BRIEF REPORT: CLINICAL SCIENCE
Incidence of Hepatocellular Carcinoma in HIV-Infected Patients With Cirrhosis: A Prospective Study María Luisa Montes Ramírez, MD,* José M. Miró, MD,† Carmen Quereda, MD,‡ Antoni Jou, MD,§ Miguel Ángel von Wichmann, MD,k Juan Berenguer, MD,¶ Juan J. González-García, MD,* Asunción Hernando, MD,# Enrique Ortega, MD,** José Sanz, MD,†† and José R. Arribas, MD,* GESIDA 37/03.FIPSE 364665/03–N5 NEAT Study Group
Abstract: This study assesses the incidence of hepatocellular carcinoma (HCC) in a prospective cohort of HIV-infected patients, the majority receiving antiretroviral therapy, with liver cirrhosis from different etiologies, enrolled between 2004 and 2005 with median follow-up of 5 years. We followed 371 patients, 25.6% with decompensated cirrhosis at baseline. The incidence rate of HCC was 6.72 per 1000 person-years [95% confidence interval (CI): 2.6 to 10.9]. There was a trend toward a higher cumulative probability of developing HCC at 6 years of follow-up (considering death and liver transplant as competing risks) in patients with decompensated versus compensated cirrhosis at baseline (6% vs. 2%, P , 0.06). Key Words: HIV, viral hepatitis, liver cirrhosis, hepatocellular carcinoma, incidence (J Acquir Immune Defic Syndr 2014;65:82–86)
INTRODUCTION Augmented survival of subjects infected with the HIV has increased the relevance of comorbidities not directly Received for publication April 25, 2013; accepted July 16, 2013. From the *HIV Unit, Service of Internal Medicine, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain; †Service of Infectious Diseases, Hospital Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain; ‡Service of Infectious Diseases, Hospital Ramón y Cajal, Madrid, Spain; §HIV Clinical Unit, Internal Medicine Department and Fundació de la Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain; kUnit of Infectious Diseases, Hospital Donostia, Donostia-San Sebastián, Spain; ¶Infectious Diseases and HIV Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; #HIV Unit, Hospital 12 de Octubre and Universidad Europea de Madrid, Madrid, Spain; **Unit of Infectious Diseases, Hospital General Universitario de Valencia, Valencia, Spain; and ††Service of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain. J.R.A. is an investigator for Programa de Intensificación de la Actividad Investigadora en el SNS (I3SNS); IdiPAZ AIDS and Infectious Diseases Investigator Group is partially supported by “Red de Investigación en SIDA” (AIDS Research Network) (RIS) RD07/0006/2007, GESIDA 37/03.FIPSE 364665/03 and N5 NEAT Study Group. The authors have no conflicts of interest to disclose. The GESIDA 37/03.FIPSE 364665/03–N5 NEAT Study Group Investigators are listed in Appendix 1. Correspondence to: María Luisa Montes Ramírez, MD, Consulta de Medicina Interna 2, Hospital Universitario La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain (e-mail: [email protected]). Copyright © 2013 by Lippincott Williams & Wilkins
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related to HIV, such as chronic liver disease.1 End-stage liver disease is currently a frequent cause of death in HIVinfected patients, being responsible for half of the deaths in some centers.2,3 Hepatocellular carcinoma (HCC) is an emerging complication of cirrhosis in HIV-infected patients and a main cause of liver-related deaths.4,5 Treatment with potent antiretrovirals, better antihepatitis C virus treatments, and improved medical management of advanced liver disease may be associated with a decreased risk of hepatic decompensation, which increases survival of coinfected patients with cirrhosis and hence the probability of developing HCC.6–8 We lack an accurate estimate—based on prospective cohort data—of the incidence of HCC in HIV-infected patients with liver cirrhosis who receive adequate antiretroviral therapy (ART). The few studies that analyzed the incidence of HCC in HIV-infected cirrhotic patients were retrospective and included HIV-infected cirrhotic patients who received suboptimal ART and were infrequently treated for chronic viral hepatitis.9–13 In this study, we have investigated the incidence of HCC in a nationwide prospective cohort of HIV-infected patients with liver cirrhosis followed for a median of 60 months. We also report epidemiological features, clinical presentation, and outcome of HCC.
PATIENTS, MATERIALS AND METHODS Study Design As previously reported,14 this multicenter cohort (9 hospitals from 4 regions in Spain) included HIV-infected subjects with a diagnosis of liver cirrhosis. Patients were enrolled from June 2004 to June 2005 and are still under active follow-up. The local ethics committees approved the study, and all patients gave dated and written informed consent. Liver cirrhosis was diagnosed by a liver biopsy15,16 before the diagnosis of liver decompensation, or Bonacini score of at least 8.17 Liver cirrhosis was classified as decompensated or compensated based on the presence or the absence of history of hepatic decompensation (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, upper gastrointestinal bleeding, or hepatorenal syndrome). Patients with decompensated cirrhosis were enrolled only if the first episode of decompensation had occurred during the year before the baseline visit.
J Acquir Immune Defic Syndr Volume 65, Number 1, January 1, 2014
J Acquir Immune Defic Syndr Volume 65, Number 1, January 1, 2014
Hepatitis C was diagnosed based on a positive serology or positive HCV plasma RNA by polymerase chain reaction. Hepatitis B was diagnosed based on a positive serology. We used the European Association for the Study of the Liver criteria for diagnosis of HCC.18 All patients had a baseline visit and then 1 follow-up visit in specialized HIV clinics every 6 months. In each visit, we reviewed clinical events, laboratory data, ChildPugh score, consumption of alcohol and illicit drugs, type of ART regimen, type of treatment for hepatitis C and/or B, results of abdominal ultrasound, and liver transplant criteria.
Hepatocellular Carcinoma in HIV Subjects
Statistical Analyses The primary end point was survival defined as time from baseline visit to the diagnosis of HCC. Qualitative variables are described with frequencies and percentages. Quantitative variables are described with mean, standard deviation (SD), median, and interquartile range (IQR). Comparisons between categorical variables were made by the x2 of the Fisher test when appropriate. Comparisons between continuous variables were made using the Student t test or Mann– Whitney U test, depending on the normality of distributions. Normality of the variables was tested with the Kolmogorov– Smirnov–Lilliefords test.
TABLE 1. Comparison of Baseline Characteristics Between Patients With and Without Hepatocellular Carcinoma (HCC) Characteristic Male Age, median (IQR), yrs Duration of HIV infection, median (IQR), yrs HIV transmission route Intravenous drug use Heterosexual Homosexual Blood derivatives Other Diagnosis of cirrhosis Liver decompensation Bonacini score .8 Liver biopsy Causes of cirrhosis Chronic HCV infection Chronic HBV infection Alcohol use (.80 g/d during .5 yrs) Alcohol consumption 6 mo before baseline visit Drugs consumption Heroine Cocaine Cannabis Methadone Child-Pugh score A B C CDC C3 stage Patients on ART Decompensated cirrhosis at baseline Time since diagnosis of cirrhosis, median (IQR), years Plasma HIV RNA ,50 copies/mL CD4+ cell count nadir, median (IQR), cells/mL CD4+ cell count at baseline, median (IQR), cells/mL HCV therapy at any time Response to HCV therapy Sustained virological response End of treatment or no response Still on treatment
Non-HCC Group (N = 361) 285 (78.9) 41.7 (39–44.9) 13.5 (9.7–17.1) 318 35 7 4 7
HCC Group (N = 10)
P
8 (80) 42.8 (42.1–43.8) 14.4 (13.0–17.7)
1 0.367 0.353
(88.1) (9.7) (1.9) (1.1) (1.9)
8 (80) 4 (40) 0 0 0
0.347 0.014 1 1 1
87 (24.1) 43 (11.9) 231 (64.0)
5 (50) 1 (10) 4 (40)
0.170
345 (95.8) 28 (8.6) 116 (32.1) 60
9 (90) 1 (10) 1 (10) 2
0.451 0.878 0.181 0.676
4 12 15 39 240 48 39 317 317 90 1.5 213/345 150 380 231/345
(1) (3.2) (4) (10.5) (73.7) (14.7) (11.9) (87.8) (87.8) (24.9) (0.4–3.1) (61.7) (72–255) (232–598) (66.9)
69/237 (29.1) 153/237 (66.2) 9/237 (3.9)
0 0 0 1
1 1 1 1
7 (70) 0 3 (30) 9 (90) 9 (90) 5 (50) 1.9 (0.1–3.5) 8/9 (88.9) 86 (60–114) 348 (145–443) 6/9 (66.7) 1/6 (16.7) 4/6 (66.7) 1/6 (16.7)
0.134
1 1 0.132 0.784 0.162 0.145 0.215 1 0.272
Data expressed as numbers and percentages in parenthesis unless otherwise stated.
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Time to event was calculated as months from baseline visit to HCC diagnosis (in months). Survival functions were performed by the Kaplan–Meier method. Survival curves were compared using the log-rank test. The probability of developing HCC was estimated using the multiple decremental method, considering death and liver transplant as competing risks, and the difference were compared with the Gray test. The multivariate analysis was using the Fine and Gray model. The cumulative incidence and the incidence rate were calculated as measures of frequency of the event and rate ratio as a measure of association. Contrast analysis was based on the exact method or normal approximation as required. The impact of prognostic factors on the diagnosis of HCC was not analyzed because of the low number of incident HCC. SPSS 16.0 software was used for analysis (SPSS Inc, Chicago, IL). For all tests, we considered a statistically significant bilateral P value , 0.05.
RESULTS We included 371 HIV-infected subjects with liver cirrhosis from different etiologies, chronic hepatitis C being the principal one (95%); chronic hepatitis B was present in 9% of subjects. More than 75% of subjects were diagnosed of liver cirrhosis in the 3 years before their inclusion in the cohort. After a median follow-up of 60.4 months (IQR, 24.2–66.9), we diagnosed HCC in 10 patients (2.7%). Baseline characteristics of subjects with and without HCC were similar (Table 1). Most subjects were receiving ART, and .60% had undetectable HIV viral load. During follow-up, there were 98 deaths, 92 in non-HCC group and 6 in HCC group, and 15 subjects underwent a liver transplantation: 13 in the non-HCC group and 2 in the HCC group. Forty-one subjects were lost to follow-up (with same proportions in both groups); median time since baseline visit to the last visit before loss to follow-up was 17 months (IQR, 6–35). The first case of HCC was diagnosed after 10 months of follow-up. At that time, 37 subjects have died, 65% of these deaths were because of hepatic causes, and 2 subjects underwent liver transplantation. The median time of followup for subjects who died was 5 months (IQR, 2–8). Cases of liver transplant were at 5 and 9 months, respectively. Of the 10 patients with HCC, 9 were HCV and 1 hepatitis B virus (HBV) coinfected. The median time from
the last clinic visit to the date of HCC diagnosis was 2.6 months (IQR, 1.9–4.0). At the clinic visit immediately before HCC diagnosis, all subjects had CD4+ cell counts .100 cells per microliter, all were receiving ART, and 90% had undetectable HIV viral load; these proportions were not significantly different from non-HCC group. Most patients had Child-Pugh score A or B. In the visit before HCC diagnosis, serum levels of alpha-fetoprotein were measured in 4 patients and 2 (50%) of whom had levels ,20 IU/mL. Liver ultrasound studies were performed in 4 patients, and in no case, space-occupying lesions were observed. The median interval between the date of HCC diagnosis and the date of the previous abdominal ultrasound was 6.98 months (IQR, 2.26–10.82). Regarding HCC characteristics at the time of diagnosis, 60% were multiple, 90% of lesions were of ,5 cm, 50% showed portal thrombosis, none had extrahepatic extension, and 40% fulfilled the Milan criteria; 5 subjects were evaluated for liver transplant. After diagnosis of HCC, 6 (60%) patients died. Liver transplantation was performed in 2 patients. One liver transplanted patient was lost to follow-up. Three patients were still alive after 18, 27, and 39 months after HCC diagnosis. As shown in Table 2, the overall incidence rate of HCC in our cohort was 6.72 per 1000 person-years [95% confidence interval (CI): 2.6 to 10.9]. The cumulative incidence rate of HCC was 2.7% (95% CI: 1.3 to 4.9). Incidence rates were significantly higher in patients with decompensated liver cirrhosis at baseline (20.0 per 1000 person-years [95% CI: 2.5 to 37.5]) than in those with compensated cirrhosis (4.0 per 1000 person-years [95% CI: 0.5 to 7.6]; P = 0.032). Incidence of HCC was similar in patients with and without HCV coinfection, HBV coinfection, and HCV and/or HBV coinfection. Kaplan–Meier survival probability estimates of developing HCC at 6 years of follow-up (considering death and liver transplant as competing risks) was 3% (95% CI: 1.5 to 5). This probability was higher in patients with decompensated cirrhosis at baseline 5.8% (95% CI: 2.1 to 12.2) than in those with compensated cirrhosis 2.0% (95% CI: 0.7 to 4.3), with borderline statistical significance (P = 0.06) and a hazard ratio of 3.0 (95% CI: 0.87 to 10.3; P = 0.081). This probability was 1.1% at 2 years and 2.0% at 4 and 6 years in the compensated group versus 2.2% at 2 years and 5.8% at 4 and 6 years in the decompensated liver cirrhosis group.
TABLE 2. Incidence of Hepatocarcinoma (HCC)
Study Group Whole cohort Decompensation of cirrhosis at baseline HCV coinfection
HBV coinfection
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Decompensated Compensated Chronic HCV Absent or cured Chronic HBV Absent, postvaccination, cured, or core
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No. HCC/No. Patients at Risk
Cumulative Incidence % (95% CI)
10/371 5/95 5/276
2.7 (1.3–4.9) 5.26 (1.7–11.9) 1.8 (0.6–4.2)
9/354 1/16 1/29 8/305
2.5 6.3 3.5 2.6
(1.2–4.8) (0.2–30.2) (0.1–17.8) (1.1–5.1)
Incidence Rate No. HCC Per 1000 PersonYears (95% CI) 6.7 (2.6–10.9) 20.0 (2.5–37.5) 4.0 (0.5–7.6) 6.3 18.7 10.1 6.6
(2.2–10.4) (218.0–55.4) (29.7–29.8) (2.0–11.1)
Rate Ratio Incidence Rate Exposed/Incidence Rate Nonexposed (95% CI)
P
5.0 (1.1–21.5)
0.032
0.3 (0.04–2.6)
0.610 1.000
1.5 (0.04–11.5)
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DISCUSSION In our contemporary cohort, the incidence of HCC in HIV-infected patients with liver cirrhosis receiving adequate ART was 6.7 per 1000 patients-years. The incidence of HCC was lower in patients with compensated cirrhosis. The incidence of HCC in our study is substantially higher than the incidence rates reported in previous studies, which varied between 0 and 2.8 per 1000 patients-year.9,10,12,13,19 Our higher incidence is probably because of the fact that all of our patients had cirrhosis and the longer follow-up time associated to the improved survival of our patients. In previous studies, many coinfected patients received suboptimal ART, and uncontrolled HIV infection shortened the survival of HCV coinfected patients with endstage liver disease to such an extent that possibly HCC did not have a chance to emerge. Recently, Merchante et al12 in a retrospective review of HIV/HCV–coinfected patients by calendar year found that the incidence of HCC increased from 0.2 to 2.8 per 1000 person-years between 2000 and 2009. Our results are also consistent with an increased incidence of HCC in recent years. Interestingly, non–HIV-infected subjects with compensated cirrhosis have a 1–8% annual incidence of HCC (depending on the etiology of the cirrhosis), and those with chronic hepatitis have an approximate annual risk of 1%,20 figures very similar to those obtained in our study. An important finding of our study was a clear trend toward a higher incidence of HCC among patients with decompensated cirrhosis as compared with those with compensated cirrhosis after adjusting using competitive risks of death or liver transplant. Previous studies did not use a cumulative function analysis for the calculation of a cumulative probability for the development of HCC. In our previous analysis of the natural history of liver cirrhosis in HIV/HCV–coinfected patients, we found a relatively high 3-year survival in patients with compensated liver cirrhosis (87%); in contrast, 2-year survival of patients with decompensated cirrhosis was only 50%.21 Given these large differences in mortality, it seems that adjustments for competitive risks are critical aspects of the analysis. Patients with and without HCC development had similar baseline characteristics (Table 1). Both groups had a very high rate of HCV coinfection, were almost always receiving effective ART, had similar immune reconstitution, and have received anti-HCV therapy with similar frequency. Liver decompensation at baseline occurred in half of the patients who developed HCC compared with 24.1% in patients free of HCC development. However, because of the limited sample size, this difference was not significant. The main limitation of our study is the low number of end points that compromise our statistical power. However, follow-up of the cohort continues and further analysis will provide evidence of changing trends in the incidence of HCC in HIV-infected patients with liver cirrhosis and viral hepatitis coinfection. In summary, our prospective cohort of cirrhotic patients with an adequate control of HIV infection shows a relatively low probability of developing HCC although the incidence of HCC seems to be higher than the previously reported. Incidence of HCC is even higher in patients with decompensated liver disease at baseline. Ó 2013 Lippincott Williams & Wilkins
Hepatocellular Carcinoma in HIV Subjects
ACKNOWLEDGMENT The authors thank Marta Pulido, MD, for editing the manuscript and editorial assistance. REFERENCES 1. González-García J, Navarro San Francisco C, Condes E, et al. Evaluación de la prevalencia de la coinfección por VHC, características de la hepatopatía y tratamiento específico de los pacientes infectados por VIH en España. Estudio GESIDA 57/07. IV Congreso Nacional de GESIDA, Toledo, November 27–30, 2012, PO41. 2. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;32:492–497. 3. Martín-Carbonero L, Soriano V, Valencia E, et al. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIVinfected patients. AIDS Res Hum Retroviruses. 2001;17:1467–1471. 4. Salmon-Ceron D, Rosenthal E, Lewden C, et al. Emerging role of hepatocellular carcinoma among liver-related causes of deaths in HIV-infected patients: the French National Mortalité 2005 Study. J Hepatol. 2009;50: 736–745. 5. Ioannou GN, Bryson CL, Weiss NS, et al. The prevalence of cirrhosis and hepatocellular carcinoma in patients with HIV infection. Hepatology. 2013;57:249–257. 6. Sulkowski M. Hepatocellular carcinoma in HIV-infected patients comes of age: the convergence of epidemiology and treatment effectiveness. J Hepatol. 2009;50:655–658. 7. Pineda JA, García-García JA, Aguilar-Guisado M, et al. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology. 2007;46:622–630. 8. Bräu N, Salvatore M, Ríos-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006;44:47–55. 9. García-García JA, Romero-Gómez M, Girón-González JA, et al. Incidence of and factors associated with hepatocellular carcinoma among hepatitis C virus and human immunodeficiency virus coinfected patients with decompensated cirrhosis. AIDS Res Hum Retroviruses. 2006;22: 1236–1241. 10. Kramer JR, Giordano TP, Souchek J, et al. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in U.S. veterans with hepatitis C. Am J Gastroenterol. 2005;100:56–63. 11. Bruno R, Sacchi P, Puoti M, et al. Natural history of compensated viral cirrhosis in a cohort of patients with HIV infection. J Acquir Immune Defic Syndr. 2007;46:297–303. 12. Merchante N, Merino E, López-Aldeguer J, et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain. Clin Infect Dis. 2013;56:143–150. 13. Bruyand M, Dabis F, Vandenhende MA, et al. HIV-induced immune deficiency is associated with a higher risk of hepatocarcinoma, ANRS CO3 Aquitaine Cohort, France, 1998-2008. J Hepatol. 2011;55:1058–1062. 14. López-Diéguez M, Montes ML, Pascual-Pareja JF, et al. The natural history of liver cirrhosis in HIV-hepatitis C virus-coinfected patients. AIDS. 2011;25:899–904. 15. Forner A, Ayuso C, Real MI, et al. Diagnosis and treatment of hepatocellular carcinoma [in Spanish]. Med Clin (Barc). 2009;132:272–287. 16. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022. 17. Bonacini M, Hadi G, Govindarajan S, et al. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1997;92:1302–1304. 18. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012; 56:908–943. 19. Murillas J, Del Río M, Riera M, et al. Increased incidence of hepatocellular carcinoma (HCC) in HIV-1 infected patients. Eur J Intern Med. 2005;16:113–115. 20. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.
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21. García-Samaniego J, Rodríguez M, Berenguer J, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001;96:179–183.
APPENDIX 1. GESIDA 37/03.FIPSE 364665/ 03–NEAT IG5 INVESTIGATORS STUDY GROUP INVESTIGATORS M. L. Montes Ramírez, J. R. Arribas, F. X. Zamora Vargas, J. J. González-García (Hospital Universitario La Paz, Madrid); M. A. Hernando, F. Pulido, R. Rubio, M. Lagarde, M. Matarranz (Hospital Universitario 12 de Octubre, Madrid); J. B. Berenguer, M. Ramírez Schacke,
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I. Gutiérrez (Hospital General Universitario Gregorio Marañón, Madrid); C. Quereda, T. S. Alonso (Hospital Universitario Ramón y Cajal, Madrid); A. A. Caso, J. Sanz-Moreno, J. de Miguel Prieto, E. C. García (Hospital Universitario Príncipe de Asturias, Madrid). E. O. González, L. O. R. de Arellano (Hospital General Universitario de Valencia), C. T. Llacher, A. J. Pastor (Hospital Germans Trias i Pujol, Badalona); J. M. Miró, J. M. Miro, M. López-Dieguez, C. Manzardo, F. Agüero, M. Laguno, and J. Mallolas (Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain). M. Á. Von Wichmann de Miguel, J. A. Iribarren, F. Rodriguez-Arrondo (Unit of Infectious Diseases, Hospital Universtario Donostia, DonostiaSan Sebastián, Spain); H. Esteban, E. Barquilla, L. Serrano (Fundación SEIMC-GESIDA, Madrid).
Ó 2013 Lippincott Williams & Wilkins
Incidence of Hepatocellular Carcinoma in HIV-Infected Patients With Cirrhosis: A Prospective Study María Luisa Montes Ramírez, MD,* José M. Miró, MD,† Carmen Quereda, MD,‡ Antoni Jou, MD,§ Miguel Ángel von Wichmann, MD,k Juan Berenguer, MD,¶ Juan J. González-García, MD,* Asunción Hernando, MD,# Enrique Ortega, MD,** José Sanz, MD,†† and José R. Arribas, MD,* GESIDA 37/03.FIPSE 364665/03–N5 NEAT Study Group
Abstract: This study assesses the incidence of hepatocellular carcinoma (HCC) in a prospective cohort of HIV-infected patients, the majority receiving antiretroviral therapy, with liver cirrhosis from different etiologies, enrolled between 2004 and 2005 with median follow-up of 5 years. We followed 371 patients, 25.6% with decompensated cirrhosis at baseline. The incidence rate of HCC was 6.72 per 1000 person-years [95% confidence interval (CI): 2.6 to 10.9]. There was a trend toward a higher cumulative probability of developing HCC at 6 years of follow-up (considering death and liver transplant as competing risks) in patients with decompensated versus compensated cirrhosis at baseline (6% vs. 2%, P , 0.06). Key Words: HIV, viral hepatitis, liver cirrhosis, hepatocellular carcinoma, incidence (J Acquir Immune Defic Syndr 2014;65:82–86)
INTRODUCTION Augmented survival of subjects infected with the HIV has increased the relevance of comorbidities not directly Received for publication April 25, 2013; accepted July 16, 2013. From the *HIV Unit, Service of Internal Medicine, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain; †Service of Infectious Diseases, Hospital Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain; ‡Service of Infectious Diseases, Hospital Ramón y Cajal, Madrid, Spain; §HIV Clinical Unit, Internal Medicine Department and Fundació de la Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain; kUnit of Infectious Diseases, Hospital Donostia, Donostia-San Sebastián, Spain; ¶Infectious Diseases and HIV Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; #HIV Unit, Hospital 12 de Octubre and Universidad Europea de Madrid, Madrid, Spain; **Unit of Infectious Diseases, Hospital General Universitario de Valencia, Valencia, Spain; and ††Service of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain. J.R.A. is an investigator for Programa de Intensificación de la Actividad Investigadora en el SNS (I3SNS); IdiPAZ AIDS and Infectious Diseases Investigator Group is partially supported by “Red de Investigación en SIDA” (AIDS Research Network) (RIS) RD07/0006/2007, GESIDA 37/03.FIPSE 364665/03 and N5 NEAT Study Group. The authors have no conflicts of interest to disclose. The GESIDA 37/03.FIPSE 364665/03–N5 NEAT Study Group Investigators are listed in Appendix 1. Correspondence to: María Luisa Montes Ramírez, MD, Consulta de Medicina Interna 2, Hospital Universitario La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain (e-mail: [email protected]). Copyright © 2013 by Lippincott Williams & Wilkins
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related to HIV, such as chronic liver disease.1 End-stage liver disease is currently a frequent cause of death in HIVinfected patients, being responsible for half of the deaths in some centers.2,3 Hepatocellular carcinoma (HCC) is an emerging complication of cirrhosis in HIV-infected patients and a main cause of liver-related deaths.4,5 Treatment with potent antiretrovirals, better antihepatitis C virus treatments, and improved medical management of advanced liver disease may be associated with a decreased risk of hepatic decompensation, which increases survival of coinfected patients with cirrhosis and hence the probability of developing HCC.6–8 We lack an accurate estimate—based on prospective cohort data—of the incidence of HCC in HIV-infected patients with liver cirrhosis who receive adequate antiretroviral therapy (ART). The few studies that analyzed the incidence of HCC in HIV-infected cirrhotic patients were retrospective and included HIV-infected cirrhotic patients who received suboptimal ART and were infrequently treated for chronic viral hepatitis.9–13 In this study, we have investigated the incidence of HCC in a nationwide prospective cohort of HIV-infected patients with liver cirrhosis followed for a median of 60 months. We also report epidemiological features, clinical presentation, and outcome of HCC.
PATIENTS, MATERIALS AND METHODS Study Design As previously reported,14 this multicenter cohort (9 hospitals from 4 regions in Spain) included HIV-infected subjects with a diagnosis of liver cirrhosis. Patients were enrolled from June 2004 to June 2005 and are still under active follow-up. The local ethics committees approved the study, and all patients gave dated and written informed consent. Liver cirrhosis was diagnosed by a liver biopsy15,16 before the diagnosis of liver decompensation, or Bonacini score of at least 8.17 Liver cirrhosis was classified as decompensated or compensated based on the presence or the absence of history of hepatic decompensation (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, upper gastrointestinal bleeding, or hepatorenal syndrome). Patients with decompensated cirrhosis were enrolled only if the first episode of decompensation had occurred during the year before the baseline visit.
J Acquir Immune Defic Syndr Volume 65, Number 1, January 1, 2014
J Acquir Immune Defic Syndr Volume 65, Number 1, January 1, 2014
Hepatitis C was diagnosed based on a positive serology or positive HCV plasma RNA by polymerase chain reaction. Hepatitis B was diagnosed based on a positive serology. We used the European Association for the Study of the Liver criteria for diagnosis of HCC.18 All patients had a baseline visit and then 1 follow-up visit in specialized HIV clinics every 6 months. In each visit, we reviewed clinical events, laboratory data, ChildPugh score, consumption of alcohol and illicit drugs, type of ART regimen, type of treatment for hepatitis C and/or B, results of abdominal ultrasound, and liver transplant criteria.
Hepatocellular Carcinoma in HIV Subjects
Statistical Analyses The primary end point was survival defined as time from baseline visit to the diagnosis of HCC. Qualitative variables are described with frequencies and percentages. Quantitative variables are described with mean, standard deviation (SD), median, and interquartile range (IQR). Comparisons between categorical variables were made by the x2 of the Fisher test when appropriate. Comparisons between continuous variables were made using the Student t test or Mann– Whitney U test, depending on the normality of distributions. Normality of the variables was tested with the Kolmogorov– Smirnov–Lilliefords test.
TABLE 1. Comparison of Baseline Characteristics Between Patients With and Without Hepatocellular Carcinoma (HCC) Characteristic Male Age, median (IQR), yrs Duration of HIV infection, median (IQR), yrs HIV transmission route Intravenous drug use Heterosexual Homosexual Blood derivatives Other Diagnosis of cirrhosis Liver decompensation Bonacini score .8 Liver biopsy Causes of cirrhosis Chronic HCV infection Chronic HBV infection Alcohol use (.80 g/d during .5 yrs) Alcohol consumption 6 mo before baseline visit Drugs consumption Heroine Cocaine Cannabis Methadone Child-Pugh score A B C CDC C3 stage Patients on ART Decompensated cirrhosis at baseline Time since diagnosis of cirrhosis, median (IQR), years Plasma HIV RNA ,50 copies/mL CD4+ cell count nadir, median (IQR), cells/mL CD4+ cell count at baseline, median (IQR), cells/mL HCV therapy at any time Response to HCV therapy Sustained virological response End of treatment or no response Still on treatment
Non-HCC Group (N = 361) 285 (78.9) 41.7 (39–44.9) 13.5 (9.7–17.1) 318 35 7 4 7
HCC Group (N = 10)
P
8 (80) 42.8 (42.1–43.8) 14.4 (13.0–17.7)
1 0.367 0.353
(88.1) (9.7) (1.9) (1.1) (1.9)
8 (80) 4 (40) 0 0 0
0.347 0.014 1 1 1
87 (24.1) 43 (11.9) 231 (64.0)
5 (50) 1 (10) 4 (40)
0.170
345 (95.8) 28 (8.6) 116 (32.1) 60
9 (90) 1 (10) 1 (10) 2
0.451 0.878 0.181 0.676
4 12 15 39 240 48 39 317 317 90 1.5 213/345 150 380 231/345
(1) (3.2) (4) (10.5) (73.7) (14.7) (11.9) (87.8) (87.8) (24.9) (0.4–3.1) (61.7) (72–255) (232–598) (66.9)
69/237 (29.1) 153/237 (66.2) 9/237 (3.9)
0 0 0 1
1 1 1 1
7 (70) 0 3 (30) 9 (90) 9 (90) 5 (50) 1.9 (0.1–3.5) 8/9 (88.9) 86 (60–114) 348 (145–443) 6/9 (66.7) 1/6 (16.7) 4/6 (66.7) 1/6 (16.7)
0.134
1 1 0.132 0.784 0.162 0.145 0.215 1 0.272
Data expressed as numbers and percentages in parenthesis unless otherwise stated.
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Montes Ramírez et al
Time to event was calculated as months from baseline visit to HCC diagnosis (in months). Survival functions were performed by the Kaplan–Meier method. Survival curves were compared using the log-rank test. The probability of developing HCC was estimated using the multiple decremental method, considering death and liver transplant as competing risks, and the difference were compared with the Gray test. The multivariate analysis was using the Fine and Gray model. The cumulative incidence and the incidence rate were calculated as measures of frequency of the event and rate ratio as a measure of association. Contrast analysis was based on the exact method or normal approximation as required. The impact of prognostic factors on the diagnosis of HCC was not analyzed because of the low number of incident HCC. SPSS 16.0 software was used for analysis (SPSS Inc, Chicago, IL). For all tests, we considered a statistically significant bilateral P value , 0.05.
RESULTS We included 371 HIV-infected subjects with liver cirrhosis from different etiologies, chronic hepatitis C being the principal one (95%); chronic hepatitis B was present in 9% of subjects. More than 75% of subjects were diagnosed of liver cirrhosis in the 3 years before their inclusion in the cohort. After a median follow-up of 60.4 months (IQR, 24.2–66.9), we diagnosed HCC in 10 patients (2.7%). Baseline characteristics of subjects with and without HCC were similar (Table 1). Most subjects were receiving ART, and .60% had undetectable HIV viral load. During follow-up, there were 98 deaths, 92 in non-HCC group and 6 in HCC group, and 15 subjects underwent a liver transplantation: 13 in the non-HCC group and 2 in the HCC group. Forty-one subjects were lost to follow-up (with same proportions in both groups); median time since baseline visit to the last visit before loss to follow-up was 17 months (IQR, 6–35). The first case of HCC was diagnosed after 10 months of follow-up. At that time, 37 subjects have died, 65% of these deaths were because of hepatic causes, and 2 subjects underwent liver transplantation. The median time of followup for subjects who died was 5 months (IQR, 2–8). Cases of liver transplant were at 5 and 9 months, respectively. Of the 10 patients with HCC, 9 were HCV and 1 hepatitis B virus (HBV) coinfected. The median time from
the last clinic visit to the date of HCC diagnosis was 2.6 months (IQR, 1.9–4.0). At the clinic visit immediately before HCC diagnosis, all subjects had CD4+ cell counts .100 cells per microliter, all were receiving ART, and 90% had undetectable HIV viral load; these proportions were not significantly different from non-HCC group. Most patients had Child-Pugh score A or B. In the visit before HCC diagnosis, serum levels of alpha-fetoprotein were measured in 4 patients and 2 (50%) of whom had levels ,20 IU/mL. Liver ultrasound studies were performed in 4 patients, and in no case, space-occupying lesions were observed. The median interval between the date of HCC diagnosis and the date of the previous abdominal ultrasound was 6.98 months (IQR, 2.26–10.82). Regarding HCC characteristics at the time of diagnosis, 60% were multiple, 90% of lesions were of ,5 cm, 50% showed portal thrombosis, none had extrahepatic extension, and 40% fulfilled the Milan criteria; 5 subjects were evaluated for liver transplant. After diagnosis of HCC, 6 (60%) patients died. Liver transplantation was performed in 2 patients. One liver transplanted patient was lost to follow-up. Three patients were still alive after 18, 27, and 39 months after HCC diagnosis. As shown in Table 2, the overall incidence rate of HCC in our cohort was 6.72 per 1000 person-years [95% confidence interval (CI): 2.6 to 10.9]. The cumulative incidence rate of HCC was 2.7% (95% CI: 1.3 to 4.9). Incidence rates were significantly higher in patients with decompensated liver cirrhosis at baseline (20.0 per 1000 person-years [95% CI: 2.5 to 37.5]) than in those with compensated cirrhosis (4.0 per 1000 person-years [95% CI: 0.5 to 7.6]; P = 0.032). Incidence of HCC was similar in patients with and without HCV coinfection, HBV coinfection, and HCV and/or HBV coinfection. Kaplan–Meier survival probability estimates of developing HCC at 6 years of follow-up (considering death and liver transplant as competing risks) was 3% (95% CI: 1.5 to 5). This probability was higher in patients with decompensated cirrhosis at baseline 5.8% (95% CI: 2.1 to 12.2) than in those with compensated cirrhosis 2.0% (95% CI: 0.7 to 4.3), with borderline statistical significance (P = 0.06) and a hazard ratio of 3.0 (95% CI: 0.87 to 10.3; P = 0.081). This probability was 1.1% at 2 years and 2.0% at 4 and 6 years in the compensated group versus 2.2% at 2 years and 5.8% at 4 and 6 years in the decompensated liver cirrhosis group.
TABLE 2. Incidence of Hepatocarcinoma (HCC)
Study Group Whole cohort Decompensation of cirrhosis at baseline HCV coinfection
HBV coinfection
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Decompensated Compensated Chronic HCV Absent or cured Chronic HBV Absent, postvaccination, cured, or core
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No. HCC/No. Patients at Risk
Cumulative Incidence % (95% CI)
10/371 5/95 5/276
2.7 (1.3–4.9) 5.26 (1.7–11.9) 1.8 (0.6–4.2)
9/354 1/16 1/29 8/305
2.5 6.3 3.5 2.6
(1.2–4.8) (0.2–30.2) (0.1–17.8) (1.1–5.1)
Incidence Rate No. HCC Per 1000 PersonYears (95% CI) 6.7 (2.6–10.9) 20.0 (2.5–37.5) 4.0 (0.5–7.6) 6.3 18.7 10.1 6.6
(2.2–10.4) (218.0–55.4) (29.7–29.8) (2.0–11.1)
Rate Ratio Incidence Rate Exposed/Incidence Rate Nonexposed (95% CI)
P
5.0 (1.1–21.5)
0.032
0.3 (0.04–2.6)
0.610 1.000
1.5 (0.04–11.5)
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J Acquir Immune Defic Syndr Volume 65, Number 1, January 1, 2014
DISCUSSION In our contemporary cohort, the incidence of HCC in HIV-infected patients with liver cirrhosis receiving adequate ART was 6.7 per 1000 patients-years. The incidence of HCC was lower in patients with compensated cirrhosis. The incidence of HCC in our study is substantially higher than the incidence rates reported in previous studies, which varied between 0 and 2.8 per 1000 patients-year.9,10,12,13,19 Our higher incidence is probably because of the fact that all of our patients had cirrhosis and the longer follow-up time associated to the improved survival of our patients. In previous studies, many coinfected patients received suboptimal ART, and uncontrolled HIV infection shortened the survival of HCV coinfected patients with endstage liver disease to such an extent that possibly HCC did not have a chance to emerge. Recently, Merchante et al12 in a retrospective review of HIV/HCV–coinfected patients by calendar year found that the incidence of HCC increased from 0.2 to 2.8 per 1000 person-years between 2000 and 2009. Our results are also consistent with an increased incidence of HCC in recent years. Interestingly, non–HIV-infected subjects with compensated cirrhosis have a 1–8% annual incidence of HCC (depending on the etiology of the cirrhosis), and those with chronic hepatitis have an approximate annual risk of 1%,20 figures very similar to those obtained in our study. An important finding of our study was a clear trend toward a higher incidence of HCC among patients with decompensated cirrhosis as compared with those with compensated cirrhosis after adjusting using competitive risks of death or liver transplant. Previous studies did not use a cumulative function analysis for the calculation of a cumulative probability for the development of HCC. In our previous analysis of the natural history of liver cirrhosis in HIV/HCV–coinfected patients, we found a relatively high 3-year survival in patients with compensated liver cirrhosis (87%); in contrast, 2-year survival of patients with decompensated cirrhosis was only 50%.21 Given these large differences in mortality, it seems that adjustments for competitive risks are critical aspects of the analysis. Patients with and without HCC development had similar baseline characteristics (Table 1). Both groups had a very high rate of HCV coinfection, were almost always receiving effective ART, had similar immune reconstitution, and have received anti-HCV therapy with similar frequency. Liver decompensation at baseline occurred in half of the patients who developed HCC compared with 24.1% in patients free of HCC development. However, because of the limited sample size, this difference was not significant. The main limitation of our study is the low number of end points that compromise our statistical power. However, follow-up of the cohort continues and further analysis will provide evidence of changing trends in the incidence of HCC in HIV-infected patients with liver cirrhosis and viral hepatitis coinfection. In summary, our prospective cohort of cirrhotic patients with an adequate control of HIV infection shows a relatively low probability of developing HCC although the incidence of HCC seems to be higher than the previously reported. Incidence of HCC is even higher in patients with decompensated liver disease at baseline. Ó 2013 Lippincott Williams & Wilkins
Hepatocellular Carcinoma in HIV Subjects
ACKNOWLEDGMENT The authors thank Marta Pulido, MD, for editing the manuscript and editorial assistance. REFERENCES 1. González-García J, Navarro San Francisco C, Condes E, et al. Evaluación de la prevalencia de la coinfección por VHC, características de la hepatopatía y tratamiento específico de los pacientes infectados por VIH en España. Estudio GESIDA 57/07. IV Congreso Nacional de GESIDA, Toledo, November 27–30, 2012, PO41. 2. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;32:492–497. 3. Martín-Carbonero L, Soriano V, Valencia E, et al. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIVinfected patients. AIDS Res Hum Retroviruses. 2001;17:1467–1471. 4. Salmon-Ceron D, Rosenthal E, Lewden C, et al. Emerging role of hepatocellular carcinoma among liver-related causes of deaths in HIV-infected patients: the French National Mortalité 2005 Study. J Hepatol. 2009;50: 736–745. 5. Ioannou GN, Bryson CL, Weiss NS, et al. The prevalence of cirrhosis and hepatocellular carcinoma in patients with HIV infection. Hepatology. 2013;57:249–257. 6. Sulkowski M. Hepatocellular carcinoma in HIV-infected patients comes of age: the convergence of epidemiology and treatment effectiveness. J Hepatol. 2009;50:655–658. 7. Pineda JA, García-García JA, Aguilar-Guisado M, et al. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology. 2007;46:622–630. 8. Bräu N, Salvatore M, Ríos-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006;44:47–55. 9. García-García JA, Romero-Gómez M, Girón-González JA, et al. Incidence of and factors associated with hepatocellular carcinoma among hepatitis C virus and human immunodeficiency virus coinfected patients with decompensated cirrhosis. AIDS Res Hum Retroviruses. 2006;22: 1236–1241. 10. Kramer JR, Giordano TP, Souchek J, et al. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in U.S. veterans with hepatitis C. Am J Gastroenterol. 2005;100:56–63. 11. Bruno R, Sacchi P, Puoti M, et al. Natural history of compensated viral cirrhosis in a cohort of patients with HIV infection. J Acquir Immune Defic Syndr. 2007;46:297–303. 12. Merchante N, Merino E, López-Aldeguer J, et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain. Clin Infect Dis. 2013;56:143–150. 13. Bruyand M, Dabis F, Vandenhende MA, et al. HIV-induced immune deficiency is associated with a higher risk of hepatocarcinoma, ANRS CO3 Aquitaine Cohort, France, 1998-2008. J Hepatol. 2011;55:1058–1062. 14. López-Diéguez M, Montes ML, Pascual-Pareja JF, et al. The natural history of liver cirrhosis in HIV-hepatitis C virus-coinfected patients. AIDS. 2011;25:899–904. 15. Forner A, Ayuso C, Real MI, et al. Diagnosis and treatment of hepatocellular carcinoma [in Spanish]. Med Clin (Barc). 2009;132:272–287. 16. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022. 17. Bonacini M, Hadi G, Govindarajan S, et al. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1997;92:1302–1304. 18. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012; 56:908–943. 19. Murillas J, Del Río M, Riera M, et al. Increased incidence of hepatocellular carcinoma (HCC) in HIV-1 infected patients. Eur J Intern Med. 2005;16:113–115. 20. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.
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21. García-Samaniego J, Rodríguez M, Berenguer J, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001;96:179–183.
APPENDIX 1. GESIDA 37/03.FIPSE 364665/ 03–NEAT IG5 INVESTIGATORS STUDY GROUP INVESTIGATORS M. L. Montes Ramírez, J. R. Arribas, F. X. Zamora Vargas, J. J. González-García (Hospital Universitario La Paz, Madrid); M. A. Hernando, F. Pulido, R. Rubio, M. Lagarde, M. Matarranz (Hospital Universitario 12 de Octubre, Madrid); J. B. Berenguer, M. Ramírez Schacke,
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I. Gutiérrez (Hospital General Universitario Gregorio Marañón, Madrid); C. Quereda, T. S. Alonso (Hospital Universitario Ramón y Cajal, Madrid); A. A. Caso, J. Sanz-Moreno, J. de Miguel Prieto, E. C. García (Hospital Universitario Príncipe de Asturias, Madrid). E. O. González, L. O. R. de Arellano (Hospital General Universitario de Valencia), C. T. Llacher, A. J. Pastor (Hospital Germans Trias i Pujol, Badalona); J. M. Miró, J. M. Miro, M. López-Dieguez, C. Manzardo, F. Agüero, M. Laguno, and J. Mallolas (Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain). M. Á. Von Wichmann de Miguel, J. A. Iribarren, F. Rodriguez-Arrondo (Unit of Infectious Diseases, Hospital Universtario Donostia, DonostiaSan Sebastián, Spain); H. Esteban, E. Barquilla, L. Serrano (Fundación SEIMC-GESIDA, Madrid).
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