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Risk of hepatocellular carcinoma after DAA treatment in cirrhotic HIV-HCV-coinfected patients: where do we stand?
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Lacombe, Karine
"The frequency of de novo HCC markedly decreased between the interferon period and the DAA period, from 15% (Peg-interferon with ribavirin era) to 1.62% (DAA with peg-Interferon era) and 0.87% (DAA-only era).
"There was no statistical difference in the recurrence rate of HCC in patients on an interferon (IFN)-based regimen compared with those on a DAA combination (2/8, 25% versus 4/19, 21%, P = 0.1). .....This emphasizes the crucial need for regular screening for HCC in coinfected patients with residual cirrhosis after achieving HCV cure"
There was no statistical difference in the recurrence rate of HCC in patients on an interferon (IFN)-based regimen compared with those on a DAA combination (2/8, 25% versus 4/19, 21%, P = 0.1)........In the context of HIV, where a large number of individuals have been treated with DAA, no data have been reported on an excess risk of HCC occurrence or recurrence after DAA treatment. Therefore, the article from Merchante et al. [14] in this issue of AIDS addresses a very timely topic. By analyzing the HCC cases collected within the GEHEP 002 cohort set in Spain, the authors aimed to answer three questions: the evolving incidence of HCC in HIV-HCV-coinfected patients treated with anti-HCV drugs over time, the proportion of those seen during the DAA era and the probability of HCC recurrence in those already managed for HCC before DAA introduction. Three hundred and forty-six cases of HCC were included in the cohort, of which 322 were diagnosed in individuals also infected with HCV........
There was no statistical difference in the recurrence rate of HCC in patients on an interferon (IFN)-based regimen compared with those on a DAA combination (2/8, 25% versus 4/19, 21%, P = 0.1). Although the number of patients treated after a first episode of HCC was small, there was no trend to suggest that there might be an enhanced risk of HCC occurrence or recurrence after DAA treatment in this population.".....This emphasizes the crucial need for regular screening for HCC in coinfected patients with residual cirrhosis after achieving HCV cure [16], even when noninvasive markers of fibrosis show a pseudoregression of a score below the threshold for cirrhosis [17]. Screening should be performed at least 6 monthly and consists of an ultrasound examination by an expert radiologist with a CT-scan or MRI, in case of doubt of the presence of intraparenchymal nodules [18]......The occurrence or recurrence of HCC after DAA treatment still remains a debated topic in 2018 [19]. More prospective and well-designed cohort studies with a larger number of participants and longer follow-up may help bring the controversy to an end. There should be no reservations about the positive long-term impact of eradicating HCV in individuals with a high risk of developing end-stage liver disease [20]......."
Together with the increase in life expectancy of HIV-infected individuals with antiretroviral therapy (ART), morbidity and mortality from liver disease has sharply increased in individuals coinfected with hepatitis C or B and exhibit advanced liver fibrosis and cirrhosis [1,2]. Since 2009, hepatocellular carcinoma (HCC) has emerged as a more common feature of end-stage liver disease in this population [3] and a recent retrospective multicohort analysis reported an increase in HCC by 11% per calendar year between 2001 and 2014, with an incidence of 1.6 [95% confidence interval (CI) = 1.3-2.0] cases per 1000 person-years of follow-up [4].
The advent of direct antiviral agents (DAAs) against HCV has led to a sustained virological response (SVR) of more than 95% in all categories of infected individuals including those coinfected with HIV [5,6], and yielded great hope in decreasing liver-related morbidity. However, there has been some controversy that has arisen from observational data collected in cohorts of HCV-monoinfected cirrhotic patients who were treated with DAA after a first presentation of HCC [7]. Clinical teams across Europe described an unexpectedly high rate of HCC recurrence after SVR [8,9], whereas others reported a stable early recurrence rate in patients exposed to DAAs [10].
The reasons underlying the risk of an increased rate of HCC recurrence after HCV cure are not well understood. This may be partly linked to the sudden break in the balance between the pro-tumor and antitumor function of the immune system, which may be dysregulated by the sudden disappearance of HCV immune stimulation [11]. However, this is largely speculative. Another interpretation is that there might be some bias in the studies in relation to the length of the observation period or censoring as well as a bias to a higher propensity of treating patients with more advanced disease, and thus exposing these individuals to a higher risk of recurrence of HCC [12]. More recently, others have published data supporting no evidence of a short-term increase in the incidence of primary HCC in DAA-exposed patients [13].
In the context of HIV, where a large number of individuals have been treated with DAA, no data have been reported on an excess risk of HCC occurrence or recurrence after DAA treatment. Therefore, the article from Merchante et al. [14] in this issue of AIDS addresses a very timely topic. By analyzing the HCC cases collected within the GEHEP 002 cohort set in Spain, the authors aimed to answer three questions: the evolving incidence of HCC in HIV-HCV-coinfected patients treated with anti-HCV drugs over time, the proportion of those seen during the DAA era and the probability of HCC recurrence in those already managed for HCC before DAA introduction. Three hundred and forty-six cases of HCC were included in the cohort, of which 322 were diagnosed in individuals also infected with HCV. The frequency of de novo HCC markedly decreased between the interferon period and the DAA period, from 15% (Peg-interferon with ribavirin era) to 1.62% (DAA with peg-Interferon era) and 0.87% (DAA-only era). There was no statistical difference in the recurrence rate of HCC in patients on an interferon (IFN)-based regimen compared with those on a DAA combination (2/8, 25% versus 4/19, 21%, P = 0.1). Although the number of patients treated after a first episode of HCC was small, there was no trend to suggest that there might be an enhanced risk of HCC occurrence or recurrence after DAA treatment in this population.
Although reassuring, the data suggest that the risk of HCC is not abolished after HCV eradication, as already reported by the authors in an earlier work [15]. This emphasizes the crucial need for regular screening for HCC in coinfected patients with residual cirrhosis after achieving HCV cure [16], even when noninvasive markers of fibrosis show a pseudoregression of a score below the threshold for cirrhosis [17]. Screening should be performed at least 6 monthly and consists of an ultrasound examination by an expert radiologist with a CT-scan or MRI, in case of doubt of the presence of intraparenchymal nodules [18].
The occurrence or recurrence of HCC after DAA treatment still remains a debated topic in 2018 [19]. More prospective and well-designed cohort studies with a larger number of participants and longer follow-up may help bring the controversy to an end. There should be no reservations about the positive long-term impact of eradicating HCV in individuals with a high risk of developing end-stage liver disease [20].
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