Systematic Review With Meta-analysis

Effectiveness of Direct-acting Antiviral Treatment for Hepatitis C in Patients With Hepatocellular Carcinoma

Sichan He; Ian Lockart; Maryam Alavi; Mark Danta; Behzad Hajarizadeh; Gregory J. Dore

Disclosures

Aliment Pharmacol Ther. 2019;51(1):34-52. 

In This Article

Discussion

The advent of DAA therapy has transformed HCV management, leading to increased treatment uptake and improved outcomes in all populations including patients with a diagnosis of HCC. Our systematic review and meta-analysis provide evidence of high DAA efficacy among patients with prior or present HCC, although around 4% lower SVR than patients without HCC. The lower SVR among patients with HCC was not related to the presence of cirrhosis, as comparison of DAA outcomes among those with HCC and without HCC (all with cirrhosis) showed a similar reduction. We also found comparable ITT SVR and mITT SVR, indicating minimal impact of HCC-related mortality prior to SVR on overall DAA outcome in the study population. DAA therapy outcomes among study populations based on proportion with HCC curative management did show lower SVR in those studies that included patients with noncurative HCC management; however, these analyses are limited by the absence of individual-level data on HCC management and limited data on timing of HCC management and DAA therapy.

The mechanism of SVR reduction in HCC patients remains unclear. Hypotheses include immunological, virological or hepatic mechanisms. Impaired immunity among patients with HCC may present a barrier to HCV clearance.[85] HCV viral populations in patients with HCC, including higher rates of DAA resistance, could influence outcomes. Reduced blood supply could make DAA delivery to HCV-infected hepatocytes within HCC lesions less efficient.[86] Regional fibrosis caused by radioembolisation may also induce virologic failure.[31] Active HCC has been associated with reduced SVR.[30,31]

In studies where all patients received curative HCC management, the SVR was 90.4%. The SVR was higher at 95.4% among patients who received liver transplantation. The removal of HCC and substantial improvement of liver function by transplantation enabled improved baseline characteristics and a superior response to DAA therapy. In contrast, studies in which some patients received noncurative HCC management, the SVR was lower at 78.9%. Although this finding may suggest the stage of HCC or HCC management had some impact on virologic response, there are key limitations to this data. First, the analysis is based on the overall proportion with HCC curative management in each study (100% vs less than 100%). Thus, even in studies where some patients received noncurative HCC management, the large majority received curative HCC management. Second, individual-level data, based on HCC management received, were not available. Third, the timing of DAA therapy in relation to HCC management was not well reported. Ideally, individual-level data comparing patients with and without curative HCC management, and by timing (eg less than and greater than 6 months from HCC management) would be required to further explore this issue. Previous studies have suggested lower SVR in those with noncurative HCC management: Huang et al[52] found SVR of 92.1% compared to 97.3% in those with curative HCC patients, albeit nonsignificant (P = .33); Beste et al[30] reported significantly higher SVR in patients with prior HCC cured by liver transplantation (94.0%, 88.3–97.0) than in patients with present or active HCC (74.4%, 95% CI 70.0–78.3). In a recent meta-analysis,[33] similar to our study, SVR was reduced in HCC patients (89.6%) compared to non-HCC patients (93.3%), and within HCC patients, those who underwent curative HCC management DAA therapy had the highest SVR.

Importantly, 'noncurative HCC management' does not universally represent advanced stage of HCC. For example, the studies by Zanetto et al[82] (patient n = 23) and Pascual et al[65] (patient n = 15) included in this category reported DAA outcomes in patients on waitlist for liver transplantation and all patients achieved SVR. Despite the presence of active tumour status at the time of DAA therapy, patients had early stage HCC awaiting 'curative HCC management'.

DAA therapy outcomes had variability by genotype, with SVR 92.0% in genotype 1, 89.3% in genotype 2 and 77.1% in genotype 3. Previous studies had reported that HCV genotype 1 and 2 patients achieved higher SVR, with lower response in genotype 3,[30,52,87] with our result in line with these findings. The major factor influencing DAA outcomes was unrelated to HCC—the DAA regimen received. Early generation DAA regimens, such as SOF + RBV, had lower SVR rates, in line with clinical trial outcomes. Emamaullee et al[88] found only 57% SVR with a 24-week course of SOF + RBV. In our analysis, suboptimal regimens resulted in an SVR of 76.3%. In contrast, higher efficacy was found with both PI-containing (SVR 89.2%) and SOF + NS5A inhibitor (SVR 96.9%) DAA therapy.

In a recently issued report by the United States Food and Drug Administration (FDA),[89] rare but serious liver injuries or failures were seen in patients with advanced liver disease who had received PI-containing DAA therapy including GLE/PIB (Mavyret) and ELB/GRA (Zepatier). In decompensated liver disease, PIs are contradicted[90] and have been highlighted by practice guidelines.[91–93] High efficacy and safety of DAA therapy have broadly increased its uptake in patients with cirrhosis and/or HCC. This vulnerable patient group is likely to have more liver-related comorbidities that require close surveillance. Thus, in patients with HCV-related HCC, particularly with the presence of cirrhosis, monitoring of liver function and the selection of DAA regimens should be considered, preferably via multidisciplinary approach (MDT)[94]—which is becoming a common practice in many tertiary medical centres—to achieve optimal treatment outcomes.

Given the recent controversy around DAA therapy and HCC recurrence risk, many clinicians may be deferring DAA therapy to await CR to curative HCC management, despite more recent studies showing decreased risk of HCC and mortality[95,96] in HCV-HCC patients treated with DAA therapy. In a recent Clinical Practice Update by the American Gastroenterological Association[29] on interaction between DAAs for HCV and HCC, the authors recommended deferring therapy for HCC until a CR is determined. DAA therapy in an HCC population should be governed by the individual patients' clinical state. In patients undergoing curative HCC management, we believe DAA therapy delivered prior to confirmation of curative response should be an option. This recommendation is based on these key factors: (a), no conclusive evidence of an increased HCC recurrence rate; (b), a high expected SVR rate (around 90%); and (c), a high risk of hepatic decompensation if untreated. In our study, a high overall SVR of 88.3% was seen in all patients with prior or present HCC, and was slightly higher (90.4%) in those studies with all patients receiving curative HCC management. Additionally, in studies that reported post-DAA liver function status, 95.3% showed significant improvement.

Our study has clear limitations that should be considered. Among 5522 patients with HCV and HCC in the 56 included studies, 4178 patients were in 42 studies in which all had undergone curative HCC management. Even in the remaining 14 studies, one third of patients had undergone curative HCC management. Thus, there was limited capacity to evaluate the impact of HCC management on DAA outcomes. This limitation is compounded by the lack of individual-level data. Characterisation of the stage of cirrhosis was poor, and only four studies had greater than 50% patients with advanced cirrhosis. Although median interval between CR to HCC management (or first/last HCC therapy) to initiation of DAA therapies was 11 months, the timing of DAA therapy and HCC management was often poorly characterised. Finally, a meta-regression was not able to be undertaken due to a lack of capacity to obtain sufficient data on key variables.

In summary, the virologic response to DAA therapy was significantly lower in patients with prior or present HCC compared to those without HCC. Among HCC patients, SVR was higher in patients receiving curative HCC management, and there are clear potential benefits for early DAA therapy in this population with a high risk of hepatic decompensation.

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