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Barcelona: Reports of Unexpected Cases of Liver Cancer in People Undergoing Treatment With DAAs

July 2016

Doctors in Barcelona recently reported an unexpected increase in liver cancer recurrence in people who had been or who are being treated for chronic hepatitis C virus (HCV) infection with new potent all-oral medicines called direct acting antivirals (DAAs). All participants had previously been treated for liver cancer. They had been treated successfully with different combinations of DAAs. In their report, the Barcelona doctors focused on patients treated for HCV between October 2014 and December 2015.

We urge our readers to treat this report from Barcelona with caution. The possible association between exposure to DAAs and liver cancer recurrence may be an association that has arisen by chance. Large numbers (tens of thousands) of people in North America and Western Europe have been treated with DAAs and there have not been reports of multiple cases of recurrent liver cancer in such patients by major clinics. The analysis from Barcelona may have been inadvertently biased by its small size and because the researchers included people at very high risk for recurrence of liver cancer.


Study Details

As all participants had undergone treatment for liver cancer, they subsequently were considered cured and were under routine clinical and laboratory surveillance for the return of liver cancer. For instance, many participants underwent regular CT, MRI (magnetic resonance imaging) and ultrasound scans of their liver every six months.

The Barcelona doctors focused on 58 participants whose average profile was as follows:

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  • age -- 66 years
  • 69% men, 31% women
  • 95% had cirrhosis
  • 94% were infected with HCV genotype 1b
  • the distribution of commonly used anti-HCV regimens included the following: Harvoni (sofosbuvir + ledipasvir) -- 36%; the 3D regimen (Holkira Pak -- dasabuvir + ombitasvir + paritaprevir boosted with ritonavir) -- 26%; sofosbuvir + simeprevir -- 26%; sofosbuvir + daclatasvir -- 10%

The distribution of therapy for the first occurrence of liver cancer was as follows:

  • surgery -- 35%
  • radiation -- 55%
  • injection of chemotherapy into the tumour -- 10%


Results

At the time the Barcelona doctors submitted their report, they noted that 40 participants have been monitored for 12 consecutive weeks after the cessation of DAA therapy. Of these 40 people, 39 (98%) have been cured from HCV.

Here is the situation among the remaining 18 participants:

  • three have not yet completed their course of DAAs
  • 11 completed their course of DAAs but virological results are not yet available
  • three others who completed their course of DAAs have promising preliminary virological results
  • one person died due to liver failure


Focus on Liver Cancer After DAA Therapy

Overall, the entire group of 58 participants has been monitored for nearly six months and their current status is as follows:

  • 55 participants are alive
  • three participants have died

Among the three participants who died, their deaths occurred 12, 10 and five months after DAAs had been initiated.

A total of 15 cases of liver cancer recurrence have been found through CT or MRI scans.


A High Rate and a Theory

The Barcelona doctors claim that the recurrence rate for liver cancer in their report is relatively high, approaching 28%. They do not think that these results are due to tumours being detected very early because of "more intense screening [for liver cancer]." Furthermore, these doctors do not think that DAAs directly caused cancer, as they did not find any evidence for this. Rather, they proposed a complex idea whose key elements are as follows:

  • Billions of copies of HCV are produced every day by infected liver cells.
  • Once DAA regimens are initiated, HCV levels in the blood quickly become undetectable, sometimes in days or weeks.
  • This massive and relatively sudden fall in HCV levels results in the decrease of proteins associated with inflammation also circulating in the blood and immune system. The sudden absence of HCV and inflammatory-associated proteins may somehow impair the immune system's ability to keep liver tumours under monitoring and control.

Readers should note that this idea, though immunologically interesting, has not been proven.


Counterpoint

The Barcelona doctors note that reviews of clinical trials of interferon-based therapy for chronic HCV infection have not found any signal of increased risk for liver cancer. That is true, but a meta-analysis of interferon treatment for HCV infection done by researchers at the University of Toronto, reported earlier in this issue of TreatmentUpdate, has found that even among people who were cured there was still a small risk for the subsequent development of liver cancer. Furthermore, a report from Vienna, also in this issue of TreatmentUpdate, notes that cases of liver cancer have occurred among people who were treated with interferon and not DAAs. In that report, about 11% of participants treated with interferon later developed liver cancer.

Some researchers at the University of Palermo in Italy have reviewed the report from Barcelona. They issued this caution: "A definitive estimate of the likelihood of [liver cancer] recurrence is difficult." This difficulty arises because of many factors (that are beyond the scope of our article).

The Barcelona doctors calculated that they found a 28% rate of liver cancer recurrence and they say that this was greater than what they expected. Yet, according to the Italian researchers who reviewed the Barcelona data and then recalculated the estimated risk of liver cancer, the risk of recurrence should have been between 7% and 13%. The Italian researchers therefore see no need for alarm. Note that the numbers of patients upon which both teams used to base their calculations is small and much caution is needed, as these estimates are not robust.

It is possible that the report from Barcelona contains a major flaw: It was inadvertently over-represented with patients who were at very high risk for the recurrence of liver cancer. This could have biased their conclusions.

Whatever the ultimate reason for the apparently increased rate of liver cancer recurrence noted by the Barcelona doctors, their report has ignited disagreement and controversy. To seek clarity on this issue, many people in the liver field will now look to large databases that have data on hundreds, and in some cases thousands, of patients.


References

  1. Cammà C, Cabibbo G, Craxì A. Direct-acting antiviral agents and risk for HCC early recurrence: much ado about nothing. Journal of Hepatology. 2016; in press.
  2. Reig M, Mariño Z, Perelló C, et al. Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution. Journal of Hepatology. 2016; in press.
  3. Reig M, Torres F, Mariño Z, et al. Reply to Camma et al and Torres et al. Journal of Hepatology. 2016; in press.
  4. Pol S. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CIRVIR and CO23 CUPILT cohorts). Journal of Hepatology. 2016; in press.
  5. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2011 Mar;53(3):1020-2.
  6. Meniconi RL, Komatsu S, Perdigao F, et al. Recurrent hepatocellular carcinoma: a Western strategy that emphasizes the impact of pathologic profile of the first resection. Surgery. 2015 Mar;157(3):454-62.
  7. Kim DJ, Clark PJ, Heimbach J, et al. Recurrence of hepatocellular carcinoma: importance of mRECIST response to chemoembolization and tumor size. American Journal of Transplantation. 2014 Jun;14(6):1383-90.


Related Stories

Caution Needed About Claims of Increased Risk of Liver Cancer Recurrence With Use of DAAs
Vienna Doctors Urge Caution When Assessing Possible Associations Between Liver Cancer Recurrence and Use of DAAs
Large Review From Three French Studies Finds No Link Between Use of DAAs and Recurrence of Liver Cancer



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.

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