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Don’t Deny Liver Transplantation to HIV Patients With Hepatocellular Carcinoma in the Highly Active Antiretroviral Therapy Era

Liver and Multivisceral Transplant Centre, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy

Massimiliano Berretta

Division of Medical Oncology A, National Cancer Institute –Centro di Riferimento Oncologico, Aviano (PN), Italy

Michele Masetti, Roberto Montalti, Stefano Di Sandro, Cristiano Quintini

Liver and Multivisceral Transplant Centre, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy

Mauro Codeluppi

Department of Internal Medicine and Medical Specialties, Infectious Diseases Clinic, University of Modena and Reggio Emilia, Modena, Italy

Umberto Tirelli

Division of Medical Oncology A, National Cancer Institute—Centro di Riferimento Oncologico, Aviano (PN), Italy

Giorgio E. Gerunda

Liver and Multivisceral Transplant Centre, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy

To the Editor:

In an era of highly active antiretroviral therapy (HAART), liver transplantation is becoming an effective therapy in HIV patients suffering from hepatitis C virus (HCV)/hepatitis B virus (HBV) cirrhosis.¹ The increase in survival of patients with HIV infection, attributed to HAART, has prompted the medical community to consider therapeutic strategies including the possibility of major surgery and solid organ transplantation to contrast the clinical picture of end organ failure.

In this clinical setting, several studies have consistently associated an increased risk of death as a result of hepatocellular carcinoma (HCC) with HIV infection.² In a large French survey, HCC-related death in HIV patients rose from 11% in 1997 to 25% in 2001.³ Moreover, some reports have emphasized a more aggressive course of HCC with respect to HCC seen in HIV-negative individuals.^4,5 In particular, the HCC is diagnosed at a younger age, and is generally more advanced (infiltrating or metastatic) at diagnosis.⁶ Recent evidences suggest a crucial role of the HIV TAT protein to drive hepatocarcinogenesis in patients with virus- or alcohol-mediated cirrhosis^7,8; a coexistent weaker antitumor response because of a chronically low CD4⁺ and CD8⁺ lymphocyte counts must also be kept in due consideration. Consequently, a more frequent screening than every 6 months has been warranted because of the swifter course of HCC.⁶

A better prevention strategy is thought to increase the possibility of curative therapy in these young patients. However, no report in the English literature has yet stressed the importance of liver transplantation as a curative treatment of HCC in HIV patients.

As an example, in 2004 the HIV-HCC Cooperative Italian-Spanish Group⁶ reported on a series of 41 HIV patients with coexistent HCC. Of these 41, 15 patients (35%) had early-stage, single-nodule disease; therefore, with a potential indication, with respect to the internationally accepted Milan criteria (single tumor < 5 cm, or up to three tumors with each 3 cm),⁹ to liver transplantation with curative intent.

None of these 15 patients underwent liver transplantation: Two were treated with surgical resection, and the others with nonsurgical locoregional treatment. The reported survival in HIV-HCC patients with treatment was 51% at 1 year and 41% at 2 years, and there was a statistically significant difference with HIV-HCC patients without treatment (11% at 1 year; no patients alive at 2 years).

Since 2003, we have been enrolling HIV patients in our liver transplantation program. Indications to treatment are presence of (1) end-stage liver disease because of cirrhosis (Child-Turcotte-Pugh score B7; MELD score 14) and (2) coexistent HIV infection treated by HAART, nondetectable HIV viral load in the last 12 months, and absolute number of CD4 cells 200/mm³. According to these indications, eight HIV-positive patients, of whom five (62.5%) have coexistent HCC, have undergone transplantation in our center so far.

In our experience of 250 liver transplantations (LTx), 74 non-HIV patients (29.6%) had HCC as indication to transplantation; all patients had HCC within the boundaries of Milan criteria.⁹ After a mean follow-up of 758 days post-LTx, only three patients (4%) had recurrence of HCC and died as a result of disseminated disease at 100, 137, and 477 days post-LTx. Among the five HIV patients with HCC, after a mean follow-up of 223 days, four (80%) of five are alive with no recurrence of HCC; one patient died as a result of cardiac infarction with functioning graft and no HCC recurrence.

We strongly support the importance of an aggressive multidisciplinary approach in these HIV patients who are not being given the same opportunity as HIV-negative patients of an aggressive surgical therapy of HCC because of a published dismal prognosis. In HIV-negative patients affected by HCC on virus- or alcohol-related cirrhosis, many reports have consistently associated liver transplantation with improved long-term survival in cases of early-stage HCC,^10,11 with respect to liver resection or other alternative treatments. These time-honored results are pushing the transplantation community to reconsider the possibility of performing transplantation for HCC patients with advanced disease.¹² Another point in favor of this view is that survival of HIV patients after liver transplantation has recently been reported as similar to that of HIV-negative patients¹³; consequently, HIV patients must not be denied liver transplantation as a possible curative therapy.

We believe that the acknowledged good outcome in terms of disease-free survival in HIV-negative patients with HCC after liver transplantation can be obtained in HIV patients with curable HCC using some ad hoc strategies that are not commonly pursued in HIV-negative patients.

In our opinion, these strategies must encompass the following: (1) accurate patient selection before transplantation, with regards to control of HIV status and HCC stage; (2) compliance to HAART therapy by all HIV patients after transplantation; (3) a multidisciplinary transplant team with proven expertise in regard to the pharmacologic interactions between HAART and immunosuppressive agents; (4) immunosuppression kept to the lowest range possible without rejection, and favor of the use of new drugs with antitumoral properties (such as sirolimus); and (5) a transplant center not contrary in principle to readapt criteria for access to liver transplantation to the peculiar necessity of HIV patients with HCC (long waiting list period may increase the risk of nonoperability in case of HCC progression).

On the basis of our experience, we recommend that an HIV-positive patient in good clinical condition, with full control of virologic and immunologic disease and no signs or symptoms of other AIDS-related diseases with early-stage HCC be considered a suitable candidate for liver transplantation. A multidisciplinary approach involving surgeons, infectologists, and oncologists is the fundamental step forward to further improvement of long-term survival in these troublesome, but most of the time young, patients in the HAART era. Controlled studies are now warranted, after our preliminary observation, to address the validity of an aggressive approach in HIV patients with HCC.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Moreno S, Fortun J, Quereda C, et al: Liver transplantation in HIV-infected patients. Liver Transpl 11:76-81, 2005[CrossRef][Medline]

2. Serraino D, Boschini A, Carrieri P, et al: Cancer risk among men with, or at risk of, HIV infection in Southern Europe. AIDS 14:553-559, 2000[CrossRef][Medline]

3. Rosenthal E, Poiree M, Pradier C, et al: Mortality due to hepatitis C-related liver disease in HIV infected patients in France (Mortavic 2001 study). AIDS 17:1803-1809, 2003[CrossRef][Medline]

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8. Vogel J, Hinrichs S, Napolitano M, et al: Liver cancer in transgenic mice carrying the HIV TAT gene. Cancer Res 51:6686-6690, 1991[Abstract/Free Full Text]

9. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699, 1996[Abstract/Free Full Text]

10. Llovet JM, Fuster J, Bruix J: The Barcelona approach: Diagnosis, staging and treatment of hepatocellular carcinoma. Liver Transpl 10:S115-S120, 2004[CrossRef][Medline]

11. Majno P, Mentha G, Mazzaferro V: Resection, transplantation, either or both? Other pieces of the puzzle. Liver Transpl 11:1177-1180, 2005[CrossRef][Medline]

12. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: Comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 8:765-774, 2002[CrossRef][Medline]

13. Ragni MV, Belle SH, Im K, et al: Survival of human immunodeficiency virus-infected liver transplant recipients. J Infect Dis 188:1412-1420, 2003[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Di Benedetto, F. Articles by Gerunda, G. E. Search for Related Content PubMed PubMed Citation Articles by Di Benedetto, F. Articles by Gerunda, G. E. Social Bookmarking                            What's this?