Introduction
Liver cancer is the sixth most common incident cancer worldwide and the fourth most common cause of cancer death [1]. Hepatocellular carcinoma (HCC), which is the most frequent primary liver cancer, is a leading cause of death among patients with cirrhosis [2]. Hepatitis C virus (HCV) infection is the main risk factor for HCC in Europe, Japan and the United States [2]. Despite enormous efforts in the last years, HCC still has a poor prognosis, with overall 5-year survival around 10–15% [3]. However, patients with HCC can benefit from effective treatment options that improve survival in almost all stages of the disease at diagnosis. These include the application of potential curative therapies, which can lead to 5-year survival rates of 70% in patients diagnosed at an early stage and treated [2].
HCC is an increasing cause of morbidity and mortality in HIV-infected patients, mainly driven by HCV coinfection [4–8]. Recent data from the HEPAVIR cohort indicate that HCC is currently the second cause of death in HIV/HCV-coinfected patients with cirrhosis in Spain [9]. In addition to, survival of HCC in HIV-infected patients has been extremely poor. In a previous study, the overall median survival of HCC was only 3 months and it did not increase over time during a 10-year period [4]. Whether this short survival is a consequence of an increased aggressiveness of HCC in the setting of HIV has been a matter of controversy. Previous retrospective studies conducted more than 10 years ago suggested that the time from HCV infection to the development of HCC is shorter in the presence of HIV and that HCC is more frequently symptomatic, multinodular and had a more advanced stage at diagnosis [10–12]. In line with this, HIV infection was associated with a poorer prognosis of untreated HCC when compared with a control non-HIV group in a recent international multicohort study [13]. However, most of HCC cases included in the above-mentioned studies were at an advanced stage and did not received specific treatment for HCC. In addition to, the possible impact of previous HCC surveillance was not analyzed. Thus, it is reasonable to speculate whether the differences in survival found in these studies might be due to a later diagnosis or to lower rates of treatment against HCC, and not to a specific negative impact of HIV infection. As the cornerstone for improving survival of HCC is the application of a potential curative therapy [2], analyses of the impact of HIV on the survival of HCC must consider the rates and appropriateness of HCC treatment received by HIV-infected patients before drawing any definite conclusion about the implication of HIV on prognosis.
Because of these, the objective of our study was to assess the impact of HIV infection on the survival of HCC in HCV-infected patients.
Patients and methods
Study design and patients
The GEHEP-002 cohort (ClinicalTrials.gov ID: NCT02785835) recruits all the HCC cases diagnosed in HIV-infected patients in 32 centers in Spain. HCC cases occurring before 31 December 2010 were retrospectively included as previously reported [4]. From this date, all consecutive new HCC cases are recruited at HCC diagnosis. Patients are included in the cohort provided that they met the American Association for the Study of Liver Diseases criteria for the diagnosis of HCC [14]. For this retrospective study, the information recorded in the last update of data made in 31 December 2018 was used. HCC cases diagnosed in HIV/HCV-coinfected patients among those included in the GEHEP-002 cohort were selected for the current study.
A control population comprised of all consecutive HCC cases diagnosed in HCV-monoinfected patients before 31 December 2018 at the Liver Unit from the Hospital Universitario de Valme was used to evaluate the impact of HIV on survival.
Clinical data, follow-up, surveillance and treatment
The GEHEP-002 cohort has a standardized protocol of follow-up in which epidemiological, clinical and laboratory parameters are routinely collected. This information was used for this analysis. Alcohol consumption was self-reported. Liver function was assessed by means of the Child–Turcotte–Pugh scoring system. Surveillance of HCC was done by the performance of an abdominal ultrasound every 6 months following the recommendations of guidelines in force [14–17]. Surveillance was offered to all HIV-infected patients with cirrhosis attending the participant centers during the study period. In HIV/HCV-coinfected patients with cirrhosis who achieved sustained virological response (SVR), surveillance was maintained after viral eradication. For analyses, diagnosis by surveillance was considered when all scheduled ultrasound had been performed at least within 1 year prior to HCC diagnosis. Otherwise, HCC diagnosis was considered to have been made out of a screening program.
HCC staging and treatment were established by the Barcelona-Clinic Liver-Cancer (BCLC) staging system [2]. Management of HCC was done according to the European Association for the Study of the Liver recommendations [15] and the guidelines in force in Spain [16,17]. According to this, patients with very early-stage (BCLC 0) and early-stage (BCLC A) HCC have a solitary lesion or up to three nodules that are less than 3 cm in diameter (without macrovascular invasion or extrahepatic spread) and preserved liver function. These patients can benefit from potential curative therapies, which include resection, liver transplantation or ablation. Patients with intermediate-stage HCC (BCLC B) do not have symptoms, but they have large multifocal lesions without vascular invasion or spread beyond the liver and can benefit from transarterial chemoembolization (TACE) if liver function is preserved. Patients with advanced-stage disease (BCLC C) are characterized by the presence of one or more of the following features: extrahepatic metastases, vascular invasion and/or mild cancer-related symptoms. Systemic therapies can be applied to these patients, whereas those with end-stage disease (BCLC D), which includes those with poor liver function or marked cancer-related symptoms, do not benefit from any specific therapy for HCC. Treatment decisions regarding HCC in the GEHEP-002 cohort were taken by multidisciplinary teams at each center which included hepatologists, surgeons, interventional radiologists and oncologists, as well as the caring physician for HIV infection.
Surveillance, diagnosis and management of HCC in the control group was done according to the same recommendations and guidelines followed by the GEHEP-002 cohort [14,15,17].
Vital status and causes of death were obtained from clinical records. Patients lost to the follow-up or their next of kin were contacted via telephone whenever possible. In patients lost to the follow-up, the electronic clinical record from each patient was also accessed to assess vital status.
Statistical analyses
To ascertain if HIV-infected patients had a lower access to therapy which ultimately could influence survival, we assessed the proportion of patients receiving therapy for HCC as indicated by the BCLC stage at diagnosis in the GEHEP-002 cohort and in the control non-HIV group. For these analyses, best therapy received was considered among those receiving several lines of therapy. Second, we assessed the impact of HIV on survival. For this purpose, we pooled the information from the GEHEP-002 cohort and the control HIV-negative group in a single dataset in which we investigated potential predictors of mortality, including HIV infections as covariable. Death of any cause was the primary end-point for these analyses.
Continuous variables and survival times are expressed as median (Q1–Q3), whereas categorical variables are presented as numbers (percentages). Continuous variables were compared by means of the Student's t test or the Mann–Whitney U, depending on the normality tests. The chi-square and the Fisher tests were used for comparisons between categorical variables. For survival analyses, the date of HCC diagnosis was considered as the baseline time-point, defined as the date when the patient firstly met the American Association for the Study of Liver Diseases. criteria for HCC. The time-to-event was computed as the time elapsed from baseline to the emergence of death of any cause or the censoring date, 31 December 2018. Kaplan–Meier estimates were calculated for survival end points and curves were compared using the log-rank test. Those variables with a P value or less 0.1 on univariate analyses were entered in multivariate Cox models, which also included age, sex and HIV infection. For these analyses, death of any cause during follow-up was considered the outcome variable. The presence of statistical interactions between previous surveillance, BCLC stage at diagnosis and HIV coinfection was evaluated by means of multivariate Cox regression analyses. Associations with a P less than 0.05 were considered significant. Hazard ratio and the respective 95% confidence intervals (CI) were calculated. The statistical analysis was carried out by means of the SPSS statistical software package release 24.0 (IBM Corporation, Somers, New York, USA) and Stata SE 9.0 (Statacorp, College Station, Texas, USA).
Ethical aspects
The study was designed and conducted following the Helsinki declaration. The Ethics committee of the Hospital Universitario de Valme approved the study.
Results
Features of the study population
Three hundred and seventy-three cases of HCC in HIV-infected patients have been included in the GEHEP-002 cohort before 31 December 2018. Of them, 342 (91.7%) were diagnosed in HIV/HCV-coinfected patients and were included in the study. One hundred and thirty-five HCC cases were diagnosed in HCV-monoinfected patients during the study period at the Liver Unit from Hospital Universitario de Valme and were included as a control HIV-negative group. The main characteristics of the study population are summarized in Table 1. The median (Q1–Q3) value of α-fetoprotein at HCC diagnosis was 54.4 (7.1–536.8) ng/dl in HIV/HCV-coinfected patients whereas it was 27.7 (6.8–252.4) ng/dl in the HIV-negative group (P = 0.086). The proportion of HCC cases that were diagnosed within a ultrasound surveillance program was lower in HIV-infected patients (Table 1). A significantly lower proportion of HIV-infected patients were diagnosed at very early or early stage, as 33.3% of HIV-infected patients were classified as BCLC stage 0 or A at initial presentation whereas the respective figure was 56.3% in the HIV-negative population (P < 0.001) (Table 1).
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Table 1: Features of the study population (n = 477).
Treatment strategies for hepatocellular carcinoma
Two hundred and twenty-nine (67%) HIV/HCV-coinfected patients from the GEHEP-002 cohort were treated for HCC. Among those treated, 131 (38% of the entire cohort) received a potentially curative therapy against HCC (ablative therapies n = 61, hepatic resection n = 47, liver transplantation n = 23) and 99 (29% of the entire cohort) received noncurative therapies (TACE n = 53, sorafenib n = 46). One hundred and twelve (33%) did not received any treatment for HCC. In the control group, 55 (41%) received potentially curative therapies (ablative therapies n = 24, hepatic resection n = 14, liver transplantation n = 17), 32 (24%) received noncurative therapies (TACE n = 24, sorafenib n = 8) and 48 (35%) did not received any treatment for HCC. Two patients (one at BCLC stage 0/A and one at BCLC stage C) from the GEHEP-002 cohort and three patients (all at BCLC stage 0/A) from the control group with a recent diagnosis of HCC were pending treatment decisions at the moment of analysis.
Figure 1 shows the proportion of patients receiving therapy for HCC as indicated by BCLC stage at diagnosis by HIV status. Patients pending treatment decisions at the moment of analysis were excluded in this analysis. For each BCLC stage, the proportion of HIV-infected patients receiving appropriate treatment was higher than that observed in the HIV-negative control group. In the specific case of patients with very early o early-stage HCC, 97 (85%) out of 113 HIV/HCV-coinfected patients received a potentially curative therapy whereas this occurred in 50 (68%) out of 73 HIV-negative individuals (P = 0.001).
Fig. 1: Proportion of patients receiving treatment against hepatocellular carcinoma, as indicated by Barcelona Clinic Liver-Cancer stage, according to HIV status.
Impact of HIV on survival
After a median follow-up of 11 (3–31) months, 334 (70%) patients died. Thirteen (2.7%) patients were lost to the follow-up. Death occurred in 244 (71%) out of 342 HIV/HCV-coinfected patients and 90 (67%) out of 135 HCV-monoinfected. Among HIV-infected patients, 187 (77%) of deaths were HCC-related, whereas 25 (10%) were non-HCC liver-related deaths and 32 (13%) were nonliver-related deaths, including three AIDS-related deaths. Causes of death in HCV-monoinfected patients were: HCC 64 (84%), five (7%) non-HCC liver-related causes and seven (9%) nonliver-related causes.
After HCC diagnosis, the median (Q1–Q3) survival time was 9 (2–30) months in HIV-infected patients whereas it was 16 (6–32) months in the control group (P = 0.161) (Fig. 2). The probability of 1, 3 and 5-year survival after HCC diagnosis was 50, 31 and 24% in HIV-infected patients whereas it was 69, 34 and 21% in HIV-negative patients (P = 0.161) (Fig. 2).
Fig. 2: Probability of survival after hepatocellular carcinoma diagnosis according to HIV status (n = 457).
Impact of HIV on survival according to Barcelona-Clinic Liver-Cancer stage at diagnosis
Figure 3 shows the impact of HIV on survival according to BCLC stage at HCC diagnosis. The probability of 1, 3 and 5-year survival after HCC diagnosis in those diagnosed at BCLC stage 0-A was 94, 66 and 57% in HIV-infected patients whereas it was 90, 54 and 33% in HIV-negative patients (P = 0.006) (Fig. 3 a). In patients with intermediate stage HCC, 1, 2 and 3-year survival were 67, 42, 27% and 56, 18 and 0% in HIV-positive and HIV-negative patients, respectively (P = 0.056) (Fig. 3 b). In patients with advanced stage HCC, 6, 12 and 18-month survival was 43, 26 and 21% in HIV-infected individuals and 62, 37 and 22% in those HIV uninfected (P = 0.74) (Fig. 3 c).
Fig. 3: Probability of survival after hepatocellular carcinoma diagnosis according to Barcelona Clinic Liver-Cancer stage at presentation and HIV status.
Fig. 3 (Continued): Probability of survival after hepatocellular carcinoma diagnosis according to Barcelona Clinic Liver-Cancer stage at presentation and HIV status.
Impact of HIV on survival according to hepatocellular carcinoma therapy received
We further analyzed the impact of HIV infection according to the treatment strategy for HCC received. Among 186 patients receiving curative therapies, the median survival was 74 and 72 months in HIV-positive and negative patients, respectively (P = 0.647). When the analysis was restricted to the 97 HIV-positive and 50 HIV-negative patients with BCLC stage 0/A HCC receiving curative therapies, the respective figures were 115 and 72 months, respectively (0.189). Similarly, among 77 patients who received TACE as first-line therapy for HCC, the median survival time was 16 months in HIV-infected patients and 13 months in the control group (P = 0.593). In the case of Sorafenib, survival tended to be lower for HIV-positive patients than for those HIV-uninfected (7 vs. 16 months, P = 0.081). In 159 patients not receiving therapy against HCC, median survival was time was 2 months in HIV-infected patients whereas it was 6 months in those not infected by HIV (P = 0.002).
Independent predictors of mortality
After multivariate analyses adjusted by sex, HIV infection, previous SVR and HCC diagnosis within an ultrasound surveillance program, the independent predictors of mortality after HCC diagnosis were age, BCLC stage at HCC presentation and α-fetoprotein level at HCC (Table 2). HIV infection did not show independent association with mortality (AHR 1.57; 95% CI: 0.88–2.78; P = 0.12) (Table 2).
Table 2: Predictors of death of any cause: Univariate and multivariate analysis.
As BCLC stage at diagnosis showed a strong impact on mortality, we also performed multivariate analyses stratified by BCLC stage at diagnosis. In patients diagnosed at BCLC 0/A, B or C stage, HIV infection was not associated with mortality (Supplementary Table 1, https://links.lww.com/QAD/B753). By contrast, HIV infection was independently associated with mortality in patients diagnosed at BCLC stage D (AHR 5.44; 95% CI: 1.26–23.39; P = 0.023) (Supplementary Table 1, https://links.lww.com/QAD/B753).
Discussion
The results of this study indicate that HIV coinfection has no impact on the survival after the diagnosis of HCC in HCV-infected patients. Although the mortality of HCC is numerically higher in HIV/HCV-coinfected patients, these differences seem to be driven by a later diagnosis of HCC in HIV-infected patients and not by HIV infection itself or a lower access to HCC therapy.
The influence of HIV on the natural history and prognosis of HCC has been a matter of controversy in the last 20 years with previous retrospective studies yielding conflicting results [10–13,18–20]. Puoti et al.[11] reported a poorer survival of 41 HCC cases in HIV-infected patients when compared with HIV-negative controls, but up to 60% of HIV-infected patients did not receive any treatment for HCC in that study. By contrast, Bräu et al.[12] found similar survival rates in 63 HIV-infected individuals with HCC than in HIV-negative controls. A lower survival of HIV-infected patients than controls was also seen in the study by Berretta et al.[18], but survival time was not different between HIV-positive and negative patients when analyses were adjusted by type of HCC treatment received. Finally, Gelu-Simeon et al.[20] also reported a worse survival in 55 HIV-infected patients with HCC than that of a control group, but HIV-infected patients received less frequently curative therapies. Limitations of the above-mentioned studies are the small sample sizes, inclusion of HCC of mixed causes and the inclusion of older HCC cases that may not be representative of the current access to early diagnosis and therapy in HIV-infected patients.
Some relevant conclusions can be drawn from our study. First, HIV-infected patients are diagnosed less frequently at early stages that are tributary to curative therapies. This later diagnosis of HCC could be partially explained by a lower implementation of ultrasound surveillance, as rates of diagnosis by ultrasound surveillance were lower than in the control HIV-negative group. Second, as a consequence of late diagnosis, overall survival of HCC in HIV-infected patients tends to be lower than in HIV-negative individuals. However, HCC stage at diagnosis, and not HIV itself, is the main predictor of mortality and explains these differences. In fact, HIV-infected patients showed similar survival rates than controls for each BCLC stage, except for end-stage HCC. Thus, BCLC stage, but not HIV coinfection, was an independent predictor of mortality in the study population. Moreover, multivariate analyses stratified by BCLC stage did not show any independent association of HIV with mortality, except for terminal HCC. Finally, access to and appropriateness of HCC therapy was similar in both populations, which excludes that survival differences between groups were due to suboptimal management of HCC in the HIV group. In fact, survival of HIV-infected patients with early stage HCC receiving curative therapies was not inferior to that seen in HIV-negative counterparts. Taken all these finding together, HIV infection does not appear to be itself a worse predictor of outcome in HCV-related HCC after adjusting for confounding factors.
As stated above, early diagnosis is crucial to improve survival of HCC. In the line of this, surveillance of HCC in HIV-infected patients has been endorsed by the recent guidelines of the European AIDS Clinical Society [21]. However, HIV-infected patients are weighed down by the low performance of ultrasound surveillance in this setting [22]. Our group has recently demonstrated that ultrasound surveillance does not seem to translate into an earlier HCC diagnosis in HIV-infected patients [22]. As the current study shows, this has unequivocal consequences on treatment opportunities which ultimate compromise survival. The reasons for the low performance of ultrasound surveillance are unclear. It has been reported that HCC presents more frequently with an infiltrative type and/or with portal thrombosis [10,11,23,24], whereas in a recent retrospective analysis of histopathological reports there were no differences in the histological patterns by HIV status [25]. In our study, vascular invasion at diagnosis was more frequent in HIV-positive individuals than in the control group. If an aggressive pattern is more frequent in HIV-infected patients, global rates of early diagnosis of ultrasound could be compromised. An alternative explanation is faster progression of HCC in the setting of HIV-associated impaired immune system despite effective antiretroviral therapy. Altered tumor immunosurveillance induced by chronic HIV infection could facilitate faster tumor growth and progression of HCC as it has been suggested with other neoplasms [26]. In a context of accelerated progression, a substantial subset of patients can progress very fast between surveillance examinations and fall into an advanced stage when diagnosis is firstly made. Given the consequences of late diagnosis, our study reinforces the need for exploring alternative surveillance strategies in HIV-infected patients at high-risk for HCC.
With the exception of Sorafenib, our study suggests a similar efficacy of treatment options for HCC in the setting of HIV infection. In fact, HIV had no impact on recurrence of HCC or survival after liver transplantation in a prospective Spanish study [27] but no data exist to our knowledge on the efficacy of other curative options or TACE in HIV-infected patients. Given that survival after curative therapies or TACE appears to be similar in HIV-positive and negative patients, our findings support current recommendations for considering treatment options for HCC in HIV-infected patients in a similar fashion that for HIV-noninfected individuals [14–16]. This was not the case for Sorafenib, as survival after treatment was significantly lower in HIV-infected patients in our study. These data are in the line of a previous real-life study of Sorafenib use in HIV-infected patients conducted in the GEHEP-002 cohort that showed a low efficacy and a poor tolerability of this drug in the HIV scenario [28]. New systemic therapies for HCC, especially immune checkpoint blockers, are promising therapeutic options in advanced HCC [29]. Given that Sorafenib has limited efficacy in HIV-infected patients, these patients should not be systematically excluded from coming clinical trials and should be considered a priority target population for these new drugs.
The main limitation of this study is the retrospective design. Although patients are included in the GEHEP-002 cohort once the diagnosis of HCC is made, decisions regarding treatment for HCC were made at the discretion of multidisciplinary teams in each participant center. However, management in the cohort was uniformly done according to clinical practical guidelines in force during the study period. A second relevant limitation was that HCC cases in the control group came from a single center, which could theoretically influence the results if management of HCC in that center would not have been representative of the whole HCV-monoinfected population. However, these cases showed the same features as those reported in a larger multicenter Spanish registry of 686 non-HIV cases conducted in the same centers participating in the GEHEP-002 cohort [30]. In that national registry, 47% cases were diagnosed by screening, 54% were at BCLC stage 0 or A at presentation and 41% received potentially curative therapies [30], which are even worst figures to that observed in our control group.
In summary, the survival of HCC in HIV-infected patients is comparable with that seen in HIV-uninfected ones with the same HCC stage at diagnosis and similar access to therapy. In addition to, treatment rates and efficacy of treatment options, with the exception of Sorafenib, are not influenced by HIV. However, the overall mortality is still somewhat higher in HIV-infected individuals as a consequence of late diagnosis. Although HIV does not seem to influence the natural history of HCC once it has been developed, future research should clarify if HIV influences the biological oncogenic process to the development HCC in patients infected by HCV.
Acknowledgements
The authors wish to thank the following members of the GEHEP-002 cohort for their contribution to this work: Miguel Raffo (Complejo Hospitalario de Huelva, Huelva), Miguel A. López-Ruz (Hospital Universitario Virgen de las Nieves, Granada) and Mohamed Omar (Complejo Hospitalario de Jaén, Jaén).
Author contributions: N.M. had full access and to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: N.M. and J.A.P. Acquisition, analysis, or interpretation of data: all authors. Statistical analysis: N.M., M.R.-F., J.M. and J.A.P. Drafting of the article: N.M. Critical revision of the article for important intellectual content: all authors.
Obtained funding: N.M., J.M., J.A.P. Study supervision: N.M.
The current work was supported by grants from the Consejería de Salud de la Junta de Andalucía (PI-0014/2014), the Servicio Andaluz de Salud (grant number SAS/111239) and the Fondo de Investigaciones Sanitarias ISCIII (grant number PI13/01621 and Project ‘PI16/01443’), funded by Instituto de Salud Carlos III, integrated in the national I + D + i 2013–2016 and cofunded by European Union (ERDF/ESF, ‘Investing in your future’). A.R.-J. is the recipient of a Miguel Servet Research Contract by the Ministerio de Ciencia, Promoción y Universidades of Spain (CP18/00111). J.A.P. is the recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS). In addition to, this work has been partially funded by the Grupo para el Estudio de las Hepatitis Víricas (GEHEP) de la SEIMC (2017 grant to project GEHEP-002 and 2018 grant to project GEHEP-002), the SPANISH AIDS Research Network RD16/0025/0010 as part of the Plan Nacional R + D + I and cofinanced by ISCIII Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER).
Conflicts of interest
There are no conflicts of interest.
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