HIV-associated immunosuppression increases risk of liver cancer

Immune suppression caused by HIV increases the risk of liver cancer, say researchers with the Swiss HIV cohort. Their report, published in the October 18^th edition of AIDS, also suggests that the effect is most pronounced in the presence of hepatitis B virus infection. Liver cancer, they say, may become a significant issue in areas of the world where hepatitis B is endemic such as sub-Saharan Africa and Asia as lifesaving treatment allows people with HIV to live longer.

Deaths due to liver disease are becoming more common as people with HIV live longer thanks to antiretroviral therapy. Co-infection with hepatitis B or C virus is common among people with HIV, and there is evidence that co-infection with HIV and hepatitis B or hepatitis C increases the risk of cirrhosis and liver-related deaths.

However, there has been no clear evidence that HIV itself has an impact on the risk of liver cancer. A large 2001 study found that CD4 cell count at AIDS diagnosis did not predict cancer risk and suggested that the excess risk could be attributed to the high prevalence of hepatitis virus co-infection.

To further investigate the link between immune suppression and liver cancer, investigators undertook a case-control study using data from the Swiss HIV cohort. Investigators searched the cohort database for cases of liver cancer and identified 26 cases of hepatocellular carcinoma (HCC). For each patient, investigators then attempted to select ten matched control patients without cancer. They obtained a total of 251 controls.

When investigators compared markers of immune function between the two groups, they found that CD4 cell count taken within a year of diagnosis was associated with risk of liver cancer. Each 100 cells/mm³ decrease was associated with a 33% increase in risk (odds ratio [OR] 1.33, 95% CI: 1.06 - 1.68). Compared to a CD4 cell count above 500 cells/mm³, a CD4 cell count between 200 and 499 cells/mm³ was associated with an OR of 5.32 (1.15 - 24.5), and a CD4 cell count below 200 cells/mm³ was associated with an OR of 6.70 (1.24 - 36.1). Changes in CD4 cell percentage (OR for each 10% decrease 1.65, 1.01 - 2.71) and a history of AIDS (OR 2.40, 1.06 - 5. 44) were also associated with an increased risk of cancer.

The investigators state: “Our present nested case-control study showed, for the first time, a specific association between HCC risk and low CD4+ cell count in the year preceding hepatocellular carcinoma diagnosis. These findings, therefore, complement previous reports that declining CD4+ cell counts increase overall liver-related deaths, predominantly due to liver failure, among [people with HIV]”.

Several factors did not appear to be linked to cancer, including CD4 cell count at enrolment into the cohort, HIV viral load and history of antiretroviral use. The investigators suggest that this last finding speaks against the hypothesis that HIV treatment, which is known to be toxic to the liver, may hasten liver damage and increase the risk of cancer.

The investigators made another striking finding: all cases of cancer were associated with infection with either hepatitis B or hepatitis C. Of the 26 cases, ten were in people with hepatitis B infection, eleven were in people with hepatitis C infection, and five were in people with both infections. Moreover, infection by each virus fell clearly into HIV transmission categories. Among injecting drug users, 13 of 14 had hepatitis C virus infection, while among men who have sex with men (MSM) and heterosexuals, eleven of twelve had hepatitis B virus infection. There were no cases of cancer in the absence of hepatitis virus infection. This link between hepatitis virus infection and cancer remained unexplored because, as the investigators write, “matching for transmission category hampered us from evaluating the importance of hepatitis virus infections as independent risk factors for hepatocellular carcinoma”.

Investigators then looked at the impact of CD4 cell count on cancer risk in the two transmission populations. “The association between lower CD4 cell counts and HCC risk was also particularly strong for MSM/heterosexual/other and hence, due to the strong dichotomy mentioned above, for hepatitis B-related hepatocellular carcinoma.” In addition to corroborating evidence that hepatitis B virus worsens liver damage, especially at low CD4 cell counts, the investigators add that, “the hypothesis that immune suppression might actually reduce [hepatocellular carcinoma] risk due to less immune destruction of [hepatitis B virus]-infected hepatocytes appears…unlikely.”

Hepatitis C infection predominated in injecting drug users, and in this group there was no evidence of an increased risk of liver cancer with lower CD4 cell counts. This is at odds with other evidence that HIV increases liver disease and liver-related death in co-infected individuals, and the investigators offer that the injecting drug users control group was more immunodeficient than their gay men counterparts and this may have masked any effect of hepatitis C on cancer risk.

While preliminary, the study provides some interesting findings on the role of hepatitis C and hepatitis C in liver cancer among people with HIV. And the results might be far reaching, the investigators end: “The present findings are also relevant for the millions of [people with HIV] worldwide who live in [hepatitis B virus] endemic areas in sub-Saharan Africa and Asia as their survival also improves on [antiretroviral therapy]”.