HIV RNA, CD4+ Percentage, and Risk of Hepatocellular Carcinoma by Cirrhosis Status

Torgersen, J; Kallan, Michael J.; Carbonari, Dena M.; Park, Lesley S.; Mehta, Rajni; D’Addeo, Kathryn; Tate, Janet P.; Lim, Joseph K.; Goetz, Matthew Bidwell; Rodriguez‐Barradas, Maria C.; Gibert, Cynthia L.; Bräu, Norbert; Brown, Sheldon T.; Roy, Jason; Taddei, Tamar H.; Justice, Amy C.; Re, Vincent Lo

doi:10.1093/jnci/djz214

Cited by 22 publications

(24 citation statements)

References 34 publications

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“…(2) continuous variable per 1.0 log 10 copies/mL increase; and (3) cumulative value with increasing consecutive months of detectable HIV (compared to those with undetectable HIV ), as previously described. (13) We performed two secondary analyses. First, we determined aHRs of HCC, accounting for death as a competing risk.…”

Section: Discussionmentioning

confidence: 99%

“…H. Nina Kim , 1 Craig W. Newcomb, 2 Dena M. Carbonari, 2 Jason A. Roy, 3 Jessie Torgersen, 2 Keri N. Althoff, 4 Mari M. Kitahata, 1 K. Rajender Reddy, 2 Joseph K. Lim, 5 Michael J. Silverberg, 6 Angel M. Mayor, 7 Michael A. Horberg, 8 Edward R. Cachay, 9 Gregory D. Kirk, 4 Jing Sun , 4 Mark Hull, 10 M. John Gill, 11 Timothy R. Sterling, 12 Jay R. Kostman, 13 Marion G. Peters, 14 Richard D. Moore, 4 Marina B. Klein, 15 and Vincent Lo Re, III 2 , for the North American AIDS Cohort Collaboration on Research, Design of IeDEA # BaCKgRoUND aND aIMS: Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/ HBV coinfection are poorly characterized.…”

Section: Risk Of Hcc With Hepatitis B Viremia Among Hiv/hbv-coinfected Persons In North Americamentioning

confidence: 99%

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Risk of HCC With Hepatitis B Viremia Among HIV/HBV‐Coinfected Persons in North America

et al. 2021

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Background and Aims Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV. Approach and Results We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995‐2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time‐updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non‐White), 115 HCC cases were diagnosed over 65,392 person‐years (incidence rate, 1.8 [95% CI, 1.5‐2.1] events/1,000 person‐years). Risk factors for HCC included age 40‐49 years (aHR, 1.97 [1.22‐3.17]), age ≥50 years (aHR, 2.55 [1.49‐4.35]), HCV coinfection (aHR, 1.61 [1.07‐2.40]), and heavy alcohol use (aHR, 1.52 [1.04‐2.23]), while time‐updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56‐1.43]) and time‐updated CD4+ percentage <14% (aHR, 1.03 [0.56‐1.90]) were not. The risk of HCC was increased with time‐updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42‐3.47]) and was higher with each 1.0 log10 IU/mL increase in time‐updated HBV DNA (aHR, 1.18 [1.05‐1.34]). HBV suppression with HBV‐active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24‐0.73]). Conclusion Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.

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Section: Discussionmentioning

confidence: 99%

Section: Risk Of Hcc With Hepatitis B Viremia Among Hiv/hbv-coinfected Persons In North Americamentioning

confidence: 99%

Risk of HCC With Hepatitis B Viremia Among HIV/HBV‐Coinfected Persons in North America

et al. 2021

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“…Several observational studies have reported higher cancer incidence in persons with nonsuppressed viremia (using different thresholds, and in persons both with and without cART) for both AIDS-defining cancers [ 9–12 , 15 , 16 , 22 ] and virus-related non-AIDS-defining cancer [ 11 , 13 , 14 , 16 , 17 ]. However, only 2 of these studies have clearly separated the effects of viremia before and after initiation of cART; in these, pre-ART VL was considered as a potential variable, but this was not included in the final model [ 9 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Associations Between Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid Levels and Incidence of Invasive Cancer in People With HIV After Initiation of Combination Antiretroviral Therapy

Elvstam

Marrone

Medstrand

et al. 2021

Open Forum Infectious Diseases

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Background HIV viremia could be involved in the increased risk of cancer in people with HIV (PWH) receiving combination antiretroviral therapy (cART). We analyzed the association between plasma HIV RNA levels in PWH starting cART and incident invasive cancer using the Swedish cohort InfCare HIV linked with national registers. Methods Adults starting cART 1996–2017 were included if they had ≥1 viral load (VL) measurement before receiving any antiretroviral agent (pre-ART VL) and ≥2 VLs ≥6 months after start of cART. Viremia during cART was analyzed both as viremia-copy-years and categorized as suppression (<50 copies/mL), low-level viremia (LLV, 50–999 copies/mL), and non-suppression (≥1000 copies/mL). The main outcome was a composite of invasive malignancies with increased incidence among PWH. We fitted proportional subhazard models (including sex, age, pre-ART CD4 count, and injection drug use) for both pre-ART VL and viremia during cART. Results After 32,105 person-years, 3,254/4,931 participants (66%) were classified as suppressed, 438 (9%) as LLV, and 1221 (25%) as non-suppressed. Neither viremia category nor cumulative viremia during cART had a statistically significant association with cancer. Higher pre-ART VL was associated with cancer (adjusted subhazard ratio, 1.4; 95% confidence interval, 1.0–1.8); this remained statistically significant with viremia during cART in the model. In subanalysis, the association with pre-ART VL was statistically significant for AIDS-defining and infection-related non-AIDS-defining cancer, but not for other malignancies. Conclusions In this nationwide cohort, pre-ART VL was an independent predictor of invasive cancer, whereas viremia profile during cART was not associated with cancer incidence.

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“…Although multiple studies have confirmed that higher HIV RNA and long-term detectable HIV were independently associated with higher risk of HCC, especially in HIV patients with HBV/HCV infection 99 , yet the mechanism by which HIV induces HCC initiation has not been defined. Because the HIV is mainly infected with CD4 + T cells and induced their depletion, researchers are focusing on the relationship between CD4 + T-cell death and HCC initiation.…”

Section: Hiv-induced Hepatoma Cells' Transformationmentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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HIV RNA, CD4+ Percentage, and Risk of Hepatocellular Carcinoma by Cirrhosis Status

Cited by 22 publications

References 34 publications

Risk of HCC With Hepatitis B Viremia Among HIV/HBV‐Coinfected Persons in North America

Risk of HCC With Hepatitis B Viremia Among HIV/HBV‐Coinfected Persons in North America

Associations Between Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid Levels and Incidence of Invasive Cancer in People With HIV After Initiation of Combination Antiretroviral Therapy

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

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