palmer journal

7/29/2019 Palmer Journal

1/11

Melissa Palmer, M.D., Series Editor

Practical GastroenteroloGy aPril 2012 33

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #73

Melissa Palmer, M.D., Hepatologist, Clinical

Professor of Medicine, New York University.

HEPATITIS C: A NEW ERA OF TREATMENT, SERIES #4

Hepatitis C Patient Management Issuesin the Era of Protease Inhibitor BasedTriple Therapy

IntroductIon

Melissa Palmer

Hepatitis C (HCV) affects approximately 180

million people worldwide, with genotype 1

(G1) being the most common as well as the most

difcult strain to cure. With the addition of a protease

inhibitor (PI) [either Telaprevir (TVR) or Boceprevir(BOC)] to pegylated interferon (PIFN) plus ribavirin

(RBV), the percentage of G1 HCV patients capable of

achieving a sustained virologic response (SVR), dened

as HCVRNA undetectable 24 weeks after treatment

termination, has dramatically improved. However,

patient management has become increasingly complex.

The incidence and severity of side effects including

rash, anemia, anorectal problems and dysgeusia have

increased. In addition, the clinician must now be aware

of an abundance of potential drug-to-drug interactions

(DDIs).

This article, the 4th in this series, will review themost commonly encountered side effects associated

with BOC or TVR plus PIFN/RBV (triple therapy)

and will outline strategies for successful management

aimed at increasing adherence without compromising

efcacy. Pharmacologic characteristics of TVR and

BOC in addition to DDIs associated with triple therapy

will also be addressed.

rasH

Skin rashes occur in approximately 2428% of patients

being treated with PIFN/RBV. With the exception of

injection site reactions, these rashes are primarily due

to RBV. (1,2,3) While the mechanism of RBV-inducedrash is unknown, it has been postulated that it may be

due to the histamine-like qualities of RBV and/or to the

photosensitivity caused by RBV. (4,5)

While rash is not a signicant problem for patients

taking BOC triple therapy, in clinical trials, rash has

been reported to occur in 56% of patients taking TVR

triple therapy, and may occur with or without pruritus.

(6,7,8,9,10) The mechanism of TVR-induced rash is

unknown and there are no risk factors associated with

rash development. Although typically more severe than

the rash encountered with RBV, over 90% of TVR-

induced rashes have been categorized in clinical trialsas mild-moderate (Grade 1 or 2 respectively). Most

involved less than 30 % body surface area and less than

10 % progressed in severity. (11,12) Table 1 depicts how

to determine % BSA in adult patients by weight. (13)

While about half of patients experienced rash during the

rst four-weeks of TVR triple therapy, it may occur at

any time during the 12 week course. In clinical trials,

6% of patients required discontinuation of TVR due to

rash. Once TVR was discontinued the incidence of rash

was comparable to that of PIFN/RBV. 1% of patients

Hep_C_April_12.indd 33 4/19/12 8:36 PM


2/11

Hepatitis C Patient Management

hepatitis c: a new era of treatment, series #4

34 PracticalGastroenteroloGy aPril2012

required termination of triple therapy due to rash.

(7,8) While rash resolution may take weeks, in clinical

trials eventually all dermatologic events resolved aftertreatment termination.

While serious skin rashes occur infrequently, it is

crucial for the clinician to be aware of this potential

life-threatening complication, as all patients require

triple therapy treatment discontinuation, hospitalization

and prompt dermatologic evaluation. Stevens-Johnson

Syndrome (SJS) is a dermatologic condition in which

cell death leads to the separation of the epidermis

from the dermis. Mucous membrane involvement with

ulcerations and erosions on lips and conjunctiva may

also occur. During clinical trials, SJS was suspected in

two patients and conrmed in one patient who receivedTVR. All reported cases eventually resolved. (6)

Drug-reaction with eosinophilia and systemic

symptoms (DRESS) syndrome is considered to be

a drug hypersensitivity manifesting as rash, fever,

internal organ inammation, lymphadenopathy, and

eosinophilia. As opposed to SJS which has an acute

presentation, DRESS has a slower, more progressive

course. There were three cases of conrmed and an

additional eight cases of suspected DRESS in TVR

clinical trials. Of these cases, one patient was lost to

follow-up and the other patients recovered. (6)

The clinician must be able to condently distinguishbetween and aggressively manage TVR-induced rashes.

Inaccurate rash assessment and management may lead

to lack of patient adherence to therapy, inappropriate

early termination of treatment leading to decreased

treatment efcacy or delayed termination of treatment

and referral to a dermatologist with potential life-

threatening outcomes. It is important to remember that

TVR must never be dose-reduced and once TVR has

been discontinued, it must never be restarted.

Table 2 provides a summary of the grading and

recommended management strategies of TVR-induced

skin rashes adapted during Phase 3 clinical trials. (14)Figures 1-4 provide photographs from patients with

Grade 1-3 TVR-induced rashes.

AnemiAAnemia is a common side of HCV therapy. In clinical

trials of PIFN/RBV mean decline in hemoglobin ranged

between 2.5 g/dL and 3.7 g/dL. and dose reductions

due to anemia were required in 9% -22% of patients.

(15,16) The anemia associated with PIFN is due to bone

marrow suppression and is slowly progressive such

that it typically accounts for the continued decline inhemoglobin concentration during the second and third

months of treatment. The anemia associated with RBV

is due to dose-dependent red blood cell hemolysis in

addition to down-regulation of erythropoietin receptors.

RBV-associated anemia typically occurs during the

rst four weeks of therapy with hemoglobin reductions

between 2-3 gm./dL. (15,16) RBV-associated hemolysis

is the primary reason for dose reductions and treatment

(continued on page 36)

Adult < 80 kg

Aatoc structur BSA %

Anterior Head

Posterior Head

Anterior Torso

Posterior Torso

Anterior Leg each

Posterior Leg each

Anterior Arm each

Posterior Arm each

Genitalia/perineum

4.5

4.5

18

18

9

9

4.5

4.5

1

Adult > 80 kg

Aatoc Structur BSA %

Head and Neck

Anterior Torso

Posterior Torso

Leg Each

Arm Each

Genitalia/Perineum

2

25

25

20

5

0

Tabl 1.Dtrato of Prct Body Surfac Ara

(BSA) in Adults by Weight Adapted from OSullivan,

Susan B., Schmitz, Thomas J. Physical Rehabilitation.

5th ed. F.A. Davis Company, Philadelphia, 2007. p. 1098,

Fig 27.9 (13)



3/11




(continued from page 34)

Grade 1 Mild Rash

Defnition Localized rash and/or rash with limited distribution, pruritus

Management

See fgure 1

1. Topical corticosteroid cream (avoid oral corticosteroids)

2. Oral antihistamines

3. Oatmeal- based soaps and lotions

4. Hypoallergenic skin products

5. Loose-ftting cotton clothing

6. Luke warm instead o hot baths/showers

7. Adequate hydration

8. Sun avoidance/use sunscreen with high SPF9. Use mild clothes detergent

10. Observe or worsening or systemic symptoms

11. Continue TVR

Grade 2 Moderate Rash

Defnition Diuse rash involving < 50% BSA superfcial skin peeling, pruritus

or mucous membrane involvement with no ulceration

Management

See fgure 2

Steps 1-10

I rash progresses:

a. Permanent TVR Discontinuation

b. I no improvement within 7 days- discontinue RBV

c. I rash worsens prior to 7 days discontinue RBV earlier

Grade 3 Severe Rash

Defnition Generalized rash involving either > 50 % BSA or rash associated

with vesicles, bullae or ulceration other than SJS

Management

See fgures 3 and 4

Steps 1-10

Immediate discontinuation o TVR

I no improvement within 7 days- discontinue RBV and/or IFN

I rash worsens prior to 7 days discontinue RBV and/or IFN earlier

Consider consultation with a dermatologist

Grade 4 Lie Threatening or Systemic Involvement

Defnition SJS/DRESS

Management Immediate discontinuation o all treatment

Hospitalization

Consultation with a dermatologist

Table 2. Management o Telaprevir-Associated Rash Adapted rom reerence 14



4/11




termination due to anemia in patients taking PIFN/ RBV.

(17) Studies have shown that G1 patients with inosine

triphosphatase (ITPA) deciency, a benign inheritedenzymopathy in which inosine triphosphate accumulates

in red blood cells, are protected from RBV- associated

hemolytic anemia. These patients are less likely to

require RBV dose reductions. (18,19)

Avoidance of prolonged dose reductions of PIFN

and especially RBV has historically been a crucial factor

in optimizing treatment efcacy. Retrospective analysis

of PIFN/RBV trials demonstrated that G1 patients not

achieving a rapid virologic response (RVR), dened

as HCVRNA undetectable four weeks after therapy

has begun, were statistically signicantly less likely

to achieve SVR when cumulative RBV dose exposure(due to dose reduction, premature cessation, or skipped

doses) was < 60%. (20) This study also demonstrated

that the impact of RBV dose reduction is signicantly

lessened once the HCVRNA level is undetectable.

The addition of either BOC or TVR to PIFN/ RBV

increases the incidence of anemia, which is due to

PI induced bone marrow suppression. In clinical

trials of BOC triple therapy versus a control group

treated with PIFN/RBV, 49% of patients experienced

anemia, dened as a hemoglobin level < 10 g/dL, and

26 % of patients required RBV dose reduction due to

anemia versus 29% and 13% respectively in controls.Erythropoietin alpha (EPO) was administered to patients

(at the investigators discretion) in 43% of patients on

BOC triple therapy versus 24% of controls. In patients

on BOC triple therapy 3% required blood transfusions

and approximately 3% discontinued therapy early due

to anemia versus


5/11




lower BMI, lower hemoglobin, advanced liver disease

and genotype 1b. (29) (Table 3) Thus, patients withthese characteristics, especially those with advanced

liver disease, should be monitored for anemia at more

frequent intervals. It is contraindicated to dose reduce

BOC or TVR, or to use BOC or TVR as monotherapy

under any circumstances. RBV dosages may be held

for up to fourteen days. Permanent discontinuation

of RBV requires permanent discontinuation of BOC

or TVR due to the risk of developing drug resistance.

Anorectal Disorders

Anorectal adverse events including hemorrhoids,

pruritus, pain, burning and diarrhea occur morecommonly in TVR-based regimens compared to

PIFN/ RBV alone (29 % vs. 7% respectively), and

have not been a signicant problem with BOC-based

regimens. (30) While the exact mechanism of anorectal

events is unknown, it is postulated that it may involve the

20 gram fat diet requirement necessary for absorption

of TVR, although this has not been conrmed. There

are no predictors for the development of anorectal

disorders, and there is no correlation with skin rash.

In clinical trials, most anorectal adverse events occurred (continued on page 40)

Table 4. Dysgeusia Management Strategies (37,38,39)

Consumeroomtemperaturefoodsandavoidconsumingfoodsattemperatureextremes Attentiontogoodoralhygiene

Avoidcigarettesmoking

Rinsemouthwithbakingsoda,notcommercialmouthwashesasmanyofthesecontainalcohol

Useplasticutensilsinsteadofmetallicatware

Addmoreseasoningsandspicestofoods,suchassalt,oregano,basil,cinnamon,andginger

Chooseproteinproductswithamildavorsuchaschicken,turkey,tofu,dairyproductsandeggs

Addsugartodecreasesaltyorbittertastes

Reduceconsumptionofbitterormetallictastingfoods

Addfatsandsaucestofoods Suckonhard,sugarlesscandiesand/orchewsugarfreegum.

Drinkmorewaterwithmealstohelpwithswallowingorrinseawaybadtaste

Eatsmallmealsseveraltimesaday

Considerzincsupplementation100mg/day

Treatmucositis

Treatoralinfections

within the rst two weeks of TVR triple therapy and

were considered to be mild to moderate in severity. Only1% of patients discontinued therapy due to anorectal

symptoms.

A baseline anorectal exam prior to initiation of

therapy with treatment of pre-existing anorectal

disorders is recommended. In clinical trials on-treatment

anorectal exam typically revealed hemorrhoids and non-

specic pruritus-induced erythema. General clinical

symptomatic care should be recommended to patients.

This may include sitz baths, topical corticosteroid

creams, topical numbing preparations such as lidocaine

gel, calmoseptine topical cream, pramoxine topical

cream, diarrheal management, loperamide, stoolsofteners, and ber. Oral antihistamines and mild

analgesics have also been used. Good anorectal hygiene

should be discussed with the patient. This includes

avoiding scented lotions and /or toilet paper, as well as

nylon and tight tting undergarments that can contain

moisture. Anorectal symptoms typically resolve either

during TVR therapy or after TVR is completed, thus

all attempts should be made to prevent early TVR

termination.



6/11





Dysgeusia

Dysgeusia, an altered taste sensation, occurred inapproximately 40% of patients taking BOC triple

therapy and in 10% of those patients taking TVR

triple therapy in clinical trials. While typically mild to

moderate in intensity, it is a side effect that can be quite

bothersome to patients, and thus could potentially lead to

decreased patient compliance with therapy. While there

have been no clinical studies specifcally addressing

Figure 3. Grade 3 TVR-induced Rash

Photo courtesy of Melissa Palmer, MD

Figure 4.Vesicular Grade 3 TVR-induced Rash


dysgeusia treatment in HCV patients on triple therapy,

it is advantageous for the healthcare practitioner tobe familiar with commonly recommended therapies.

Zinc supplementation has been used successfully in the

treatment of idiopathic dysgeusia. (31) Since oral zinc

supplementation may slow HCV disease progression,

may reduce the incidence of HCV-related hepatocellular

carcinoma (HCC) and may improve response to

antiviral treatment, it seems reasonable to suggest

Figure 1.Grade 1 TVR-induced Rash


Figure 2.Grade 2 TVR-induced Rash




7/11




Boceprevir

TID (q 7-9 hours)

Must be dosed with food (high fat not a

requirement)

4 (200 mg) tabs TID

Cannot be used as monotherapy

Cannot be dose reduced

No dose adjustment with renal impairment

Telaprevir

Q 8 hours (q 7-9 hours)

With high fat food ( 20 grams of fat required)

2 (375 mg) tabs q8h

Cannot be used as monotherapy

Cannot be dose reduced

No dose adjustment with renal impairment

Table 6.Pharmacologic Characteristics of BOC and TVR

zinc as a treatment option for dysgeusia. (32,33,34) Itshould also be kept in mind that while daily dosages

up to 100mg of zinc may boost the immune system and

improve response to interferon, an excess of this amount

of zinc may be immunosuppressive. (35).

Good oral hygiene should be encouraged.

Meticulous, but not excessive brushing (3-4 times per

day) and gentle fossing is crucial, unless gums are

already inammed. The mouth should be rinsed with

baking soda, but not commercial mouthwashes as many

of these contain alcohol. Mucositis may be diminished

Bagel with cream cheese

1/2 cup of nuts

3 tablespoons of peanut butter

1 cup of ice cream

2 ounces of American or cheddar cheese

2 ounces of potato chips

1/2 cup of trail mix

1 cup of granola (33 g)3 slices of homemade French toast

2 cups 3.3% whole milk

2 oz. chocolate candy bar with almonds or peanuts

2 2oz. plain doughnuts

1 slice pecan pie

1 medium avocado

3.5 oz. lean hamburger in bun

3.5 oz. salami4 slices of bologna

1 3.5 oz broiled pork chop

3 3.5 oz. sausage patties

2 cups chow mein noodles

1 7 oz. fried chicken breast

2 small roasted chicken legs

Table 5. Examples of Foods with 20g of Fat (42)

by lubricating the corners of the mouth and the lips with

petroleum jelly on a regular basis, especially prior to

bedtime. A topical corticosteroid such as uocinomide

(Lidex) 0.05%, or clobetasol (Temovate) 0.05% may

enhance the healing process. A corticosteroid mouth

rinse such as dexamethasone elixir may also be helpful.

Use of oral corticosteroids is contraindicated due to

potential DDIs with BOC or TVR. Topical anesthetics

such as Xylocaine or Orabase B, or an anesthetic

mouthwash or spray such as Hurricane liquid shouldalso be considered.

Mouth infections such as herpes or fungal infections

may occur due to neutropenia, which is increased in

incidence with BOC-based triple therapy compared

with PIFN/RBV (23% versus 18% respectively). (36)

Oral thrush requires mycostatin, usually taken as a swish

and swallow preparation. Difucan (fuconazole) should

be used with caution due to potential DDIs. Increasing

the ow of saliva, which contains antibacterials, can

be achieved by recommending chewing sugarless



8/11




Drugs with Absolute Contraindications Drugs with Relative Contraindication(If used medication dose adjustment is recommended)

AluzosinAtorvastatin (TVR)Carbamazepine (BOC)CisaprideDidanosine (contraindicated with ribavirin)DihydroergotamineDrospirenone (BOC)ErgonovineErgotamineLovastatinMethylergonovine

Midazolam (orally administered)Phenobarbital (BOC)Phenytoin (BOC)PimozideRiampinSt. Johns wortSildenafl or tadalafl (when usedor the treatment o pulmonaryarterial hypertension)

SimvastatinTriazolam

AlprazolamAmiodaroneAtorvastatin ( BOC)Amlodipine (TVR)BepridilBosentanBudesonide (inhaled)Buprenorphine (BOC)Carbamazepine (TVR)ClarithromycinColchicine

CyclosporineDesipramineDexamethasone (systemic)DigoxinDiltiazem (TVR)EavirenzEthinyl estradiolErythromycin (TVR)Escitalopram (TVR)FelodipineFlecainideFluticasone (inhaled)KetoconazoleMethadone

Methylprednisolone (systemic)Midazolam (intravenous)NiedipineNorethindrone(TVR)Phenobarbital (TVR)Phenytoin (TVR)Prednisone (systemic)PropaenoneQuinidineRiabutinRitonavir (Norvir) in combination with atazanavir (Reyataz)or darunavir (Prezista), or with Kaletra (lopinavir/ritonavir)

Salmeterol (inhaled)

Sildenafl (contraindicated i or pulmonary arterialSirolimusTacrolimusTadalafl (contraindicated i or pulmonary arterial hypertension)Tenoovir disoproxil umarate (TVR)TrazodoneVardenaflVerapamil (TVR)VoriconazoleWararinZolpidem (TVR)

Table 7.Drugs with Absolute and Relative Contraindications for use with BOC or TVR

(continued on page 44)



9/11




gum and drinking plenty of uids throughout the day.

Additional management strategies for dysgeusia are

listed in table 4. (37,38,39)

Pharmacologic Characteristics of BOC andTVR

BOC and TVR must be administered three times per

day due to their short half-lives and poor gastrointestinal

(GI) absorption. BOC requires twelve pills per day,

dosed as four 200 mg pills three times per day (every

7-9 hours). TVR requires six pills per day, dosed as two

375 mg pills every 8 hours (range 7-9 hours). It should

be noted that studies of TVR dosed at four pills every

12 hours proved to be equally efcacious. (40) While

both PIs must be taken with food, in contrast to BOC,

TVR must be taken within 30 minutes of consuming

a high fat (20 grams of fat) meal in order to enhanceGI absorption (41) Examples of foods containing 20

grams of fat are detailed in Table 5. (42) Neither PI

can be dose reduced or used as monotherapy. No dose

adjustment is required for renal impairment. (Table 6)

Both BOC and TVR are strong reversible inhibitors

of cytochrome P 450 (CYP) 3 /4 A and the CYP 3 A,

respectively, and are substrates and inhibitors of

P-glycoprotein, a protein that transports a variety of

drug substrates. Due to their mode of metabolism and

transport, the likelihood for DDIs is increased, which

Figure 5. SVR rates in patients with and without RBV Dose

Reduction with TVR-based Triple Therapy.(26)Adapted from Poordad F, Sulkowski MS, Reddy R, et al. Program and

abstracts of the Digestive Disease Week; May 7-10, 2011; Chicago,

Illinois. Abstract 626. SVR rates are independent of ribavirin dose

reduction with TVR-based triple therapy

Figure 6. SVR in patients with Hb < 10 g/dL by Erythropoietin

and/or RBV Dose Reduction with BOC-based Triple Therapy(22)

Adapted from Sulkowski M, Poordad F, Manns MP, et al. Program and

abstracts of the Digestive Disease Week; May 7-10, 2011; Chicago,

Illinois. Abstract Su1865. SVR rates are independent of ribavirin

dose reduction or erythropoietin use with BOC based triple therapy

in turn can cause serious drug toxicity and/or decreased

drug efcacy. Since more than half of all medications

are metabolized via CYP 3A, (43) prior to starting BOC

or TVR triple therapy, health-care practitioners musttake a meticulous medication history with attention to

both prescription and over-the-counter medications

including herbal therapies. Since there are hundreds

of potential DDIs an exhaustive review is beyond the

scope of this article and there are many easy to use apps

and websites such as Epocrates that comprehensively

address DDIs with BOC and TVR. A list of drugs with

absolute and relative contraindications can be found

in Table 7.

Examples of medications that are absolutely

contraindicated during BOC or TVR triple therapy are

the HMG-CoA reductase inhibitors simvastatin andlovastatin. When combined with inhibitors of CYP 3/4A,

HMG-CoA reductase inhibitor toxicities can increase

leading to severe myopathies or even rhabdomyolysis.

(44) Thus, using an alternative lipid-lowering agent is

recommended during BOC or TVR therapy. If a drug

on the relative contraindicated list is used its dose must

be adjusted in the appropriate manner. For example,

the antianxiolytic effect of alprazolam is prolonged

when combined with either TVR or BOC, and therefore

alprazolam requires a dose reduction prior to its use.




10/11




The effectiveness of estrogen-containing birth control

pills is reduced when used with either BOC or TVR,

thus two alternative forms of contraception are requiredduring therapy.

ConClusion

With the FDA approval of BOC and TVR, treatment

of HCV has become more rewarding, yet much

more complex for both the patient and the healthcare

practitioner. Adapting to new concepts such as

stringent dosing requirements, awareness of drug- drug

interactions, avoidance of PI dose reductions, and more

liberal use of RBV dose reductions are necessary.

Patient education surrounding these issues, as well as

prompt and aggressive management by the healthcareprovider of adverse events will result in a decreased

incidence of premature discontinuation, a reduction of

drug toxicities, improvements in treatment adherence

and overall success of therapy.n

References

1. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, GallerGW, McCone J, et al. Peginterferon alfa-2b or alfa-2a withribavirin for treatment of hepatitis C infection. N Engl J Med2009;361:580-593.

2. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferonalfa-2b plus ribavirin compared with interferon alfa-2b plusribavirin for initial treatment of chronic hepatitis C: a random-

ized trial. Lancet. 2001;358:958965. [PubMed]3. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a

plus ribavirin for chronic hepatitis C virus infection. N Engl JMed. 2002;347:975982.

4. Fried MW. Side effects of therapy of hepatitis C and their man-agement. Hepatology. 2002;36:S237S244. [PubMed]

5. Stryjek-Kaminska D, Ochsendorf F, Rder C, Wolter M, ZeuzemS. Photoallergic skin reaction to ribavirin. Am J Gastroenterol.1999;94:16861688

6. FDA Antiviral Drugs Advisory Committee. TelaprevirBrieng Document April 28, 2011. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf, 2011 [accessed feb 28 2012].

7. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevirfor previously untreated chronic hepatitis C virus infection. NEngl J Med. 2011;364:24052416

8. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment ofHCV infection. N Engl J Med. 2011;364:24172428

9. Poordad F, McCone J, Jr., Bacon BR, Bruno S, Manns MP,Sulkowski MS, Jacobson IM, et al. Boceprevir for untreatedchronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206.

10. Bacon BR, Gordon SC, Lawitz E, Marcellin P, VierlingJM, Zeuzem S, Poordad F, et al. Boceprevir for previouslytreated chronic HCV genotype 1 infection. N Engl J Med2011;364:1207-1217.

11. Cacoub P, Bourlire M, Lbbe J, Dupin N, Buggisch P,Dusheiko G, Hzode C, Picard O, Pujol R, Segaert S, Thio B,Roujeau JC. Dermatological side effects of hepatitis C and itstreatment: Patient management in the era of direct-acting antivi-rals. J Hepatol. 2012 Feb;56(2):455-63.

12. Telaprevir EU Summary of Product Characteristics [online].Available at http://www.ema.europa.eu (Accessed Feb 28 2012).

13. OSullivan, Susan B., Schmitz, Thomas J. Physical

Rehabilitation. 5th ed. F.A. Davis Company, Philadelphia,2007. p. 1098, Fig 27.914. http://www.incivek.com/hcp/assess-and-manage-rash accessed

Feb 28 201215. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon

alfa-2b plus ribavirin compared with interferon alfa-2b plus rib-avirin for initial treatment of chronic hepatitis C: a randomisedtrial. Lancet. 2001;358:958965.

16. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2aplus ribavirin for chronic hepatitis C virus infection. N Engl JMed. 2002;347:975982.

17. Sulkowski MS, Wasserman R, BrooksL, Ball L, Gish R.Changes in haemoglobin during interferon alpha-2b plus ribavi-rin combination therapy for chronic hepatitis C virus infection. JViral Hepat 2004; 11(3): 243 250.

18. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, ShiannaKV, et al. ITPA gene variants protect against anaemia in patientstreated for chronic hepatitis C. Nature 2010;464:405-408.

19. Thompson AJ, Fellay J, Patel K, Tillmann HL, Naggie S, Ge D,et al.Variants in the ITPA gene protect against ribavirin-inducedhemolytic anemia and decrease the need for ribavirin dosereduction. Gastroenterology 2010;139:1181-1189.

20. Reddy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirindose reductions in hepatitis C virus genotype 1patients complet-ing peginterferon alfa-2a/ribavirin treatment. Clin GastroenterolHepatol 2007; 5: 1249.

21. Sulkowski MS, Shiffman ML, Afdhal NH, et al. Hepatitis Cvirus treatment-related anemia is associated with higher sus-tained virologic response rate. Gastroenterology 2010;139:160211.

22. Sulkowski MS, Poordad F, Manns MP, et al. Anemia duringtreatment with peginterferon alfa-2b/ribavirin with or withoutboceprevir is associated with higher SVR rates: analysis ofpreviously untreated and previous-treatment failure patients. JHepatol 2011; 54(Suppl. 1): S194.

23. Sulkowski MS, Reddy R, Afdhal NH, et al. Anemia had noeffect on efcacy outcomes in treatment-nave patients whoreceived telaprevir-based regimen in the advance and illuminatephase 3 studies. J Hepatol 2011; 54(Suppl. 1): S195.

24. Poordad F, Sulkowski MS, Reddy R, et al. Program andabstracts of the Digestive Disease Week; May 7-10, 2011;Chicago, Illinois. Abstract 626

25. Poordad F, Sulkowski MS, Reddy R, et al. Program andabstracts of the Digestive Disease Week; May 7-10, 2011;Chicago, Illinois. Abstract 626

26. Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa main-tains ribavirin dose in HCV-infected patients: a prospective, dou-ble-blind, randomized controlled study. Gastroenterology2004;126: 130211.

27. Alavian SM, Tabatabaei SV, Behnava B. Impact of eryth-ropoietin on sustained virological response to peginterferonand ribavirin therapy for HCV infection: a systematic reviewand meta-analysis. J Viral Hepat. 2012 Feb;19(2):88-93. doi:10.1111/j.1365-2893.2011.01532.x. Epub 2011 Oct 30.

28. Sievert W, Dore GJ, McCaughan GW, Yoshihara M,Crawford DH, Cheng W, Weltman M, Rawlinson W, RizkallaB, Depamphilis JK, Roberts SK; CHARIOT Study Group.Virological response is associated with decline in hemoglo-bin concentration during pegylated interferon and ribavirintherapy in hepatitis C virus genotype 1. Hepatology. 2011Apr;53(4):1109-17. doi: 10.1002/hep.24180.

29. Foster, Graham et al. Impact Of Anemia And Ribavirin DoseReduction On Svr To A Telaprevir-Based Regimen In PatientsWith Hcv Genotype 1 And Prior Peginterferon/RibavirinTreatment Failure In The Phase 3 Realize Study Presented at the22nd Conference of the Asian Pacic Association for the Studyof the Liver (APASL) Taipei, Taiwan February 16-19, 2012



11/11




30. http://www.incivek.com/hcp/anorectal-adverse-events accessedFeb 28 2012

31. Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M,Heckmann JG, Hummel T. Zinc gluconate in the treatmentof dysgeusia--a randomized clinical trial. J Dent Res. 2005Jan;84(1):35-8.

32. Ebara M, Fukuda H, Hatano R, et al Metal contents in theliver of patients with chronic liver disease caused by hepatitisC virus. Reference to hepatocellular carcinoma. Oncology.2003;65(4):323-30.

33. Matsuoka S, Matsumura H, Nakamura H, et al Zinc supplemen-tation improves the outcome of chronic hepatitis C and livercirrhosis. J Clin Biochem Nutr. 2009 Nov;45(3):292-303.

34. Takagi H, Nagamine T, Abe T, et al Zinc supplementationenhances the response to interferon therapy in patients withchronic hepatitis C. J Viral Hepat. 2001 Sep;8(5):367-71.

35. Peregrin, T. (2006). Improving taste sensation in patientswho have undergone chemotherapy or radiation therapy.Journal of the American Dietetic Association, 106, 1536-1540.doi:10.1016/j.jada.2006.07.021

36. Reddy , R et al An Evaluation of Neutropenia in the Pivotal

Studies of Boceprevir Plus Peginterferon alfa-2b/RibavirinAASLD 2011 San Fran

37. American Institute for Cancer Research. (2010). Nutrition ofthe cancer patient. [Brochure]. Washington, DC. Retrievedfrom http://www.aicr.org/site/DocServer/Nutrition_of_Patient.pdfdocID=1567

38. Hong, J. H., Omur-Ozbek, P., Stanek, B. T., Dietrich, A. M.,Duncan, S. E., Lee, Y. W., & Lesser, G. (2009). Taste and odorabnormalities in cancer patients. The Journal of SupportiveOncology, 7, 58-65. Retrieved from http://www.supportiveon-cology.net/journal/articles/0702058.pdf

39. Rehwaldt, M., Wickman, R., Purl, S., Tariman, J., Blendowski,C., Shott, S., & Lappe, M. (2009). Self-care strategies to copewith taste changes after chemotherapy. Oncology NursingForum, 36, E 47-56. doi: 10.1188/09.ONF.E47-E56

40. Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G,Drenth JP, et al. Telaprevir is effective given every 8 or 12 hourswith ribavirin and peginterferon alfa-2a or -2b to patients withchronic hepatitis C. Gastroenterology 2011;140:459-468

41. van Heeswijk R, Boogaerts G, De Paepe E, Vangeneugden T, DeBacker K, Beumont M, Garg V. The Effect of Different Types ofFood on the Bioavailability of the Investigational HCV ProteaseInhibitor Telaprevir [abstract 19]. In: 6th International Workshopon Clinical Pharmacology of Hepatitis Therapy. Cambridge,MA; June 22-23, 2011.

42. http://www.incivek.com/how-to-take-incivek retrieved Feb 282012

43. Flockhart DA, Tanus-Santos JE. Implications of cytochromeP450 interactions when prescribing medication for hyperten-sion. Arch Intern Med 2002;162:405-412.

44. Williams D, Feely J. Pharmacokinetic-pharmacodynamicdrug interactions with HMG-CoA reductase inhibitors. ClinPharmacokinet 2002;41:343-370.k

Our

36th Year

REPRINTSSpecial rates are available for

quantities of 100 or more.

For further details email us at:

[email protected]

PRACTICAL GASTROENTEROLOGY

palmer journal

Documents