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Page 2 of 18 Franco et al. Hepatoma Res 2018;4:74 I http://dx.doi.org/10.20517/2394-5079.2018.94

tive vaccine is currently available, HCV infection is amenable to cure if potent antivirals fully and quickly
suppress virus replication. Sustained virologic response (SVR), i.e., cure, is achieved following therapy com-
[6,7]
pletion in > 95% of treated individuals . Direct-acting antivirals (DAAs) have shown superior safety and
efficacy compared to interferon-based regimens (> 95% vs. 40% cure rates, respectively), and revolutionized
[8]
HCV treatment paradigms towards broader access to cure . The 69th World Health Assembly endorsed the
global health sector strategy to eliminate HCV infection by 2030, which can become a reality with expanded
[9]
use of DAAs . Here, we describe the current prospects of HCV eradication in the DAA era and ongoing
challenges to achieve elimination goals.

CLINICAL IMPACT OF DIRECT-ACTING ANTIVIRALS
[10]
In 2012, Lok et al. reported successful treatment of patients who were null responders to peg-interferon
and ribavirin, infected with genotype 1a and 1b HCV, who received a 24-week course of asunaprevir, a pro-
tease inhibitor, and daclatasvir, a non-structural protein 5A inhibitor. This preliminary, proof of concept
study demonstrated that SVR (virologic cure) could be achieved by the combination of two DAAs in patients
who did not respond to the standard of care at the time. It also signified the culmination of a sequence of
[11]
major breakthrough discoveries that followed the cloning of HCV for the first time in 1989 . Such prog-
ress in basic science allowed, over the ensuing years, for elucidation of key functions of the HCV genome
and the virus life cycle; engineering of “sub-genomic” replicons; and development of functional cell-based
in vitro systems suitable to screen compound candidates for effective treatment [12,13] . Lok’s study led the way
of an impressive wave of clinical studies, that applied several combinations of DAAs at an extraordinarily
[14]
fast pace . From these clinical studies, we learned that DAAs proved to be safe and effective in addressing
unmet needs of key subpopulations, traditionally unreached by interferon-based therapies. State-of-art treat-
ment options were made available for patients with human immunodeficiency virus (HIV) co-infection [15-22] ,
decompensated cirrhosis [23-28] , post-liver transplantation [29-33] , chronic kidney disease [34,35] , renal transplant
patients [36-38] , and children [39,40] . These clinical studies also defined best practices in overcoming HCV resis-
tance. Highly efficacious retreatment strategies could still be utilized for the few patients experiencing DAA-
failure and emergence of resistance associated substitutions [41-46] .

The field quickly evolved towards the recognition that HCV can be eradicated from most, if not all, infected
[47]
individuals, expanding the benefits of virus clearance . Virologic cure has been shown to universally de-
crease liver inflammation, reflected by improved aminotransferase levels and reduced rates of liver fibrosis
progression. In some patients, achieving SVR also leads to cirrhosis regression and improvement in clinical
[48]
signs of portal hypertension and end-stage liver disease . Numerous studies have demonstrated strong as-
sociations between SVR and significant reductions in the risk of HCC, liver-related mortality and liver trans-
plantation [49-51] . In addition to these major clinical benefits, cure of HCV infection ameliorates or facilitates
management of extra-hepatic manifestations such as cryoglobulinemia, non-Hodgkin’s lymphoma, diabetes
and porphyria cutanea tarda [52-54] . The lower complexity of DAA therapy has made investigators and clini-
cians challenge the preconceived notion that expeditious HCV treatment would only benefit highly selected
[55]
patients who exhibited liver fibrosis METAVIR stage 2 at a minimum . Well-designed cohort and modeling
studies have suggested that early therapy in patients with no significant liver fibrosis have tremendous clini-
cal benefits with SVR [56-58] . Similarly, patient reported outcome assessments from pivotal DAA trials have
shown improvements in overall health-related quality of life and work productivity following successful
HCV therapy [59-61] . These findings build on previous studies reporting reductions in fatigue after HCV cure
[62]
with interferon and ribavirin . Taken together, this body of work highlights the extraordinary clinical ben-
efit potential of expanding use of DAAs [Table 1].

In addition, the medical field has clarified the lack of accurate data regarding HCC risk following DAA
therapy [63,64] . Initially, concerns were raised that abrupt HCV viral load suppression using DAAs could hypo-
thetically abolish the immune system surveillance or “brake” defenses to tumor progression. Further meta-