Project 1

The Role of HIV Infection in the Etiology and Clinical Manifestations of Hepatocellular Carcinoma

Project 1 will conduct an HCC hospital-based, case-control study to define the role of HIV and related immunosuppression in the etiology of HCC. We will compare 600 HCC cases to an equivalent number of controls from the Orthopedic Ward. A second control group will match the 120 HIV-associated HCC cases identified with 240 HIV-infected controls without HCC and allow examination of the association between HIV-related immunosuppression, HIV viremia, and ART history with HCC.

SPECIFIC AIMS: Hepatocellular carcinoma (HCC) is one of the few cancers with increasing incidence in the US, attributed largely to prolonged infection with hepatitis B or C viruses (HBV, HCV). Worldwide, HCC is among the most common and most lethal cancers, with some evidence for increasing HCC rates in sub-Saharan Africa. With improved survival following effective antiretroviral therapy (ART), liver disease including HCC has become a leading cause of death among HIV-infected persons. Paradoxically, as HIV-infected persons survive longer, the burden of HCC is expected to increase substantially in aging African populations with endemic HBV, sporadic HCV, and generalized HIV epidemics. Substantial data support a role for HIV infection in accelerating development of liver fibrosis and end-stage liver disease in coinfection with either HBV or HCV. However, an independent effect of HIV on HCC risk, beyond that attributable to coinfection with viral hepatitis, has not been clearly demonstrated. Further, the role of HIV-related immune suppression in increasing HCC risk remains poorly characterized. Data to address these issues remains sparse because HCC remains a rare event in HIV-infected populations. In prior collaborations, Drs. Ocama, Kirk and colleagues have documented increasing HCC incidence rates in Uganda, a high prevalence of liver fibrosis associated with HIV, and demonstrated the feasibility of conducting high-level research on HCC and HIV in Uganda. To address these issues, the Specific Aims of Project 1 include:

Aim 1. To establish whether HIV infection independently increases the risk for HCC. In a hospital-based case-control study design, incident HCC cases (N=600) will be identified at the Mulago Hospital and the Uganda Cancer Institute (UCI) and matched to controls from the Orthopedic wards by age, gender and residence. We will examine whether HIV infection is associated with HCC controlling for other known etiologic factors including HBV, HCV and environmental factors (aflatoxin, alcohol, smoking,).

Aim 2. To determine the role of HIV-related immune suppression and antiretroviral therapy on risk for HCC. Among HIV-infected HCC cases (N=120 from Aim 1) and matched HIV-infected controls (N=240) recruited from the IDI cohort, we will examine whether markers of immune suppression (current or nadir CD4 count), levels of HIV viremia, or ART exposure history are associated with HCC risk.

Aim 3. To identify differences in the clinical presentation, prognosis, and etiological factors in HIV-associated HCC compared to non-HIV HCC. To determine if important clinical or prognostic differences exist in HIV-associated HCC, we will compare and contrast key clinical (e.g., type and duration of symptoms, tumor marker levels, multifocality, de novo HCC vs. HCC occurring in the setting of cirrhosis, survival) to non-HIV-associated HCC cases. Second, we will determine if the prevalence and magnitude of risk associated with traditional HCC etiological factors (e.g., HBV, HCV, alcohol, aflatoxin, smoking, obesity) differs substantially in HIV-associated HCC compared to non-HIV-associated HCC.