HEPATITIS C 2014
TREATMENTS
PAST AND
PRESENT
2014 list of Hep C Medications
PEGYLATED INTERFERON alfa 2a and 2b
RIBIVIRIN-Copegus, Rebetrol and Ribasphere
BOCEPREVIR-VICTRELLIS
TELAPREVIR-INCIVEK
SIMEPREVIR-OLYSIO
SOFOSBUVIR-SOVALDI
THE WORKHORSES OF THE PAST & PRESENT
Peginterferon alfa 2a (Pegasys)
Peginterferon alfa-2b (Pegintron)
Ribavirin;(Copegus, Rebetrol and Ribasphere)
PEGINTERFERON ALFA-2A (PEGASYS)
Pegasys has been one of the basic medications
used for the treatment of chronic Hepatitis C,
since October 2002, when it was first FDA
approved. Another medication, Peginterferon afa2b was approved by the FDA in 2001, and that,
also, is used in combination with ribavirin in
patients with genotypes 1 and 4. ( Interferon has
been used for over 20 years prior to this time)
Mechanism of action: The biologic activity of
Pegasys is derived from it’s interferon alph-2
moeity which addresses the immune
responses against the hepatitis C virus.
The medicine binds to and activates the
human type 1 interferon receptors on the
hepatocytes which activates multiple
intracellular transduction pathways. This
culminates by initiating a number of anti-viral
effects, such as blocking viral protein
synthesis and inducing viral DNA mutagenesis.
It has a sustained absorption, delayed
clearance and a prolonged ½ life in
comparison to native interferon alfa 2a.
INDICATIONS:
Pegasys is indicated, in combinations with Ribavirin, for the
treatment of chronic Hepatitis C in patients over the age of 5,
including those with compensated liver disease, co-morbid HCV and
HIV (with a CD4 count greater than 100 cells/mm3. It has also been
approved to be used with Ribavirin and an approved HCV N53/4A
protease inhibitor in genotype 1 HCV infections
It is contraindicated in patients with autoimmune hepatitis, hepatic
decompensation, patients with cirrhosis and in patients with known
hypersensitivity to any form of alfa interferon.
Peginterferon alfa-2a vs Peginterferon alfa 2-b?
The difference is in the formulation
“The IDEAL study is one of the largest trials of both forms of
peginterferon alfa, designed as a head to head comparison of
the two forms of peginterferon alfa )2a vs 2B) and to also
compare two doses of peginterferon alfa 2-b. Treatment naïve
patients with genotype 1 infections were randomly assigned to
one of three treatment arms. (1) standard dose (1.5 mcg/kg)
peginterferon alfa 2b plus ribavirin (800-1400mg/day), (2) low
dose (imcg/kg) peginteferon alfa 2b plus ribavirin (100-1200
mg/day). Patients wh had an early virologic response had
markedly higher SVR rates than those who did not achieve an
early virologic responsee. The rates of sustained virologic
responses and the incidence of adverse side effects DID NOT
differ substantially across these regimens!”
Pegasys is an injection of 180 mcg/1.0 ml vial for a single use, either in a pre-filled
syringe or in an autoinjector. The medication is given SQ once weekly into the abdomen
or the thigh. Dosages may be modified for people with Thrombocytopenia,Leukopenia,
renal insufficiency, increased ALT’s and Depression;
Clinical Use: It is used in combination with Ribavirin, with or without a direct acting
antiviral such as boceprevir, simeprevir or sofosbuvior for the treatment of chronic
hepatitis C. It is active against ALL genotypes of HCV.,
The duration of treatment depends on several factors, including the medications with
which it is combined, the HCV genotype, the presence or absence of cirrhosis, The
patient’s HIV status, prior treatment experience and the response to prior treatment (
relapse, partial response or non response.
Discontinuation of therapy is considered if the patient has not demonstrates a 2log 10
decline in HCV RNA after 12 weeks of therapy, or they have a detectable HCV RNA after
24 weeks of therapy.
COST: $6,000.00 for a 12 week supply, up to $24,00 for a 48 week supply,
PLUS the cost of ribavirin and any other antiviral medications.
SI
SIDE EFFECTS:Headache, fatigue, and influenza type symptoms, including myalgia,
pyrexia, arthralgia, nausea, anorexia (and weight loss!)
In addition, significant hematologic toxicity such as neutropenia and thrombocytopenia
can occur.
Eye issues can be a problem and it is suggested that a baseline Opthalmic exam should
be performed, and immediate re-checks should be made if problems arise.
Neuropsychiatric effects such s insomnia, depression and irrability can occur, and preexisting conditions can be aggravated into life-threatening neuropsychiatric, autoimmune,
ischemic, or infectious disorders.
In patients with cirrhosis, life-threatening hepatic decompensation can occur.
DRUG INTERACTIONS: Only a few clinically significant drug interactions are associated
with Pegasys, “No effect on the pharmokinetics of representative drugs metabolized by
the cytocrome P450 system have been notes except for the inhibition of P450 1A2
enzyme, a 25% increase in theophyllin AUC, and a 10% increase in methadone AUC.
Serum theophyllin levels should be monitored in patients concomitantly receiving
pegasys and appropriate dose adjustments made when these drugs are used together.
For patients using both Pegasys and methadone, monitoring for signs and symptoms of
methadone toxicity is recommended.
SUMMARY: Peginterferon alfa-2a “has been the cornerstone of treatment for
chronic hepatitis C since it’s introduction….more than a decade ago.”
It continues to be an important role player in 2014, in combination with ribavirin,
and the addition of sofosbuvir. That combination is used for the treatment of
genotypes 1 and 4. The inclusion of simeprevir to the Pegasys and ribavirin is an
alternative.
“Regimens with peginterferon alfa that are no longer considered preferred are
( a) peginterferon alfa plus ribavirin plus either boceprevir or telaprevir for
genotype 1 or (b) peginterferon alpha plus ribavirin for genotypes 2 or 3.
Peginterferon is pricey, but less expensive that the direct acting antivirals such
as sofosbuvir and simeprivir. It is loosing favor because of its extensive adverse
effects, the need for weekly injections, and it’s limited efficacy with certain
patient populations, such as cirrhotics, HIV-co-infected or people who carry the
IL2BB TT genotype.
In the future, it is likely that peginterferon alfa will become obsolete as numerous
interferon free combination regimens become available and become
recommended for all hepatitis C genotypes.
RIBAVIRIN
Ribavirin is another long term therapy for the treatment of chronic hepatitis
C.
It’s exact mechanism of action is not completely understood, however it is
believed to have 4 potential sites of action. 1. augmentation of the host T
cell immune clearance of HCV, (2) inhibition of the host enzyme inosine
monophosphate dehydroginase (IMPDH) that results in depleted pools of
guanosine triphosphate, an essential substrate for viral RNA syntheses (3)
direct inhibition of HCV replecation and (4) induction of RNA metagenesis
that drives HCV to an abnormally high error rate.
Several companies manufacture Ribavirin, as name brand products and a
few other companies produce generic versions.
INDICATIONS: Depend upon the brand of Ribavirin used*
Copegus is approved for use with pegintereferon alfa-2a for the treatment of chronic
hepatitis C with compensated liver disease.
Rebetrol tablet formulation is approved for use with peginterferon alfa-2a for the
treatment of chronic hepatitis C with compensated liver disease.
Ribasphere capsule is approved for use with inteferon alfa 2-b (Intron A) and
pegylinterferon alpha 2b PegIntron) for the treatment of chronic Hepatitis C.
Recently, the NSS5a, a polymerase inhibitor sofosbuvir (Sovaldi) was approved by
the FDA for use with rifampin to treat chronic hepatitis C genotype 2 and 3
infections, and for patients with genotype 1 who are interferon ineligible.
RIBIVIRIN should never be used as monotherapy for the treatment of heptaitis C.
For all preparations, ribavirin is contraindicated in pregnant women, male partners
of females who are pregnant, patients with hemoglobinopathies and co
administration with didanosine (Videx). (immunosupressant)
2 FORMS OF BIRTH CONTROL MUST BE USED DURING TREATMENT and for 6
MONTHS FOLLOWING TREATMENT ( birth defects)
Dosages: 200mg, 400mg, 500mg, and 600mg capsules.
It is also available in an oral solution. The specific doses are dependent upon
the brand used.
Copegus: 200mg tablets, taken BID with food. Fixed dosage 800mg BID in two
divided doses.
Weight based, 1000mg/day for persons less that 75 kig, and 1200 for
those above 75kg
Rebetrol: 200mg capsules and an oral solution 40mg/ml) taken with food. Daily
dose ranges from 800 mg/day to 1400 mg/day in two divided doses.
The fixed doseing is 800mg in two divided doses. When given as weight-based,
the dose is 800mg/day for body weight less than 66kg, 1000 mg a day for 6680 Kg, and 1200 mg/day for 81-105 Kg. for those greater that 105kg, in all
instances the ribavirin should be given in 2 divided doses.
Ribasphere: is available in 200mg, 400mg, and 600mg tablets and 200mg
capsules and should be taken with food. Daily dosage ranges from 800 mg to
1200 mg/day when given with pergnterfer
on alfa 2-c the doses range from 800mg to 1400 mg,/day
RENAL INSUFFICIENCY: increases the levels of ribavirin significantly . Patients with a
creatinine clearance of 30-60 ml/min have a 2 fold increase in ribavirin area under
the curve (AUC) and those with a creatinine clearance 10-30 ml/min have a threefold increase in ribavirin AUC. Ribavirin is not significantly removed by dialysis.
Ribavirin requires dosage modification in patients who have a creatinine clearance
less than 50ml/min and the exact dosage adjustment should be made based on the
prescribing information for the specific brand of ribavirin used.
Ribavirin levels are not significantly impacted by mild, moderate, or severe
dysfunction.
CLINICAL USE: The dose and duration depend upon the hepatitis C genotype, the
patient’s prior treatment experience, and the concomitant medications used for
therapy.
Ribavirin should never be used alone for the treatment of Hepatitis C.
Ribavirin has been used in combinaiton with peginterferon alfa 2a and peginterferon
b, boceprevir, simeprevir, and sofosbuvir.
Ribavirin has been used in combination with sofosbuvir as dual therapy.
p
COST: The exact cost is difficult to report depending on multiple factors, such as
brand name, duration of treatment and availability of some generic products. A rough
estimate is that a 12 week course of pegintereferon and ribaviron is approxinmately
$9,000.00, with the ribavirin accounting for about $2,500.00. The cost for a 48
week course of treatment can be around $10,000.
ADVERSE EFFECTS: Severe hemolytic anemia which can occur suddenly and
Worsen cardiac disease, even leading to MI’s; Birth defects, including both
teratogenic and embryocidal effects.
It is very important to avoid use during pregnancy in both the woman AND
her male partner. Pregnancy tests need to be performed throughout the
therapy, and pregnancy should be avoided for 6 months following treatment.
Less serious side effects include fatigue, nausea, rashes and itching.
MAJOR DRUG INTERACTIONS: When given with didanosine, the levels increase
to potentially life threatening toxicities, It can interact with HIV nucleoside
analog reverse transcriptase inhibitors, and an accumulation in azathioprine
(Imran) may result in azathioprine related nyelotoxicity.
RESISTANCE: In vitro resistence of Hepatitis C. Virus is “poorly defined”, but
possible.
SUMMARY: Ribavirin is and has been an integral part in the
treatment of Hepatitis C. When it is used with interferon or
peginterferon, it significantly reduces relapse rates,significantly
improves the virological response, and plays a significant role in
the treatment of all types of hepatitis C genotypes.
Although the dosing is complicated, the side affects are fierce,
and anema is a problem, it is still the gold standard. Other
medications are in the wings, but not on the market as of this
moment.
THEY COME AND GO…
Boceprevir (Victrellis)
Telaprevir Incivek
Boceprevir was approved by the FDA on May 13, 2011.
It is/was a first generation hepatitis C protease inhibitor that
played a valuable role in the treatment of genotype 1 infections
during the years, 2011, 2012, and 2013.
The addition of Boceprevir to pegylated interferon and ribavirin
clearly improves SVR rated in patients with genotype 1 infection,
but Boceprevir is limigted by its moderate potency, low genetic
barrier to resistance, high pill burden, and a long duration of
therapy.
It has been replaced by newer direct acting agents as a
component of preferred regimens of treatment for HCV genotype
1.
The use of Boceprevir is likely to be limited in the future.
Telaprevir
Telaprevir was approved on May 23, 2011 for treatment of adults
with chronic Hepatitis C. It, too provided a major advantage in
treating patients with genotype 1 chronic hepatitis C when used
in combination with peginterferon and ribavirin, during the years
of 2011, 2012, and 2013.
It, too has lost favor due to major drug-drug interactions,
potential severe cutaneous adverse reactions, high pill burden,
rapid development of resistance with virologic breakthrough,
and, of course, with the development of newer and better direct
acting agents.
It has been replaced as the treatment of choice and likely has a
“limited role” in the future.
Simeprivir (Olysio)..a second generation
Protease inhibitor…
A protease inhibitor. It binds to and inhibits a protein that is
responsiblle for cleaving and processing the HCV-encoded
polyprotein. (NS3/4A) This protein is a critical step in the viral
life cycle of HCV. Simeprivir is considered a second
generation HCV protease inhibitor because of it’s enhanced
affinity and specifity to the N53/4A when compared with the
first generation protease inhibitors with a linear structure.
This medication received it’s FDA approval on November 22,
213 for use as a component of combination therapy for
Hepatitis C.
Indications: in combination with peginteferon and ribavirin
for the treatment of adult patients with chronic Hepatitis C
genotype 1 infection and compensated liver disease.
Including those with cirrhosis. It is used in both treatment
naïve and treatment experienced.
Dosage: 150mg po QD with food
Duration of treatment: from 12 to 24 weeks*
Cost: 12 weeks $66,360.00 , plus the cost of the
peginterferon and the ribavirin.
Adverse effects: photosensitivity, rashes (during
the first 4 weeks of therapy), transient
elevations is serum bilibruin, and possibly a
cross reaction to sulfa drugs.)
Major drug interactions: My reduce medications
that are metabolized through the CYP3A
system, like rifampin,SAINT JOHN’S WORT,and
most anticonvulsants.
Medications that have a moderate or strong
inhibition of the CTP3A may significantly increase levels of
Simiprivir (clarithromycin, ketoconazole, ritonavir and
MILK THISTLE.
Continued:
COST: 12 weeks $ 66,000, plus pegasys and ribivirin. But
increases when used for 24-48 weeks.
FUTURE: As treatment moves toward a goal of interferon free
regimen, “Simeprivir will likely play a future role, especially in
combination with other direct acting agents.”
‘THE NEW KID ON THE BLOCK’
SOFOSBUVIR
SOVALDI
DOB: 12/06/2013
SOVALDI
(sofosbuvir)
400 mg
Sovaldi is a neucleotide analog inhibitor of
hepatitis C virus NS5B polymerase inhibitor
indicated for the treatment of chronic hepatitis
C (CHC) infection as a component of a
combination antiviral treatment regimen.
DOSAGE: One 400mg tablet,
taken daily, with or without
food.
TREATMENT
Genotype 1 or 4
Sovaldi+
peginteferon+ribavirin
-------------------------------------------Genotype 2 CHC
Sovaldi+ ribavirin
--------------------------------------------Genotype 3 CHC 3
Sovaldi + ribavirin
DURATION
Neutrino
12 weeks
---------------------------------------------12 weeks
-------------------------------------------24 weeks
***
Sovaldi in combination with ribavirin for 24
weeks can be considered as a theraputic
option for CHC patients with genotype 1
infection who are ineligible to receive an
interferon-based regimen.
Patients with Hepatocellular Carcinoma
Awaiting Liver Transplantation: Sovaldi in
combination with ribavirin is
recommended for up to 48 weeks or until
the time of liver transplantation, to prevent
post-transplant HCV re-infection.
RESPONSE RATES (NEUTRINO STUDY)
Overall SVR response
Genotype 1
Genotype 1a
Genotype 1b
Genotype 4
SOVALDI+Peg-Inf+Rib @ 12
weeks.
90%
(295/327
89%
(261/292)
92%
(54/66)
96%
(27/28)
OUTCOMES FOR SUBJECTS WITHOUT SVR
ON TREATMENT VIROLOGIC FAILURES
Failure
0/327
Relapse
9% (28/326)
Other
1% (4/327)
Side effects: Most commonly are:
Fatigue
Headaches
Nausea
Insomnia
Anemia
Although the probabilities of these occurring is
20% or less, they are up to 18% more common
with the addition of ribavirin.
Drug-Drug interactions:if used with Solvai
Anticonvulsants: carbamazepine, phenytoin,
phenobarbital, oxcarbazepine. Will Decrease
the concentration and theraputic effect of
Sovaldi.
Antimycobacterials: rifabutin, rifampin,
rifapentine (potent PGP inducers) is expected
to decrease the theraputic effect of Sovaldi.
HERBAL SUPPLEMENTS: ST. JOHN’S WORT
also will decrease theraputic effect .
Continued: No dosage adjustments
are needed for cyclosporine,
darunavir/ritonavir, efavirenz,
emtricitabine, METHADONE,
raltegravir, rilpivirine, tacrolimus or
tenfovir disoproxil fumarate.
THIS IS WHERE WE ARE RIGHT NOW.
As we race toward the goal of
developing Interferon free therapeutic
regimens for the treatment and CURES
for Hepatitis C, believe that several laps
of the relay have already been run.
Changes and new developments appear
on the horizon every day. We are
running a race toward a cure that can
and is being WON.
Resource sites:
Sovaldi Full prescribing information
http://hepatitisc.uw.edu/page/treatment/drugs
Cleveland Clinic Journal of Medicine, March 2014-Dr. Oshea