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Digestive Diseases and Sciences

, Volume 64, Issue 4, pp 1041–1049 | Cite as

What Comes First: Treatment of Viral Hepatitis or Liver Cancer?

  • Jordan J. FeldEmail author
  • Lisette A. P. Krassenburg
Review

Abstract

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the most important underlying causes for the development of hepatocellular carcinoma (HCC) worldwide. Determining the optimal approach for management of the viral infection and the HCC depends on the virus and the stage of the cancer. In patients with HCV-associated HCC, there are multiple reasons to first treat the HCC. Firstly, in case of a curable HCC, the urgency for HCC treatment is important to avoid progression during HCV treatment. Secondly, the presence of HCC itself appears to reduce the rates of sustained virological response (SVR) achieved with direct-acting antivirals (DAAs). And finally, the evidence does not support the concept of an increase in HCC recurrence due to DAAs, so a patient can safely be treated after HCC cure. For patients with very advanced HCC, the benefits of HCV therapy are questionable. In contrast, those who develop HCC in the setting of chronic HBV infection, treatment with nucleoside analogues (NAs) is recommended prior to treating HCC, to prevent further liver injury and reduce the risk for HCC recurrence. Ultimately, earlier diagnosis and treatment of HBV and HCV will hopefully reduce the incidence of HCC worldwide.

Keywords

Hepatitis C virus (HCV) Sustained virological response (SVR) Hepatocellular carcinoma (HCC) Direct-acting antivirals (DAAs) Hepatitis B virus (HBV) 

Jordan J. Feld

Lisette A. P. Krassenburg

Key Messages

  • Chronic HBV and HCV infection are the leading causes of hepatocellular carcinoma (HCC) globally.

  • Patients with potentially curable HCC complicating HCV infection should undergo therapy for HCC prior to antiviral therapy because of the urgency of treating the cancer and the reduced rate of sustained virological response reported in the presence of active HCC.

  • In patients with advanced HCC, the value of HCV therapy should be carefully considered.

  • The balance of evidence does not suggest that HCV treatment with direct-acting antivirals increases the rate of HCC recurrence after a complete response to curative therapy.

  • All patients with HCC complicating chronic HBV infection should be treated with antiviral therapy to reduce the risk of progressive liver disease and potentially decrease the risk of HCC recurrence. High barrier to resistance agents like entecavir or tenofovir are preferred therapies.

Introduction

Despite an effective vaccine and well-tolerated therapy for hepatitis B virus (HBV) and curative therapy for hepatitis C (HCV), chronic HBV and HCV infections continue to be major public health threats. Both infections cause progressive liver damage over many years that may ultimately lead to cirrhosis and its complications, but it is the predisposition to hepatocellular carcinoma (HCC) that drives the largest burden of mortality worldwide. HCC is the fifth most common cancer globally but is second in terms of cancer-related mortality [1]. While any cause of cirrhosis predisposes to HCC, it is estimated that at least 60% of HCCs occur in people with underlying chronic HBV and/or HCV infection [2].

With the dismal prognosis and limited treatment options for HCC, prevention is by far the best strategy. Vaccination for HBV has been a resounding success, with clear evidence of a reduction in HCC incidence following introduction of universal vaccination [3]. For those with chronic infection, treatment reduces but does not eliminate the risk of HCC, particularly in those with underlying cirrhosis [3]. Remarkable progress in the treatment of HCV means that most infected individuals can now be cured with short courses of well-tolerated therapy with direct-acting antivirals (DAAs). Cure of HCV prior to the development of cirrhosis effectively eliminates the risk of HCC in the absence of other subsequent liver injuries [4]. For those with cirrhosis at the time of treatment, sustained virological response (SVR) markedly reduces but does not eliminate the risk of HCC, necessitating ongoing surveillance for HCC even after cure [4, 5, 6].

When patients with chronic viral hepatitis present with HCC, the optimal management strategy depends on many factors. Whether to treat the viral hepatitis or the HCC first depends on the relevant virus, the stage of HCC, the severity of underlying liver disease, as well as other factors. In this review, we address the question of ‘What comes first, viral hepatitis or liver cancer?’, in chronic HBV and HCV infection in a number of different clinical scenarios (Table 1). Because the issue is more controversial in the setting of chronic HCV infection, HCV is addressed first and in more depth.
Table 1

Treatment of viral hepatitis or HCC first

Viral hepatitis

HCC stage

Order of treatment

Rationale

HCV

Curative options

HCC then HCV

Urgency of HCC therapy

Reduced SVR rate with active HCC

Transplant or resection may be preferred

Consider waiting 3 m post-HCC therapy to start DAAs

Non-curative options

HCC—then HCV or consider no HCV therapy

Reduced SVR rate with active HCC

If poor HCC prognosis and/or response to therapy, DAA therapy of questionable value

HBV

Curative options

HBV then HCC

All patients with chronic HBV and HCC need therapy with high barrier NA

Improve liver function, prevent HBV-reactivation and reduce risk of recurrence

Non-curative options

HBV then HCC

Maintain liver function even if poor prognosis for HCC

May improve liver function enough to allow for additional HCC treatment options

Unclear need for NA with immunotherapy for HCC but prudent to use until more data

Chronic HCV Infection with HCC

The development of highly effective well-tolerated DAAs has led to widespread treatment uptake for HCV with an ambitious goal to eliminate HCV as a public health threat by 2030 [7]. The target that the World Health Organization (WHO) has set is a reduction in new infections by 90% and a reduction in mortality by 65% [7]. The mortality target will require not only prevention of HCC but optimal management of HCC in those in whom it develops.

HCC in Those with Chronic HCV—When Does This Occur?

In almost all clinical scenarios, patients diagnosed with HCV should promptly be offered therapy. With the extremely high SVR rates with current DAA regimens, almost all treated individuals will be cured. SVR prior to the development of cirrhosis effectively eliminates the risk of subsequent HCC in the absence of other liver injury (e.g. alcohol, fatty liver disease etc.) [5, 8]. Even for those with cirrhosis, the risk of HCC is reduced following SVR (see discussion of ‘Effect of SVR on HCC Incidence’ below). As such, for those with known HCV, HCC in the setting of active HCV infection is only an issue for the small number of people who do not respond to therapy or in settings where access to DAA therapy remains limited, either due to availability of the drugs (low- and middle-income countries) or restrictions based on provider-type/access, fibrosis level or sobriety from drugs/alcohol [9].

Unfortunately, a high percentage of those living with HCV remain unaware of their infection. Chronic infection causes few or no symptoms, even in those who have progressed to compensated cirrhosis, meaning that without screening, people are often diagnosed only when they present with complications of decompensated cirrhosis or HCC. Thus, the more common current scenario of HCC complicating chronic HCV infection is in patients with a very late diagnosis of HCV. Sadly, in many such cases, patients present due to symptoms, which often means the HCC is too far advanced for curative therapy. Which to treat first, the HCV or the HCC, depends to some degree on the stage of the HCC.

HCV with Curative Options for HCC

Curative options for HCC include radiofrequency ablation (RFA), resection and liver transplantation. Ablation and some non-curative therapies like transarterial chemoembolization (TACE) and/or stereotactic body radiation therapy (SBRT) may be used to downstage large tumors to allow for subsequent transplantation [10]. For patients with a potentially curative option for HCC, the HCC should be treated prior to the HCV in almost all scenarios.

The first consideration is timing. Although not usually a rapidly growing tumor, an HCC with curative options may well progress over the 12 weeks required for HCV treatment. Although there are case reports of regression of HCC during or following HCV therapy, this is not a well-documented phenomenon and is likely a rare event [11]. As such, HCC should be treated first because the HCV can wait, and the HCC cannot.

Another important consideration is the response to HCV therapy. A large study from the Veteran’s Affairs (VA) health system in the US was the first to report that the presence of HCC affected the probability of SVR with DAA therapy [12]. Of 17,487 patients from the VA cohort treated with DAAs, the SVR rate was 91.1% in those with no history of HCC. However, in the 482 patients with HCC who were not transplanted, only 349 (74.4%) achieved SVR. In those with HCC who were treated for HCV after transplantation, 133 of 142 (94%) achieved SVR. In the non-transplanted group, SVR rates were highest among those who were treated with resection (78%, 95% CI 68.2–85.4%), compared to those who received ablation (70%, 95% CI 62.6–76.6%), TACE (70.0%, 95% CI 63.6–75.7%) or palliative treatment with sorafenib (59%, 95% CI 56–70.9%). Another single-centre study documented a similar pattern [13]. Of 64 patients with HCC present at the time of DAA initiation, 42% did not achieve SVR compared to a non-SVR rate of only 3% among the 71 patients who received DAAs after either resection or transplantation for HCC. These data suggest that the presence of active HCC affects the rate of SVR.

The biological explanation for the effect of HCC on SVR is not certain but plausible theories have been proposed. HCC is a very vascular tumor and may shunt blood and thus DAAs to the tumor, leaving some areas of the liver with suboptimal drug penetration, which could lead to viral relapse. Alternatively, the tumor may act as a sanctuary for virus, preventing DAAs from reaching their target [13]. The highest rates of SVR were achieved with transplantation or resection for HCC, both of which would prevent any mismatch of virus and drug due to the presence of tumor. The added benefit of transplantation is that the liver is no longer cirrhotic, which itself is a modest predictor for DAA non-response.

Collectively these data make a strong case for treating the HCC prior to antiviral therapy. Whether the improved SVR rates with transplantation and resection should impact the choice of therapy for the HCC is uncertain but given that these approaches also generally have better HCC-related outcomes, they may be particularly favorable options for patients with HCC in the setting of chronic HCV infection [14]. Another advantage of treating HCV after transplantation is the option to use an HCV-infected donor organ, potentially speeding up the time to transplant [15].

HCV with Non-curative Options for HCC

For patients with advanced HCC with no curative options, the question of HCV treatment is not only one of timing but of whether antiviral therapy should be given at all. As is the case with anyone with a very short life expectancy, the value of HCV treatment for those with very advanced HCC is questionable [16]. Although DAAs are generally very well tolerated, they may cause some side effects, potentially worsening quality of life, and they are very unlikely to appreciably extend life.

If non-curative options with a proven survival benefit, such as TACE, are available, treating the HCV infection may be more reasonable. However, again, one must carefully consider the benefit of viral eradication. The main rationale of treatment would be to prevent or reverse hepatic decompensation related to progressive HCV-related liver injury. Unfortunately, identification of those with advanced cirrhosis who will benefit from HCV therapy in the short- to medium term is not well defined. The best data come from a recent study by El-Sherif et al. that evaluated patients with Child–Pugh (CP) B or C cirrhosis who received antiviral therapy in Gilead-sponsored clinical trials [17]. They developed a scoring system assigning 1 point for each of 5 factors: Albumin > 3.5, ALT > 60 U/L, no ascites, BMI < 25 kg/m2 and no encephalopathy. Those with 0 or only 1 point were very unlikely to recompensate to CP-A with therapy, whereas for the few patients with 4 or 5 points, ~ 75% improved to CP-A. For those with 2–3 points, about ~ 50% improved with treatment. Although the score was not validated in those with HCC, it may be reasonable to use the score to identify those with HCC and advanced cirrhosis who are unlikely to benefit from antiviral therapy (scores of 0 or 1) in the short to medium term. For those with higher scores, it may be reasonable to consider HCV therapy in some patients, particularly if they respond very well to initial HCC treatment. As with patients with curative options for HCC, the HCC should be treated before the HCV based on the same rationale that active HCC may reduce SVR rates. Furthermore, if there is a limited or no response to the HCC treatment, there is unlikely to be any utility to HCV therapy at all.

Effect of HCV Therapy on HCC Recurrence

Perhaps the most controversial question that remains in the HCV field is whether DAAs may increase the risk of HCC recurrence after potentially curative therapy. The issue was first raised when Reig and colleagues reported an unexpectedly high early tumor recurrence rate in patients with HCV-related HCC receiving treatment with DAAs [18]. Out of 58 patients, with a mean follow-up of 5.7 months, 16 had recurrent HCC (27.6%) including 10 with new lesions and 3 with extra-hepatic metastases. This initial study from Barcelona was uncontrolled, making it difficult to draw strong conclusions, however it made the question of increased HCC recurrence with DAA therapy an area of major controversy in the field. Multiple other studies have since evaluated this important question with somewhat conflicting results.

Conti et al. [19] reported similar findings to the Barcelona group with 17 of 59 (29%) developing recurrent HCC within 6 months of DAA therapy. Similarly, Yang et al. [20] found that 5 of 18 (28%) patients who were transplanted for HCV-related HCC had recurrent disease within 6 months of DAA therapy whereas 6 of 63 (9.5%) experienced recurrence among those who did not receive HCV treatment. However, multiple other studies have not found an increased HCC recurrence rate after DAA therapy. A large French study found near identical HCC recurrence rates among 189 patients who received DAAs and the 78 who did not, and they also reported a low post-transplant HCC recurrence rate (2.2 per 100 patient-months) among 314 patients who received DAAs after transplant for HCV-related HCC [21]. Cabibbo et al. [22] reported a relatively high rate of HCC recurrence in 143 patients who received DAAs after curative HCC therapy, however, the 6-, 12- and 18-month recurrence rates of 12%, 26.6% and 29.1% were very similar to those in historical untreated controls. They found that tumor size and prior recurrence were the main risk factors for recurrent HCC. More recently, a Japanese study found no difference in the recurrence rate after successful RFA in 147 patients treated with DAAs and 156 patients treated with interferon [23].

Timing of treatment may also matter. Tsai et al. [24] found that the 6-month recurrence rate was significantly higher in patients who received DAA therapy within 4 months (51.5%) compared to beyond 4 months (18.8%) after of curative-intent HCC treatment. This strongly suggests that early HCC recurrence may be the result of residual HCC at the time of DAA therapy. Whether HCV treatment could have accelerated the growth of these tumors is unclear. Some have proposed that rapid clearance of HCV from the liver may lead to reduced inflammatory cells in the liver, which could promote HCC growth due to reduced cytokine production and other non-specific mechanisms [25].

With significant controversy in the literature, Waziry et al. [26] performed a systematic review and meta-analysis to try to answer the question. They compared the risk of de novo HCC and recurrent HCC after DAA therapy to that reported after interferon-based therapy. Although they found that the absolute rates of both primary and recurrent HCC were higher after DAAs than after interferon, once the results were controlled for study follow-up time and patient age, the differences were no longer significant. Although this study helped bring some important clarity to this issue, a major limitation was the lack of person-level data. The interferon studies had much longer follow-up than the DAA studies, but the rates of primary and recurrent HCC were reported at mean follow-up for the cohort, rather than on a year-by-year basis. This creates a significant challenge to compare the incidence rates across studies. As illustrated in Fig. 1, depending on whether the rates of HCC were stable or varied over time, one could come to very different conclusions based on the same point estimates for cumulative incidence. Unfortunately, controlling for follow-up time does not really get around this issue. Therefore, although this analysis is very helpful and suggests that DAAs do not increase the risk of HCC recurrence (or de novo HCC), additional cohort data with person-level data and adequate follow-up time will be required to definitively answer the question.
Fig. 1

Difficulty in interpreting HCC risk based on mean incidence and follow-up time. The three graphs illustrate 3 different hypothetical scenarios comparing the incidence of HCC occurrence or recurrence with DAA and interferon-based therapy assuming 10 year mean follow-up in the interferon group and only 2 years in the DAA group. In each case, 100 HCCs occur at 10 years in the interferon group, giving an average of 10 HCCs per year. a If the incidence of HCCs remains constant over time, the estimated cumulative incidence for DAAs will be similar to the cumulative incidence in interferon-treated patients when longer follow-up time is available. Similar to the 100 HCCs observed in 10 years with interferon, 20 will be seen with DAAs after 2 years. b However, if the HCC incidence is highest in the early years after SVR, the aggregate data at 10 years for interferon would underestimate the early risk for HCC. Although the same 100 HCCs occur in the interferon group, 90 occur in the first 2 years and then 10 occur over the subsequent 8 years. If the same 90 occur in the DAA group with only 2 years of follow-up, the rate of 45 per year will appear much higher than the 10 per year with interferon giving the false impression that DAAs increase the risk, when in fact it is the follow-up time that is the issue. c In the third scenario, where the risk of HCC increases with age, the opposite to 1B occurs. Of the 100 HCCs in the interferon group, only 10 occur in the first 2 years and 90 over the following 8 years. Because of the short follow-up time after DAAs, the acceleration in incidence will be missed and only the 10 HCC in the first 2 years will be observed giving an apparent incidence of only 5 per year. The scenarios illustrate that even if there is no biological difference between the recurrence rate with DAAs and interferon, the difference in follow-up time can lead to spurious conclusions if the incidence varies with time, highlighting the need for person-level data and/or equivalent follow-up time to compare event rates between groups.

Singal et al. recently reported on data from 31 sites across North America on 795 patients who had a complete response to HCC treatment for HCV-related HCC [27]. Of these, 304 (38.2%) patients received DAAs and 491 remained untreated. After adjusting for study site, age, sex, Child–Pugh score, AFP level, tumor burden and HCC therapy, 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 0.69–1.33). The tumor stage of the recurrence was also similar between groups. Although this was still not a prospective study, the authors performed multiple sensitivity analyses and found no evidence that DAA therapy affected the type, rate or time of recurrence.

Although still not entirely conclusive, the balance of the evidence does not support a higher rate of recurrence with DAA therapy. It still seems prudent to wait some period of time (3 months) and to confirm no recurrence with cross-sectional imaging after HCC therapy before treating HCV. The rationale for the delay is not that earlier therapy increases the risk of recurrence but because very early recurrence is often a marker of aggressive biology and ongoing HCV therapy in the setting of an aggressive early recurrence may be particularly challenging. Furthermore, given the controversy around this issue, documenting the absence of recurrent disease prior to starting DAAs seems prudent.

Could the Effect of HCC on SVR Impact Interpretation of HCC Incidence Data?

Observational data from the interferon era have fairly convincingly shown that SVR is associated with a markedly reduced risk of HCC [5, 6]. Early data from DAA-treated patients have shown a similar effect, with those achieving SVR having a lower rate of HCC than patients who fail a course of antiviral therapy [8]. Notably however, the absolute rates of HCC post-SVR in DAA-treated patients have consistently been higher than those reported in patients cured with interferon-based therapy [8]. Coupled with the concern about HCC recurrence, this initially led to fears that DAAs may somehow cause HCC. However, the effect is not related to the therapy but rather to the patients. The excellent safety and tolerability of DAAs makes it possible to treat patients with much more advanced cirrhosis than those treated with interferon. In addition, older patients and those with other co-morbidities (e.g. alcohol, fatty liver) that may increase the risk of HCC can also be safely and successfully treated with DAAs. After controlling for the age and severity of cirrhosis, the incidence of HCC is not increased in patients treated with DAAs compared to those who received interferon [26, 28].

However, the lower rate of SVR in the patients with active HCC and the very high SVR rate with DAAs could actually influence the apparent beneficial effects of SVR on HCC incidence, particularly with relatively short-term follow-up. At least theoretically, undiagnosed HCC could be the cause of non-SVR rather than non-SVR being the cause of HCC. To illustrate the point, consider a cohort of 1000 patients, 400 with cirrhosis and 10 with undiagnosed HCC at the time of treatment (personal communication A. Branch). If one assumes that the presence of HCC modestly reduces the SVR rate from 90% for patients with cirrhosis to 80%, compared to 95% in those without cirrhosis, some interesting results emerge. In this example, SVR has no effect on HCC incidence and HCC occurs only in patients with cirrhosis at a constant rate of 2% per year. In the 10 patients with undiagnosed HCC, 8 achieve SVR and 2 are in the non-SVR group. Of the 400 cirrhotics without HCC, 360 (90%) achieve SVR and 40 do not and 560 of the 590 (95%) non-cirrhotics also achieve SVR. After 12 months of follow-up, in the SVR group, there will be a total of 15 HCCs: 8 pre-existing HCCs and 2% of the 360 cirrhotics who achieved SVR (n = 7), giving a rate of 15/928 or 1.6% per year. In the non-SVR group, there will only be 3 total HCCs: 2 pre-existing and 2% of 40 cirrhotics who did not achieve SVR (n = 1). However, because there are so few in the non-SVR group overall, the rate of HCC is actually 3 of 72 or 4.2% per year. To clarify whether this effect is real, longer follow-up is required because the HCCs undiagnosed at the time of treatment will become less relevant to the HCC incidence post-SVR over time. On balance, this scenario seems relatively unlikely, but it highlights the need for longer term follow-up data in the DAA era to confirm that the benefits of SVR are indeed related to viral clearance.

HCV and Surveillance for HCC

The risk of HCC post-SVR is clearly reduced but not eliminated. Currently, guidelines recommend indefinite ultrasound surveillance post-SVR in all patients with advanced fibrosis pre-treatment. Kanwal and colleagues found that patients with a diagnosis of cirrhosis before DAA treatment had an incidence of HCC post-SVR of 1.82% per year, which was 4.7-fold higher than in patients without cirrhosis at baseline [8]. Because cirrhosis may be difficult to diagnose confidently, they also evaluated the risk of HCC based on pre-treatment FIB-4 scores. Patients with a pre-treatment FIB-4 score above 3.25 had an annual HCC incidence of 2.16% after SVR. In contrast, the incidence of HCC post-SVR was 0.34% per year for those with a pre-treatment FIB-4 below 1.45 and 0.45% per year for those with a FIB-4 between 1.45 and 3.25. Similarly, the risk of HCC after interferon-based therapy was 1.09–1.39% per year in those with cirrhosis compared to 0.23% per year in those with F3 fibrosis before treatment [5, 6]. The higher risk in patients with cirrhosis in the DAA era likely relates to the treatment of older patients with more advanced liver disease [4]. Collectively, these data highlight that the risk of HCC post-SVR is largely limited to those with cirrhosis before treatment.

Zangneh and colleagues used these data to evaluate the cost-effectiveness of HCC surveillance after SVR [29]. They found that ultrasound surveillance post-SVR is likely to be cost-effective for patients with a diagnosis of cirrhosis with incremental cost-effectiveness ratios (ICER) of $43,229 per quality-adjust life year (QALY) for biannual or $34,307/QALY for annual surveillance. However, for those without cirrhosis before treatment, the ICER rose to $188,157/QALY and $111,667/QALY for biannual and annual surveillance post-SVR, respectively, well above any standard willingness-to-pay thresholds. Conveniently, they found that values of the AST to platelet ratio index (APRI) or FIB-4 before treatment could be used to identify those for whom post-SVR surveillance was likely to be cost-effective. Surveillance was only cost-effective for those with pre-treatment APRI > 2.0 or FIB-4 > 3,25. Furthermore an important consequence of the low HCC incidence post-SVR is the increased rate of false positive diagnoses with its potential costs and impact on patients [29]. These findings may argue for a change in guidelines to limit surveillance to those with cirrhosis before treatment rather than all those with advanced fibrosis, as is currently recommended. It will be interesting to see if any determinants after SVR will allow for further risk stratification to avoid the need for life-long surveillance in all patients with cirrhosis.

Conclusion on HCV and HCC

In patients with HCV-associated HCC, the HCC should always be treated first. Aside from the importance of not delaying HCC therapy, the presence of HCC appears to reduce SVR rates with DAAs and there is no known benefit of viral clearance on HCC biology. The balance of evidence does not support the concept that HCV eradication increases the HCC recurrence rate but waiting for some months after HCC treatment before treating HCV seems prudent. In patients with very advanced HCC, the value of treating HCV at all is questionable, particularly if there is limited or no response to initial HCC therapy. Continued collection of high-quality data on HCC incidence and recurrence after DAA therapy is required given the short follow-up time of most studies to date, which can significantly impact interpretation of the reported results.

Chronic HBV Infection with HCC

With over 240 million people infected worldwide, chronic HBV infection is still the leading cause of HCC globally [30]. Therapy is either finite with interferon or long-term with oral nucleos(t)ide analogues (NAs). Although NAs are not curative, they are extremely well tolerated, and therapy is associated with many proven benefits, including a reduction in the incidence of HCC. The safety profile of NAs makes them the mainstay of treatment in the setting of HBV-associated HCC. In patients with HCC, HBV therapy is important to prevent HBV reactivation, improve liver function in those with decompensated disease and to prevent HCC recurrence.

HBV Reactivation

HBV reactivation is a well-recognized complication of immunosuppressive therapy, particularly cytotoxic cancer chemotherapy. In most non-liver-related malignancies, the biggest challenge is identifying individuals with HBV, as many patients are unaware of their infection and screening is sub-optimal [31]. In the case of HCC, most patients will be diagnosed with HBV either before HCC occurs or in the work-up of HCC after initial presentation. Once chronic HBV is recognized (HBsAg-positive) in a patient with HCC, there are few if any scenarios when HBV treatment should not be promptly initiated. Treatment with TACE and SBRT have been reported to cause HBV reactivation and associated hepatitis, which can be prevented with prophylactic antiviral therapy [32, 33]. If transplantation is considered for HCC, HBV therapy is also required. Although RFA or resection are not necessarily immunosuppressive, HBV reactivation has been reported to occur following both types of treatment, with higher rates reported after hepatic resection [34]. Antiviral therapy lowers the risk of reactivation and may also improve post-resection recovery by reducing even low-level inflammation related to viral replication.

Recently, immunotherapy with checkpoint inhibitors has been approved as a therapeutic strategy for HCC [35]. What these agents will do to HBV is less clear. PD-1/PDL1 antagonists are being studied as a therapy for chronic HBV with the hope that PD-1/PDL1 blockade may reverse T cell exhaustion and lead to immune clearance of HBV [36]. Very limited effects on HBV have been seen in the small numbers of HBV patients included in the HCC trials with PD-1 inhibitors to date [35]. In one pilot study of nivolumab for chronic HBV, one of 12 patients cleared HBsAg following an ALT flare [37]. In this trial patients were on suppressive therapy with tenofovir. Although NA therapy may not be necessary in patients receiving immunotherapy for HCC, it seems prudent to treat all HBsAg-positive patients with NAs until more data are available.

Hepatic Function

The development of HCC in a patient with chronic HBV may precipitate hepatic decompensation. Treatment with NAs is remarkably safe and effective even in decompensated HBV cirrhosis with many patients recompensating after starting therapy [38]. It is the efficacy of therapy in advanced disease that has made transplant for decompensated HBV-related cirrhosis rare. If decompensation is due directly to HCC with no active HBV component, NA therapy may not be helpful, however there is no harm in starting therapy with the hope of some hepatic improvement. One study reported lactic acidosis in patients treated with entecavir (ETV) with decompensated HBV cirrhosis, however it was not clear if the drug was indeed causative in these cases [39]. It is likely safe to use any of the approved NAs but the more potent agents with higher barrier to resistance such as ETV, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), would be preferable to avoid any concerns about relapse with resistant virus, which can lead to decompensation in patients with advanced cirrhosis [40].

Even in the absence of decompensation, cirrhosis with any level of viremia is now an indication for antiviral therapy according to international treatment guidelines [41]. While HCC may occur in the absence of cirrhosis, over 95% of HBV-related HCCs occur in patients with established or regressed cirrhosis. Even in those without cirrhosis at the time of diagnosis of HCC, treatment with an NA seems prudent to prevent progression to cirrhosis, as well as the other benefits discussed.

HCC Recurrence

Multiple studies have shown that long-term NA therapy reduces but does not eliminate the risk of incident HCC, particularly in patients with cirrhosis [42, 43]. By extrapolation, treatment with NAs after HCC treatment may reduce HCC recurrence. Cho et al. recently reported on outcomes of 607 patients with HBV-associated HCC treated with RFA or hepatic resection [44]. They found that patients treated with TDF or ETV had a lower rate of HCC recurrence than untreated patients or those treated with lamivudine or a similar low potency NA. Using inverse probability weighting to account for baseline differences between groups, those who received ETV or TDF had an adjusted hazard ratio of 0.46 (p < 0.001) compared to no treatment and 0.59 (p = 0.007) compared to lamivudine. Recurrent viremia was an independent risk factor for HCC recurrence in both the untreated and low potency NA group. A systematic review and meta-regression analysis including 14 studies and 1284 patients also found that the use of ETV was associated with a lower risk of HCC recurrence and improved overall survival compared to treatment with lamivudine [45], similar to findings from a previous meta-analysis [46]. Collectively, these data make a strong case for using a high potency agent HBV agent to control HBV-related liver disease and reduce the risk of HBV recurrence.

Occult HBV

Occult HBV infection is defined as the presence of HBV DNA in serum or liver tissue in the absence of HBsAg. Many studies have reported an increased risk of HCC among patients with occult HBV infection, however quantifying the risk is difficult due to the major challenge in doing prospective studies in this population [47]. The relevance may be greatest in people with other underlying risks for HCC such as chronic HCV infection [48]. Whether occult infection affects the risk of HCC recurrence and whether treatment to suppress HBV DNA would reduce the risk of primary or recurrent HCC is unknown. Based on current evidence, there are no data to support treating occult HBV infection to prevent primary or recurrent HCC or to prevent HBV reactivation.

Conclusion on HBV and HCC

While not curative, HBV therapy with NAs is highly effective and extremely safe and well-tolerated. All patients with HBV-associated HCC who remain HBsAg-positive should be treated with a potent, high barrier NA indefinitely to prevent or ameliorate HBV-related liver injury and possibly to reduce the risk of HCC recurrence.

Conclusion

Viral hepatitis continues to be the major cause of HCC globally. Improved screening will hopefully lead to higher diagnosis and treatment rates of both HBV and HCV. The decision of which to treat first, the viral infection or the cancer, would be best answered by treating the virus first and preventing the cancer altogether.

Notes

Compliance with ethical standards

Conflict of interest

Dr. Jordan J. Feld reports receiving research funds from Abbvie, Gilead Sciences and Janssen as well as consulting fees from Abbvie, Gilead Sciences, Enanta, Contravir and Roche. Lisette A. P. Krassenburg reports no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Toronto Centre for Liver Disease, Toronto General Hospital, Sandra Rotman Centre for Global HealthUniversity of TorontoTorontoCanada
  2. 2.Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands

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