Hepatocellular carcinoma in human immunodeficiency virus (HIV)-infected patients: Is it really different, and if so, why?
2007; Elsevier BV; Volume: 47; Issue: 4 Linguagem: Inglês
10.1016/j.jhep.2007.07.011
ISSN1600-0641
AutoresFrançoise Degos, Cristina Tural,
Tópico(s)Hepatitis B Virus Studies
ResumoThe present issue of the Journal [[1]Bräu N. Fox R.K. Xiao P. Marks K. Naqvi Z. Taylor L.E. et al.Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: A U.S.–Canadian multicenter study.J Hepatol. 2007; 47: 527-537Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar] includes a US-Canadian study that represents the largest cohort of HIV patients with hepatocellular carcinoma (HCC) ever reported, in which the course and characteristics of the disease were investigated. Surprisingly, survival was similar in HCC patients regardless of HIV-infected status. This observation poses several questions:(1) What is the incidence of HCC – usually associated with viral hepatitis – in HIV carriers? Are the predictive factors of HCC development well determined in this population? If this is so, how many new patients can be expected over the next decades? [2Deffic-Burba S. Poynard T. Sulkowski M.S. Wong J.B. Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States.J Viral Hepat. 2007; 14: 107-115Crossref PubMed Scopus (132) Google Scholar, 3Powles T. Macdonald D. Nelson M. Stebbing J. Hepatocellular carcinoma in HIV-infected individuals: tomorrow’s problem?.Expert Rev Anticancer Ther. 2006; 11: 1553-1558Crossref Scopus (11) Google Scholar]; (2) Are there any specific clinical features of HCC in HIV-infected patients? What is the natural history of HCC? Is the prognosis of HCV or HBV-related HCC comparable in different series of HIV-infected patients and comparable with the prognosis of HCC in HIV-negative patients with HBV or HCV? Can we propose any beneficial treatments of HCC in HIV-infected patients? Does HIV infection preclude certain therapeutic options, particularly liver transplantation?; (3) Important discrepancies in prognosis have been found in the two large series currently available comparing the outcome of HCC in HIV co-infected patients with large series of patients with HCC mostly related to HBV or HCV infection [[4]Puoti M. Bruno R. Soriano V. Donato F. Gaeta G.B. Quinzan G.P. et al.Hepatocellular carcinoma in HIV patients: epidemiological features, clinical presentation and outcome.AIDS. 2004; 18: 2285-2293Crossref PubMed Scopus (207) Google Scholar]. Why might such discrepancies arise?1. Viral hepatitis in HIV patients and incidence of HCCOf the 40 million persons infected with HIV, 2–4 million are chronic HBV carriers, and 4–5 million are chronic HCV carriers [[5]Alter M. Epidemiology of viral hepatitis and HIV co-infection.J Hepatol. 2006; 44: S6-S9Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar]. The prevalence of HIV and HCV or HBV co-infection depends on the geographic region. HIV and HBV co-infection is most prevalent in regions where HBV infection is endemic such as sub-Saharan Africa and Asia. In these regions, chronic HBV infection is usually acquired within the first years of life through perinatal or vertical transmission, which implies that many young adults are susceptible to HIV infection by sexual route. By contrast, HCV and HIV co-infection is predominantly found in individuals with large or repeated exposure to blood derivatives before widespread testing procedures reduced the risk of contamination or in intravenous drug users (in southern Europe, more than 80% of HIV infected intravenous drug users also have HCV co-infection) [[6]Rockstroh J.K. Mocroft A. Soriano V. Tural C. Losso M.H. Horban A. et al.Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy.J Infect Dis. 2005; 192: 992-1002Crossref PubMed Scopus (334) Google Scholar]. Recently, some cases of acute sexually transmitted HCV infection have been reported among HIV-infected men who have sex with men [[7]Gotz H.M. van Doornum G. Niesters H.G. den Hollander J.G. Thio H.B. de Zwart O. A cluster of acute hepatitis C virus infection among men who have sex with men – results from contact tracing and public health implications.AIDS. 2005; 19: 969-974Crossref PubMed Scopus (212) Google Scholar].Several cohort studies in co-infected patients have shown the progressive increase of the mortality due to end-stage liver disease (ESLD). In a multicenter French study in HIV-infected patients, the mortality rate attributable to cirrhosis and/or HCC had increased from 1.5% of deaths in 1995 to 12.6% in 2003 [[8]Rosenthal E. Pialoux G. Bernard N. Pradier C. Rey D. Bentata M. et al.Liver related mortality in human immunodeficiency virus infected patients between 1995 and 2003 in the French GERMIVIC joint study network.J Viral Hepat. 2007; 14: 183-188Crossref PubMed Scopus (124) Google Scholar]. In another large European multicenter study, ESLD was the most frequent cause of non-AIDS-related mortality, accounting for nearly 15% of all deaths. Factors associated with liver-related mortality were HCV co-infection and low CD4+ count [[9]Weber R. Sabin C.A. Friis-Moller N. Reiss P. El-Sadr W.M. Kirk O. et al.Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study.Arch Intern Med. 2006; 166: 1632-1641Crossref PubMed Scopus (931) Google Scholar].Almost all studies concur that HIV co-infection increases the risk of cirrhosis and shortens time to cirrhosis in HCV-infected patients [10Kramer J.R. Giordano T.P. Souchek J. Richardson P. Hwang L.Y. El Serag H.B. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in US veterans with hepatitis C.Am J Gastroenterol. 2005; 100: 56-63Crossref PubMed Scopus (130) Google Scholar, 11Posthouwer D. Makris M. Yee T.T. Fischer K. van Veen J.J. Griffioen A. et al.Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study.Blood. 2007; 109: 3667-3671Crossref PubMed Scopus (73) Google Scholar]. In particular, a multicenter study of 847 anti-HCV positive patients with congenital bleeding disorders, of whom 210 were HIV and HCV co-infected, found a significantly higher cumulative incidence of cirrhosis in HIV and HCV co-infected patients than in HCV monoinfected patients after 35 years of infection (11.5% vs 35%) [[11]Posthouwer D. Makris M. Yee T.T. Fischer K. van Veen J.J. Griffioen A. et al.Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study.Blood. 2007; 109: 3667-3671Crossref PubMed Scopus (73) Google Scholar].Although it would seem plausible that HIV infection increases the likelihood of HCC development due to the negative impact of HIV on the natural history of HCV infection, practically there is no evidence to support this hypothesis. For instance, in a study to determine whether HIV increases the risk of HCC – by comparing the incidence of HCC in HCV monoinfected patients and HIV and HCV co-infected patients between 1991 and 2000 – the authors could not demonstrate a higher incidence of HCC in the co-infected group [[10]Kramer J.R. Giordano T.P. Souchek J. Richardson P. Hwang L.Y. El Serag H.B. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in US veterans with hepatitis C.Am J Gastroenterol. 2005; 100: 56-63Crossref PubMed Scopus (130) Google Scholar]. Thus, HIV–HCV co-infection increases the progression to cirrhosis, but whether it also increases the incidence of HCC remains to be elucidated.1.1 Predictive factors for HCC developmentWhen discussing predictive factors for HCC in HIV-infected patients, the role of highly active antiretroviral therapy (HAART) as a moderator of HCC risk should be considered. One study [[12]Giordano T.P. Kramer J.R. Souchek J. Richardson P. El Serag H.B. Cirrhosis and hepatocellular carcinoma in HIV veterans with and without the hepatitis C virus.Arch Intern Med. 2004; 164: 2349-2354Crossref PubMed Scopus (150) Google Scholar] showed that the incidence of cirrhosis in HIV and HCV co-infected patients increased from the pre-HAART to the HAART era, a result that may imply that the improved survival due to HAART led to longer exposure to HCV and hence a higher risk of cirrhosis; however, it should be taken into account that the risk of cirrhosis was still higher after adjusting for survival time. Other factors in association with hepatitis virus could increase the risk of HCC. As in monoinfected patients, heavy alcohol intake will favor the development of cirrhosis and HCC and the severity of liver disease can also be boosted by any drug-induced hepatitis. Some studies have found an association between obesity and the risk of HCC in the general population [[13]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4380) Google Scholar]. Insulin resistance is strongly associated with obesity and contributes to liver steatohepatitis, which is associated with more severe liver necroinflammatory activity, fibrosis and cirrhosis [[14]Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Crossref PubMed Scopus (949) Google Scholar]. The link between insulin resistance and the development of HCC has been established [[13]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4380) Google Scholar], and it might be a risk co-factor in the HIV setting due to high rate of insulin resistance induced by HAART [[15]Samaras K. Wand H. Law M. Emery S. Cooper D. Carr A. Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia.Diabetes Care. 2007; 30: 113-119Crossref PubMed Scopus (240) Google Scholar].Although there is currently some confusion surrounding the role of HAART in accelerating or preventing the development of HCC in HIV, the beneficial effect of HAART in slowing liver fibrosis progression and improving survival in HIV and HCV co-infected patients should be kept in mind [[16]Qurishi N. Kreuzberg C. Luchters G. Effenberger W. Kupfer B. Sauerbruch T. et al.Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection.The Lancet. 2003; 362: 1708-1713Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar]. Moreover, a recent study that aimed at estimating the future disease burden of HCV and HIV infection in the United States concluded that the predicted increase HCV mortality can only be tackled by better access to antiretroviral therapy or antiretroviral therapy with greater efficacy [[2]Deffic-Burba S. Poynard T. Sulkowski M.S. Wong J.B. Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States.J Viral Hepat. 2007; 14: 107-115Crossref PubMed Scopus (132) Google Scholar].1.2 Clinical characteristicsHIV infection is known to influence the course of both HBV and HCV infections. In HBV infection it impairs the quantity and quality of the innate and adaptive immune response, leading to a more rapid progression of liver fibrosis and a higher incidence of decompensated cirrhosis (although incidence of HCC is not clearly affected) [[17]Puoti M. Bruno R. Filice G. Carosi G. Natural history of chronic hepatitis B in coinfected patients.J Hepatol. 2006; 44: S65-S70Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar]. Early initiation of HAART could help prevent severe immune dysfunction.HIV significantly modifies the course of HCV infection, increasing the risk of cirrhosis and accelerating fibrosis progression leading to cirrhosis at an earlier age (12–16 years) [[18]Massard J. Radziu V. Thabut D. Moussali J. Lebray P. Benhamou Y. et al.Natural history and predictors of disease severity in chronic hepatitis C.J Hepatol. 2006; 44: S19-S24Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar]. This phenomenon leads to the more rapid development of cirrhosis, found in the non-tumoral liver in most cases of HCC. Moreover, the up-regulation of the Fas ligand by HCV E2 and HIV glycoprotein gp120 in HepG2 cells could enhance the formation of the death-inducing signaling complex in fas-induced apoptosis downstream of Fas receptor activation, thereby favoring carcinogenesis [[19]Balasubramanian A. Koziel M. Groopman J.E. Ganju R.K. Molecular mechanism of hepatic injury in co infection with hepatitis C virus and HIV.Clin Infect Dis. 2005; 41: S32-S37Crossref PubMed Scopus (29) Google Scholar]. In the two large series of patients with HCC in HIV and HCV co-infected patients published to date [1Bräu N. Fox R.K. Xiao P. Marks K. Naqvi Z. Taylor L.E. et al.Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: A U.S.–Canadian multicenter study.J Hepatol. 2007; 47: 527-537Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 4Puoti M. Bruno R. Soriano V. Donato F. Gaeta G.B. Quinzan G.P. et al.Hepatocellular carcinoma in HIV patients: epidemiological features, clinical presentation and outcome.AIDS. 2004; 18: 2285-2293Crossref PubMed Scopus (207) Google Scholar], the characteristics of HIV co-infected patients were similar, that is, they were younger than non-HIV patients (by 10 years), aetiology was similar – three-quarters had HCV, and one-quarter had HBV associated tumour – heavy alcohol consumption was documented (32–46%), the personal history of most patients included drug abuse (75–85%), and HCC occurred in patients with relatively preserved liver function (Child A and B). The characteristics of the tumours were also similar: 35–44% were solitary tumours, with a median size of 4.2 cm, and 32% patients had portal thrombosis. The median level of serum alfa-fetoprotein (AFP), considered by some authors as indicative of poor prognosis, was found higher than in monoinfected patients in both series. Overall survival was similar in both series – approximately median survival of 6 months – which is considered a very poor prognosis. This prognosis might reflect an advanced stage of the disease in patients not receiving surveillance but with a natural history that parallels HCC in non-HIV individuals. Alternatively, the poor outcome might reflect a more aggressive biological pattern. Prospective studies are required to elucidate this issue.In these series, 50–60% of the patients received unproven or ineffective therapy, whereas more aggressive treatments, based on tumour and liver disease characteristics, are worth trying. None of the patients was considered for liver transplantation, which is no longer contraindicated in HIV patients. Although the tumour stage was similar in HIV and non-HIV patients, only a few HIV patients received potentially curative therapies [20Francoz C. Belghiti J. Durand F. Indications of liver transplantation in patients with complications of cirrhosis.Best Pract Res Clin Gastroenterol. 2007; 21: 175-190Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 21Ettorre G.M. Vennareecci G. Boschetto A. Giovanelli L. Antonini M. Carboni F. Resection and transplantation: evaluation of surgical perspectives in HIV positive patients affected by end-stage liver disease.J Exp Clin Cancer Res. 2003; 22: S167-S169PubMed Google Scholar, 22Bruno R. Puoti M. Sacchi P. Filice C. Carosi G. Filice G. Management of hepatocellular carcinoma in human immunodeficiency virus infected patients.J Hepatol. 2006; 44: S41-S50Abstract Full Text Full Text PDF Scopus (30) Google Scholar] compared to non-HIV patients in both series.Clearly, clinicians should be more willing to consider more aggressive surveillance and application of effective therapies in this subset of patients, who have a very poor survival at present. Although the HIV-infected patients included in the two series show similar clinical patterns, very different conclusions are drawn from the two studies. In the US-Canadian series [[1]Bräu N. Fox R.K. Xiao P. Marks K. Naqvi Z. Taylor L.E. et al.Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: A U.S.–Canadian multicenter study.J Hepatol. 2007; 47: 527-537Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar], patients with HCC had a poor prognosis (median survival of 6 months), and optimal screening was not defined. Indeed, survival curves were similar for HIV-positive and HIV-negative patients or HCV monoinfected and HIV/HCV co-infected patients. The European study [[4]Puoti M. Bruno R. Soriano V. Donato F. Gaeta G.B. Quinzan G.P. et al.Hepatocellular carcinoma in HIV patients: epidemiological features, clinical presentation and outcome.AIDS. 2004; 18: 2285-2293Crossref PubMed Scopus (207) Google Scholar] found a median survival of 700–725 days in monoinfected patients in both series (Brescia HCC study and CLIP database). Results are however difficult to compare because of the lack of a common staging system used. In the US–Canada cohort more than half of the patients belonged to BCLC C or D. In this stage of the disease, the natural history of untreated individuals is of a median survival of 6 and 3 months, respectively [23Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.The Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3757) Google Scholar, 24Beaugrand M. Sala M. Degos F. Sherman M. Bolondi L. Evans T. et al.Treatment of advanced hepatocellular carcinoma (HCC) by Seocalcitol (a vitamin D analogue). An international randomized double-blind, placebo-controlled study in 747 patients.J Hepatol. 2005; 42: 517Google Scholar]. Conversely, in patients at intermediate stage of the disease (BCLC-B) the median survival of untreated patients is 15 months [23Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.The Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3757) Google Scholar, 24Beaugrand M. Sala M. Degos F. Sherman M. Bolondi L. Evans T. et al.Treatment of advanced hepatocellular carcinoma (HCC) by Seocalcitol (a vitamin D analogue). An international randomized double-blind, placebo-controlled study in 747 patients.J Hepatol. 2005; 42: 517Google Scholar]. Thus, differences in outcome might reflect differences in staging between both studies. The reasons for these discrepancies in HCC outcome require closer investigation. Is the difference the result of a more aggressive detection policy in Europe? Is it because the outcomes of effective therapies, namely surgery, radiofrequency and chemoembolization, are different? The former is more likely.In conclusion, HCC in HIV patients (generally co-infected with HCV) is currently detected at advanced stages of the disease, and thus prospective detection according to reported surveillance programs is recommended [[25]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar]. Second, we should consider all types of HCC treatment not just for HIV-negative patients but also for HIV co-infected patients, given that the very poor prognosis in HIV co-infected patients may be improved by both aggressive therapeutic options and best supportive care. In addition, with the advent of sorafenib as an efficacious treatment of HCC in advanced stages [[26]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Raoul J, Zeuzem S, et al. For the SHARP Investigators Study Group. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). ASCO Proceedings 2007; LBA1.Google Scholar], prospective studies assessing the effects of this treatment in HIV patients are warranted. The present issue of the Journal [[1]Bräu N. Fox R.K. Xiao P. Marks K. Naqvi Z. Taylor L.E. et al.Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: A U.S.–Canadian multicenter study.J Hepatol. 2007; 47: 527-537Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar] includes a US-Canadian study that represents the largest cohort of HIV patients with hepatocellular carcinoma (HCC) ever reported, in which the course and characteristics of the disease were investigated. Surprisingly, survival was similar in HCC patients regardless of HIV-infected status. This observation poses several questions: (1) What is the incidence of HCC – usually associated with viral hepatitis – in HIV carriers? Are the predictive factors of HCC development well determined in this population? If this is so, how many new patients can be expected over the next decades? [2Deffic-Burba S. Poynard T. Sulkowski M.S. Wong J.B. Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States.J Viral Hepat. 2007; 14: 107-115Crossref PubMed Scopus (132) Google Scholar, 3Powles T. Macdonald D. Nelson M. Stebbing J. Hepatocellular carcinoma in HIV-infected individuals: tomorrow’s problem?.Expert Rev Anticancer Ther. 2006; 11: 1553-1558Crossref Scopus (11) Google Scholar]; (2) Are there any specific clinical features of HCC in HIV-infected patients? What is the natural history of HCC? Is the prognosis of HCV or HBV-related HCC comparable in different series of HIV-infected patients and comparable with the prognosis of HCC in HIV-negative patients with HBV or HCV? Can we propose any beneficial treatments of HCC in HIV-infected patients? Does HIV infection preclude certain therapeutic options, particularly liver transplantation?; (3) Important discrepancies in prognosis have been found in the two large series currently available comparing the outcome of HCC in HIV co-infected patients with large series of patients with HCC mostly related to HBV or HCV infection [[4]Puoti M. Bruno R. Soriano V. Donato F. Gaeta G.B. Quinzan G.P. et al.Hepatocellular carcinoma in HIV patients: epidemiological features, clinical presentation and outcome.AIDS. 2004; 18: 2285-2293Crossref PubMed Scopus (207) Google Scholar]. Why might such discrepancies arise? 1. Viral hepatitis in HIV patients and incidence of HCCOf the 40 million persons infected with HIV, 2–4 million are chronic HBV carriers, and 4–5 million are chronic HCV carriers [[5]Alter M. Epidemiology of viral hepatitis and HIV co-infection.J Hepatol. 2006; 44: S6-S9Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar]. The prevalence of HIV and HCV or HBV co-infection depends on the geographic region. HIV and HBV co-infection is most prevalent in regions where HBV infection is endemic such as sub-Saharan Africa and Asia. In these regions, chronic HBV infection is usually acquired within the first years of life through perinatal or vertical transmission, which implies that many young adults are susceptible to HIV infection by sexual route. By contrast, HCV and HIV co-infection is predominantly found in individuals with large or repeated exposure to blood derivatives before widespread testing procedures reduced the risk of contamination or in intravenous drug users (in southern Europe, more than 80% of HIV infected intravenous drug users also have HCV co-infection) [[6]Rockstroh J.K. Mocroft A. Soriano V. Tural C. Losso M.H. Horban A. et al.Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy.J Infect Dis. 2005; 192: 992-1002Crossref PubMed Scopus (334) Google Scholar]. Recently, some cases of acute sexually transmitted HCV infection have been reported among HIV-infected men who have sex with men [[7]Gotz H.M. van Doornum G. Niesters H.G. den Hollander J.G. Thio H.B. de Zwart O. A cluster of acute hepatitis C virus infection among men who have sex with men – results from contact tracing and public health implications.AIDS. 2005; 19: 969-974Crossref PubMed Scopus (212) Google Scholar].Several cohort studies in co-infected patients have shown the progressive increase of the mortality due to end-stage liver disease (ESLD). In a multicenter French study in HIV-infected patients, the mortality rate attributable to cirrhosis and/or HCC had increased from 1.5% of deaths in 1995 to 12.6% in 2003 [[8]Rosenthal E. Pialoux G. Bernard N. Pradier C. Rey D. Bentata M. et al.Liver related mortality in human immunodeficiency virus infected patients between 1995 and 2003 in the French GERMIVIC joint study network.J Viral Hepat. 2007; 14: 183-188Crossref PubMed Scopus (124) Google Scholar]. In another large European multicenter study, ESLD was the most frequent cause of non-AIDS-related mortality, accounting for nearly 15% of all deaths. Factors associated with liver-related mortality were HCV co-infection and low CD4+ count [[9]Weber R. Sabin C.A. Friis-Moller N. Reiss P. El-Sadr W.M. Kirk O. et al.Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study.Arch Intern Med. 2006; 166: 1632-1641Crossref PubMed Scopus (931) Google Scholar].Almost all studies concur that HIV co-infection increases the risk of cirrhosis and shortens time to cirrhosis in HCV-infected patients [10Kramer J.R. Giordano T.P. Souchek J. Richardson P. Hwang L.Y. El Serag H.B. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in US veterans with hepatitis C.Am J Gastroenterol. 2005; 100: 56-63Crossref PubMed Scopus (130) Google Scholar, 11Posthouwer D. Makris M. Yee T.T. Fischer K. van Veen J.J. Griffioen A. et al.Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study.Blood. 2007; 109: 3667-3671Crossref PubMed Scopus (73) Google Scholar]. In particular, a multicenter study of 847 anti-HCV positive patients with congenital bleeding disorders, of whom 210 were HIV and HCV co-infected, found a significantly higher cumulative incidence of cirrhosis in HIV and HCV co-infected patients than in HCV monoinfected patients after 35 years of infection (11.5% vs 35%) [[11]Posthouwer D. Makris M. Yee T.T. Fischer K. van Veen J.J. Griffioen A. et al.Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study.Blood. 2007; 109: 3667-3671Crossref PubMed Scopus (73) Google Scholar].Although it would seem plausible that HIV infection increases the likelihood of HCC development due to the negative impact of HIV on the natural history of HCV infection, practically there is no evidence to support this hypothesis. For instance, in a study to determine whether HIV increases the risk of HCC – by comparing the incidence of HCC in HCV monoinfected patients and HIV and HCV co-infected patients between 1991 and 2000 – the authors could not demonstrate a higher incidence of HCC in the co-infected group [[10]Kramer J.R. Giordano T.P. Souchek J. Richardson P. Hwang L.Y. El Serag H.B. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in US veterans with hepatitis C.Am J Gastroenterol. 2005; 100: 56-63Crossref PubMed Scopus (130) Google Scholar]. Thus, HIV–HCV co-infection increases the progression to cirrhosis, but whether it also increases the incidence of HCC remains to be elucidated.1.1 Predictive factors for HCC developmentWhen discussing predictive factors for HCC in HIV-infected patients, the role of highly active antiretroviral therapy (HAART) as a moderator of HCC risk should be considered. One study [[12]Giordano T.P. Kramer J.R. Souchek J. Richardson P. El Serag H.B. Cirrhosis and hepatocellular carcinoma in HIV veterans with and without the hepatitis C virus.Arch Intern Med. 2004; 164: 2349-2354Crossref PubMed Scopus (150) Google Scholar] showed that the incidence of cirrhosis in HIV and HCV co-infected patients increased from the pre-HAART to the HAART era, a result that may imply that the improved survival due to HAART led to longer exposure to HCV and hence a higher risk of cirrhosis; however, it should be taken into account that the risk of cirrhosis was still higher after adjusting for survival time. Other factors in association with hepatitis virus could increase the risk of HCC. As in monoinfected patients, heavy alcohol intake will favor the development of cirrhosis and HCC and the severity of liver disease can also be boosted by any drug-induced hepatitis. Some studies have found an association between obesity and the risk of HCC in the general population [[13]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4380) Google Scholar]. Insulin resistance is strongly associated with obesity and contributes to liver steatohepatitis, which is associated with more severe liver necroinflammatory activity, fibrosis and cirrhosis [[14]Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Crossref PubMed Scopus (949) Google Scholar]. The link between insulin resistance and the development of HCC has been established [[13]El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4380) Google Scholar], and it might be a risk co-factor in the HIV setting due
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