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Hepatitis C Virus Infection
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Epidemiology

Hepatitis C virus (HCV) is a single-stranded RNA virus that is most efficiently spread through direct blood exposure to contaminated blood or blood products. Both HIV and HCV can be transmitted by percutaneous exposure to blood, through sexual intercourse, and from a mother to her infant. However, the relative efficiency of transmission by these routes varies. HCV is approximately 10 times more infectious than HIV through percutaneous blood exposures, but sexual transmission of HCV is inefficient compared with HIV. Transmission of HIV and HCV through contaminated blood products is now rare because of effective screening of blood and blood-derived products in the United States.

Heterosexual transmission of HCV is uncommon but more likely occurs in persons with partners who are coinfected with HIV and HCV. Likewise, existing data suggest that sexual contact is a relatively inefficient mode of HCV transmission between MSM, but sexual HCV transmission has been increasingly reported among sex networks of HIV-infected men, particularly those engaged in high-risk sex practices. Cases of acute HCV infection are increasingly recognized and reported in this patient population (1088Gotz HM, van Doornum G, Niesters HG, et al. A cluster of acute hepatitis C virus infection among men who have sex with menresults from contact tracing and public health implications. AIDS 2005;19:969-74.).

HCV infection occurs in approximately 2%-5% of infants born to HCV-seropositive mothers. In a majority of studies, the incidence of HCV transmission from mother to infant increases if the mother is coinfected with HIV (1089Polis CB, Shah SN, Johnson KE, Gupta A. Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis 2007;44:1123-31., 1091Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003;124:97-104.). Overall, rates of HCV vertical and perinatal transmission are relatively low, although increased in the setting of HIV coinfection (1029Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880-9., 1092Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006;44(Suppl 1):6-9.).

In the United States, HIV/HCV coinfection is most prevalent in persons who have a history of hemophilia or injection- drug use, in whom HCV infection rates approach 70%-95% compared with 1%-20% in those who acquired HIV through sex (1092Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006;44(Suppl 1):6-9., 1093Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002;288:199-206.). Although studies have suggested that sexual transmission of HCV is inefficient, the exact risk related to different types of sexual activity is unknown. Risk factors for the sexual transmission of HCV include anal-receptive intercourse and concurrent sexually transmitted infection.

Cirrhosis develops in approximately 20% of persons with chronic HCV infection within 20 years after acute infection, although the range and time to development of cirrhosis varies widely. Risk factors for the development of substantial liver disease are older age at the time of infection, male sex, concomitant alcohol use (>20-50 g/day), and advanced immunosupression (CD4+ count of ≤200 cells/µL) (1094Brau N, Salvatore M, Ros-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol 2006;44:47-55., 1096Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-32., 1096Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-32.). Compared with HCV monoinfection, the natural history of HCV infection is accelerated in the setting of HIV (1097Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001;33:562-9.), with more rapid progression to cirrhosis, decompensated liver disease, hepatocellular carcinoma (HCC), and death (1098Merchante N, Girn-Gonzlez JA, Gonzlez-Serrano M, et al. Survival and prognostic factors of HIV-infected patients with HCV-related end-stage liver disease. AIDS 2006;20:49-57.). Because of its high prevalence and rapid progression, liver disease caused by chronic HCV is a leading cause of death among persons with HIV (997Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol 2005;42:799-805., 999Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166:1632-41.). Reports of the effect of immune restoration with ART on liver-related mortality are conflicting, with some studies reporting decreases and others little change in the rate of liver-related mortality (1099Mehta SH, Thomas DL, Torbenson M, et al. The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection. Hepatology 2005;41:123-31., 1100Qurishi N, Kreuzberg C, Lchters G, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 2004;362:1708-13.). In addition to liver disease, HCV infection might be associated with changes in cognitive and psychiatric function (1101Ryan EL, Morgello S, Isaacs K, Naseer M, Gerits P. Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology 2004;62:957-62.), decreased quality of life (1102Fleming CA, Christiansen D, Nunes D, et al. Health-related quality of life of patients with HIV disease: impact of hepatitis C coinfection. Clin Infect Dis 2004;38:572-8.), and increased prevalence of diabetes mellitus (1103Mehta SH, Moore RD, Thomas DL, Chaisson RE, Sulkowski MS. The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. J Acquir Immune Defic Syndr 2003;33:577-84.), all of which potentially affect HIV management.

The effect of HCV infection on HIV disease progression and immune reconstitution is uncertain (1093Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002;288:199-206., 1104Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000;356:1800-5., 1105Chung RT, Evans SR, Yang Y, et al. Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects. AIDS 2002;16:1915-23.), although not likely to be clinically relevant based on current observations (1106Sullivan PS, Hanson DL, Teshale EH, Wotring LL, Brooks JT. Effect of hepatitis C infection on progression of HIV disease and early response to initial antiretroviral therapy. AIDS 2006;20:1171-9.). Patients with underlying viral hepatitis are at increased risk for progression to ARV-related hepatotoxicity (1068Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000;283:74-80.), although most coinfected patients (approximately 90%) do not have severe hepatotoxicity. The risk for ART-associated hepatotoxicity might be related to the underlying degree of liver fibrosis (1107Aranzabal L, Casado JL, Moya J, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2005;40:588-93.).

Clinical Manifestations

Both acute and chronic HCV infections are typically minimally symptomatic or asymptomatic. Fewer than 20% of patients with acute infection have symptoms characteristic of acute hepatitis, including low-grade fever, mild right upper quadrant pain, nausea, vomiting, anorexia, dark urine, and jaundice. Unexplained elevations of serum ALT or AST levels might be the only laboratory finding during acute infection. Recognition of acute HCV infection is important because antiviral treatment targeting HCV initiated during this period is associated with higher response rates (1108Jaeckel E, Cornberg M, Wedemayer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345(2):1452-7., 1109Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-8.).

Chronic hepatitis C infection is often asymptomatic, although complaints of fatigue are common. Serum cryoglobulins might be present but rarely (<5%) cause symptomatic skin (vasculitis), renal (membranoproliferative glomerulonephritis), or neurologic manifestations. HCV-infected patients might experience cutaneous manifestations, including porphyria cutanea tarda. The rate of these manifestations in the setting of HIV is unknown. With progression of liver disease, patients might experience stigmata of cirrhosis with portal hypertension and ESLD, including spider angiomata, palmar erythema, splenomegaly, caput medusa, ascites, jaundice, pruritus, asterixis, and encephalopathy.

Diagnosis

HIV-infected patients should be tested routinely for evidence of chronic HCV infection. Initial testing for HCV should be performed using the most sensitive immunoassays licensed for detection of antibody to HCV (anti-HCV) in blood (1110National Institutes of Health. Consensus development conference statement: management of hepatitis C: 2002-June 10-12, 2002. Hepatology 2002;36(Suppl 1):3-20.).

False-negative anti-HCV immunoassay results might occur among HIV-infected persons with advanced immunosuppression, but this is uncommon with the most sensitive immunoassays (third-generation assays) (1090Chamot E, Hirschel B, Wintsch J, et al. Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users. AIDS 1990;4:1275-7., 1111Thio CL, Nolt KR, Astemborski J, et al. Screening for hepatitis C virus in human immunodeficiency virus-infected individuals. J Clin Microbiol 2000;38:575-7.). If serologic test results are negative or indeterminate and HCV infection is suspected based on elevations of serum aminotransferases or risk factors such as injection-drug use, testing for HCV RNA should be performed (1112Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected patient. Clin Liver Dis 2003;7:179-94.). True-negative antibody tests might also occur early in the course of acute HCV, in which elevations in serum aminotransferases and detectable viremia are evident before seroconversion; therefore, HCV RNA testing also should be performed when acute HCV infection is suspected.

To confirm the presence of chronic infection, all HCV-seropositive persons should be tested for plasma HCV RNA using a qualitative or quantitative assay. Quantitative HCV RNA level (i.e., viral load) does not correlate with degree of liver damage and does not serve as a surrogate for measuring disease severity, but it does provide important prognostic information about the response to antiviral therapy. Serial quantitative HCV RNA testing should be limited to persons receiving HCV treatment. Diagnostic assays using reverse transcriptase-polymerase chain reaction (RT-PCR) or transcription-mediated amplification (TMA) have been approved by the FDA for qualitative detection of HCV RNA. A single positive HCV RNA result is sufficient to confirm the diagnosis of active HCV infection, but a single negative result cannot exclude viremia because RNA levels might transiently decline below the limit of detection in persons with active infection, especially during the acute phase of infection. A repeat qualitative assay can be performed to confirm the absence of active infection.

Quantitative tests for HCV RNA include quantitative RT-PCR or branched DNA (bDNA) signal amplification assays. Newer real-time PCR assays have excellent sensitivity with lower limits of detection similar to qualitative assays and a broad dynamic range (e.g., COBAS TaqMan HCV Test; Roche Molecular Systems Inc., Branchburg, NJ). An HCV RNA standard has been established that permits normalization of viral titers in international units (IUs); nonetheless, substantial variability exists among available assays, and if serial values are required to monitor antiviral therapy, continued use of the same quantitative assay for all assessments is strongly recommended.

Six distinct HCV genotypes have been described (1113Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.). Genotype 1 infection accounts for approximately 75% of all HCV infections in the United States and approximately 90% of infections among blacks (1114Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705-14.). In HCV-monoinfected patients, genotype information is used to guide both the duration of treatment and the dosing of RBV. In contrast, in persons with coinfection, only the dosing of RBV is genotype specific. HCV genotyping should be performed in all HIV-infected persons considering HCV treatment to guide RBV dosing and because it is the best predictor of response to IFN-based treatment and might, therefore, influence the decision to treat and/or perform liver biopsy. Repeat HCV genotype testing is not indicated.

Baseline and periodic monitoring of serum ALT and AST levels should be performed. Levels often fluctuate among patients with chronic HCV infection, regardless of HIV infection, and long periods during which these values are normal might be observed. Although higher serum ALT and AST levels are, to some degree, predictive of more rapid disease progression, (1091Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003;124:97-104.) substantial liver disease might be present even in the presence of persistently normal ALT levels.

Computed tomography (CT), MRI, and ultrasonography have limited utility in staging liver disease because they are often abnormal only in advanced disease. Ultrasonography is recommended as the initial test for evaluation of persons with liver cirrhosis for the detection of hepatic mass lesions suspicious for HCC. Because of cost, the use of bi- or triphasic CT with contrast or MRI scanning should typically be limited to evaluation of hepatic mass lesions in patients with cirrhosis.

Liver biopsy remains the preferred test for evaluation of HCV-related disease (fibrosis) stage and is useful to assess prognosis and guide treatment decisions. Although ultrasound guidance reduces the risk (1115Lindor KD, Bru C, Jorgensen RA, et al. The role of ultrasonography and automatic-needle biopsy in outpatient percutaneous liver biopsy. Hepatology 1996;23:1079-83.), liver biopsies might result in major complications, including excessive bleeding (<0.5%), bile peritonitis (0.09%), and, rarely, internal organ injury, although the overall mortality rate is <1 in 10,000 (978Van Thiel DH, Gavaler JS, Wright H, Tzakis A. Liver biopsy: its safety and complications as seen at a liver transplant center. Transplantation 1993;55:1087-90., 979Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495-500.). Further, disease staging by biopsy is expensive and subject to sampling error because of the heterogeneity of hepatic fibrosis. In some studies, disease progression has been observed during short periods in persons with minimal fibrosis. Therefore, although liver biopsy is helpful in the evaluation of coinfected persons, it is not required before the initiation of therapy for HCV infection, particularly in patients with a high probability of responding to treatment.

Noninvasive testing strategies to evaluate liver fibrosis are an area of active research. Several tests are available that can reliably separate patients with minimal fibrosis from those with cirrhosis, but these tests fail to distinguish intermediate stages of fibrotic disease (1116Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317-25., 1117Wilson LE, Torbenson M, Astemborski J, et al. Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology 2006;43:788-95., 1118Myers RP, Benhamou Y, Imbert-Bismut F, et al. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients. AIDS 2003;17:721-5., 1119Nunes D, Fleming C, Offner G, et al. HIV infection does not affect the performance of noninvasive markers of fibrosis for the diagnosis of hepatitis C virus-related liver disease. J Acquir Immune Defic Syndr 2005;40:538-44.). Although some tests are proprietary commercial assays (e.g., HCV FibroSURE, Laboratory Corporation of America Holdings), others are based on laboratory tests that are routinely obtained in most HIV-infected persons (FIB-4: age, ALT, AST, and platelet count; APRI: AST-Platelet Ratio Index). Additional studies are evaluating liver stiffness using transient elastography as a surrogate for liver fibrosis (1120de Ledinghen V, Douvin C, Kettaneh A, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2006;41:175-9.). Prospective studies are ongoing to determine the test(s) with the best predictive value for disease progression.

Preventing Exposure

The primary route of HCV transmission among IDUs is drug injection via a syringe previously used by an infected person. An increased frequency of injection, a longer duration of injection-drug use, and cocaine use are additional factors that increase the potential for HCV transmission (1121Thomas DL, Vlahov D, Solomon L, et al. Correlates of hepatitis C virus infections among injection drug users. Medicine (Baltimore) 1995;74:212-20.). Strategies should be pursued to encourage IDUs to stop using injection drugs, preferably by entering a substance abuse treatment program (AII).

In addition to sharing syringes, other factors associated with injection, such as sharing drug solution containers, "cookers," filters, "cottons," and mixing water, also increase the likelihood of HCV transmission (1122Hagan H, Thiede H, Weiss N, et al. Sharing of drug preparation equipment as a risk factor for hepatitis C. Am J Public Health 2001;91:42-6.). If IDUs are unwilling or unable to discontinue the use of injection drugs, they should be advised not to share needles or drug preparation equipment to reduce the risk for transmission of HCV infection (BII). Access to sterile injection equipment can be facilitated through enrollment of IDUs in NEPs (1000Vlahov D, Junge B, Brookmeyer R, et al. Reductions in high-risk drug use behaviors among participants in the Baltimore needle exchange program. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:400-6., 1001Hagan H, Jarlais DC, Friedman SR, Purchase D, Alter MJ. Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma syringe exchange program. Am J Public Health 1995;85:1531-7., 1002Hagan H, McGough JP, Thiede H, et al. Syringe exchange and risk of infection with hepatitis B and C viruses. Am J Epidemiol 1999;149:203-13.).

Persons considering tattooing or body piercing should be informed of potential risks for acquiring HCV infection, which could be transmitted if equipment is not sterile or if proper infection-control procedures are not followed (AIII).

Although efficiency of sexual transmission of HCV is relatively low, safe-sex practices should be encouraged for all HIV-infected persons; barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens, including HCV (AII).

Preventing Disease

All HIV-infected persons should be screened for active HCV infection. HCV-seronegative persons with elevations in serum aminotransferase levels should be screened for acute infection with assays to detect HCV RNA.

Higher rates of viral clearance have been reported in HIV-infected and -uninfected persons treated with IFN-based therapy for acute HCV infection (1108Jaeckel E, Cornberg M, Wedemayer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345(2):1452-7., 1109Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-8.). On the basis of this information and in the absence of contraindications, acutely infected persons (<6 months from the time of HCV exposure) should be routinely offered treatment for HCV infection to prevent the development of chronic HCV infection (BII). The optimal time to initiate therapy for acute HCV is unknown but it might be as soon as 8-12 weeks after acquisition of the infection (1109Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-8.) (see Treatment Recommendations).

Chronically infected persons should be counseled about methods to prevent liver damage and HCV transmission, evaluated for chronic liver disease, and considered for treatment of HCV infection. All HIV/HCV-coinfected patients should be offered antiviral treatment to prevent development of HCV-related liver disease complications (AI). All HIV-infected patients with HCV coinfection should be advised to avoid or limit alcohol consumption (AII) because alcohol ingestion, particularly in quantities greater than 20-50 grams (approximately 2-5 drinks) per day, might accelerate the progression of liver disease (1123Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998;28:805-9.). Enrollment of active substance abusers into drug and/or alcohol treatment programs is strongly recommended. Persons with liver disease should limit ingestion of potentially hepatotoxic medications (e.g., acetaminophen <2 grams/day). Because iron overload might worsen liver disease, patients should avoid iron supplementation in the absence of documented iron deficiency.

Because of its increased morbidity, HIV-infected persons who are coinfected with HCV should be tested for previous or concurrent HBV infection. Despite evidence of decreased response to hepatitis B vaccine in immunosuppressed persons, those without previous HBV infection should be vaccinated. Likewise, because acute HAV infection is more likely to be fulminant in persons with underlying hepatitis, HAV-susceptible HIV-infected persons with risk factors for HAV infection should receive hepatitis A vaccination (AII). As with hepatitis B vaccination, the response to hepatitis A vaccination is reduced in those with CD4+ counts <200 cells/µL. Certain specialists recommend delaying hepatitis A vaccination until the CD4+ count is >200 cells/µL on ART (BIII). Antibody response should be assessed 1 month after vaccination; nonresponders should be revaccinated (BIII).

Among coinfected persons with cirrhosis, measures to identify and prevent complications of advanced liver disease are identical to those established in persons without HIV and should be performed routinely (BI). All patients with ascites should undergo paracentesis for analysis to verify that portal hypertension is the etiology and to exclude infection (ascites polymorphonuclear cell count >250 cells/mL) (1079Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology 2004;39:841-56.). Assessment of the serum-ascites albumin gradient (SAAG) is advisable; SAAG ≥1.1 mg/dL strongly suggests ascites secondary to portal hypertension. Management includes sodium restriction (>2 g/day) and diuretics to alleviate fluid retention. The recommended diuretic regimen is spironolactone alone or combined with furosemide (ratio of 40 mg furosemide: 100 mg spironolactone). Consideration should be given to primary prophylaxis against spontaneous bacterial peritonitis (SBP) through the administration of oral antibiotics such as norfloxacin (400 mg/day) or TMP-SMX (1 double-strength tablet/day) in those with an ascites total protein <1 grams/dL (1080Singh N, Gayowski T, Yu VL, Wagener MM. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med 1995;122:595-8.). Secondary antibiotic prophylaxis is recommended for all persons with a history of SBP (AI). Upper endoscopy should be performed in all persons with cirrhosis, particularly those with thrombocytopenia, at the time of diagnosis and then every 1-2 years to identify substantial varices (1124Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices. Gastroenterology 2004;126:1175-89.). For persons with varices, nonselective beta blockers (e.g., nadolol or propranolol) are the mainstay of both primary and secondary prevention of variceal hemorrhage; esophageal variceal ligation or banding is another preventive option, particularly for persons who cannot tolerate beta blockers. Hepatic encephalopathy, caused by the accumulation of unmetabolized ammonia and other false neurotransmitters absorbed from the gut in the setting of liver dysfunction, might be subtle in early stages (916Mas A. Hepatic encephalopathy: from pathophysiology to treatment. Digestion 2006;73(Suppl 1):86-93.). Preventive measures include restriction of animal dietary protein consumption and the use of nonabsorbable disaccharides (e.g., lactulose) and/or antibiotics (e.g., neomycin, rifaximin).

Patients with HCV-related cirrhosis are at increased risk for HCC (1081Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26(Suppl 1):34-38.). Whether there is additional risk in the setting of HIV infection is unclear (998Bruno R, Sacchi P, Filice C, Puoti M, Filice G. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis: an emerging issue. J Acquir Immune Defic Syndr 2002;30:535-6.). Although the optimal screening strategy to detect HCC is unknown, screening is recommended in patients with documented cirrhosis using hepatic ultrasound imaging performed at 6-12-month intervals (BIII) (1082Gebo KA, Chander G, Jenckes MW, et al. Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review. Hepatology 2002;36(Suppl 1):584-92.). The utility of serum AFP for HCC screening in persons with HIV is unknown. Because of relatively poor specificity and sensitivity, results of AFP testing should be confirmed with liver imaging studies. In the absence of contraindications, HIV/HCV-coinfected persons with decompensated liver disease and/or early HCC might be candidates for orthotopic liver transplantation because HIV infection is not a contraindication to organ transplantation with the use of effective ART (1083Miro JM, Laguno M, Moreno A, Rimola A. Management of end stage liver disease (ESLD): what is the current role of orthotopic liver transplantation (OLT)? J Hepatol 2006;44(Suppl 1):140-5.). Persons with cirrhosis should undergo periodic assessment of their liver disease status through the application of validated prognostic models (e.g., Model for End-Stage Liver Disease [MELD] score) that predict mortality risk and are used to determine the medical need for liver transplantation (1084). Where feasible, HIV/HCV-coinfected persons with well-controlled HIV infection found to have liver decompensation (defined as Child-Pugh-Turcotte score ≥7 and/or MELD score >10) or evidence of early HCC should be referred for orthotopic liver transplantation (BIII).

Treatment of Disease

Antiviral treatment for HCV infection should be considered for all HIV-infected persons with acute or chronic HCV infection (AI). In the absence of contraindications to pegIFN or RBV, treatment for HCV infection should be offered routinely to persons in whom the potential benefits of therapy are judged to outweigh the potential risks, including (but not limited to) persons with the following conditions (BII):

  • HCV genotype 2 or 3 infection
  • HCV genotype 1 infection with a low HCV RNA level (<800,000 IU/mL) (although certain specialists might not recommend treatment of patients with HCV genotype 1 infection and low or intermittently undetectable HCV RNA, response to pegIFN plus RBV is improved in those with HCV RNA levels <800,000 IU/mL compared with those with levels above this threshold, which might favor treatment in this group)
  • Significant hepatic fibrosis (bridging fibrosis or cirrhosis)
  • Stable HIV infection not requiring ART
  • Acute HCV infection (<6 months' duration)
  • Cryoglobulinemic vasculitis
  • Cryoglobulinemic membranoproliferative glomerulonephritis
  • Strong motivation to treat their HCV infection

The goals of therapy include eradication of HCV infection; prevention of hepatic fibrosis progression; and, among persons with HCV-related cirrhosis, prevention of ESLD, HCC, and death. Although viral eradication is not anticipated in most treated persons, histologic and clinical benefits of therapy have been observed in the absence of virologic response (1125Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-9.).

On the basis of well-designed, randomized, controlled trials, pegIFN plus RBV is the recommended treatment for hepatitis C in HIV-infected persons (AI). Sustained virologic response (SVR) rates range from 14%-29% for HCV genotype 1 infection and 43%-73% for HCV genotypes 2 and 3 infection (1036Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-50., 1125Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-9., 1126Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004;18:F27-36., 1127Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004;292:2839-48.). Whereas fixed-dose RBV (800 mg/day) is recommended for HIV-infected persons with genotype 2 or 3 disease, the appropriate RBV dose for persons with genotype 1 disease has not been determined because the pivotal trials studied only fixed-dose RBV. Among HIV seronegative persons with genotype 1, pegIFN plus weight-based RBV (1,000 mg/day for persons weighing <75 kg; 1,200 mg for persons weighing ≥75 kg) was more effective than fixed-dose RBV (1128Hadziyannis SJ, Sette HJ, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55.). Although the efficacy of weight-based RBV has not yet been established in coinfected persons, several studies indicate that this strategy is not associated with increased risk for adverse effects (e.g., anemia). Accordingly, certain specialists recommend the use of weight-based RBV combined with pegIFN in HIV-infected persons with HCV genotype 1 disease (AII).

For HCV genotypes 1,4,5, or 6, the recommended treatment regimen is either pegIFN alfa-2a (180 mcg) or pegIFN alfa-2b (1.5 mcg/kg) administered by subcutaneous injection weekly plus oral RBV twice daily (<75 kg or 165 lbs body weight, 600 mg each morning and 400 mg each evening; ≥75 kg or 165 lbs body weight, 600 mg twice daily) for a total duration of 48 weeks (AI). For HCV genotype 2 or 3, the recommended treatment is either pegIFN alfa-2a (180 mcg) or pegIFN alfa-2b (1.5 mg/kg) administered by subcutaneous injection weekly plus oral RBV in a fixed dose of 400 mg twice daily for a total duration of 48 weeks (AI).

The optimal treatment regimen and duration of treatment for acute HCV in coinfected patients has not been determined. Among HIV-seronegative persons, regimens including pegIFN with or without RBV in dosing schedules described above have been administered for 24 weeks' duration with good results. Therefore, in the absence of better information, HIV-infected persons with acute HCV infection should be treated with one of the previously recommended regimens for ≥24 weeks' duration (BIII). Because the efficacy of shorter treatment duration has not been adequately evaluated in HIV-infected persons with acute or chronic HCV infection, the recommended duration of treatment is 48 weeks for chronic infection with all HCV genotypes, including 2 and 3 (BII); on the basis of this information, certain specialists would also treat HIV-infected patients with acute HCV infection for a total duration of 48 weeks.

Treatment for HCV infection with pegIFN plus RBV should NOT be routinely administered to persons in whom the potential risks of therapy are judged to outweigh the potential benefits including (but not limited to) persons with the following conditions (DII):

  • Pregnancy, or who are not willing to use birth control;
  • Advanced HIV-associated immunosuppression uncontrolled on ART;
  • Hepatic decompensation (e.g., coagulopathy, hyperbilirubinemia, encephalopathy, ascites) because liver transplantation, where feasible, should be the primary treatment option for such patients (CIII);
  • Severe, uncontrolled comorbid medical conditions (e.g., cancer or cardiopulmonary disease);
  • Severe, active depression with suicidal ideation, although HCV treatment may be considered after the successful implementation of psychiatric care and treatment for depression;
  • Significant hematologic abnormality (e.g., hemoglobin <10.5 g/dL, absolute neutrophil count <1,000/µL, platelet count <50,000/µL), although HCV treatment may be considered after the correction of hematologic abnormalities (e.g., treatment of underlying causative conditions and/or use of hematopoietic growth factors);
  • Renal insufficiency (creatinine >1.5 or creatinine clearance <50 cc/min), although in such persons, treatment with pegIFN alone may be considered;
  • Sarcoidosis because of increased risk for severe disease exacerbation with IFN therapy;
  • Active, uncontrolled autoimmune conditions (e.g., systemic lupus erythematosus [SLE] or rheumatoid arthritis) because of increased risk for severe disease exacerbation with IFN therapy.

Patients with contraindications to the use of RBV (e.g., unstable cardiopulmonary disease, pre-existing anemia unresponsive to erythropoietin, renal failure, or hemoglobinopathy) can be treated with pegIFN alfa (2a or 2b) monotherapy (AII). However, substantially lower SVR rates are expected in persons not receiving RBV. Additionally, persons with modifiable contraindications to treatment should be reassessed at regular intervals to evaluate their candidacy for therapy. Active injection-drug use does not represent an absolute contraindication to treatment of HCV infection; treatment of active IDUs should be considered on a case-by-case basis, considering comorbid conditions, adherence to medical care, and risk for reinfection. Management of HCV-infected IDUs is enhanced by linking IDUs to drug treatment programs. Alcohol use negatively affects HCV disease progression and treatment; therefore, alcohol abstinence is strongly recommended before and during antiviral therapy. A history of alcohol abuse is not a contraindication to therapy.

Management of HCV in the Context of ART

The optimal timing of initiation of ART relative to treatment for HCV infection has not been established. Although control of HIV replication and higher CD4+ count as a result of successful ART might be associated with improved response to treatment for HCV infection, this theoretical possibility has not been demonstrated in clinical trials. In addition, data from randomized controlled trials indicate that no substantial relationship exists between pretreatment CD4+ count and higher SVR rates. Also, because persons with CD4+ counts <200 cells/µL have usually been excluded from clinical trials, the efficacy and safety of pegIFN plus RBV has not been established in this population. Therefore, the majority of experts recommend initiation of ART and control of HIV viral replication before initiating treatment for HCV infection for HIV-coinfected patients with CD4+ counts <200 cells/µL (CIII). However, limited evidence suggests that for persons unable to tolerate ART because of hepatotoxicity or who have persistently elevated serum aminotransferase levels (>2 times the ULN), treatment of HCV infection before initiating ART might reduce the risk for recurrent hepatotoxicity or progression of liver disease (1129Labarga P, Soriano V, Vispo ME, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis 2007;196:670-6.) and should be considered in this situation, regardless of CD4+ count (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

The most appropriate intervals with which to monitor patients for whom treatment for HCV infection is deferred (e.g., those with no or minimal fibrosis or inflammatory changes on liver biopsy) have not been determined, but because of unpredictable progression of fibrosis, even among those with limited fibrosis on initial liver biopsy, serial liver biopsies should be performed every 2-3 years (1130Sulkowski MS, Mehta SH, Torbenson MS, et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS 2007;21:2209-16.).

Assessment of HCV RNA level is the best measure of treatment response and should be performed at baseline and after completion of the first 12 weeks of therapy for HCV infection (1131Davis GL. Monitoring of viral levels during therapy of hepatitis C. Hepatology 2002;36(Suppl 1):145-51.). An early virologic response (EVR) is defined as either an undetectable HCV RNA level or a decrease of ≥2 log10, as measured by quantitative HCV RNA assays, at the end of 12 weeks of treatment. Patients who do not achieve an EVR by week 12 have a limited chance (<3%) of achieving SVR regardless of duration of therapy, and most specialists recommend that treatment should be discontinued after 12 weeks (AI). If an EVR is documented, treatment should be continued (AI) and a quantitative or qualitative HCV RNA assay should be performed at the end of 24 weeks of treatment. If HCV RNA levels are undetectable at the end of 24 weeks of treatment, therapy should be continued for a total duration of 48 weeks. If HCV RNA levels remain detectable after 24 weeks of treatment, therapy should be stopped (AI). An HCV RNA assay should be repeated both at the completion of 48 weeks of treatment and 24 weeks after completion of treatment (AI). An SVR is defined as the absence of detectable HCV RNA, using an HCV RNA assay with a lower limit of detection of at least 50 IU/mL, measured at 24 weeks after completion of treatment.

In the context of treatment monitoring, relapse is defined as the absence of detectable HCV RNA at the end of treatment that is not sustained after the discontinuation of therapy. Breakthrough is the re-emergence of detectable HCV RNA following suppression below the limit of detection despite the continuation of therapy. Virologic failure or nonresponse is defined as the failure to suppress HCV RNA below detection at any time during treatment. Certain specialists recommend the continuation of treatment despite virologic failure in persons with advanced liver fibrosis based on the observation that approximately one third of coinfected patients who underwent liver biopsy had histologic improvement in fibrosis, despite the absence of a virologic response in one trial (1125Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-9., 1132Rodriguez-Torres M, Rodriguez-Orengo JF, Ros-Bedoya CF, et al. Effect of hepatitis C virus treatment in fibrosis progression rate (FPR) and time to cirrhosis (TTC) in patients co-infected with human immunodeficiency virus: a paired liver biopsy study. J Hepatol 2007;46:613-9.).

However, more recent data suggest this approach is ineffective and it is not recommended.

HIV-infected patients who achieve an SVR should be monitored with serial HCV RNA testing at 6-12 month intervals for an additional 1-5 years to exclude late relapse or reinfection with HCV, especially those at risk for continued exposure (CIII) (1133Soriano V, Maida I, Nez M, et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004;9:987-92.).

The major toxicities of IFN-alfa (pegylated or standard) include influenza-like symptoms (e.g., fever, myalgia, headache, and fatigue), neuropsychiatric abnormalities (e.g., depression, irritability, and cognitive dysfunction), cytopenias (e.g., thrombocytopenia and neutropenia, including a reversible reduction in CD4+ count), retinopathy, neuropathy, and exacerbation of autoimmune disease. Depression might be severe enough to trigger suicide. Depending on the severity of these toxicities and individual patient tolerance, side effects might be dose limiting or interfere with the ability to complete a course of treatment.

The major toxicities of RBV include dose-dependent hemolytic anemia, cough, and dyspepsia. RBV potentiates the intracellular activity of didanosine through inhibition of inosine monophosphate dehydrogenase. Because the interaction of RBV and didanosine might lead to clinically significant inhibition of mitochondrial DNA polymerase gamma, resulting in severe pancreatitis, lactic acidosis and, in some patients, death, the combination of RBV and didanosine is strictly contraindicated (EI) (1134Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004;38:79-80.). Zidovudine can potentiate RBV-related anemia, and if other ARVs are available, modification of the ART regimen to remove zidovudine is recommended before treatment for HCV infection (BII) (1135Alvarez D, Dieterich DT, Brau N, et al. Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. J Viral Hepat 2006;13:683-9.). Persons in whom the discontinuation of zidovudine is not feasible should be monitored closely (every 2 weeks) for the new onset of severe anemia during the first 8 weeks of treatment. Studies support the use of erythropoietin for the management of clinically significant anemia during HCV treatment. The use of epoetin alfa might permit RBV doses to be optimized and has been associated with improved quality of life (1136Sulkowski MS, Dieterich DT, Bini EJ, et al. Epoetin alfa once weekly improves anemia in HIV/hepatitis C virus-coinfected patients treated with interferon/ribavirin: a randomized controlled trial. J Acquir Immune Defic Syndr 2005;39:504-6.).

Mental health should be evaluated before initiation of therapy for HCV infection and should be monitored at regular intervals during treatment. Certain specialists recommend the use of standardized depression screening tools such as the Center for Epidemiologic Studies Depression Scale (CES-D). Adverse neuropsychiatric effects of pegIFN-alfa and RBV might be modified by the use of adjunctive agents such as antidepressants.

As with HBV coinfection, in HCV-coinfected persons, IRIS might be manifested by dramatic increases in serum aminotransferases as CD4+ counts rise within the first 6-12 weeks after starting ART. The signs and symptoms are characteristic of hepatitis flares. After introduction of ART, serum aminotransferases should be monitored closely; some experts recommend monthly for the first 3-6 months and then every 3 months thereafter. Any association between abnormal aminotransferases and clinical jaundice or synthetic dysfunction (elevated INR) should prompt consultation with a hepatologist.

In this setting, distinguishing hepatotoxicity or other causes of hepatitis (acute HAV or acute HBV infections) from IRIS is difficult. All classes of ARVs have been associated with hepatotoxicity, which might be dose-dependent or idiosyncratic. The risk for hepatotoxicity has been consistently associated with elevated pre-ART aminotransferases and the presence of HBV or HCV coinfection (1065Kontorinis N, Dieterich D. Hepatotoxicity of antiretroviral therapy. AIDS Rev 2003;5:36-43., 1066Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003;34(Suppl 1):1-33., 1067Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;18:2277-84., 1069Torti C, Lapadula G, Casari S, et al. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER cohort. BMC Infect Dis 2005;14:58., 1070Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001;15:1261-8., 1071Meraviglia P, Schiavini M, Castagna A, et al. Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation. HIV Med 2004;5:334-43., 1072Saves M, Vandentorren S, Daucourt V, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. AIDS 1999;13:F115-21., 1073Monforte V, Roman A, Gavalda J, et al. Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors. J Heart Lung Transplant 2001;20:1274-81., 1137Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA;283:74-80. 2000.). Despite the increased risk for hepatotoxicity in the setting of HCV or HBV coinfection, the majority of (80%-90%) coinfected patients do not develop hepatotoxicity (1067Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;18:2277-84.), and clinically significant hepatotoxicity is rare; aminotransferases return to baseline in the majority of cases, even if the offending medication is continued (1066Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003;34(Suppl 1):1-33., 1074Sherman KE, Shire NJ, Cernohous P, et al. Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir. Clin Infect Dis 2005;41:1186-95.). Therefore, discontinuing treatment in the presence of hepatotoxicity is probably not necessary unless the patient has symptoms of hypersensitivity (fever, lymphadenopathy, rash), symptomatic hepatitis (nausea, vomiting, abdominal pain, or jaundice), or elevations of serum aminotransferase levels >10 times the ULN. The development of jaundice is associated with severe morbidity and mortality and should trigger discontinuation of the offending drug(s) (1075Reuben A. Hy's law. Hepatology 2004;39:574-8.). No reliable clinical or laboratory parameter is available that will distinguish hepatotoxicity from IRIS. Similarly, liver biopsy might not be diagnostic and are not recommended except in the presence of hepatotoxicity grade 4 or fulminant hepatitis. Prospective studies are evaluating the incidence of presumptive IRIS within the first 12 months of ART initiation. No studies exist to inform the optimal management of persons who experience IRIS in this setting.

Management of Treatment Failure

No data are available on which to base recommendations for treatment of HIV/HCV coinfected patients who fail to respond to initial treatment for HCV infection. Certain patients might benefit from retreatment with interferon-based regimens depending on their previous response, tolerance, and adherence to and the type of previous therapy, the potential potency of the new treatment regimen, the severity of liver disease, viral genotype, and other underlying factors that influence response. On the basis of limited data in persons with HCV monoinfection, extension of the duration of treatment with pegIFN plus RBV might enhance SVR rates in coinfected persons who experience a virologic response to HCV treatment followed by relapse after adequate therapy. For persons with advanced fibrosis (e.g., bridging fibrosis or cirrhosis) and for HIV/HCV-coinfected persons who fail to demonstrate an EVR on a pegIFN and weight-based RBV regimen, clinical trials indicate that maintenance pegIFN therapy is not associated with decreased risk for hepatic events or with slowing of liver fibrosis progression in HIV-infected and -uninfected persons (1138Sherman KE, Andersen JW, Butt AA, et al. Sustained long term antiviral maintenance with pegylated interferon in HCV/HIV coinfected (SLAM-C): early virologic response and effect on fibrosis in treated and control subjects (Abstract). 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA, 2008.). Therefore, maintenance pegIFN therapy is not recommended (AI).

Preventing Recurrence

For HIV/HCV coinfected patients, treatment-induced SVR appears to be durable and low rates of recurrent viremia have been observed in persons with undetectable HCV RNA >1 year after completion of therapy (1133Soriano V, Maida I, Nez M, et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004;9:987-92.). Persons with HIV infection who achieve SVR should be counseled to stop using injection drugs, and those who continue to inject drugs should be counseled to use safe injection practices to prevent reinfection. Use of barrier precautions and other methods to prevent sexual transmission of HIV should be adequate to prevent reinfection with HCV via sexual practices.

Special Considerations During Pregnancy

Pregnant HIV-infected women should be tested for HCV infection to allow appropriate management during pregnancy and following delivery, and for their infants after birth (1139American College of Obstetricians and Gynecologists. Viral hepatitis in pregnancy. Int J Gynaecol Obstet 1998;63:195-202.). The treatment of chronic hepatitis C during pregnancy is contraindicated (EIII). Both peginterferon and RBV are contraindicated in pregnancy. Although interferons are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents (1087Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005;65:807-11.).

RBV is an FDA category X drug because of its teratogenicity at low doses in multiple animal species. Defects noted in animals include limb abnormalities, craniofacial defects, exencephaly, and anophthalmia. RBV should not be used during pregnancy (EIII). Women of childbearing potential and men receiving RBV should be counseled about the risks and need for consistent contraceptive use during and for 6 months after completion of RBV therapy. However, inadvertent pregnancy during paternal exposure has not been associated with adverse events (1140Hegenbarth K, Maurer U, Kroisel PM, et al. No evidence for mutagenic effects of ribavirin: report of two normal pregnancies. Am J Gastroenterol 2001;96:2286-7.). Pregnancies that occur in women taking RBV should be reported to the Ribavirin Pregnancy Registry (800-593-2214 or http://www.ribavirinpregnancyregistry.com).

Evaluation of HCV-infected pregnant women, including liver biopsy, can be delayed until >3 months after delivery to allow potential pregnancy-related changes in disease activity to resolve. Hepatitis A and hepatitis B vaccination can be administered during pregnancy.

Elective Cesarean delivery does not appear to reduce the risk for HCV transmission from mother to child in HIV-uninfected women, but might be protective against transmission of HCV among HIV-infected women (1089Polis CB, Shah SN, Johnson KE, Gupta A. Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis 2007;44:1123-31., 1141Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet 2000;356:904-7.). The adjusted odds for perinatal transmission of HCV with scheduled Cesarean delivery among HIV-infected, HCV-seropositive women was 0.36 (0.2-0.8) compared with other modes of delivery. However, another study was unable to confirm the protective effect of Cesarean delivery, possibly because two thirds of the women with HIV/HCV coinfection received an elective Cesarean delivery (1142European Paediatric Hepatitis C Virus Network. A significant sexbut not elective cesarean sectioneffect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005;192:1872-9.). Although elective Cesarean delivery in HIV/HCV-coinfected women might be considered based on HIV-related indications, data are insufficient to support its routine use for prevention of HCV transmission (DIII).

Infants born to HIV/HCV-coinfected women should be tested for HCV RNA at 2 and 6 months and for HCV antibody after 15 months of age (CIII).

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Hepatitis C virus (HCV) disease
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Genotype 1, 4, 5, or 6 (AI)
transparent gifgrey bulletPeginterferon alfa-2a 180 µg SQ weekly, or
transparent gif
transparent gifgrey bulletPeginterferon alfa-2b 1.5 mg/kg SQ weekly
transparent gif
+
transparent gifgrey bulletRibavirin PO (wt-based dosing) (AII)
transparent gif
<75 kg: 600 mg qAM and 400 mg qPM; ≥75 kg: 600 mg qAM and 600 mg qPM Genotype 2 or 3 (AI)
transparent gifgrey bulletPeginterferon alfa-2a 180 µg SQ weekly, or
transparent gif
transparent gifgrey bulletPeginterferon alfa-2b 1.5 mg/kg SQ weekly
transparent gif
+
transparent gifgrey bulletRibavirin (fixed dose) PO 400 mg qAM and 400 mg qPM
transparent gif
Duration of therapy:
transparent gifgrey bullet48 weeks - genotypes 1 or 4, 5 or 6 (AI) and genotypes 2 and 3 (BII)
transparent gif
transparent gifgrey bulletAt least 24 weeks - treatment of acute HCV infection (<6 months from HCV exposure) (BIII)
transparent gif
In patients for whom ribavirin is contraindicated (e.g. unstable cardiopulmonary disease, pre-existing anemia unresponsive to erythropoietin, renal failure, or hemoglobinopathy)
transparent gifgrey bulletPeginterferon alfa-2a 180 µg SQ weekly (AII), or
transparent gif
transparent gifgrey bulletPeginterferon alfa-2b 1.5 µg/kg SQ weekly (AII)
transparent gif
In patients with decompensated liver disease
transparent gifgrey bulletLiver transplantation if feasible (CIII)
transparent gif
For patients with CD4+ count <200 cells/µL, initiation of ART may be considered before HCV treatment (CIII)

Didanosine + ribavirin may lead to increased mitochondrial toxicities; concomitant use is contraindicated (EI).

HCV therapy is not recommended in patients with hepatic decompensation. Liver transplantation, if feasible, should be the primary treatment option (CIII).

Interferon is abortifacient in high doses and ribavirin is teratogenic. HCV treatment is not recommended in pregnant women or women who are not willing to use birth control (EIII).

References

916. Mas A. Hepatic encephalopathy: from pathophysiology to treatment. Digestion 2006;73(Suppl 1):86-93.
978. Van Thiel DH, Gavaler JS, Wright H, Tzakis A. Liver biopsy: its safety and complications as seen at a liver transplant center. Transplantation 1993;55:1087-90.
979. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495-500.
997. Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol 2005;42:799-805.
998. Bruno R, Sacchi P, Filice C, Puoti M, Filice G. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis: an emerging issue. J Acquir Immune Defic Syndr 2002;30:535-6.
999. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166:1632-41.
1000. Vlahov D, Junge B, Brookmeyer R, et al. Reductions in high-risk drug use behaviors among participants in the Baltimore needle exchange program. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:400-6.
1001. Hagan H, Jarlais DC, Friedman SR, Purchase D, Alter MJ. Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma syringe exchange program. Am J Public Health 1995;85:1531-7.
1002. Hagan H, McGough JP, Thiede H, et al. Syringe exchange and risk of infection with hepatitis B and C viruses. Am J Epidemiol 1999;149:203-13.
1029. Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880-9.
1036. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-50.
1065. Kontorinis N, Dieterich D. Hepatotoxicity of antiretroviral therapy. AIDS Rev 2003;5:36-43.
1066. Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003;34(Suppl 1):1-33.
1067. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;18:2277-84.
1068. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000;283:74-80.
1069. Torti C, Lapadula G, Casari S, et al. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER cohort. BMC Infect Dis 2005;14:58.
1070. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001;15:1261-8.
1071. Meraviglia P, Schiavini M, Castagna A, et al. Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation. HIV Med 2004;5:334-43.
1072. Saves M, Vandentorren S, Daucourt V, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. AIDS 1999;13:F115-21.
1073. Monforte V, Roman A, Gavalda J, et al. Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors. J Heart Lung Transplant 2001;20:1274-81.
1074. Sherman KE, Shire NJ, Cernohous P, et al. Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir. Clin Infect Dis 2005;41:1186-95.
1075. Reuben A. Hy's law. Hepatology 2004;39:574-8.
1079. Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology 2004;39:841-56.
1080. Singh N, Gayowski T, Yu VL, Wagener MM. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med 1995;122:595-8.
1081. Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26(Suppl 1):34-38.
1082. Gebo KA, Chander G, Jenckes MW, et al. Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review. Hepatology 2002;36(Suppl 1):584-92.
1083. Miro JM, Laguno M, Moreno A, Rimola A. Management of end stage liver disease (ESLD): what is the current role of orthotopic liver transplantation (OLT)? J Hepatol 2006;44(Suppl 1):140-5.
1087. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005;65:807-11.
1088. Gotz HM, van Doornum G, Niesters HG, et al. A cluster of acute hepatitis C virus infection among men who have sex with menresults from contact tracing and public health implications. AIDS 2005;19:969-74.
1089. Polis CB, Shah SN, Johnson KE, Gupta A. Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis 2007;44:1123-31.
1090. Chamot E, Hirschel B, Wintsch J, et al. Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users. AIDS 1990;4:1275-7.
1091. Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003;124:97-104.
1092. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006;44(Suppl 1):6-9.
1093. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002;288:199-206.
1094. Brau N, Salvatore M, Ros-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol 2006;44:47-55.
1095. Benhamou Y. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology 2001;34:283-7.
1096. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-32.
1097. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001;33:562-9.
1098. Merchante N, Girn-Gonzlez JA, Gonzlez-Serrano M, et al. Survival and prognostic factors of HIV-infected patients with HCV-related end-stage liver disease. AIDS 2006;20:49-57.
1099. Mehta SH, Thomas DL, Torbenson M, et al. The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection. Hepatology 2005;41:123-31.
1100. Qurishi N, Kreuzberg C, Lchters G, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 2004;362:1708-13.
1101. Ryan EL, Morgello S, Isaacs K, Naseer M, Gerits P. Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology 2004;62:957-62.
1102. Fleming CA, Christiansen D, Nunes D, et al. Health-related quality of life of patients with HIV disease: impact of hepatitis C coinfection. Clin Infect Dis 2004;38:572-8.
1103. Mehta SH, Moore RD, Thomas DL, Chaisson RE, Sulkowski MS. The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. J Acquir Immune Defic Syndr 2003;33:577-84.
1104. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000;356:1800-5.
1105. Chung RT, Evans SR, Yang Y, et al. Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects. AIDS 2002;16:1915-23.
1106. Sullivan PS, Hanson DL, Teshale EH, Wotring LL, Brooks JT. Effect of hepatitis C infection on progression of HIV disease and early response to initial antiretroviral therapy. AIDS 2006;20:1171-9.
1107. Aranzabal L, Casado JL, Moya J, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2005;40:588-93.
1108. Jaeckel E, Cornberg M, Wedemayer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345(2):1452-7.
1109. Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-8.
1110. National Institutes of Health. Consensus development conference statement: management of hepatitis C: 2002-June 10-12, 2002. Hepatology 2002;36(Suppl 1):3-20.
1111. Thio CL, Nolt KR, Astemborski J, et al. Screening for hepatitis C virus in human immunodeficiency virus-infected individuals. J Clin Microbiol 2000;38:575-7.
1112. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected patient. Clin Liver Dis 2003;7:179-94.
1113. Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.
1114. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705-14.
1115. Lindor KD, Bru C, Jorgensen RA, et al. The role of ultrasonography and automatic-needle biopsy in outpatient percutaneous liver biopsy. Hepatology 1996;23:1079-83.
1116. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317-25.
1117. Wilson LE, Torbenson M, Astemborski J, et al. Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology 2006;43:788-95.
1118. Myers RP, Benhamou Y, Imbert-Bismut F, et al. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients. AIDS 2003;17:721-5.
1119. Nunes D, Fleming C, Offner G, et al. HIV infection does not affect the performance of noninvasive markers of fibrosis for the diagnosis of hepatitis C virus-related liver disease. J Acquir Immune Defic Syndr 2005;40:538-44.
1120. de Ledinghen V, Douvin C, Kettaneh A, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2006;41:175-9.
1121. Thomas DL, Vlahov D, Solomon L, et al. Correlates of hepatitis C virus infections among injection drug users. Medicine (Baltimore) 1995;74:212-20.
1122. Hagan H, Thiede H, Weiss N, et al. Sharing of drug preparation equipment as a risk factor for hepatitis C. Am J Public Health 2001;91:42-6.
1123. Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998;28:805-9.
1124. Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices. Gastroenterology 2004;126:1175-89.
1125. Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-9.
1126. Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004;18:F27-36.
1127. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004;292:2839-48.
1128. Hadziyannis SJ, Sette HJ, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55.
1129. Labarga P, Soriano V, Vispo ME, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis 2007;196:670-6.
1130. Sulkowski MS, Mehta SH, Torbenson MS, et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS 2007;21:2209-16.
1131. Davis GL. Monitoring of viral levels during therapy of hepatitis C. Hepatology 2002;36(Suppl 1):145-51.
1132. Rodriguez-Torres M, Rodriguez-Orengo JF, Ros-Bedoya CF, et al. Effect of hepatitis C virus treatment in fibrosis progression rate (FPR) and time to cirrhosis (TTC) in patients co-infected with human immunodeficiency virus: a paired liver biopsy study. J Hepatol 2007;46:613-9.
1133. Soriano V, Maida I, Nez M, et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004;9:987-92.
1134. Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004;38:79-80.
1135. Alvarez D, Dieterich DT, Brau N, et al. Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. J Viral Hepat 2006;13:683-9.
1136. Sulkowski MS, Dieterich DT, Bini EJ, et al. Epoetin alfa once weekly improves anemia in HIV/hepatitis C virus-coinfected patients treated with interferon/ribavirin: a randomized controlled trial. J Acquir Immune Defic Syndr 2005;39:504-6.
1137. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA;283:74-80. 2000.
1138. Sherman KE, Andersen JW, Butt AA, et al. Sustained long term antiviral maintenance with pegylated interferon in HCV/HIV coinfected (SLAM-C): early virologic response and effect on fibrosis in treated and control subjects (Abstract). 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA, 2008.
1139. American College of Obstetricians and Gynecologists. Viral hepatitis in pregnancy. Int J Gynaecol Obstet 1998;63:195-202.
1140. Hegenbarth K, Maurer U, Kroisel PM, et al. No evidence for mutagenic effects of ribavirin: report of two normal pregnancies. Am J Gastroenterol 2001;96:2286-7.
1141. Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet 2000;356:904-7.
1142. European Paediatric Hepatitis C Virus Network. A significant sexbut not elective cesarean sectioneffect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005;192:1872-9.
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