Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. According to the International Agency for Research on Cancer, liver cancer is the fifth most common cancer in men worldwide (523,000 cases/y, 7.9% of all cancers) and the seventh most common cancer in women (226,000 cases/y, 6.5% of all cancers). Liver cancer has a high mortality rate; the geographic distribution of mortality is similar to that of incidence. Most of the burden of liver cancer is in developing countries, where almost 85% of the cases occur. Hepatocellular carcinoma (HCC) is the most common form of liver cancer; most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. Variations in the age-, sex-, and race-specific rates of HCC in different geographic regions are likely to be related to differences in the prevalence of hepatitis viruses in the populations, as well as the timing of the spread of the viral infection and the age of individuals at the time of the infection. Most cases of HCC (>80%) occur in sub-Saharan Africa and in Eastern Asia, with typical incidence rates of more than 20 per 100,000 individuals. Southern European countries (such as Spain, Italy, and Greece) tend to have mid-incidence levels (10.0–20.0 per 100,000 individuals), whereas North America, South America, Northern Europe, and Oceania have a low incidence of HCC (<5.0 per 100,000 individuals) (Figure 1). Recent decreases in the incidence of HCC were reported among Chinese populations in Hong Kong, Shanghai, and Singapore; the incidence in Japan also is decreasing. However, cases of HCC are increasing in low-incidence areas such as the United States and Canada. HCC rarely is seen during the first 4 decades of life, except in populations in which HBV infection is hyperendemic. The mean ages of diagnosis with HCC were 55–59 years in China and 63–65 years in Europe and North America. In low-risk populations, the highest incidence of HCC is among individuals aged 75 or older. However, in Qidong, China, where HCC burden is among the world's highest, the age-specific incidence rates among men increases until age 45 years and then plateaus; among women, the incidence rate increases until age 60 years and then plateaus. HCC is predominant among men, with the highest male:female ratios in areas of high incidence (Figure 1). HBV and HCV promote cirrhosis, which is found in 80%–90% of patients with HCC. The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection), region or ethnicity (it is highest in Asians), and stage of cirrhosis (it is highest in individuals with decompensated disease).1Fattovich G. Stroffolini T. Zagni I. et al.Hepatocellular carcinoma in cirrhosis: incidence and risk factors.Gastroenterology. 2004; 127: S35-S50Abstract Full Text Full Text PDF PubMed Scopus (1954) Google Scholar Approximately 5% of the world population (350–400 million people) is chronically infected with HBV; 75% of infected people are Asian,2McMahon B.J. Alberts S.R. Wainwright R.B. et al.Hepatitis B-related sequelae Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers.Arch Intern Med. 1990; 150: 1051-1054Crossref PubMed Google Scholar with a lower prevalence (0.3%–1.5%) in Western countries. There is high ecologic correlation between areas of HBV prevalence and HCC incidence and mortality worldwide (Figure 2). Chronic HBV infection accounts for approximately 50% of the total cases and virtually all childhood HCC; it is the dominant risk factor in most areas of Asia and sub-Saharan Africa that have a high incidence of HCC, with the exception of Japan, where the major risk factor for HCC is chronic HCV infection. HB surface antigen (HBsAg) seroprevalence among persons with HCC varies widely: it is 3% in Sweden, 10% in the United States, 10%–15% in Japan, 19% in Italy, 55% in Greece, and 70% in South Korea. The global prevalence of HCV is estimated to be 2% (approximately 180 million people worldwide) and varies considerably among different regions (Figure 2). Phylogenetic studies of HCV diversity described the chronology of the spread of HCV epidemics in Japan, Europe, and the United States; these findings account for the geographic differences in the timing of the burden of HCV-related HCC.3Mizokami M. Orito E. Molecular evolution of hepatitis viruses.Intervirology. 1999; 42: 159-165Crossref PubMed Scopus (23) Google Scholar Based on these studies, HCV began to infect large numbers of young adults in Japan in the 1920s, in southern Europe in the 1940s, and in North America in the 1960s and 1970s.4Tanaka Y. Kurbanov F. Mano S. et al.Molecular tracing of the global hepatitis C virus epidemic predicts regional patterns of hepatocellular carcinoma mortality.Gastroenterology. 2006; 130: 703-714Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar The HCV epidemic in the United States originated from contaminated needles and/or injection drug use. The virus spread into national blood supplies and circulated until the late 1980s; the rate of new infections was greatly reduced thereafter. Although the seroprevalence of HCV is similar among the general populations of Japan, southern Europe, and North America, markers of HCV infection are highest among individuals with HCC in Japan (80%–90%), followed by Italy (44%–66%), and then the United States (30%–50%).5El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4467) Google Scholar The incidence of HCC is almost 3-fold higher in Japan than Italy and almost 6-fold higher than in the United States. The burden of HCC in the United States therefore eventually might equal that of Japan. The age distribution of HCC in different regions is determined partly by type of virus and timing of infection. In areas that have a high incidence of HCC in Asia, HBV infection largely is acquired by mother–child transmission, whereas transmission among siblings of young ages is more common in Africa. Therefore, individuals in these regions develop HCC at earlier ages than in low-incidence areas, where the main risk factors for HCV infection are encountered later in life. Differences in age-related prevalence of HCC might affect applicability and outcomes of therapies such as liver transplantation. The high male:female ratio of HCC might result, in part, from the higher prevalence of HBV and HCV infection among men than women. It is estimated that more than 90% of countries routinely vaccinate newborns against HBV, and approximately 70% are now delivering 3 immunization doses. In 1984, Taiwan became the first country to vaccinate newborns against HBV, and give HB immunoglobulin to infants of high-risk (HBsAg-positive) and HB e antigen (HBeAg)-positive mothers. Since then, the number of HBV carriers in the juvenile population has been greatly reduced, and the incidence of HCC among children aged 6–14 years was reduced by 65%–75%.6Chang M.H. Hepatitis B virus and cancer prevention.Recent Results Cancer Res. 2011; 188: 75-84Crossref PubMed Scopus (38) Google Scholar However, the HBV-related incidence of HCC is projected to increase for several decades because of the high prevalence of chronic HBV infection and prolonged latency to HCC development. Prospective cohort studies showed a 5- to 100-fold increase in the risk of developing HCC among persons chronically infected with HBV. Meta-analyses of case-control and cross-sectional studies indicated that the lifetime relative risk for HCC was 15–20 among HBsAg-positive individuals, compared with HBsAg-negative individuals. A systematic review of longitudinal (cohort) studies published through June 2007, by Fattovich et al,7Fattovich G. Bortolotti F. Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.J Hepatol. 2008; 48: 335-352Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar estimated the incidence rates of HCC in subjects with chronic HBV infection in East Asian countries to be 0.2 per 100 person-years in inactive carriers (HBsAg-positive but with normal levels of alanine aminotransferase [ALT]), 0.6 person-years for those with chronic HBV infection without cirrhosis, and 3.7 person-years for those with compensated cirrhosis. There have been few adequate studies in Europe or North America to determine the incidence of HCC in HBsAg-positive individuals—most studies included only small numbers of HBsAg-positive patients. Nevertheless, the summary HCC incidence rate was 0.02 per 100 person-years in inactive carriers, 0.3 in subjects with chronic HBV without cirrhosis, and 2.2 in subjects with compensated cirrhosis. Most HBV-infected individuals who develop HCC have cirrhosis secondary to chronic necroinflammation. HBV can cause HCC in the absence of cirrhosis, although most cases of HBV-related HCC (70%–90%) occur in patients with cirrhosis.8Yang J.D. Kim W.R. Coelho R. et al.Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma.Clin Gastroenterol Hepatol. 2011; 9: 64-70Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Factors that have been reported to increase HCC risk among HBV carriers are demographic (male sex, older age, Asian or African ancestry, family history of HCC), viral (higher levels of HBV replication; HBV genotype; longer duration of infection; co-infection with HCV, human immunodeficiency virus [HIV], or hepatitis D virus), clinical (cirrhosis), and environmental (exposure to aflatoxin, heavy intake of alcohol or tobacco). In many high-risk areas, particularly those in Asia, HBV is transmitted from mother to newborn (vertical transmission); as many as 90% of infected babies develop chronic infections. This pattern is different in areas that have a low incidence of HCC; HBV infection usually is acquired in adulthood, through sexual and parenteral routes (horizontal transmission). More than 90% of these cases of acute HBV infection resolve spontaneously. The higher frequency and longer period of chronic HBV infections contribute to a greater risk for HCC in areas where HBV infection is common. The risk of HCC is increased in patients with higher levels of HBV replication, determined by tests for HBeAg and levels of HBV DNA. One large study evaluated the effect of HBV replication on the risk of HCC among 11,893 Taiwanese men who were followed up for a mean of 8.5 years. The incidence rate of HCC was 1169 per 100,000 person-years among men who were HBsAg-positive and HBeAg-positive, 324 per 100,000 person-years for those who were only HBsAg-positive, and 39 per 100,000 person-years for those who were HBsAg-negative. Similarly, the relative risks of HCC among men who were HBsAg-positive and HBeAg-positive were increased 60-fold, and 10-fold among those who were only HBsAg-positive.9Yang H.I. Lu S.N. Liaw Y.F. et al.Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (1062) Google Scholar A community-based Taiwanese prospective study, the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer–Hepatitis B Virus (REVEAL-HBV), reported that in a cohort of 3653 HBsAg-positive participants, the incidence of cirrhosis and HCC increased in proportion to the serum level of HBV DNA, from less than 300 (undetectable) to 1,000,000 or more copies/mL (Figure 3). These associations remained significant after adjustment for age, sex, smoking, alcohol consumption, and HBeAg serostatus.10Chen C.J. Yang H.I. Iloeje U.H. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B.Hepatology. 2009; 49: S72-S84Crossref PubMed Scopus (273) Google Scholar The increased incidence in HCC in relation to HBV-DNA level also was observed in a study that showed that inactive carriers of HBV (seronegative for HBeAg, serum levels of HBV DNA <10,000 copies/mL, and normal liver enzyme levels) had an almost 5-fold greater risk for HCC than controls (HBsAg-negative).11Chen J.D. Yang H.I. Iloeje U.H. et al.Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death.Gastroenterology. 2010; 138: 1747-1754Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar It is not clear if the findings from REVEAL-HBV pertain to Western populations, who acquire HBV as adults and have different risk factors for disease (obesity, diabetes, and alcohol use). Levels of viral replication also are affected by antiviral treatment. There is moderately strong evidence that effective antiviral therapy, which suppresses HBV infection in HBsAg-positive patients, substantially reduces but does not completely eliminate risk for HCC. In a large Asian study, patients with chronic HBV and cirrhosis or advanced fibrosis were given 100 mg/d of lamivudine or placebo for up to 5 years. A smaller percentage of patients given lamivudine developed HCC (3.9%), compared with those given placebo (7.4%), which mostly achieved a reduced level of HBV DNA.12Liaw Y.F. Sung J.J. Chow W.C. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (1997) Google Scholar Lower-quality evidence from nonrandomized trials and observational studies has indicated that therapy with interferon or lamivudine reduces the risk for HCC.13Sung J.J. Tsoi K.K. Wong V.W. et al.Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma.Aliment Pharmacol Ther. 2008; 28: 1067-1077Crossref PubMed Scopus (312) Google Scholar Several HBV genotypes (A–H) have been identified, based on differences of 8% or more in their whole-genome sequence. HBV genotypes have distinct geographic and ethnic distributions: genotypes A and D predominate in Africa, Europe, and India; genotypes B and C predominate in Asia; genotype E predominates in West Africa; and genotype F predominates in Central and South America. In the United States, HBV genotypes A and D are more common in black and white persons, whereas HBV genotypes B and C are more common among persons of Asian ancestry. HBV genotypes seem to affect clinical outcomes. In studies performed in Asia, there was a greater association between genotype C infection and severe liver disease, cirrhosis, and HCC than genotype B; in Western Europe and North America, individuals with genotype D had a greater incidence of severe liver disease or HCC than those with genotype A. However, some data associate genotype B HBV with the development of HCC in young carriers without cirrhosis. A study from Taiwan showed that genotype B was significantly more common in patients with HCC younger than age 50 than in age-matched carriers with inactive infections (80% vs 52%).14Kao J.H. Chen P.J. Lai M.Y. et al.Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.Gastroenterology. 2003; 124: 327-334Abstract Full Text PDF PubMed Scopus (480) Google Scholar Most of these participants did not have cirrhosis. A 15-year Taiwanese study of 460 carriers of HBV reported that genotype B was the most frequent genotype among 26 children with HBV-related HCC (found in 74%).15Ni Y.H. Chang M.H. Wang K.J. et al.Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma.Gastroenterology. 2004; 127: 1733-1738Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Mutations in the region of the HBV genome that encode the basal core promoter, such as T1762 and A1764,16Liu C.J. Chen B.F. Chen P.J. et al.Role of hepatitis B viral load and basal core promoter mutation in hepatocellular carcinoma in hepatitis B carriers.J Infect Dis. 2006; 193: 1258-1265Crossref PubMed Scopus (154) Google Scholar have been associated with increased incidence of HCC, whereas those in the precore region (G1896A) have been associated with decreased incidence of HCC.17Yang H.I. Yeh S.H. Chen P.J. et al.Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 1134-1143Crossref PubMed Scopus (503) Google Scholar Aflatoxin B1 (AFB1) is a mycotoxin produced by fungi of the Aspergillus species (A flavus and A parasiticus) that grows readily on foods such as corn and peanuts stored in warm, damp conditions. In animals, AFB1 is a powerful hepatocarcinogen, leading the International Agency for Research on Cancer to classify it as a carcinogen. Once ingested, AFB1 is metabolized to an active intermediate, AFB1-exo-8,9-epoxide, which can bind to and damage DNA. AFB1 causes a mutation at serine 249 in the tumor-suppressor p5318Garner R.C. Miller E.C. Miller J.A. Liver microsomal metabolism of aflatoxin B 1 to a reactive derivative toxic to Salmonella typhimurium TA 1530.Cancer Res. 1972; 32: 2058-2066PubMed Google Scholar that was detected in 30%–60% of HCC tumor samples collected from individuals in aflatoxin-endemic areas, most of whom had HBV infections.19Bressac B. Kew M. Wands J. et al.Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.Nature. 1991; 350: 429-431Crossref PubMed Scopus (1232) Google Scholar, 20Turner P.C. Sylla A. Diallo M.S. et al.The role of aflatoxins and hepatitis viruses in the etiopathogenesis of hepatocellular carcinoma: a basis for primary prevention in Guinea-Conakry, West Africa.J Gastroenterol Hepatol. 2002; 17: S441-S448Crossref PubMed Scopus (69) Google Scholar Assays have been developed to measure aflatoxin metabolites in urine and AFB1–albumin adducts in serum, and to detect specific aflatoxin-associated DNA mutations in tissues. Areas in which AFB1 exposure is an environmental problem also have a high prevalence of chronic HBV infection. Although AFB1 might contribute to hepatocarcinogenesis by other mechanisms, its role in the pathogenesis of HCC is mediated primarily by its effects on chronic HBV infection. For example, prospective studies in Shanghai, China, showed that urinary excretion of aflatoxin metabolites increased the risk of HCC up to 4-fold, and HBV infection increased the risk 7-fold. However, individuals who excreted AFB1 metabolites and were carriers of HBV had as much as a 60-fold increase in risk of HCC.21Qian G.S. Ross R.K. Yu M.C. et al.A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China.Cancer Epidemiol Biomarkers Prev. 1994; 3: 3-10PubMed Google Scholar Importantly, prevention of HBV-related HCC would reduce the effects of aflatoxin on HCC risk. Studies with sensitive amplification assays have shown that HBV DNA persists in serum or liver, as an occult HBV infection, among persons who have serologic recovery from transient HBV infection (who are HBsAg-negative). In many instances, occult hepatitis B is associated with antibodies to hepatitis B core antigen and/or anti-HBs. A systematic review identified 16 studies of the association between occult HBV and HCC risk; 6 of these studies found no significant association. None of the studies included in this review was population-based—most had a small number of cases or controls, 11 were from Asia (only 1 was performed in the United States), and they had varied and few adjustments for confounders. A pooled adjusted estimate could be calculated for only 4 longitudinal studies (3 from Japan) that indicated a modest association between occult HBV infection and HCC (relative risk, 2.83).22Shi Y. Wu Y.H. Wei W. et al.Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis.Liver Int. 2012; 32: 231-240Crossref PubMed Scopus (111) Google Scholar A recent small case-control study from Hong Kong showed a high prevalence of occult HBV in patients with cryptogenic HCC.23Wong D.K. Huang F.Y. Lai C.L. et al.Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma.Hepatology. 2011; 54: 829-836Crossref PubMed Scopus (110) Google Scholar However, there is no convincing evidence that occult HBV is an independent risk factor for HCC or a cofactor with HCV infection in most regions of the world. There is much evidence that HCV infection can cause HCC. Prospective studies have shown a significant increase in the incidence of HCC among HCV-infected cohorts, compared with HCV-negative cohorts.24Goodgame B. Shaheen N.J. Galanko J. et al.The risk of end stage liver disease and hepatocellular carcinoma among persons infected with hepatitis C virus: publication bias?.Am J Gastroenterol. 2003; 98: 2535-2542Crossref PubMed Scopus (50) Google Scholar The rate of HCC among HCV-infected persons ranges from 1% to 3% over 30 years. Similarly, HCV infection is associated with a 15- to 20-fold increase in risk for HCC compared with HCV-negative subjects in cross-sectional and case-control studies. HCV increases the risk for HCC by inducing fibrosis and, eventually, cirrhosis. Although HCC has been reported among individuals without or with low levels of fibrosis,25De Mitri M.S. Poussin K. Baccarini P. et al.HCV-associated liver cancer without cirrhosis.Lancet. 1995; 345: 413-415Abstract PubMed Scopus (0) Google Scholar, 26Haydon G.H. Jarvis L.M. Simmonds P. et al.Association between chronic hepatitis C infection and hepatocellular carcinoma.Lancet. 1995; 345: 928-929Abstract PubMed Google Scholar, 27Tong M.J. Lai L.P. Murakami-Mori K. Development of hepatocellular carcinoma after clearance of hepatitis C virus with interferon therapy.West J Med. 1997; 167: 103-105PubMed Google Scholar the risk of HCC increases with fibrosis stage; most cases of HCV-related HCC occur among patients with advanced fibrosis or cirrhosis, making it a condition listed for HCC surveillance in current recommendations. Once HCV-related cirrhosis is established, HCC develops at an annual rate of 1%–4%; although rates up to 8% have been reported in Japan. The incidence of cirrhosis (and consequently HCC) 25–30 years after HCV infection ranges from 15% to 35%,28Freeman A.J. Dore G.J. Law M.G. et al.Estimating progression to cirrhosis in chronic hepatitis C virus infection.Hepatology. 2001; 34: 809-816Crossref PubMed Scopus (535) Google Scholar and is highest among recipients of HCV-contaminated blood products and hemophiliac patients, and lowest among women who received a single dose of contaminated anti-D immunoglobulin. HCC risk also might vary based on the amount of virus in the contaminated product or repeated exposure. Other risk factors for HCC include the sex of the HCV-infected individual, comorbidities (co-infection with HBV or HIV, diabetes, obesity, steatosis), viral genotype (HCV 1b), level of alcohol consumption, and age. Among patients with HCV-related cirrhosis, low numbers of platelets or increased levels of α-fetoprotein are risk factors for HCC. HCV viremia of any level is a strong risk factor for HCC; conversely, treatment that eliminates the virus decreases risk for HCC. Evidence from randomized controlled studies and several nonrandomized studies of HCV-infected patients with and without cirrhosis indicates a 57% to 75% reduction in risk of HCC in patients who received interferon-based therapy and achieved a sustained viral response. There are at least 6 HCV genotypes, which differ in 30%–35% of nucleotides in the complete genome. There are also several subtypes; HCV subtypes 1a and 1b are the most common in the United States and Europe, whereas in Japan, 73% of HCV-infected individuals carry subtype 1b. Reports of the association between HCV genotype and HCC risk are inconsistent. However, a meta-analysis of 21 studies that calculated age-adjusted risk estimates reported that patients infected with HCV genotype 1b had an almost 2-fold greater risk of developing HCC than patients with other HCV genotypes (pooled relative risk, 1.78). The pooled risk estimate remained significant but lower in an analysis limited to 8 studies conducted in patients with cirrhosis (pooled relative risk, 1.60).29Raimondi S. Bruno S. Mondelli M.U. et al.Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis.J Hepatol. 2009; 50: 1142-1154Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar There is no consistent evidence that other viral factors, such as HCV load or quasispecies, affect the risk of progression to cirrhosis or HCC. A study performed in Taiwan reported a correlation between level of HCV RNA and the risk of HCC,30Lee M.H. Yang H.I. Lu S.N. et al.Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study.J Clin Oncol. 2010; 28: 4587-4593Crossref PubMed Scopus (136) Google Scholar but studies from the United States and Europe have not made this association. Many studies examined the effect of HIV infection on the progression of HCV-related liver disease, measured by fibrosis, cirrhosis, HCC, decompensated liver disease, and liver-related death. These studies mostly used the retrospective cohort or cross-sectional study design. Despite the limitations of these studies and some inconsistent results, it was evident that persons co-infected with HIV have faster progression to cirrhosis and decompensated liver disease, especially during immunosuppression. However, the effect of antiretroviral therapy on liver disease in patients co-infected with HCV and HIV is not clear. At least 4 studies included in a systematic review did not associate antiretroviral therapy with risk for HCC, although it is difficult to make general conclusions because of the small number of cases of HCC in these studies. Antiretroviral therapy might reduce the risk for HCC, given the association between HIV co-infection and accelerated liver disease.31Kramer J.R. Giordano T.P. El-Serag H.B. Effect of human immunodeficiency virus and antiretrovirals on outcomes of hepatitis C: a systematic review from an epidemiologic perspective.Clin Gastroenterol Hepatol. 2007; 5: 1321-1328Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar HBV infection persists in 25% of HIV-infected adults, compared with less than 5% of adults without HIV infection. Furthermore, individuals co-infected with HIV and HBV have an increased risk for liver-related mortality. However, there are few data on the effects of co-infection with HBV and HIV on risk for HCC. Population-based studies have associated high levels of coffee consumption (>2 cups/d) with reduced serum levels of ALT and γ-glutamyl transferase and reduced incidence of chronic liver disease. Consumption of high levels of caffeine was associated with milder fibrosis in patients with chronic HCV infection.32Modi A.A. Feld J.J. Park Y. et al.Increased caffeine consumption is associated with reduced hepatic fibrosis.Hepatology. 2010; 51: 201-209Crossref PubMed Scopus (194) Google Scholar Coffee consumption also was associated inversely with progression of liver disease among participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial who had hepatitis C–related bridging fibrosis or cirrhosis and did not have a sustained virologic response to peginterferon and ribavirin treatment.33Freedman N.D. Everhart J.E. Lindsay K.L. et al.Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C.Hepatology. 2009; 50: 1360-1369Crossref PubMed Scopus (144) Google Scholar In the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis study, consumption of caffeine from sources other than coffee or of decaffeinated coffee was not associated with reduced levels of liver enzymes or fibrosis. Several studies have suggested an inverse relation between coffee drinking and risk of HCC. One meta-analysis of studies published through 2007 included 10 studies (2260 cases of HCC; 6 case-control studies from southern Europe and Japan and 4 cohort studies from Japan). Given the geographic location of these studies, most patients with HCC probably were infected with HCV, or possibly HBV. Al