Experts around the world have gathered for 5-days in Paris to attend the annual European Association for the Study of Liver (EASL) meeting, the 2018 International Liver Congress. One of the highlights in the congress is the updates of hepatitis C virus (HCV) clinical practice guidelines that may change the way clinicians practise.1 The major changes in the guidelines include the loosening of criteria for diagnosing HCV and the addition of new direct-acting antivirals (DAA) treatment regimens. Interesting presentations from independent researchers also showed the effectiveness of a nationwide public health program.2, 3 However, under the light of the recent controversy stirred up by the Cochrane review, the EASL made a response that puts the creditability of Cochrane in questions.4, 5 Nevertheless, the continuous advancement in the management of HCV supports the notion that a goal of eliminating viral hepatitis by 2030 is possible.
Towards the elimination of viral hepatitis by 2030
As an oncogenic virus that is carried by an estimated 71 million people worldwide and the leading cause of liver-related deaths of 670,000 deaths annually,6, 7 HCV has gained its presence on the public health threats radar. As the virus continues to threaten, the World Health Organization (WHO) decided to wage a war on the viral infection in May 2016, introducing global targets for care and management of HCV, and setting a goal to eliminate viral hepatitis by 2030.8, 9 The development and application of DAA puts mankind on the upper hand in the battle with HCV, as it drastically reduces liver-related deaths through achieving a high rate of sustained viral response (SVR).7
Stepping up the game in diagnosis
On the journey to eliminate HCV, diagnosing the infection has always been an obstacle the field has to overcome, considering that the infection is usually asymptomatic and tends to remain until secondary symptoms to serious liver damages are developed.10 To align with the target set by the WHO, the EASL panel kept the recommendation for a regional or national screening test for HCV but the strategies should be designed based on the local epidemiology and within the local framework of national plans.1
There are no major changes for the current way of diagnosing HCV, with the first-line diagnostic test still being anti-HCV antibody in serum or plasma.1 A positive result is then followed-up by a test for HCV RNA to confirm the presence of ongoing infection.1
While serum, plasma, or whole blood collected on dried blood spot tested with a real-time polymerase chain reaction (PCR) or transcription mediated amplification (TMA) assay with a lower limit of detection of ≤15 international units (IU)/ml for confirming an infection remains unchanged, the guideline added a point-of-care HCV RNA assay with lower limit of detection ≤1,000 IU/ml as a recommendation.1
The point-of-care assay has received prequalification from the WHO, and has the potential to simplify testing algorithms, increase diagnosis rate and facilitate linkage to treatment.1, 11 The risk of false-negative is not a major concern as a study found that only 0.16% of the HCV genotype 1 patients have a HCV RNA level below 1,000 IU/ml.12
Introducing new treatment options
One of the highlights of this annual event is the addition of new DAA regimens as the recommended treatment for HCV infection.1 The EASL decided to add the sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) triple combination therapy regimen and the glecaprevir/pibrentasvir (GLE/PIB) double combination therapy regimen in the 2018 guidelines. Table 1 described the recommended treatment regimen, their presentations, and posology.
The newly added treatment options have been tested for efficacy and safety in various trials and approved in Europe.13, 14 The SOF/VEL/VOX 8 weeks regimen was tested against the SOF/VEL 12 weeks regimen in the POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4 trials, where over 90% of the patients achieved SVR.13 However, owing to the higher relapse rate among patients with genotype 1a with Q80K polymorphism being the suspected cause, the new therapy failed to demonstrate noninferiority to the existing SOF/VEL therapy.15
GLE/PIB was tested in the ENDURANCE-1, ENDURANCE-3, ENDURANCE-4, EXPEDITION-1, EXPEDITION-2, SURVEYOR-2, and CERTAIN-2 trial, which showed a high percentage of patients infected with HCV across all genotypes achieving SVR.14
Both SOF/VEL/VOX and GLE/PIB regimens resulted in a low rate of adverse events and withdrawal due to adverse events, providing evidence on the safety of the treatments.15-18
Based on the results of the clinical trials, SOF/VEL/VOX is recommended for treating the more complicated HCV genotype 3 infection and as an retreatment option, whereas the GLE/PIB is recommended for HCV of all genotypes.1 A summary of the recommended treatment and their corresponding genotypes is provided in Table 2.
The EASL panel members also recommended the simplification of HCV treatment, encouraging the use of pangenotypic regimens even when the knowledge of the genotype and subtype infected is absent.1
HCV patients coinfected with human immunodeficiency virus (HIV) are also encouraged to be treated with interferon-free regimens, but should be carefully monitored on renal adverse events if the patient is also receiving tenofovir disoproxil fumarate (due to the inhibiting activity on p-glycoprotein).1
“These were very well-written guidelines, and there is no reason that they should not apply on this side of the Atlantic as in Europe,” commented by Dr. David Bernstein, chief of the division of hepatology at North Shore University Hospital in Manhasset, New York, US.19
Other encouraging findings from around the world
Other than the updates to the treatment guidelines, researchers from around the world also brought some good news from their research.
The HCV elimination program in Georgia and Iceland reported some encouraging results.2, 3 The program in Georgia diagnosed 29.3% of their HCV infected adults, treated 76.7% of them, in whom 95.7% reached SVR in just 2 years after the program is initiated.2
The program launched in Iceland took a different approach. By targeting the high risk population including people who inject drugs that accounted for the majority of HCV infections, the country diagnosed and treated 91.3% of these people and achieved 96% SVR, indicating a huge success for the program.3 Although the two programs are still at the early stage, the results have shown the possibility of eliminating HCV through the implementation of a nationwide program.
Response to the controversial Cochrane review
In response to the controversial Cochrane review published in September last year, which claimed that they failed to recognize the clinical benefits in DAA due to the lack of quality evidence,4 the EASL criticized the methodology used in the Cochrane review as well as its ignorance of the natural history of HCV infection and associated systemic diseases, noting that the conclusion of the Cochrane review will grievously affect the treatment with HCV.5
In defense of the use of DAA, Prof. JM Pawlotsky of the French National Reference Center for Viral Hepatitis B, C and Delta and the Head of Department of Virology at Hôpital Henri Mondor, Créteil, France added the following comment, “well, time for Cochrane authors to go back to the real world, understand the value of surrogates in infectious diseases, discuss with some of the 4 million patients treated so far, and accept that it is not because they do not see something that it does not exist…”5
The controversy began with studies that found patients received DAA treatments still having an elevated risk for developing hepatocellular carcinoma (HCC) compared with patients received interferon-based treatment.20, 21 The studies embarked on various groups publishing their findings on the correlation between DAA and HCC recurrence, but failed to reach a robust conclusion due to the various limitations in the study designs.22-30
The panel chair of the EASL HCC 2018 guidelines, Professor Peter Galle of University Medical Centre in Mainz, Germany, said that there is growing evidence that suggests the correlation between DAA treatment and HCC recurrence is due to selection bias, in which patients who received DAA were generally sicker, hence a higher risk for HCC recurrence, but the speculation is not enough to rule out the concern entirely.31
Under such uncertainties, the EASL panel made the recommendation in the updated guidelines for HCC to closely monitor patients that have HCV-associated cirrhosis and those who previously had HCC but are treated with curative intent, as the rate of HCC recurrence in this population is high even after achieving SRV with DAA treatment.32
Although the congress was shrouded in the debate over the use of DAA, the evolution in the treatment guidelines, the latest findings with the development of new treatment strategies, and progresses made in the nationwide HCV elimination programs, all marked as the advancement in combating HCV. Keeping the current rate, the day where hepatitis is no longer a public health threat should be near.
1. Pawlotsky J-M, Negro F, Aghemo A, et al. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018. [Epub ahead of print]
2. Tsertsvadze T, Gamkrelidze A, Chkhartishvili N, et al. Hepatitis C care cascade in the country of Georgia after 2 years of starting national hepatitis C elimination program [abstract PS-096]. Presented at: International Liver Congress 2018. 11 – 15 April 2018; Paris, France.
3. Tyrfingsson T, Runarsdottir V, Hansdottir I, et al. Marked reduction in the prevalence of hepatitis C viremia among people who inject drugs during 2nd year of the Treatment as Prevention (TraP HepC) program in Iceland [abstract PS-095]. Presented at: International Liver Congress 2018. 11 – 15 April 2018; Paris, France.
4. Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017. Issue 9. Art. No.: CD012143.
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11. Grebely J, Lamoury FM, Hajarizadeh B, et al. Evaluation of the Xpert HCV Viral Load point-of-care assay from venepuncture-collected and finger-stick capillary whole-blood samples: a cohort study. Lancet Gastroenterol Hepatol. 2017;2(7):514-520.
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13. European Medicines Agency. Vosevi – Summary of product characteristics (Accessed April 23, 2018, at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004350/WC500235373.pdf).
14. European Medicines Agency. Maviret – Summary of product characteristics (Accessed April 23, 2018, at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004430/WC500233677.pdf).
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17. Rockstroh J, Lacombe K, Viani RM, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 study. J Hepatol. 2017;66(Suppl 1):S102.
18. Foster G, Gane E, Asatryan A, et al. ENDURANCE-3: safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3-infected patients without cirrhosis. J Hepatol. 2017;66(1):S33.
19. Susman E. Europe Gets Updated HCV Tx Guidelines – EASL panel touts ‘ease of use’ of direct-acting antivirals. MedPage Today. 2018 (Accessed April 18, 2018, at https://www.medpagetoday.com/meetingcoverage/easl/72350).
20. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65(4):719-726.
21. Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016;65(4):727-733.
22. Foster GR, Irving WL, Cheung MC, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016;64(6):1224-1231.
23. Cheung MC, Walker AJ, Hudson BE, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016;65(4):741-747.
24. Pol S. Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma. J Hepatol. 2016;65:734-740.
25. Sugimoto K, Kim SR, Kim SK, et al. Comparison of daclatasvir and asunaprevir for chronic HCV 1b infection with telaprevir and simeprevir plus peginterferon and ribavirin, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma. Oncology. 2015;89(Suppl. 2):42-46.
26. Kobayashi M, Suzuki F, Fujiyama S, et al. Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection. J Med Virol. 2017;89(3):476-483.
27. Petta S, Cabibbo G, Barbara M, et al. Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon. Aliment Pharmacol Ther. 2017;45(1):160-168.
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29. Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. J Hepatol. 2017;67(6):1204-1212.
30. Kanwal F, Kramer J, Asch SM, et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology. 2017;153(4):996-1005. e1001.
31. Highleyman L. EASL updates liver cancer guidelines at International Liver Congress. infohep. 2018 (Accessed April 23, 2018, at http://www.infohep.org/EASL-updates-liver-cancer-guidelines-at-International-Liver-Congress/page/3256817/).
32. Galle PR, Forner A, Llovet JM, et al. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018. [Epub ahead of print]