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Management of hepatocellular carcinoma in HIV- infected patients
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Journal of Hepatology
Volume 44, Issue (Supplement 1), Pages S146- S150 (2006)
Raffaele Brunoa, Massimo Puotib, Paolo Sacchia, Carlo Filicea, Giampiero Carosib, Gaetano Filicea
a Division of Infectious and Tropical Diseases, IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy
b Department of Infectious and Tropical Diseases Spedali Civili di Brescia, University of Brescia, Brescia, Italy
Hepatocellular carcinoma (HCC) resulting from chronic infection with hepatitis B or C virus (HBV, HCV) is a significant health problem. Concurrent infection with human immunodeficiency virus (HIV) may accelerate the progression from cirrhosis to HCC. Current guidelines advise screening patients with cirrhosis at 6- month intervals using ultrasonography and measurement of alpha- fetoprotein levels. In early- stage HCC, resection and liver transplantation are curative, as is percutaneous ethanol injection for small tumours in patients who are not candidates for surgery. HIV- infected patients do not qualify for liver transplantation. For late- stage HCC, chemoembolization can improve survival. Prevention of hepatitis and cirrhosis are key goals in reducing the impact of HCC. Numerous issues in HCC prevention, diagnosis, and management still remain to be resolved through large- scale, randomized clinical trials.
Article Outline
- Abstract
- 1. Introduction
- 2. Risk factors for HCC
- 3. Overt and occult HBV infection
- 4. Chronic HCV infection
- 5. Diabetes
- 6. Role of HIV- 1 Tat
- 7. Natural history of HIV co- infection and HCC
- 8. Screening for HCC
- 9. Treatment
- 10. Early- stage HCC
- 11. Advanced HCC
- 12. Prevention of HCC and recurrence
- 13. HIV/HCV co- infection
- 14. Directions for future research
- 15. Conclusion
1. Introduction
More than 80% of cases of hepatocellular carcinoma (HCC) are preceded by cirrhosis, the leading cause of which is chronic infection with hepatitis B or C virus (HBV, HCV) [1-3]. Globally, HBV infection is more common than HCV [4], being endemic in parts of East Asia and Africa [5]. In more developed countries, HCV infection is the primary aetiologic factor for HCC [2,4,6], and the HCC incidence is comparatively low. Over the last two decades, however, the number of cases of HCC has risen in the USA, Japan, and parts of Europe [5]. In USA, the proportion of HCC cases related to HCV infection increased from 11 to 21% during the 1990s in patients 65 years of age and older, and the proportion related to HBV increased from 6 to 11% [7].
Similarity in the routes of transmission for hepatitis and human immunodeficiency virus (HIV) infections increases the likelihood that a certain percentage of persons will be co- infected with HBV or HCV (or both) and HIV [3,6]. Although HIV- infected individuals have a higher incidence of certain cancers than noninfected persons, up until a few years ago, HCC was not one of them [3]. More recent investigation, however, suggests that HIV infection does, in fact, raise the risk for HCC [6,8]. As HIV- infected persons live longer, especially in Western countries where they have access to highly active antiretroviral therapy (HAART), HCC may begin to emerge in patients who would have otherwise succumbed to complications stemming from their primary HIV disease. For this reason, HCC is projected to become an increasingly significant clinical problem in the HIV population [9].
In its advanced stages, HCC is incurable. Early diagnosis and prevention, therefore, become key to controlling the healthcare burden of this disease. At present, there are no universal guidelines for managing HCC in clinical practice. Such recommendations might be problematic in any case, in view of the wide geographic variations in disease epidemiology and treatment availability [2]. Guidelines for managing HCC arising in connection with HIV co- infection are especially lacking. The recommendations for HCC management developed in 2000 by the European Association for the Study of the Liver (EASL) [10] are in the process of being updated and will be available in 2006.
To aid clinicians in the management of HCC, this article reviews the current state of knowledge regarding the natural history of HCC, risk factors, patient screening, and indications for curative and palliative therapies. Information relevant to patients co- infected with HIV is provided. The article concludes with an overview of the numerous issues in the field of HCC that need to be clarified through future research.
2. Risk factors for HCC
Cirrhosis related to chronic HBV and HCV infection is well established as the major risk factor for HCC. Other important risk factors are diabetes, excess alcohol consumption, and nonalcoholic fatty liver disease. An adjunctive hypothetic risk factor in HIV population may be HIV- 1 Tat gene [3,10]
3. Overt and occult HBV infection
It has been well established that chronic HBV carriers have a 5-15 fold increase in the risk of HCC compared with the general population [11]. Among HIV- infected patients, approximately 10% are chronic carriers of HBV infection [8]. Occult infection with HBV also appears to increase the oncogenic risk. Occult HBV infection, i.e. lack of chronic hepatitis B surface antigen (HBsAg), has been linked to cirrhosis in persons with chronic HCV infection [12]. A recent study of HCC patients found that HBV DNA was present in 63% of the HBsAg- negative patients [12]. Persistent low- level replication and ongoing transcription, with production of pro- oncogenic proteins, might contribute to tumour formation. Moreover, occult HBV has been observed in a range from 10% of HIV patients with HB anticore IgG antibody in ACTG cohort to 89,5% in Swiss cohort [13,14].
4. Chronic HCV infection
HCC in association with HCV infection appears to develop more slowly than that related to HBV infection. Upon diagnosis of HCC, HCV- infected individuals are generally older, age 60-70 years, than HBV- infected persons [3]. Liver damage in HCV- associated HCC appears to be caused indirectly, by immunologically mediated destruction of hepatocytes [3].
5. Diabetes
Epidemiological studies have not confirmed either an association between diabetes and HCC or the temporal relationship between the two [15]. Diabetes is, however, associated with chronic liver disease, particularly nonalcoholic fatty liver disease and a severe form, nonalcoholic steatohepatitis, which can lead to cirrhosis and HCC. A recent report has cited a higher risk for HCC among patients with diabetes [15]. A diagnosis of diabetes doubled the risk for chronic nonalcoholic liver disease and HCC and preceded their appearance. Insulin resistance is frequent among HIV patients and may be an adjunctive risk factor in developing nonalcoholic liver disease [16].
6. Role of HIV- 1 Tat
Predisposition to tumour development in HIV infection may involve expression of HIV- 1 Tat protein [17]. Transgenic mice, which express the HIV- 1 tat gene in all tissues and organs, have been shown to develop liver cell dysplasia. Administration of a hepatotrophic carcinogen to these mice causes development of HCC, among other hepatic neoplasms. Tat may play the same role in HIV- infected humans, contributing to the development of the tumours common in AIDS.
7. Natural history of HIV co- infection and HCC
HCC in persons co- infected with HIV is primarily attributable to chronic HCV infection, present in approximately 30% of HIV- infected patients [8]. Co- infection rates may be as high as 75% in injection drug users [8]. The incidence of HCC in HIV/HCV co- infected patients appears to be increasing. A recent large French survey on the cause of death in HIV seropositives described the increase of the prevalence of hepatocellular carcinoma as a non- AIDS related cause of liver related death: from 4.7% in 1995 to 11% in 1997 and 25% in 2000 [18].
The clinical course of HCC in HIV- infected groups is not well described, as most studies have been small. Most evidence indicates that HIV/HCV individuals progress to cirrhosis more quickly than do HCV- infected individuals without HIV and that the HCC is more aggressive [3,9]. In one study of seven patients with HIV/HCV- co- infection, six developed HCC before the age of 45 [6]. A large case- control study conducted recently among patients with stable HIV disease confirmed these observations. HCC was diagnosed at a younger age in HIV than in non- HIV individuals, and the HCC was more advanced (infiltrating or metastatic) at diagnosis. Occurrence of HCC seems to not be related to stage to HIV disease [8].
8. Screening for HCC
The 2000 EASL guidelines describe patient selection and surveillance intervals [10]. At present, the optimal screening protocol is unknown [19]. In brief, patients with Child- Pugh class A cirrhosis should be screened, as should those with Child- Turcotte- Pugh class B cirrhosis if liver transplantation is feasible. Patients with Child- Turcotte- Pugh class C cirrhosis are potential candidates for liver transplantation and thus should be screened only if transplantation is available and they can meet the eligibility criteria. A screening interval of every 6 months has been established to allow detection of tumours <3cm in diameter. Patients whose screening results are abnormal should be followed up at referral centres for diagnosis and staging.
Ultrasonography and measurement of alpha- fetoprotein (AFP) levels are the two methods used most commonly to screen patients with cirrhosis for HCC [20].
Although AFP values >400ng/ml are considered diagnostic of HCC, no threshold value indicative of the need for additional studies has been established [19]. False- positive results with AFP, and dependency on the skill of the operator for ultrasonography, are some of the limitations of these methods [10]. Nevertheless, a recent report of follow- up ultrasonographic surveillance of patients with compensated cirrhosis has indicated that survival among those who developed HCC detected during the last 5- year period of surveillance was longer than that associated with HCC occurrence during the earlier periods of surveillance [21]. The investigators attributed these results to the impact of new developments in the management of HCC, including improved detection of early cancers and use of radical therapies.
Better imaging techniques for detecting small tumours include ultrasound contrast imaging, helical computed tomography and magnetic resonance imaging with contrast enhancement [22], as well as arterial phase imaging. Pseudolesions must be differentiated, however. More sensitive HCC biomarkers have been identified based on transcriptomics and proteomics but have yet to be validated [20,23]. In addition, gene expression profiling has distinguished two subclasses of HCC associated with shorter (cell proliferation, antiapoptosis) and longer patient survival [24].
Because of the swifter course of HCC in HIV- infected patients, they warrant more frequent screening than every 6 months [8]. In the case- control study of HCC in HIV patients described earlier [8], more advanced HCC at diagnosis in the HIV- positive patients did not appear to be related to a delay in diagnosis: five of the eight patients who had had a negative ultrasound evaluation 6 months previously were found at HCC diagnosis to have metastatic disease or a tumour >5cm.
9. Treatment
Treatments for HCC are usually classified as curative or palliative [2]. Curative treatments are surgical resection and liver transplantation, and percutaneous ethanol injection in patients with small tumours who are not candidates for resection. Most patients cannot undergo resection or liver transplantation because of underlying cirrhosis or advanced disease at diagnosis [20].
Local ablative therapies include (in addition to percutaneous ethanol injection) arterial embolization, proton beam radiation, radiofrequency ablation, and intrahepatic infusion of yttrium- 90 microspheres [20,25]. Palliative treatments also include chemotherapy, hormonal compounds, and immunotherapy [2]. A modest survival advantage has been shown for chemoembolization in randomized, controlled trials and one meta- analysis [25,26]. The ideal chemotherapeutic agent for HCC has thus far not been developed [25].
10. Early- stage HCC
A solitary tumour <5cm, or up to threemonths tumours <3cm, in a patient with well- preserved liver function constitutes early- stage HCC [2,10]. Patients with early- stage disease can be successfully treated with curative therapies, although the response rate and survival benefit can be variable [2]. Surgical resection and transplantation yield 5- year survival rates ranging from 60 to 70% [2]. Recurrence, however, can be as high as 50% at 3 years and 70% at 5 years [2,10]. Resection is the preferred treatment for HCC patients without cirrhosis [27]. Patients with multiple tumours or impaired liver function should undergo liver transplantation rather than resection [10]. The shortage of donor livers, together with expanding qualification criteria for transplantation, strains the potential of transplantation as a treatment option [20].
Percutaneous ethanol injection induces a complete response in about 80% of patients whose tumours are 3cm. Response rates are lower with large or multinodal tumours [10]. Five- year survival is 50% in patients who attain complete response, and recurrence rates are comparable to those with resection [10]. For tumours up to 5cm, radiofrequency ablation is also commonly used [11].
11. Advanced HCC
Most patients with HCC (approximately 50%) have advanced disease at diagnosis [10,20]. Patients with advanced disease are candidates for loco- regional or systemic treatments rather than curative approaches [10]. Transarterial chemoembolization is the only palliative therapy that has been shown, with careful patient selection, to improve survival [2,11].
12. Prevention of HCC and recurrence
In areas where HBV infection is highly prevalent, vaccination against HBV has lowered the occurrence of HCC [10]. A nationwide HBV vaccination programme of newborns in Taiwan reduced the incidence of childhood infection and mortality from HCC [28]. Among HIV patients vaccination against HBV is strongly recommended.
Among HBV- infected patients with cirrhosis or advanced fibrosis, continuous treatment with lamivudine appears to significantly delay clinical progression and reduce the incidence of HCC [29]. HCV treatment with interferon has not conclusively lowered HCC rates in patients with cirrhosis, despite some reports of positive results. Interferon appears to be most effective if given before cirrhosis develops. Long- term studies of interferon (including peginterferon) plus ribavirin have not been reported [30].
Promising results for prevention of HCC recurrence after resection have been obtained with retinoids (polyprenoic acid), lipiodol and internal radiation, interferon, and adoptive immunotherapy [27,30]. In a study done in Tokyo, adoptive immunotherapy after curative resection for HCC reduced the overall risk of recurrence by 41% and lengthened the recurrence- free interval [31]. Overall survival, however, was not significantly different.
13. HIV/HCV co- infection
Early diagnosis of HCC is particularly important in patients co- infected with HCV and HIV. In a study of 13 HIV/HCV- co- infected patients diagnosed with HCC, the latency period was estimated to be approximately 10 years [9]. HIV patients are also likely to have other risk factors predisposing them to HCC, such as alcohol abuse and concurrent HBV infection. HIV/HCV- co- infected patients should receive treatment for chronic HCV infection using antiviral therapy, e.g. combination interferon and ribavirin.
14. Directions for future research
Large, multicentre randomized clinical trials following standardized protocols are needed in HCC. The small size of existing randomized trials also limits the conclusions possible from meta- analyses. Numerous issues need to be resolved by further research (Table 1).
Table 1. Clinical research recommendations for patients with HCC
- Safety and efficacy of new agents, alone and in combination
- Different treatment schedules
- Response of different subpopulations (e.g. co- infected vs non- co- infected)
- Natural history of HCC
- Mono- infected vs co- infected
- Role of early diagnosis in improving outcomes
- 3 months vs 6 months ultrasound screening
- Primary and secondary chemoprevention
- Prevention in patients with advanced fibrosis and cirrhosis
- Prevention of recurrence in cured patients
- Role of orthotopic liver transplantation
- Efficacy of adjuvant therapy
The effect of early diagnosis on outcomes, particularly for patients co- infected with HCV and HIV, needs clarification, and the criteria for surveillance need to be better defined. A key issue, which needs to be established, regards the benefit of a more frequent (3 months vs 6 months) ultrasound screening programme.
More information is needed on the survival benefit of treating tumours >3cm and on the use of adjuvant therapy with liver transplantation. The ability to decrease HCC recurrence after resection and transplantation would be an important advance. Further investigation is needed for new HCC therapies, including anti- angiogenesis agents, inhibitors of cell cycle enzymes and growth factors, and novel delivery systems for radiation therapy [25].
15. Conclusion
At present, randomized, controlled clinical studies are still lacking for many aspects of HCC management. New therapeutic approaches are continually being developed. As their safety and efficacy become established, they will fill a critical need as the demand for donor organs for liver transplantation outpaces the supply. Even with curative treatments, HCC recurs; methods for preventing recurrence have been elusive. Patients co- infected with HIV and hepatitis viruses require heightened attention because they face a more rapid progression to HCC.
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