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Treatment
The treatment of chronic hepatitis C has changed from regimes associated with
limited sustained virological response (SVR), dened as no viral RNA detected in
serum 24 months after completion of therapy, and considered a cure [170], to
regimes associated with SVRs from 90% to 100% in most of the hepatitis C virus
genotypes 12weeks after completion of treatment [170–172]. A negative RNA at
12weeks post treatment completion was dened as sustained virological response
(SVR), i.e., cure in pivotal trials, however, to conrm SVR at 24 and 48weeks post
treatment provides conrmatory evidence of cure [172, 173].
Interferon is a cytokine that participates in the innate immune response to viral
infections [174]. Recombinant alpha interferon was approved for the treatment of
chronic hepatitis C in 1992 [175]. Alpha interferon therapy was associated with
normalization of serum activity of transaminases in patients with chronic hepatitis
C but not with (SVR), which was dened as the absence of hepatitis C virus RNA
in serum 24weeks after completion of antiviral therapy [176]. Ribavirin, a nucleo-
side analogue with antiviral activity against avivirus, decreased serum activity of
aminotransferases and some improvement in liver histology in patients with chronic
hepatitis C [177] but, not with a decrease in the serum HCV RNA [177]. In combi-
nation with interferon, ribavirin was associated with SVR s of 34% and 38%, when
administered for 24 and 48weeks, respectively [178]. Ribavirin was approved for
the treatment of chronic hepatitis C in combination with interferon in 1999.
Pegylation of interferon led to its prolonged bioavailability, which allowed for
weekly subcutaneous administration. Pegylated interferon and ribavirin for
48weeks (depending on viral load) was associated with an SVR in 41% to 56% of
patients with genotype 1, 74–81% in those with genotypes 2 and 3, and 77% in
those with genotype 4 [89]. The proportion of African American patients who
achieved SVR with this type of regimen was 28% [179]; this result suggested that
racial and genetic factors had a substantial impact on the response to this therapeutic
regimen. Subsequently, it was discovered that subjects with a favorable genetic
polymorphism in IL28B had an increased probability of reaching SVR in associa-
tion with treatment with pegylated interferon alpha and ribavirin in contrast to those
patients with an unfavorable IL28B genotype. In this regard, a gene coding for IFN-
lambda 4 (IFNL4) was documented to be associated with hepatitis C virus clearance
in African American patients [180].
Breakthrough ndings of the HCV life cycle [181–183], and identication of
proteins fundamental in the replication of the HCV [184] have facilitated the devel-
opment of drugs that act directly on the virus, known as direct-acting antiviral
agents (DAA) (Fig.6.3). The hepatitis C virus undergoes a series of steps to per-
petuate infection: (1) entry into the hepatocyte via receptor binding and endocyto-
sis, (2) fusion and uncoating of the virion, (3) translation and polyprotein processing,
(4) replication, (5) virion assembly, and (6) transport and release. Telaprevir and
boceprevir are inhibitors of the protease NS3-4A, DAAs that were approved in 2011
for the treatment of chronic hepatitis C.The NS3-4A protease breaks the junctions
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Hepatitis C virus
Preventing the entry of the virus into the hepatocyte by blocking the
sites to which it binds including the tetraspanin CD81, low density
lipoprotein-R (LDL-R), scavenger receptor class B type 1 (SCAR-
B1), the ight junction elements claudin (CLDN-1), and occluding
(OCLN)
Inhibitors of NS3 and NS4A to prevent production of viral proteins
Inhibitors of NS5B polymerase, NS5A, and cyclophilin Ato prevent viral
replication
IInhibitorsofNS5Ato prevent virion assembly andrelease inclucing amantadine
and imino sugars
Fig. 6.3 The diagram depicts the hepatitis C virus cycle from entrance into the hepatocyte to the
exit of a new virion and therapeutic targets
6
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between NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B [185]. In addi-
tion to its role in polyprotein processing, NS3 is necessary for HCV replication and
viral assembly and production [186]. Triple therapy with either telaprevir or
boceprevir, in combination with pegylated interferon and ribavirin was associated
with SVR rates of 75 and 66%, respectively [187, 188], in patients with chronic
hepatitis C genotype 1; for boceprevir, the response rate could vary depending on
whether patients responded to pegylated interferon and ribavirin with the absence of
HCV RNA at week four of treatment, milestone dened as interferon responsivity,
which, when achieved, was associated with SVRs of 90%. In patients who had not
experienced an SVR in association with standard therapy, the response to triple
therapy was lower than in patients who had not been treated [187, 188]. These thera-
peutic regimes were associated with complications inherent to those of what had
been considered standard therapy, i.e., pegylated interferon and ribavirin, such as
anemia [187, 188]. The complications added to the regimen from telaprevir included
rash, which could be severe, requiring medication discontinuation, in 55% of
patients, and anal discomfort in approximately 26%; from boceprevir, dysgeusia
was reported by 37% of patients [188]. As both drugs inhibit drug-metabolizing
enzymes from the cytochrome P-450 complex, e.g., CYP2C, CYP3A4, and CYP1A,
drug interactions were a substantial problem, requiring a change in medication regi-
men or dose reductions in the medications used to treat comorbidities. Treatment
with telaprevir or boceprevir paradigms were also associated with the risk of resis-
tant associated amino acid variants, the prevention of which required absolute
adherence to the treatment regimen, and the additional risk of persistence in patients
who did not respond to the protease inhibitors paradigm; follow-up studies, how-
ever, documented that the prevalence of the resistant mutants decreased over time,
with a reversal to a wild-type predominance [189]. The use of telaprevir and
boceprevir is not the standard of therapy as new medications with improved efcacy
and tolerability have been approved [190].
In 2013, two new medications were approved for the treatment of chronic hepa-
titis C, including genotypes 1 through 6. Simeprevir is an NS3-4A protease inhibitor
that has activity against genotypes 1, 2, and 4, although it is inactive against the
resistant associated amino acid variant that carries the Q80K substitution in the NS3
sequence. In combination with standard therapy, simeprevir treatment in patients
with chronic hepatitis C genotype 1 for 24 or 48weeks was associated with an SVR
of 74.7–86.1% [191]; in patients who had been treated and who had not responded
to therapy, i.e., treatment-experienced patients, simeprevir therapy for 12, 24, and
48 weeks, in combination with pegylated interferon alpha 2 a and ribavirin for
48weeks, was associated with an SVR of 38% to 89%, depending on the type of
failure to prior treatment, e.g., null or partial response, or relapse after response
[192]. Sofosbuvir is a uridine nucleotide analogue that inhibits HCV RdRp, which
is phosphorylated to its triphosphate form and incorporated into forming RNA
chains, resulting in chain termination; it has activity against genotypes 1 through 6,
referred to as having pangenotypic activity. In vitro, sofosbuvir does not act against
variants that have an S282T in the RdRp sequence; however, these variants did not
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appear to replicate successfully invitro or invivo and had not been associated with
a virological breakthrough in patients on treatment, and were only found in those
patients who relapsed after treatment had been stopped [193]. The drugs could be
administered in combination with standard therapy, i.e., pegylated interferon and
ribavirin, or in combination with ribavirin, depending on the infecting genotype, on
prior response to standard therapy, and eligibility to receive interferon.
The availability of DDA in interferon-free regimens revolutionized the treatment
of chronic hepatitis C, as predicted during the conduct of fundamental clinical trials
[170, 171, 194].
Medications including ledipasvir, ombitasvir, daclatasvir, elbasvir, velpatasvir,
and pibrentasvir are NS5A inhibitors with coverage against several genotypes, and
an intermediate barrier to resistance. NS5A inhibitors inhibit hyperphosphorylation
of NS5A phosphoprotein, which is required for HCV RNA replication, and also,
cause the transfer of NS5A from the endoplasmic reticulum to lipid droplets in
HCV replicon-containing cells leading to a signicant reduction of HCV RNA in
cell culture [195].
Harvoni® is a combination tablet that contains 90mg of ledipasvir, an NS5A
inhibitor, and 400mg of sofosbuvir, an NS5B inhibitor that was approved by the
FDA in 2014. The NS5B inhibitors act on the catalytic site of NS5B polymerase;
after they incorporate themselves into the RNA chain, they cause mRNA termina-
tion. Sofosbuvir a nucleotide NS5B polymerase inhibitor and [196]. Results from a
meta-analysis showed that the addition of ribavirin did not add benet to sofosbu-
vir/ledipasvir for the treatment genotype 1 infection. In a controlled clinical trial,
the overall SVR associated with sofosbuvir/ledipasvir in chronic HCV infection
genotype 1 was 96%, 98% in the treatment-naïve group versus 95% in the treatment-
experienced group, 95% in the 12-week therapy group versus 98% in the 24-week
therapy group, 95% without ribavirin vs. 97% with ribavirin [197].
Velpatasvir is a pangenotypic second generation NS5A inhibitor with a higher
barrier to resistance than ledipasvir and daclatasvir and which acts as a defective
substrate for NS5A to prevent HCV replication. It is used as a xed dose co-
formulation with sofosbuvir under the name of Epclusa®. In a double blind placebo
controlled study of 12 weeks, the use of sofosbuvir-velpatasvir in patients with
chronic HCV genotypes 1 to 6 was associated with a 99% SVR regardless of prior
exposure to treatment, including patients with compensated cirrhosis [198].
Pibrentasvir is a second generation NS5A inhibitor provided in a tablet in com-
bination with glecaprevir under the name of Mavyret®, with a pangenotypic effect,
and approved for use in patients with renal failure including patients on
hemodialysis.
Sofosbuvir a nucleotide NS5B polymerase inhibitor and [196] ledipasvir, an
NS5A inhibitor for the treatment of hepatitis C genotypes 1, 4, 5, and 6 infections is
effective. A meta-analysis showed no additional benet when ribavirin was added to
sofosbuvir/ledipasvir for the treatment genotype 1 infection [199].
Dasabuvir is a non-nucleoside NS5B polymerase inhibitor, which binds to the
palm domain of NS5B preventing the elongation of HCV RNA, used in
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combination with paritaprevir/ritonavir-ombitasvir with or without ribavirin for the
treatment of hepatitis C genotype 1 infection with or without cirrhosis but, in the
compensated state (Child–Pugh A).
The guidelines to treat chronic hepatitis C are updated regularly by the collabora-
tion of the American Association for the Study of Liver Disease (AASLD) and the
Infectious Diseases Society of America (IDSA), and they will not be reviewed in
this chapter. The reader is referred to the AASLD-IDSA HCV guidance website
(www.HCVGuidelines.org), where indication to test for resistance and treatment
duration is provided [200]. In general, in preparation for treatment, factors to con-
sider are viral load, genotype, degree of brosis, presence or absence of cirrhosis in
compensated versus decompensated state, prior treatment, and drug interactions. At
present, current illicit drug use is not a contraindication for the treatment of chronic
HCV [172]. The SVR rates between patients who use drugs during treatment versus
those who do not use tend to be similar. Furthermore, the probability of transmitting
HCV from patients being treated for HCV to other individuals, especially if drug
paraphernalia is shared, decreases, although patients must be informed of the risk of
reinfection by usual transmission modes after successful treatment of chronic HCV.
Hepatitis B reactivation can occur in patients treated with DAA for chronic HCV.A
retrospective study that included 62,920 subjects who had been treated for HCV with
this type of medications documented that nine had evidence of HBV reactivation dur-
ing treatment; of these, eight were HBsAg positive, and one was hepatitis B anti-core
positive. Seventeen other patients had some increases in serum HBV DNA concentra-
tions not sufciently high to meet the denition of reactivation as per the study (i.e.,
HBV >1000IU/mL or HBsAg detection in a person who was previously negative),
and only three of the nine had an increase in ALT twice the upper limit of normal
[201]. These results suggested that the probability of major ares is low; however, it
is recommended that patients coinfected with HBV be treated to suppression prior to
HCV treatment with DAA and that all patients be screened for hepatitis B virus infec-
tion prior to initiation of therapy; it is recommended in patients who have hepatitis B
anti-core in serum, to check concentrations of HBV DNA.Post treatment follow up is
also recommended to determine if ares occur overtime.
Improvement of quality of life measures has been documented in patients who
have exhibited an SVR in association with antiviral therapy [202]. Specically, at
baseline (i.e., before antiviral therapy), patients with chronic hepatitis C showed
impairment in several functions of the short form (SF)-36 questionnaire including
physical function, general health, vitality, and social function, in contrast to a con-
trol group of subjects; in association with SVR post treatment, there was docu-
mented improvement in health stress, vitality, and social functioning [90], ndings
generally supported in combined analyses of clinical studies [203]. In addition, anti-
viral therapy in association with SVR has been reported to decrease cirrhosis pro-
gression, deter the development of liver disease complications, and improve survival
[204]. Generalized pain and manifestations of sicca syndrome associated with
chronic hepatitis C virus infection, measured by the Health-Related Quality of Life
(HRQOL), have also been documented to decrease in association with SVR [90].
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Treatment ofConditions Associated withChronic Hepatitis C
Cryoglobulinemia
There is some reported experience on the effect of direct-acting antiviral (DAA)
drugs on cryoglobulinemic vasculitis with encouraging results, i.e., eradication of
the virus is associated with a reduction of cryoglobulins and increase in C4 levels,
and a substantial decrease in the vasculitis complications [205]. In patients with
serious complications of vasculitis, including glomerulonephritis, peripheral neu-
ropathy, and chronic skin ulcers, rituximab may be considered. Rituximab is a
chimeric monoclonal antibody against the CD20 antigen expressed on pre-B cells
and mature lymphocytes. It is also expressed by the cells expanded and activated
in patients with cryoglobulinemic vasculitis. High-dose pulsed glucocorticoid
therapy may be useful in severe conditions and can be considered in combination
with rituximab; the chronic use of low or medium doses of glucocorticoids has not
been supported [206]. Apheresis was recommended for the treatment of complica-
tions from severe hyperviscosity syndrome [206]. The addition of cyclophospha-
mide to apheresis has been proposed, although the experience is minimal [206].
Colchicine was reported as a therapeutic option, but the reported experience is
also limited [206].
A prospective 15-year study has offered the opportunity to document the natu-
ral history of patients with chronic hepatitis C and cryoglobulinemia. Nine hun-
dred fty patients with chronic hepatitis C, 246 (25.8%) of whom had mixed
cryoglobulinemia, and 184 of these (74%) cryoglobulinemia syndrome were
included; 141 patients with cryoglobulinemia syndrome and 601 without mixed
cryoglobulinemia completed the study, which was from 1990 to 2010. None of the
patients had a spontaneous clearance of cryoglobulins. A switch from type II to
type III cryoglobulinemia was documented in 1.6% at a rate of 0.08% per year.
The 15-year probability of developing cirrhosis was signicantly higher in patients
without mixed cryoglobulinemia, 24.9%, than in patients with cryoglobulinemia
syndrome, 14.2%, and the risk of developing hepatocellular carcinoma was also
signicantly different, 20.3% in patients without mixed cryoglobulinemia and
7.5% with cryoglobulinemia syndrome. Renal insufciency, neuropathies, and B
cell non-Hodgkin lymphoma were developed signicantly more frequently in
patients with cryoglobulinemia syndrome, 32.6, 31.2, and 15%, respectively; in
those without mixed cryoglobulinemia, the rate of developing the complications
reported was less than 10%. Antiviral therapy with interferon and ribavirin was
associated with a sustained virological response, dened as the absence of serum
hepatitis C RNA 6months after treatment and associated with improved progno-
sis [176], was 44% in patients with cryoglobulinemia syndrome, and 53% in
patients without mixed cryoglobulinemia. The 15-year survival rate was 70% for
both groups, despite the complications reported to be more common in patients
with cryoglobulinemia syndrome [131].
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Porphyria Cutanea Tarda
The treatment of porphyria cutanea tarda (PCT) includes avoiding the sun and other
known triggers of expression, including alcohol, cigarette smoking, and estrogen
exposure, and removal of iron, and anti-malarial medications that remove tissue
porphyrins. The published experience of the treatment of patients with PCT in asso-
ciation with chronic hepatitis C is minimal and inconsistent, with reports document-
ing response [141, 207, 208] or lack of it [209] to antiviral therapy with interferon
and ribavirin. In addition, reports document the development of PCT after this type
of antiviral therapy [210, 211]. The literature on treatment with DAA in patients
with HCV and PCT is limited; in a series of 12 patients, two patients had PCT and,
on therapy with DAA, one experienced a reduction of plasma porphyrins, and the
other its disappearance, at the end of treatment [212].
Nephropathy
The treatment goal of hepatitis C associated glomerulopathies is to eradicate the
virus by antiviral therapy; however, there are limited data on the success of this
approach. In patients with rapidly progressing renal disease, steroids, immunosup-
pressors, plasmapheresis, and monoclonal antibody rituximab are recom-
mended [150].
Xerostomia andXerophthalmia
Therapy of primary Sjogren’s syndrome with interferon has been reported to be
associated with improvement in glandular function [213]. A study published in
French reported improvement of sicca symptoms in patients with chronic hepatitis
C treated and cured with interferon and ribavirin. Specic reports on the effect of
DAAs on this complication of chronic hepatitis C were not found.
Lichen Planus
The therapy of lichen planus has been corticosteroids and other various immuno-
suppressants orally or topically, depending on the location, and phototherapy [162].
Antiviral therapy with interferon alone or with ribavirin in patients with chronic
hepatitis C has been associated with worsening of lichen planus [214, 215].
Improvement of symptoms secondary to oral lichen planus has been associated with
treatment with DAAs [216, 217].
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Liver Transplantation
Liver disease from chronic hepatitis C is a common indication for liver transplanta-
tion in Europe and the United States (www.unos.org); however, infection of the
graft happens in all the patients [218, 219] and which has been calculated to prog-
ress to cirrhosis within 5–10 years post transplantation [220]. Graft infection is
associated with graft loss and the need for retransplant [219, 220]. Ballooning
degeneration and hyperbilirubinemia are histological and clinical features that pre-
dict the development of cirrhosis in the transplanted liver in patients with recurrent
hepatitis C [221]. Fibrosing cholestatic hepatitis is a particularly aggressive type of
liver injury associated with recurrent hepatitis C that leads to graft loss in months
after its presentation, which is characterized by marked hyperbilirubinemia [222,
223]. Post transplant immunosuppression is one of the factors contributing to the
recurrence of HCV infection in the graft and the rapid progression to brosis and
cirrhosis [222]. It has been reported that the administration of corticosteroid boluses
and anti-lymphocyte antibodies to treat rejection are associated with increased
severity of liver disease upon viral recurrence and that relatively low doses of ste-
roids and their slow tapering, and the absence of steroids in pharmacological main-
tenance regimens are associated with a decrease in disease progression [219, 224];
however, hard conclusions have not been derived.
A retrospective study that included 39 patients who had undergone liver trans-
plantation between 1991 to 1999 and who had cirrhosis post liver transplantation
documented that 18 had one episode of decompensation within a median of
7.8months after the operation with 93% of patients developing ascites [220]. The
variables associated with decompensation, retransplantation, or death have been
reported to be a Child–Pugh class B or C, serum albumin lower than 3.5g, presence
of cirrhosis within 15.3 (range 3.7–46.1) months from the operation, high serum
cyclosporine levels at the time of the diagnosis of cirrhosis, and hepatic venous
pressure gradient (HVPG) ≥10mmHg [220, 225]. The cumulative probability for
decompensation, and graft and patient survival at 1year was 42%, 71%, and 74%,
respectively [220], and signicantly lower than that of patients who have not under-
gone liver transplantation [220, 224]. In association with sustained virological
response, antiviral therapy has been reported to deter the progression of liver dis-
ease in graft viral hepatitis C [226]. SVR rates in the post transplant setting had been
relatively low, but, have improved in association with treatment with DAA [227].
A systematic review and meta-analysis from studies published on the subject of
treatment of chronic HCV post recurrence in liver transplant patients with genotype
1 and that included 885 patients documented an overall pooled estimate proportion
of SVR12 as 93% (95% CI: 0.89, 0.96) with moderate heterogeneity identied
(τ
2
=0.01, P<0.01, I2=75%). The highest pooled estimate SVR12 proportion was
for sofosbuvir/ledipasvir, followed by paritaprevir/ritonavir/ombitasvir/dasabuvir,
daclatasvir/simeprevir ± ribavirin, sofosbuvir/simeprevir ± RBV, and asunaprevir/
daclatasvir. The METAVIR is an algorithm for the grading of activity in chronic
hepatitis C [75]. The pools of patients with METAVIR stages F0 to F2 tended to
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show a higher proportion of SVR12, 97% (95% CI: 0.93, 0.99) versus 85% (95%
CI: 0.79, 0.90) for stages F3-F4 (P<0.01); the use of ribavirin was not associated
with any signicant differences in outcome. These data suggested that DAAs are
well tolerated and efcacious in treating recurrent HCV post liver transplantation
[228]. The use of DAA in the post transplant setting continues to evolve.
Patients with chronic hepatitis C should be evaluated for treatment, and moni-
tored for disease progression, including the development of hepatocellular carci-
noma; in cases of brosis stages 3 to 4, or documented cirrhosis, surveillance for
HCV should continue regardless of HCV cure, as patients remain at risk for
HCC.Vaccination against viral hepatitis A and B is recommended.
Acknowledgments The author acknowledges Dr. Cesar del Rosario for having contributed
Figure6.2.
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