World J Gastroenterol. 2016 Feb 28;22(8):2630-5. doi: 10.3748/wjg.v22.i8.2630.
Ombitasvir, paritaprevir, ritonavir, dasabuvir and ribavirin in cirrhosis after complete destruction of hepatocellular carcinoma.
- 1Zahariy Krastev, Deian Jelev, Krasimir Antonov, Tanya Petkova, Evelina Atanasova, Nadezhda Zheleva, Bojidar Tomov, Yana Boyanova, Lyudmila Mateva, Clinic of Gastroenterology, University Hospital “St. Ivan Rilski”, 1431 Sofia, Bulgaria.
We observed a sustained viral response (SVR) of ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin therapy, for 12 wk, in two cases with compensated liver cirrhosis and fully destroyed early hepatocellular carcinoma (HCC). Patients were infected with hepatitis C virus (HCV) genotype 1b and were previous null responders/relapsers to interferon-alpha/ribavirin (IFN/RBV). There was a rapid suppression of HCV RNA to undetectable levels within the first two treatment weeks. SVR was achieved even after marked reduction of the RBV dose. The treatment was well tolerated. Both subjects experienced worsening of liver disease during therapy, in different patterns: severe, transient, predominantly direct hyperbilirubinemia without cytolysis (case 1) or progressive increase of aminotransferases (grade 4) without severe hyperbilirubinemia (case 2). Adverse events spontaneously resolved. The patients remained in a good clinical condition without hepatic decompensation. There was no re-occurrence of HCC. This is the first report for treatment of HCV cirrhosis after complete HCC destruction.
KEYWORDS: Dasabuvir; Hepatitis C virus cirrhosis; Hepatocellular carcinoma; Ombitasvir; Paritaprevir; Ribavirin; Ritonavir
Interferon-free therapy with direct acting antivirals (DAA) is a spectacular treatment advance for genotype 1 patients with compensated HCV-cirrhosis. Different studies have shown rates of sustained virological response (SVR) above 95%. A fixed-dose combination with ombitasvir, paritaprevir/ ritonavir and dasabuvir (3-D) induces SVR rate of 99% in genotype 1b irrespective of the presence of cirrhosis. This data provided a rational to apply 3-D regimen in a more difficult to treat subgroup of cirrhotic patients with history of cured HCC.
To the best of our knowledge this is the first report for DAA treatment of HCV cirrhosis and early HCC that had been completely destroyed by local treatment procedures in advance. We observed a rapid suppression of serum HCV RNA to undetectable levels within the first two weeks of 3-D regimen. SVR was achieved even after a marked reduction of the RBV dose to only 200 mg daily in the first case. This is in line with the results of recent study that reported 100% SVR rate in HCV genotype 1b patients with compensated cirrhosis after 3-D ribavirin-free therapy for 12 weeks (1).
Both our subjects experienced signs of worsening of liver disease during therapy, manifested in two different patterns: a severe, early, transient predominantly direct hyperbilirubinemia without cytolysis (case 1) or progressive increase of serum aminotransferases (grade 4) without severe hyperbilirubinemia (case 2). The above adverse events were transient and spontaneously resolved. Both patients remained in a good clinical condition and with persistently compensated liver disease. There were no signs of ascites, encephalopathy or GI bleeding.
We did not observe reoccurrence of HCC and newly developed liver nodules both during the 3-D therapy and post-treatment follow-up. Recent study surprisingly reported an unexpected high rate of HCC reoccurrence after DAA treatment in patients with prior hepatocellular carcinoma who were with complete HCC treatment response before antiviral therapy (2). It was hypothesized that disruption of immune surveillance may facilitate the emergence of metastatic clones (2). Further studies are needed to confirm or reject the above phenomenon. In the meantime this patient subgroup should be treated with DAA, but it is obvious that they should be closely monitored for many years after antiviral therapy.
In our patients we are performing contrast enhanced US and/or CT scan on 3-month interval. One year post therapy both of them are still without reoccurrence of HCC and without development of new liver nodules. The liver function evaluated through the serum concentration of total bile acids don’t worsened during the first year post therapy (table 1) . We observed a spectacular doubling of the absolute lymphocytes number as surrogate marker of the post treatment improved immunity (table 2)
Table 1 – Total bile acids serum levels during 48 weeks follow up
Table 2 – Absolute lymphocytes during 48 weeks follow up
There are still many open questions regarding IFN-free therapy in liver cirrhosis and particularly in subjects who were successfully cured from early HCC. It is unknown whether the elimination of HCV infection will be sustained over the years and what the long-term treatment impact on chronic liver disease will be, including a regression of fibrosis and cirrhosis. It is also not clear which cirrhotic patients will mostly benefit from therapy in terms of prolonged survival and a slowing down of the progression to HCC.
Importance of the study: authors have described the first two cases in the literature with HCV-related cirrhosis and completely destroyed early HCC, treated with IFN-free therapy. The article highlights the obtained clinical data regarding efficacy, safety and tolerability of a 3-D regimen. Results suggest that IFN-free therapy might be a suitable treatment option for this specific patient subgroup.
(1) Feld JJ, Moreno C, Trinh R, Tam E, Bourgeois S, Horsmans Y, …., Poordad F (2016) Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks. J Hepatol 64: 301-307.
(2) Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, ….., Bruix J (2016) Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution. J Hepatol; doi: 10.1016/j.jhep.2016.04.008. [Epub ahead of print].
Zahariy Krastev, MD, PhD, DSc (Med), Professor of Medicine,
Clinic of Gastroenterology, University Hospital “St. Ivan Rilski”,
15 Acad. Ivan Geshov Blvd,