Saturday, March 19, 2016

Ledipasvir-sofosbuvir combo safe, effective for elderly hep C patients

 Ledipasvir-sofosbuvir combo safe, effective for elderly hep C patients

March 18, 2016

By Lorraine L Janeczko

NEW YORK (Reuters Health) - The combination of ledipasvir and sofosbuvir (LDV/SOF) is safe, effective and well tolerated in people over 65 who have genotype 1 hepatitis C, researchers have found.

"This study, which is the largest analysis ever done in the population over 65, found that the combination of the NS5A inhibitor ledipasvir with the nucleotide polymerase inhibitor sofosbuvir for hepatitis C is not only highly effective but is also safe and tolerable," Dr. Sammy Saab from the David Geffen School of Medicine at the University of California, Los Angeles, told Reuters Health.

Dr. Saab has multiple financial ties, including stock ownership, to Gilead Sciences, which makes LDV/SOF.

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Of Interest
International Conference on Viral Hepatitis (ICVH) 2016.

Conference News

New Hep C Treatments Cause Adverse Effects in the Elderly
Medscape Medical News

Shortened Hep C Combo Passes Real-World Test
Medscape Medical News, March 18, 2016

Rhode Island Hep C Complications Projected to Continue
Medscape Medical News, March 17, 2016

Opioid Substitutes Do Not Impede Hep C Combo Drugs
Medscape Medical News, March 16, 2016

Hep B Cure Talks, Hep C Treatment Gaps Lead Conference
Medscape Medical News, March 9, 2016

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Accessing the Cure: Helping Patients With Hepatitis C Overcome Barriers to Care

Accessing the Cure: Helping Patients With Hepatitis C Overcome Barriers to Care

This case study from the National Viral Hepatitis Roundtable and Project Inform describes the cost-sharing mechanisms that create significant barriers to accessing new hepatitis C treatments, which require a strong advocate response to improve patient access

Published Online: March 18, 2016
Christine Rodriguez, MPH, and Andrew Reynolds
Source

ABSTRACT
Hepatitis C virus (HCV) is an illustrative example of the dilemma faced by patients in the American healthcare landscape: HCV is a chronic, progressive disease for which a cure exists, but at such high prices that cost-sharing innovations create significant barriers to care, treatment, and cure. Previous HCV treatments were ineffective and had a wide range of severe side effects, so much so, that both patients and their providers chose to wait for newer and more effective options. Yet, once these options became available, cost-sharing mechanisms, such as plan premiums, deductibles, co-payments, and coinsurance, created barriers to treatment, producing a large pool of patients infected with HCV who are willing but unable to access a cure. In response, advocacy organizations like the National Viral Hepatitis Roundtable and Project Inform have developed innovative strategies to improve access to HCV care and treatment.
 
Am J Manag Care. 2016;22(4 Suppl):S108-S112
Hepatitis C virus (HCV) is an illustrative example of the dilemma faced by patients in the American healthcare landscape: HCV is a chronic, progressive disease for which a cure exists, but at such high prices that cost-sharing innovations create significant barriers to care, treatment, and a cure. Previous HCV treatments were ineffective and had a wide range of severe side effects, so much so, that patients and their providers chose to wait for newer and more effective options. Yet, once these options became available, cost-sharing mechanisms such as plan premiums, deductibles, co-payments, and coinsurance created barriers to treatment, producing a large pool of patients infected with HCV who were willing but unable to access a cure. In response, advocacy organizations like the National Viral Hepatitis Roundtable (NVHR) and Project Inform have developed innovative strategies to improve access to HCV care and treatment.

Overview of HCV

HCV is the most common blood-borne pathogen in the United States, with 3.2 to 5 million individuals currently infected. If left untreated, up to 30% of those with HCV will develop cirrhosis—scarring that damages the liver, causing it to not function properly—in 20 to 30 years. Among patients with cirrhosis, there is a 1% to 5% annual risk of developing liver cancer, and a 3% to 6% annual risk of hepatic decompensation—disease progression requiring a liver transplant. Once an individual is diagnosed with a decompensated liver, their risk of death in the next year runs 15% to 20%.1,2 However, early treatment and cure of HCV can virtually eliminate all of these long-term complications.

State of HCV Treatment

Prior to 2013, HCV treatment was long (24-48 weeks), carried a host of severe side effects that were intolerable for many, and relatively ineffective (sustained virologic response [SVR], the equivalent of virologic cure, with rates ranging from 45%-80%). Consequently, many patients and their providers chose to wait for better options. In 2013, the pegylated-interferon free direct-acting antiviral (DAA) era began. With these new medications, and several more in the years since, the HCV treatment landscape has changed dramatically: the new regimens are shorter (average 12 weeks), have fewer side effects, and cure 90% to 100% of patients depending on genotype, severity of disease, treatment experience, and other factors.

The Benefits of Curing HCV

In their guidance for managing and treating HCV, the American Association for the Study of Liver Diseases and Infectious Diseases Society of America state: “Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy.”3 The goal of treatment is to cure the patient.

Once a cure is achieved, most patients experience improved liver functioning, and many experience a reversal of fibrosis (mild scarring) over time. Even patients with cirrhosis (severe scarring) experience improved liver function and a reduction in the risk of developing end-stage liver complications. There is also evidence that cirrhosis can be reversed once SVR is achieved. This reduction in fibrosis and return to normal liver function comes with a host of other benefits, including the fact that cured patients live longer. Additional benefits of cure can be found in the Figure.4

In addition to the clinical benefits, treating HCV is cost-effective. In a review of both the clinical and financial value of HCV treatments, the California Technology Assessment Forum found that although treating all patients regardless of liver disease severity is expensive, it meets the benchmark for cost-effectiveness in terms of the benefits gained.5 Waiting for more advanced liver disease to treat HCV significantly increases cost, and the cost per cure is lower for both treatment-naïve and non-cirrhotic patients, providing further evidence for the effectiveness of early HCV treatment.6,7 Additionally, curing HCV lowers healthcare costs—now and in the future—for all patients, including those with end-stage liver disease. Studies show that patients who are treated and cured of HCV have significantly lower medical expenses than those who are not, with savings increasing as the severity of HCV-related liver disease increases.8 When combined, the cost-effectiveness of treatment and long-term savings associated with curing HCV further cement the rationale for treating all patients with HCV.

Impact of Cost Sharing on Patient Access

In spite of the clinical benefits and cost-effectiveness of new DAAs, patient access has been limited. With the confluence of high-cost drugs, a millions-large potential patient pool, and pent-up demand for highly tolerable curative treatments, payers turned to heavy-handed utilization management strategies. The resulting spate of treatment denials prompted numerous lawsuits against commercial plans,9,10  Medicaid plans,11 and correctional systems.12-14 In response to such a landscape and patient advocates’ concerns, CMS sent guidance in late 2015 to state Medicaid directors regarding the circumstances under which Medicaid law permits utilization management, clarifying that management strategies based on cost containment violate federal law.15 Although blanket treatment denials have hit Medicaid beneficiaries particularly hard, issues of cost sharing for commercial health insurance and Medicare beneficiaries are another important piece of this troubling puzzle. According to according to its Chief Development Operations Officer, Alan Richardson, from January through September 2015, of patients seeking treatment access assistance through the Patient Advocate Foundation’s Hepatitis C CareLine, 39% had commercial insurance and 25% were Medicare beneficiaries.

The latest innovations in HCV drug development fit neatly into the often cost-prohibitive benefit structures that health insurance plans have increasingly adopted. Commercial health insurers have numerous cost-sharing mechanisms at their disposal, including plan premiums, deductibles, co-payments, and coinsurance. Recent data show that insurers and, subsequently, employers, have steadily shifted the cost of healthcare to beneficiaries.16 Further, prescription drug plans have gradually instituted tiered formularies, initially beginning with just 2 tiers—1 for generics and 1 for brand-name medications—to the majority of plans now having 4 or 5 tiers, with the highest tier (ie, with the greatest cost sharing) reserved for so-called “specialty” or high-cost medications.17

Although the Affordable Care Act (ACA) implemented out-of-pocket (OOP) expense limits (not applicable to premiums) for nongrandfathered plans offered through the marketplace—up to $6850 for an individual and $13,700 for families in 201618—these up-front costs can be prohibitive for those with chronic conditions requiring high-cost medications, such as for HCV. Due to the fractured and complex nature of healthcare coverage in the United States, with myriad cost-sharing variations, there is significant variability across payers and plans. However, 2015 data from the Kaiser Family Foundation (eAppendix 1 [eAppendices available at www.ajmc.com]) show the significant burden of cost sharing.19 Fewer than half of all households described as nonelderly or nonpoor possess financial resources greater than mid-range OOP limits for their private insurance. This plummets to 18% when considering those at 100% to 250% of the federal poverty level.19 One can imagine a similar, if not grimmer, scenario among Medicare beneficiaries, approximately half of whom earned less than $23,500 in 2013. Many will find themselves additionally encumbered by premiums for supplemental coverage.20

Prescription drug formulary tiering is another mechanism by which patients encounter burdensome cost sharing. New DAAs for HCV are often classified as “specialty” drugs and placed on the highest cost-sharing tier. A 2015 Avalere Health study demonstrated that over a quarter of Silver-level marketplace plans placed HCV medications on specialty tiers.21 A similar picture emerged from a late 2015 examination of Florida’s Silver-level plans by The AIDS Institute, which also illustrated another trend—particularly among high/specialty drug tiers—toward cost sharing via coinsurance rather than co-payment.22

Christine Rodriguez, MPH, and Andrew Reynolds
Coinsurance—charging patients a percentage of a medication’s cost rather than a fixed co-payment—can result in significant costs to the patient, especially those with high deductibles and/or who require high-cost medication. In 2013, of employer-sponsored commercial prescription drug coverage plans with specialty tiers (23%), nearly half imposed coinsurance, with rates for specialty drugs averaging 30%, but reaching as high as 50%.23 Nearly 100% of both Part D plan and Medicare Advantage drug plan beneficiaries have plans with a specialty tier, with nearly half of Part D plans and 81% of Medicare Advantage plans charging the maximum allowable 33% coinsurance rate. The same report cited that costs for one of the DAA agents could exceed $5000 for a beneficiary in the first month alone. The Kaiser Family Foundation figure found in eAppendix 2 offers a snapshot of this troubling trend in Medicare Part D Drug Plans.24

Although cost-sharing strategies have a sensible place in healthcare financing, the placement of HCV curative therapies exclusively on specialty tiers and the trend toward coinsurance is highly problematic for patients, especially those of modest means, given the lack of generic alternatives. DAA treatments for HCV are the standard of care25; there is no other equally safe and effective, yet less expensive, option for patients to try first. This puts patients with HCV in the quandary of either paying the cost—potentially sacrificing other necessities or incurring debt—or giving up on curing their chronic, potentially fatal illness.26

Further, increased cost sharing negatively impacts treatment adherence. A 2012 literature review found that 85% of studies examined demonstrated that increases in cost sharing led to decreases in adherence.27 In the case of HCV, poor adherence can lead to preventable drug resistance. Adherence—and subsequent cure—is vital for patients with HCV due to the often-overlooked multi-systemic nature of the virus, as well as its associated comorbidities, many of which exacerbate the progression and/or manifestation of HCV. Several such conditions also require prescription medication, at additional cost, particularly those that are also chronic (eg, diabetes, HIV, depression). Moreover, cure as prevention, that is, curing those at potential risk of transmitting the virus thus preventing further transmission, is critical to a public health elimination strategy, as HCV is infectious and incidence is rising in certain populations.28

Solutions

In response to burdensome cost sharing for HCV patients, Project Inform and the NVHR are pursuing independent and collaborative strategies at the individual, state policy, and federal policy levels. At the micro level, Project Inform co-hosts (in collaboration with several other community-based organizations) HELP-4-HEP, a peer-managed, toll-free telephone helpline for those affected by HCV. Through HELP-4-HEP, patients can receive (among other information and resources) assistance locating co-pay and other financial assistance for treatment, assistance navigating appeals processes, and referrals to local support groups to help ease the emotional hardship of living with a chronic, life-threating virus, and the challenges that come with the related financial burdens.29

In California, Project Inform publishes an annual Covered California plan choice guide30 and a formulary analysis,31 addressing HIV, hepatitis B, and HCV medications. The plan choice guide provides information and resources for consumers to choose the most appropriate marketplace plan to meet their needs, while the formulary analysis helps consumers easily see what HCV drugs are on each plans’ formularies, find what tier the medications are on, and identify some of the utilization controls placed on the medications.

Project Inform, in collaboration with other health advocates, also participated in a Covered California Specialty Drug Task Force. Consequently, Covered California adopted changes to help consumers to better understand and manage their prescription drug costs. Among other changes in the 2016 plan year, all marketplace plans will now provide out-of-pocket cost estimates for specific drugs; and for tier-4 drugs, will charge no more than $250 per month for a single 30-day drug supply for Silver, Gold, and Platinum plans, and no more than $500 per 30-day supply for Bronze plans.32

Additionally, Project Inform and other partners worked to pass Assembly Bill (AB) 339, which limits cost sharing on specialty drugs, consistent with rules adopted by Covered California, but applied to private plans operating outside the exchange. In addition, AB 339 ensures coverage for drugs with no therapeutic equivalent across all plans, and the states that place most or all drugs to treat a condition on the highest cost formulary tiers may be considered discriminatory; additionally, plans shall not reduce the benefit for those with chronic conditions.33

These state-level policy changes not only improve Californians’ access to medications by limiting cost sharing, but also serve as useful examples for advocates in other states. To that end, NVHR provides open forums for partners like Project Inform to share this, and other strategies, with advocates around the country through webinars, monthly policy calls, and resource tools posted on the NVHR website.

At the federal level, NVHR continues to advocate, both independently and in coalition, with HHS on this issue, specifically for guidance and enforcement mechanisms as they relate to discriminatory benefit design under Section 1557 of the ACA, which addresses nondiscrimination protections for those with chronic conditions, among others.34 Regardless of the intentions behind the cost-sharing strategies outlined above, their effect is for patients with more costly, chronic conditions like HCV to self-select out of plans, and greatly reduces the plan options available. Plans designed in a way that actively dissuades patients from selecting them undermines both the intent and the spirit of the ACA. As such, it is critical that HHS provide explicit guidance, examples, oversight, and enforcement mechanisms to ensure equitable access to coverage and reasonable cost sharing for those living with chronic conditions.

Conclusions

For individuals living with HCV, the immense hope created by a cure has been stifled due to the current crisis in treatment access, and highly burdensome cost sharing in commercial health insurance and Medicare plans represent significant barriers. The potential effects on patients are immense physically, psychologically, and financially. Project Inform and NVHR are proud partners in addressing the issues presented by cost sharing across health insurance payers, and employ strategies at multiple levels of intervention to achieve the greatest impact and broadest support for our communities. From individual assistance and sharing best practices, to state- and federal-level policy advocacy, Project Inform and NVHR are dedicated to removing such obstacles to achieve universal treatment access for everyone living with HCV.
Author Affiliations: National Viral Hepatitis Roundtable (CR), Washington DC; Project Inform (AR), San Francisco, CA.

Source of Funding: None.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. The National Viral Hepatitis Roundtable receives funding from several hepatitis C pharmaceutical companies through corporate membership dues and grants.

Authorship Information: Concept and design (CR, AR); drafting of the manuscript (CR, AR); critical revision of the manuscript for important intellectual content (CR, AR); administrative, technical, or logistic support (CR).

Address correspondence to: Christine Rodriguez, MPH, National Viral Hepatitis Roundtable, 1424 K St NW, 2nd Fl, Washington, DC 20005. E-mail: crodriguez@nvhr.org.
 
REFERENCES

1. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012; 156(4):271-278. doi:10.7326/0003-4819-156-4-201202210-00004.

2. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010; 138(2):513-521. doi:10.1053/j.gastro.2009.09.067.

3. When and in whom to initiate HCV therapy. American Association for the Study of Liver Diseases website. http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy. Updated October 22, 2015. Accessed December 8, 2015

4. Marinho RT, Vitor S, Velosa J. Benefits of curing hepatitis C infection. J Gastrointestinal Liver Dis. 2014; 23(1):85-90.

5. Tice JA,  Ollendorf DA, Chahal HS, et al; Institute for Clinical and Economic Review. The comparative clinical effectiveness and value of novel combination therapies for the treatment of patients with genotype 1 chronic hepatitis C infection: a technology assessment [final report]. California Technology Assessment Forum website.  http://ctaf.org/sites/default/files/assessments/CTAF_HCV2_Final_Report_013015.pdf. Published January 30, 2015. Accessed December 8, 2015.

6. Rein DB, Wittenborn JS, Smith BD, Liffmann DK, Ward JW. The cost-effectiveness, health benefits, and financial costs of new antiviral treatments for hepatitis C virus. Clan Infect Dis. 2015; 61(2):157-168. doi:10.1093/cad/civ220.

7. Younossi ZM, Park H, Saab S, Ahmed A, Dieterich D, Gordon SC. Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection. Aliment Pharmacol Ther. 2015;41(6):544-563. doi:10.1111/apt.13081.

8. Younossi Z, Henry L. The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C. Dig Liver Dis. 2014;46(suppl 5):S186-S196. doi:10.1016/j.dld.2014.09.025.

9. Abram S. Woman sues Anthem Blue Cross for denying hepatitis C drug Harvoni. Los Angeles Daily News website. http://www.dailynews.com/health/20150601/woman-sues-anthem-blue-cross-for-denying-hepatitis-c-drug-harvoni. Published June. 1, 2015. Accessed December 14, 2015.

10. Kass D. Anthem sued again over Gilead hep C drug coverage. Law360 website. http://www.law360.com/articles/683462/anthem-sued-again-over-gilead-hep-c-drug-coverage. Published July 27, 2015, Accessed December 14, 2015.

11. Harper J. Indiana ACLU sues to demand Medicaid reimburse for hepatitis C drugs. WFYI Indianapolis website. https://www.wfyi.org/news/articles/indiana-aclu-sues-to-demand-medicaid-reimburse-for-hepatitis-c-drugs. Published December 8, 2015. Accessed December 14, 2015.

12. Snowbeck C. Minnesota prison inmates sue to gain access to costly hepatitis C medications. Star Tribune website. http://www.startribune.com/minnesota-prison-inmates-sue-to-gain-access-to-costly-hepatitis-c-medications/305114781/. Published May 26, 2015. Accessed December 14, 2015.

13. Loftus P. Prisoners sue Massachusetts for withholding hepatitis C drugs. Wall Street Journal website. http://blogs.wsj.com/pharmalot/2015/06/11/prisoners-sue-massachusetts-for-withholding-hepatitis-c-drugs/. Published June 11, 2015. Accessed December 14, 2015.

14. Collins SPK. Political prisoner sues for being denied hepatitis C treatment. ThinkProgress website. http://thinkprogress.org/health/2015/08/07/3688893/mumia-hep-c-treatment-denial/. Published August 7, 2015. Accessed December 14, 2015.

15. Mooney DeBoy A. Assuring Medicaid beneficiaries access to hepatitis C (HCV) drugs [Medicaid Drug Rebate Program notice No. 172]. Medicaid.gov website. https://www.medicaid.gov/Medicaid-CHIP-Program-Information/By-Topics/Benefits/Prescription-Drugs/Downloads/Rx-Releases/State-Releases/state-rel-172.pdf. Published November 5, 2015. Accessed December 14, 2015.

16. Spiro T, Calsyn M, O’Toole M. The great cost shift: why middle-class workers do not feel the health care spending slowdown. Center for American Progress website. https://www.americanprogress.org/issues/healthcare/report/2015/03/03/105777/the-great-cost-shift/. Published March 3, 2015. Accessed December 14, 2015.

17. McCarty S, Cusano D. Specialty tier pharmacy benefit designs in commercial insurance policies: issues and considerations [issue brief]. State Health Reform Assistance Network website. http://www.statenetwork.org/wp-content/uploads/2014/08/State-Network-Georgetown-Specialty-Tier-Pharmacy-Benefit-Designs-August-2014.pdf. Published August 2014. Accessed December 14, 2015.

18. Out-of-pocket maximum/limit. HealthCare.gov website. https://www.healthcare.gov/glossary/out-of-pocket-maximum-limit/. Accessed December 12, 2015.

19. Claxton G, Rae M, Panchal N. Consumer assets and patient cost sharing [issue brief]. Kaiser Family Foundation website. http://files.kff.org/attachment/issue-brief-consumer-assets-and-patient-cost-sharing. Published February 2015. Accessed December 14, 2015.

20. Cubanski J, Swoope C, Damico A, Neuman T. How much is enough? out-of-pocket spending among Medicare beneficiaries: a chartbook. Kaiser Family Foundation website. http://files.kff.org/attachment/how-much-is-enough-out-of-pocket-spending-among-medicare-beneficiaries-a-chartbook-report. Published July 2014. Accessed December 14, 2015.

21. Pearson CF. Avalere analysis: exchange benefit designs increasingly place all medications for some conditions on specialty drug tier. Avalere Health website. http://avalere.com/expertise/life-sciences/insights/avalere-analysis-exchange-benefit-designs-increasingly-place-all-medication/print. Published February 11, 2015. Accessed December 12, 2015.

22. Hepatitis B & C drugs difficult to access in Florida’s health plans. The AIDS Institute website. http://www.theaidsinstitute.org/sites/default/files/attachments/10-05-15%20TAI%20Release%20-%20FL%20QHPs%20(1).pdf. Published October 2015. Accessed December 12, 2015.

23. Buxbaum J, de Souza J, Fendrick AM. Using clinically nuanced cost sharing to enhance consumer access to specialty medications. Am J Manag Care. 2014;20(6):e242-e244.

24. Hoadley J, Summer L, Hargrave E, Cubanski J, Newman T. Medicare Part D in its ninth year: the 2014 marketplace and key trends, 2006-2014. Kaiser Family Foundation website. http://files.kff.org/attachment/medicare-part-d-in-its-ninth-year-the-2014-marketplace-and-key-trends-2006-2014-report. Published August 18, 2014. Accessed December 14, 2015.

25. Recommendations for testing, managing, and treating hepatitis C. American Association for the Study of Liver Diseases website. http://www.hcvguidelines.org/. Accessed December 12, 2015.

26. Gleason PP, Starner CI, Gunderson BW, Schafer JA, Sarran HS. Association of prescription abandonment with cost share for high-cost specialty pharmacy medications. J Manag Care Pharm. 2009;15(8):648-658.

27. Eaddy MT, Cook CL, O’Day K, Burch SP, Cantrell CR. How patient cost-sharing trends affect adherence and outcomes: a literature review. P T. 2012;37(1):45-55.

28. Suryaprasad AG, White JZ, Xu F, et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect Dis. 2014;59(10):1411-1419. doi:10.1093/cid/ciu643.

29. Help-4-Hep website [main page description]. http://www.help4hep.org/. Accessed December 15, 2015.

30. Project Inform, APLA Health & Wellness, San Francisco AIDS Foundation, Los Angeles LGBT Center, Access Support Network, San Francisco City Clinic. How to choose a health plan in Covered California. Project Inform website. http://www.projectinform.org/pdf/CCguide.pdf.
Published November 19, 2015. Accessed December 15, 2015.

31. Project Inform, APLA Health & Wellness, San Francisco AIDS Foundation, Los Angeles LGBT Center, Access Support Network, San Francisco City Clinic. Covered California’s 2016 formularies. Project Inform website. http://www.projectinform.org/pdf/CCformularies.pdf. Published December 2, 2015. Accessed December 15, 2015.

32. Prescription drugs. Covered California website. http://www.coveredca.com/individuals-and-families/getting-covered/prescription-drugs/. Accessed December 10, 2015

33. Assembly Bill No. 339. California Legislative Information website. http://www.leginfo.ca.gov/pub/15-16/bill/asm/ab_0301-0350/ab_339_bill_20150213_introduced.pdf. Published February 13, 2015. Accessed February 2016.

34. 42 USC: §18116. nondiscrimination. US Government Printing Office website. https://www.gpo.gov/fdsys/pkg/USCODE-2010-title42/html/USCODE-2010-title42-chap157-subchapVI-sec18116.htm. Published 2010. Accessed February 2016. 

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Friday, March 18, 2016

EMA to Review New Hepatitis C Drugs for Possible Hepatitis B Reactivation/Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax

EMA reviews direct-acting antivirals for hepatitis C Review to investigate possible hepatitis B re-activation

The European Medicines Agency (EMA) has started a review of medicines known as direct-acting antivirals used for treating chronic (long-term) hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus). 

Direct-acting antivirals (Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax) are important medicines for the treatment of chronic hepatitis C and can be used without interferons, which are less well tolerated. Until recently, interferons were part of treatment regimens for hepatitis C. Interferons are known to act against both hepatitis B and C viruses, which may be present at the same time in some patients.  

The review follows cases of hepatitis B re-activation in patients who have been infected with hepatitis B and C viruses, and who were treated with direct-acting antivirals for hepatitis C. Hepatitis B reactivation refers to a return of active infection in a patient whose hepatitis B infection had been inactive. 

EMA will now assess the extent of hepatitis B re-activation in patients treated with direct-acting antivirals for hepatitis C and evaluate whether any measures are needed to optimise the treatment.
While the review is ongoing, patients should speak to their doctor or pharmacist if they have any questions or concerns. 

More about the medicines
The following direct-acting antivirals have been approved in the EU for treating chronic hepatitis C: Daklinza (daclatasvir), Exviera (dasabuvir), Harvoni (sofosbuvir / ledipasvir), Olysio (simeprevir), Sovaldi (sofosbuvir) and Viekirax (ombitasvir / paritaprevir / ritonavir). They work by blocking the action of proteins in the hepatitis C virus which are essential for it to make new viruses.
More information on these medicines can be found on EMA’s website: ema.europa.eu/Find medicine/Human medicines/European public assessment reports. 

Download the statement..

More about the procedure
The review of direct-acting antivirals for the treatment of hepatitis C has been initiated at the request of the European Commission, under Article 20 of Regulation (EC) No 726/2004. 
The review is being carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations. 

The PRAC recommendations will then be forwarded to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt a final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all EU Member States.




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Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

Corresponding authors: Raoel Maan , Adriaan J. van der Meer
How to cite: Maan R and van der Meer AJ. Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease [version 1; referees: 3 approved]. F1000Research 2016, 5(F1000 Faculty Rev):367 (doi: 10.12688/f1000research.7399.1)

Copyright: © 2016 Maan R and van der Meer AJ. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests:
Raoel Maan received financial compensation for consultancy from AbbVie. Adriaan J. van der Meer received financial compensation for lecture activities for MSD and Gilead.

First published: 17 Mar 2016, 5(F1000 Faculty Rev):367 (doi: 10.12688/f1000research.7399.1) Latest published: 17 Mar 2016, 5(F1000 Faculty Rev):367 (doi: 10.12688/f1000research.7399.1)

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Abstract
Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population

Natural history
Chronic hepatitis C virus (HCV) infection continues to be a major global public health problem, with recent estimates suggesting that 64–103 million people are infected worldwide1. Chronic infection leads to slowly progressive hepatic fibrosis, which may eventually lead to cirrhosis2,3. Once cirrhosis is established, patients have an increased risk of developing complications such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding, and hepatocellular carcinoma (HCC). Although the incidence of HCV infection is declining in the West, it has been estimated that the incidence of patients with HCV-induced cirrhosis will not peak until 20304. At the moment, chronic HCV infection is already the leading indication for liver transplantation in many Western countries5. Not to be forgotten, however, is that the natural history of chronic HCV infection extends beyond the liver as well. Before the stage of cirrhosis, there may already be extrahepatic manifestations that impair the patient’s health-related quality of life (HRQoL), of which fatigue is most frequently reported (approximately 50% of patients)6–8. In terms of solid clinical endpoints, patients are at increased risk of diabetes mellitus, renal failure, cardiovascular events, and malignant lymphoma9. The impaired overall survival among those with chronic HCV infection is thus the result of an increase in both liver-related as well as non-liver-related deaths, as was recently highlighted in an unique natural history study from Taiwan which included 19,636 participants who were followed for a mean duration of 16.2 years10.
Antiviral therapy
Before 2011, treatment for chronic HCV infection depended on the administration of pegylated interferon alpha (PegIFN) and ribavirin (RBV), which was accompanied by the occurrence of many side effects such as flu-like symptoms, depression, and cytopenias. These side effects were bothersome, especially because the IFN-based regimens had a limited chance of attaining a sustained virological response (SVR [HCV RNA negativity in the circulation 12–24 weeks after cessation of antiviral therapy]). If physicians were not already reluctant to treat out of fear for severe adverse events in the specific population of patients with advanced liver disease, PegIFN and RBV were often unsuccessful. In patients with compensated cirrhosis, SVR rates ranged from 10 to 44% for HCV genotypes 1 and 4 and 33 to 72% for HCV genotypes 2 and 3. When patients were known to have decompensated cirrhosis, SVR rates even dropped to 0–16% for HCV genotypes 1 and 4 and 44–57% for HCV genotypes 2 and 311. However, because of safety issues, IFN therapy, in case of unstable liver disease, was mostly restricted to specialized centers. As a result, many patients were unable to attain an SVR, which is considered to be the marker for viral clearance based on its long-term durability12.
The successful development of protease inhibitors for the treatment of the human immunodeficiency virus initiated the development of the first direct-acting antivirals (DAAs) for the treatment of HCV infection. In 2011, the protease inhibitors telaprevir and boceprevir were the first DAAs to be introduced. When added to PegIFN and RBV, the duration of therapy could be halved to 24–28 weeks in about 50% of patients, while SVR rates improved substantially in both treatment-naïve and treatment-experienced patients with HCV genotype 113–17. Unfortunately, among those with cirrhosis, the treatment duration could not be easily reduced and the improvement in the rate of SVR was only limited with an increase to approximately 50%. The downsides include the following: these first two DAAs were not very effective against HCV genotypes other than genotype 1; treatment became more complex with various dosing schedules, durations, and stopping rules; the pill burden was large; the rates of resistance-associated variants (RAVs) were high; and there were many potential drug-drug interactions. Moreover, the first real-world data raised important safety issues, especially among patients with compensated cirrhosis, and PegIFN remained a necessity18. The development of antiviral therapy has moved at an incredible pace during the 3 years following the first proof-of-concept that chronic HCV infection could be eradicated without PegIFN19. At the moment, IFN-free regimens, in which multiple classes of DAAs are combined, revolutionize the treatment of chronic HCV infection. Short and well-tolerated regimens have reported SVR rates of around 95%, even among patients with cirrhosis20–24. Unfortunately, the high costs of the DAAs currently make these drugs unavailable for the majority of patients worldwide. Also, in wealthy countries it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget, even though modeling data indicated that the IFN-free regimens are cost effective in the long term. As a consequence, physicians are often limited to treat only those patients with advanced liver disease, the specific population on which we will focus in the current review.
Life cycle of the hepatitis C virus
Hepatitis C virus is a small enveloped virus of approximately 55–65 nanometers in size and is a member of the genus Hepacivirus, belonging to the Flaviviridae family. It contains a single-stranded RNA genome of positive polarity. This genome is approximately 9600 nucleotides in length and consists of a highly conserved 59 untranslated region, followed by a single open reading frame that encodes a polyprotein of 3010 to 3033 amino acids. Cellular and viral proteases cleave this large protein into ten smaller viral gene products: three structural proteins (core, E1, and E2); an ion channel (p7); and six nonstructural proteins (NS2, NS3A, NS4A, NS4B, NS5A, and NS5B) (Figure 1). Structural proteins are required for assembly and are used for the determination of the seven main HCV genotypes (and subgenotypes)5. The p7 and NS2 protease are required for the release of infectious particles. The other nonstructural proteins (NS3A, NS4A, NS4B, NS5A, and NS5B) are closely involved in HCV replication25. NS3 and its cofactor NS4A form a stable heterodimeric complex, which cleaves the HCV polyprotein at four sites. NS4B is the presumed central organizer of the HCV replicase complex and a main inducer of intracellular membrane rearrangements. The NS5A protein is essential for RNA replication and assembly of infectious virus particles. The RNA-dependent NS5B protein is the RNA polymerase catalyzing the amplification of the viral RNA genome25,26. Figure 2 shows the entry of HCV into the hepatocytes, as well as its life cycle and replication process26. In addition, several host factors have been involved in the HCV life cycle, which may represent new targets for antiviral treatment. These include epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2), which are two receptor tyrosine kinases that have recently been identified as HCV entry factors27. Another host factor, microRNA-122 (miR-122), is a hepatocyte-abundant microRNA which binds to the 5’ untranslated region of the HCV genome. Hereby, it is thought to promote HCV RNA stability and accumulation and to protect the HCV genome from the innate immune response28. Cyclophilin A (CypA) is a protein that is involved in the replication of HCV by binding to the NS5A protein of all HCV genotypes29. Lastly, apolipoprotein E (apoE) is a component of lipoviral particles, which is involved in the HCV infection of hepatocytes30.


Figure 1. The hepatitis C virus (HCV) genome.
The hepatitis C virus (HCV) genome encoding three structural proteins and seven non-structural proteins. The direct-acting antivirals are listed below the proteins and include the NS3/4A (or protease) inhibitors, the NS5A inhibitors, and the NS5B polymerase inhibitors (both nucleosides and non-nucleosides). The direct-acting antivirals approved by the US Food and Drug Administration and the European Medicines Agency are highlighted in bold.

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39ab5450-541f-4ec1-869a-519a6dd589fd_figure2.gif
Figure 2. Life cycle of the hepatitis C virus.
Adapted from Feeney et al.26. Schematic overview of the life cycle of the hepatitis C virus (HCV). In order to enter the hepatocyte, HCV interacts with co-receptors, resulting in its endocytosis. Then the virus fuses with the endosome and uncoats its RNA. Host ribosomes translate the RNA into a polyprotein, which is cleaved by host and virally encoded proteases into the three structural and seven non-structural proteins. The non-structural proteins form a complex on a “membranous web” that replicates HCV RNA. The Golgi assembles the HCV RNA with viral structural proteins, leading to the formation of infectious viral particles, which are exocytosed from the cell. © 2015 BMJ Publishing Group Ltd. All rights reserved.
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Mechanism of action of antiviral drugs
Although still not fully elucidated, IFN is thought to induce a large number of genes (called IFN-stimulated genes) with antiviral properties, leading to a multi-faceted attack on the virus. In addition, it also has some direct antiviral actions as well as important interactions with the adaptive and innate immune responses31. RBV is a guanosine analogue with activity against several RNA and DNA viruses. Different hypotheses regarding its mechanism of action have been proposed, of which the theory of lethal mutagenesis seems most reasonable31. Protease inhibitors target the NS3/4A serine protease and thereby inhibit the cleavage of this protein and thus HCV replication26. Current approved “-previrs” include telaprevir, boceprevir, simeprevir, and paritaprevir (Figure 1). The NS5A inhibitors, also known as “-asvirs”, target another nonstructural protein and block the replication of HCV RNA at the stage of membranous web biogenesis32. So far, daclatasvir, ledipasvir, and ombitasvir have been approved (Figure 1). Both NS3/4A protease inhibitors and NS5A inhibitors have very potent antiviral activity but exhibit a low barrier to viral resistance. The NS5B inhibitors, or “-buvirs”, can be divided into two main classes: nucleos(t)ide inhibitors and non-nucleotide inhibitors (Figure 1). By binding to the active site of the NS5B RNA-dependent RNA polymerase, nucleos(t)ide inhibitors (e.g., sofosbuvir) cause premature chain termination. The non-nucleotide inhibitors (e.g., dasabuvir) bind outside the active site, causing a conformational change, and thereby decrease the polymerase activity of the enzyme26.
Current treatment regimens

There are extensive data from phase III or IV studies on the efficacy of IFN-free regimens, but patients with compensated and decompensated cirrhosis were often underrepresented. Currently, more data are emerging from real-world studies on the efficacy of these regimens, which included patients with the most severe cirrhosis. Table 1–Table 4 show the data from phase III or IV studies available on the efficacy of IFN-free antiviral therapy. Below, we will discuss the treatment regimensin a more conceptual way for the treatment of patients with compensated cirrhosis.

Table 1. Rates of SVR for patients with compensated cirrhosis HCV genotype 1 (phase III/IV studies).

a. Abbreviations: ASV, asunaprevir; BCV; beclabuvir; DCV, daclatasvir; DSV, dasabuvir; ELB, elbasvir; GPV, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OMB, ombitasvir; PAR/r, paritaprevir/ritonavir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced; VPV, velpatasvir


RegimenDurationPatientsSVR rateStudy (reference)
LDV – SOF ± RBV12–24 weeksNaïve97–100%ION-121
LDV – SOF ± RBV12–24 weeksTE82–100%ION-220
LDV – SOF
LDV – SOF - RBV		24 weeks
12 weeks		TE
TE		97%
96%		SIRIUS84
SIM – SOF12 weeksNaïve
TE		88%
79%		OPTIMIST-222
SIM – SOF ± RBV12 weeksNaïve
TE		75%
73–88%		Trio Network85
SIM – SOF ± RBV12 weeksNaïve
TE		87–93%
80–82%		HCV-Target86
OMB – PAR/r – DSV + RBV12–24 weeksNaïve
TE		94–95%
90–97%		TURQUOSE-II23
OMB – PAR/r – DSV12 weeksTE100%TURQUOSE-III24
GPV – ELB12 weeksNaïve97%C-EDGE87
SIM – SOF12 weeksNaïve
TE		95%
92%		Pearlman et al.88
SIM – SOF12 weeksNaïve
TE		83%Aqel et al.89
SIM – SOF ± RBV12 weeksNaïve
TE		91–94%
88–95%		Saxena et al.46
SIM – SOF12 weeksNaïve and TE87%Shiffman et al.90
DCV – ASV – BCV ± RBV12 weeksNaïve and TE87–98%Unity-291
VPV – SOF12 weeksNaïve and TE99%ASTRAL-145


Table 2. Rates of SVR for patients with compensated cirrhosis HCV genotype 2–4 (phase III/IV studies).

a. Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced; VPV, velpatasvir

HCV GenotypeRegimenDurationPatientsSVR rateStudy (reference)
HCV genotype 3DCV – SOF12 weeksNaïve and TE58–97%ALLY-343
HCV genotype 2
HCV genotype 3		SOF + RBV12 weeks
12 weeks		Naïve91%
34%		FISSION40
HCV genotype 2
HCV genotype 3		SOF + RBV12 weeks
12 weeks		Naïve94%
21%		POSITRON39
HCV genotype 3
HCV genotype 2
HCV genotype 3		SOF + RBV24 weeks
12 weeks
24 weeks		Naïve
TE
TE		92%
78%
62%		VALENCE92
HCV genotype 2

HCV genotype 3

HCV genotype 3		SOF + RBV



16 weeks
24 weeks
16 weeks
24 weeks
16 weeks
24 weeks		TE

Naïve

TE		87%
100%
57%
82%
47%
76%		BOSON STUDY44



HCV genotype 2SOF + RBV12 weeksNaïve
TE		67%
76%		Trio Network85
HCV genotype 2

HCV genotype 3		SOF + RBV

SOF + RBV		12 weeks
16 weeks
12 weeks
16 weeks		TE

TE		60%
78%
19%
61%		FUSION39

HCV genotype non-1SOF – VPV12 weeksNaïve and TE100%ASTRAL-145
HCV genotype 2SOF – VPV12 weeksNaïve and TE100%ASTRAL-293
HCV genotype 3SOF – VPV12 weeksNaïve and TE91%ASTRAL-393
HCV genotype 3DCV – SOF + RBV12 weeks
16 weeks		Naïve and TE83%
89%		ALLY-3+94

Table 3. Rates of SVR for patients with decompensated cirrhosis HCV genotype 1 (phase III/IV studies).

a. Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced; VPV, velpatasvir

b. *Also included patients with HCV genotype 2, 3, and 4

c. #Fewer than 10 patients were included in a specific subgroup



RegimenDurationPatientsSVR rateStudy (reference)
LDV – SOF ± RBV12 – 24 weeksNaïve and TE86–89%SOLAR-182
LDV – SOF ± RBV12 – 24 weeksNaïve and TE84–92%SOLAR-295
SOF + RBV
SIM – SOF
SIM – SOF + RBV		12 weeks
12 weeks
12 weeks		Naïve and TE
Naïve and TE
Naïve and TE		52%
74%
66%		HCV-Target96
DCV – SOF + RBV12 weeksNaïve and TE56–94%*ALLY-197
LDV – SOF
LDV – SOF + RBV
DCV – SOF
DCV – SOF + RBV		12 weeks
12 weeks
12 weeks
12 weeks		Naïve and TE
Naïve and TE
Naïve and TE
Naïve and TE		81%
86%
60%#
82%		UK cohort EAP81

SIM – SOF ± RBV12 weeksNaïve and TE69–79%Saxena et al.46
SIM – SOF ± RBV12 weeksNaïve and TE68%Aqel et al.89
SIM – SOF12 weeksNaïve and TE67–77%Shiffman et al.90
SIM – SOF
SIM – SOF + RBV		12 weeks
12 weeks		Naïve and TE
Naïve and TE		52–65%
44–65%#		Backus et al.98
SOF – VPV
SOF – VPV + RBV
SOF – VPV		12 weeks
12 weeks
24 weeks		Naïve and TE88%
96%
92%		ASTRAL-499


Table 4. Rates of SVR for patients with decompensated cirrhosis HCV genotype non-1 (phase III/IV studies).
a. Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; TE, treatment-experienced

b. *Also included patients with HCV genotype 2, 3, and 4

c. #Fewer than 10 patients were included in a specific subgroup

HCV genotypeRegimenDurationPatientsSVR rateStudy (reference)
HCV genotype 4LDV – SOF ± RBV12 – 24 weeksNaïve and TE57–86%SOLAR-295
HCV genotype 2
HCV genotype 3		SOF + RBV12 weeksNaïve and TE81%
39%		HCV-Target96
HCV genotype 2
HCV genotype 3
HCV genotype 4		DCV – SOF + RBV12 weeksNaïve and TE80%#
83%#
100%#		ALLY-197
HCV genotype 3
Other HCV genotypes
than 1 and 3		LDV – SOF ± RBV
DCV – SOF ± RBV
LDV – SOF + RBV
DCV – SOF ± RBV		All 12 weeks

Naïve and TE

43–59%#
70–71%#
89%
85–100%#		UK cohort EAP81

HCV genotype 2SOF + RBV12 weeksNaïve and TE44–71%#Backus et al.98
HCV genotype non-1SOF – VPV
SOF – VPV + RBV
SOF – VPV		12 weeks
12 weeks
24 weeks		Naïve and TE50–100%#
85–100%#
50–100%#		ASTRAL-499

HCV genotype 1
In the Western world, HCV genotype 1 is the most prevalent (>50%). The initial development of DAAs was therefore mainly focused on this genotype. Although IFN-free therapy is preferred, the combination of a second-generation NS3/4A protease inhibitor, a NS5A inhibitor, or a NS5B inhibitor with PegIFN and RBV for 12–48 weeks has been assessed33–36. Although not approved, even the addition of a NS3/4A protease inhibitor and a NS5A inhibitor to PegIFN and RBV for 24 weeks could have been an option for the treatment of chronic HCV genotype 1 infection37. For patients who are unable to tolerate PegIFN, the combination of a NS5B inhibitor and RBV was assessed, but phase III studies were never performed due to the lack of efficacy. When focusing on the regimens that did reach SVR rates of more than 90%, the optimal regimen consists of at least two classes of DAAs, with or without the addition of RBV. The combination of a NS5B inhibitor with a NS5A inhibitor and/or a NS3/4A protease inhibitor is enough to create a high barrier to resistance20–22. In cirrhotic patients, some regimens show lack of efficacy, which could be improved by the addition of RBV and/or the extension of antiviral therapy to 24 weeks. As the development of novel DAAs is still ongoing, recent data have shown that second-generation regimens, including a NS5A inhibitor and a NS3/4A protease inhibitor, may be equally effective for this genotype38. Thus, inclusion of a NS5B inhibitor may not be a necessity.
Since there is a difference in efficacy among patients with HCV genotype 1a and 1b, different regimens were applied among these patients23,24. RAVs that are present at baseline or emerge during antiviral therapy may account for this difference between the two subtypes. Therefore, before initiating most regimens, subtyping of the HCV genotype 1 is required. However, lower response rates in patients with HCV genotype 1a seem to be a problem only when a NS3/4A protease inhibitor is incorporated into the treatment regimen20,21,23. At the price of additional side effects, this effect may be partly overcome by adding RBV to the treatment regimen.
HCV genotype 2
Historically, patients with HCV genotype 2 were the easiest to treat, even when patients had cirrhosis. Currently, an IFN-free combination including a NS5B inhibitor and RBV seems sufficient to clear the virus39–41. When patients are intolerant to RBV, a regimen with a NS5B inhibitor and a NS5A inhibitor could be an attractive option, as both have antiviral activity against this genotype. This combination, however, has not been extensively investigated in clinical trials42.
HCV genotype 3
Patients with HCV genotypes 2 and 3 were found to be relatively IFN sensitive and required a shorter duration of therapy with lower doses of RBV to achieve higher rates of SVR as compared to patients with HCV genotypes 1 and 4. Even with PegIFN and RBV, however, HCV genotype 3 was more difficult to cure than genotype 2, particularly in patients with established cirrhosis. In the current IFN-free era, HCV genotype 3 has actually replaced HCV genotype 1 as the most challenging genotype. In contrast to its effect in non-cirrhotic patients with HCV genotype 3, the combination of a NS5B inhibitor and RBV in cirrhotic patients is suboptimal and has a high virological relapse rate39–41. The addition of a NS5A inhibitor to this regimen could improve response rates, but the incremental efficacy of a 12-week regimen remains limited43. Although the duration has not been investigated within clinical trials, current guidelines recommend a 24-week regimen including a NS5B inhibitor and a NS5A inhibitor with or without RBV. So far, none of the currently approved DAAs have optimal antiviral activity against HCV genotype 3, so the “re-introduction” of PegIFN for this genotype needs to be considered among those who are able to tolerate its side effects44. Recently, a pan-genotypic regimen for 12 weeks, including a NS5B and NS5A inhibitor, seemed highly effective for HCV genotype 3, even among treatment-experienced patients with cirrhosis45.
HCV genotype 4
When PegIFN-based treatment was considered, patients with HCV genotype 4 used to be grouped with patients infected with HCV genotype 1. With the DAAs, these patients respond to the same regimens as well, and possibly even better. Although data in cirrhotic patients are scarce, due to the low prevalence of this genotype in most Western countries, the combination of a NS5B inhibitor and RBV is a plausible option. A regimen including two DAAs from separate classes (a NS5B inhibitor, a NS5A inhibitor, or a second-generation NS3/4A protease inhibitor) could also be used to eradicate chronic HCV genotype 4. When physicians want to reduce the chance of virological relapse, RBV could be added to the regimen, provided that patients are able to tolerate this.
Decompensated cirrhosis
In general, patients with decompensated cirrhosis (Child-Pugh B/C) have lower response rates than patients with compensated cirrhosis (Child-Pugh A)46. Reasons for these lower response rates may include reduced drug delivery due to shunting leading to HCV reservoirs, altered drug metabolism and uptake due to impaired liver synthetic function, or impaired immune responses which are present in cirrhotic patients47.

Obviously, among patients with decompensated cirrhosis, the IFN-free regimens are far better tolerated as compared to the PegIFN and RBV combination therapy, which has been the standard of care for the last 15 years. However, as more real-world data are emerging, safety issues regarding the use of DAAs among those patients with the most advanced liver disease have arisen. Two patients with hepatic decompensation developed severe drug-induced liver injury leading to death and liver transplantation. Both patients were treated with sofosbuvir, a NS5A inhibitor, and RBV48. A recent study by Welker et al. described the occurrence of lactate acidosis among patients treated with sofosbuvir-based regimens, with or without the addition of RBV49. Whether the clinical deterioration could be attributed to the use of DAAs or RBV or whether this is merely in line with the poor natural history of patients with decompensated cirrhosis remains a matter of debate. Likewise, the occurrence of hepatic decompensation during antiviral treatment has been reported for several treatment regimens, leading the FDA to discourage the use of dasabuvir, ombitasvir, and paritaprevir/ritonavir for patients with decompensated liver disease50. Also, because of the real-world safety issues which were encountered with the first-generation protease inhibitors telaprevir and boceprevir among patients with cirrhosis and low platelets or low albumin levels, one could argue that protease inhibitors may not represent an ideal class of DAAs for those with the most severe cirrhosis18. Simeprevir, a first-generation second-wave protease inhibitor, has actually never been registered for patients with decompensated cirrhosis. It is clear that further studies with a focus on the safety profile of the IFN-free regimens among patients with decompensated liver disease are urgently needed. It would be highly relevant to be able to predict which of these patients can and cannot be safely treated with the IFN-free regimens.
Resistance-associated variants
The high efficacy of IFN-free regimens will lead to high rates of SVR, even among the population that was difficult to treat and/or difficult to cure in the era of IFN-based therapy. However, as pointed out earlier, lower response rates were observed among patients with advanced liver disease. The emergence of RAVs seems a relevant factor in case antiviral therapy is not successful. Although heterogeneous methods were used to detect RAVs, it has been estimated that 53–91% of patients with virological relapse harbor HCV isolates that are resistant to one, two, or three DAAs51. The presence of RAVs before IFN-free treatment initiation could be an important cause of virological failure as well, and fuels the ongoing debate of whether we should perform pretreatment viral sequencing. Relevant in this respect is that the second-generation DAAs, which are coming shortly, are thought to have a higher genetic barrier to resistance. Another option to overcome the RAVs are the advanced cellular drugs that target the host factors involved in the HCV life cycle, which have the general advantage of being pan-genotypic. Silencing of miR-122 in vitro showed remarkable inhibition of HCV replication and led to the possibility of targeting miR-122 as an antiviral strategy28,52. Other possible options include the HCV entry inhibitors erlotinib and dasatinib, or the cyclophilin inhibitor alisporivir27,53. In combination with DAAs, the drugs targeting host factors could be effective, especially for those patients with resistant viral strains. Still, in order to globally eradicate HCV, an effective vaccine seems necessary54.
Clinical relevance of successful antiviral therapy
In parallel with the impressive development of highly potent and well-tolerated DAAs, various cohort studies increased our understanding of the clinical relevance of these new drugs. Over the last couple of years, many researchers have published results that indicate that patients who attain SVR have a beneficial clinical outcome in terms of both liver-related and liver-unrelated endpoints. The growing body of evidence in favor of SVR is, obviously, relevant for patients and physicians. However, it is also very much needed for policy-makers who need to decide on the reimbursement of the highly effective but costly IFN-free regimens.
Liver histology
In contrast to what was believed during the largest part of the last century, it is now widely accepted that hepatic fibrosis can regress in cases where the underlying cause of liver damage is adequately treated. Chronic HCV infection is probably the liver disease in which this is best documented. The largest histological study in which patients underwent a second liver biopsy 24 weeks after cessation of antiviral therapy indicated that, on average, the degree of hepatic fibrosis regressed among those with SVR and was rather stable among those without SVR55. The most impressive result of this study, however, was that 75 of the 153 patients with cirrhosis before therapy no longer scored a METAVIR F4 in their post-treatment liver biopsy. Yet, from a previous study from Japan, we already learned that regression of hepatic fibrosis is likely to take more time56. Shiratori et al. included 593 patients in whom the time to the post-treatment liver biopsy ranged from 1 to 10 years. Among those with SVR, the authors found that regression of fibrosis was more pronounced in cases where the biopsy was repeated after more than 3 years of follow-up. Still, even in cases with much longer follow-up, histological studies have been unable to show that all HCV-infected patients with cirrhosis who attained SVR improve their METAVIR F4 score. The concept of a point of no return with respect to the extent of liver damage seems plausible, especially because the vascular abnormalities within a cirrhotic liver have never been shown to improve, and shunting of blood through vascularized portacaval septa can lead to hypoperfusion of liver parenchyma, with hypoxemia as a contributing factor for hepatic inflammation and fibrosis57–59. On the other hand, the semi-quantitative fibrosis scores may also be somewhat too crude to appreciate all histological improvements following the eradication of HCV infection. Indeed, a recent study assessed the change in the total area of fibrosis among 38 Italian patients with cirrhosis who attained SVR60. Among the minority (39%), in whom the METAVIR F4 score was not reduced after a median duration of 5.6 years in between both liver biopsies, the total area of hepatic fibrosis was still significantly reduced. While the discussion on whether cirrhosis is reversible is ongoing, it may actually be more relevant to consider the relationship between HCV eradication and the clinical sequelae of cirrhosis61.
Liver-related morbidity and mortality
Most of the Western studies that assessed the association between HCV eradication and hepatic decompensation or HCC have solely included patients with advanced liver disease, who are most at risk for these cirrhosis-related complications. However, as we have long depended on IFN-based treatment regimens, these studies predominantly included cirrhotic patients with relatively favorable characteristics. Veldt et al. were one of the first groups to show that the incidence in liver failure was markedly reduced among patients with chronic HCV infection and advanced liver fibrosis who attained SVR62. Interestingly, this beneficial outcome was apparent immediately upon HCV clearance. Hereafter, larger studies with longer follow-up duration not only confirmed these results but also showed a significant association between SVR and a reduced occurrence of HCC, with strong hazard ratios (HRs) adjusted for many potential confounders63–65. In a recent meta-analysis, in which the results of all available cohort studies among patients with advanced liver disease were pooled, the results indicated that within this population the HR of SVR for the occurrence of HCC was 0.23 (95% confidence interval [CI] 0.16–0.35)66. Combining studies that included patients with all stages of fibrosis resulted in a pooled HR of 0.24 (95% CI 0.18–0.31) regarding SVR and HCC occurrence, although these studies were mostly performed in Japan, where the incidence of HCC is substantially higher. Considering the potential benefits of SVR on these cirrhosis-related morbidities, it is not surprising that patients with cirrhosis who clear their chronic HCV infection have a reduced liver-related mortality65,67. Still, it is noteworthy that patients with advanced liver disease are not free from cirrhosis-related complications following HCV eradication. A combined cohort including 1000 patients with advanced liver fibrosis and IFN-induced SVR showed that the annual risk of HCC remains at about 1% following HCV eradication in patients with cirrhosis68. The risk of HCC depends on age, the presence of diabetes mellitus, and laboratory markers of liver disease severity. One may thus expect a rising incidence of HCC following successful antiviral therapy in the era of DAAs, which will enable older patients with more advanced liver disease to attain SVR.
Extrahepatic consequences
While a large number of studies indicated potential liver-related benefits of SVR, more recent efforts have focused on the association between antiviral therapy and extrahepatic disease. With respect to patient-reported outcomes, eradication of HCV infection decreases both the frequency and the severity of fatigue8. This may be an important reason for the improved HRQoL which has been observed upon SVR69. Although difficult to quantify in daily practice, these effects are probably more directly noticeable for patients and their health-care providers than the prevention of future clinical complications.

Even a few years ago, it was reported that the risk of diabetes mellitus is about three times lower among patients with SVR as compared to patients without SVR70. The deteriorating consequences of diabetes mellitus are diverse but surely include renal failure and cardiovascular events. A reduced incidence of both of these solid endpoints in cases of antiviral therapy use was recently shown in a nationwide cohort study from Taiwan, in which 12,384 treated patients and 24,768 propensity score-matched untreated controls were included. The cumulative 8-year incidences of end-stage renal disease (0.15% vs. 1.32%), acute coronary syndrome (2.21% vs. 2.96%), and ischemic stroke (1.31% vs. 1.76%) were significantly lower among treated as compared to untreated patients (p<0.05 for all), and the effect of antiviral therapy remained statistically significant in multivariate analysis71. These findings were immediately confirmed, and assigned to SVR, in a large population-based study which is expected to include about 80% of all IFN-treated chronic HCV-infected patients in Scotland72. Apart from diabetes mellitus, we were recently presented with another possible explanation for these findings, as Gragnani et al. showed that HCV eradication led to the disappearance of cryoglobulinemia and resolved manifestations of the mixed cryoglobulinemia syndrome in nearly all patients73. Other potential extrahepatic benefits of SVR that have been presented within recent years include a reduced occurrence of malignant lymphomas and reduced hospitalization because of acute alcohol intoxication or violence-related injuries72,74. Through these effects on extrahepatic morbidity, patients with SVR have not only a reduced liver-related mortality but also a reduced liver-unrelated mortality72,75.
All-cause mortality
The most important new insights with regard to the clinical benefit of antiviral therapy probably concern the association between SVR and a prolonged overall survival as the most definitive clinical endpoint. In 2011, Backus et al. were the first to show that SVR was statistically significantly associated with a reduced all-cause mortality (HR 0.70, 0.64, and 0.51 for HCV genotype 1, 2, and 3, respectively) in a large cohort of 16,864 patients with chronic HCV infection who were followed for a median duration of 3.8 years76. However, these results were derived from the specific patient population of American veterans, among which there is substantial comorbidity, risk behavior, and a rather high mortality rate. Another report extended this finding to the general HCV-infected patient population with advanced liver disease67. Among the 530 patients with chronic HCV infection and advanced liver fibrosis who were followed for a median of 8.4 years, the cumulative 10-year overall survival was 91% among those with SVR, versus 74% among those without SVR (HR 0.26, 95% CI 0.14–1.49). In contrast to those who were unsuccessfully treated, patients with SVR had a survival rate that was comparable to that of the age- and sex-matched general population77. Importantly, in both reports, the HR of SVR for all-cause mortality was extensively adjusted for baseline characteristics known to influence both the chance of successful IFN therapy and the long-term clinical outcome. Various representable cohorts have confirmed the strong association between SVR and reduced all-cause mortality hereafter72,78. The pooled HR of SVR was 0.50 (95% CI 0.37–0.76) based on all studies which did not specifically include patients with advanced fibrosis and 0.26 (95% CI 0.18–0.37) when only studies among those with advanced liver disease were considered79.
Decompensated cirrhosis
The above-described studies, which suggest a clinical benefit of SVR, were performed among patients treated with IFN-based regimens, so that even those included with cirrhosis had relatively favorable baseline characteristics. Indeed, in the IFN era, patients with decompensated cirrhosis were frequently withheld from antiviral therapy but were also unlikely to attain SVR if treatment was initiated. Consequently, the clinical relevance of attaining SVR is largely unknown apart from the fact that achievement of SVR would be desirable to prevent HCV recurrence in cases of liver transplantation. Because of the beneficial safety profile of the DAAs, our experience with antiviral therapy in patients with chronic HCV infection and decompensated cirrhosis is increasing rapidly. Still, because these therapeutic options have just surfaced, studies with sufficient follow-up to assess the true clinical impact of IFN-free therapy among the patients with the most advanced liver disease have to be awaited. In the meantime, several interesting observations in the short term have been presented, which focus on the Model for End-Stage Liver Disease (MELD) score. Deterding et al. treated 34 HCV-infected patients with Child-Pugh B/C with various IFN-free regimens. At 12 weeks post-treatment, the MELD score improved in 68%, remained stable in 23%, and worsened in 10% of patients80. Based on the first experiences in England, Foster et al. reported the change in MELD score 4 weeks after the cessation of DAA therapy81. Of the 220 patients, 105 (47.7%) had no significant change in MELD score; in 92 (41.8%) patients, MELD score improved by ≥2 points; and in 23 (10.5%) patients, MELD score worsened by ≥2 points. Additional analyses indicated that the MELD score more frequently improved rather than declined among younger patients (<65 years) and patients with a high albumin level (>35 g/L). Still, MELD improvements are mostly moderate, so the important question of whether liver transplantation can really be averted remains. If not, the slight improvement in MELD score may actually negatively impact the patient’s chances on the waiting list. Because clinical trials showed excellent SVR rates with IFN-free therapy among liver transplant recipients with chronic HCV infection, it may be questioned whether patients with decompensated cirrhosis should be treated before or after transplantation82,83. Within the next 2 years, more data will hopefully become available, which may be able to guide this decision for the individual patient. Preferably, patients with decompensated cirrhosis should therefore be treated within registry studies during the upcoming years.
Conclusion
The implementation of IFN-free treatment regimens has broadened the horizon for patients with chronic HCV infection tremendously. Within a timeframe of 5 years, important treatment developments resulted in near-perfect SVR rates, even among patients with the most advanced liver disease. As successful antiviral therapy may be lifesaving, these developments were long awaited. Some hurdles have to be taken, however, before the health burden of this chronic disease can truly be reduced. For instance, the access to DAAs needs to be broadened so that patients can be treated regardless of the severity of hepatic fibrosis. Reducing the costs of these drugs probably remains a key factor before this goal can be achieved. As developments are still ongoing, prices will hopefully fall as a result of mutual competition. Also, it is important to increase the number of patients who are diagnosed, as the majority of patients are currently unaware of their chronic viral hepatitis. Pan-genotypic regimens are currently being evaluated in phase III trials as well, which will hopefully simplify antiviral therapy even more. Until that time, treatment selection is required and prioritizing treatment is needed to limit the economic burden. Treating those with advanced hepatic disease first seems reasonable, but remains far from ideal.
Abbreviations
DAAs, direct-acting antivirals; FDA, US Food and Drug Administration; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; HRQoL, health-related quality of life; IFN, interferon; MELD, Model for End-Stage Liver Disease; miR-122, microRNA-122; PegIFN, pegylated interferon alpha; RAVs, resistance-associated variants; RBV, ribavirin; SVR, sustained virological response.
Competing interests
Raoel Maan received financial compensation for consultancy from AbbVie. Adriaan J. van der Meer received financial compensation for lecture activities for MSD and Gilead.

Grant information
The author(s) declared that no grants were involved in supporting this work.
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