Reduced Risk Of Hepatocellular Carcinoma Research Articles

Beyond the Liver: A Comprehensive Review of Strategies to Prevent Hepatocellular Carcinoma

Background/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, primarily developing in the context of chronic liver disease. Traditional prevention has focused on liver-specific interventions like antiviral therapies and surveillance. However, extrahepatic factors also significantly contribute to HCC risk. This review explores comprehensive strategies for HCC prevention, including both hepatic and extrahepatic factors. Methods: An extensive literature search of peer-reviewed articles up to October 2024 was conducted, focusing on studies addressing HCC prevention strategies. Studies that focused on both hepatic and extrahepatic factors were included. Data were extracted and synthesized to provide an overview of current prevention strategies and their effectiveness in reducing HCC incidence. Results: Hepatitis B vaccination and antiviral treatments for hepatitis B and C significantly reduce HCC incidence. Lifestyle modifications—such as reducing alcohol consumption, maintaining a healthy weight through diet and exercise, and smoking cessation—are crucial in lowering HCC risk. Environmental measures to limit exposure to aflatoxins and other hazards also contribute to prevention. Regular surveillance of high-risk groups enables early detection and improves survival rates. Emerging strategies like immunotherapy and gene therapy show potential for further reducing HCC risk. Conclusions: A comprehensive approach combining medical interventions, lifestyle changes, and environmental controls is essential for effectively decreasing HCC incidence globally. Implementing these combined measures could significantly reduce the global burden of HCC.

Hepatocellular carcinoma among patients with chronic hepatitis B in the indeterminate phase.

Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.

SGLT2i impact on HCC incidence in patients with fatty liver disease and diabetes: a nation-wide cohort study in South Korea.

This study evaluated the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cancer development, particularly in hepatocellular carcinoma (HCC), in individuals with concomitant fatty liver disease (FLD) and type 2 diabetes mellitus (T2DM). Using data from Korea's Health Insurance Review and Assessment Service, we performed Kaplan-Meier and Cox regression analyses in patients with non-alcoholic fatty liver disease (NAFLD) and T2DM (NAFLD-T2DM cohort) and those with chronic viral hepatitis (CVH) alongside FLD and T2DM (FLD-T2DM-CVH cohort). In the propensity score (PS) matched NAFLD-T2DM cohort (N = 107,972), SGLT2i use was not associated with the occurrence of overall cancer, including HCC. However, old age, male sex, liver cirrhosis, and hypothyroidism were identified as independent risk factors for HCC occurrence, whereas statin and fibrate usage were associated with reduced HCC risk in this cohort in multivariate Cox analysis. In the PS-matched FLD-T2DM-CVH cohort (N = 2798), a significant decrease in HCC occurrence was observed among SGLT2i users (P = 0.03). This finding remained consistent in the multivariate Cox regression analysis (Hazard ratio = 2.21, 95% confidence interval = 1.01-4.85, P = 0.048). In conclusion, SGLT2i may be a beneficial option for diabetes management in patients with concomitant T2DM, FLD, and CVH while affirming the overall safety of SGLT2i in other types of cancer.

Abstract 4865: Income dynamics and the risk of hepatocellular carcinoma in individuals with type 2 diabetes: A nationwide population-based cohort study

Abstract Introduction: Type 2 diabetes (T2D) is associated with over 2 times increased risk of hepatocellular carcinoma (HCC). Low-income status is associated with a higher risk of developing HCC, more advanced stage, and mortality. Evidence is limited on whether income dynamics are associated with the risk of developing HCC in individuals with T2D who are susceptible to income changes. We examined whether income levels and income changes are associated with HCC risk. Methods: Using representative data from the Korean National Health Insurance Service (NHIS), 2,227,893 adults with T2D (aged ≥ 20 years) without a cancer history were included between 2015-2016. Income levels were measured based on health insurance premiums and categorized into 4 levels (quartiles [Q], 1 [low income], to 4 [high income]). These quartiles excluded the very low-income individuals who qualified as Medical Aids beneficiaries (MAB), which comprised a 5th income category. To identify income change, income levels were collected annually from the baseline year backward 4 years. The incident HCC, defined based on ICD-10 codes and special reimbursement codes, was identified until December 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to assess the association between income parameters and HCC after adjusting for sociodemographic factors, comorbidities, and diabetes duration and treatment. Income parameters included 1) the baseline income status, 2) the cumulative number of years being in each income level, and 3) changes in income level between the two time points (4 years ago vs. baseline). Results: During follow-up (median, 3.9 years), 9,887 HCC cases developed. Individuals who had experienced at least one episode of MAB during the five years showed a significantly higher HCC risk than those who had never qualified as MAB (HRs ranging from 1.52 to 2.01). In contrast, individuals who had experienced high-income status (Q4) during the five years had a lower HCC risk than those who had never experienced (HRs ranging from 0.79 to 0.92; HRn=5 years vs. n=0 years 0.79, 95% CI 0.75-0.83; P for trend <0.05). Individuals in the low-income status (MAB-Q1) at the first assessment (4 years ago) but experienced increased income had a reduced risk of HCC, which linearly declined with increasing income rise. Also, those who experienced a substantial increase in income up to the top quartile (Q4) had the lowest HCC risk (HR 0.73, 95% CI 0.60-0.88; P for trend<0.05) than those who maintained the low-income status. Conclusions: Experiencing any very low- or high-income state was independently associated with increased or decreased HCC risk. Improved income levels among those in the low-income status had an inverse linear association with reduced HCC risk. Our findings underline the need for increased public policy awareness of the impact of income dynamics on HCC risk in adults with T2D. Citation Format: Jongha Baek, Benjamin C. Amick III, Clare C. Brown, Mario Schootman, Marie-Rachelle Narcisse, Seung-Hyun Ko, Pearl A. McElfish, Michael R. Thomsen, Seong-Su Lee, Kyungdo Han, Yong-Moon Mark Park. Income dynamics and the risk of hepatocellular carcinoma in individuals with type 2 diabetes: A nationwide population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4865.

Effects of N-acetylcysteine on hepatocellular carcinoma in chronic hepatitis C.

Hepatitis C virus (HCV) infection significantly contributes to global hepatocellular carcinoma (HCC) incidence. N-Acetylcysteine (NAC), known for its antioxidant properties, is a potential therapeutic agent. However, evidence on its efficacy in reducing HCC risk among HCV patients is limited. A retrospective cohort analysis using Taiwan's National Health Insurance Research Database (2008-2018) included ≥18-year-old HCV patients. NAC usage (≥28 cumulative defined daily doses [cDDDs]) was assessed for its association with HCC risk using Cox regression models and propensity score matching. The study comprised 269,647 HCV patients, with detailed NAC dosage characterization and hazard ratios (HRs) for HCC risk. Post-matching, NAC usage emerged as the significant predictor of reduced HCC risk (adjusted HR: 0.39, 95% CI: 0.37-0.41, P<0.0001). Dose-response analysis showed reduced HCC risk with increasing cDDDs of NAC (P<0.0001). Higher daily NAC dosage (≥1 DDD) was associated with significantly lower HCC risk (adjusted HR: 0.33, 95% CI: 0.31-0.36, P<0.0001). The study provides compelling evidence for NAC's potential in reducing HCC risk among HCV patients. Insights into dose-dependent effects and optimal daily intensity thresholds offer valuable directions for future therapeutic strategies and clinical trials targeting HCC burden in HCV-infected individuals.

Dynamic evaluation of liver fibrosis to assess hepatocellular carcinoma risk in patients with chronic hepatitis B receiving nucleoside analogs treatment.

Despite good hepatitis B virus (HBV) inhibition by nucleoside analogs (NAs), cases of hepatocellular carcinoma (HCC) still occur. This study proposed a non-invasive predictive model to assess HCC risk in patients with chronic hepatitis B (CHB) receiving NAs treatment. Data were obtained from a hospital-based retrospective cohort registered on the Platform of Medical Data Science Academy of Chongqing Medical University, from 2013 to 2019. A total of 501 patients under NAs treatment had their FIB-4 index updated semiannually by recalculation based on laboratory values. Patients were divided into three groups based on FIB-4 index values: < 1.45, 1.45-3.25, and ≥ 3.25. Subsequently, HCC incidence was reassessed every six months using Kaplan-Meier curves based on the updated FIB-4 index. The median follow-up time of CHB patients after receiving NAs treatment was 2.5 years. HCC incidences with FIB-4 index < 1.45, 1.45-3.25, and ≥ 3.25 were 1.18%, 1.32%, and 9.09%, respectively. Dynamic assessment showed that the percentage of patients with FIB-4 index < 1.45 significantly increased semiannually (P < 0.001), and of patients with FIB-4 index ≥ 3.25 significantly decreased (P < 0.001). HCC incidence was the highest among patients with FIB-4 index ≥ 3.25. The FIB-4 index effectively predicted HCC incidence, and its dynamic assessment could be used for regular surveillance to implement early intervention and reduce HCC risk.

Protective effect of N-acetylcysteine against hepatocellular carcinoma in hepatitis B virus carriers.

Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC), contributing to cancer development through direct genomic integration and chronic inflammation. N-acetylcysteine (NAC), known for its antioxidant properties, is widely utilized in cancer prevention. However, clinical evidence regarding its protective effect against HCC in HBV carriers remains sparse. In this retrospective cohort study spanning 2008 to 2018, we utilized Taiwan's National Health Insurance Research Database (NHIRD) to include 1,061,174 chronic HBV carriers. Participants were stratified into NAC users and non-users using Propensity Score Matching. We assessed the incidence of HCC in both cohorts, examining the relationship between NAC usage duration and HCC incidence, and evaluating the dose-response effect. NAC users exhibited a significantly lower risk of developing HCC (adjusted hazard ratio [aHR]: 0.38; 95% confidence interval [CI]: 0.36-0.40; P < 0.0001). A dose-response relationship was evident, with higher cumulative defined daily doses (cDDDs) of NAC correlating with reduced HCC risk, revealing a significant trend (P < 0.0001). Notably, a daily NAC intensity of > 1.4 DDDs was associated with a decreased risk of HCC in HBV patients. Our results demonstrate that the use of NAC, in a dose-dependent manner, is intricately linked with a diminished incidence of HCC in individuals chronically infected with the HBV.

Metformin and Hepatocellular Carcinoma Risk Reduction in Diabetic Patients with Chronic Hepatitis C: Fact or Fiction?

Patients with chronic hepatitis C (CHC) and concomitant type 2 diabetes mellitus (DM) show a higher risk of developing hepatocellular carcinoma (HCC). Successful antiviral therapy has reduced the incidence of post-therapy HCC, but the presence of DM still represents an unfavourable predictive factor even in cured patients. Metformin (MET) is recommended as a first-line therapy for DM, and its use is associated with a significant reduction in HCC among diabetic patients with chronic liver disease of different etiology, but very few studies specifically address this issue in patients with CHC. the aim of this review is to evaluate whether the use of MET induces a significant decrease in HCC in diabetic patients with CHC, treated or untreated with antiviral therapy. A search of PubMed, Medline, Web of Sciences and Embase was conducted for publications evaluating the role of MET in reducing the risk of HCC in patients with DM and CHC, with no language and study type restrictions up to 30 June 2023. Only studies fulfilling the following inclusion criteria were considered: (1) data on the incidence of HCC in the follow-up of diabetic patients with CHC only; (2) follow-up ≥24 months; (3) sufficient data to establish the rate of diabetic patients with CHC treated with metformin or other antidiabetic medications; and (4) data on the type of antiviral treatment and the clinical outcome. Three studies met the inclusion criteria. A prospective cohort study considering only patients with DM and untreated advanced CHC, or non-responders to interferon (IFN) therapy, showed that the use of MET was associated with a significant decrease in HCC incidence, liver-related death and liver transplants. A recent retrospective study focusing on a large-scale nationwide cohort of patients with CHC in Taiwan successfully treated with IFN-based therapy stratified patients into 3 groups: non-MET users, MET users and non-diabetic patients, with 5-year cumulative rates of HCC of 10.9%, 2.6% and 3.0%, respectively, showing a significantly higher HCC risk in non-MET users compared with MET users and with non-diabetic patients, while it was not significantly different between MET users and non-diabetic patients. In a recent Italian cohort study focusing on 7007 patients with CHC treated and cured with direct-acting antiviral agents (DAAs), a combined effect of DM and MET therapy was found, showing a higher incidence of HCC in diabetic patients not taking MET compared with those without DM and those with DM taking MET. according to the current evidence, the use of MET should be encouraged in diabetic patients with CHC in order to reduce the risk of HCC; however, a well-designed randomized controlled trial is needed to establish the generalizability of the beneficial effects of MET in this particular subset of patients.

The interplay between chronic hepatitis B and diabetes mellitus: A narrative and concise review.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder among individuals with chronic hepatitis B (CHB), contributing to additional adverse impacts on both hepatic and extrahepatic systems. Existing evidence suggests a potential positive association between CHB and the development of insulin resistance and T2DM. The presence of T2DM in CHB patients is associated with an increased risk of liver fibrosis, cirrhosis, decompensation, and hepatocellular carcinoma (HCC) occurrence. Moreover, it elevates the risk of non-liver cancers and all-cause mortality in this population. T2DM also serves as the key element in metabolic dysfunction-associated steatotic liver disease, which is prevalent in the CHB population. Although specific guidelines for managing T2DM in CHB patients have not been proposed, some studies indicated that intensive glycemic control may benefit the prognosis of these patients. Additionally, specific antidiabetic agents, such as metformin and thiazolidinediones, promise to reduce HCC risk. However, unresolved questions, including the optimal glycemic control target and the selection of antidiabetic agents for CHB patients, remain and thus warrant further investigations through well-designed prospective trials. Implementing a standardized protocol encompassing regular monitoring, risk stratification, and early intervention using a multidisciplinary framework may improve the outcomes of diabetic CHB patients.

The incidence of hepatocellular carcinoma and clearance of hepatitis B surface for CHB patients in the indeterminate phase: a systematic review and meta-analysis.

Nearly 30%-40% of patients with chronic hepatitis B do not fall into any of the traditional natural history classification and thus are classified as indeterminate. However, it is unclear whether patients in the indeterminate phase (IP) are at a higher risk for hepatocellular carcinoma (HCC) than those in the defined phases (DP) and would benefit from antiviral therapy. We performed a systematic review and meta-analysis of HCC incidence and HBsAg clearance among patients in the IP versus DP. We defined the clinical phases as per the AASLD 2018 hepatitis B guidance. We searched PubMed, Embase, Medline, and Web of Science for relevant studies that reported HCC incidence or HBsAg clearance in IP versus DP patients published between January 2007 and March 2023. Annual HCC incidence and HBsAg clearance rates were pooled using a random/common-effects model. We analyzed data from 14 studies, comprising 7798 IP patients (222 patients developed HCC and 239 achieved HBsAg clearance) and 10,725 DP patients. The pooled annual HCC incidence was 2.54 cases per 1,000 person-years (95% CI, 1.14-4.39) and HBsAg clearance rate was 12.36 cases per 1,000 person-years (95% CI, 10.70-14.13) for the IP patients. IP patients were associated with significantly higher HCC incidence risk (RR = 1.64, 95% CI, 1.34-2.00) and slightly lower annual HBsAg clearance rate (RR = 0.83, 95% CI, 0.70-0.99) than the DP patients. In addition, HBeAg-negative IP patients (2.31%; 95% CI, 0.87-4.45) showed a significantly higher HCC incidence than those who were HBeAg positive (0.00%; 95% CI, 0.00-0.99) (p< 0.001). The Asia-Pacific region IP patients (4.30%; 95% CI, 2.07-7.27) were also associated with a higher HCC incidence versus Europe (0.05%; 95% CI, 0.00-1.39) (p< 0.001). However, there were no significant differences between different strategies (treated vs. untreated: 2.56%; 95% CI, 1.01-4.63 vs. 1.61%; 95% CI, 0.00-5.81, p = 0.09), and heterogeneity was substantial across the studies (I2 = 89%). The systematic review and meta-analysis showed a high HCC incidence and low HBsAg clearance among patients in the IP, especially for HBeAg-negative patients and the Asian population. We emphasize that future multicenter prospective cohort studies or randomized trials are needed to verify if expanding antiviral therapy for patients in the IP is associated with reduced HCC risk or good treatment outcomes.

Tenofovir alafenamide and tenofovir disoproxil fumarate reduce incidence of hepatocellular carcinoma in patients with chronic hepatitis B

Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB. The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated. Of the 1,632 patients (TAF, n= 1,093; TDF, n= 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 (p <0.001) vs. 0.56 (p= 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 (p <0.001) vs. 0.58 (p= 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively). This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis. Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB. NCT01940341; NCT02836249; NCT01940471; NCT02836236.

SAT-147 - Effects of interferon-based therapies in functional cure and hepatocellular carcinoma risk reduction in patients with chronic hepatitis B: real-world evidence from 2-year data of OASIS project

SAT-147 - Effects of interferon-based therapies in functional cure and hepatocellular carcinoma risk reduction in patients with chronic hepatitis B: real-world evidence from 2-year data of OASIS project

Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes.

Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

Meta-analysis: Chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin.

Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks. To examine by an updated meta-analysis the association between these medications and HCC risk. Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model. Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37-0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27-0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31-1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I2 = 0%). Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.

Abstract C106: Risk of hepatocellular carcinoma among people living with HIV in the United States

Abstract Background: Hepatocellular carcinoma (HCC) is the primary histological subtype of liver cancer, comprising up to 75% of such cases in the U.S. People living with HIV (PLWH) have a higher risk of HCC than the general population. A higher proportion of PLWH are coinfected with hepatitis B (HBV) or hepatitis C virus (HCV) due to shared transmission modalities such as injection drug use. Highly active antiretroviral therapy has improved survival from HIV infection, creating increased opportunities to develop liver cancer due to prolonged hepatic inflammation caused by chronic infection with HBV or HCV. Methods: We used data from the HIV/AIDS Cancer Match (HACM), a population-based HIV and cancer registry linkage in the U.S. We compared HCC risk in PLWH to the general population using standardized incidence ratios (SIRs), standardized by race/ethnicity, age group, HIV transmission risk group, calendar period, and registry. SIRs were estimated by race/ethnicity, age group, HIV transmission risk group, and calendar period. Poisson regression was used to estimate incidence rate ratios (RRs) among PLWH by race/ethnicity, age group, HIV transmission risk group and calendar period. In addition, data from Symphony Health, a Texas based health aggregator of medical claims determined the prevalence of HBV and/or HCV infection among people with HCC. Adjusted odds ratios identified predictors of HBV and HCV infection in PLWH with HCC. Results: There were 1,530 incident HCC cases from 2001–2016 in PLWH during over 4 million person-years of follow up. Compared to the general population, the overall SIR was 2.92 (95% CI 2.75-3.09). The risk of HCC was strongly elevated across all racial/ethnic and age groups. Rates were highest among NH-White PLWH (SIR 3.86; 95% CI 3.48-4.27) PLWH aged 40-49 (SIR 4.81; 95% CI 4.31-5.35) or aged 20-39 (SIR 4.15; 95% CI 2.82-5.89). Among PLWH, HCC risk was similar across racial/ethnic groups but increased with age. Compared to men who had sex with men (MSM), men who injected drugs had almost 4 times the risk of HCC (RR 3.93; 95% CI 3.38-4.55) while female PWID had a 60% increased risk (RR 1.61; 95% CI 1.28-2.01), and men with other or unknown HIV transmission had a 50% increased risk (RR 1.48; 95% CI 1.27-1.73). Between 2001-2004 and 2013-2016, rates of HCC declined 16% (RR 0.84; 95% CI 0.69-1.03). Using Symphony Health data, there were a total of 146 HCC cases, 38 coinfected with HBV, 84 with HCV, and 16 triply infected cases. Compared to MSMs, persons who inject drugs (PWID) had 85% decreased odds of HBV infection (aOR 0.15; 95% CI 0.05-0.50) and 8 times the odds of HCV infection (aOR 8.03; 95% CI 2.61-24.7). Conclusions: Utilizing recently updated population-based linked-surveillance data, we found risk of HCC has declined over time among PLWH, though rates remain significantly elevated compared to the general population, with particularly high risk among people who inject drugs. Prevention and treatment of HBV and HCV are needed to reduce HCC risk in this population. Citation Format: Jennifer K. McGee-Avila, Ilona Argirion, Thomas R. O’Brien, Eric Engels, Marie-Josèphe Horner, Qianlai Luo, Meredith Shiels. Risk of hepatocellular carcinoma among people living with HIV in the United States [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C106.

Abstract C110: The role of generation on hepatocellular carcinoma risk among US Mexicans in Los Angeles

Abstract Background. Incidence of hepatocellular carcinoma (HCC) is nearly twice as likely to occur among Hispanics/Latinos compared to their Non-Hispanic White counterparts. Studies show that birthplace may play a role specifically where US-born Hispanic/Latinos are at a greater risk of developing HCC compared to foreign-born Hispanic/Latinos, which may be due to acculturation. Given this information, we looked at how generations in the US impact HCC risk among US Mexicans. Methods. The Multiethnic Cohort (MEC), a prospective study with over 215,000 participants in Los Angeles, CA and Hawaii. The MEC regularly performs linkages with the Surveillance, Epidemiology, End Results (SEER) Program. International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes C.22 and histology codes 8170-8175 to identify HCC cases up until December 31st, 2017. We subset our sample to self-identified Mexicans with information on parental birthplace (n=32,239). Generation status was categorized by 1st generation as born in the Mexico with both parents born in Mexico; 2nd generation as US-born with at least one parent born in Mexico; and 3rd generation as US-born with both parents also born in the US. To assess HCC risk, we performed multivariable Cox models adjusting for age, sex, body mass index (BMI), smoking status, alcohol intake, history of diabetes, and daily coffee consumption. Results. After an average follow-up time of 23.4 years there were a total of 220 HCC incident cases. With successive generation, US-Mexicans were more likely to be current smokers, have a greater intake of alcohol, consume more coffee, and have an elevated BMI. In addition, there was an increase in age-adjusted HCC incidence rates (per 100,000) with each increasing generation (1st generation: 20.9, 2nd generation: 27.5, 3rd generation: 34.7). In the multivariable model, 2nd and 3rd generation US Mexicans had a 35% (95% CI: 1.00-1.84) and 61% (95% CI: 1.10-2.36) increased risk of HCC compared to 1st generation US Mexicans, respectively (Ptrend=0.009). While we did not observe significant heterogeneity by diabetes status (Pheterogeneity=0.41); those who did not have diabetes and were 3rd generation had an 82% (95% CI: 1.17-2.84) increased risk of HCC compared to a 1st generation US Mexicans who also did not have diabetes. There was also no heterogeneity by BMI status (Pheterogeneity=0.92) and alcohol intake (Pheterogeneity=0.46) for the association between generation status and HCC risk. Among HCC cases, similar distributions of tumor grade or stage at diagnosis were observed across generations. Conclusions. 2nd and 3rd generation US Mexicans have a significantly higher risk of HCC compared to 1st generation US Mexicans. Targeted interventions focusing on healthier lifestyle behaviors are much needed for US-born Mexicans reduce HCC risk. Citation Format: Nicholas Acuna, Kali Zhou, Paulo Pinheiro, Tiffany Lim, Lynne Wilkens, Loic Le Marchand, Veronica Wendy Setiawan. The role of generation on hepatocellular carcinoma risk among US Mexicans in Los Angeles [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C110.

Tenofovir use is associated with a decreased risk of hepatocellular carcinoma among men with HIV irrespective of coinfection status

Tenofovir is recommended as part of the first-line antiretroviral therapy (ART) to treat people living with HIV (PLWH) with HBV coinfection. However, the effects of tenofovir-containing ART on hepatocellular carcinoma (HCC) risk among PLWH with/without chronic hepatitis virus infections remain unclear. This study included 23,838 PLWH. All of them were males aged ≥20 years and followed prospectively during 2000-2017. Four major nationwide registries - the Human Immunodeficiency Virus surveillance database, Taiwan Cancer Registry, Death Certification System, and National Health Insurance Database - were applied to define ART and comorbidities and ascertain newly diagnosed HCC. Tenofovir-containing ART was identified through prescription records. Cox proportional hazards models were used to determine the association of tenofovir use with HCC incidence. HCC incidence was lower among ever users of tenofovir than among never users (24.2 and 85.7 per 100,000 person-years, respectively). Ever users had significantly reduced HCC risk (adjusted hazard ratio 0.20, 95% CI 0.13-0.31). The effect of tenofovir use on reduced risk for HCC consistently favored never users across many prespecified subgroups, including HBV or HCV coinfection (p <0.05). The findings were consistent in subgroups of PLWH diagnosed with HIV before tenofovir's approval and in those born before the nationwide roll-out of neonatal HBV vaccination. Our findings underscore the need for randomized controlled trials of tenofovir in combination with long-acting injectable ART regimens to assess its safety and efficacy in PLWH, particularly in those with HBV or HCV coinfection. Tenofovir's effect on the risk of hepatocellular carcinoma (HCC) among people living with HIV with hepatitis B or C coinfection remains under investigated. This nationwide prospective cohort study, comprising 23,838 men living with HIV, showed that tenofovir-containing antiretroviral therapy was associated with reduced risk of HCC (adjusted relative risk: 0.20, 95% CI 0.13-0.31), which was consistently observed across many prespecified subgroups. The effect of tenofovir use on HCC risk should be further investigated in PLWH, particularly following the development of long-acting injectable ART regimens.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR. The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

Effects of H1-Antihistamines on hepatocellular carcinoma risk in patients with type 2 diabetes mellitus

PurposeH1-antihistamines (AHs) may exert protective effects against cancer. We investigated the association of AH use with hepatocellular carcinoma (HCC) risk in type 2 diabetes mellitus (T2DM) patients without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. MethodsThe data of patients with T2DM enrolled from Taiwan's National Health Insurance Research Database were examined for the period of January 1, 2008, to December 31, 2018. We used the Kaplan–Meier method and Cox proportional hazards regression to evaluate the AH use–HCC risk association. ResultsAfter 1:1 propensity score matching was performed, the two cohorts were each divided into AH users (n = 47,990) and nonusers (n = 47,990). The risk of HCC was significantly lower in AH users than in AH nonusers (adjusted hazard ratio [aHR]: 0.55 95% confidence interval [95% CI], 0.46 to 0.67; IRR: 0.70; 95% CI, 0.60 to 0.84), respectively. The dose–response relationship between AH use and HCC risk was also observed (aHRs: 0.58, 0.56, 0.50, and 0.41 for 28–35, 36–49, 50–77, and >77 cumulative defined daily doses of AH, respectively). ConclusionAH use can reduce HCC risk in T2DM patients without HBV or HCV infection in a dose-dependent manner.

Hormone replacement therapy is associated with reduced hepatocellular carcinoma risk and improved survival in postmenopausal women with hepatitis B: A nationwide long-term population-based cohort study.

Postmenopausal women with hepatitis B virus (HBV) infection are more likely to have accelerated liver fibrosis, eventually advancing to liver cirrhosis or hepatocellular carcinoma (HCC). The association between sex hormones and HBV-related HCC risk is unclear. We investigated whether hormone replacement therapy (HRT) is beneficial to postmenopausal women with HBV infection. This retrospective study selected the data of 44,465patients with HBV infection between January 2000 and December 2018 from Taiwan’s National Health Insurance Research Database. After excluding patients with preexisting liver diseases, liver cirrhosis, or liver malignancies, we grouped the remaining 10,474 patients by whether they had undergone HRT for at least 3 months (n = 5,638) and whether they had not received HRT (n = 4,836). After propensity score matching, we assigned 3080 patients to an HRT cohort and matched them (1:1) with those in a non-HRT cohort. The incidence of HCC (P < 0.022) and all-cause mortality rate (P < 0.001) were lower in the HRT cohort than in the non-HRT cohort. The liver cirrhosis risk was not significantly higher in the HRT cohort (P = 0.355). HRT is associated with reduced HCC risk and improved survival outcomes but is unrelated to liver cirrhosis development in postmenopausal women.