV, most clinicians start HIV therapy first if it is indicated, and treat HCV after the patient is stable on the HIV regimen. An exception to this is the situation where a patient is unable to tolerate any HIV treatment regimen, and this intolerance is thought to potentially relate to their underlying HCV-related liver disease. In this situation, some experts have recommended starting HCV therapy for 1 to 3 months, followed by the institution of HIV therapy.

               In conclusion, HCV therapy is similar in many ways to HIV therapy, except that fewer than 50% of the recipients of HCV therapy will have the desired therapeutic outcome. HCV therapy decisions are complex and fraught with considerable risks and benefits that are not immediately apparent to inexperienced practitioners. It is imperative that patients are counseled about their risk of progressive liver disease, the risk of medication side effects, and the potential benefits, or lack of benefits of current anti-HCV therapy. An additional issue in HIV-HCV co-infected people relates to the potential interactions of anti-HCV therapy with ART. Patients need to understand how their virologic status (HCV RNA level and genotype) and histologic status (stage and grade) affect the expected results of treatment. This requires extensive counseling and education of the patient regarding published data. The studies should be presented in a manner that provides information about the viral and host prognostic factors of the study population, known side effects of the medications, HCV natural history data, and current guidelines for treatment, before the patient can truly make an informed decision about HCV therapy.

Deresinski S. Hepatitis C Virus (HCV)-HIV Coinfection: 2b or Not 2b? Clin Infect Dis 2009;48:v-vi.

Schulze Zur Wiesch J, et al. Sustained Virological Response after Early Antiviral Treatment of Acute Hepatitis C Virus and HIV Coinfection. Clin Infect Dis 2009;49:466–472.

Treatment of Hepatitis B

               The goal of treating chronic HBV infection is to stop the progression of liver injury, either by suppressing viral replication or eliminating infection. Since chronically HBV-infected people have minimal progression of liver injury if the HBV DNA level is negative, despite persistence of HbsAg, patients with HBV DNA are most in need of therapy. Thus, indications for therapy include evidence of ongoing viral replication, measured either by the presence of HBeAg or HBV DNA for at least 6 months, persistent elevation of ALT levels, and evidence of chronic HBV on liver biopsy (216,226). Unlike HCV, liver disease will progress in most people with evidence of active HBV replication, thus the liver biopsy is not absolutely necessary, however, biopsy is useful in identifying evidence of other causes of liver disease, and if early (compensated) cirrhosis is identified, additional studies and considerations are warranted.

               IFNα-2b was approved by the FDA for use in chronic HBV infection in 1992. The recommended dosage is higher than that for HCV (5 MU SQ daily or 10 MU SQ TIW). Approximately 35% of IFN-treated patients will lose their markers of HBV replication (HbeAg and HBV DNA) (216,226,227), and several studies have shown that "priming" patients with prednisone prior to IFN does not increase the efficacy of therapy (228,229). Factors that predict a favorable response of HBV to IFN therapy include low pretreatment levels of HBV DNA (< 200 pg/ml), high serum ALT (> 100 U/L), and evidence of active inflammation in the liver (216,226). HBV clearance appears to occur more frequently in patients who are not immunosuppressed, female, have had a short duration of HBV infection, are HBeAg-positive, have horizontal rather than perinatal acquisition of the virus. Patient who do not meet these criteria have IFN response rates of < 5% (216).

               Although HBV is a DNA-containing virus, it replicates using an RNA intermediate that serves as the template for the HBV RNA dependent, DNA polymerase (reverse transcriptase or RT). Due to the similarity between the HBV RT and the HIV RT, anti-HIV medications were evaluated for evidence of activity against the HBV polymerase. Lamivudine (Epivir®, GlaxoSmithKline) was found to lower HBV replication by approximately 1,000- to 10,000-fold in most patients (226). Subsequent clinical studies in HBeAg-positive subjects resulted in the clearance of eAg in 16 to 33% of recipients (100 mg/d for 1 year) and to a histologic improvement in the HAI by > 2 points in up to 55% of recipients (230-233). Factors predicting response to lamivudine are similar to those for interferon (HbeAg positivity, elevated ALT, and low initial HBV-DNA levels). Hepatic fibrosis was also shown to decrease in lamivudine recipients regardless of their HbeAg response (230,233-235). Patients who achieve HBeAg seroconversion or lose their HBeAg by week 52 appear to maintain this response for at least 6 months, thus it is reasonable to continue lamivudine until seroconversion is documented in immunocompetent individuals. In HIV-HBV co-infected patients, lamivudine should be continued as part of the HIV regimen, even after documentation of HIV resistance to lamivudine, however, the HIV regimen should contain three active drugs in addition to the lamivudine. Following discontinuation of lamivudine, a flare in ALT is frequently seen. In addition, patients with mutant strains of HBV ("precore" mutants) can not be treated with IFN, however, lamivudine is capable of suppressing HBV replication in many of these patients (236). Resistance to lamivudine involves mutation at the YMDD domain of the viral polymerase, which frequently develop after 6 months or more of therapy (234,237,238). However, lamivudine-resistant HBV does not appear to replicate as well as wild type virus, thus lamivudine should theoretically be continued in HIV-positive people with HBV infection. There are three published studies of combination interferon and lamivudine (232,233,239). These three trials provide little support for the use of interferon-lamivudine combination therapy instead of lamivudine monotherapy. If there is any benefit, it is additive and not synergistic. Studies are being considered which would combine multiple nucleoside (or nucleotide) analogs or a single nucleoside/tide drug with immunomodulator therapy such as thymosin and/or using pegylated interferons. Famciclovir is the prodrug of penciclovir, an acyclic guanine derivative that also inhibits HBV DNA polymerase. Unfortunately, famciclovir appears to suppress HBV less rapidly and to a lesser extent than lamivudine, and lamivudine resistant HBV are not susceptible to famciclovir, consequently, this drug has not emerged as an attractive alternative to lamivudine (226).

               Adefovir dipivoxil is an adenine nucleotide analogue with broad-spectrum activity that has shown a good antiviral effect on HBV in several clinical trials (240-242). Although it also has good anti-HIV activity, it was shown to cause renal injury in patients treated with doses of > 30 mg per day or higher. Studies of adefovir in chronic HBV infection are underway to determine the safety and efficacy of lower doses. One advantage of adefovir is that lamivudine-resistant strains are generally susceptible to adefovir (241). Another nucleotide analog, tenofovir, presumably has anti-HBV activity, and appears to have considerably less renal toxicity. Studies to determine the activity of tenofovir (Viread®, Gilead Sciences) against HBV are underway.

               Figure 6 provides an algorithm for an approach to therapy of chronic HBV infection. Lamivudine should be strongly considered in all HBV infected patients with evidence of active replication. In select patients with low levels of HBV DNA and markedly elevated ALT, IFN therapy should be considered. Clearly, resistance to lamivudine will develop following long-term administration; however, due to a decrease in viral fitness, lamivudine should be continued in these subjects. The role of other drugs (adefovir, tenofovir) is unclear at present, but the availability of additional therapeutic options for HBV, with apparent activity against lamivudine-resistant strains, offers promise for improved therapy in the future.

               Therapy for biliary tract disease requires diagnosis of the cause of the process, and either specific antimicrobial therapy for the offending pathogen, or relief of the biliary obstruction. Relief of obstruction will frequently require an invasive procedure, usually ERCP (with sphincterotomy or stent placement), and in some instances surgical intervention is required.

               Most patients with acute pancreatitis (85% to 90%) resolve spontaneously with supportive medical care focused on analgesia, "resting" the pancreas to minimize pancreatic inflammation (NPO and nasogastric suction), maintenance of normal intravascular volume, frequent monitoring of vital signs and treatment of complications (184). Demerol (50mg to 100 mg q 4-6 hrs, IM or IV) is better tolerated than morphine sulfate, which may induce spasm of the sphincter of Oddi. No drugs have been shown to improve the course of acute pancreatitis, and prophylactic antibiotics are not recommended, but should be reserved for patients with established infection. Nutritional support must be maintained, and patients with fulminant pancreatitis need intensive monitoring and therapy. It is important to closely monitor calcium and magnesium levels, and prompt replacement of deficiencies is imperative.

Acknowledgments

I would like to thank Stephanie O'Conner for assistance with the preparation of the manuscript. This work was supported by a Merit Review grant of the Veterans Administration and by a grant from the National Institutes of Health (AA-12671).

Tables and Figures

Table 1.  Infectious Causes of Hepatitis in HIV-Positive People [Download PDF]

Table 2.  Potentially Hepatotoxic Medications Commonly Used to Treat Complications of HIV Infection. [Download PDF]

Table 3.  Potentially Hepatotoxic Medications Commonly used to Treat HIV  [Download PDF]

Table 4.  Testing and Immunization for Hepatitis A and Hepatitis B in HIV-Positive Adults And Adolescents.

Table 5.  Summary of Current Approved Treatment Options For Hepatitis B and Hepatitis C:  Dosing, Response and Adverse Effect Information. [Download PDF]

Figure 1.  HBV serology

Figure 2.  Approach to HCV diagnosis including laboratory testing schemes

Figure 3.  Algorithm of approach to asymptomatic patient with hepatocellular abnormalities on LFT's

Figure 4.  Algorithm of approach to asymptomatic patient with cholestatic abnormalities on LFT's

Figure 5.  Algorithm for the therapy of HCV infection

Figure 6.  Algorithm for the therapy of HBV infection.

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