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7/29/2019 Palmer Journal
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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
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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)
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(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
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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
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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.
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(continued from page 38)
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
Photo courtesy of Melissa Palmer, MD
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
Photo courtesy of Melissa Palmer, MD
Figure 2.Grade 2 TVR-induced Rash
Photo courtesy of Melissa Palmer, MD
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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
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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)
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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.
(continued from page 42)
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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
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