INTRODUCTION

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease
worldwide [1]. The long-term impact of HCV infection is highly variable, ranging
from minimal histological changes to extensive brosis and cirrhosis with or without
hepatocellular carcinoma (HCC). The number of chronically infected persons
worldwide is estimated to be about 160 million, but most are unaware of their
infection. The implementation of extended criteria for screening for HCV is a subject
of major debate among different stakeholders. Clinical care for patients with HCVrelated liver disease has advanced considerably during the lasttwo decades,
thanksto an enhancedunderstanding of the pathophysiology of the disease, and
because of developments in diagnostic procedures and improvements in therapy
and prevention. These EASLRecommendations on Treatmentof HepatitisC are
intended to assist physicians and other healthcare providers, as well as patients and
other interested individuals, in the clinical decision-making process by describing
the current optimal managementofpatientswithacuteandchronicHCVinfections.These
recommendations apply to therapies that have been approved in the European
Union at the time of their publication.
----------------------------------------------------------------------------------------------------------------------------------------Hepatitis (inflammation of the liver) refers to a group of viral infections that affect
the liver. The most common types are hepatitis A, hepatitis B and hepatitis C. Each
is caused by a different virus.
Transformative advances in drug treatments approved by the Food and Drug
Administration are giving the 3.2 million Americans with chronic hepatitis C a
chance for a longer, healthier life without the virus. Thats welcome news for baby
boomerswho make up three of four adults with the hepatitis C virusand millions
of other Americans, many of whom dont yet know they are infected and carriers.
Hepatitis C is the most common chronic blood-borne infection in the United States.
There is no vaccine for this disease, but hepatitis C can be prevented by avoiding
behaviors that can spread the virusincluding sharing needles, syringes or other
equipment to inject drugs. A diagnosis of hepatitis C no longer means months and
months of painful drug injections, which for decades were the only option. Science
is making strides in therapies, giving patients new alternatives.
Hepatitis C is a deadly yet often overlooked disease that silently damages the liver over time. It is rarely
even treated, due to its nature of showing no symptoms as well as the mostly out-of-pocket cost of
treatment. Currently, less than 100 hepatitis C patients are undergoing treatment in the Philippines.
But in spite of all these barriers, there is now renewed hope for a cure.

Apart from the standard treatment composed of a combination therapy of peg-interferon (pegylated
interferon) and ribavirin, there is now a new addition to the treatment regimen that is poised to increase a
patients chance for virus eradication significantly, said Dr. Stuart Gordon, Director of the Division of
Hepatology and Hepatology Research at the Henry Ford Health System in Michigan and Professor of
Medicine at Wayne State University School of Medicine, Michigan.

Hepatitis C affects 3.2 million Americans and kills more people each year than
HIV/AIDS in the United States.
Approximately 3.2 million Americans are currently living with chronic hepatitis C, an
infection caused by the hepatitis C virus.1 Hepatitis C slowly destroys the liver over
time and can lead to serious and potentially life-threatening complications,
including liver cancer and the need for liver transplants.2 In addition to serious liver
damage, the complications of untreated hepatitis C can include Type 2 diabetes,
rheumatologic disorders and thyroid disease.3,4,5 Since the discovery of the virus in
1989, effectively treating hepatitis C has been a challenge. For years, the only
available treatment options were ineffective for many patients and often difficult to
tolerate.6 Initial treatment regimens involved up to a year of weekly interferon
injections and ribavirin tablets, which can cause side effects such as depression,
nausea, severe reductions in certain blood cells and flu-like symptoms.7 These often
difficult-to-tolerate treatment regimens, combined with low cure rates, caused many
patients to stop treatment before it was completed.

What is hepatitis C infection?

Hepatitis C infection is an infection of the liver caused by the hepatitis C virus(HCV). It is difficult for
the human immune system to eliminate hepatitis C from the body, and infection with hep C usually
becomes chronic. Over decades, chronic infection with hepatitis C damages the liver and can cause
liver failure. In the U.S., the number of new cases of hepatitis C infection has declined from a peak of
200,000 annually to about 17,000 in 2007. When the virus first enters the body, however, there
usually are no symptoms, so these numbers are estimates. Up to 85% of newly-infected people fail
to eliminate the virus and become chronically infected. In the U.S., more than three million people
are chronically infected with hepatitis C. Infection is most commonly detected among people who are
40 to 60 years of age, reflecting the high rates of infection in the 1970s and 1980s. There are 8,000
to 10,000 deaths each year in the US related to hepatitis C infection. Hepatitis C infection is the
leading cause of liver transplantation in the US and is a risk factor for liver cancer.
Hepatitis C Treatment-Naive Recommendations
The goal of HCV treatment is to cure the virus, which can be done with a combination of drugs. The
specific meds used and the duration of treatment depend on a number of factors, including HCV genotype
(genetic structure of the virus), past treatment experience, degree of liver damage, ability to tolerate the
prescribed treatment, and whether the person is waiting for a liver transplant or is a transplant recipient. In
some cases, HCV treatment may be limited by your health insurance plan or drug formulary.
There are a number of approved therapies to treat HCV, such as Harvoni (sofosbuvir/ledipasvir), Daklinza

(daclatasvir), Olysio (simeprevir), Sovaldi (sofosbuvir), Technivie and Viekira Pak. Sovaldi and Olysio may
be prescribed together with or without ribavirin, or each may be separately combined with ribavirin and in
some cases peginterferon as well. Harvoni is two drugs formulated in to one daily pill, whereas Technivie
and Viekira Pak are a combination of medications that may be prescribed with or without ribavirin.
When hepatitis C treatment is working, the virus usually becomes undetectable within four to 12 weeks
and remains that way throughout treatment. People are considered cured when they have achieved what
is known as a sustained virologic response (SVR), or continuation of this undetectable status, 12 to 24
weeks after completing therapy.

BODY
What Medical Treatments Are Available?
If you are diagnosed with chronic hepatitis C, your doctor may recommend taking a
combination of medicines to try to prevent the virus from harming your liver. These
antiviral medicines are called interferon and ribavirin. Treatment with this combo usually
lasts between 24 and 48 weeks.
Since these drugs can lead to serious side effects, its important to discuss your
treatment options with your doctor. Not everyone who has chronic hepatitis C will
benefit from taking medicines.

For most people, hepatitis is a silent disease until it causes substantial damage to
the liver. That process may take several years, and can lead to liver failure, liver
transplantation and liver cancer. Hepatitis C is a bit like smoking, the longer youve
had it, the higher your risk of developing complicationsin this case, liver cancer
and end-stage liver disease. Its a progressive disease that takes years, even
decades, before the patient develops cirrhosis or cancer, Murray says. The good
news is that when you cure hepatitis C, you also lower its risks, though you dont
completely erase the years of damage to your liver.

Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C
virus (HCV).[1] The infection is oftenasymptomatic, but chronic infection can lead to scarring of the
liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those
with cirrhosis will go on to develop liver failure, liver cancer, or lifethreatening esophageal and gastric varices.[1]
HCV is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly
sterilized medical equipment, andtransfusions. An estimated 150200 million people worldwide are
infected with hepatitis C.[2][3][4] The existence of hepatitis C originally identifiable only as a type of
non-A non-B hepatitis was suggested in the 1970s and proven in 1989. [5] Hepatitis C infects only
humans and chimpanzees.[6] It is one of five known hepatitis viruses: A, B, C, D, and E.
The virus persists in the liver in about 85% of those infected. This chronic infection can be treated
with medication: the standard therapy is a combination of peginterferon and ribavirin, with
either boceprevir or telaprevir added in some cases. Globally, an estimated 5095% of people
treated are cured.[7][8] With more recently developed medications cure rates are around 80 to 95%.
[8]

Those who develop cirrhosis or liver cancer may require a liver transplant. Hepatitis C is the leading

reason for liver transplantation, though the virus usually recurs after transplantation.
[9]

No vaccine against hepatitis C is available. About 343,000 deaths due to liver cancer from hepatitis

C occurred in 2013, up from 198,000 in 1990.[10] An additional 358,000 in 2013 occurred due to
cirrhosis.[10]

What is the treatment for hepatitis C infection?

There are six genotypes of hepatitis C, and they may respond differently to treatment. Careful
screening is necessary before starting treatment to determine the best treatment for the patient.
Combination antiviral therapy with interferoninjection and oral ribavirin (Rebetol,Copegus,
Ribasphere, RibaPak, Moderiba) has been the mainstay of hepatitis C treatment in the past.
Unfortunately, interferon is not widely available globally, it is not always well tolerated, some virus
genotypes respond better to interferon than others, many people who take interferon do not finish
their treatment, and only 60% of patients respond to the treatment. This means that while hepatitis C
is generally considered to be a curable disease, for many people this was not a reality.
Pegylated interferon: Interferons are a family of naturally occurring proteins that are produced by
the body to fight viral infections. To produce pegylated interferon, the interferon is processed by
attaching ethylene glycol to it. This process is called pegylation and it slows the elimination of
interferon from the body so that its effects are more prolonged. There are currently two types of
pegylated interferons.

pegylated interferon alpha 2b (Peg-Intron A), and

pegylated interferon alpha 2a (Pegasys).

Both pegylated interferon alpha 2b and 2a; are given as a subcutaneous injection once a week.
Optimally, pegylated interferon therapy should be combined with oral ribavirin. In persons who
cannot take ribavirin, monotherapy with pegylated interferon may be used; however, monotherapy
has been shown to achieve sustained virologic response rates of only25%. Older preparations
(nonpegylated forms) of interferon are even less effective than pegylated interferon.
Ribavirin: The antiviral agent, ribavirin (Rebetol, Copegus), is a nucleoside analogue that is taken
by mouth. Nucleoside analogues are man-made molecules that closely resemble the biochemical
units that make up genetic material (RNA and DNA). Ribavirin works by fooling the virus into using it
instead of the normal building blocks of RNA, thereby slowing viral reproduction. Ribavirin has not
worked well when used alone for hepatitis C.
Combined pegylated interferon and ribavirin: Combined therapy with both pegylated interferon
and ribavirin produces a sustained virologic response or cure in 28% to 50% of patients with
genotype 1. (Genotype 1 is the most common genotype in the U.S., but also the most resistant to
treatment.) For unknown reasons, response rates are lower in African American persons and higher
in Caucasians. In patients with genotype 2, sustained response rates are higher (76% to 82%).
Duration of therapy depends on the genotype. Recommended duration of treatment for Genotype 1
is 48 weeks and for genotype 2 and 3 is 24 weeks.
Combination therapy is associated with more side effects than therapy with pegylated interferon
alone. (See below.) In research studies, up to 20% of patients receiving combination therapy
required a reduction in the doses or discontinuation of therapy because of the side effects.
Nevertheless, combination therapy represented significant progress in the treatment of chronic
hepatitis C.
Some patients treated successfully with combination therapy still have detectable virus after 24
weeks of treatment. Few of these patients go on to have a sustained response. Therefore, patients
on combination therapy should have hepatitis C virus RNA measured at 24 weeks of therapy. In
those who are still positive for the virus at that time, consideration is given to stopping treatment,
since the chance of a sustained response with further treatment is small.

Newer drugs and therapeutic medications for hepatitis C

Scientific advances have led to the development of new drugs for hepatitis C, which may be more
effective and better tolerated than existing therapies. There are few newer therapeutic medications in
the market, which are approved by FDA, and many others are in process of development.
Telaprevir (Incivek) and boceprevir (Victrelis) are therapeutic drugs used in addition to interferon
and ribavirin. These combinations are commonly known as triple therapy (comprising of three

medications- interferon, ribavirin and a new agent). The response to triple therapy was better than
with pegylated interferon and ribavirin, reaching approximately 80%. Telaprevir(Incivek) was
withdrawn from the market in 2014 by the manufacturer due to the availability of better drugs.
Sofosbuvir (Sovaldi) and simeprevir (Olysio) are oral therapeutic drugs, which were approved by
the FDA in 2013. These drugs can be used in combination with ribavirin and interferon, but
with simeprevir it is possible to eliminate the interferon. The effectiveness of treatment with these
combinations of medications is extremely high (greater than 90%), and it now provides an all oral
treatment.
Some of these new medications are also are known as direct acting antivirals (DAA) because they:

Directly attack and help kill the hepatitis C virus in the body

Are highly effective with a rate of sustained responses of >90%.

Are taken as all oral regimens i.e. pill only form

Ledipasvir and sofosbuvir (Harvoni) is a combination that is taken as one pill once a day is the
latest addition to the list of direct acting antivirals approved in 2014. With this therapy, the
effectiveness is even greater with a rate of sustained responses of 94%-99% with fewer side effects.
Duration of therapy also is reduced to 12 weeks (instead of the traditional 48 weeks with interferon
and ribavirin).
Ombitasvir, paritaprevir and ritonavir co-packaged with dasabuvir tablets (Viekira Pak), another
combination of oral direct acting antivirals was approved by the FDA in December 2014. The
sustained response rate of this combination was 91%-100%. As these medications are very new,
data is still limited, and more data is expected to be available in the near future.
Many other medications are under investigation but are not approved yet. The latest treatment
guidelines by American Association for the Study of Liver Disease (AASLD) and Infectious Disease
Society of America (IDSA) recommends use of these newer medications (direct acting antivirals) as
the primary treatment for hepatitis C infection and no longer recommend treatment with pegylated
interferon and ribavirin. The choice of direct acting antiviral varies by specific virus genotype and the
presence or absence of cirrhosis. In the U.S., specific insurance providers also might influence the
choice due to the high cost of direct acting antivirals. Patients are encouraged to discuss these
options with their physician on an individual basis.

How effective is hepatitis C treatment?

Treatment responses are mainly defined by results of the HCV RNA testing. The patterns of
response to antiviral treatment have been described as follows:

rapid viral response

end of treatment response

sustained virologic response,

relapse,

partial response

no response

Rapid viral response: Rapid viral response is defined as the absence of detectable HCV RNA in
serum using a sensitive test 4 weeks after initial treatment. Favorable response this early predicts
longer term treatment success.
End of treatment response: End of treatment response is defined as absence of HCV RNA in
blood using a sensitive test at the end of treatment, whatever duration of treatment has been
chosen.
Sustained virologic response: The optimal response is a sustained virologic response (SVR),
defined as the absence of detectable HCV RNA in serum using a sensitive test at the end of the
treatment and six months later. Most of these individuals will remain in remission (no signs of the
disease, cure) indefinitely, with no detectable hepatitis C virus RNA in the blood or liver. Moreover,
follow-up biopsies show a marked reduction in inflammation and there even can be regression of
scarring. Longer follow-up of these patients is necessary, however, to evaluate definitively whether
sustained responders will avoid the complications of cirrhosis and live longer.
Relapsers: Relapsers are patients who initially eliminate the RNA from their blood, but then develop
detectable RNA again shortly after discontinuing therapy. The RNA becomes detectable again within
six months and usually within the first three months of stopping treatment.
Partial responders: Patients whose HCV RNA levels decline (two log decrease), but never become
undetectable at 24 weeks are referred to as partial responders.
No response: Patients who have sustained levels of detectable HCV RNA during therapy are known
as non-responders. Patients in whom HCV RNA becomes undetectable during the early period of
treatment, but reappears before the end of therapy should probably likewise be considered nonresponders. This reappearance of HCV RNA during therapy is referred to as a 'break through' of
HCV.

Treating hepatitis C

Hepatitis C can often be treated successfully by taking a combination of

medicines for several months.
If the infection is diagnosed in the early stages, known as acute hepatitis,
treatment may not need to begin straight away. Instead, you may have
another blood test after a few months to see if your body fights off the virus.
If the infection continues for several months, known as chronic hepatitis,
treatment will usually be recommended.
Your treatment plan
Treatment for hepatitis C involves:
making lifestyle changes to help prevent further damage to your liver
and reduce the risk of spreading the infection
taking a combination of two or three medications to fight the virus
this is known as combination therapy
You'll normally need to take medication for 12 to 48 weeks. This length of time
will depend on the exact medicines you're taking and which version (strain) of
the hepatitis C virus you have. Your doctor will advise you about this.
There are six main strains of the virus. In the UK, the most common strains
are known as "genotype 1" and "genotype 3".
During treatment, you should have blood tests to check if your medication is
working. If the test shows treatment is having little effect, it may be stopped as
further treatment may be of little use.
Lifestyle measures
There are some things you can do to help limit any damage to your liver and
prevent the infection spreading to others. These can include:
eating a healthy and balanced diet
exercising regularly
cutting out alcohol or limiting your intake

 stopping smoking
keeping personal items, such as toothbrushes or razors, for your own
use
not sharing any needles or syringes with others
Read some FAQs about living with hepatitis C for more information.
Hepatitis C medications
Currently, treatment for chronic hepatitis C usually involves taking two main
medicines:
pegylated interferon a medication that encourages the immune
system to attack the virus
ribavirin an antiviral medication that stops the virus reproducing
These medications may just be taken together, although they're often
combined with a third medication, such as simeprevir or sofosbuvir.
These are newer hepatitis C medications that have been shown to make
treatment more effective. Read more about all these medications below.
Pegylated interferon and ribavirin
Pegylated interferon is usually taken as a weekly injection. You can be trained
to inject yourself at home. It usually needs to be taken for up to 48 weeks,
depending on your circumstances.
Ribavirin is available as capsules, tablets or an oral solution. It's normally
taken twice a day with food. It needs to be taken alongside pegylated
interferon for up to 48 weeks.
For more information see the National Institute for Health and Care
Excellence (NICE) guidelines on peginterferon alfa and ribavirin for the
treatment of chronic hepatitis C.
Simeprevir and sofosbuvir

Simeprevir and sofosbuvir are two of the newest hepatitis C medications

recommended by NICE in 2015. They also work by stopping the hepatitis C
virus from reproducing.
Simeprevir may be recommended if you have genotype 1 or genotype 4
hepatitis C. Sofosbuvir is usually given to people with genotype 1 hepatitis C,
although it can be used to treat the other genotypes in some cases.
Both medications come as a tablet that's taken with food once a day. They're
usually taken for either 12, 24 or 48 weeks, depending on your circumstances.
For more information see the NICE guidelines on simeprevir for treating
genotypes 1 and 4 chronic hepatitis C and sofosbuvir for treating chronic
hepatitis C.
Other medications
A number of other medications are also available to treat hepatitis C such as
daclatasvir, ombitasvir and paritaprevir although these haven't yet been
recommended by NICE.
You can read about the draft NICE recommendations on the treatment of
hepatitis C with daclatasvir, ledipasvir, ombitasvir, paritaprevir, ritonavir and
dasabuvir on the NICE website. These recommendations havent been
finalised yet, but are unlikely to change.
Research into even more effective medications is ongoing.
How effective is treatment?
The effectiveness of treatment for hepatitis C can depend on the strain of the
virus you have.
Genotype 1 used to be more challenging to treat and, until quite recently, less
than half of people treated would be cured.
However, with the newer medications now available, the chances of a cure
can be much higher. Combinations of tablets can now have a cure rate of
more than 90%.
This is higher than the chances of curing most other hepatitis C genotypes.

Treatment for genotype 3 will usually involve the standard treatments of

pegylated interferon and ribavirin. About 70-80% of those treated will be
cured.
If the virus is successfully cleared with treatment, it's important to be aware
that you're not immune to the infection. This means, for example, that you
could become infected again if you continue to inject drugs after treatment.
If treatment doesn't work, it may be repeated, extended or tried using a
different combination of medicines.
Side effects of treatment
Side effects of combination therapy involving interferon are quite common.
The new tablet treatments have far fewer side effects and most people feel
unaffected by them.
If your treatment involves interferon, side effects can include:
flu-like symptoms, such as a headache, fatigue (extreme tiredness) and
a high temperature (fever)
a reduced number of red blood cells (anaemia), which can make you
feel tired and out of breath
a rash
depression
itchy skin
feeling and being sick
constipation or diarrhoea
problems sleeping (insomnia)
loss of appetite and weight loss

Hepatitis C medications can have unpredictable reactions when taken with

other medicines or remedies. Always check with your specialist, GP or
pharmacist before taking other types of medication.
Any side effects may improve with time as your body gets used to the
medications. Tell your care team if any side effect is becoming particularly
troublesome.
Coping with side effects can be challenging, but you should continue to take
your medication as instructed. Missing doses may reduce the chances of you
being cured. Treatment
HCV induces chronic infection in 5080% of infected persons. Approximately 4080% of these clear
with treatment.[72][73] In rare cases, infection can clear without treatment.[14]Those with chronic hepatitis
C are advised to avoid alcohol and medications toxic to the liver,[12] and to be vaccinated for hepatitis
A and hepatitis B.[12] Ultrasound surveillance forhepatocellular carcinoma is recommended in those
with accompanying cirrhosis.[12]

Medications
Treatment with antiviral medication is recommended in all people with proven chronic hepatitis C
who are not at high risk of dying from other causes.[74] People with the highest complication risk
should be treated first, with the risk of complications based on the degree of liver scarring. [74] The
initial recommended treatment depends on the type of hepatitis C virus with which a person is
infected.[74]

HCV genotype 1a: 12 weeks of ledipasvir and sofosbuvir OR 12 to 24 weeks

of paritaprevir, ombitasvir, dasabuvir, and ribavirin[74]

HCV genotype 1b: 12 weeks of ledipasvir and sofosbuvir OR 12 weeks of paritaprevir,

ombitasvir, and dasabuvir[74]

HCV genotype 2: 12 to 16 weeks of sofosbuvir and ribavirin [74]

HCV genotype 3: 12 weeks of sofosbuvir, ribavirin, and pegylated interferon[74]

HCV genotype 4: 12 weeks of ledipasvir and sofosbuvir OR paritaprevir, ritonavir, ombitasvir,

and ribavirin, OR 24 weeks of sofosbuvir and ribavirin[74]

HCV genotype 5 or 6: sofosbuvir and ledipasvir [74]

Sofosbuvir with ribavirin and interferon appears to be around 90% effective in those with genotype 1,
4, 5, or 6 disease.[75] Sofosbuvir with just ribavirin appears to be 70 to 95% effective in type 2 and 3
disease but has a higher rate of adverse effects.[76][75] Treatments that contain ledipasvir and
sofosbuvir for genotype 1 has success rates of around 93 to 99% but is very expensive. [77] In
genotype 6 infection, pegylated interferon and ribavirin is effective in 60 to 90% of cases. [7] There is
some tentative data for simeprevir use in type 6 disease as well.[7]
Prior to 2011, treatments consisted of a combination of pegylated interferon alpha and ribavirin for a
period of 24 or 48 weeks, depending on HCV genotype.[12] This produces cure rates of between 70
and 80% for genotype 2 and 3, respectively, and 45 to 70% for genotypes 1 and 4. [76] Adverse effects
with these treatments were common, with half of people getting flu like symptoms and a third
experiencing emotional problems.[12] Treatment during the first six months is more effective than
once hepatitis C has become chronic.[25]

Surgery
Cirrhosis due to hepatitis C is a common reason for liver transplantation[25] though the virus usually
(8090% of cases) recurs afterwards.[9][78] Infection of the graft leads to 1030% of people developing
cirrhosis within five years.[79] Treatment with pegylated interferon and ribavirin post transplant
decreases the risk of recurrence to 70%.[80]

Alternative medicine
Several alternative therapies are claimed by their proponents to be helpful for hepatitis
C including milk thistle, ginseng, and colloidal silver.[81] However, no alternative therapy has been
shown to improve outcomes in hepatitis C, and no evidence exists that alternative therapies have
any effect on the virus at all.[

The standard of care up to 2014

The primary goal of HCV therapy is to cure the infection. A sustained
virological response (SVR) is dened as undetectable HCV RNA 12 weeks
(SVR12) or 24weeks (SVR24) after treatment completion. The infection is
cured in more than 99% of patients who achieve an SVR. The SVR is
generally associated with resolution of liver disease in patients without
cirrhosis. Patients with cirrhosis remain at risk of life-threatening
complications; however hepatic brosis may regress and the risk of
complications such as hepatic failure and portal hypertension is reduced.
Recent data suggest that the risk of HCC and all-cause mortality is
signicantly reduced, but not eliminated, in cirrhotic patients who clear HCV

compared to untreated patients and nonsustained virological responders

[2,3]. HCV may also affect
neurocognition and effective viral suppression is associated with reversal of
cerebral magnetic resonance abnormalities [4]. Until 2011, the combination
of pegylated interferon (PegIFN)a and ribavirin for 24 or 48weeks was the
approved treatment for chronic hepatitis C [5]. With this regimen, patients
infected with HCV genotype 1 had SVR rates of approximately 40% in North
America and 50% in Western Europe. Higher SVR rates were achieved in
patients infected with HCV genotypes 2, 3, 5, and 6 (up to about 80%, and
higher for genotype 2 than for genotypes 3, 5, and 6) and intermediate SVR
rates were achieved in those with HCV genotype 4 [6]. In 2011, telaprevir
and boceprevir were licensed for use in HCV genotype 1 infection. These two
drugs are rst-wave, rstgeneration direct-acting antivirals (DAAs). Both
target the HCV NS3-4A serine protease and are thus referred to as protease
inhibitors. Both telaprevir and boceprevir must be administered in
combination with PegIFN-a and ribavirin. In the Phase III trials of boceprevir
and telaprevir in HCV genotype 1 treatment-nave patients, triple therapy
regimens achieved higher SVR rates than PegIFN-a and ribavirin dual
therapy, of the order of 65% to 75% [710]. However, the side effect proles
of these triple combination therapies and the costs per SVR in patients with
advanced hepatic brosis are such that they should ideally no longer be used
in patients infected with HCV genotype 1, as soon as other, more efcacious
and better tolerated options are available.
ThreenewHCVDAAshavebeenlicensedintheEUin2014,for use as part of
combination therapies for HCV infection. Sofosbuvir, a pangenotypic
nucleotide analogue inhibitor of HCV RNA-dependent RNA polymerase, has
been approved in January 2014. Simeprevir, a second-wave, rst-generation
NS34A protease inhibitor active against genotypes 1 and 4 has been
approved in May 2014. Daclatasvir, a pangenotypic NS5A inhibitor, has been
approved in August 2014. Each of these three DAAs can be used as a
component of a triple combination regimen with PegIFN-a and ribavirin,
yielding SVR rates of 60100% according to the DAA used, the HCV
genotype, the presence of detectable pre-existing amino acid substitutions
conferring resistance to the DAA used and the severity of liver disease.
Although these combinations are better tolerated than triple combination
including telaprevir or boceprevir, their side effect proles and management
remain challenging because of the use of PegIFN-a and of ribavirin. With
three new HCV DAAs approved, IFN-free combinations were broadly used
across Europe in 2014, initially as part of early access programs, essentially

in patients with advanced liver disease (brosis METAVIR score F3 or F4). The
combination of sofosbuvir and ribavirin is indicated in patients infected with
HCV.
AbbVie's VIEKIRAX Approved In Japan For Genotype 1 Chronic Hepatitis C
ABBVIE'S VIEKIRAX (OMBITASVIR/PARITAPREVIR/RITONAVIR TABLETS)
RECEIVES APPROVAL IN JAPAN FOR THE TREATMENT OF GENOTYPE 1 CHRONIC
HEPATITIS C
- NEW INTERFERON AND RIBAVIRIN-FREE TREATMENT OPTION FOR PATIENTS WITH
MOST COMMON TYPE OF HEPATITIS IN JAPAN, GENOTYPE 1 CHRONIC HEPATITIS C,
INCLUDING THOSE WITH COMPENSATED CIRRHOSIS[1]
- VIEKIRAX CONSISTS OF A 12-WEEK, TWO DIRECT-ACTING ANTIVIRAL, FIXED-DOSE
COMBINATION OF PARITAPREVIR/RITONAVIR WITH OMBITASVIR, DOSED ONCE
DAILY[1]
- APPROXIMATELY 1.5 TO 2 MILLION PEOPLE ARE LIVING WITH HEPATITIS C IN JAPAN,
ONE OF THE HIGHEST RATES OF HEPATITIS C INFECTION IN THE INDUSTRIALIZED
WORLD[2],[3]
Sep 28, 2015
NORTH CHICAGO, Ill., Sept. 28, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global
biopharmaceutical company, today announced that the Japanese Ministry of Health,
Labour and Welfare (MHLW) approved VIEKIRAX(ombitasvir/paritaprevir/ritonavir),
as a new interferon and ribavirin-free treatment option for adult patients with
chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, including those with
compensated liver cirrhosis.1 VIEKIRAX consists of a 12-week, two direct-acting
antiviral, xed-dose combination of paritaprevir/ritonavir with ombitasvir, dosed
once daily.
"Today's approval represents an important step forward for the treatment of
Japanese patients, a population with specic needs based on patient and viral
characteristics," said Jean-Michel Pawlotsky, MD, PhD, professor of medicine at the
University of Paris-Est, France. "VIEKIRAX is a valuable new addition to a number of
treatments that are changing the face of hepatitis C, making it possible to achieve
high virologic cure rates, even in patients whose disease has progressed to
compensated liver cirrhosis."
Japan has one of the highest rates of hepatitis C infection in the industrialized world,
with approximately 1.5 to 2 million people living with HCV.2, 3 Genotype 1 is the

most common HCV genotype in Japan with 60 to 70 percent of patients infected

and, of those, about 95 percent are infected with the genotype 1b (GT1b) subtype.4
"We are pleased to provide VIEKIRAX as a new treatment that offers a high
probability of virologic cure for GT1b HCV patients and are working to support
access to our treatment in Japan," said Michael Severino, M.D., executive vice
president, research and development and chief scientic officer, AbbVie. "We are
also prioritizing disease education and awareness by collaborating with stakeholders
to identify and address the diverse challenges across Japan, such as supporting
screening and diagnosis initiatives, and providing accurate information to the
medical community about treatment options."
The approval is supported by the Phase 3 GIFT-I study.1 An overall 95 percent
(n=140/148) of treatment-nave and 94 percent (n=102/109) of treatmentexperienced GT1b HCV infected patients achieved SVR12 with VIEKIRAX.1
The primary endpoint was achieved, demonstrating 95 percent (n=106/112) SVR12
in a sub-group of treatment-nave, non-cirrhotic, adult GT1b HCV infected Japanese
patients who were eligible for therapy with interferon (IFN) and had a high viral
load. A secondary endpoint in GT1b HCV patients with compensated cirrhosis
achieved 91 percent (n=38/42) SVR12.5
Across all treatment arms three patients (n=3/363) experienced on-treatment
virologic failure, eight patients (n=8/354) experienced post-treatment relapse and
three patients discontinued treatment due to adverse events. The most commonly
reported adverse events (>5 percent in any arm) were nasopharyngitis, headache,
peripheral edema, nausea, pyrexia and decreased platelet count.5 In April 2015,
AbbVie was granted priority review by the MHLW for VIEKIRAX, on the basis of
clinical usefulness of the treatment and recognizing the severity and unmet need of
the disease in Japan.
About the GIFT-I Study5
GIFT-I comprises 363 patients in two sub-studies.
In sub-study 1, 321 genotype 1b (GT1b) patients without cirrhosis, both treatmentnave and interferon (IFN) [with or without ribavirin (RBV)] treatment-experienced,
were randomized to receive either ombitasvir/paritaprevir/ritonavir (Arm A)
[OBV/PTV/r] or placebo (Arm B) [2:1 randomization ratio, stratied by treatment
history, past response, viral load and IFN eligibility]. Patients initially randomized to
placebo (Arm B) then received OBV/PTV/r for an additional 12 weeks of open-label
treatment. Sustained virologic response was assessed 12 weeks post-treatment
(SVR12) as a primary efficacy endpoint in a sub-group of previously untreated, non-

cirrhotic GT1b patients who were eligible for therapy with IFN and had a high viral
load, dened as an HCV RNA level 100,000 IU/mL and received at least one dose
of the double-blind, active study drug.
In sub-study 2, 42 GT1b treatment-nave and IFN (with or without RBV) treatmentexperienced patients with compensated cirrhosis received open-label treatment for
12 weeks (Arm C) with SVR12 and assessed as a secondary efficacy endpoint.
One patient from each arm (n=3/363) experienced on-treatment virologic failure
[Arm A, 0.5% (n=1/215); Arm B, 0.9% (n=1/106); Arm C, 2.4% (n=1/42)]. Across all
arms, eight patients (n=8/354) experienced post-treatment relapse [Arm A, 2.4%
(n=5/209); Arm B, 1.0% (n=1/105); Arm C, 5.0% (n=2/40)].
AbbVie studied its two direct-acting antiviral treatment regimen without RBV in
Japan due to patient and viral characteristics specic to the Japanese population,
including high prevalence of GT1b.

Gilead Submits New Drug Application to U.S. Food and Drug

Administration for Fixed-Dose Combination of Sofosbuvir/Velpatasvir for
Treatment of All Six Genotypes of Hepatitis C
Date(s): 28-Oct-2015 5:52 PM
For a complete listing of our news releases, please click here
-- If Approved, Combination Would Be First All-Oral, Pan-Genotypic Single-Tablet
Regimen for Chronic HCV Infection --- Filing is Company's Third in Three Years for a New HCV Medicine -FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 28, 2015-- Gilead Sciences, Inc.
(Nasdaq:GILD) today announced that it has submitted a New Drug Application (NDA)
to the U.S. Food and Drug Administration (FDA) for an investigational, once-daily
xed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir
(SOF), approved as Sovaldi in December 2013, and velpatasvir (VEL), an
investigational pan-genotypic NS5A inhibitor, for the treatment of chronic genotype
1-6 hepatitis C virus (HCV) infection. The NDA is supported by clinical studies
exploring the use of 12 weeks of SOF/VEL for patients with genotype 1-6 HCV
infection, including patients with compensated cirrhosis and 12 weeks of SOF/VEL
with ribavirin for patients with decompensated cirrhosis.
"As the rst xed-dose combination of two pan-genotypic, direct-acting antivirals,
SOF/VEL represents an important step forward in the treatment of patients with

hepatitis C," said Norbert Bischofberger, PhD, Executive Vice President of Research
and Development and Chief Scientic Officer at Gilead. "Genotype 1 is the most
prevalent form of HCV in the United States, but worldwide, more than half of people
living with HCV are infected with other genotypes. SOF/VEL complements our
current HCV portfolio of Sovaldi and Harvoni, offering high cure rates and the
potential to simplify treatment and eliminate the need for HCV genotype testing."
The FDA has assigned SOF/VEL a Breakthrough Therapy designation, which is
granted to investigational medicines that may offer major advances in treatment
over existing options. The NDA for SOF/VEL is supported by data from four Phase 3
ASTRAL trials, which evaluated the xed-dose combination in hepatitis C genotypes
1-6. Of the 1,035 patients treated with SOF/VEL for 12 weeks in the ASTRAL-1,
ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 percent) achieved the primary efficacy
endpoint of SVR12. The ASTRAL-4 study randomized 267 patients with
decompensated cirrhosis (Child-Pugh class B) to receive 12 weeks of SOF/VEL with
or without ribavirin (RBV), or 24 weeks of SOF/VEL. Those who received SOF/VEL
plus RBV for 12 weeks achieved an SVR12 rate of 94 percent, while those who
received SOF/VEL for 12 weeks and 24 weeks achieved SVR12 rates of 83 percent
and 86 percent, respectively.
Patients treated with SOF/VEL for 12 weeks in ASTRAL-1, ASTRAL-2 and ASTRAL-3
had similar adverse events compared with placebo-treated patients in ASTRAL-1.
The most common adverse events were headache, fatigue and nausea. The most
common adverse events in ASTRAL-4 were fatigue, nausea and headache.
Gilead plans to submit a regulatory application for approval of SOF/VEL in the
European Union by the end of the year.
The SOF/VEL xed-dose combination is an investigational product and its safety and
efficacy have not been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and
commercializes innovative therapeutics in areas of unmet medical need. The
company's mission is to advance the care of patients suffering from life-threatening
diseases. Gilead has operations in more than 30 countries worldwide, with
headquarters in Foster City, California.
Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995 that are subject to risks,
uncertainties and other factors, including the risk that FDA may not approve the

SOF/VEL xed-dose combination, and that any marketing approvals, if granted, may
have signicant limitations on its use. In addition, Gilead may be unable to le for
regulatory approval of SOF/VEL in other geographies in the currently anticipated
timelines. Further, additional clinical studies of SOF/VEL may produce unfavorable
results. As a result, Gilead may not be able to successfully commercialize SOF/VEL.
These risks, uncertainties and other factors could cause actual results to differ
materially from those referred to in the forward-looking statements. The reader is
cautioned not to rely on these forward-looking statements. These and other risks
are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter
ended June 30, 2015, as led with the U.S. Securities and Exchange Commission. All
forward-looking statements are based on information currently available to Gilead,
and Gilead assumes no obligation to update any such forward-looking statements.
U.S. full prescribing information for Sovaldi and Harvoni is available
atwww.gilead.com.
Sovaldi and Harvoni are registered trademarks of Gilead Sciences, Inc. or its related
companies.

CONCLUSION
What are the goals of therapy for hepatitis C infection?
The ultimate goals of antiviral therapy are to:

eliminate hepatitis C,

prevent transmission of HCV,

improve or normalize the liver tests,

improve histology (microscopic appearance of inflammation and scarring),

prevent progression to cirrhosis and liver cancer,

prolong survival, and

improve the quality of life of people with hepatitis C.

As previously mentioned, only a sustained virologic response provides the possibility of achieving all
of these goals since most patients who have a sustained response will remain in remission
indefinitely. The rest of the patients (non-responders, partial responders, and relapsers) may show
improvement in blood tests with or without relief of symptoms.

What is the current research and what is in the future for hepatitis C?
As our knowledge of hepatitis C increases, more and more patients are being diagnosed with
chronic infection. Current research includes diagnosis, natural history, treatment, and vaccine
development.

Diagnosis: More accurate tests are being developed to detect even smaller amounts of the

virus.
Natural history: There is much we do not know about the natural history of chronic hepatitis

C. Why do some people clear the virus spontaneously? What makes some people develop
cirrhosis when others appear to have little liver damage? What predicts response to treatment
or re-treatment?
Treatment: New medications are being developed in the hopes of improving response rates

even further. In addition, newer oral medications not requiring interferon are in early stages of
testing that have SVRs upwards of 95%.
Vaccine development: Scientists have not been able to develop an effective vaccine
against hepatitis C. This is partly due to the ability of hepatitis C to change (mutate) and evade
the body's immune responses. Attempts to develop a vaccine, however, are continuing.

Unlike other serious chronic diseases, hepatitis C has the ability to be cured
When it comes to hepatitis C, the outlook for the future is better, but the past is
catching up with us especially if you are a baby boomer, Murray says. Still, this
is a fortuitous time because better hepatitis C treatments are becoming available
just as the patient population at risk of long-term complications is about to peak.
There are treatments for chronic hepatitis and many reasons to get tested now
more than ever because of the availability of safe and effective therapies.
WHEN AND IN WHOM TO INITIATE HCV THERAPY
Printer-friendly versionPDF version
Successful hepatitis C treatment results in sustained virologic response (SVR), which
is tantamount to virologic cure, and as such, is expected to benet nearly all
chronically infected persons. When the US Food and Drug Administration (FDA)
approved the rst IFN-sparing treatment for HCV infection, many patients who had
previously been warehoused sought treatment, and the infrastructure
(experienced practitioners, budgeted health-care dollars, etc) did not yet exist to
treat all patients immediately. Thus, the panel offered guidance for prioritizing
treatment rst to those with the greatest need. Since that time, there have been
opportunities to treat many of the highest-risk patients and to accumulate realworld experience of the tolerability and safety of newer HCV medications. More
importantly, from a medical standpoint, data continue to accumulate that
demonstrate the many benets, within the liver and extrahepatic, that accompany

HCV eradication. Therefore, the panel continues to recommend treatment for all
patients with chronic HCV infection, except those with short life expectancies that
cannot be remediated by treating HCV, by transplantation, or by other directed
therapy. Accordingly, prioritization tables are now less useful and have been
removed from this section.
Despite the strong recommendation for treatment for nearly all HCV-infected
patients, pretreatment assessment of a patients understanding of treatment goals
and provision of education on adherence and follow-up are essential. A wellestablished therapeutic relationship between practitioner and patient remains
crucial for optimal outcomes with new direct-acting antiviral (DAA) therapies.
Additionally, in certain settings there remain factors that impact access to
medications and the ability to deliver them to patients. In these settings,
practitioners may still need to decide which patients should be treated rst. The
descriptions below of unique populations may help physicians make more informed
treatment decisions for these groups.
Clinical Benefit of Cure
The proximate goal of HCV therapy is SVR (virologic cure), defined as the continued absence of detectable HCV
RNA at least 12 weeks after completion of therapy. SVR is a marker for cure of HCV infection and has been shown to
be durable, in large prospective studies, in more than 99% of patients followed up for 5 years or more. (Swain,
2010); (Manns, 2013) Patients in whom an SVR is achieved have HCV antibodies but no longer have detectable
HCV RNA in serum, liver tissue, or mononuclear cells, and achieve substantial improvement in liver histology.
(Marcellin, 1997); (Coppola, 2013); (Garcia-Bengoechea, 1999) Assessment of viral response, including
documentation of SVR, requires use of an FDA-approved quantitative or qualitative nucleic acid test (NAT) with a
detection level of 25 IU/mL or lower.
Patients who are cured of their HCV infection experience numerous health benefits, including a decrease in liver
inflammation as reflected by improved aminotransferase (ie, alanine aminotransferase [ALT], aspartate
aminotransferase [AST]) levels and a reduction in the rate of progression of liver fibrosis. (Poynard, 2002b) Of 3010
treatment-naive HCV-infected patients with pretreatment and posttreatment biopsies from 4 randomized trials of 10
different IFN-based regimens (biopsies separated by a mean of 20 months), 39% to 73% of patients who achieved an
SVR had improvement in liver fibrosis and necrosis (Poynard, 2002b), and cirrhosis resolved in half of the cases.
Portal hypertension, splenomegaly, and other clinical manifestations of advanced liver disease also improved. Among
HCV-infected persons, SVR is associated with a more than 70% reduction in the risk of liver cancer (hepatocellular
carcinoma [HCC]) and a 90% reduction in the risk of liver-related mortality and liver transplantation. (Morgan, 2013);
(van der Meer, 2012); (Veldt, 2007)
Cure of HCV infection also reduces symptoms and mortality from severe extrahepatic manifestations, including
cryoglobulinemic vasculitis, a condition affecting 10% to 15% of HCV-infected patients. (Fabrizi, 2013); (Landau,
2010) HCV-infected persons with non-Hodgkin lymphoma and other lymphoproliferative disorders achieve complete
or partial remission in up to 75% of cases following successful therapy for HCV infection. (Gisbert, 2005);
(Takahashi, 2012); (Svoboda, 2005); (Mazzaro, 2002); (Hermine, 2002) These reductions in disease severity

contribute to dramatic reductions in all-cause mortality. (van der Meer, 2012); (Backus, 2011) Lastly, patients who
achieve SVR have substantially improved qualities of life, which include physical, emotional, and social health.
(Neary, 1999); (Younossi, 2013) Because of the many benefits associated with successful HCV treatment,
clinicians should treat HCV-infected patients with antiviral therapy with the goal of achieving an SVR, preferably early
in the course of chronic HCV infection before the development of severe liver disease and other complications.

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Previously contributing authors: Mary D. Nettleman, MD, MS and MACP and Suresha Rajaguru, MD.

Gilead Submits New Drug Application to U.S. Food and Drug

Administration for Fixed-Dose Combination of Sofosbuvir/Velpatasvir for
Treatment of All Six Genotypes of Hepatitis C. HCV New Drug Research.
October 8, 2015

HCV Guidance: Recommendations for Testing,

Managing, and Treating Hepatitis C. Infectious
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October 22, 2015