The pathogenesis of HCC in viral hepatitis
Up to 75% of cases of HCC worldwide are thought to be associated with hepatitis B or C[8
]. While the continual inflammation and repair of cirrhosis is an important pathogenic factor in both diseases, the degree of viral replication is more closely related to HCC risk in HBV than in HCV infection. The risk of HCC in active chronic hepatitis B is some 90-fold greater than age-matched healthy controls but only 9-fold greater in inactive carriers of HBV where viral load is low. Also, viral titres seem to correlate directly with the risk of HCC in hepatitis B[9
In hepatitis C, the presence of cirrhosis is a prerequisite to the development of HCC, which occurs in between 1%-4% of patients per annum once cirrhosis is established. Indeed, the increased risk of HCC in cirrhotic patients persists in the absence of the virus after successful eradication with IFN therapy[10
These differences probably represent the different underlying pathogeneses of HCC in HBV versus
]. In the former, the random integration of viral DNA into the host chromosomes (an incidental process not necessary for viral replication) leads to secondary chromosomal rearrangement and genomic instability. The HBV DNA product protein HBx (crucial to replication) transactivates genes involved in cell-cycle control (c-jun and c-myc for example). In vitro
HBx has been shown to disrupt cell-cycle control and inhibit DNA repair and apoptosis all of which have oncogenic potential in their own right[12
By contrast, the HCV does not integrate into host cell DNA. Some HCV core proteins do enter the nucleus and modify a variety of signal transduction pathways. Additionally, oxidative cellular injury occurs as a direct result of HCV core protein expression both in vitro
and in vivo
]. Although this may participate in the carcinogenic process to a small degree, the principal oncogenic effect of HCV is mediated indirectly through activation of the immune-mediated inflammation and its downstream effects on cell proliferation and apoptosis.
The incidence of HCC in the HIV positive cohort
The 2001 French Mortavic study[14
] was a prospective 1-year cohort study of 25 178 HIV positive patients across 65 national centres comparing the incidence and causes of death to similar cohorts in 1995 and 1997. Deaths from end-stage liver disease (ESLD) rose significantly from 1995 to 2001 (1.5% to 14.3%) and the proportion of those deaths due to HCC also rose 5-fold (4.7% to 25%). Nearly all deaths from HCC were in patients with HCV co-infection. Deaths from AIDS during this period fell from 91.6% to 48.7% and overall mortality from 8.15% to 1.05%. The authors thus concluded that increased longevity in the HAART era is the principle reason for increased ESLD and HCC in the 2001 cohort. A large retrospective cohort study of US veterans (following 14 018 male veterans from 1997 to 2004) has also confirmed a much higher risk of HCC in the HIV population, nearly exclusively in association with HCV (and to a lesser extent HBV) co-infection[15
]. A third retrospective cohort-spanning the pre-HAART and HAART eras-revealed a much higher incidence of HCC in patients with HIV/HCV co-infection than average and the difference was much more marked in the HAART era (only 5 diagnosis of HCC were made in the entire cohort of 11 678 patients in the pre-HAART era, versus
22 in the HAART era)[1
]. Smaller, retrospective cohort studies in Europe have yielded similar results. One study of 2383 HIV positive patients found a higher-than-expected incidence of HCC (6 cases in total, four of which had HCV co-infection) compared with the population average[16
It is noteworthy that studies examining cohorts in the pre-HAART era or in countries where HAART is not readily available, have frequently found the incidence of HCC to be lower or equal to average population rates[17,18
]. The more recent studies, however, proffer convincing evidence that HCC incidence is higher than the population average and rising amongst the HIV-positive population receiving HAART-nearly exclusively in association with HCV or HBV infection- and cite increased longevity as the principal cause of this phenomenon.
However, none of the above studies indicates that there is a higher incidence of HCC in HIV and viral hepatitis co-infection compared to isolated HCV or HBV infection- as one might expect if HIV accelerates the disease progression of viral hepatitis towards HCC.
HCC oncogenesis in viral hepatitis-is HIV a true additional risk factor?
While the HIV virus itself is not considered to be particularly oncogenic in its own right, a number of cancers are well known to occur with increased frequency in people with HIV infection. For the most part this is a consequence of impaired immunity and failure to clear several common oncogenic viruses such as HHV8 in Kaposi sarcoma (KS), EBV in non-Hodgkin’s (NHL) and HPV in anal and cervical cancer.
studies in murine models have revealed a potential role for the HIV Tat gene in liver tumorigenesis. Transgenic mice expressing this gene have a greater incidence of hepatocellular carcinoma. This is thought to be mediated by extra-hepatic growth signals rather than by direct disruption of the hepatocyte cell cycle by the Tat product and the effect is not specific for hepatocarcinoma; these animals suffer a higher incidence of other extra-hepatic tumours (leiomyosarcomas, squamous cell papillomas and carcinomas, adenocarcinomas of skin adnexa and B-cell lymphomas). In humans, however, large retrospective cohort studies in the HAART era have shown no increased incidence of HCC in HIV monoinfection[1
There is clearer evidence that HIV can accelerate disease progression of both HBV and HCV and thus indirectly increase the chance of subsequent HCC. HIV affects the natural history of HCV infection in two important ways: firstly, it increases the likelihood of chronic infection following the acute episode[19
] and secondly, it hastens the development of cirrhosis once chronic infection is established[20,21
]. This has important implications for the subsequent development of HCC and any screening strategy. HIV co-infection has also been shown to accelerate the progression of HBV infection[22
], with patients suffering from more severe disease at an earlier stage. Increased liver injury in viral hepatitis may also be mediated indirectly in HIV by antiretroviral therapy-related hepatotoxicity and by immune reconstitution syndrome. Indeed, HCV infection seems to increase the risk of HAART-related hepatotoxicity[23
]. It must also be considered that once HCC has developed, a putatively weaker anti-tumour response due to chronically low CD4+ and CD8+ lymphocyte counts may result in more rapid growth and spread of disease.
Despite evidence for acceleration of cirrhosis in viral hepatitis with HIV co-infection, attempts to demonstrate a specific increase in HCC in this context-over and above that observed in HCV or HBV monoinfection- have so far yielded variable results.
In the US veterans studies mentioned above, direct comparisons were made between HCV mono-infected subjects and groups with HIV/HCV co-infection.
Mcguinnis et al (2001)[15
] compared the incidence of HCC between 14 018 HIV positive and 28 036 age-, sex- and location-matched HIV-negative controls in a large retrospective cohort study from 1997 to 2004. A higher age-matched incidence of HCC was clearly demonstrated in the HIV positive group (incidence rate ratio 1.68) but when adjusted for HCV infection and/or alcohol consumption the incidence rate rations were similar, suggesting HIV co-infection confers no additional risk of HCC compared to HCV infection alone.
A precursor of this study (another retrospective cohort of US veterans) compared the incidence of cirrhosis and HCC in 26 641 HCV-only with 4761 HCV/HIV co-infected subjects between 1991 and 2000[24
]. The incidence of HCC in both groups was found to be the same in the HAART era and lower in the HIV/HCV co-infection group in the pre-HAART era. This would corroborate the premise that HIV patients did not survive sufficiently long in the pre-HAART era to develop HCC, but also suggests that in the HAART era HIV status does not seem to alter the likelihood of progression to HCC in HCV infection.
These studies, however, are subject to several sources of error. In one retrospective cohort the authors concede that up to 50% of the apparent HCV-only group were never tested for HIV (which would bias the study towards the null) and it was also subject to changes in disease reporting and coding during the study period which may have lead to significant acquisition bias. More importantly, a recurring confounding factor is the rising incidence of cirrhosis (and therefore HCC) throughout the study period in patients with isolated HCV infection. This may reflect earlier acquisition of HCV in this group (often in the 1970s in the US) compared to their HIV co-infected counterparts and highlights a recurring deficiency in such retrospective cohort studies: they rarely include data on when infection was acquired. Although HCC rates may be similar in HIV/HCV and HCV-only groups in the immediate post-HAART era, the HIV/HCV co-infected cohort may well have acquired HCV more recently and thus the equal incidence may actually belie accelerated disease progression in this group.
The 2004 Italian cooperative group on AIDS and Tumours (GICAT) study examined 41 cases of HCC in HIV positive individuals (from a joint Italian and Spanish database) and compared them with 384 HIV-negative controls diagnosed over the same period (1995-1998)[25
]. This is the largest study purporting to show an acceleration of liver disease towards HCC in HIV and viral hepatitis co-infection. The HIV group with HCC were much younger at presentation (age 40-46 vs
60-70) and had more advanced infiltrating disease. There was also a trend to more advanced cirrhosis at presentation in the HIV positive population. Accordingly, few of the HIV patients were offered active treatment and survival rates were poor. Again, HCV co-infection was clearly the main risk factor in both the HIV positive group and negative controls. In this study, the younger age at diagnosis and the limited data available on the timing of HCV infection in both HIV co-infected and HCV-only groups suggested HIV-HCV co-infected patients develop HCC some 10 years earlier than expected (compared with a previous series examining HCC in HIV-negative patients with post-transfusion HCV).
Three further studies have also described earlier develop-ment of HCC (and poorer outcome) in HIV co-infected subjects compared with HBV or HCV monoinfection, including one cohort of British haemophiliac men and boys[26
], one of homosexual men in the United States[27
] and a Spanish retrospective cohort of 2383 HIV positive subjects[28
]. The total numbers of cases of HCC in each study were very low, however.
Convincing evidence for an HIV-induced acceleration of disease progression in viral hepatitis towards HCC thus remains lacking. Of note is a glaring lack of studies specifically addressing HBV and HIV co-infection-presumably because this is far less prevalent than HCV/HIV co-infection in the developed countries which have the advanced information infrastructure needed to carry out retrospective trawls of large databases.
If one postulates the ideal study to address whether HIV is a true additional risk factor for HCC in viral hepatitis, it would consist of a prospective cohort of HIV/HCV/HBV co-infected and HCV- and/or HBV-only subjects with all subjects cross-tested for co-infection before allocation to groups (and at regular intervals thereafter). It would also instigate screening for HCC on a regular basis. It might be reasonable to expect that even if HIV has an accelerative effect on HCC pathogenesis this might be countered viral suppression by HAART, therefore such a study would undertake regular monitoring of HIV viral load in the HIV co-infected group. Crucially, if the duration of HIV and HBV/HCV infection is known for each patient, fewer patients and years of follow-up would be necessary to detect an accelerative affect of HIV on progression to HCC.
It is telling that almost none of the studies mentioned above include any such parameters. On the basis of existing evidence, we can only conclude that if an additional risk of progression to HCC in viral hepatitis is conferred by HIV it is not large enough to be detected by relatively crude retrospective examination within the short space of time (relative to normal HCC pathogenesis) that has passed since the introduction of HAART.