DAA treatment reduces risk of HCC for most hepatitis C patients

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People cured of hepatitis C after a course of direct-acting antiviral (DAA) treatment do not have a higher risk of developing hepatocellular carcinoma (HCC) – and probably have a reduced risk – according to studies from Italy and Canada presented at American Association for the Study of Liver Diseases (AASLD) Liver Meeting in Boston.

However, the Italian study led by researchers from the University of Padova, also found that those people who did develop liver cancer during or shortly after antiviral treatment were more likely to develop an aggressive form of cancer, perhaps because of changes in immune surveillance in the liver as a result of treatment.

Hepatitis C can be cured with a course of direct-acting antiviral (DAA) treatment, but eliminating the infection may not heal the liver sufficiently to prevent the development of liver cancer. Furthermore, there is evidence that people with cirrhosis previously treated for HCC have a high rate of recurrence of liver cancer.

Two studies, conducted in Italy and Spain, both found that around 30% of people previously treated for liver cancer experienced a recurrence within a median of 6 months after completing hepatitis C treatment. Both research groups considered the rate of recurrence in their patients to be unusual and warned doctors to be on the lookout for liver cancer recurrence.

To investigate whether these findings hold true in a larger population, researchers at hospitals in the Veneto region of northern Italy analysed the incidence of hepatocellular carcinoma in a prospective study of 3075 consecutive patients with stage F3 or F4 fibrosis treated with direct-acting antivirals between January 2015 and June 2016; 72% had cirrhosis, in the vast majority of cases less advanced (Child-Pugh class A, 65%). People previously diagnosed with liver cancer were excluded from the analysis, as were people who had undergone liver transplantation prior to DAA treatment.

The population was almost two-thirds (63%) male, 62% had HCV genotype 1 infection, 12.7% had genotype 2, 17% had genotype 3, and 7.7% had genotype 4.

After an average follow-up period of approximately 10 months from the time of beginning hepatitis C treatment (300 days), 41 people had developed liver cancer, an incidence of 1.64 cases per 100 person-years (PY). Incidence ranged from 0.23 per 100 PY for people without cirrhosis to 1.93 per 100 PY for those with cirrhosis. Incidence was higher in those with Child-Pugh class B cirrhosis (2.92) than in those with Child Pugh class A (1.64), but this difference was not statistically significant.

These incidence rates compare to observed incidence rates of 2.8 per 100 person years among untreated hepatitis C patients in the same region of Italy previously reported by the same research network.

Incidence was higher among people with HCV genotype 3 or 4 infection, but genotype was not significantly associated with the development of HCC. Multivariate analysis showed that the only factors associated with development of HCC were baseline aspartate transaminase (AST) and platelet counts.

The baseline APRI score – indicating the degree of liver scarring – was the strongest predictor of development of liver cancer, with each 1-point increase in APRI score being associated with a 10% increase in the risk of liver cancer.

Although the study found a reduced risk of liver cancer among those who were cured of HCV infection, it also found an unusually high proportion of the cases that did occur were more aggressive, manifesting as multiple HCC nodules or infiltrative HCC. 16 of 41 cases took this form (39%), and these aggressive cases of HCC were more frequently seen in the first 6 months after the initiation of DAA treatment. Single-nodule cases of HCC were more likely to occur at least 6 months after DAA initiation.

Speaking at an AASLD press conference, Alfredo Alberti, professor of gastroenterology at the University of Padova, said that changes in the immunological and tumour-suppressive environment in the liver as a result of the rapid elimination of viral replication might permit more rapid growth of tumours already present in the liver. Participants in the study were screened for the presence of tumours by ultrasound 3 months before initiating treatment, so the presence of tumours at the time of treatment initiation cannot be ruled out definitively.

A larger study, of the entire population of people treated for hepatitis C in British Columbia, Canada, between 1990 and 2013 found that the risk of liver cancer was reduced by 80% in people cured of hepatitis C compared to those who were not cured. This study did not look at the relationship between exposure to DAAs and liver cancer risk.

The study identified 8,147 people treated with interferon-based regimens, 57% of whom were cured. Treated individuals were followed for a median of 5.6 years.

Liver cancer incidence was highest among people with cirrhosis who did not achieve a sustained virological response (2.1 cases per 100 PY of follow up). In comparison, liver cancer incidence was .64 per 100 PY for those with cirrhosis who achieved SVR, .72 per 100 PY for those without cirrhosis who did not achieve SVR12, and .11 per 100 PY for those without cirrhosis who achieved SVR12.

In a multivariable analysis liver cancer was associated with cirrhosis, age over 50 years, HCV genotype 3 infection versus genotype 1, alcohol consumption, and being male among those who were not cured of hepatitis C. Among those who were cured, only cirrhosis, age over 50, and being male were associated with an increased risk of liver cancer.

Researchers at the BC Centre for Disease Control, the University of British Columbia, BC Cancer Agency and the University of Toronto concluded that although curing hepatitis C infection greatly reduces the risk of developing liver cancer, it does not eliminate the risk entirely. Older people and those with cirrhosis are at higher risk than others, underlining the importance of early diagnosis and treatment.

Abstract 1
Recent data have suggested the possibility of increased risk of HCC during and after DAAs treatment in HCV patients with advanced liver disease. We have therefore analyzed incidence of “de novo” HCC in a large cohort of HCV patients with advanced liver disease treated with oral DAAs and monitored by the NAVIGATORE web-based platform in Italy. 2279 HCV patients (66.6% males, 85.7% with cirrhosis, of whom 91% Child A and 9% Child B, 62% HCV-1, 11.2% HCV-2, 18.5% HCV-3, 8.45% HCV-4,) were included. Patients with a past history of HCC were excluded. The 2279 patients were treated with approved DAAs regimens and monitored monthly. At the time of this analysis, mean follow-up from initiation of DAA therapy was 224.9 days. During this period, 27 patients developed HCC, and the overall calculated incidence x100 patient-years was 2.1 (95% CI: 1.40-3.10). The corresponding incidence values in different subgroups are described in the table. These values were not significantly different by log-Rank test. HCC was diagnosed at week 4 in 3 patients, at week 8 in 2 patients, at week 12 in 6 patients, between week 12 and week 24 in 7 patients and after end of treatment in 9 patients. HCC was nodular with a typical vascular pattern in 46% while in 54% HCC had a more aggressive pattern being infiltrative and multifocal. SVR12 was achieved in 20 out of 27 patients who developed HCC, while the remaining 7 patients were relapsers. Multivariate analysis indicated that only baseline AST and Platelets count were statistically associated with HCC risk, while gender, Age, HCV genotype and DAA regimen were not. The best baseline predictor of the HCC risk was APRI, and the HCC risk increased linearly by 10% at each 1 point increase in APRI value. These results indicate that in cirrhotic patients the incidence of HCC during the first 6-9 months following initiation of DAAs therapy is not different from that expected in untreated patients according to historical controls. However, the atypical HCC pattern seen in about half of the cases deserves better understanding.

Authors
Antonietta Romano, Franco Capra, Sara Piovesan, Liliana Chemello, Luisa Cavalletto, Georgios Anastassopoulos, Valter Vincenzi, Pier-Girogio Scotton, Sandro Panese, Diego Tempesta, Martina Gambato, Francesco P Russo, Tosca Bertin, Maurizio Carrara, Antonio Carlotto, Giada Carolo, Giovanna Scroccaro, Alfredo Alberti

Abstract 2
The risk of hepatocellular carcinoma(HCC) post HCV cure is not well-established for the North American population. We assessed the effect of sustained virologic response(SVR) on the risk of HCC among a large population based cohort in Canada. The BC Hepatitis Testers Cohort includes ~1.5 million individuals tested for HCV between 1990–2013, linked with data on medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients who received interferon based treatments were followed from the end of last treatment to HCC occurrence, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using cumulative incidence function and multivariable Cox proportional hazard models. Of 8147 eligible individuals who initiated treatment, 4663(57%) achieved SVR and 3484(43%) did not. Each group was followed for a median of 5.6yr [range: 0.5-12.9]. The annual HCC incidence rate(IR) was 1.1/1000 person-yr(PY) in the SVR and 7.2/1000 PY in the no-SVR groups. The IR was higher among those with cirrhosis at treatment (SVR: 6.4, no-SVR: 21.0/1000 PY). The cumulative HCC incidence post treatment increase was steeper in the no-SVR vs. the SVR group (Fig 1). In the multivariable model, SVR was associated with reduced HCC risk (hazard ratio (HR)=0.20, 95%CI:0.13-0.30), while cirrhosis(HR=2.61, 95%CI:1.68-4.04), older age(50-59yr: HR=4.15, 95%CI:2.76-6.23; 60+yr: HR=6.37, 95%CI:3.9-10.41 vs. ≤49yr), being male(HR=1.98, 95%CI:1.33-2.96), genotype 3 vs. 1 (HR=1.85, 95%CI:1.25-2.73), and alcohol consumption(HR=1.46, 95%CI:1.0-2.15) were associated with higher HCC risk. In those with SVR, cirrhosis(HR=3.16), older age (50-59yr: HR=4.73; 60+yr:HR=5.44 vs. ≤49yr), and being male (HR=3.3) were associated with higher HCC risk. SVR substantially reduces but does not eliminate the risk of HCC, which is higher among those with cirrhosis and older.

Authors
Naveed Z Janjua, Mei Y Chong, Margot E Kuo, Amanda Yu, Hasina Samji, Zahid Butt, Maria Alvarez, Darrel Cook, Jason Wong, Ryan Woods, Mark Tyndall, Morris Sherman, Eric M Yoshida, Mel Krajden

HIV and Hepatitis material
Abstract 1
Abstract 2


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