BMC Infectious Diseases MS: 3178466623400730.R1 Page 1 Prevalence and Risk Factors for Significant Liver Fibrosis Among HIV-Monoinfected Patients

Background: HIV-monoinfected patients may be at risk for significant liver fibrosis, but its prevalence and determinants in these patients are unknown. Since HIV-monoinfected patients do not routinely undergo liver biopsy, we evaluated the prevalence and risk factors of significant hepatic fibrosis in this group using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI). Methods: We conducted a cross-sectional study among HIV-infected patients negative for hepatitis B surface antigen and hepatitis C antibody in the Penn Center for AIDS Research Adult/Adolescent Database. Clinical and laboratory data were collected from the database at enrollment. Hypothesized determinants of significant fibrosis were modifiable risk factors associated with liver disease progression, hepatic fibrosis, or hepatotoxicity, including immune dysfunction (i.e., CD4 T lymphocyte count <200 cells/mm 3 , HIV viremia), diseases associated with hepatic steatosis (e.g., obesity, diabetes mellitus), and use of antiretroviral therapy. The primary outcome was an APRI score >1.5, which suggests significant hepatic fibrosis. Multivariable logistic regression identified independent risk factors for significant fibrosis by APRI. Results: Among 432 HIV-monoinfected patients enrolled in the CFAR Database between November 1999 and May 2008, significant fibrosis by APRI was identified in 36 (8.3%; 95% CI, 5.9 – 11.4%) patients. After controlling for all other hypothesized risk factors as well as active alcohol use and site, detectable HIV viremia (adjusted OR, 2.56; 95% CI, BMC Infectious Diseases MS: 3178466623400730.R1 Page 3 1.02 – 8.87) and diabetes mellitus (adjusted OR, 3.15; 95% CI, 1.12 – 10.10) remained associated with significant fibrosis by APRI. Conclusions: Significant fibrosis by APRI score was found in 8% of HIV-monoinfected patients. Detectable HIV viremia and diabetes mellitus were associated with significant fibrosis. Future studies should explore mechanisms for fibrosis in HIV-monoinfected patients. BMC Infectious Diseases MS: 3178466623400730.R1 Page 4 BACKGROUND As survival of HIV-infected individuals has improved with widespread use of combination antiretroviral therapy (ART), non-HIV-related conditions are now common causes of morbidity among HIV-infected patients in the developed world. In particular, liver disease has emerged as an increasingly significant contributor to mortality among HIV-infected patients due to the high prevalence of viral hepatitis coinfection [1]. However, additional factors apart from viral hepatitis could contribute to hepatic fibrosis, including antiretroviral medications [2, 3], concomitant metabolic diseases [4], and immunosuppression [5]. Consequently, HIV-infected patients without viral hepatitis coinfection might also be at risk for liver disease. However, few studies have examined the prevalence and potential risk factors for significant hepatic fibrosis among HIVmonoinfected patients (i.e., those without viral hepatitis coinfection) [2, 6, 7]. Identifying risk factors, particularly those that are modifiable, could help reduce the risk of liver disease in this population, especially as it ages. To address this issue, we evaluated the prevalence and risk factors for significant hepatic fibrosis among HIV-monoinfected patients. Since liver biopsy results are generally not available on sufficiently large numbers of HIV-monoinfected patients to permit appropriate epidemiologic analyses, we used a non-invasive measure of significant liver fibrosis, the aspartate aminotransferase (AST)-to-platelet ratio index (APRI). This index has previously been validated as a surrogate marker of significant hepatic fibrosis in HIV/HCV-coinfected patients [8-10], and has recently been used to determine advanced fibrosis in HIV-monoinfected patients [2]. Our hypothesized determinants of significant fibrosis were modifiable risk factors associated with liver BMC Infectious Diseases MS: 3178466623400730.R1 Page 5 disease progression, hepatic fibrosis, or hepatotoxicity, including immune dysfunction (i.e., CD4 T lymphocyte count <200 cells/mm 3 , HIV viremia) [11], diseases associated with hepatic steatosis (e.g., obesity, diabetes mellitus) [12-14], and ART use [15, 16].