Hepatitis C and Hepatocellular Cancer: To Treat or Not to Treat

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Abbreviations

CA19‐9

carbohydrate antigen 19‐9

CI

confidence interval

CT

computed tomography

DAA

direct‐acting antiviral

HCC

hepatocellular carcinoma

HR

hazard ratio

MRI

magnetic resonance imaging

NK

natural killer

Rb

retinablastoma protein

RNA

ribonucleic acid

SREBP

sterol regulatory element binding protein

SVR

sustained virological response

TACE

transarterial chemoembolization

TERTp

telomerase reverse transcriptase

TGF‐β

transforming growth factor β

VEGF

vascular endothelial growth factor

Key Points

• In the treatment of hepatitis C with and without cirrhosis, DAA therapy is associated with reduced risk for HCC compared with no treatment.

• In those with HCC that has been controlled, DAA therapy for hepatitis C infection has been associated with improved survival.

• The DAA era has led to increased treatment of older individuals with more advanced liver disease that likely contributed to early reports of aggressive recurrence of HCC.

Case Presentation

A 76‐year‐old man was referred for evaluation of recently diagnosed hepatitis C virus (HCV) infection and a mass in the liver. He was diagnosed with HCV infection when he was evaluated for right upper quadrant pain in the emergency department, where a single‐phase contrast computed tomography (CT) scan showed a heterogeneous mass in the dome of the liver (Fig. 1). His medical history was notable for diabetes, hypertension, and chronic obstructive pulmonary disease. He had no prior surgical history. His medications included metformin, lisinopril, and albuterol inhalers. He reported drinking two beers per day and smoking one pack of cigarettes per day. He used intravenous drugs in the 1970s.

FIG 1.

Single‐phase CT scan showing heterogeneous mass in the dome of the liver on axial and coronal images.

His physical examination revealed a blood pressure of 134/80 mm Hg, pulse 80, and weight 70 kg. There was no scleral icterus; his lung examination revealed reduced breath sounds and scattered wheezes, and his heart examination revealed distant heart sounds. His abdominal examination revealed splenomegaly. A few spider angiomata were seen on his anterior chest wall. No palmar erythema or gynecomastia was noted.

His laboratory data included a white cell count of 3000/µL, hemoglobin 15 g/dL, platelet count 80,000/µL, aspartate aminotransferase 84 IU/mL, alanine aminotransferase 44 IU/mL, total bilirubin 1.3 mg/dL, international normalized ratio 1.4, albumin 3.5 g/dL, creatinine 1.5 mg/dL, alpha‐fetoprotein 28 ng/mL, and carbohydrate antigen 19‐9 (CA19‐9) of 20 U/mL. His HCV RNA was 280,000 IU/mL, and he had genotype 3 infection.

1. With regard to evaluation and management of this patient, what is the next best step?

1. Liver transplantation

2. Surgical resection

3. Biopsy of dome lesion

4. Magnetic resonance imaging (MRI) with arterial, venous, and delayed contrast phases

A subsequent MRI demonstrated an arterially enhancing 5‐cm mass in the dome of the liver with washout with a second 1.2‐cm lesion in segment 6, both diagnostic of hepatocellular carcinoma (HCC) (LI‐Rads‐liver imaging reporting and data system [LI‐RADS] 5 lesions) (Fig. 2).

FIG 2.

MRI demonstrating arterially enhancing 5‐cm mass in the dome of the liver with a second 1.2‐cm lesion in segment 6, both diagnostic HCC (LI‐RADS 5 lesions).

2. Based on his presentation and history, what would you recommend?

1. Surgical resection

2. Transplantation with HCV‐positive donor

3. Microwave ablation

4. Transarterial chemoembolization (TACE)

He underwent TACE and returned to the clinic 3 months later. He had stopped smoking and drinking and gained 10 lb. A follow‐up MRI showed no viable tumor in either treated lesion. He endorsed a desire to live and inquired if there were additional treatment options to prolong his survival.

3. With regard to treatment options, please select the best answer.

1. Reconsider transplantation

2. Prophylactic therapy with sorafenib

3. Treatment for his HCV infection with direct‐acting antiviral (DAA) therapy

4. Prophylactic therapy with nivolumab

A follow‐up MRI was scheduled for 6 months, and it was recommended that he begin sofosbuvir/velpatasvir for treatment of his chronic hepatitis C.

4. His family members tell you they have read that treatment of HCV with HCC makes the liver cancer “go wild.” Please select the best answer to respond to their query with regard to HCV treatment with DAAs in the setting of HCC.

1. DAA therapy has been reported to increase the risk for recurrent HCC with worse survival after sustained virological response (SVR).

2. DAA therapy in the setting of HCC leads to higher SVR rates.

3. DAA therapy with SVR in the setting of prior controlled HCC has been associated with improved survival.

4. Regardless of whether SVR is achieved, DAA therapy has been associated with reduced risk for HCC in those with cirrhosis.

He was treated with 12 weeks of sofosbuvir/velpatasvir and achieved SVR. An MRI done 24 weeks after he completed therapy shows no evidence of viable HCC in either lesion and no new lesions.

Discussion

This 76‐year‐old man presented with a liver lesion in the context of chronic HCV infection. As is often the case with incidental findings, the CT was single‐phase imaging; thus, an MRI with arterial, venous, and delayed contrast phases was required to confirm the diagnosis of HCC. Characteristic arterial enhancement and washout in the portal phase confirmed the diagnosis of HCC without necessitating invasive liver biopsy. He was not a candidate for resection because of portal hypertension, and he was not offered liver transplantation given his medical comorbidities and advanced age. He was treated with locoregional therapy with TACE without additional adjuvant chemotherapy given a role for this has not been shown presently. Once his disease was controlled, he was offered treatment for his HCV and achieved SVR.

Despite the high efficacy of DAA therapies, there remains a substantial pool of individuals who have not been diagnosed or treated for HCV. This case illustrates some of the challenges you may encounter when caring for patients who present with a first diagnosis of chronic hepatitis C and HCC.

When HCV‐induced cirrhosis occurs, the annual risk for HCC is approximately 1% to 8% in those with untreated infection. In those with chronic hepatitis C, the cycle of hepatic inflammation, oxidative stress, necrosis, and regeneration leads to progressive accumulation of driver genetic events in regenerating hepatocytes, which escape immune surveillance and lead to tumor initiation and progression. ² , ³ Whether HCV viral proteins are directly oncogenic in human HCC is unclear, although specific proteins such as NS3, NS4B, and HCV core protein have been shown to be oncogenic in transgenic mice. HCV‐induced HCC can be considered a classic model for inflammation‐driven cancer because these immune‐related changes create a permissive environment that eventually promotes tumorigenesis (Fig. 3).

FIG 3.

Potential mechanisms of HCV‐induced HCC.

Early reports raised concerns of an adverse effect of DAA HCV treatment on the natural course of HCC with unexpectedly higher rates of HCC incidence and recurrence in those who received DAAs with an aggressive tumor behavior suggesting an oncogenic effect of the DAA treatment. ⁴ , ⁵  One early report noted an HCC occurrence rate of 3.2% in 285 patients and an HCC recurrence rate of 28.8% in 59 patients who achieved SVR with DAAs. ² A second report noted a high rate of early tumor recurrence in patients with treated HCC after initiation of DAA therapy in 16 of 58 individuals. ³ In the DAA era, we are treating older individuals with more advanced liver disease who would not have had their HCV infection treated in the prior interferon era, and this likely explains the initial reports of early HCC occurrence and recurrence. Although there have been no randomized trials exploring DAA therapy versus no therapy in those with HCC and HCV, which would address this potential concern, additional studies with greater power have addressed the effect of DAA therapy on the natural course of HCC occurrence in patients with HCV infection, with studies consistently showing a reduction in risk for HCC with DAA‐induced SVR (Table 1). ⁶ , ⁷ , ⁸ , ⁹ A recent retrospective cohort study compared the overall survival between patients with treated HCC with active hepatitis C infection who received DAA therapy with those with treated HCC with active hepatitis C infection who did not receive DAA therapy. ¹⁰ The DAA‐treated group who achieved SVR demonstrated a significant reduction in risk for death of 71% compared with those patients who did not achieve SVR. These data show that patients who are likely to have a good outcome with HCC treatment will likely benefit from DAA treatment for HCV, but patients with advanced HCC or tumors associated with poor outcome are unlikely to benefit. It is also important to note that a recent report showed that SVR rates in those who receive DAA therapy for hepatitis C may be lower in those with hepatitis C and HCC. ³

TABLE 1.

Longer‐Term Studies on the Effect of DAAs on the Epidemiology of HCC

Study, Year (Reference)	Region, Centers	Cohort Design	Patients, n		De Novo HCC, %		HCC Recurrence, %		Risk for Death in DAA‐SVR Versus NT (HR; 95% Cl)	Follow‐up
			DAA‐SVR	No SVR	DAA‐SVR	No SVR	DAA‐SVR	No SVR		DAA‐SVR	No SVR
Singal et al. (2019) 10	North America, multicent er	Retrospective	383	414	NA	NA	NA	NA	0.29; 0.18‐0.47	941 person‐ years	526 person‐ years
Backus et al. (2019) 9	US, Veterans Affairs	Retrospective	13,992	1067	1.9	11.5	NA	NA	0.26; 0.22‐0.31	1.6 years, mean	1.6 years, mean
Nahon et al. (2018) 8	France, multicent er	Prospective	336	439	5.9%	12.7%	NA	NA	NA	67.5 months	67.5 months
Kanwal et al. (2017) 6	US, Veterans Affairs*	Retrospective	19,518	2982	0.9	3.45	NA	NA	NA	20,415 person‐ years	2547 person‐ years
Ioannou et al. (2018) 7	US, Veterans Affairs		4499	734	1.4	8.1%	NA	NA	NA	30,434 person‐ years	3181 person‐ years

^*Included patients with and without cirrhosis.

Thus, when evaluating a patient with hepatitis C and cirrhosis, clinicians should recognize that treatment of hepatitis C will significantly reduce the risk for HCC, although these patients should remain in a screening program for HCC after SVR. In appropriate patients with hepatitis C and HCC, studies suggest that successful treatment of hepatitis C will improve survival in this population as opposed to offering no therapy for hepatitis C.