Outcome of hepatocellular carcinoma in human immunodeficiency virus-infected patients

Digestive and Liver Disease 45 (2013) 516–522

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Oncology

Outcome of hepatocellular carcinoma in human immunodeficiency virus-infected patients Annagiulia Gramenzi a , Sara Tedeschi b , Maria Chiara Cantarini a , Virginia Erroi a , Fabio Tumietto b , Luciano Attard b , Leonardo Calza b , Francesco Giuseppe Foschi c , Paolo Caraceni a , Michele Pavoni b , Alessandro Cucchetti d , Mauro Bernardi a , Pierluigi Viale b , Gabriella Verucchi b , Franco Trevisani a,∗ a

Department of Medical and Surgical Sciences, Semeiotics Unit, Alma Mater Studiorum – University of Bologna, Bologna, Italy Department of Medical and Surgical Sciences, Unit of Infectious Diseases, Alma Mater Studiorum – University of Bologna, Bologna, Italy c Unit of Internal Medicine, Faenza Hospital, Faenza, Italy d Department of Medical and Surgical Sciences, Transplant Surgery Unit, Alma Mater Studiorum – University of Bologna, Bologna, Italy b

a r t i c l e

i n f o

Article history: Received 24 July 2012 Accepted 3 December 2012 Available online 16 January 2013 Keywords: Cirrhosis HIV infection Liver cancer Prognosis

a b s t r a c t Background: Although the number of human immunodeficiency virus-infected patients with chronic liver disease is increasing, the impact of human immunodeficiency virus on hepatocellular carcinoma outcome remains unclear. Aims: This single centre study investigated whether human immunodeficiency virus infection per se affects the hepatocellular carcinoma prognosis. Methods: Forty-eight human immunodeficiency virus-infected and 234 uninfected patients consecutively diagnosed with hepatitis virus-related hepatocellular carcinoma from January 2000 to December 2009 were retrospectively enrolled. Hepatocellular carcinoma was staged according to Cancer of the Liver Italian Program criteria. Survival and independent prognostic predictors were evaluated. Survivals were also compared after adjustment and matching by propensity score. Results: Compared to human immunodeficiency virus-uninfected subjects, infected patients were more likely to be males, were younger, had fewer comorbidities and the tumour was more often detected during surveillance. Liver function, tumour characteristics and treatments did not significantly differ between the two groups. Nevertheless, median survival of human immunodeficiency virus-infected patients was approximately half that of their counterpart (16 months [95% confidence interval: 7–25] vs. 30 months [95% confidence interval: 25–35]; p = 0.0354). Human immunodeficiency virus infection, Cancer of the Liver Italian Program score and hepatocellular carcinoma treatment were independently associated with mortality. Notably, human immunodeficiency virus infection doubled the risk of dying. These results were confirmed by propensity analysis. Conclusion: Human immunodeficiency virus infection per se worsens the prognosis of patients with virusrelated hepatocellular carcinoma. © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction Patients infected by human immunodeficiency virus (HIV) are frequently exposed to risk factors for hepatocellular carcinoma (HCC), particularly hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The advent of highly active antiretroviral

∗ Corresponding author at: Dipartimento di Medicina Clinica, Semeiotica Medica, via Albertoni, 15, 40138 Bologna, Italy. Tel.: +39 051 636 2923; fax: +39 051 636 2930. E-mail address: [email protected] (F. Trevisani).

treatment (HAART) in 1996 has made it possible to prevent the development of the acquired immunodeficiency syndrome (AIDS), dramatically reducing the risk of both AIDS-related infections and two viral-related cancers, such as Kaposi’s sarcoma and non-Hodgkin lymphoma. Consequently, the life expectancy of HIVinfected subjects is greatly improved. On the other hand, according to a French registry, the relative impact of the mortality from liverrelated diseases has radically increased, from 1.5% of deaths in 1995 to 17% in 2005, with an HCC-related mortality rate increasing from 5% to 25% of these events [1]. An increasing HCC incidence, despite the favourable effect of HAART on the immune-surveillance against tumours, has been confirmed in a linkage study of population-based

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HIV/AIDS and cancer registries of 14 United States areas [2]. This dismal trend of liver-related mortality can be principally attributed to the prolonged survival of HIV-positive patients, allowing chronic liver disease to fully develop its natural history. In fact, HIV infection not only leads to higher rates of both HBV and HCV chronic co-infections [3,4], but also accelerates the development of liver fibrosis, increasing the risk of cirrhosis [3–6] and anticipating the occurrence of HCC, as indirectly suggested by a younger age at the time of diagnosis and a shorter interval between timing of exposure to hepatitis viruses and HCC development [4,7–10]. Moreover, the risk of HCC is thought to be proportional to the severity of immunodeficiency [11–13], although this remains a matter of debate [5,14–23]. The influence of HIV infection on the clinical outcome of HCC is much less delineated. As an impaired immune response favours cancer progression, it is reasonable to expect a worse HCC behaviour in HIV-infected patients. However, the HAART-induced improvement of immune-surveillance could have greatly reduced – or even annulled – this handicap in most cases. The available data on this issue come from relatively small series of patients and are conflicting [7–9,19,24]. This topic remains unsettled even after two recent studies. The first is a multicentre investigation showing a tendentially worse prognosis in HIV co-infected patients with respect to their counterpart [10], but the difference seems to have an iatrogenic rather than a biological origin, since HIVpositive individuals were systematically “undertreated” compared to HIV-uninfected patients. The second study describes a single centre experience in which 23 HIV-infected patients with HCC were matched with HIV-negative subjects for aetiology, severity of liver disease, tumour burden and year of diagnosis. In this unbiased series, HIV status did not influence treatment access, delivery or outcome [25]. Therefore, there is no definitive answer to the question of whether HIV co-infected HCC patients have a different prognosis from that of HIV-uninfected individuals with comparable liver function, tumour stage and treatment. To elucidate this issue, we compared the outcome of HIV-infected and uninfected patients with HCC after adjustment for the confounding factors by a propensity analysis model.

2. Patients and methods 2.1. Patients and study design All patients with HBV- and/or HCV-related chronic liver disease, consecutively diagnosed with HCC between January 2000 and December 2009 at the Infectious Diseases Unit and at the “Semeiotica Medica” Internal Medicine Unit of St. Orsola-Malpighi Hospital (University of Bologna) were enrolled. Forty-eight patients were HIV-infected, while the 234 HIV-negative subjects served as a “control group”. Patients with HCC not associated with HBV or HCV infections were excluded. The prospectively collected data of these patients were retrospectively examined. The following parameters, recorded at the time of HCC diagnosis, were analyzed: sex, age, modality and calendar year of HCC diagnosis, seromarkers of HBV, HCV and hepatitis virus Delta (HDV) infection, alcohol intake (considered an additional major cause of liver damage when patients declared a daily intake >80 g for men and 60 g for women for ≥10 years), co-morbidities (expressed as Charlson comorbity index [26]), liver tests, serum alpha-fetoprotein (AFP), Child–Pugh score [27] and cancer stage according to the Cancer of the Liver Italian Program (CLIP) model [28]. HCC treatment and cause of deaths were also considered.

517

Death was attributed to HCC when patients showed radiological and/or clinical evidence of tumour progression with macrovascular and/or biliary invasion at the time of death. Instead, death was considered as due to liver failure when liver function progressively deteriorated with the occurrence/worsening of jaundice, ascites and hepatic encephalopathy without radiological signs of HCC progression. In order to offer a uniform and optimized therapeutic approach to all patients, treatment of HCC (and its recurrences) were established by a multidisciplinary team (Bologna Liver Oncology [BLOG] team, encompassing hepatologists, oncologists, liver surgeons and radiologists) according to current guidelines, but also considering individual clinical features and the ongoing therapeutic trial protocols in our hospital (i.e. liver transplantation in HIV-infected patients). If a combined therapy was utilized, the most effective approach was assumed as “index treatment” following this hierarchy: orthotopic liver transplantation (OLT), hepatic resection, percutaneous ablative procedures (ethanol injection or radiofrequency ablation), transcatheter arterial chemoembolization (TACE), others/palliation. For patients who underwent potentially curative approaches (surgical or ablative procedures), data concerning HCC recurrence, time to recurrence and its treatment were also collected. In HIV-positive patients, data on HIV transmission, infection stage, CD4+ lymphocyte count, viral RNA levels and antiretroviral therapy at the time of HCC diagnosis were examined. 2.2. Aetiology of liver disease Aetiology of liver disease was classified as: (a) HBV: for HBsAgpositive patients; (b) HCV: for patients with anti-HCV serum antibodies; (c) multiaetiology: for patients with both HBV and HCV infections or with viral infection(s) associated with alcohol abuse. 2.3. Diagnosis and staging Cirrhosis was histologically confirmed in 65 patients (11 HIVinfected, 54 HIV-uninfected) while, in the remaining cases, it was unequivocally diagnosed according to clinical-laboratory features and ultrasonographic and endoscopic signs of portal hypertension. Liver dysfunction was graded by Child–Pugh classification [27]. Patients were considered “under surveillance” for early HCC detection if they were regularly screened with ultrasonography (±serum AFP measurement) every 6 months (±1 month). Otherwise, HCC was considered to be diagnosed outside surveillance. HCC was confirmed by liver cytology/histology in 41 patients (15 HIV-infected, 26 HIV-uninfected) or diagnosed according to Italian and, after 2001, EASL and 2005 AASLD guidelines. Briefly, following Italian guidelines [29], diagnosis was based on the combination of an AFP value >200 ng/mL with typical features in one imaging technique (dynamic computed tomography [CT] or magnetic resonance imaging [MRI]). For EASL guidelines [30], the presence of typical HCC features in only one or two imaging techniques, according to the nodule size, was required. For 2005 AASLD guidelines [31], only one positive imaging techniques was sufficient. For all the cited guidelines, radiological criteria are not considered suitable for characterizing nodules ≤1 cm, which must be followed-up with 3-monthly ultrasonography. HCC was staged by multiphase CT scan and/or MRI and classified as: (a) solitary; (b) paucifocal (2–3 nodules); (c) multifocal (>3 nodules); (d) massive/infiltrating. All patients had a chest Xray, whereas additional investigations to detect distant metastases were performed when extrahepatic involvement was suspected or, systematically, in candidates for surgery. Cancer stage was scored according to the CLIP system [28]. The BCLC system could not be used since information on performance

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status was not available for some patients of the HIV-uninfected group, as the BCLC system was not systematically utilized before its endorsement by the 2005 AASLD guidelines [31]. HIV infection stage and AIDS-defining illness were determined according to the 1993 Centers for Disease Control and Prevention (CDCP) classification criteria [32]. The “nadir” of CD4+ lymphocyte count was defined as the lowest count ever reached. 2.4. Statistical analysis Discrete variables were expressed as absolute values and relative frequencies, continuous data as mean ± standard deviation or median (range), according to their distribution. The Mann–Whitney U test was used to compare continuous data, and the Chi-square test or Fisher’s exact tests were used for categorical variables, as appropriate. Survival was calculated from time of HCC diagnosis to death, with values censored at 31st December 2010, i.e. the end of the study period or at the last patient evaluation (for drop-outs). OLT, being a therapeutic option for HCC patients, was not considered a censoring event. For survival analyses, patients who underwent multiple sequential treatments were allocated to the “index treatment”. Survival estimates were obtained by Kaplan–Meier analysis and compared with the log-rank test. Survival is expressed as median and 95% confidence interval (CI). As potential predictors of survival, we tested: median age, sex, HIV status, aetiology of liver disease, median platelet count, modality of HCC diagnosis (under/outside surveillance), calendar year of HCC diagnosis (divided into two periods: 2000–2004 vs. 2005–2009), comorbidities (Charlson indexes), metastases, CLIP stage, HCC treatment. Child–Pugh class, AFP level, gross tumour pathology and vascular invasion were not tested, being variables collinear to the CLIP staging system. HIV-positive patients were also tested for: CD4+ lymphocyte count at cancer presentation (dichotomized at 350/mmc [the cut-off to start antiretroviral treatment] and 200/mmc [the risk threshold for opportunistic infections] [33]), CD4+ lymphocyte nadir (dichotomized at the median value), HIV-RNA (detectable/undetectable), HAART, previous diagnosis of AIDSdefining illness. Variables associated (p ≤ 0.05) with survival at Cox univariate analysis were entered in the Cox multivariate stepwise regression model to identify the independent prognostic factors. For each independent prognostic factor, the adjusted hazard ratio (HR) and 95% CI were calculated. To control results for demographic and clinical characteristic imbalances between HIV-infected and uninfected patients, a propensity score was developed and multivariate logistic regression analysis to calculate propensity score was applied. The model was then used to provide a one-to-two match without replacement between HIV-uninfected and infected patients using the nearestneighbour method [34]. Survival analysis was then repeated in the matched subgroup. A two-tailed p value <0.05 was considered statistically significant. All statistical analyses were performed using the SPSS 13.0 statistical package (SPSS Incorporated, Chicago, IL, USA). 2.5. Ethics The study conforms to the ethics guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the hospital. 3. Results HCC developed in a cirrhotic liver in all patients. The main characteristics of the patients are summarized in Table 1. With

Table 1 Demographic and clinical characteristics of all patients. HIV-infected (n = 48) Age 49 ± 6 Mean ± SD (years) Males 46 (95.8%) Modality of HCC diagnosis 38 (79.2%) Surveillance Other 10 (20.8%) Calendar year of HCC diagnosis 2000 1 (2.1%) 2001 1 (2.1%) 2 (4.2%) 2002 2003 3 (6.3%) 6 (12.5%) 2004 5 (10.4%) 2005 2006 10 (20.8%) 8 (16.7%) 2007 2 (4.2%) 2008 10 (20.8%) 2009 Aetiology 3 (6.3%) HBV 29 (60.4%) HCV 16 (33.3%) Multiaetiology Alpha-fetoprotein (ng/mL) ≤20 16 (33.3%) 21–200 22 (45.8%) >200 10 (20.8%) Charlson comorbidity index 0 (0–7) Overall 0 (0–8) Age-related Gross pathologic type Solitary 21 (43.8%) 12 (25%) Paucifocal Multifocal 11 (22.9%) 4 (8.3%) Massive/infiltrating 4 (8.3%) Presence of vascular invasion Presence of metastases 2 (4.2%) HCC within Milano 25 (52.1%) criteria 15 (31.3%) Presence of ascites 26 (54.2%) Presence of oesophageal-gastric b varices Platelet count 96 ± 54 Mean ± SD (×103 /␮L) Child–Pugh class 21 (43.8%) A 17 (35.4%) B 10 (20.9%) C CLIP score 6 (12.5%) 0 18 (37.5%) 1 14 (29.2%) 2 7 (14.6%) 3 3 (6.3%) 4–6 Treatment 9 (18.8%) OLT 9 (18.8%) Resection Ablative procedures 7 (14.6%) 16 (33.3%) TACE 7 (14.6%) Other/palliation 7/25 (28.0%) HCC relapsea 9 (5–40) Median relapse time (months) 6/7 (85.7%) Retreatment after relapse

HIV-uninfected (n = 234)

p

64 ± 10 166 (70.9%)

<0.001 <0.001

132 (56.4%) 102 (43.6%)

0.003

13 (5.6%) 29 (12.4%) 21 (9.0%) 27 (11.5%) 32 (13.7%) 31 (13.2%) 33 (14.1%) 11 (4.7%) 14 (6.0%) 23 (9.8%)

0.011

35 (15.0%) 149 (63.7%) 50 (21.4%)

0.093

103 (44.0%) 75 (32.1%) 56 (23.9%)

0.179

1 (0–8) 3 (0–9)

0.001 <0.001

100 (42.7%) 67 (28.6%) 47 (20.1%) 20 (8.5%) 37 (15.8%)

0.260

8 (3.4%) 116 (49.6)

0.681 0.874

67 (28.6%) 123/196 (62.8%)

0.729 0.322

119 ± 68

0.026

135 (57.7%) 71 (30.3%) 28 (12.0%)

0.132

60 (25.6%) 71 (30.3%) 48 (20.5%) 32 (13.7%) 23 (9.8%)

0.238

33 (14.1%) 32 (13.7%) 32 (13.7%) 78 (33.3%) 59 (25.2%) 52/97 (53.6%) 10 (1–47) 47/52 (90.4%)

0.949

0.638

0.026 0.761 1

CLIP, Cancer Liver Italian Program; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; OLT, orthotopic liver transplantation; SD, standard deviation; TACE, transcatheter arterial chemoembolization. a Patients undergoing potentially curative treatments. b Data not available in 38 HIV-negative patients.

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Table 2 Characteristics of human immunodeficiency virus-infected patients at the time of HCC diagnosis. HIV infection diagnosis (calendar year) Before 1990 1990–1999 2000–2006 Risk factors for HIV infection Intravenous drug use MSM Other HIV CDCP stage A1 A2 A3 B1 B2 B3 C1 C2 C3 AIDS Total CD4+ count Mean ± SD (cells/mm3 ) Nadir CD4+ count Median (range) (cells/mm3 ) Patients with undetectable HIV-RNA Patients ongoing HAART

20 (41.7%) 23 (47.9%) 5 (10.4%) 33 (68.8%) 8 (16.7%) 7 (14.6%) 3 (6.3%) 18 (37.5%) 11 (22.9%) 0 3 (6.3%) 1 (2.1%) 0 1 (2.1%) 11 (22.9%) 3 (6.3%) 377.3 ± 191.7 143 (5–464) 36 (75%) 44 (91.7%)

AIDS, acquired immunodeficiency syndrome; CDCP, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus; MSM, men sex with men; HAART, highly active antiretroviral treatments.

respect to their counterpart, HIV-positive patients were more likely to be males, about 15 years younger, and their HCCs were more often detected during surveillance and in recent years. Moreover, platelet count was lower in HIV-positive individuals. Aetiology of liver disease did not significantly differ, although a tendentially higher prevalence of multiaetiology was observed in HIV-infected patients. Overall and, in particular, age-related comorbidities were more frequent in HIV-uninfected patients. No significant differences were seen for the remaining baseline characteristics and HCC treatment. Namely, potentially curative therapies and TACE were equally distributed. Tumour recurrence was significantly higher in HIV-uninfected patients. Retreatment rate at HCC recurrence was high and similar in the two groups. Most HIV-infected patients had been diagnosed with the infection before 2000, and more than two-thirds had been intravenous drug users (Table 2). At HCC presentation, the median CD4+ cell count was 398.5/mm3 (range 37–1004), 39 patients (81.3%) had CD4+ cell counts ≥200/mm3 , and 26 (68.4%) ≥350/mm3 . Forty-four patients (91.7%) were on HAART and 36 (75%) had undetectable plasma HIV-RNA. Two-thirds of the patients belonged to CDCP stage A and only 3 patients (6.3%) had been previously diagnosed with an AIDS-defining illness. Seventeen HIV-infected (35.4%) and 48 (20.5%) HIV-uninfected patients had been treated with antiviral therapy for HCV infection before HCC development, and/or were still being treated with nucleos(t)ide analogues for HBV infection. 3.1. Survival analysis: whole population After a mean follow-up of 28.5 months (95% CI: 25–31 months), 190 (67.4%) patients died: 37 (77.1%) HIV-infected and 153 (65.4%) HIV-uninfected patients. HCC progression was the main cause of death in both groups, accounting for 21 deaths (56.8%) among HIV-infected patients and 93 (60.8%) among HIV-uninfected subjects (p = 0.710). The second major cause of death was liver failure (24.3% vs. 24.8% respectively; p = 1).

Fig. 1. Overall survival of unselected human immunodeficiency virus (HIV)-infected and uninfected patients.

Median survival of HIV-infected patients was approximately half that of their counterparts (16 months [95% CI: 7–25] vs. 30 months [95% CI: 25–35]; p = 0.0354). Survival rates at 1, 3 and 5 years were 62.5%, 32.4% and 20.6% in HIV-infected patients, and 76.1%, 44.4% and 25.1% in HIV-uninfected patients respectively (Fig. 1). At the univariate analysis, HIV infection, sex, modality of HCC diagnosis, metastases, CLIP stage and treatment were associated with mortality (Table 3). Multivariate Cox regression analysis selected HIV infection, CLIP score ≥3 and HCC treatment as independent prognostic factors (Table 3). Notably, HIV infection doubled the risk of dying during the follow-up period. In HIV-infected patients, no significant association was found between survival and viraemia or HAART. Conversely, a CD4+ count ≥200/mm3 was significantly associated with survival at univariate analysis (p = 0.0015). However, CD4+ count did not emerge as an independent risk factor of death when adjusted for CLIP score and treatment. 3.2. Survival analysis: propensity score matched subgroup All variables but sex associated with survival at the univariate analysis in the whole population (Table 3) were entered in the propensity model. Sex could not be included in the model since the match would have been impossible, due to the great differences between HIV-infected and uninfected patients. The propensity analysis matched 48 HIV-infected patients with 96 uninfected subjects. Their characteristics are summarized in Table 4. In this subgroup, after a mean follow-up of 30 months (95% CI: 22–38 months), 92 patients (63.9%) died: 37 (77.1%) HIV-infected and 55 (57.3%) uninfected patients. The median survival was 16 months (95% CI: 7–25) in HIV-infected patients and 34 months (95% CI: 24–45) in the matched control patients (p = 0.0039). Survival rates at 1, 3 and 5 years were 62.5%, 32.4% and 20.6% in HIV-infected patients, and 81.8%, 47.5% and 35.0% in HIV-uninfected subjects respectively (Fig. 2). The univariate analysis disclosed five variables significantly associated with mortality: HIV infection (p = 0.0039), aetiology of liver disease (p = 0.0493), presence of metastases (p = 0.0000), CLIP stage (p = 0.0000) treatment (p = 0.0000). Two variables (sex and modality of HCC diagnosis) showed a trend towards association (p < 0.10). Multivariate analysis confirmed that only HIV infection (HR 2.45 [95% CI 1.57–3.82]), CLIP score ≥3 and HCC treatment were independently associated with the death risk.

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Table 3 Variables associated with mortality in the whole population. Variables

Female sex Modality of HCC diagnosis Surveillance Other Metastases HIV-infection CLIP score 0 1 2 3 4–6 Treatment OLT Resection Ablative procedures TACE Other/palliation

Univariate analysis

Multivariate analysis

Hazard ratio (95% CI)

p

Hazard ratio (95% CI)

p

1.38 (1.01–1.90)

0.049

1.29 (0.91–1.84)

0.156

1 1.57 (1.17–2.10) 3.89 (1.89–7.98) 1.47 (1.02–2.10)

1 1.11 (0.78–1.56) 1.03 (0.48–2.20) 2.07 (1.4–3.05)

0.566

0.003 <0.001 0.038

1 1.58 (1.02–2.43) 2.21 (1.40–3.50) 4.68 (2.83–7.74) 12.80 (7.30–22.43)

0.037 0.001 <0.001 <0.001

1 1.43 (0.92–2.23) 1.63 (0.99–2.70) 3.37 (1.92–5.93) 4.85 (2.55–9.22)

0.119 0.067 <0.001 <0.001

1 2.31 (1.21–4.41) 2.81 (1.46–5.41) 4.71 (2.69–8.23) 18.55 (10.26–33.56)

0.018 0.002 <0.001 <0.001

1 3.02 (1.57–5.83) 3.64 (1.88–7.07) 5.16 (2.93–9.08) 14.98 (7.99–28.06)

<0.001 <0.001 <0.001 <0.001

0.939 <0.001

CI, confidence interval; CLIP, Cancer Liver Italian Program; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; OLT, orthotopic liver transplantation; TACE, transcatheter arterial chemoembolization.

Table 4 Characteristics of patients after matching with the propensity analysis score.

Age Mean ± SD (years) Males Modality of HCC diagnosis Surveillance Other Aetiology HBV HCV Multiaetiology Alpha-fetoprotein (ng/mL) ≤20 21–200 >200 Charlson comorbidity index Overall Age-related Gross pathologic type Solitary Paucifocal Multifocal Massive/infiltrating Presence of vascular invasion Presence of metastases Child–Pugh class A B C CLIP score 0 1 2 3 4–6 Treatment OLT Resection Ablative procedures TACE Other/palliation HCC relapsea Median relapse time (months) Retreatment after relapse

HIV-infected (n = 48)

HIV-uninfected (n = 96)

p

D

49 ± 6 46 (95.8%)

61 ± 10 78 (81.3%)

<0.001 0.02

−1.455 0.468

38 (79.2%) 10 (20.8%)

67 (69.8%) 29 (30.2%)

0.320

0.217 −0.217

3 (6.3%) 29 (60.4%) 16 (33.3%)

15 (15.6%) 57 (59.4%) 24 (25.0%)

0.217

−0.301 0.020 0.183

16 (33.3%) 22 (45.8%) 10 (20.8%)

42 (43.8%) 34 (35.4%) 20 (20.8%)

0.416

−0.217 0.213 0

0 (0–7) 0 (0–8)

0 (0–8) 2 (0–9)

0.008 <0.001

−0.279 −0.783

21 (43.8%) 12 (25%) 11 (22.9%) 4 (8.3%) 4 (8.3%) 2 (4.2%)

42 (43.8%) 33 (34.4%) 18 (18.8%) 3 (3.1%) 14 (14.6%) 3 (3.1%)

21 (43.8%) 17 (35.4%) 10 (20.9%)

44 (45.8%) 35 (36.5%) 17 (17.7%)

6 (12.5%) 18 (37.5%) 14 (29.2%) 7 (14.6%) 3 (6.3%)

12 (12.5%) 36 (37.5%) 28 (29.2%) 14 (13.6%) 6 (6.3%)

9 (18.8%) 9 (18.8%) 7 (14.6%) 16 (33.3%) 7 (14.6%) 7/25 (28.0%) 9 (5–40) 6/7 (85.7%)

18 (18.8%) 18 (18.8%) 14 (14.6%) 32 (33.3%) 14 (14.6%) 25/50 (50.0%) 18 (1–47) 20/25 (80.0%)

0.398 0.423 1

0 −0.207 0.101 0.226 −0.199 0.059

0.902

−0.041 −0.023 0.081

1

0 0 0 0 0

1

0.086 0.982 1

0 0 0 0 0 −0.463 −0.021 0.152

CLIP, Cancer Liver Italian Program; D, standardized difference; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; OLT, orthotopic liver transplantation; SD, standard deviation; TACE, transcatheter arterial chemoembolization. a Patients undergoing potentially curative treatments.

A. Gramenzi et al. / Digestive and Liver Disease 45 (2013) 516–522

Fig. 2. Overall survival of human immunodeficiency virus (HIV)-infected and uninfected patients after matching with the propensity analysis.

4. Discussion The actual impact of HIV infection on HCC outcome remains largely undefined even after a recent multicentre retrospective study examining this topic in the largest cohort of HIV-infected patients published so far [10]. These patients showed a tendentially worse survival (HR 1.424 [95% CI 0.963–2.11]) with respect to their HIV-uninfected counterparts, but this difference seems to be mainly attributable to a diverse therapeutic approach according to HIV status. In fact, despite a less advanced cancer stage, HIVinfected patients more frequently received first-line treatments of unproved efficacy and, at cancer recurrence, the retreatment rate was unduly lower considering the recurrence burden. Moreover, in segregating patients by treatment, no prognostic difference could be demonstrated between HIV-infected and uninfected cohorts. Thus, even this study provides ambiguous information on the biological influence of HIV infection on HCC outcome, the results being biased by an iatrogenic confounding factor. Our study, conducted in a single referral centre for HCC, provides clear evidence that, in an equal-access, unbiased setting, HIV co-infection adversely affects the prognosis of patients with a virusrelated HCC, doubling the death risk compared with HIV-uninfected individuals. This risk further increased to 2.5 after adjustment for the confounding factors with the propensity score matching analysis. This finding is in sharp contrast with what was recently reported by a case-control study conducted in a French tertiary referral centre, showing that HIV status did not affect the prognosis of HCC patients [25]. However, this study was clearly underpowered to detect an equivalence in patient prognosis due to a very small number of HIV-infected cases who, indeed, disclosed lower 1-year (65% vs. 76%) and 3-year (44% vs. 48%) survival rates with respect to matched controls. In our study, regardless of HIV status, most patients died from tumour progression, indicating that the dismal impact of retroviral infection is mediated by an accelerated course of the oncologic disease rather than by non-oncologic events. Importantly, this occurred despite the fact that both the first-line treatment (including OLT, an opportunity offered even to HIV-infected cases in the setting of a pilot study) and re-treatments were tailored to the tumour stage and general conditions by a multidisciplinary team of experts, regardless of HIV positivity. HIV-infected and uninfected patients underwent curative or effective treatments in the same proportions: despite this and the fact that >85% of patients in both groups had the tumour recurrence treated, the adverse impact of retroviral infection remained very evident.

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Nonetheless, some points need discussion. HIV-infected and uninfected HCC cases differed in several features. First, HIV-positive patients were younger and more frequently males. These differences have already been reported [7–10,24] and attributed to the epidemiology of retroviral infection, largely linked to the habit of sharing syringes by intravenous users of illicit drugs. Most intravenous drug users are in fact males and are infected by both HIV and hepatitis viruses at a young age. It can be speculated that the lower age of co-infected patients at HCC diagnosis is the result of these peculiar epidemiological features, flanked by an accelerated hepatic carcinogenesis – due to a faster progression of liver disease [3–6] – and by a more rapid cancer growth [9]. Returning to the core result of our study (concerning patient survival), the exclusion of age and sex from the propensity model did not weaken its results since these factors were not independently associated with survival. Moreover, the prognostic irrelevance of these variables has been robustly confirmed in each treatment subset by a huge case series of HCC patients [35]. Second, the proportion of HCC diagnosed during surveillance was higher in HIV-infected patients. Intuitively, this should give rise to a better distribution of cancer stages that, instead, did not differ between groups. This unexpected result could be attributed to the suboptimal discriminatory ability for early stages of CLIP, having been generated from a patient cohort in which intermediate or advanced tumours largely prevailed [36]. However, even the analysis of HCC gross pathology did not disclose significant differences between groups. Thus, it is tempting to hypothesize that a greater biological aggressiveness of the tumour, resulting in an accelerated growth, attenuated the benefit of semiannual surveillance in HIV-infected patients. Indeed, this assumption is supported by the results of a recent study reporting that HIV–HCV coinfected patients were diagnosed with a more advanced HCC than HCV monoinfected individuals, despite the fact that both groups of patients underwent 6-monthly ultrasonographic surveillance [9]. The greater HCC aggressiveness in coinfected patients might stem from a high histological degree, but this datum was not reported by the cited study, and could not be suitably addressed in the current one due to the lack of tumour histology in most cases. Third, HCC recurrences were less common in HIV-infected patients. This does not necessarily indicate a less aggressive disease and, considering that the time span between initial treatment and first recurrence did not differ between the two groups, a more plausible explanation lies in the shorter survival of HIV-infected patients. Fourth, the median survival of HIV-infected patients in our study was 16 months, a value in between the previously reported figures, ranging from 6 to 35 months [7–10]. This large variability is likely the result of different distributions of HCC stages and therapeutic approaches. Fifth, the survival of our HIV-infected patients was unaffected by CD4+ cell count, detectable HIV-RNA and HAART. A possible explanation is that almost all the patients were on HAART, and most had a CD4+ cell count ≥200/mm3 and undetectable viraemia. Nevertheless, due to the sample size, it cannot be excluded that the strong prognostic impact of HCC stage and treatments may have obscured a possible survival disadvantage linked to the degree of immunodeficiency. 4.1. Limitations The retrospective design and the small number of HIV-infected patients are the main limitations of our study. Considering the low prevalence of HIV-infected patients with HCC in developed countries, a multicentre study is needed to collect a large series of such patients. Nonetheless, our study deals with one of the largest single centre cohorts, and the single centre design made it

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possible to guarantee a standard-of-care HCC management to both HIV-infected and uninfected patients, thus strengthening the reliability of our results. On the other hand, our findings cannot be generalized, being generated by a tertiary referral centre. Another limitation of our study derives from the lack of a standardized procedure of surveillance of cirrhotic patients that can be planned only in prospective studies. To limit this bias we strictly defined surveillance as a 6 monthly (±1 month) repetition of liver ultrasonography, avoiding possible misinterpretation caused by surveillances made with different intervals or based on serum AFP measurement alone. Last, the small number of HIV-infected patients precluded suitable results from sub-analyses of HIV CDCP stages, so that we cannot exclude the possibility that the general strong prognostic shortcoming we observed would be attenuated in patients belonging to very early stages of HIV infection. In conclusion, our findings indicate that retroviral infection per se adversely affects the outcome of HCC developing in hepatitis virus infected patients. Conflict of interest statement No author has a condition that could be construed as a conflict of interest. References [1] Rosenthal E, Salmon-Céron D, Lewden C, et al. Liver-related deaths in HIVinfected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 study in collaboration with the Mortalité 2005 survey). HIV Medicine 2009;10:282–9. [2] Sahasrabuddhe VV, Shiels MS, McGlynn KA, et al. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer 2012;2:6, http://dx.doi.org/10.1002/cncr.27694 [Epub ahead of print]. [3] Puoti M, Torti C, Bruno R, et al. Natural history of chronic hepatitis B in coinfected patients. Journal of Hepatology 2006;44:S65–70. [4] Massard J, Ratziu V, Thabut D, et al. Natural history and predictors of disease severity in chronic hepatitis C. Journal of Hepatology 2006;44:S19–24. [5] 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. American Journal of Gastroenterology 2005;100:56–63. [6] Posthouwer D, Makris M, Yee TT, et al. Progression to end-stage liver disease in patients with bleeding disorders and hepatitis C: an international, multicenter cohort study. Blood 2007;109:3667–71. [7] Puoti M, Bruno R, Soriano V, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS 2004;18:2285–93. [8] Brau N, Fox RK, Xiao P, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.–Canadian multicenter study. Journal of Hepatology 2007;47:527–37. [9] Bourcier V, Winnock M, Ait Ahmed M, et al. Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir). Clinics and Research in Hepatology and Gastroenterology 2012;36:214–21. [10] Berretta M, Garlassi E, Cacopardo B, et al. Hepatocellular carcinoma in HIVinfected patients: check early, treat hard. Oncologist 2011;16:1258–69. [11] Clifford GM, Rickenbach M, Polesel M, et al. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS 2008;22:2135–41. [12] Guiguet M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4 ): a prospective cohort study. Lancet Oncology 2009;10:1152–9. [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. Journal of Hepatology 2011;55:1058–62.

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