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The incidence of hepatocellular carcinoma (HCC) has risen dramatically in the United States over the past three decades.1,2 Registry data from the Surveillance, Epidemiology, and End Results (SEER) Program demonstrated the age-adjusted incidence increased from 1.4 per 100,000 during the time period from 1976 to 1980 to 3.0 per 100,000 from 1996 to 1998.2 Much of the rise in HCC has been attributed to the growing number of patients with hepatitis C virus (HCV) and cirrhosis. Not surprisingly, HCC is increasingly recognized in patients coinfected with HCV and HIV. Swaminath presents a particularly instructive case in which a coinfected patient was diagnosed with HCC after achieving an SVR to antiviral therapy for HCV. The case report raises important issues about HCV in coinfected patients, including the natural history of HCV, the efficacy of antiviral therapy, and surveillance for HCC.
Approximately 15–30% of patients with HIV are coinfected with HCV due to shared routes of transmission for both viruses.3,4 Rates of HCV were reported to be as high as 85% in HIV-infected injection drug users.4 HIV coinfection was associated with more severe HCV-related liver injury and an increased rate of progression to cirrhosis compared to HCV infection alone.5,6 Moreover, coinfected patients who responded to highly active antiretroviral therapy (HAART) had rates of fibrosis progression that were similar to HCV monoinfected patients,7 highlighting the importance of effective HIV management in this setting. Alcohol abuse, present in the case report, was also associated with HCV progression in coinfected patients. In one study, the projected time to cirrhosis in HCV-infected patients with a CD4 count of 200 cells/μL or higher, who consumed more than 50 g of alcohol daily was only 16 years.8
Studies of coinfected patients have shown a shorter interval to the development of HCC than in patients with HCV alone. As illustrated by the case report, HCC develops on a background of cirrhosis in patients with HCV. Other factors that interact with HCV to increase the risk of HCC include alcohol abuse, tobacco use, and diabetes, which serves as a marker for insulin resistance and nonalcoholic fatty liver disease.9 Pertinent to the present case, alcohol use in excess of 40 g/day and 80 g/day was shown to increase the risk of HCC in HCV patients by two- and four-fold, respectively.10 Although HIV is associated with the development of Kaposi sarcoma related to human herpes 8 virus infection and with cervical cancer related human papilloma virus,11 HIV has not been directly implicated in hepatocarcinogenesis.
Retrospective studies suggested that successful antiviral therapy for HCV might reduce the risk of HCC.12-16 Data from a recent multicenter trial including peginterferon alfa-2a plus ribavirin for the treatment of HCV in coinfected patients showed promising results. Patients with genotype-1 infection had an SVR of 29% and the SVR for those with genotype 2 or 3 was 62%.17 Hepatic decompensation was observed in a few patients with more advanced cirrhosis. Therefore, coinfected patients with cirrhosis should be selected carefully and monitored closely during antiviral therapy. Clinicians should be familiar with the HAART regimen that patients are taking and avoid the combination of ribavirin and DDI, which was associated with the development of lactic acidosis.
Hepatocellular carcinoma was identified in the patient in the case report after a particularly short, but successful course of treatment for HCV. A number of possible explanations exist. First, the tumor might have been present but unrecognized prior to antiviral therapy, although the four-year interval between treatment and diagnosis of HCC makes this possibility seem unlikely. Second, continued alcohol use could have contributed to tumor development. Finally, HCC might have developed despite an SVR as previously reported.18-22 In one case, HCC was identified 12 years after SVR.20 Risk factors for HCC after SVR include advanced fibrosis stage and older age.21,22 These findings have lead some authors to promote screening for HCC twice per year in high risk patients and once per year in low risk patients for more than ten years after SVR.23
The cost-effectiveness of surveillance for HCC was addressed in a position paper by the American Association for the Study of Liver Disease (AASLD).24 The cost per year of life saved by HCC surveillance in cirrhotic patients was estimated at $26,000 to $112,996, compared to $25,000 per life year saved with colorectal cancer screening. The AASLD also published practice guidelines for HCC surveillance.25 The guidelines suggest that monitoring should be performed in high risk hepatitis B carriers regardless of the degree of fibrosis and in patients with HCV, alcohol, hemochromatosis and other causes of liver disease, who have evidence of cirrhosis. Additionally, ultrasound and alpha fetoprotein (AFP) was recommended at an interval of 6–12 months. The European Association for the Study of the Liver (EASL) recommended surveillance for HCC by ultrasound and AFP on a 6–12 month basis as well.26 The EASL also recommends surveillance only in patients who would be considered suitable for treatment of HCC.
The diagnosis of HCC can be established based on cytology or histology. The AASLD guidelines provided recommendations for follow-up and noninvasive criteria for the diagnosis of HCC in cirrhotic patients based on the size and imaging characteristics of a lesion.25 Accordingly, subcentimeter lesions should be followed at a 3–4 month interval to check for enlargement. Follow-up imaging can revert to the standard interval if stability is documented over 18–24 months. Lesions between 1 and 2 cm in size that show characteristic hypervascularization on two cross-sectional imaging studies meet the noninvasive criteria for HCC. Biopsy was suggested for lesions 1–2 cm in size without characteristic enhancement. Noninvasive criteria for the diagnosis of HCC for lesions greater than 2 cm include hypervascularzation on one dynamic imaging study or an AFP level greater than 200 ng/mL. The patient in the case report met the latter noninvasive criteria with a markedly elevated AFP level and characteristic findings on a contrast-enhanced MRI. Treatment options for HCC are outlined in the literature review accompanying the case report.
In conclusion, HCV is common in patients with HIV and tends to follow a more aggressive natural history than in patients with HCV alone. Management of HCV in coinfected patients includes treatment of HIV when indicated, avoidance of alcohol, and consideration of antiviral therapy consisting of peginterferon and ribavirin. As demonstrated in the case report, HCC can develop in cirrhotic patients even after a SVR, highlighting the importance of HCC surveillance in patients with cirrhosis.