To the Editors:
Chronic infection with HIV alone does not cause hepatocellular carcinoma (HCC) in humans.1,2 HIV is transmitted in similar ways to the two hepatitis viruses (hepatitis B [HBV] and hepatitis C [HCV]) that cause HCC in humans, and coinfection between HIV and HBV or HCV is common in clinical practice.3 Since the introduction of highly active antiretroviral therapy (HAART) in the treatment of HIV/AIDS, an increased occurrence of HCC has been reported in a number of large analyses of patients with HIV/AIDS coinfected with HCV or, to a lesser extent, HBV.2,4-7 A plausible explanation for an increasing incidence of HCC in individuals coinfected with HIV and a hepatitis virus is that the considerably longer survival of patients now receiving HAART compared with those who earlier had been treated with largely ineffective antiretroviral drugs allowed sufficient time for hepatitis virus-induced HCC to develop.7 Another possible explanation is that the immune deficiency caused by HIV infection results in higher hepatitis viral loads, which are known to increase the risk of malignant transformation.8 Alternatively, coinfection with HIV might directly enhance the hepatocarcinogenic effects of the hepatitis viruses. In this regard, the observation in transgenic mice that HIV tat protein expressed constitutively in the liver enhances the effect of a number of carcinogens9 and results in a high incidence of HCC after a long latency10 may be relevant. Furthermore, tat-binding protein interacts with HBV x gene in a such a way as to regulate HBV transcription,11 and HBV x protein induces HIV-1 replication and transcription in synergy with tat protein and T-cell activation signals.12
A retrospective analysis of the occurrence of HCC in patients with HIV/AIDS with hepatitis virus coinfection before the HAART era would be of limited use because of the brief survival of these patients at that time, and a prospective study of the development of the tumor in patients with HIV/AIDS with dual infection receiving or not receiving HAART is ethically unacceptable. A case-control comparison of the occurrence of HIV in patients with hepatitis virus-induced HCC with that in matched asymptomatic carriers of hepatitis virus might, however, provide some information in this regard.
Both HBV and HIV are endemic in sub-Saharan Africa, and HCC occurs commonly in the black population of the subcontinent. HBV is the dominant risk factor for the tumor in this population. HIV and HBV infections currently coexist in between 4.8% and 17% of patients with HIV in South Africa,13 the great majority of whom are blacks, and the figure is appreciably higher if occult HBV infection is taken into consideration.14
We have compared the prevalence of HIV coinfection in 178 southern African black patients with HBV-induced HCC from the time before HAART became available in South Africa with that in 185 age- and sex-matched apparently healthy carriers of HBV from the same time period. Ethical approval for the study was granted by the Research Ethics Committee of the Faculty of Medical Sciences of the University of Cape Town and the Human Ethics Committee of the University of Witwatersrand.
Sera were screened for HIV-1/HIV-2 antibodies and/or p24 antigen with the Architect HIV Ag/Ab Combo Assay (Abbott Diagnostics, Wiesbaden, Germany). Samples found reactive were confirmed using the Enzygnost Anti HIV1/2 Plus enzyme immunoassay (Dade Behring, Marburg GmbH, Germany). The χ2 test was used to determine the statistical significance of the findings.
HIV-1/HIV-2 antibodies were detected in six of the 178 patients (3.36%) with HBV-induced HCC and in none of the 185 apparently healthy carriers of HBV (P = 0.036).The prevalence of HIV in the black carriers is in keeping with prevalences recorded in this population at that time.15
Our finding of a statistically significant increase in the incidence of HBV/HIV coinfection in patients with HCC in comparison with asymptomatic carriers of HBV is compatible with the belief that HIV coinfection synergistically enhances the hepatocarcinogenic potential of HBV and emphasizes the need for further investigation into a possible synergistic interaction between these two viruses in this context.
Because the molecular genesis of HBV-induced and HCV-induced HCC differs,16 an interaction between HBV and HIV in the development of HCC does not mean that a similar interaction would occur with HCV.
This preliminary study has a number of limitations. A larger cohort of patients with HBV-induced HCC and of control subjects needs to be studied to provide a more secure statistical comparison. The present study was conducted on stored sera from patients and control subjects from the pre-HAART era. This limited the size of the populations studied. In addition, the HIV carrier rate in the general black African population was far lower at that time than it is now.13,15 To undertake the study on recent patients would have strengthened the statistical comparison but would have introduced the variable of the prolonged survival of patients with HIV/AIDS receiving HAART. In addition, small volumes only of serum were available, preventing testing for HCV to rule out the possible confounding effect of coinfection with this virus on the results obtained. Other potentially confounding factors such as behavioral differences between the patients with HCC and the control subjects should also be included in future comparisons as should the CD4 counts of those infected with HIV.
Michael C. Kew, DSc, FRCP*
Heidi Smuts, PhD†
Ann Stewart, DipMedTech‡
*Department of Medicine, University of Cape Town and Groote Schuur Hospital and Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
†Department of Microbiology, National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa and Division of Medical Virology, University of Cape Town, Cape Town, South Africa
‡Division of Medical Virology, University of Cape Town, Cape Town, South Africa
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