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 afa-2b 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 pre-existing 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 75kgRebetrol: 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 66-80 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 pergnterferon 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 three-fold 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.

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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.

TelaprevirTelaprevir 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 generationProtease 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.

Continued: Medications that have a moderate or strong inhibition of the CTP3A may significantly increase levels of Simiprivir (clarithromycin, ketoconazole, ritonavir and MILK THISTLE.

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 DURATION

Genotype 1 or 4Sovaldi+ peginteferon+ribavirin--------------------------------------------Genotype 2 CHCSovaldi+ ribavirin---------------------------------------------Genotype 3 CHC 3Sovaldi + ribavirin

Neutrino12 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 1Genotype 1aGenotype 1bGenotype 4

SOVALDI+Peg-Inf+Rib @ 12 weeks.90% (295/32789% (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:FatigueHeadachesNauseaInsomniaAnemiaAlthough 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 SolvaiAnticonvulsants: 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