Side effects of new and old HCV...

Massimo Puoti

Dept. of Infectious Diseases

AO Ospedale Niguarda Cà Granda

Milan, Italy

Side effects of new and old HCV medications

The O.pe.r.a. StudySafety of PEG IFN and Ribavirin in 1523 HIV/HCV patients treated in Italy from 2004 to 2008

Psychiatric 21%SubjectiveIntol. 21%

Skin 9%

Gastro 9%

Infections 5%

Others 10%

No withdrawal 71%

Drop Out 12%

AE (16%)

• 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g)

No eRVR or cirrhosis; PR

Telaprevir in Genotype 1 Patients

TVR + PReRVR non cirrhosis; stop at Wk 24: 63%

PR

Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.

Time Point Criterion Stopping RuleWk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapyWk 24 Detectable HCV RNA Discontinue PRAny Discontinuation of PR for any reason Discontinue TVR

Treatment Naive and Previous Relapsers

Previous Partial or Null Responders

TVR + PR

480 24124

PR

eRVR: HCVRNA undetectable at 4 & 12 weeks

Boceprevir in Genotype 1 Patients• 800 mg (four 200-mg capsules) q8hr with meal or light snack

• All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks

• If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks

• EMA label recommends fixed-duration therapy for all trt-expd patients: LI + 32 wks triple + 12 wks PR

BOC + PR

PRPR

BOC + PR

Boceprevir [package insert]. May 2011. EMA. Boceprevir [package insert] 2011.

Treatment Naïve w/o cirrhosis

Previous Relapsers or Partial Responders w/o cirrhosis

Wks480 28124

PRPR

8 36

BOC + PR

24

Time Point Criterion Stopping RuleWk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapyWk 24 Detectable HCV RNA Discontinue all therapyAny Discontinuation of PR for any reason Discontinue BOC

Early response stop at Wk 28: 59%

Early response: HCVRNA undetectable at 8 & 24 weeks

PR BOC + PRPts with cirrhosis or Null Responders

Boceprevir-Related Adverse Events in Clinical Trials

• Most notable adverse events occurring more frequently with boceprevir-based therapy vs pegIFN/RBV (600-1400 mg/d) alone• Anemia, neutropenia, and dysgeusia

Adverse Event, % Boceprevir + PegIFN/RBV

PegIFN/RBV

Treatment-naive patients Anemia Neutropenia Dysgeusia

(n = 1225)502535

(n = 467)301916

Treatment-experienced patients Anemia Dysgeusia

(n = 323)4544

(n = 80)2011

Boceprevir [package insert]. May 2011.

Telaprevir-Related Adverse Events in Clinical Trials

• Most notable adverse events occurring more frequently with telaprevir-based therapy vs pegIFN/RBV (1000-1200 mg/d) alone• Rash, anemia, and anorectal symptoms

Adverse Event, % Telaprevir + PegIFN/RBV

(n = 1797)

PegIFN/RBV(n = 493)

Rash 56 34Anemia 36 17Anorectal symptoms 29 7

Telaprevir [package insert]. May 2011.

Safety and tolerability with DAAs

Common AEs with PR include:1–3

– Fatigue, headache, nausea, pyrexia and myalgia– Anemia and neutropenia– Depression, irritability and insomnia– Rash

Additional management considerations with DAAs– Telaprevir:4–6 Rash, Anorectal symptoms, Anemia– Boceprevir:7,8 Anemia and Dysgeusia

1. Pegintron EMA Summary of Product Characteristics; 2. Pegasys EMA Summary of Product Characteristics3. Rebetol EMA Summary of Product Characteristics; 4. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

5. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A; 6. Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):147. Poordad F, et al. NEJM 2011;364:1195–206; 8. Bacon BR, et al. N Engl J Med 2011;364:1207–17AE: adverse event

Side Effects of new and old HCV medications

Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE

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9

Summary of rash data from placebo-controlled Phase II and III trials: telaprevir treatment phase

>90% of all rash = mild/moderate

Inci

denc

e of

rash

(%)

Features: Typically pruritic and eczematous, and involving <30% BSA Progression was infrequent (<8% of cases)

Time to onset: Approximately 50% of rashes started during the first 4 weeks But rash can occur at any time during telaprevir treatment

Inci

denc

e of

rash

(%)

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf;

Data on file: TVR/DoF/January2011/EMEA01

(N=1346) (N=764)

Reported within a special search category

Summary of rash data from Phase II and III placebo-controlled trials:* discontinuations

*During telaprevir treatment phase; analyzed within SSC

Improvement of rash occurs after telaprevir discontinuation Rashes may take weeks for complete resolution

Dis

cont

inua

tions

(%)

Dis

cont

inua

tions

(%)Telaprevir alone All treatment at the

same time

INCIVO (telaprevir) draft EU SmPC [TBC]

Grading of skin eruption severity

Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body)

Moderate: diffuse rash involving ≤50% of body surface area

Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment

SCAR: generalized bullous eruption, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM)


Mild rash Moderaterash

Severerash

Estimating body surface area (BSA)

9%

9%

Front18%

Back18% 9%

18% 18%

Hettiaratchy S, et al. BMJ 2004;329:101–3

Adult body BSA

Perineum 1%

Arm 9%

Head (front and back) 9%

Leg 18%

Chest 18%

Back 18%

Roujeau JC, Stern RS. N Eng J Med 1994;331:1272–85Roujeau JC, et al. Dermatol Sinica 2009;27:203–9; Mockenhaupt M. J Dtsch Dermatol Ges 2009;7:142–160

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

Collective term for severe drug-related skin conditions that can be associated with significant morbidity

SCAR ( Severe Cutaneous Adverse Reactions) reported with telaprevir

3 cases suggestive of SJS

11 cases suggestive of DRESS

(of which 1 case considered not related to telaprevir, onset 11 weeks after telaprevir

discontinuation)

SCAR encompasses

several conditions

Acute generalizedexanthematous pustulosis

(AGEP) and Erythema Multiforme Major (EMM)

Drug rash/reaction with eosinophilia and

systemic symptoms (DRESS)

Toxic epidermal necrolysis (TEN) and Stevens-

Johnson Syndrome (SJS)

Telaprevir interruption guidance

Rash

Mild

Moderate

Severe

TELAPREVIR must not be restarted if discontinued

SCAR

Permanently discontinue telaprevir immediatelyMonitor for progression or systemic symptoms until the rash is resolved. If no improvement within 7 days of stopping telaprevir (or earlier if rash worsens), sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon should be considered

Permanent and immediate discontinuation of telaprevir, peginterferon and ribavirin is required

Monitor for progression or systemic symptoms until the rash is resolved


Monitor for progression or systemic symptoms until the rash is resolved For moderate rash that progresses, permanent discontinuation of telaprevir should be considered. For moderate rash that progresses to severe (≥50% body surface area), permanently discontinue telaprevir

Drug considerations: mild and moderate rash

Treating patients with mild or moderate rash Use topical corticosteroids Permitted topical antihistaminic drugs may be tried Limit exposure to sun/heat Suggest baking soda or oatmeal baths, and loose-fitting clothes Treatment of rash with systemic corticosteroids is not recommended*

Rash

Mild

Moderate

Monitor for progression or systemic symptoms until the rash is resolved

For moderate rash that progresses, permanent discontinuation of telaprevir should be considered

If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted. Interruption of ribavirin may be required sooner if the rash worsens despite discontinuation of telaprevir

Peginterferon alfa may be continued unless interruption is medically indicated

For moderate rash that progresses to severe (≥50% body surface area), permanently discontinue telaprevir

*Concomitant telaprevir and systemic dexamethasone should be used with caution or alternatives should be considered. Co-administration with fluticasone or budesonide is not recommended unless the potential benefit outweighs the risk of corticoseroid side effects INCIVO (telaprevir) draft EU SmPC [TBC]

When to suspect DRESS

Roujeau JC, et al. Dermatol Sinica 2009; 27:203–209Walsh SA, et al. Clin Exp Dermatol 2011;36:6–11

Jeung Y-J, et al. Allergy Asthma Immunol Res 2010;2:123–126Wolf R, et al. Clin Dermatol 2005;23:171–181

Alarm signs: – Relatively late eruption (2–6 weeks

after treatment initiation)– Prolonged fever >38.5°C– Facial oedema– Lymphadenopathy (at least 2 sites)

What to do? Check for biological alterations

– Eosinophilia (absolute count and/or %)– Atypical lymphocytes– Leucocytosis– Lymphocytosis– Involvement of at least one internal

organ (liver, kidney, lungs); raised alanine aminotransferase, creatinine

– Platelet levels below normal

If DRESS is suspected– Stop all drugs– Hospitalize the patient

When to suspect SJS/TEN

Roujeau JC, et al. Dermatol Sinica 2009; 27:203–209; French LE, et al. Allergol Int 2006;55:9–16 Jeung Y-J, et al. Allergy Asthma Immunol Res 2010;2:123–126; Mockenhaupt M, et al. J Invest Dermatol 2008;128:35–44

Acute onset and rapid progression of skin and mucous lesions– Small blisters arising on purple macules, widespread and

usually predominantly on the trunk– Severe and painful erosions of mucous membranes

(buccal, ocular, genital) Epidermal detachment led by confluence of blisters

– Stevens-Johnson Syndrome: 1–10% of body surface area– Toxic epidermal necrolysis: >30% of body surface area)

Positive Nikolsky sign (epidermis detaches easily under lateral pressure with thumb)

High fever Erythema

What to do? Stop all drugs

Hospitalize the patient

Get dermatological advice

Side Effects of new and old HCV medications –Key messages

Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy

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Anorectal disorders* during the telaprevir treatment period in Phase 2 and 3 studies

Mechanism is unknown

*Reported within a special search category1. http://www.fda.gov/downloads/AdvisoryCommittees/Committees/Meeting

Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf; 2. Telaprevir EU SmPC

Proportion (%) of patients with:1T12/PR

(750 mg q8h)N=1346

Placebo/PR48

N=764

AE 26.2 5

AE of at least Grade 3 0.7 0

AE leading to permanent discontinuation of telaprevir/placebo 0.5 0

In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing2

Anorectal signs and symptoms: management

Standard, short-term symptomatic care may be warranted

Consider proprietary combination hemorrhoid preparations according to the nature of the event

Hézode C. Liver International 2012;32 Suppl 1:32-8

Topical local anaesthetics

(e.g. lidocaine2% cream)

Topical local anaesthetics

(e.g. lidocaine2% cream)

Topical cortico-steroids

Topical cortico-steroids

Anti-histamines

Anti-histamines



Anorectal discomfort is frequent but manegeable with prompt symptomatic treatment

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Summary of anemia data from Phase II and III placebo-controlled studies

Incidence and severity of anemia increased with telaprevir combination treatment compared with PR alone

T12/PR Control T12/PR Control

Hemoglobin <10 g/dL Hemoglobin <8.5 g/dL

Pat

ient

s (%

)


Summary of anemia data from the boceprevir SPRINT-2 study over course of therapy

Incidence and severity of anemia increased with boceprevir combination treatment compared with PR alone

BOC RGT

Control

Hemoglobin <10 to 8.5 g/dL Hemoglobin <8.5 g/dL

Pat

ient

s (%

)

BOC44/PR48

BOC RGT

ControlBOC44/PR48

Poordad F, et al. N Engl J Med 2011;364:1195–206

Management of anemia observed with telaprevir and boceprevir in clinical trials

Telaprevir Phase II/III placebo-

controlled trials1

Boceprevir Phase III trials2,3

Ribavirin dose reductions due to anemia

21.6% (telaprevir arms) vs 9.4% (control)

21% (boceprevir arms) vs 13% (control)*

EPO use Not permitted (1% use) 41–46% (boceprevir arms) vs 21–24% (control)

Transfusions

Telaprevir/placebo dosing phase: 2.5% (telaprevir arms) vs 0.7% (control) Overall study period:4.6% (telaprevir arms) vs 1.6% (control)

2–9% (boceprevir arms) vs 0–1% (control)

Discontinuation

Telaprevir alone: 1.9%All treatment at the same time: 0.9% (telaprevir arm) vs 0.5% (control)

0–3% (boceprevir arms) vs 0–1% (control)

1. INCIVO (telaprevir) draft EU SmPC [TBC] 2. Poordad F, et al. N Engl J Med 2011;364:1195–206

3. Bacon BR, et al. N Engl J Med 2011;364:1207–17 *SPRINT-2 data only2

SVR by minimum RBV dose/day during telaprevir/Pbo treatment phase (1 of 2)

Patie

nts

with

SVR

(%)

n/N=

Never reduced

800–1000 mg

346/439

291/395

≤ 600 mg

38/51

Treatment-naïve patients

133/292

13/24

16/38

Never reduced

800–1000 mg

73/89

27/29

≤ 600 mg

20/24

Prior relapsers

11/55

2/7

2/6

PRT12/PR or T12/PR48

Pbo: placebo Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459–S460

SVR according to timing of first RBV dose reduction in T12/PR or T12/PR48 groups

Patie

nts

with

SVR

(%)

n/N=

0 to 4 >4 to 12

160/221

85/99

>12 to 24

171/237

Treatment-naïve patients Previously treated patients

Time to first dose reduction (weeks)*>24 to 48

36/43

6/10

19/24

40/53

6/8

0 to 4 >4 to 12 >12 to 24Time to first dose reduction (weeks)*

>24 to 48

*Time from first dose to first dose reduction Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459–S460

SVR according to time of first RBV dose reduction (during telaprevir/Pbo treatment phase) and HCV RNA status

Treatment-naïve patients in ADVANCE/ILLUMINATE (N=885)

Time after first dose (weeks) HCV RNA status

RBV dose reduction status SVR with T12/PR

0–4 Undetectable • Had RBV dose reduction• No RBV dose reduction

40/45 (89)347/405 (86)

0–4 Detectable • Had RBV dose reduction• No RBV dose reduction

120/176 (68)168/259 (65)

>4 to 12 Undetectable • Had RBV dose reduction• No RBV dose reduction

163/206 (79)502/594 (85)

>4 to 12 Detectable • Had RBV dose reduction• No RBV dose reduction

8/31 (26)2/48 (4)

Small sample sizes among previously treated patients limit interpretation of data in REALIZE, however similar trends were observed

Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459–S460

SVR according to permanent RBV discontinuation during overall treatment phase and HCV RNA status (TVR)

Treatment-naïve patients in ADVANCE/ILLUMINATE (N=885)

HCV RNA status RBV discontinuation status SVR with T12/PR

Undetectable • Did not discontinue• Discontinued RBV

591/659 (90)84/171 (49)

Detectable • Did not discontinue• Discontinued RBV

0/8 (0)0/47 (0)

Small sample sizes among previously treated patients limit interpretation of data in REALIZE, however similar trends were observed

Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459–S460

Efficacy end points: EPO vs RBV dose reduction for managing anemia with boceprevir

*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohortCI: confidence interval; EOT: end of treatment

Patie

nts

(%)

∆ (95% CI)–0.7% (–8.6, 7.2)*

203/249 205/251 178/249 178/251 19/196 19/197

Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559

RBV DREPO




Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided

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CharacteristicCirrhotics (F4)

N=169Non-cirrhotics (F0–3)

N=493Male, n (%) 126 (75) 334 (68)Caucasian race, n (%) 156 (92) 459 (93)Black race, n (%) 8 (5) 22 (4)Years of age, median (range) 54 (24–68) 50 (21–70)HCV RNA ≥800,000 IU/mL, n (%)* 150 (89) 436 (88)

Body mass index, mean (SD) 28 (5.4) 27 (4.6)

HCV genotype, n/N (%)‡

1a1bMissing

97 (57)71 (42)1 (1)

255 (52)229 (46)

9 (2)

Prior response, n (%)Null responderPartial responderRelapser

60 (36)37 (22)72 (43)

124 (25)87 (18)

282 (57)

Lab measures, median (range)Platelet count, 109/LHemoglobin, g/LNeutrophil count, 109/L

167 (88–425)156 (123–189) 3.3 (1.3–17)

225 (86–549)154 (105–228) 3.5 (1.2–8.9)

REALIZE: Baseline Characteristics According to Cirrhosis Status

Pol.S et al. Hepatology 2011: 54: 374A

REALIZE: AEs in ≥25% of TVR-treated Patients during Any Treatment Phase

AE, n (%)Cirrhotics (F4)

N=139Non-cirrhotics (F0–3)

N=391

Rash SSC 93 (67) 206 (53)

Pruritus SSC 82 (59) 205 (52)

Fatigue 62 (45) 214 (55)

Headache 54 (39) 167 (43)

Anemia SSC 59 (42) 134 (34)

Nausea 52 (37) 129 (33)

Influenza-like illness 55 (40) 124 (32)

Insomnia 39 (28) 113 (29)

Anorectal symptoms 33 (24) 101 (26)

Diarrhea 33 (24) 102 (26)

Pyrexia 34 (25) 97 (25)


REALIZE: Laboratory Abnormalities in cirrhotics

n (%) Cirrhotics (F4) N=139

Non-cirrhotics (F0–3) N=391

Hemoglobin≤10g/dL≤8.5g/dL

63 (46)

19 (14)

156 (40)

49 (13)

NeutrophilsGrade 3 (500 to <750/mm3)Grade 4 (<500/mm3)Grade 3/4

35 (25)

10 (7)

45 (32)

68 (17)

9 (2)

77 (19)

PlateletsGrade 3 (25,000 to <50,000/mm3)Grade 4 (<25,000/mm3)Grade 3/4

16 (12)

2 (1)

18 (13)

12 (3)

1 (<1)

13 (3)


REALIZE: AEs Leading to Study Drug Discontinuation in Pooled TVR arms

Cirrhotics (F4) N=139

Non-cirrhotics (F0–3) N=391

Discontinuation of all study drugs during TVR treatment phase, n (%)

Any AERash SSCAnemia SSCPruritus SSC

10 (7)3 (2)

1 (<1)1 (<1)

17 (4)1 (<1)3 (<1)

0

Discontinuation of TVR during TVR treatment phase, n (%)

Any AERash SSCAnemia SSCPruritus SSC

21 (15)8 (6)4 (3)2 (1)

46 (12)14 (4)11 (3)2 (<1)


Compassionate Use of Protease Inhibitors in viral C Cirrhosis partial responders or relapsers: interim analysis after 16 weeks in 455 pts. (26-34% with phase 3 exclusion criteria; 15-16% with esophageal varices)

Peg‐IFN α‐2a + RBVTVR + Peg‐IFN α‐2a + RBV Follow-up

484 160 128Weeks

72

SVR assessment

BOC + Peg‐IFN α‐2b + RBV Follow-upPeg-IFN + RBV

36

http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdfhttp://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf

BOC: 800 mg/8h; Peg‐IFNα‐2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day

TVR: 750 mg/8h; Peg‐IFNα‐2a: 180 µg/week; RBV: 1000 to 1200 mg/day

Interim analysis

Patients, n Telaprevirn=296

Boceprevirn=159

Serious adverse events (%) 48.6 38.4

Premature discontinuationDue to SAEs (%)

26.014.5

23.97.4

Death (%) 2.0 1.3

Infection (Grade 3/4) (%) 8.8 2.5

Asthenia (Grade 3/4) (%) 4.7 5.7

RashGrade 3 (%)Grade 4 (SCAR) (%)

6.80.7

00

Pruritus (Grade 3/4) (%) 3.7 0.6

Hepatic decompensation (%) 4.4 4.4

Preliminary safety findings

Clinical Trials vs Real World

n=530 n=323n=734n=727 n=159n=296

Clinical trials(including cirrhotics)

Real world(cirrhotics only)

Treatment-naïve Treatment-experienced Treatment-experienced

TelaprevirBoceprevir

n=132 n=80n=363n=361

PegIFN/RBV

(courtesy F. Poordad)

Causes of death

• Septicemia, • Septic shock, • Pneumopathy, • Oesophageal varices

bleeding, • Encephalopathy, • Lung carcinoma

• Bronchopulmonary infection,

• Sepsis

Telaprevir Boceprevir

Patients Telaprevir (n=296)

Boceprevir (n=159)

Anemia (%)Grade 2 (8.0 – <10.0 g/dL)Grade 3/4 (<8,0 g/dL)EPO useBlood transfusion

19.610.156.815.2

22.610.166.010.7

Neutropenia (%) Grade 3 (500 – <1000/mm3)Grade 4 (<500/mm3)G-CSF use

4.00.72.4

4.40.63.8

Thrombopenia (%) Grade 3 (25 000 – <50 000)Grade 4 (<25 000)Thrombopoïetin Use

11.81.31.7

6.30.61.9

Preliminary safety findings





Patients with cirrhosis should be treated with great caution and careful monitoring especially if advanced. Surveillance and prompt treatment of infections and decompensation play a key role

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Phase 2 studies with HCV PI in HIV/HCV

Naggie S et al. Submitted 2011

Proportion of patients with advanced fibrosis in HIV/HCV coinfected patients enrolled in previous studies with PR and in DAA Phase 2 studies

Ribavirin dose reductions in the event of anemia*

*in patients without cardiac disease; †400mg in patients receiving 1,400mg/day Copegus and Rebetol SmPCs

• Hb <10g/dL: 600mg/day• Hb <8.5g/dL: RBV discontinuation

Copegus + Telaprevir

• Hb <10g/dL: reduce by 200mg†

(may reduce by 200mg more than once)• Hb <8.5g/dL: RBV discontinuation

Rebetol+Boceprevir

Boceprevir in HCV/HIV co-infection: patient disposition

Sulkowski M, et al. IDSA 2011: Abstract LB-37

n (%) PR BOC/PR

Treated 34 (100) 64 (100)

Discontinued during treatment phase

Due to AE

Due to treatment failure

Did not wish to continue

Non Compliance with protocol

Lost to follow up

18 (53)

3 (9)

14 (41)

1 (3)

0

0

24 (38)*

13 (20)

6 (9)

3 (5)

1 (2)

1 (2)

Completed treatment phase 12 (35) 40 (63)

*Four subjects in the BOC/PR group discontinued treatment for reasons unrelated to AE or treatment failure;AE: adverse event

Telaprevir in HIV/HCV Reasons for early discontinuation from study drugsReason T/PR (N=38) PR (N=22)Discontinued during treatment phase

16 (45) 9 (41)

Futility Rules 2 (5) 7 (32)Adverse events* 3 (8) 0 (0)Other** 11 (32) 2 (9)

*Adverse events were haemolytic anaemia, cholelitiasis , nausea and vomiting (n=3)** Other reasons include: lost to follow up (n=3), withdrawal of consent (n=1), noncompliance (n=4), lack of response (n=1), thought completed therapy (n=1), moved (n=1), patient decision (2).

Telaprevir in HCV/HIV co-infection: summary of rash and hematologic AEs


n (%) PR (n=22) TPV/PR (n=38)

Severe Rash

Mild and Moderate Rash

0

5 (23)

0

13 (34)

Anemia

AEs leading to discontinuation

Grade 3-4 (<8.0 g/dL)

Erythropoietin use

Transfusions

0

5 (23)

1 (5)

1 (5)

1 (2)

11 (29)

3 (8)

4 (11)

Neutropenia

Grade 1-4 (<1.55 x 109/L)

Grade 3-4 (<07.5 x 109/L)

?

?

?

?)

Boceprevir in HCV/HIV co-infection: summary of hematologic AEs


n (%) PR (n=34) BOC/PR (n=64)

Anemia

Serious AEs

AEs leading to discontinuation

Grade 1-4 (<11g/dL)

Grade 3-4 (<8.0 g/dL)

Erythropoietin use

Transfusions

2 (6)

1 (3)

18 (53)

1 (3)

7 (21)

2 (6)

1 (3)

1 (2)

40 (63)

3 (5)

24 (38)

4 (6)

Neutropenia

Grade 1-4 (<1.55 x 109/L)

Grade 3-4 (<07.5 x 109/L)

3 (74)

(12)

10 (86)

(27)

Side Effects of new and old HCV medications – Key messages





Safety profile in persons living with HIV is similar to anti HIV –but data on cirrhotics are lacking

54


• Rash• Anorectal disorders• Anemia• Side effects in cirrhotics• Side effects in HIV• DDI in the management of AE

55

Telaprevir and Antidepressants

DDI with escitalopram (major substrate of CYP3A4, mixed metabolism):

Co-administered drug Dosage

LSM ratio (90% CI), based on AUC

Co-administered drug Telaprevir

Escitalopram 10 mg 0.65 (0.60–0.70)

↔

Others not studied:Class Drug CYP3A4 substrate CYP3A4 inhibitor CYP3A4 inducer

SSRI Fluoxetine Minor Moderate (mixed metabolism)

SSRI Citalopram Major (mixed metabolism)

SSRI Paroxetine Minor (mixed metabolism)

SSRI Sertraline Minor (mixed metabolism)

SSRI Fluvoxamine Moderate (mixed metabolism)

Other Bupropion

Other Venlafaxine Minor (mixed metabolism)

TCA Trazodone Major (mixed metabolism)

TCA Mirtazapine Major (mixed metabolism)

Caution is warranted, and consider dose

reductionsof trazodone

SSRI: selective serotonin re-uptake inhibitors; TCA: tricyclic antidepressant; AUC: area under curve; LSM: least squares mean; CI: confidence interval

van Heeswijk R, et al. IWCPHT 2010. Abstract 12http://pharmacoclin.hug-ge.ch/actualites.html

Spina E, et al. Clinical Therapeutics 2008;30:1206-27

Contraindications with Telaprevir/Boceprevir

Telaprevir & Boceprevir EU SmPC

Class Agent Telaprevir1

Antihistamines Astemizole,† terfenadine†

Diphenhydramine hydroxyzine, levocetirizineand desloratadine can be used

CI

Benzodiazepines Oral midazolam, oral triazolam†

oxazepam can be usedCI

Digestive motility stimulants

Cisapride† DomperidoneMetoclopramide could be given

CI

Contraceptives (oral) Estroprogestatives Oral contraceptive

may not be reliable

PDE5 inhibitors* Sildenafil, tadalafilDose reduction maximum 25 mg SIL/24 hr;

10 mg TAD/72 hr; VAR 2.5 mg/24 H BOC or 2.5 mg per 72 h TPV

CI

*Pulmonary arterial hypertension; †removed/not available in all countriesBOLD: DDI study completed







Management of AE should take into consideration DDI58



Anorectal discomfort is frequent but manageable with prompt symptomatic treatment

Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided.



Management of AE should take into consideration DDI59

Side effects of new and old HCV...

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