Hepatocellular carcinoma (HCC) is an emerging complication of cirrhosis in HIV-infected patients. In this sense, the Mortalité Study in France has reported a 10-fold increase in the mortality attributable to HCC in HIV-infected individuals from 2000 to 2005 . Besides, we have recently reported a progressive increase in the incidence of HCC in HIV-infected patients during the last decade in Spain . Similar findings have been reported in the United States [3,4]. In HIV-infected patients, HCC is mainly linked to hepatitis coinfection. Thus, hepatitis C virus (HCV) coinfection accounted for the 93% of the cases of HCC diagnosed in HIV-infected individuals in our cohort  and the incidence of HCC in the HIV/HCV-coinfected population has experienced a 14-fold increase from 2000 to 2009 .
Eradication of HCV with antiviral therapy can reduce the risk of HCC in patients with chronic hepatitis C. Several studies have shown that the incidence of HCC is lower in HCV-infected patients who achieved sustained virological response (SVR) with interferon (IFN)-based treatment [5–9]. Additionally, a meta-analysis of 14 studies comparing 906 patients with SVR to 2402 without SVR showed that achieving SVR was associated with a risk reduction of HCC of 0.35 . However, studies conducted in patients with cirrhosis have confirmed that although the incidence of HCC significantly decreases in patients who achieved SVR, the risk of HCC is not entirely eliminated in patients with cirrhosis [7–11].
There is scant data regarding the impact of SVR on the risk of developing HCC in HIV-infected patients with chronic hepatitis C. In two previous studies [12,13] assessing the impact of SVR on the incidence of liver decompensation and liver-related death in HIV/HCV-coinfected patients, there were no subsequent cases of HCC among 254 coinfected patients who achieved SVR. On the contrary, we have reported that cases of HCC in HIV/HCV-coinfected patients with previous SVR may occur . Besides these apparent conflicting data, little is known regarding the characteristics of patients who developed HCC in spite of eradication of HCV with therapy.
Our objective was to describe the frequency and the characteristics of HCC cases that appeared in HIV/HCV-coinfected patients with previous SVR and to compare these cases to those diagnosed in patients without SVR.
Patients and methods
Study design, patients, and data collection
This was a retrospective cohort study that includes the cases of HCC diagnosed in HIV/HCV-coinfected patients in 26 hospitals from Spain before 31 December 2012. Patients were included in this study provided that they met the American Association for the Study of Liver Diseases (AASLD) 2005 criteria for the diagnosis of HCC . The date of HCC diagnosis was the date when the patient first met the AASLD 2005 criteria for HCC.
HCC cases were identified from specific databases of HIV-infected patients of the participant centers and by using the database of the clinical documentation services of each institution. In addition, a systematic search of the local cancer registry for cases of HCC was performed in each hospital. Information obtained from clinical records was included in a common database, specifically created for this study. Vital status and causes of death were established from database and clinical records. Patients lost to the follow-up or their next of kin were contacted via telephone to assess their vital status.
HCC surveillance was done according to the caring physician criteria, based on consensus recommendations in effect along the study period. AASLD 2005 practice guidelines  recommendations were adopted in the cohort since its publication. Therapy against HCC was categorized as curative or noncurative as established by the updated AASLD practice guidelines . Finally, therapy against HCV was offered according to the physician criteria and guidelines recommendations in force during the study period  and followed common treatment strategies that have been described elsewhere . SVR was defined as undetectable plasma HCV RNA 24 weeks after the completion of treatment.
The main characteristics of HCC cases were analyzed. For these analyses, the following variables were collected and included: age, sex, risk factor for HIV infection, known or estimated date of HIV transmission, HCV genotype and HCV viral load, previous therapy against HCV and type of response, hepatitis B virus (HBV) surface antigen, previous alcohol consumption, CD4+ cell count, previous antiretroviral therapy (ART), clinical, radiological or histological evidence of cirrhosis at the moment of HCC diagnosis and Child–Turcotte–Pugh (CTP) stage, alpha-fetoprotein level, number of liver mass lesions, diameter of the largest lesion, presence of an infiltrating mass, evidence of portal thrombosis or extrahepatic metastases, Milan criteria for liver transplantation , stage of HCC at diagnosis as established by the Barcelona Clinic Liver Cancer (BCLC) staging system , modality of therapy against HCC given including absence of therapy and vital status.
Continuous variables are expressed as median (Q1–Q3). Categorical variables are presented as numbers [percentage; 95% confidence interval (CI)]. A comparison between the characteristics of HCC cases diagnosed in patients with and without previous SVR was made. Comparisons between continuous variables were made using the Mann–Whitney U-test. Comparisons between categorical variables were made by the χ 2 test or the Fisher test, when appropriate. The survival of HCC cases was also analyzed. For this analysis, the baseline time point was considered to be the date of HCC diagnosis, defined as the date when the patient first met AASLD 2005 criteria of HCC. The time-to-event was computed as the months elapsed from this time point to the date of death, loss to follow-up, or 31 December 2012. Kaplan–Meier estimates of the cumulative probability of survival were used and survival curves were compared using the log-rank test.
The statistical analysis was carried out using the SPSS 19 Statistical Software Package (SPSS; Chicago, Illinois, USA).
The study was designed and conducted following the Helsinki declaration. The Ethics committee of the Hospital Universitario de Valme approved this study.
Features of the study population
One hundred and eighty-two cases of HCC in HIV-infected patients were diagnosed in the participant hospitals until 31 December 2012. One hundred and sixty-seven (92%) of them occurred in HIV/HCV-coinfected patients and they represent the study population. The first case of HCC was diagnosed in September 1999. The main characteristics of the population are depicted in Table 1. Sixty-five (39%) patients had been treated against HCV before the diagnosis of HCC. In 13 cases, HCC was diagnosed after consecution of SVR, accounting for 7.8% of the overall cases. The median (Q1–Q3) elapsed time from the end of therapy against HCV to diagnosis of HCC was 28 (20–39) months in these patients.
Characteristics of hepatocellular carcinoma cases diagnosed in patients with previous sustained virological response
Table 2 summarizes the main features of HCC cases diagnosed in patients with previous SVR. The median (Q1–Q3) age was 46 (45–49) years and 11 patients were men. Other causes of HCC, such as alcohol consumption or HBV coinfection, were ruled out in all instances except for one patient who reported excessive alcohol consumption (case 1) and another patient who showed positive hepatitis B virus surface antigen (HBsAg; case 4). In all cases, there was evidence of preexisting cirrhosis. Six patients harbored CTP stage A at diagnosis of HCC, whereas four and three patients harbored stage B and C, respectively. Ten patients were infected by HCV genotype 3. The median (Q1–Q3) CD4+ cell count at HCC diagnosis was 438 (296–652) cells/ml.
Diagnosis of HCC was made after a substantial period of time after the consecution of SVR in most of the cases. Namely, diagnosis was made after 2.5 years in seven patients, with two cases, 1 and 13, in whom the diagnosis of HCC was made after 66 and 71 months, respectively (Table 2). Information regarding previous abdominal ultrasound examinations was available in 11 patients. In six of them, an ultrasound examination not showing hepatic nodules was done in the 6 months before HCC diagnosis (Table 2). In the remaining patients, routine HCC surveillance was not done.
HCC cases were in an advanced stage at diagnosis in a large proportion of patients (Table 2). Seven patients received therapy against HCC: three received potentially curative therapies and four patients received noncurative therapies. HCC prognosis was poor and eight out of the 13 patients died due to HCC. The median survival time was 3 (1–39) months.
Comparisons between hepatocellular carcinoma cases diagnosed in patients with and without previous sustained virological response
Table 3 summarizes comparisons between HCC cases diagnosed in patients with and without previous SVR. There was a higher proportion of genotype 3-infected patients among HCC cases developed in patients with previous SVR when compared with those diagnosed in patients without previous SVR (Table 3). Although differences were not statistically significant, HCC cases diagnosed in previous responders tended to show a higher proportion of multilocular presentation and met Milan criteria for liver transplantation at diagnosis less frequently (Table 3). Additionally, HCC was complicated with portal thrombosis more frequently in these patients (Table 3). The median (Q1–Q3) survival of HCC was 3 (1–39) months among cases developed in patients with previous SVR, whereas it was 6 (2–20) months in the remaining individuals (P = 0.7; See Figure 1, supplementary material, http://links.lww.com/QAD/A398).
Our study confirms that HIV/HCV-coinfected patients with previous SVR may develop HCC in the mid term and long term. These cases account for a significant proportion of the total cases of HCC in this population. However, there is no evident differential characteristic when compared with cases in patients without SVR. Finally, our findings reinforce the need to continue surveillance of HCC with ultrasound examinations in patients with cirrhosis who respond to anti-HCV therapy.
This study is, to our knowledge, the first to describe the frequency and characteristics of HCC developed in patients with previous SVR in the setting of HIV/HCV-coinfection. As it has been reported in the HCV-monoinfected population, HCC may occur in dually infected individuals in spite of SVR. In fact, these cases accounted for 7.8% of the total cases of HCC diagnosed in HIV/HCV-coinfected patients in our cohort. Besides, our study shows that these cases may emerge after a long period from the consecution of SVR. Thus, the majority of cases in our series appeared after 1.5 years since the end of anti-HCV therapy and the elapsed time for some cases was even longer than 5 years, as it has been also shown in HCV-monoinfected patients . This finding supports the current recommendation of clinical guidelines to maintain HCC surveillance indefinitely in patients with cirrhosis who cleared HCV with therapy .
In our study, HCC cases that occurred among previous responders had no apparent differential characteristics when compared with the remaining population. A higher frequency of genotype 3 infection was the only statistically significant finding in these cases. In our opinion, this observation may be due to the higher probability of response to therapy of this genotype, as associations between HCV genotype and HCC risk have been inconsistent across studies. In this sense, a meta-analysis of 21 studies found a two-fold greater risk of HCC in patients infected by genotype 1b , whereas a recent French study suggested an independent association of genotype 3 with HCC development . Further studies should elucidate whether HCV genotype plays a role in the emergence of HCC. Finally, the possible implication of occult HBV infection in the development of HCC in previous responders was reasonably ruled out, as the frequency of positive anti-HBc was identical in both groups.
The clinical presentation of HCC cases developed in patients with previous SVR seemed to be more aggressive than that in the remaining patients. Although differences were not statistically significant, probably due to lack of power as a consequence of the small number of cases in the SVR group, there was a trend for a higher frequency of multilocular presentation and portal thrombosis. Besides, the probability of meeting Milan criteria for liver transplantation was lower in this group. Although a worse clinical course of HCC in these patients cannot be definitely ruled out, a reasonable explanation for these findings is that HCC surveillance was discontinued in nearly half of these patients, which may lead to a late diagnosis of HCC. However, HCC therapy was given to a similar proportion of patients that in the global cohort and survival was not significantly different among groups.
Boceprevir and telaprevir, the first approved directly acting antivirals (DAAs) against HCV, significantly increase the rates of SVR among patients with HCV genotype 1 infection [23–26]. Immediate therapy for patients at high risk of liver decompensation and deferred treatment for the rest of individuals, those who can await newer DAAs, is the strategy followed in many countries. As a consequence of this, most patients who are being treated with telaprevir or boceprevir in some cohorts of HIV/HCV-coinfected patients are those with cirrhosis [27,28]. However, treating at the stage of cirrhosis, though necessary, may be too late in terms of HCC prevention. As our study shows, eradication of HCV with therapy does not fully eliminate the risk of HCC development in HIV/HCV-coinfected patients with cirrhosis, probably due to previous long exposure to HCV before achievement of SVR. Consequently, deferring therapy with DAAs in those without cirrhosis may enhance the probability of HCC development, although SVR is achieved later in the follow-up.
This study has some limitations. First, the study was retrospectively designed. As a consequence of this, survival analyses may be interpreted cautiously. This may also raise the question of whether cases of HCC among previous responders may correspond to failures of ultrasound screening to detect small HCC at the beginning of therapy, rather than a late emergence of HCC. However, the length of the elapsed time between therapy and HCC diagnosis suggests that preexisting ultrasound detectable nodules at the start of therapy are unlikely. Second, although other potential causes of HCC in these patients were reasonably ruled out, underreporting of alcohol consumption may be a concern. It is well known that heavy alcohol ingestion has a synergistic effect with HCV in the development of cirrhosis and HCC . Thus, a heavier alcohol intake than reported cannot be excluded. Finally, the power of the study is insufficient to prove some associations. In any case, this is the first study that has documented the frequency of HCC among previous responders in the setting of HIV/HCV-coinfection and represents the largest published cohort of HCC cases in this population. These are the strengths of our study, which make relevant the results.
In summary, HIV/HCV-coinfected patients with previous SVR may develop HCC in the mid-term. Due to this, surveillance of HCC with ultrasound examinations should be maintained in HIV/HCV-coinfected patients with cirrhosis who respond to anti-HCV therapy.
The authors thank the following persons for their contribution to the study: Juan Macías (Hospital de Valme, Sevilla), Francisco Téllez (Hospital de La Línea, La Línea de la Concepción, Cádiz), Manuel Márquez-Solero (Hospital Virgen de la Victoria, Málaga), María José Ríos-Villegas (Hospital Virgen Macarena, Sevilla), Enrique Ortega (Hospital General de Valencia), Carlos Mínguez (Hospital General de Castellón), Sergio Padilla (Hospital General de Elche, Alicante), Concepción Amador (Hospital Marina Baixa, Villajoyosa, Alicante), Joaquín Portilla (Hospital General Universitario de Alicante), Joan Gregori (Hospital de Orihuela), Miguel Ángel Von Wichmann, José Antonio Iribarren, Xabier Camino and Miguel Ángel Goneaga (Hospital de Donostia, Guipúzcoa), Oscar Ferrero and Sofía Ibarra (Hospital de Basurto, Vizcaya), Josune Goikoetxea (Hospital de Cruces, Bilbao, Vizcaya), María Asunción García Gonzalo (Hospital de Galdakao, Vizcaya), Joseba Portu (Hospital de Txagorritxu, Vitoria, Álava), Luis Metola (Hospital de San Pedro, Logroño), Rafael Silvariño (Hospital de San Eloy, Baracaldo, Vizcaya), Boris Revollo, Bonaventura Clotet, and Antoni Jou (Hospital German Trias i Pujol, Badalona, Barcelona).
This work was partly supported by the Red de Investigación en SIDA (ISCIII-RETIC RD06/006 and ISCIII-RETIC RD12/0017) and the Servicio Andaluz de Salud (Reference SAS/111239). J.A.P. is the recipient of an intensification grant from the Instituto de Salud Carlos III (grant reference Programa-I3SNS).
Conflicts of interest
There are no conflicts of interest.
1. Salmon-Ceron D, Rosenthal E, Lewden C, Bouteloup V, May T, Burty C, et al. Emerging role of hepatocellular among liver-related causes of deaths in HIV-infected patients: the French National Mortalité 2005 study
. J Hepatol
2. Merchante N, Merino E, López-Aldeguer J, Jover F, Delgado-Fernández M, Galindo MJ, et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain
. Clin Infect Dis
3. Sahasrabuddhem VV, Shiels MS, McGlynn KA, Engels EA. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States
4. Ioannou GN, Bryson CL, Weiss NS, Miller R, Scott JD, Boyko EJ. The prevalence of cirrhosis and hepatocellular carcinoma in patients with HIV infection
5. Yu ML, Lin SM, Chuang WL, Dai CY, Wuang JH, Lu SN, et al. A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicentre study in Taiwan
. Antivir Ther
6. Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival
. Ann Intern Med
7. Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, de Santo JL, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C
8. Okanoue T, Itoh Y, Minami M, Sakamoto S, Yasui K, Sakamoto M, et al. Interferon therapy lowers the rate of progression to hepatocellular carcinoma in chronic hepatitis C but not significantly in an advanced stage: a retrospective study in 1148 patients. Viral Hepatitis Therapy Study Group
. J Hepatol
9. Braks RE, Ganne-Carrie N, Fontaine H, Paries J, Grando-Lemaire V, Beaugrand M, et al. Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alfa and ribavirin
. World J Gastroenterol
10. Singal AK, Singh A, Jaganmohan S, Guturu P, Mummadi R, Kuo YF, et al. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis
. Clin Gastroenterol Hepatol
11. Bruno S, Stroffolini T, Colombo M, Bolani S, Benvegnù L, Mazzella G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study
12. Berenguer J, Alvarez-Pellicer J, Martín PM, López-Aldeguer J, von-Wichmann MA, Quereda C, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus
13. Limketkai BN, Mehta SH, Sutcliffe CG, Higgins YM, Torbenson MS, Brinkley SC, et al. Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV
14. Bruix J, Sherman M. Management of hepatocellular carcinoma
15. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update
16. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV international panel
17. Pineda JA, Caruz A, Rivero A, Neukam K, Salas I, Camacho A, et al. Prediction of response to pegylated interferon plus ribavirin by IL28B gene variation in patients coinfected with HIV and hepatitis C virus
. Clin Infect Dis
18. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis
. N Engl J Med
19. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification
. Semin Liver Dis
20. Van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis
21. Raimondi S, Bruno S, Mondelli MU, Maisonneuve P. Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis
. J Hepatol
22. Nkontchou G, Ziol M, Aout M, Lhabadie M, Baazia Y, Mahmoudi A, et al. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis
. J Viral Hepat
23. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection
. N Engl J Med
24. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection
. N Engl J Med
25. Sulkowski MS, Sherman KE, Soriano V, Rockstroh J, Dieterich DT, Girard PM, et al.Telaprevir in combination with peginterferon alfa-2a/ribavirin in HCV/HIV co-infected patients: SVR24 final study results. Program and abstracts of the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 9–13 November 2012; Boston, Massachusetts, USA. Abstract 54.
26. Sulkowski M, Pol S, Cooper C, Fainboim H, Slim J, Rivero A, et al.Boceprevir plus pegylated interferon/ribavirin for the treatment of HCV/HIV co-infected patients. 19th Conference on Retroviruses and Opportunistic Infections; 5–8 March 2011; Seattle, Washington, USA. Abstract 47.
27. Hezode C, Dorival C, Zoulim F, Larrey D, Pol S, Cacoub P, et al.Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 497 cirrhotic non responders. Week 16 analysis of the French early access program (ANRS CO20-CUPIC) in real-life setting). 63rd Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA; 9–12 November 2012.
28. Mira JA, Camacho A, López Cortés LF, Márquez M, Cifuentes C, Rivero-Juárez A, et al.Rapid virological response in HIV/HCV-coinfected patients with genotype 1 receiving telaprevir or boceprevir outside clinical trials: results from HEPAVIR-THERAPY cohort. 48th Annual Meeting of the European Association for the Study of the Liver; 24–28 April 2013; Amsterdam, The Netherlands. Abstract 1860.
29. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infection in men and women
. Am J Epidemiol