Despite rising incidence of hepatocellular carcinoma (HCC) in HIV+ patients, few studies have evaluated determinants of HCC during the antiretroviral therapy era. We evaluated HIV-related and traditional risk factors for HCC in a large cohort of HIV+ patients.
We conducted a retrospective cohort study among HIV+ patients in the Veterans Aging Cohort Study from 1999-2015. Patients had HIV RNA and CD4+ cell count simultaneously assessed in the Veterans Affairs (VA) system, and follow-up began on this date. Incident HCC was determined using the VA Cancer Registry. We used multivariable Cox regression to determine adjusted hazard ratios (HR [95% confidence interval]) of HCC associated with cumulative unsuppressed HIV RNA (≥500 copies/mL), time-updated lower CD4+ count, older age, male sex, race/ethnicity, morbid obesity (body mass index ≥35 kg/m²), time-updated diabetes status, alcohol use disorder, hepatitis B virus (HBV), and hepatitis C virus (HCV) coinfection. The analysis was repeated substituting time-updated HIV RNA for cumulative unsuppressed HIV RNA. Since advanced hepatic fibrosis/cirrhosis is the strongest determinant of HCC and may overwhelm other risk factors, we stratified analyses by low and high baseline FIB-4 (<3.25 versus ≥3.25, respectively), a commonly used fibrosis index.
Among 36,525 HIV+ patients, 275 (0.8%) developed incident HCC. Overall, baseline FIB-4 ≥3.25 was the strongest factor associated with HCC (HR 15.1 [9.7-23.5]). However, 36.4% of HCC events occurred among those with FIB-4 <3.25. Among these patients, older age (HR 1.4 [1.2-1.7] per 10 years), morbid obesity (HR 2.6 [1.2-5.3]), diabetes (HR 1.5 [1.1-2.1]), ≥12 months of unsuppressed HIV RNA (HR 2.0 [1.4-2.9]), lower CD4+ count (200-349 cells/mm³: HR 1.5 [1.1-2.2]; <200 cells/mm³: HR 1.6 [1.0-2.4] versus ≥500 cells/mm³), HBV coinfection (HR 5.2 [3.7-7.3]), and HCV coinfection (HR 6.1 [4.1-9.0]) were independently associated with incident HCC. The risk of HCC was also increased with higher HIV RNA level (HR 1.3 [1.1-1.4] per 1.0 log10 copies/mL).
Among HIV+ patients without advanced liver fibrosis, higher HIV RNA and longer duration of HIV viremia, greater immunosuppression, morbid obesity, and diabetes, in addition to HBV and HCV coinfection, increased the risk of HCC. Addressing these factors before development of advanced fibrosis could help reduce the incidence of HCC in HIV+ patients.