Project 2

Pre-Malignant Cirrhosis and Hepatocellular Carcinoma in HIV-Infected Ugandans

Project 2, centered in the IDI clinic, will screen 3000 HIV-infected patients for liver cirrhosis and for high-risk HBV and aflatoxin-related biomarkers. A high-risk target group comprised of patients with cirrhosis or high-risk biomarkers will undergo HCC screening with ultrasound every 6 months to determine if early stage HCC can be detected while still potentially curable. The goal of Project 2 is to define risk factors for pre-malignant cirrhosis and to establish whether high-risk HCC screening is feasible and can identify early HCC in this setting. These proposed studies will enhance our clinical and mechanistic understanding of HIV-associated HCC, will provide an evidence-base regarding appropriate treatments in this setting, and will inform the design of future intervention strategies with the goal of reducing the burden of HIV-associated HCC in sub-Saharan Africa

SPECIFIC AIMS: The chief focus of Project 2 is the transition to pre-malignant cirrhosis and hepatocellular carcinoma (HCC) among HIV-infected persons in Uganda. Chronic infection with HBV or HCV markedly increases the risk of liver cirrhosis and HCC; the risk of HCC increases as liver fibrosis progresses to the pre-malignant stage of cirrhosis. HIV infection is known to increase the risk of many virus-associated malignancies including Kaposi’s sarcoma, cervical carcinoma, and lymphoma. Persons with HIV have an increased prevalence of viral hepatitis. In some parts of sub-Saharan Africa, 20% of HIV infected persons will have chronic HBV infection. HIV infection increases the risk of cirrhosis in persons with chronic HBV infection. However, there remain many unanswered questions regarding pre-malignant cirrhosis and development of HCC in persons with HIV; data from African populations are extremely sparse. The importance of answering these questions has increased with prolonged survival from widespread ART use in Africa, which alters the clinical expression of HIV-related disease. In economically-developed countries, HCV-related liver disease emerged in the post-ART era as a leading cause of death. In sub-Saharan Africa, chronic HBV infection is much more common than HCV, and HBV-related liver disease is a much more likely contributor to HCC. On the other hand, since ART includes compounds such as lamivudine, emtricitabine and tenofovir that also suppress HBV infection, it is possible that these HBV-active antiretroviral therapies would reduce the risk of HCC in those co-infected with HBV. Active surveillance for HCC is recommended for persons with HBV-related cirrhosis. However, there are few data to support that practice and none from sub-Saharan Africa even though the recent expansion of ART might provide, for the first time, the medical infrastructure to implement cancer screening. Thus, the aims of Project 2 are:

Aim 1. To estimate the prevalence and identify correlates of pre-malignant cirrhosis in HIV-infected persons attending an urban Ugandan HIV clinic. Elastography, a novel validated method for staging liver fibrosis, will be used to detect cirrhosis among 3,000 patients attending a well-established Kampala HIV clinic. Viral (HBV, HCV, HIV) and environmental (alcohol, aflatoxin) factors associated with cirrhosis will be rigorously evaluated. We anticipate the highest risk of pre-malignant cirrhosis in those with the lowest CD4+ lymphocyte nadir prior to ART, ongoing HBV replication, or heavy cumulative exposure to aflatoxin or alcohol, after adjusting for age, gender, obesity, herbal medicine use, and Schistosomiasis exposure.

Aim 2. Among HIV-infected persons at greatest risk for HCC, we will investigate in the Ugandan setting whether active HCC surveillance can identify potentially-curable, early HCC. From Aim 1, we will identify ~400 HIV-infected persons at greatest risk for HCC based on the presence of cirrhosis or detection of a high-risk biomarker (e.g., elevated HBV DNA levels or aflatoxin-related T249S p53 plasma biomarker). This high-risk cohort will undergo systematic HCC screening by ultrasound every 6 months for 4 years. The incidence and clinical features of HCC will be characterized, along with adherence to the screening program and other measures of feasibility. Our primary comparison will be the proportion of early HCC (e.g., size < 3 cm; 1-3 lesions) among actively-screened cases [N=28-42] compared to HCC cases diagnosed without surveillance [N=120 HIV-associated; N=480 non-HIV HCC from Project 1]. If surveillance improves earlier detection, this proof-of-principle study will provide the first data on HCC screening from sub-Saharan Africa, defining the high-risk target population, informing feasibility and trial parameters for future screening intervention trials, and providing a strong impetus for developing capacity for localized, curative treatments for early HCC (e.g., percutaneous alcohol injection, radiofrequency ablation).