Management of Hepatitis C Infection in the

Era of Direct-Acting Antiviral Therapy

Taufik Sungkar

Division of Gastroenterology and Hepatology, Faculty of Medicine,

University of Sumatera Utara
Introduction

• To date, hepatitis C viral infection remains to be a

global health challenge. Nearly 180 millions of people
were infected worldwide, with reported debilitating
complications as high as 25% including cirrhosis and
hepatocellular carcinoma.

• For many years, standard therapy consists of pegylated

interferon α (pegIFNα) with additional ribavirin (RBV).
In terms of SVR, this early era therapy showed poor rates
and varied greatly among genomes.
• Newer regimens have been developed to improve cure
rate, increase tolerability thus hopefully prevent
complications.

• In the current DAA era, recent recommendations

approve interferon-free, some are ribavirin-free, DAAs
combination, which mainly suggested according to its
genotypes.
Prevalence

N.J Burstow et al. International Journal of General Medicine 2017:10 39-52

N.J Burstow et al. International Journal of General Medicine 2017:10 39-52
Evolution of HCV therapy
Previous Interferon-Ribavirin Therapy

• Up until 2011, the combination of pegylated interferon α

(pegIFNα) with ribavirin (RBV) has been used as a
standard regimen for HCV, that consisted of 24-48
weeks of treatment duration.

• Treatment outcome varied greatly among genomes.

Despite being the most common, GT1 remains the most
difficult to control, with SVR of only 40% following
completion of 48 weeks standard therapy
Direct-Acting Antiviral (DAA)
• Hepatitis C life cycle and the targets of direct-acting
antiviral agents.
Direct-acting antivirals for HCV

T. Asselah et al. Liver Int. 2016; 36 (Suppl. S1): 47–57

Development of Direct-Acting Antiviral (DAA)

Table 1. Directly acting antivirals and sites of action

N.J Burstow et al. International Journal of General Medicine 2017:10 39-52

• First generation NS3/4A PIs include telaprevir (TVR) and
boceprevir (BOC) that had been approved in 2011 for
treating GT1 infection.
• This approach greatly improve SVR of up to 75%,
however observed effective in GT1 only. Other than
exclusively potent for GT1, side effects were also common
that includes anemia, rash, and fatigue contributing to
high drop off rate.

• Consequently, both first-generation NS3/4A inhibitor

Telaprevir and Boceprevir was withdrawn from the
market since 2014
Newer Agents of DAAs
Table 2. Interferon-free treatment regimens for chronic hepatitis C
according to cirrhosis and treatment status, as recommended by the
European Association for the study of the liver and AASLD.

N.J Burstow et al. International Journal of General Medicine 2017:10 39-52

N.J Burstow et al. International Journal of General Medicine 2017:10 39-52
Spesial Populations

• DAAs therapy for chronic hepatitis C among patients in

the liver transplant setting

o Since DAA treatment seems to substantially improve liver

function in at least some patients with decompensated cirrhosis,
there may be patients who can be spared from LT.
o A recent retrospective European study evaluated 103 HCV-
infected patients on the liver transplant waiting list because of
decompensated cirrhosis who received DAA therapy.
 o At 6 months after treatment initiation 16% of patients was
inactivated (placed ‘on hold’ due to clinical improvement but
not yet removed from the waiting list), but no one was delisted.

Table 3. Antiviral treatment regimens in liver transplant

recipients
• Hepatitis C viral infection in chronic kidney disease

o HCV in CKD population is prevalent. Prevalence of ESRD with

HCV varied from 1% to 70% according to its country of origin,
with incidence rate of 0.97 to 4.44 in dialysis patients.

o Current management of HCV in patients with renal impairment

includes combination of DAAs, often interferon-free.

o According to EASL recommendation in 2016, patients with mild

to moderately impared renal functions (eGFR ≥ 30 ml/min/1.73
m2) requires no dose adjustment to several regimens, including
SOF/RBV, SOF/LDV, SOF/VEL, RTV-PTV/OMB/DSV, GZR/EBR,
SOF/DCV or SOF/SMV. Hence to be treated in a similar fashion as
to non-CKD cases .
o With a number of DAAs being excreted and accumulated in
kidneys special considerations need to be made in severe renal
impairment. In patients with eGFR <30 ml/min/1.73 m2)
,including stage 4 and 5 CKD or hemodialysis patients, the use of
the renally excreted sofosbuvir is not recommended.

o The C-SURFER trial also studied sofosbuvir-free, grazoprevir and

elbasvir regimen for 12 weeks, which showed similarly high 94%
SVR.
Table 4. Main studies evaluating interferon-free regimen in
HCV patients with chronic kidney disease

Patrice Cacoub et al. Journal of Hepatology 2016 vol. 65 j S82–S94

Patrice Cacoub et al. Journal of Hepatology 2016 vol. 65 j S82–S94
HCV and HBV coinfection

• The goal of therapy in HBV and HCV coinfection is to

eradicate HCV infection and inhibit HBV replication.

• Evaluation of liver disease progression, predominance of

one virus over another, and comorbidities are essential
for optimal antiviral regimens.

• For patients with active hepatitis C, the same regimens

following the same rules as for monoinfected patients
should be applied based on AASLD and EASL
recommendations
• For patients with active hepatitis B before, during or
after HCV clearance or with established cirrhosis,
nucleoside or nucleotide analog (NA), tenofovir or
entecavir is indicated.

• Prior initiating DAA-based treatment for hepatitis C,

patients should be tested for HBs antigen, anti-HBc
antibodies and anti-HBs antibodies. If HBs antigen is
present or if HBV DNA is detectable in HBs antigen-
negative, anti-HBc antibody-positive patients (“occult”
hepatitis B), concurrent HBV nucleoside/nucleotide
analog therapy is indicated.
HCV and HIV coinfection

• Patients with HCV and HIV coinfection are treated

according to genotype and prior treatment status as
follows:
(1) Genotype 1a, treatment-naïve patients may be treated
with any of the following regimen:
a. Sofosbuvir/ledipasvir for 12 weeks without ribavirin
b. Sofosbuvir/velpatasvir for 12 weeks without ribavirin
c. Ombitasvir/paritaprevir/ritonavir and dasabuvir for 12 weeks
with ribavirin
d. Grazoprevir/elbasvir for 12 weeks without ribavirin if HCV
RNA=800,000 IU/ml or 16 weeks with ribavirin if HCV RNA
>800,000 IU/ml
e. Sofosbuvir/daclatasvir for 12 weeks without ribavirin
• Genotype 1a, treatment-experienced patients may be
treated with any of the following regimen:
1. Sofosbuvir/ledipasvir for 12 weeks with ribavirin or 24 weeks
without ribavirin
2. Sofosbuvir/velpatasvir for 12 weeks without ribavirin
3. Ombitasvir/paritaprevir/ritonavir and dasabuvir for 12 weeks
with ribavirin
4. Grazoprevir/elbasvir for 12 weeks without ribavirin if HCV
RNA=800,000 IU/ml or 16 weeks with ribavirin if HCV RNA
>800,000 IU/ml
5. Sofosbuvir/daclatasvir for 12 weeks with ribavirin or 24 weeks
without ribavirin
(2) Genotype 1b, treatment-naïve and treatment-
experienced patients may be treated with any of the
following regimen:

a. Sofosbuvir/ledipasvir for 12 weeks without ribavirin

b. Sofosbuvir/velpatasvir for 12 weeks without ribavirin
c. Ombitasvir/paritaprevir/ritonavir and dasabuvir for 12
weeks with ribavirin
d. Grazoprevir/elbasvir for 12 weeks without ribavirin
e. Sofosbuvir/daclatasvir for 12 weeks without ribavirin
• Genotype 2, treatment-naïve and treatment-
experienced patients may be treated with any of the
following regimen:
a. Sofosbuvir/velpatasvir for 12 weeks without ribavirin
b. Sofosbuvir/daclatasvir for 12 weeks without ribavirin

• Genotype 3, treatment-naïve and treatment-

experienced patients may be treated with any of the
following regimen:
a.Sofosbuvir/velpatasvir for 12 weeks with ribavirin or
24 weeks without ribavirin
b.Sofosbuvir/daclatasvir for 12 weeks with ribavirin
• Genotype 4 treatment-naïve patients may be treated
with any of the following regimen:
a. Sofosbuvir/ledipasvir for 12 weeks without ribavirin
b. Sofosbuvir/velpatasvir for 12 weeks without ribavirin
c. Ombitasvir/paritaprevir/ritonavir with ribavirin for 12 weeks
d. Grazoprevir/elbasvir for 12 weeks without ribavirin
e. Sofosbuvir/daclatasvir for 12 weeks without ribavirin
f. Sofosbuvir and simeprevir for 12 weeks without ribavirin
• Genotype 4 treatment-experienced patients may be
treated with any of the following regimen:

a. Sofosbuvir/ledipasvir for 12 weeks with ribavirin and 24 weeks with ribavirin

b. Sofosbuvir/velpatasvir for 12 weeks without ribavirin
c. Ombitasvir/paritaprevir/ritonavir with ribavirin for 12 weeks
d. Grazoprevir/elbasvir for 12 weeks without ribavirin if HCV RNA =800,000 or
16 weeks with ribavirin if HCV RNA >800,000 IU/ml
e. Sofosbuvir/daclatasvir for 12 weeks with ribavirin or 24 weeks without
ribavirin
f. Sofosbuvir and simeprevir for 12 weeks with ribavirin or 24 weeks without
ribavirin
Conclusions

• The last few years has shown rapidly growing discoveries

in hepatitis C treatment. Previous interferon-ribavirin-
first generation DAAs has not been a favourable options,
leading to further investigation of DAAs combinations.

• DAAs combinations has shown great SVR, some even

achieved complete SVR.