Hepatocellular carcinoma (HCC)

Introduction

Hepatocellular carcinoma (HCC) is of distinct concern in PLWHA because they are frequently coinfected with hepatitis B virus (HBV) and hepatitis C virus (HCV), placing them at a heightened risk of accelerated progression of viral hepatitis to chronic liver disease and cirrhosis. Recent data indicate that individuals with AIDS have a four-fold higher HCC risk than the general population, and the magnitude of this excess has remained relatively unchanged over time, including in the HAART era1, 2. As for the impact of HIV itself on liver tumorigenesis, studies performed in mice have reported a potential oncogenic role for HIV Tat gene. However, in humans there is no evidence for a direct role of HIV on HCC development: in a large retrospective study, Giordano et al showed that HCC rates were not higher in HIV mono-infected patients than in general population; in a retrospective cohort study on US veterans, HIV positive people were reported to have a higher risk to develop HCC than HIV negative ones, but HIV status was not independently associated with cancer after adjusting for HCV and alcohol abuse3.

In a recent, large, multicenter cohort study, Berretta et al4 compared 104 HIV-infected and 484 uninfected patients: HIV-positive patients were significantly younger than uninfected ones at HCC diagnosis and were coinfected with HBC or HCV in the great majority of cases. CD4 cell count at diagnosis was not independently associated with survival; on the contrary, patients receiving HAART and with undetectable HIV RNA at diagnosis had a better prognosis than untreated subjects or subjects with higher HIV viral load. Of interest, even though in HIV-infected patients HCC was diagnosed mostly at an early stage (66% at Barcelona Clinic Liver Cancer (BCLC) stage A or B) and then amenable for potentially curative approaches, the median survival time was significantly shorter than that observed in the HIV-negative counterpart (35 vs 59 months).

HBV is responsible for a much smaller proportion of HCC compared to HCV in HIV-positive individuals5, 6.

 

Signs and Symptoms

HCC is asymptomatic for much of its natural history. Nonspecific symptoms associated with HCC can include jaundice, anorexia, weight loss, malaise and upper abdominal pain. Physical signs of HCC can include hepatomegaly and ascites. Paraneoplastic syndromes also can occur and include hypercholesterolemia, erythrocytosis, hypercalcemia and hypoglycemia7.

 

Diagnostic Tools

Most HCCs are identified with ultrasound (US) scanning and Alfa-fetoprotein (AFP) levels. If AFP levels rises, patient should undergo liver imaging studies: if ultrasound in negative, CT/MRI should be performed (at least a 3-phase liver protocol CT or MRI including late arterial phase and portal venous phase). PET/CT is not adequate. If no mass is found, follow every 3 months with AFP and liver imaging, and rule out germ cell tumor if clinically indicated.

Incidental liver mass or nodule found during screening: if nodule < 1 cm, perform at least a 3-phase CT or MRI or CEUS (Contrast Enhanced Ultrasound) where available every 3-6 months. If mass/nodule > 1 cm, perform a 3-phase CT or MRI, and core biopsy or FNA (before biopsy, evaluate if patient is a surgery or transplant candidate. If patient is a potential transplant candidate, consider referral to transplant center before biopsy)7. If HCC diagnosis in confirmed, evaluate chest CT and bone scan if clinically indicated.

 The degree of cirrhosis should be assessed prior to any definitive treatment using the Child–Pugh classification. HIV-positive HCC patients are more likely to have compensated liver disease (Child–Pugh A)8.

 

Treatment Overview

HCC treatment is usually classified as curative or palliative. Curative treatments are represented by surgical resection, orthotopic liver transplantation (OLT) and local ablative therapies, including percutaneous ethanol injection (PEI)/radiofrequency ablation (RFA) and RFA combined with transarterial chemoembolization (TACE). Palliative treatments include systemic chemotherapy and biological drugs (i.e., sorafenib)3.


If patient is potentially resectable or transplantable, operable by performance status or comorbidity, there are two possible options7:

  • Resection, if feasibly (preferred), or locoregional therapy: Child-Pugh Class A or B, no portal hypertension, suitable tumor location, adequate liver reserve, suitable liver remnant.
  • Eligible for transplant: UNOS criteria (tumor ≤ 5 cm in diameter or 2-3 tumors ≤ 3 cm each, no macrovascular involvement, no extrahepatic disease).

Transplantation: it appears that transplantation may have superior results to
resection alone in HIV-negative8. There is no significant difference in overall survival or relapse between HIV-infected patients and uninfected. 3-year overall survival of 74% and 3-year relapse free survival of 69% are reported9. Consequently HIV-positive patients should be considered for transplantation in the same way as HIV-negative patients. HIV status itself is not a prognostic factor for HCC patients undergoing liver transplantation.

Sorafenib: early case studies reports of sorafenib in HIV-positive HCC suggested synergy with HAART, with impressive response rates but more marked toxicity (principally diarrhoea and hand-foot syndrome, more severe than expected suggesting possible interaction with concomitant use of HAART)8. The largest series of HIV-positive HCC treated with sorafenib involves 27 patients and reported partial response in 11% and stable disease in 44%10.

 

Screening and Prevention

Screening methods for hepatocellular carcinoma includes Ultrasound and AFP every 6 months in persons with cirrhosis and persons with HBV irrespective of fibrosis stage. Evidence of benefit is that earlier diagnosis allows for improved ability for surgical eradication11.

Primary prevention should promote alcohol avoidance and HBV vaccination. Moreover, the opportunity to treat HCV or HBV coinfection should be adequately evaluated3.


Drug-Drug Interactions12

Tenofovir and tacroliums: close monitoring is recommended as tacrolimus can affect renal function.

Unboosted or boosted PI and tacrolimus: coadministration could potentially increase tacrolimus concentrations.

EVG/COBI and tacrolimus: coadministration could potentially increase tacrolimus concentrations.

Maraviroc and tacrolimus: no drug/drug interactions are expected when coadministrating maraviroc and tacrolimus, but everolimus could increase maraviroc concentrations (orthostatic hypotension).

Boosted or unboosted PI or EVG/COBI, and sorafenib: coadministration could potentially increase sorafenib concentrations thus increasing the risk of QT interval prolongation.

NNRTI (except rilpivirine) and sorafenib: coadministration could potentially decrease sorafenib concentrations.

 

When to Refer7

Urgent referral if incidental liver mass or nodule found during screening.
Early surgical consultation with a multidisciplinary team is recommended as part of the initial workup.
If patient is a potential transplant candidate, consider referral to transplant center.

 

References

  1. Mania D. and Aboulafia DM. Screening guidelines for non-AIDS defining cancers in HIV-infected individuals. Curr Opin Oncol. 2013 Sep;25(5):518-525.
  2. Sahasrabuddhe VV, Shiels MS, McGlynn KA, Engels EA. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer 2012; 118:6226–6233.
  3. Pinzone MR, Fiorica F, Di Rosa M, Malaguarnera G, Malaguarnera L, Cacopardo B, Zanghì G, Nunnari G. Non-AIDS-defining cancers among HIV-infected people. Eur Rev Med Pharmacol Sci. 2012 Oct;16(10):1377-1388.
  4. BERRETTA M, GARLASSI E, CACOPARDO B, CAPPELLANI A, GUARALDI G, COCCHI S, DE PAOLI P, LLESHI A, IZZI I, TORRESIN A, DI GANGI P, PIETRANGELO A, FERRARI M, BEARZ A, BERRETTA S, NASTI G, DI BENEDETTO F, BALESTRERI L, TIRELLI U, VENTURA P. Hepatocellular Carcinoma in HIV-Infected Patients: Check Early, Treat Hard. Oncologist 2011; 16: 1258-1269.
  5. Powles T, Macdonald D, Nelson M, Stebbing J. Hepatocellular cancer in HIV-infected individuals: tomorrow's problem? Expert Rev Anticancer Ther 2006; 6: 1553-1558.
  6. Puoti M, Bruno R, Soriano V et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS 2004; 18: 2285-2293.
  7. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. Version 2.2013.
  8. British HIV Association Guidelines for HIV-associated malignancies 2013. Version 1. 25 July 2013.
  9. Vibert E, Duclos-Vallee JC, Ghigna MR et al. Liver transplantation for hepatocellular carcinoma: the impact of human immunodeficiency virus infection. Hepatology 2011; 53: 475-482.
  10. Berretta M, Di Benedetto F, Dal Maso L et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma in HIV-positive patients. Anticancer Drugs 2013; 24: 212-218.
  11. European AIDS Clinical Society (EACS) Guidelines. Version 7.0. October 2013.
  12. Drug Interactions. University of Liverpool. Updated October 2013.