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

  • Author Footnotes
    a these authors contributed equally as first author to this work
    Mei-Hsuan Lee
    Correspondence
    Corresponding author. Institute of Clinical Medicine, National Yang Ming Chiao Tung University 155 Li-Nong Street, Section 2, Peitou, Taipei 112, Taiwan. Tel.: +886 2 2826-7248; fax: +886 2 2820-5699
    Footnotes
    a these authors contributed equally as first author to this work
    Affiliations
    Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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  • Author Footnotes
    a these authors contributed equally as first author to this work
    Ping-Feng Wu
    Footnotes
    a these authors contributed equally as first author to this work
    Affiliations
    Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Faculty of Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Tzu-I Chen
    Affiliations
    Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, New Taipei City, Taiwan
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  • Chi Chan
    Affiliations
    Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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  • Hsi-Hsun Lin
    Affiliations
    Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
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  • Yi-Hsiang Huang
    Affiliations
    Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Hsuan-Yu Chen
    Affiliations
    Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
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  • Yi-Tsung Lin
    Affiliations
    Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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  • Chien-Jen Chen
    Affiliations
    Genomics Research Center, Academia Sinica, Taipei, Taiwan
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  • Author Footnotes
    a these authors contributed equally as first author to this work
Open AccessPublished:November 24, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100634

      Highlights

      • Tenofovir-containing ART on HCC risk among PLWH depending on chronic HBV and HCV status rarely been investigated
      • The nationwide cohort found tenofovir-containing ART reduced risk of HCC (adjusted HR: 0.20, 95% CI: 0.13–0.31)
      • Compared with never use, tenofovir users reduced HCC risk across many subgroups, including those with HBV/HCV
      • Study implied the need for RCTs of tenofovir in combination with long-acting ART to assess the effects on HCC risk

      Abstract

      Background & Aims

      Tenofovir is recommended as part of the first-line antiretroviral therapy (ART) to treat people living with human immunodeficiency virus (PLWH) with hepatitis B virus (HBV) coinfection. However, the effects of tenofovir-containing ART on the hepatocellular carcinoma (HCC) risk among PLWH depending on chronic hepatitis virus infection status remain unclear.

      Methods

      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 hazard ratios (HRs) with 95% confidence intervals (CIs) of tenofovir use for HCC.

      Results

      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 HR: 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 hepatitis C virus (HCV) coinfection (P < 0.05). The findings were consistent in subgroups of PLWH diagnosed with HIV before tenofovir’s approval and nonvaccinees for HBV.

      Conclusions

      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.

      Lay Summary

      Tenofovir’s effect on the risk of hepatocellular carcinoma among people living with HIV with hepatitis B or C coinfection remains under investigated. The nationwide prospective cohort comprised 23,838 men living with HIV and showed that tenofovir-containing antiretroviral therapy was associated with reduced risk of hepatocellular carcinoma (adjusted relative risk: 0.20, 95% confidence interval: 0.13–0.31). The beneficial effect of tenofovir use on hepatocellular carcinoma risk consistently favored never users across many prespecified subgroups. The effect of tenofovir use associated with hepatocellular carcinoma risk should be further investigated after introducing long-acting injectable antiretroviral regimens, which may simplify HIV treatment.

      Graphical abstract

      Keywords

      Author contributions

      Study concept and design: Mei-Hsuan Lee; acquisition of data: Mei-Hsuan Lee; analysis and interpretation of data: Mei-Hsuan Lee, Tzu-I Chen; drafting of the manuscript: Mei-Hsuan Lee; critical revision of the manuscript for important intellectual content: Mei-Hsuan Lee, Ping-Feng Wu, Tzu-I Chen, Chi Chan, Hsi-Hsun Lin, Yi-Hsiang Huang, Hsuan-Yu Chen, Yi-Tsung Lin, Chien-Jen Chen; obtained funding and study supervision: Mei-Hsuan Lee.

      Financial support

      This study was supported by the Ministry of Science and Technology, Taipei, Taiwan (109-2926-1010-504 and 109-2628-B-010-010), and the National Health Research Institute, Taiwan (NHRI-EX111-11117PI). None of the funding organizations played a role in the study design or conduct; data collection, management, analysis, or interpretation; data preparation or review; or manuscript approval.

      Declaration of interests

      The authors disclose no conflicts of interest.

      Data Availability Statement

      The usage of the claims dataset should be approved by the National Health Insurance Database Research committee.

      Introduction

      Globally, approximately 38 million people have human immunodeficiency virus infection (HIV). People living with HIV (PLWH) have an increased likelihood of hepatitis B or C virus (HBV or HCV, respectively) infection [
      • Kourtis A.P.
      • Bulterys M.
      • Hu D.J.
      • Jamieson D.J.
      HIV–HBV Coinfection — A Global Challenge.
      ,
      • Platt L.
      • Easterbrook P.
      • Gower E.
      • McDonald B.
      • Sabin K.
      • McGowan C.
      • et al.
      Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis.
      ], and this coinfection may exacerbate morbidity and mortality beyond those caused by either infection alone [
      • Sun J.
      • Althoff K.N.
      • Jing Y.
      • Horberg M.A.
      • Buchacz K.
      • Gill M.J.
      • et al.
      Trends in Hepatocellular Carcinoma Incidence and Risk Among Persons With HIV in the US and Canada, 1996-2015.
      ]. Among PLWH, 40% of liver-related causes of death are hepatocellular carcinoma (HCC) [
      • Rosenthal E.
      • Roussillon C.
      • Salmon-Ceron D.
      • Georget A.
      • Henard S.
      • Huleux T.
      • et al.
      Liver-related deaths in HIV-infected patients between 1995 and 2010 in France: the Mortavic 2010 study in collaboration with the Agence Nationale de Recherche sur le SIDA (ANRS) EN 20 Mortalite 2010 survey.
      ]. Compared with the general population, PLWH have lifelong increased risk of HCC [
      • Shiels M.S.
      • Engels E.A.
      Evolving epidemiology of HIV-associated malignancies.
      ].
      Tenofovir is a nucleotide analog reverse transcriptase inhibitor that is used in antiretroviral therapy (ART) for HIV treatment [
      • Sax P.E.
      • Wohl D.
      • Yin M.T.
      • Post F.
      • DeJesus E.
      • Saag M.
      • et al.
      Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials.
      ]. On the basis of its established efficacy and tolerability against HIV and HBV [
      • Benhamou Y.
      • Tubiana R.
      • Thibault V.
      Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ], the World Health Organization recommends a tenofovir-containing regimen as the first-line ART, particularly for PLWH with HBV coinfection [

      WHO. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Geneva, World Health Organization 2021.

      ]. However, the TREAT Asia HIV Observational Database revealed that only half of PLWH with HBV coinfection received tenofovir-containing ART, even in high-income countries [
      • Boettiger D.C.
      • Kerr S.
      • Ditangco R.
      • Chaiwarith R.
      • Li P.C.
      • Merati T.P.
      • et al.
      Tenofovir-based antiretroviral therapy in HBV-HIV coinfection: results from the TREAT Asia HIV Observational Database.
      ].
      Only a few studies have investigated HCC incidence or mortality changes after tenofovir became available. A prospective study that followed up PLWH with HBV coinfection reported that all-cause mortality had markedly decreased over time, coinciding with the introduction of tenofovir [
      • van Welzen B.J.
      • Smit C.
      • Boyd A.
      • Lieveld F.I.
      • Mudrikova T.
      • Reiss P.
      • et al.
      Decreased all-cause and liver-related mortality risk in HIV/hepatitis B virus coinfection coinciding with the introduction of tenofovir-containing combination antiretroviral therapy.
      ]. In addition, the difference in overall mortality in HIV/HBV coinfection versus HIV monoinfection has significantly diminished since tenofovir’s approval [
      • Tsai W.C.
      • Hsu W.T.
      • Liu W.D.
      • Sun H.Y.
      • Chuang Y.C.
      • Huang Y.S.
      • et al.
      Impact of antiretroviral therapy containing tenofovir disoproxil fumarate on the survival of patients with HBV and HIV coinfection.
      ]. Limited studies have compared PLWH with or without tenofovir-containing ART to determine whether tenofovir affects HCC risk.
      In this study, we used nationwide registries to evaluate whether tenofovir affects HCC incidence in PLWH with or without HBV/HCV coinfection.

      Methods

      Study Design

      This nationwide cohort study was conducted to determine HCC incidence among PLWH who received ART with or without tenofovir in 2000–2017. We integrated four national health registries provided by the Taiwanese Ministry of Health and Welfare. The administrative and claims data stored in these registries are complete, accurate, and up-to-date [
      • Chiang C.J.
      • You S.L.
      • Chen C.J.
      • Yang Y.W.
      • Lo W.C.
      • Lai M.S.
      Quality assessment and improvement of nationwide cancer registration system in Taiwan: a review.
      ]. The HIV surveillance database was used to identify people who received a diagnosis of HIV during 2000–2016. We obtained their treatment information through computerized data linkage with the National Health Insurance (NHI) Database. In addition, the Taiwan Cancer Registry was used to identify PLWH with newly diagnosed HCC and their diagnosis dates. The death certification system was used to determine if any PLWH in our cohort died between 2000 and December 31, 2017. The patient data were linked using citizenship identification numbers and birthdates. The study protocol (YM109165E) was approved by the Institutional Review Board of National Yang Ming Chiao Tung University, Taipei, Taiwan.

      Study Cohort

      According to Taiwanese law, all cases of newly diagnosed HIV or acquired immunodeficiency syndrome (AIDS) must be reported to the Taiwan Centers for Disease Control within 24 h. The HIV surveillance database includes all reported HIV cases with seropositive antibodies against HIV or detectable HIV RNA on a polymerase chain reaction test. The route of transmission is also recorded. For the period 2000–2016, a total of 30,328 PLWH aged ≥20 years were identified in the surveillance database. Of them, 28,531 (93.5%) were men. Patients with any cancer diagnosis before HIV diagnosis were excluded. Eventually, 23,838 male PLWH were included in the analysis.

      Definitions of Tenofovir Use and Comorbidities

      In Taiwan, NHI is compulsory and covers >99% of all residents [
      • Wen C.P.
      • Tsai S.P.
      • Chung W.S.
      A 10-year experience with universal health insurance in Taiwan: measuring changes in health and health disparity.
      ]. The NHI database contains detailed claims information on drug prescriptions, medical procedures, outpatient visits, inpatient hospitalizations, and dates. ART drugs were determined using Anatomical Therapeutic Chemical codes in the patients’ post-HIV-diagnosis prescription records (Supplementary Table 1). The comorbidities of chronic HBV or HCV infection, cirrhosis, and diabetes were identified using International Classification of Diseases, Ninth Revision or Tenth Revision (ICD-9 or ICD-10, respectively) codes (Supplementary Table 2) provided the following criterion was met: at least one hospital admission code with the diagnosis or with ≥3 outpatient visits; this criterion has good validity [
      • Sheu M.J.
      • Liang F.W.
      • Li S.T.
      • Li C.Y.
      • Lu T.H.
      Validity of ICD-10-CM codes used to identify patients with chronic hepatitis B and C virus infection in administrative claims data from the Taiwan National Health Insurance outpatient claims dataset.
      ].

      Follow-Up to Ascertain Newly Diagnosed HCC

      The patients were followed up from the date of HIV diagnosis. After computerized data linkage with the National Cancer Registry, HCC incidence and dates of diagnosis were determined using ICD-9 code 155 and ICD-10 code C22. In all cases, the diagnosis of HCC was established based on pathological or radiographic criteria.

      Statistical Analysis

      The baseline characteristics of users and nonusers of tenofovir-containing ART regimens were compared using chi-square tests. The duration of follow-up was calculated for each patient as the time from the HIV diagnosis date to the date of HCC diagnosis, death, or end of the study period (i.e., December 31, 2017), whichever came first. HCC incidence was derived by dividing the number of cases by the person-years of follow-up. The cumulative risk of HCC in terms of tenofovir use was estimated using the Kaplan–Meier method and compared using the log-rank test. Cox proportional hazards models were used to obtain the crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for tenofovir use on HCC risk. The proportionality assumptions (nonchanging HRs over time) of the Cox models were examined, and the assumptions were found to not be violated. The potential confounders associated with HCC included age, AIDS, HBV/HCV, diabetes, cirrhosis, and HIV diagnostic year. We initially evaluated these covariates in the univariate analyses separately. The covariates significant in the univariate models were further included in the multiple Cox’s regression models to evaluate the impacts of tenofovir-containing regimen on HCC incidence. Tenofovir was approved for HIV treatment and reimbursement of its cost began in Taiwan in 2011; thus, the year of HIV diagnosis (before or after 2011) was treated as a covariate in the multiple regression models. In the subgroup of patients receiving an HIV diagnosis before 2011 (n = 14,407, 60.4%), we evaluated the effect of tenofovir on HCC risk. We repeated the subgroup analyses after stratifying by baseline characteristics and chronic hepatitis virus infection status (HBV, HCV, or both). Taiwan launched a nationwide neonatal hepatitis B immunization program in 1986; thus, we performed sensitivity analyses by repeating all analyses in the patients born before 1986 (i.e., without HBV vaccination at birth; n = 18,020; 75.6%). There were three and zero caes of HCC among the men receiving HIV diagnosis after 2011 and HBV vacinees born after 1986, respectively. We did not perform additional analyses by restricting these groups. Statistical significance was defined as a two-sided P value of <0.05. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

      Results

      Baseline Characteristics

      The patients’ baseline characteristics are presented in Table 1. The mean age was 32.2 years, and 81.1% of the patients were 20–39 years old. Among the study population, 48.1% received a diagnosis of AIDS, and 29.3% received a diagnosis of HBV or HCV infection. Compared with nonusers, users of tenofovir were older (P < 0.001); had a lower prevalence of AIDS (P < 0.001), cirrhosis (P = 0.03), and diabetes (P = 0.003); and had a higher prevalence of HBV (P < 0.001).
      Table 1Baseline characteristics of the study population, stratified by the use of tenofovir-containing antiretroviral therapy.
      Baseline characteristicTotal (N = 23,838)

      No. (%)
      Tenofovir users (n = 14,865)

      No. (%)
      Tenofovir nonusers (n = 8,973)

      No. (%)
      Age (years)
       20–2911,306 (47.4)7,214 (48.5)4,092 (45.6)
       30–398,034 (33.7)5,091 (34.3)2,943 (32.8)
       40–493,229 (13.6)1,944 (13.1)1,285 (14.3)
       50–59942 (4.0)493 (3.3)449 (5.0)
       ≥60327 (1.4)123 (0.8)204 (2.3)
      Mean ± SD32.2 ± 9.332.9 ± 10.231.7 ± 8.7
      Diagnosis of AIDS
       No12,373 (51.9)8,061 (54.2)4,312 (48.1)
       Yes11,465 (48.1)6,804 (45.8)4,661 (51.9)
      Transmission route
       MSM16,566 (69.5)10,547 (71.0)6,019 (67.1)
       People who inject drugs4,081 (17.1)2,576 (17.3)1,505 (16.8)
       Heterosexual3,120 (13.1)1,703 (11.5)1,417 (15.8)
       Other71 (0.3)39 (0.3)32 (0.4)
      Chronic hepatitis virus infection
       HBV only2,099 (8.8)1,733 (11.7)366 (4.1)
       HCV only3,724 (15.6)2,279 (15.3)1,445 (16.1)
       HBV and HCV1,155 (4.9)878 (5.9)277 (3.1)
       None16,860 (70.7)9,975 (67.1)6,885 (76.7)
      Cirrhosis
       No23,701 (99.4)14,792 (99.5)8,909 (99.3)
       Yes137 (0.6)73 (0.5)64 (0.7)
      Diabetes
       No23,231 (97.5)14,529 (97.7)8,702 (97.0)
       Yes607 (2.6)336 (2.3)271 (3.0)
      Abbreviations: AIDS, acquired immunodeficiency syndrome; MSM, men having sex with men; HBV, hepatitis B virus; HCV, hepatitis C virus; SD, standard deviation.
      In our cohort, 14,865 (62.4%) had ever received a tenofovir-containing regimen; of them, 14,193 (95.5%) received it after 2011. Supplementary Table 3 presents the numbers of tenofovir use by HIV diagnostic year and various chronic hepatitis virus infection statuses. After 2011, higher proportions of PLWH were tenofovir users. However, the proportion of tenofovir use was still substantial (54.2%) among male PLWH diagnosed before 2011 (n = 8,065), indicating a switch in ART regimens after 2011. Moreover, 82.6% of male PLWH with HBV coinfection were prescribed a tenofovir-containing regimen (P < 0.001).

      Incidence of HCC

      The mean follow-up duration was 8.5 years. After 201,936 person-years of follow-up, 97 cases of HCC were identified, yielding an incidence rate of 48 per 100,000 person-years. The HCC incidence was lower among users of tenofovir than among nonusers (24.2 and 85.7 per 100,000 person-years, respectively). HCC incidence was higher among patients with advanced age, AIDS, cirrhosis or diabetes, and HIV diagnostic year before 2011 (P < 0.05; Table 2). The incidence rate was higher for patients who acquired HBV or HCV coinfection than those without coinfection (P < 0.001). At the end of follow-up, approximately 0.62% of users had received an HCC diagnosis compared with 1.67% of nonusers (P < 0.0001; Figure 1A). Among the male PLWH before 2011, tenofovir use was still associated with significantly lower cumulative risk of HCC (0.61% vs. 1.76%, P < 0.0001; Figure 1B) throughout the follow-up.
      Table 2Number and incidence of hepatocellular carcinoma cases by baseline characteristics.
      Baseline characteristicNumber of patients (n = 23,838)Number of HCC cases (n = 97)Person-years of follow-upIncidence rate
      per 100,000 person-years.
      P value
      Tenofovir-based regimen
       Nonusers8,9736778,17485.7
       Users14,86530123,76224.2<0.0001
      Age (years)
       20–2911,306992,9369.7
       30–398,0342571,50835.0
       40–493,2294127,644148.3
       50–59942117,557145.6
       ≥60327112,290480.3<0.0001
      Diagnosis of AIDS
       No12,37332101,52831.5
       Yes11,46565100,40764.70.0002
      Chronic hepatitis virus infection
       HBV only2,0992618,862137.8
       HCV only3,7242740,18367.2
       HBV + HCV1,1553112,619245.7
       None16,86013130,27310.0<0.0001
      Cirrhosis
       No23,70190201,04144.8
       Yes1377895782.4<0.0001
      Diabetes
       No23,23190197,51145.6
       Yes60774,425158.20.0165
      HIV diagnosis year
       Before 201114,40793160,49458.0
       After 20119,431441,4429.7<0.0001
      Abbreviations: HCC, hepatocellular carcinoma; AIDS, acquired immunodeficiency syndrome; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
      a per 100,000 person-years.
      Figure thumbnail gr1
      Figure 1Cumulative risk of hepatocellular carcinoma (HCC) in people living with human immunodeficiency virus (HIV) ever or never using tenofovir-containing antiretroviral therapy. (A) Total population; (B) people receiving an HIV diagnosis before 2011.
      Log rank tests used to examine the differences of cumulative risks and it showed significance (p<0.0001).

      Relative Risk of HCC Given Tenofovir Use

      Tenofovir-containing ART had decreased risk of HCC compared to nonusers, with the crude HR of 0.29 (0.19-0.45). Age, AIDS, chronic hepatitis virus infection, cirrhosis, diabetes and HIV diagnostic year showed significantly associations with HCC and they were included in the multiple models. Ever users of tenofovir exhibited significantly reduced risk for HCC (adjusted HR: 0.20, 95% CI: 0.13–0.31) after adjustment for age, AIDS, chronic hepatitis virus infection, cirrhosis, diabetes, and HIV diagnostic year (Table 3). In the multiple models, advanced age, HBV/HCV coinfection, and cirrhosis were associated with significant risk of HCC (P < 0.05). Among male PLWH before 2011, tenofovir use was consistently associated with decreased HCC risk (adjusted HR: 0.18, 95% CI: 0.12–0.29) when nonusers were taken as the reference group. Among PLWH who used tenofovir-containing regimen, taking PLWH used tenofovir-containing ART< 1 year as a reference group, those who used tenofovir-containing ART with longer duration had decreased risk of HCC, with the corresponding adjusted HR of 0.23 (0.09-0.62) for 1 year to< 2 years; 0.05 (0.02-0.13) for ≥ 2 years. In the subgroup analysis (Figure 2), tenofovir use was shown to be beneficial with respect to HCC, and the HCC incidence was generally lower among the subgroups with tenofovir use compared with nonusers. The effect of tenofovir use on HCC risk consistently favored never users across many prespecified subgroups. Among PLWH with hepatitis B infection only, tenofovir-containing regimen had decreased risk of HCC, with the adjusted HR of 0.16 (95% CI: 0.07–0.35).
      Table 3Tenofovir-containing regimen associated with decreased risk of hepatocellular carcinoma among men with human immunodeficiency virus infection.
      Total (N = 23,838)HIV diagnosis before 2011 (n = 14,407)
      CharacteristicsCrude HR (95% CI)Adjusted HR
      adjusted for age, diagnosis of AIDS, chronic hepatitis virus infection, cirrhosis, diabetes.
      (95% CI)
      Crude HR (95% CI)Adjusted HR
      adjusted for age, diagnosis of AIDS, chronic hepatitis virus infection, cirrhosis, diabetes.
      (95% CI)
      Tenofovir-based regimen
       Nonusersreferencereferencereferencereference
       Users0.29 (0.19–0.45)0.20 (0.13–0.31)0.28 (0.18–0.44)0.18 (0.12–0.29)
      Age (years)1.10 (1.08–1.11)1.08 (1.06–1.10)1.09 (1.07–1.10)1.09 (1.07–1.10)
      Diagnosis of AIDS
       Noreferencereferencereferencereference
       Yes1.99 (1.30–3.03)1.41 (0.91–2.18)1.86 (1.21–2.87)1.39 (0.89–2.17)
      Chronic hepatitis virus infection
       Nonereferencereferencereferencereference
       HBV only12.98 (6.67–25.27)18.58 (9.45–36.54)10.70 (5.42–21.12)17.03 (8.54–33.96)
       HCV only5.99 (3.08–11.65)6.39 (3.28–12.47)4.92 (2.52–9.60)5.93 (3.03–11.59)
       HBV and HCV21.80 (11.36–41.82)30.95 (15.77–60.74)18.38 (9.60–35.21)31.02 (15.86–60.67)
      Cirrhosis
       Noreferencereferencereferencereference
       Yes19.29 (8.93–41.67)2.51 (1.09–5.77)13.98 (5.67–34.46)1.74 (0.66–4.56)
      Diabetes
       Noreferencereferencereferencereference
       Yes3.67 (1.70–7.92)0.78 (0.35–1.77)3.30 (1.44–7.55)0.75 (0.32–1.78)
      HIV diagnosis year
       Before 2011referencereference
       After 20110.29 (0.10–0.81)0.75 (0.26–2.17)
      Abbreviations: HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HR, hazard ratio; CI, confidence interval.
      Cox’s proportional hazards models were used.
      a adjusted for age, diagnosis of AIDS, chronic hepatitis virus infection, cirrhosis, diabetes.
      Figure thumbnail gr2
      Figure 2Subgroup analysis of tenofovir-containing antiretroviral therapy for the reduced risk of hepatocellular carcinoma. Stratified by one of the following parameters and adjusted for the remaining of the following parameters: age, AIDS, cirrhosis, diabetes, and HIV diagnosis year; individuals with HBV or HCV diagnosis were additionally adjusted for anti-HBV or anti-HCV treatments.
      Cox’s proportional hazards models used in the analyses.
      Abbreviations: HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; AIDS, acquired immunodeficiency syndrome; RR, rate ratio; CI, confidence interval.

      Sensitivity Analysis

      Among male PLWH who did not receive HBV vaccination at birth (born before 1986; n = 18,020; 75.6%), users of tenofovir had lower risk of HCC than nonusers (adjusted HR: 0.20, 95% CI: 0.13–0.31; Supplementary Table 4). Among men with a diagnosis of HIV before 2011 (n = 13,073), users had significantly lower HCC risk than nonusers (adjusted HR: 0.18, 95% CI: 0.12–0.29). The findings were consistent when stratifying the patients with HBV, HCV, or HBV–HCV coinfection, with adjusted HRs of 0.16 (95% CI: 0.07–0.36), 0.34 (95% CI: 0.15–0.79), and 0.18 (95% CI: 0.08–0.37), respectively.

      Discussion

      This large-scale nationwide prospective study discovered that PLWH who had ever used tenofovir-containing ART had substantially lower risk of incident HCC than nonusers. The apparent benefits of tenofovir were consistent, regardless of age, AIDS diagnosis, and HBV/HCV coinfection, which suggests that the benefits of tenofovir may apply to a broad PLWH population. The findings were consistent when the analyses were restricted to male PLWH before approval of tenofovir-containing ART and to those who did not receive HBV vaccination at birth.
      In Taiwan, HIV is a notifiable infectious disease and must be reported in electronic registries for management and reimbursement for testing and treatments. The Centers for Disease Control provide PLWH free-of-charge inpatient and outpatient care, including ART, management of opportunistic illness, and clinical monitoring. Patients with an HIV diagnosis should be periodically monitored for HBV and HCV. Tenofovir disoproxil fumarate and tenofovir alafenamide are two tenofovir prodrugs. The tenofovir-containing regimen defined in our study included both prodrugs. However, the tenofovir alafenamide–containing regimen has been covered under the NHI only since 2017; thus, most of our patients received tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate may cause nephrotoxicity and reduce bone mineral density, whereas a tenofovir alafenamide–containing regimen causes noninferior viral suppression and leads to improved renal function and bone mineral density [
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      • Koenig E.
      • et al.
      Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.
      ].
      Lamivudine has dual antiviral activity against HBV and HIV and may delay liver disease progression [
      • Liaw Y.F.
      • Sung J.J.Y.
      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
      • et al.
      Lamivudine for Patients with Chronic Hepatitis B and Advanced Liver Disease.
      ]. Although it has been the most commonly used agent for PLWH with HBV since the mid-90s, approximately 30% of patients developed HBV resistance after 1 year of treatment [
      • Dienstag J.L.
      • Schiff E.R.
      • Wright T.L.
      • Perrillo R.P.
      • Hann H.-W.L.
      • Goodman Z.
      • et al.
      Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States.
      ]. Tenofovir with a high genetic barrier can achieve sustained HBV suppression even among PLWH with lamivudine-resistant HBV [
      • Benhamou Y.
      • Fleury H.
      • Trimoulet P.
      • Pellegrin I.
      • Urbinelli R.
      • Katlama C.
      • et al.
      Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients.
      ], and this HBV suppression can subsequently reduce liver stiffness [
      • Stockdale A.J.
      • Phillips R.O.
      • Beloukas A.
      • Appiah L.T.
      • Chadwick D.
      • Bhagani S.
      • et al.
      Liver fibrosis by transient elastography and virologic outcomes Aafter introduction of Tenofovir in lamivudine-experienced adults with HIV and hepatitis B virus coinfection in Ghana.
      ]. In the current study, 55% of male PLWH before 2011 may have switched to tenofovir-containing ART after its approval. In addition to HBV suppression, tenofovir-containing ART has a superior HIV virological response and better tolerability [
      • Sax P.E.
      • Tierney C.
      • Collier A.C.
      • Fischl M.A.
      • Mollan K.
      • Peeples L.
      • et al.
      Abacavir–Lamivudine versus Tenofovir–Emtricitabine for Initial HIV-1 Therapy.
      ]. Compared with other nucleoside reverse transcriptase inhibitors, tenofovir has less drug substitution, which implies the importance of treatment program success [
      • Velen K.
      • Lewis J.J.
      • Charalambous S.
      • Grant A.D.
      • Churchyard G.J.
      • Hoffmann C.J.
      Comparison of tenofovir, zidovudine, or stavudine as part of first-line antiretroviral therapy in a resource-limited-setting: a cohort study.
      ].
      (moved to introduction section).
      Besides HBV coinfection, we addressed PLWH with HCV coinfection, which has rarely been investigated. At least 15% of PLWH in our cohort had HCV coinfection. We observed that tenofovir decreased HCC risk among those with HCV coinfection but not HBV coinfection, implying tenofovir may have antitumor activity [
      • Choi J.
      • Kim H.J.
      • Lee J.
      • Cho S.
      • Ko M.J.
      • Lim Y.S.
      Risk of Hepatocellular Carcinoma in Patients Treated With Entecavir vs Tenofovir for Chronic Hepatitis B: A Korean Nationwide Cohort Study.
      ]. Tenofovir may induce DNA damage and cell cycle arrest in human cancer cells [
      • Bruning A.
      • Burger P.
      • Gingelmaier A.
      • Mylonas I.
      The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells.
      ]. Comparing the differences of incidence rates on extrahepatic cancers among PLWH received tenofovir-containing regimens or nonusers may provide additional evidence to examine the antitumor effects of tenofovir. However, it may take longer follow-up time to obtain sufficient numbers of events because of the young population (mean age=32 years old). Tenofovir-containing ART is an effective pre-exposure prophylaxis against HIV [
      • Mayer K.H.
      • Molina J.M.
      • Thompson M.A.
      • Anderson P.L.
      • Mounzer K.C.
      • De Wet J.J.
      • et al.
      Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.
      ] and HBV [
      • Gatanaga H.
      • Hayashida T.
      • Tanuma J.
      • Oka S.
      Prophylactic effect of antiretroviral therapy on hepatitis B virus infection.
      ]. A serological follow-up study demonstrated that tenofovir-containing ART had an excellent protective effect against incident HBV [
      • Gatanaga H.
      • Hayashida T.
      • Tanuma J.
      • Oka S.
      Prophylactic effect of antiretroviral therapy on hepatitis B virus infection.
      ], which may explain the reduced HCC risk among PWLH without neonatal HBV vaccination. Unfortunately, the claims dataset was lacked of HBV serological markers, making difficulties to evaluate new HBV infections in the study. In the future, monitoring PLWH periodically in clinical settings for the occurrence of either HBV or HCV new infections might be relevant. Moreover, limited by only 30 HCC cases among PLWH received tenofovir-containing ART, additional subgroups analyses were challenging thus the initiation time of tenofovir use on HCC risks needed to be evaluated in other large cohorts. Taken together, our findings imply that tenofovir-containing ART may have additional benefits even among those without HBV coinfection. Although HCC risk was decreased among PLWH with tenofovir use, HCC may still develop particularly for those with HBV and HCV coinfections, implying the importance of regular surveillance for HCC [
      • Wandeler G.
      • Mauron E.
      • Atkinson A.
      • Dufour J.F.
      • Kraus D.
      • Reiss P.
      • et al.
      Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: Relevance for screening strategies.
      ].
      Efficacy, durability, safety, additional need for laboratory monitoring, and adherence are key issues in the selection of antivirals for the management of PLWH. Cabotegravir and rilpivirine is a two-drug formulation administered as a monthly intramuscular injection that is approved by the US Food and Drug Administration as a complete regimen for treating HIV. This regimen does not incur a pill burden or stigma relating to HIV treatment [
      • Orkin C.
      • Arasteh K.
      • Górgolas Hernández-Mora M.
      • Pokrovsky V.
      • Overton E.T.
      • Girard P.-M.
      • et al.
      Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.
      ,
      • Swindells S.
      • Andrade-Villanueva J.-F.
      • Richmond G.J.
      • Rizzardini G.
      • Baumgarten A.
      • Masiá M.
      • et al.
      Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.
      ]. Randomized trials have indicated that it is noninferior to standard oral therapy for maintaining HIV suppression [
      • Orkin C.
      • Arasteh K.
      • Górgolas Hernández-Mora M.
      • Pokrovsky V.
      • Overton E.T.
      • Girard P.-M.
      • et al.
      Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.
      ,
      • Swindells S.
      • Andrade-Villanueva J.-F.
      • Richmond G.J.
      • Rizzardini G.
      • Baumgarten A.
      • Masiá M.
      • et al.
      Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.
      ] and for HIV prophylaxis [
      • Landovitz R.J.
      • Donnell D.
      • Clement M.E.
      • Hanscom B.
      • Cottle L.
      • Coelho L.
      • et al.
      Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.
      ]. Such long-acting injectable regimens may simplify HIV treatment, increase patient satisfaction, and facilitate adherence. These advantages may cause the long-acting injectable regimen to become a priority among the antiretrovirals against HIV. However, trials have not adequately addressed the issue of HBV or HCV coinfection, given that these viruses have similar transmission routes to HIV [
      • Orkin C.
      • Arasteh K.
      • Górgolas Hernández-Mora M.
      • Pokrovsky V.
      • Overton E.T.
      • Girard P.-M.
      • et al.
      Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.
      ,
      • Swindells S.
      • Andrade-Villanueva J.-F.
      • Richmond G.J.
      • Rizzardini G.
      • Baumgarten A.
      • Masiá M.
      • et al.
      Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.
      ,
      • Landovitz R.J.
      • Donnell D.
      • Clement M.E.
      • Hanscom B.
      • Cottle L.
      • Coelho L.
      • et al.
      Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.
      ]. Future studies should investigate the role of tenofovir in combination with the long-acting regimen in HIV–HBV/HCV coinfection, particularly in the Asian-Pacific region where chronic hepatitis B viruse are prevalent [
      • Bollinger R.C.
      • Thio C.L.
      • Sulkowski M.S.
      • McKenzie-White J.
      • Thomas D.L.
      • Flexner C.
      Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV.
      ].
      A strength of our study include the inclusion the PLWH from a nationwide surveillance database, with validated and prospectively updated data regarding tenofovir use, comorbidities, and HCC incidence. The complete follow-up of nationwide registries addresses selection bias and minimizes reverse causation. Most PLWH received their HIV diagnosis at a young age [
      • van Welzen B.J.
      • Smit C.
      • Boyd A.
      • Lieveld F.I.
      • Mudrikova T.
      • Reiss P.
      • et al.
      Decreased all-cause and liver-related mortality risk in HIV/hepatitis B virus coinfection coinciding with the introduction of tenofovir-containing combination antiretroviral therapy.
      ,
      • Tsai W.C.
      • Hsu W.T.
      • Liu W.D.
      • Sun H.Y.
      • Chuang Y.C.
      • Huang Y.S.
      • et al.
      Impact of antiretroviral therapy containing tenofovir disoproxil fumarate on the survival of patients with HBV and HIV coinfection.
      ]; thus, it may take a long time to compare the effects of various ARTs on HCC incidence. A large population-based study provides an exceptional opportunity to investigate HCC risk, especially in association with tenofovir use and HBV/HCV status. This is the first comprehensive study to evaluate the influence of tenofovir on HCC risk in PLWH with HBV/HCV coinfection.
      This study has several limitations. First, we lacked information regarding alcohol consumption, immunological recovery, viral load, HCC screening, specific fibrosis stage, and actual adherence. A large cohort study found suppressed HBV DNA decreased HCC risk among PLWH with HBV coinfection [
      • Kim H.N.
      • Newcomb C.W.
      • Carbonari D.M.
      • Roy J.A.
      • Torgersen J.
      • Althoff K.N.
      • et al.
      Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.
      ], suggesting that HBV-related seromarkers were relevant in monitoring PLWH. Unfortunately, the claims dataset lacks of personal lab information, such as HBV DNA levels. Although we performed analyses according to chronic hepatitis virus infection status, we lacked hepatitis B core antigen (anti-HBc), one critical seromarker that indicates previous HBV infection. Thus, the HCC risk for PLWH without the diagnosis of chronic hepatitis virus infection might be underestimated. However, we performed analyses among HBV nonvaccinees and the results consistently showed reduced HCC risk of tenofovir users than nonusers. In Taiwan, our government started to reimburse direct antiviral agents (DAA) for chronic hepatitis C patients since 2017. However, strict reimbursement criteria including failure of interferon-based treatment or liver fibrosis ≧F3 was needed. In 2019, all of chronic hepatitis C patients could be reimbursed without criteria for DAA treatment. Thus, most of the PLWH with chronic hepatitis C infection in the study received interferon-based regimen. However, we lacked information of sustained virological response for chronic hepatitis C. As an observational study applied national registries, there were several potential confounders could not be addressed. Beyond chronic hepatitis virus related seromarkers, we lacked the information of obesity and metabolic associated fatty liver disease to further evaluate PLWH without diagnosis of chronic hepatitis virus infections. However, we considered the information of diabetes in the multiple regression models as a proxy. Second, women were not included in the study, limiting the generalizability of the results. However, the efficacy of tenofovir should not vary by sex. Finally, most people residing in HBV-endemic areas are exposed to HBV infection through mother-to-infant transmission; thus, the impacts of tenofovir on HCC risk should be further evaluated in other populations.
      In conclusion, this large nationwide study indicated that among PLWH, ever use of tenofovir-containing ART was associated with significantly lower risk of incident HCC than nonusers. Our findings support the need for randomized controlled trials of tenofovir in combination with long-acting ARTs to assess the impact on HCC prevention.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

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