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. Author manuscript; available in PMC: 2020 Jun 1.
Published in final edited form as: Gastroenterology. 2019 Mar 13;156(8):2149–2157. doi: 10.1053/j.gastro.2019.02.046

AGA Clinical Practice Update on Interaction between Oral Direct-Acting Antivirals (DAAs) for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review

Amit G Singal 1, Joseph K Lim 2, Fasiha Kanwal 3,4
PMCID: PMC6529246  NIHMSID: NIHMS1523879  PMID: 30878469

Hepatocellular cancer (HCC) is the fastest growing cause of cancer related death in the United States [1–4]. Chronic infection with hepatitis C virus (HCV) is the leading risk factor for HCC, with an annual HCC risk of 2–4% in patients with cirrhosis. However, HCV treatment rates and the number of patients cured of HCV have increased dramatically with the advent of highly effective and well tolerated direct acting antiviral agents (DAA). Within the next decade, most HCV patients seen in clinical practice in the U.S. will likely have sustained virological response (SVR) [5].

DAAs can reduce portal hypertension, improve liver dysfunction, and promote fibrosis regression after SVR [6–9]; however, the impact on HCC incidence has been subject to significant debate. Although several studies demonstrated reduced HCC incidence after IFN-based SVR, it was unclear if this same benefit would be seen with DAAs, particularly after early studies suggested potentially higher than expected incidence and recurrence rates after DAA exposure. In addition to DAAs not offering IFN’s direct anti-proliferative property, it was hypothesized that DAAs may also adversely impact immune surveillance, resulting in higher HCC risk. However, several studies have now followed sufficient number of patients to examine the risk of de-novo and / or recurrent HCC after DAA therapy.

The purpose of this clinical practice update is to describe the interaction between DAA therapy for HCV and HCC incidence, HCC recurrence, and DAA efficacy. We summarize best practice advice regarding HCC surveillance and timing of DAA therapy.

Risk of Incident (de novo) HCC after DAA therapy

BPA 1.

Key studies that examined the risk of HCC in patients achieving SVR with DAAs are summarized in Table 1 [10–20]. Collectively, these studies included over 30,000 HCV patients from 5 countries. Overall, SVR resulted in a ~70% reduction in HCC risk; this effect was evident early (within 3–6 months) and increased over time. Patients who were treated but failed to achieve SVR with DAA remained at high risk for HCC. The relative benefit of SVR persisted after accounting for demographic and clinical differences between patients (Table 1). The absolute risk of HCC was approximately 0.90% per year in the largest cohorts with SVR..

Table 1:

Incidence of HCC in Patients Treated with DAAs for Chronic Hepatitis C Infection

Reference Country Patients N HCC Incidence rate Relative risk
Overall Patients with Cirrhosis Patients without cirrhosis
Conti 2016 (10) Italy 285; cirrhosis 9 3.16% in first 6 months
Ravi 2017 (11) U.S. 66; cirrhosis 6 9.1% in first 6 months
Cheung 2016 (12) UK 317;
decompensated
cirrhosis		 17 2.5% vs. 4% in untreated (6–15 months)
Akuta 2016 (13) Japan 958; all stages 14 0.73%
Calleja 2017 (14) Spain 3,233; all stages 30 0.93% in first 18 months
Kanwal 2017 (15) U.S. 22,500; all stages; 39% cirrhosis 271 1.18% overall. 0.90% in patients with SVR; 1.82% in SVR patients with cirrhosis ; 0.34% in SVR patients without cirrhosis AHR=0.28, 95% CI=0.22–0.36 AHR=0.32 95% CI=0.23–0.44 AHR=0.18, 95% CI=0.11–0.30
Ioannou 2017 (16) U.S. 21,948; all stages 445
(based
on
diagnos
is
codes
only)		 0.92% overall patients with SVR; 1.97% in SVR patients with cirrhosis; 0.18% in SVR patients without cirrhosis AHR= 0.29 AHR= 0.50; 95% CI 0.43–0.59 AHR =0.32; 95% CI 0.28–0.37
Innes, 2017 (17) U.K 272; all with cirrhosis and SVR 12 2.53% overall NA NA NA
Li 2018 (18) U.S. 5,834; 19.9% cirrhosis 50
(based
on
diagnos
is
codes
only)		 2.28% in SVR patients with cirrhosis NA NA NA
Romano J Hep 2018 (19) Italy 3,917; all F3 or higher 55 0.46% in F3, 1.49% in CTP-A and 3.61% in CTP-B; in the second year, 0%, 0.2%, and 0.69%, respectively AHR (failure to achieve SVR) 9.09; 5.2–16.1
Calvaruso, 2018 (20) Italy 2,249; all cirrhosis 78 2.1% in CTP-A; 7.8% in CTP-B AHR failure to achieve SVR) = 3.40, 95% confidence interval = 1.89–6.12
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The relative risk reduction associated with DAA is similar in patients with and without cirrhosis. In two recent studies, SVR was associated with 50% to 78% reduction in the risk of HCC in patients with cirrhosis and 70% to 80% risk reduction in those without cirrhosis. The relative benefit of DAAs is also evident across different stages of cirrhosis [19–20].

Although some early studies raised concerns about a potential hepatocarcinogenic effect of DAAs, subsequent studies compared HCC risk in DAA-cured patients to the risk in patients achieving SVR with IFN-based regimens. Among all treated persons, risk of HCC was similar in the DAA and the IFN groups (hazard ratio, 1.07; 95% CI, 0.55, 2.08) after adjusting for differences in patient populations including higher proportions of cirrhosis and portal hypertension among DAA-treated patients than those treated with IFN. Among persons with cirrhosis who achieved SVR, neither HCC incidence nor HCC-free survival was significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1,000 person-years; P = 0.78 and log-rank P = 0.17, respectively) [18]. Collectively, these data show that successful HCV eradication confers a benefit of reduced HCC incidence in DAA-treated patients.

HCC surveillance in patients with DAA-induced SVR

BPA 2, 3, 4, 5.

Cirrhosis (or advanced fibrosis > F3) is the most important precursor lesion for HCC in patients with HCV, and DAA-cured patients are no exception. The absolute risk of HCC remains high in patients with cirrhosis at the time of SVR with DAA, with the overall annual risk ranging between 1.8 to 2.5% in different studies [10–20]. These estimates reached or exceeded the cut-offs (0.8–1.5% per year) beyond which HCC surveillance becomes cost-effective [21–23]. Among patients with cirrhosis, HCC risk also varied based on other patient demographic and clinical characteristics, with the risk being highest in patients with advanced (Child Class B) cirrhosis; as many as 3.6% to 7.8% of patients with Child Class B cirrhosis developed HCC during the first year of follow up after SVR. In contrast, the risk of HCC was low in almost all patients without cirrhosis, with the exception of patients with a high baseline FIB-4 score, suggesting presence of advanced fibrosis [15,19, 20].

It is plausible that the relatively high incidence of HCC in the first year after DAA might in part be related to ‘missed’ HCC cases given the underuse of HCC surveillance among at-risk patients, and this incidence-prevalence bias might have inflated risk estimates. However, Calvaruso et al. prospectively followed 2,140 DAA-cured patients with HCV cirrhosis, with all being under regular surveillance prior to initiating DAAs, and HCC occurred in 78 patients during a mean follow up of 15 months. The mean interval from exposure to DAAs to an HCC diagnosis was 9.8 months (range = 2–22 months) and did not differ significantly between patients with (n = 64, 9.2 months) and without (n = 14, 12.0 months) SVR (P = 0.11), suggesting that potentially ‘missed’ cases of HCC did contribute much to early risk estimates [20]. These data highlight the importance of ensuring high quality surveillance imaging to exclude presence of HCC prior to DAA initiation.

Whether HCC risk diminishes over time after SVR remains unknown. Available data are limited by short duration of follow up, with mean follow up ranging from 12 to 15 months for most studies. One recent study examined the risk and determinants of HCC in over 19,000 patients with DAA-induced SVR followed for a mean of 2.5 years after SVR. Overall, HCC developed at an incidence rate of 1.14% (95% CI 0.99–1.30) during the first year and fell to 0.84% (95% CI 0.72–0.99) in year 2. In patients with cirrhosis, the incidence rates were 2.27% (95% CI 1.93–2.64) in year 1 and 1.73% (95% CI 1.43–2.07) in year 2, respectively [24]. These data suggest that although there may be downward trend in HCC risk over time, the absolute risk remains sufficiently high to warrant ongoing surveillance in patients with cirrhosis. A recent computer-based microsimulation model evaluated the cost-effectiveness of HCC surveillance in HCV patients with compensated cirrhosis or advanced fibrosis after SVR with DAAs. In patients with cirrhosis, compared with no surveillance, semi-annual HCC surveillance every 6 months for up to 15 years was cost-effective using willingness-to-pay threshold of $100,000/quality-adjusted life years [25].

Based on these collective data, clinicians should perform surveillance imaging in patients with cirrhosis or advanced fibrosis for exclusion of prevalent HCC prior to DAA initiation. They should then conduct ongoing HCC surveillance in patients who have progressed to cirrhosis or advanced fibrosis at the time of SVR and who are eligible for potentially curative treatments unless future studies find further diminution of risk over time.

Although early studies raised concerns that DAA might accelerate HCC aggressiveness in some patients, subsequent studies did not find differences in the degree of tumor burden between patients with early vs. delayed HCC after DAA-induced SVR [15]. Although there are no studies directly comparing surveillance intervals or surveillance modalities in DAA-treated patients, current data do not support shorter surveillance intervals or the use of alternative modalities. Therefore, clinicians should perform HCC surveillance using ultrasound with or without AFP every 6 months.

Efficacy and timing of DAA therapy in patients with active HCC

BPA 6, 7, 8, 9.

In patients with active HCC, SVR after DAA therapy may result in improved liver dysfunction and facilitate additional HCC-directed therapy; however, this theoretical benefit must be weighed against the small but statistically significant decrease in SVR among patients with active HCC and competing risk of HCC-related mortality that has been reported in several studies. The first study to suggest lower SVR rates among patients with active HCC was a single center study including 421 DAA-treated patients, in which active HCC was significantly associated with lower SVR (adjusted OR 0.12, 95%CI 0.05 – 0.26) [26]. Beste and colleagues similarly found the presence of HCC was associated with lower SVR in 482 HCC patients and 16863 non-HCC patients from the national Veterans Affairs health system (adjusted OR 0.38, 95%CI 0.29 – 0.48) [27]. Finally, 884 patients without HCC in HCV-TARGET treated with DAA therapy between December 2013 and December 2016 were compared to 82 patients with complete response to HCC therapy and 48 patients with active HCC. In multivariable analysis, presence of HCC was associated with lower odds of SVR compared to non-HCC patients (adjusted OR 0.59, 95%CI 0.36 – 1.0). Patients with active HCC also had lower SVR than those with HCC complete response, although this difference did not reach statistical significance (adjusted OR 0.81, 95%CI 0.33–2.07) [28].

These data highlight that, when possible, treating HCV prior to development of HCC is the optimal strategy. In patients who have developed HCC, delaying HCV therapy until after complete response to HCC therapy may improve SVR rates, although studies comparing this strategy to immediate treatment are needed. While awaiting these data, clinicians should consider deferring DAA therapy until after HCC treatment in patients with early stage HCC who are eligible for potentially curative therapies such as surgical resection or local ablative therapy. Timing of DAA therapy in HCC patients who are listed for liver transplantation should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction. For example, DAA therapy may be beneficial pre-transplant for patients in regions with long wait times or limited HCV-positive donor organ availability, whereas therapy may be delayed until post-transplant in regions with shorter wait times or a high proportion of HCV-positive donor organs that would otherwise go unused. In patients with intermediate or advanced HCC, the likelihood of complete response to HCC therapy is lower and competing risk of HCC-related mortality is higher than those with early stage HCC. At each of our institutions, our practice is not to treat these patients unless anticipated survival exceeds 2 years; however, there are currently insufficient data evaluating benefits and cost-effectiveness of DAA therapy in these patients. Overall, decisions regarding DAA treatment in patients with active HCC should be considered in light of several factors including: a) HCC tumor burden and the chance of complete response to HCC therapy, b) degree of liver dysfunction, c) overall life expectancy, and d) patient preferences.

Risk of HCC recurrence after DAA therapy

BPA 10.

Although data have demonstrated decreased risk of incident HCC after DAA therapy in patients with HCV cirrhosis, there continues to be debate about the risk and aggressiveness of HCC recurrence after DAA therapy in patients with a prior history of HCC. It has been hypothesized that the rapid decrease in HCV viral load with DAAs results in decreased immune surveillance of microscopic HCC tumor clones and therefore may increase risk of early HCC recurrence [29]. Conflicting data regarding the risk of HCC recurrence have created varying practice patterns and even prompted some providers to withhold DAA therapy from patients with a history of HCC.

A meta-analysis identified 24 studies, with a total of 1820 patients, that reported the proportion of patients with HCC recurrence after DAA therapy [30]. The proportion of patients with HCC recurrence varied widely between studies, ranging from 0% to 59% within 2 years (Table 2), with a pooled point estimate for recurrence of 25.1% (95% CI 19.4 – 31.2%). In subgroup analyses, HCC recurrence did not significantly differ between prospective and retrospective studies or studies with follow-up shorter or longer than 12 months; however, HCC recurrence was higher in studies conducted in the United States compared to Europe and Asia (43.3% vs. 22.1% vs. 28.9%, p<0.001). Eleven studies characterizing “early” recurrence reported 5 – 29% of patients had recurrence within 6 months after DAA therapy, with a pooled proportion of 10.3% (95%CI 6.3 – 14.4%). Most studies to date have been single-arm studies, and the proportion of patients with HCC recurrence must be interpreted within the context of naturally high recurrence rates after HCC complete response. While surgical resection and local ablative therapies are considered curative, recurrence approaches 25–35% within the first year and 50–60% within 2 years. Further, up to 25–50% of patients in some studies received TACE, which is typically not curative and associated with a high risk of recurrence.

Table 2.

Recurrence of HCC in Patients with History of HCC Treated with DAAs for Chronic Hepatitis C Infection

Reference Country Number of patients
(% early stage)		 Type of HCC treatment Follow-up period Recurrence
(95% CI)
Bielen 2017 [42] Belgium 41
(83%)		 Transplant 51%
Resection 24%
Ablation 22%
TACE 3%		 32 months 14.6
(5.6 – 29.2)
Cabibbo 2017 [37] Italy 143
(100%)		 Resection 36%
Ablation 46%
TACE 18%		 8.7 months 20.3
(14.0 – 27.8)
Ikeda 2017 [35] Japan 177
(NR)		 Resection 31%
Ablation 46%
TACE 20%
Radiation 3%		 20.7 months 34.6
(27.9 – 41.7)
Nagata 2017 [43] Japan 83
(100%)		 Resection or ablation 27.6 months 27.1
(18.2 – 36.9)
Ogawa 2017 [38] Japan 152
(95%)		 Resection 40%
Ablation 32%
TACE 15%
Multimodal 12%
Radiation 1%		 17 months 17.5
(11.9–23.9)
Reig 2017 [33] Spain 77
(97%)		 Resection 36%
Ablation 53%
TACE 10%		 8.2
months		 27.3
(17.7 – 38.6)
Virlogeux 2017 [44] France 23
(91%)		 Resection 26%
Ablation 61%
Other 13%		 35.7 months 47.8
(26.8 – 69.4)
ANRS 2016 [46] France 189
(NR)		 NR 20.2 months 12.7
(8.3 – 18.3)
ANRS 2016 [46] France 13
(NR)		 NR 21.3 months 7.6
(0.2 – 36.0)
Conti 2016 [45] Italy 59
(98%)		 Resection 32%
Ablation 41%
TACE 8%
Multimodal 17%		 5.5
months		 28.8
(17.8 – 42.1)
Rinaldi 2016 [47] Italy 15
(100%)		 Resection 14%
Ablation 86%		 2.8
months		 6.7
(0.2 – 32.0)
Gheoghe 2017 [51] Romania 20
(NR)		 NR 6 months 20.0
(5.7 – 43.7)
Granata 2017 [52] Italy 65
(83%)		 NR 18 months 27.7
(17.3 – 40.2)
Kolly 2017 [53] Germany,
Belgium,
Switzerland		 56
(NR)		 Ablation, resection or TACE 21 months 1-year 19%
2-year 44%
Minami 2017 [39] Japan 163
(91%)		 Resection 14
Ablation 147
Radiotherapy 1
TACE 1		 14.5 months 47.9
(40.0 – 55.8)
Ohki 2017 [55] Japan 20
(100%)		 Ablation 100% 24 months 35.0
(15.4 – 59.2)
Sangiovanni 2017 [56] Italy 101
(98%)		 Resection 28%
Ablation 48%
TACE 10%
Multi-modality 14%		 11.1 months 32.7
(23.7 – 42.7)
Singal 2017 [34] USA 207
(87%)		 Resection 19%
Ablation 27%
TACE 37%
Multi-modality 16%		 22.7 months 45.9
(39.0 – 52.9)
Urabe 2017 [57] Japan 63
(NR)		 NR 10.9 months 38.5
(26.2 – 51.2)
Yasui 2017 [54] Japan 46
(NR)		 NR 6 months 14.3
(5.4 – 28.5)
Zavaglia 2017 [48] Italy 31
(84%)		 Resection 42%
Ablation 19%
TACE 13%
Multimodal 26%		 8
months		 3.2
(0 – 16.7)
Tokoro2016 [58] Japan 22
(NR)		 NR 16.2 months 59.1
(36.4 – 79.3)
Torres 2016 [50] USA 8
(NR)		 Resection 50%
Ablation 38%
Proton therapy 12%		 12
months		 0
(0 – 31.2)
Tsuda 2016 [59] Japan 36
(NR)		 NR 11.4 months 25.0
(12.1 – 42.2)
Zeng 2016 [49] China 10
(100%)		 Ablation 100% 15
months		 0
(0 – 25.9)
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DAA – direct acting antiviral; HCC – hepatocellular carcinoma; NR – not reported; TACE – transarterial chemoembolization

Saraiya and colleagues identified 9 studies that included a comparator arm of IFN-treated and/or untreated patients [30]. These data suggest DAA-treated patients have similar if not lower recurrence than the comparator groups. Five studies reported no significant difference in HCC recurrence between DAA-treated and untreated patients, while two studies found significantly lower HCC recurrence among DAA-treated patients (pooled OR 0.55, 95%CI 0.25 – 0.85). All 3 studies comparing DAA-treated and IFN-treated patients reported no difference in HCC recurrence between the two groups; however, only unadjusted analyses were reported.

Since this meta-analysis, a large multi-center retrospective cohort study from the United States and Canada also found no significant difference in overall or early HCC recurrence between 304 patients who received DAA therapy after complete response to HCC treatment and 489 patients who did not receive DAA therapy. In multivariable models, DAA therapy was not associated with HCC recurrence (HR 0.90, 95%CI 0.70 – 1.16) or early HCC recurrence (HR 0.96, 95%CI 0.70 – 1.34). HCC recurrence patterns were similar in DAA-treated and untreated patients, with most recurrences being detected within Milan criteria in both groups (74.2% and 78.8% respectively, p=0.23) [34].

Similarly, uncontrolled studies initially raised concerns about higher than expected post-transplant HCC recurrence rates in patients who underwent DAA therapy while on the transplant waiting list. For example, a study among 112 patients with HCV-related HCC reported patients who were treated with DAA therapy prior to liver transplantation showed a trend toward higher HCC recurrence compared to untreated patients (27.8% vs. 9.5%, p=0.06) [31]. However, a subsequent single-center study of 149 patients with HCV-related HCC found that the risk of HCC recurrence within one year of complete response to locoregional therapy was not different between untreated patients and those treated with DAAs (adjusted HR 0.91, 95% CI 0.58 –1.42), and patients treated with DAAs had lower risk of waitlist dropout related to tumor progression or death compared to untreated patients (adjusted HR 0.30, 95%CI 0.13 – 0.69) [32].

DAA therapy does not appear to be associated with increased HCC aggressiveness; however, few data have characterized treatment response or post-recurrence prognosis. Over three-fourths of patients with HCC recurrence across studies are detected at an early stage, and most of those found at an early stage receive curative treatment with liver transplant, resection or ablation [30]. Only three studies have described response to HCC therapy. Whereas Reig and colleagues reported that 32% of patients had tumor progression within 6 months of recurrence, Singal et al reported 17% had progressive disease and Ikeda et al observed rapid tumor progression in only 5% of patients [33–35].

Current studies have notable limitations including risk for misclassification of HCC complete response prior to DAA initiation as well as ascertainment bias of HCC recurrence cases [30]. There is heterogeneity between cohorts with several studies including patients with non-early stage HCC, high AFP levels, multiple prior HCC recurrences, and treatment with locoregional therapies who are all at higher risk of HCC recurrence than their counterparts. There is also heterogeneity in exclusion of suspicious lesions prior to DAA therapy, the length of time between HCC complete response and DAA initiation, duration of follow-up, and surveillance protocols following DAA therapy. A recent multi-center study from Spain suggested that many recurrences after DAA therapy may be related to the presence of non-characterized nodules at time of DAA therapy. The authors found that patients with non-characterized nodules were nearly three-fold more likely to have reported HCC recurrence than those without nodules at baseline (RR 2.83, 95%CI 1.55 – 1.60) [36]. Overall, these study limitations preclude definitive conclusions about DAA therapy being associated with increased or decreased risk of HCC recurrence, differential time-to-recurrence, or aggressiveness of recurrent HCC and highlight the need for higher quality data.

Timing of DAA therapy after HCC complete response

BPA 11.

Overall, providers and patients must weigh the potential for increased early HCC recurrence against demonstrated long-term benefits of DAA therapy. Successful treatment with DAAs can result in fibrosis regression and improvements in portal hypertension and liver dysfunction, which is typically the major driver of death in patients with HCC complete response and untreated HCV infection [37]. Further, DAA therapy may reduce risk of late HCC recurrence, by decreasing HCV viremia and improving liver function. We believe these benefits typically outweigh the potential downsides in most patients with a history of HCC, justifying DAA therapy in these patients.

One of the most consistent correlates for early recurrence is the interval between HCC complete response and DAA initiation, with shorter intervals being associated with higher risk of recurrence. Reig and colleagues found higher recurrence (41% vs. 23%) in patients treated within 4 months of HCC complete response [33], whereas Ogawa reported this association using a cut-off of 1 year (HR 0.31, 95%CI 0.10 – 0.77) [38], and Minami et al using a cut-off of 2 years (HR 0.34) [39]. Delaying DAA therapy may allow for longer duration of immune surveillance of existing microscopic HCC clones. Delaying DAA treatment can also create a longer time to verify HCC complete response, thereby minimizing the chance of misclassification bias. The sensitivity of one-time CT or MRI for small HCC lesions is low, with sensitivities of only 40–50% for subcentimeter lesions and 60–70% for 1–2 cm lesions [40]. Given the lack of urgency for HCV therapy after HCC complete response, it appears prudent to wait at least 4–6 months after HCC complete response to initiate DAA therapy, which would typically allow for 2–3 interim multi-phase CT or MRI scans to confirm durable HCC response.

HCC surveillance in patients with a history of HCC and DAA-induced SVR

BPA 12, 13.

It is clear that there is a continued risk of HCC recurrence in patients with complete response to HCC therapy who are treated with DAAs. These patients require continued HCC surveillance [21, 22, 41], which should be conducted indefinitely with dynamic contrast-enhanced CT or MRI every 3–6 months, depending on timing of DAA therapy in relationship to HCC complete response. Clinicians should perform surveillance using dynamic contrast-enhanced CT or MRI every 3 months during the first year after HCC complete response and then can extend surveillance intervals to every 6 months. Given continued high risk of HCC recurrence, clinicians should not return to ultrasound-based surveillance. Conversely, current data also do not support shorter surveillance intervals in patients with a history of HCC and DAA-induced SVR.

Best Practice Advice Statements

Description The purpose of this clinical practice update is to evaluate the evidence describing the interaction between DAA therapy for hepatitis and HCC with regard to HCC incidence, HCC recurrence, and DAA efficacy, and summarize best practice advice regarding HCC surveillance and timing of DAA therapy.
Methods The recommendations outlined in this expert review are based on available published evidence including observational studies and systematic reviews, and incorporates expert opinion where applicable.
Best Practice Advice (BPA) Statements BPA 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.
BPA 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging prior to initiating DAA treatment.
BPA 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest risk group for HCC following DAA induced sustained virologic response (SVR). These patients should stay in HCC surveillance.
BPA 4: HCC surveillance should be performed using ultrasound with or without AFP every 6 months. Current data do not support shorter surveillance intervals, or the use of alternative surveillance modalities.
BPA 5: Future studies may show a reduction in HCC risk over time following DAA induced SVR. However, in the interim, HCC surveillance should continue indefinitely if patients are otherwise eligible for potentially curative therapy.
BPA 6: The presence of active HCC is associated with a small but statistically significant decrease in SVR with DAA therapy.
BPA 7: Patients with HCC who are eligible for potentially curative therapy with liver resection or ablation should defer DAA therapy until after HCC treatment is completed.
BPA 8: Timing of DAA therapy for patients with HCC who are listed for liver transplantation should be determined with consideration of median wait times, availability of HCV-positive organs, and degree of liver dysfunction.
BPA 9: There are insufficient data evaluating benefits and cost-effectiveness of DAA therapy in patients with active intermediate or advanced HCC. Decisions regarding DAA treatment in these patients should be considered in light of HCC tumor burden, degree of liver dysfunction, life expectancy, and patient preferences.
BPA 10: There are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time-to-recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy.
BPA 11: DAA therapy should not be withheld from patients with complete response to HCC therapy; however, DAA therapy can be deferred 4–6 months to confirm response to HCC therapy.
BPA 12: Patients with complete response to HCC therapy who are treated with DAAs have a continued risk of HCC recurrence and require HCC surveillance, which should be conducted indefinitely with dynamic contrast-enhanced CT or MRI every 3–6 months. Current data do not support more frequent surveillance in these patients.
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Acknowledgment:

This update was produced by the AGA Institute.

Grant Support: Dr. Singal’s research is supported by National Cancer Institute RO1 CA222900 and RO1 CA212008. Dr. Kanwal’s research is supported by the Veterans Administration Center for Innovations in Quality, Effectiveness and Safety (CIN 13–413), Michael E. DeBakey VA Medical Center, Houston, Texas and the Center for Gastrointestinal Development, Infection and Injury (NIDDK P30 DK 56338). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Veterans Administration or the National Institutes of Health.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of Interest: Dr. Singal has been on advisory boards and served as a consultant for Wako Diagostics, Roche, Exact Sciences, Glycotest, Bayer, Eisai, BMS, and Exelixis. He was on speakers bureau for Gilead, BMS, and Bayer and received research funding from Abbvie. Dr. Lim has received research funding (to Yale University) from AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, and Intercept, and served as a consultant for Bristol-Myers Squibb. Dr. Kanwal has received grant funding from Merck.

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