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Moghe et al. Hepatoma Res 2018;4:36 I http://dx.doi.org/10.20517/2394-5079.2018.54 Page 5 of 9

therapy with thrice weekly interferon alfa-2b and daily ribavirin for 24-48 weeks was assessed . Among
[28]
90 treatment naïve patients enrolled, 34 patients underwent a liver biopsy following completion of 48 weeks
of therapy. Compared to the pre-treatment biopsy, fibrosis stage improved in 32% (11/34), and all three
patients with cirrhosis had regression of fibrosis. Improvement in fibrosis progression was independently
associated with younger age and low pre-treatment HCV RNA level. In another study of 933 patients with
HCV who achieved SVR with interferon-based therapies, non-invasive markers (Fibrotest, Fibroscan) or
liver biopsy were used to assess severity of fibrosis. Among the patients who achieved SVR (29%), 56% (24/53)
of the patients with cirrhosis had regression of cirrhosis noted at a median follow-up of 6.3 years. However,
during that period 12% of the patients with SVR developed new cirrhosis suggesting that the net reduction
in cirrhosis was a meager 5% . Those findings led to the suggestion that HCV therapy should ideally be
[29]
initiated in earlier stages of fibrosis to achieve the benefit of cirrhosis prevention .
[30]
With the dawn of DAA era, the assessment of hepatic fibrosis incidentally shifted from liver biopsy to non-
invasive modalities principally transient elastography (TE). One limitation of TE is that a change in liver
stiffness (LS) following SVR may not entirely reflect a reduction in fibrosis as inflammatory component
contributes to stiffness and it resolves quickly with SVR . This limitation needs to be considered while
[30]
inferring from studies that examined the effect of DAA on hepatic fibrosis by using LS as a surrogate marker.
In a study of 392 patients treated with DAA, an average reduction in LS from 12.65 kPa pre-therapy to
8.55 kPa 40 weeks after achieving SVR was noted, suggesting a 32% reduction in LS. That correlated with
a significant reduction in the FIB-4 and APRI fibrosis scores . Another study demonstrated a progressive
[31]
reduction in LS among 255 patients who achieved SVR with DAA - from average score of 26.4 kPa prior to
therapy to 23.5 kPa at the end of therapy and subsequently to 21.3 kPa at 12 weeks following completion of
treatment, indicating a 20% reduction in fibrosis . In a Japanese study of 210 patients who achieved SVR
[32]
with daclatasvir and asunaprevir (NS3/4A protease inhibitor) combination, there was significant reduction
in LS values, progressively from baseline to end-of-treatment to 24 weeks following treatment completion .
[33]

EFFECT OF DAA ON THE INCIDENCE OF HCC
Several studies examined the effect of SVR from interferon-based therapies for hepatitis C on subsequent
development of HCC. A meta-analysis established with moderate level of certainty that SVR achieved with
interferon-containing regimens reduced all-cause mortality and decreased the risk of HCC at any stage of
fibrosis . In fact, the estimated risk reduction of HCC after achieving SVR with interferon-based therapies
[34]
in patients with HCV-induced fibrosis/cirrhosis was an impressive 76% . However, the reduction in HCC
[34]
risk was not uniform as risk persisted in some patients despite viral clearance, particularly among those
older than 65 years and those with advanced fibrosis or cirrhosis .
[35]

Viral clearance induced by DAA has been shown to reduce liver and non-liver related critical events and
overall mortality. In a retrospective review of 467 patients (409 with decompensated cirrhosis) treated with
DAA, viral clearance was achieved in 381 (82%) patients . MELD scores improved in treated patients
[36]
while they worsened in untreated patients. The authors concluded that viral clearance was associated with
improvement in liver functions within 6 months compared to untreated patients. In a prospective study of
patients with compensated cirrhosis, the effects of SVR on patient outcomes was studied . Patients were treated
[37]
with interferon or with DAA. Among 1323 patients included, 668 (50%) achieved SVR after a median follow up
of 58 months. Patients with SVR had reduced incidence of HCC and hepatic decompensation. In addition,
SVR was associated with reduced mortality and risk of death from liver and non-liver related causes.

However, several reports cast doubt on the beneficial effect of DAA induced SVR on the development of
HCC. In a study of 103 patients, 58 with treated HCC and complete radiologic response had DAA induced
SVR or HCV RNA negativity . At a median follow-up of 5.7 months, 3 patients died and 16 (28%) developed
[38]