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Page 4 of 9 Moghe et al. Hepatoma Res 2018;4:36 I http://dx.doi.org/10.20517/2394-5079.2018.54

It was the approval of sofosbuvir (nucleotide analog NS5B polymerase inhibitor) in 2013 that heralded the
advent of all-oral regimens and a change in treatment landscape once again [Table 1]. The next two years
[25]
saw the introduction of several other DAA - sofosbuvir in combination with ledipasvir (NS5A inhibitor), and
combination of ombitasvir (NS5A inhibitor), paritaprevir (NS3/4A protease inhibitor), ritonavir (CYP3A inhibitor)
and dasabuvir (non-nucleoside NS5B palm polymerase inhibitor), and daclatasvir (NS5A inhibitor) . The latter
[25]
was approved for treatment of HCV genotype 3 infection in combination with sofosbuvir. The regimens
could be used in both non-cirrhotic and well compensated cirrhotic patients who were either treatment
naïve or treatment experienced, and they achieved high SVR rates with reduced duration of treatment and
better tolerability . Elbasvir (NS5A inhibitor) and grazoprevir (NS3/4A protease inhibitor) fixed dose
[25]
combination was approved for treatment naïve or treatment experienced patients infected with genotype 1
or 4, with or without cirrhosis. The regimen was contraindicated in patients with Child’s B or C cirrhosis;
however, it could be used in patients with advanced renal failure without dose adjustment. All regimens had
overall SVR rates of greater than 95%. That was the second generation of DAAs.

The approval of sofosbuvir and velpatasvir (NS5A inhibitor) as a fixed dose combination initiated the
third generation of DAAs [Table 1]. Whereas the response rate to previous regimens was HCV genotype
dependent, this combination was pan-genotypic and could be used in patients with or without cirrhosis. It
also had approval to be used in decompensated cirrhosis in combination with ribavirin; however, it was not
recommended to be used in patients with severe renal impairment as defined by an eGFR of < 30 mL/min.
Two other fixed dose combinations were more recently introduced to this pan-genotypic armamentarium
of antivirals. Sofosbuvir, velpatasvir, and voxilaprevir (NS3/4A protease inhibitor) fixed dose combination
was approved for patients without cirrhosis or those with compensated cirrhosis, and without severe
renal impairment. The combination was indicated for patients previously treated with an HCV regimen
containing an NS5A inhibitor, or those with genotype 1a or 3 who were previously treated with a regimen
containing sofosbuvir without an NS5A inhibitor. Glecaprevir and pibrentasvir (NS5A inhibitor) fixed
dose combination was approved for patients without cirrhosis or those with compensated cirrhosis. The
combination could also be used in adult patients with genotype 1 infection, who were previously treated
with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both. Hepatitis
B reactivation during HCV treatment has been reported among coinfected patients resulting in fulminant
hepatic failure and death. It is therefore recommended to test all patients for current or prior HBV infection
before initiation of HCV treatment, and to monitor all coinfected patients for HBV reactivation during
therapy and during post-treatment follow up.

IMPACT OF HCV TREATMENT ON DISEASE BURDEN OF CIRRHOSIS/BRIDGING FIBROSIS
In view of the etiologic role of HCV in the progression of hepatic fibrosis and hepatocarcinogenesis, viral
clearance would be expected to cause cessation of fibrosis progression or potentially regression of fibrosis.
Similarly, it may also reduce the risk of HCC development. This issue was evaluated among patients treated
with interferon and ribavirin. A meta-analysis of four key randomized trials assessed the effects of HCV
treatment on histologic features . The pooled studies included 3010 treatment naïve patients who underwent
[27]
liver biopsies before and after treatment. Treatment regimens involved unmodified interferon or pegylated
interferon, in combination with ribavirin. To be deemed as an improvement in fibrosis, at least one-point
reduction in METAVIR fibrosis stage from baseline was required. Conversely, an increase by one or more
points was considered fibrosis progression. In addition to improvement in necrosis and inflammation, the
analysis showed a significant improvement in fibrosis progression with all treatment regimens. In 49%
(75/153) there was reversal of cirrhosis; however, fibrosis worsened in 8% to 23%. Factors independently
associated with lack of fibrosis progression included low HCV RNA level (< 3.5 million copies/mL), minimal
2
to no baseline inflammatory activity, healthier body mass index (< 27 kg/m ), younger age (< 40 years),
achievement of SVR and a lower pre-treatment fibrosis stage . In another study, the effect of combination
[27]