Treatment of Recurrent Hepatocellular Carcinoma with Sorafenib in a HIV/HCV Co-Infected patient in HAART: A Case Report
© De Nardo et al.; licensee BioMed Central Ltd. 2012
Received: 18 April 2012
Accepted: 22 June 2012
Published: 28 June 2012
Liver disease is the second cause of death among HIV patients receiving highly active antiretroviral therapy (HAART) in Europe. HIV patients have a high prevalence of chronic HBV (6–10%) and HCV (33%) co-infection, and accelerated progression of viral hepatitis. Furthermore, the long duration of both HIV and HCV diseases in the HAART era increases the risk of hepatocellular carcinoma.
We report the case of a 49 year -old HIV/HCV co-infected male patient who developed hepatocellular carcinoma. The patient underwent a partial hepatectomy, and a few months later was treated with transcatheter arterial chemoembolisation due to hepatocarcinoma recurrence. Two months later, advanced hepatocellular carcinoma was diagnosed and sorafenib therapy was initiated. The patient achieved partial response of the main lesions, complete regression of the smallest lesions and did not experience clinical progression during the 20-month follow-up period. During therapy with sorafenib, the patient was treated with HAART with good viral and immunological responses. We used the therapeutic drug monitoring to assess antiretroviral concentrations during co-administration of sorafenib. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines. No grade 3 or 4 toxicities were observed. At month 20 of treatment, new liver lesions with portal vein thrombosis were diagnosed. After 28 months of sorafenib therapy, the patient deceased for severe liver insufficiency.
Sorafenib monotherapy demonstrated a marked delay in HCC disease progression in an HIV/HCV co-infected patient. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines, suggesting a possible interaction.
KeywordsHAART Sorafenib Fosamprenavir TDM Hepatocarcinoma HIV/HCV co-infection
People infected with HIV have a greater prevalence of chronic HBV (6–10%) and HCV (33%) and accelerated progression of viral hepatitis than the general population . Since the initiation of highly active antiretroviral therapy (HAART) in 1996, the incidence of AIDS-related morbidity and mortality has dramatically decreased, resulting in increased life expectancy. However, the causes of death have shifted from AIDS-defining to non -AIDS defining diseases with increased risk of end-stage liver diseases (ESLD) . According to several studies, the complications of HCV and HBV are the second most frequent cause of death after AIDS in HIV- infected patients, accounting for around 10% of deaths [2, 3]. Two large, phase III trials demonstrated that the orally active multikinase inhibitor sorafenib is effective in leading to a longer median overall survival time, and time to progression in patients with advanced hepatocellular carcinoma (HCC) [4, 5]. Despite the clinical relevance of HCC in HIV-HCV co-infection, there is little data regarding the use of sorafenib for HCC in HIV/HCV co-infected patients. Furthermore, data on a possible interaction between sorafenib and antiretrovirals are rather scarce [6–8].
Summary of CD4 cell count and HIV-RNA values
CD4 cell/mmc (%)
Mar 2006; May 2006
Stop HAART; Start Peg-IFN + RIBA
Stop Peg-IFN + RIBA
Oct 2006 - Sep 2007
≥30000 ≤ 50000
HCC diagnosis and hepatectomy
Jan 2009 - Apr 2011
HCC is the fifth most common cancer in the world and the third most common cause of cancer death. The main risk factors for developing HCC are the presence of cirrhosis and co-infection with HBV and HCV .
HIV co-infection worsens the course of viral hepatitis causing faster progression of fibrosis and earlier development of cirrhosis. On the other hand, the introduction of HAART has increased longevity. Consequently, the manifestations of end-stage liver disease, particularly HCC, are more frequently reported .
According to current guidelines, treatment of HCC is the same for both patients with and without HIV infection, although the outcome is worse for HIV-positive patients than their HIV-negative counterparts . Until 2007, chemotherapy had not shown survival benefits for these patients because the HCC is generally a chemoresistant tumor . Sorafenib, a new biological drug recently approved in the EU and USA, has substantially changed the treatment and natural course of advanced unresectable HCC. The introduction of this drug has offered a therapeutic opportunity to patients for whom no effective treatment was previously available. Sorafenib is a tyrosine kinase inhibitor directed against several targets (including vascular-endothelial growth factor VEGFR2, platelet-derived growth factor (PDGFR)-b and Raf kinase) that has demonstrated the ability to inhibit tumor proliferation and angiogenesis in vitro. Two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial) have proved that monotherapy with oral sorafenib prolonged median overall survival and delayed the median time to progression in patients with advanced HCC .
Three cases of HIV-positive patients treated with sorafenib have been described in literature: two patients co-infected with HBV [6, 8] and one patient co-infected with HCV . Our case is the second report describing the use of sorafenib for HCC in an HIV-HCV co-infected patient. Our patient’s survival after administration of sorafenib was remarkably prolonged compared with the overall median survival observed in two recent placebo-controlled trials (20 months vs. 10,7 months  and 6,5 ), with no grade 3–4 toxicity. Since objective responses for HCC patients treated with sorafenib are very rare, this fuels the hypothesis of a possible synergistic effect of sorafenib with HAART. In particular, ritonavir, a protease inhibitor, can inhibit both in vivo and in vitro the PI3/AKT/mTOR pathway and that could provide a molecular biology rationale for explaining, at least in part, the observed objective response. As previously described , a 50% dose reduction of sorafenib to 200 mg twice daily was scheduled for safety reasons. Metabolism of sorafenib occurs primarily in the liver, mediated via cytochrome P450 (CYP) 3A4, and concomitant administration with CYP3A4 inducers or inhibitors may modify sorafenib concentrations . Emtricitabine and tenofovir have no interactions with P450 (CYP) 3A4 enzyme , but fosemprenavir (FPV) and ritonavir (RTV) are both P450 CYP3A4 inhibitors and since sorafenib is metabolized through P450 CYP3A4 that could result in an increase of the active dose of sorafenib explaining the favorable outcome for the patient. Consistent with the limited literature data, a good immune-virological response to HAART was maintained throughout the sorafenib therapy, despite low levels of fosamprenavir concentration. Different from the other two cases, at month 20 of treatment with sorafenib, our patient showed an increase in alpha-fetoprotein values. The occurrence of portal vein thrombosis and new lesions clearly identify HCC disease progression.
In conclusion, sorafenib may represent a good therapeutic option also for the treatment of HIV-HCV co-infected patients with advanced HCC who are not candidates for surgery or palliative care. However, longitudinal clinical trials are required in order to confirm both efficacy and safety of sorafenib in co-administration with antiretroviral drugs.
The authors acknowledge all contributors to this manuscript.
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