Case Report

First case of drug rash eosinophilia and systemic symptoms dueto boceprevir

Agnès Samain1,⇑, Anne-Bénédicte Duval-Modeste1, Pascal Joly1, Céline Leblanc1, Nathalie Massy2,Philippe Courville3, Odile Goria4, Ghassan Riachi4

1Dermatology Department, Inserm, U905, Institute for Research and Innovation in Biomedicine, Rouen University Hospital, Universityof Normandy, Rouen, France; 2Pharmacovigilance Department, Rouen University Hospital, University of Normandy, Rouen,

France; 3Pathology Department, Rouen University Hospital, University of Normandy, Rouen, France; 4Hepatogastroenterology Department,Rouen University Hospital, University of Normandy, Rouen, France

Abstract

Boceprevir and telaprevir are 2 specific inhibitors of the hepa-titis C (HCV) serine protease 3. Cutaneous side effects havebeen reported with high frequency, essentially rash, and dryskin. We report a case of drug rash with eosinophilia andsystemic symptoms (DRESS) due to boceprevir. A 56-year-oldAfrican woman with chronic hepatitis C complicated withcirrhosis and cryoglobulinemia received pegylated interferonalfa-2a (PegIFN) and ribavirin (RBV) for 4 weeks and thenboceprevir was added. She was also co-infected with HIV stateA2. Eight weeks after adding boceprevir she developed a gener-alized maculopapular exanthema with fever, facial oedema,apparition of lymph node and alteration of the general state.She presented an eosinophilia (up to 3.0 � 109 cells/L), nobiological inflammatory syndrome. The computed tomographyrevealed several lymph nodes located in the abdominal andinguinal areas. The cutaneous biopsy was consistent with adrug rash reaction. The HCV treatment was stopped and thepatient was treated with topical steroids. Cutaneous andsystemic symptoms disappeared in few weeks. Boceprevirwas considered the culprit drug. We report to our knowledgethe first case of DRESS due to boceprevir.� 2013 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.

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Keywords: Boceprevir; Drug rash eosinophilia and systemic symptoms;Hepatitis C.Received 29 October 2013; received in revised form 2 December 2013; accepted 6December 2013⇑ Corresponding author. Address: Dermatology Department, Rouen UniversityHospital, 1 Rue de Germont, 76031 Rouen Cedex, France. Tel.: +33 232 88 80 79;fax: +33 232 88 88 55.E-mail address: agnessamain@hotmail.com (A. Samain).Abbreviations: HCV, Hepatitis C; DRESS, Drug rash with eosinophilia and systemicsymptoms; PegIFN, Pegylated interferon alfa-2a; RBV, Ribavirin.

Introduction

Boceprevir is a specific inhibitor of the hepatitis C (HCV) serineprotease 3 [1]. Studies have shown a higher achievement of asustained virologic response in patients with a chronic HCV geno-type 1 infection [2–4]. Cutaneous side effects have been reportedin phase II and III clinical trials but no serious cases have beendescribed [2–4]. However, severe cutaneous reaction such asStevens–Johnson syndrome and drug rash with eosinophiliaand systemic symptoms (DRESS) have been described in thePhase III telaprevir trials [5,6].

We report the first case of DRESS due to boceprevir.

Case report

A 56-year-old African woman with chronic hepatitis C compli-cated with cirrhosis and cryoglobulinemia type 2 with severemembers’ sensory and motor neuropathy received boceprevir.She was co-infected with HIV state A2. Her HIV therapy consistedin raltegravir, tenofovir disoproxil and emtricitabine since8 months with good efficacy. For chronic hepatitis C, her treat-ment consisted in the association of interferon alfa-2a (PegIFN)and ribavirin (RBV) for 4 weeks, without adverse effect. Thenboceprevir was added. She had a good response to the treatment:the viral load decreased from 1.3 � 107 to 30 IU/ml in 12 weeks.Eight weeks after adding boceprevir she developed a generalizedmaculopapular exanthema with facial oedema (Fig. 1). She alsohad fever up to 40 �C and appearance of lymphadenopathies andalteration of general state. Biology tests showed an eosinophilia(up to 3.0 � 109 cells/L) and no biological inflammatory syn-drome. She doubled the concentration of the gamma-glutamyltransferase compared to values before treatment. There was notrenal failure. Histological examination of a cutaneous biopsyshowed foci of spongiosis, keratinocyte necrosis, vacuolar alter-ation of the basal cell layer and a perivascular inflammatory infil-trate composed of lymphocytic, many eosinophilia andneutrophils (Fig. 2). This result was consistent with a drug rashreaction. The computed tomography of the thorax and theabdomen revealed several lymph nodes located in the abdominal

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Fig. 1. Generalized maculopapular exanthema.

Fig. 2. Histological examination of skin biopsy HES. Spongiosis, keratinocytenecrosis, vacuolar alteration of the basal cell layer. Perivascular inflammatoryinfiltrate composed of lymphocytic, eosinophilia and neutrophils. 40�.

Case Report

and inguinal areas. HCV treatment was stopped and topical ste-roids were introduced and sufficient to relieve symptoms. No oralsteroid was necessary. Cutaneous and systemic symptoms disap-peared within a few weeks. The eosinophilia persisted more than7 weeks. Boceprevir was considered the culprit drug due to theoccurrence of the symptoms 8 weeks after beginning the drug,the generalized maculopapular rash with facial oedema, fever,

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lymphadenopathy, eosinophilia, and the improvement followinginterruption of boceprevir treatment. The role of PegIFN andRBV was not considered because of a period of use beyond12 weeks and their previous use without DRESS reaction.

Discussion

DRESS is a syndrome classically considered as a severe cutaneousdrug adverse reaction [7]. It presents clinically as an exanthemaevolving to erythroderma with facial oedema, associated withlymphadenopathy, high fever, visceral involvement (hepatitis,renal failure, pneumonitis, or hemophagocytic syndrome), andeosinophilia preceded by lymphopenia and/or atypical lympho-cytes. It is characterized by a long delay between the first drugintake and its development (3 to 8 weeks) and by its long course(more than 2 weeks) with flares even after drug discontinuation.Its pathophysiology is the consequence of the immune responseagainst Herpes virus (HHV6, EBV, and CMV) reactivation. It isinduced by some drugs (allopurinol, anticonvulsants. . .). Its earlydiagnosis is necessary for a rapid discontinuation of the culpritdrug. Its management includes a long-term follow up, andaccording to the severity either topical steroids, systemic ste-roids, intravenous gamma globulins, or antiviral [7]. The risk fac-tors include personal or family history of DRESS, AfricanAmerican origin and HIV infection [7–9].

To our knowledge we report the first case of DRESS due toboceprevir. No case has been described in the literature. Africanorigin and HIV infection were risk factors for the developmentof DRESS in our patient. No study specially focuses on comparisonof DRESS rates in African and HIV population. Some authors havesuggested a role of genetic factors and a vitamin D deficiency inAfrican population [9–12]. In HIV population, genetic factorsare also suggested and the use of antiretroviral drugs which aredrugs inducing DRESS [8,9,13]. Rare cases of DRESS due to ralte-gravir and tenofovir disoproxil are reported [14,15]. These treat-ments were not considered the culprit drug because of a tooprolonged use.

Boceprevir and telaprevir are 2 specific inhibitor of HCV serineprotease 3. The safety data of the combination of boceprevir withPegIFN and RBV was assessed in 2095 subjects with chronic hep-atitis C in a Phase 2, open-label trial (SPRINT-1) and 2 Phase 3,randomized, double-blind, placebo-controlled clinical trials(SPRINT-2, RESPOND-2) [2–4]. The most common adverse eventsobserved were anaemia, dysgeusia, and cutaneous side effects.Cutaneous side effects are reported with the imprecise terms ofdry skin and rash. In these 3 clinical trials, rash were notified in14 to 22% of cases and dry skin were notified in 18 to 22% ofcases. Compared to placebo (PegIFN and RBV alone), these per-centages were statistically significant. No patient receiving boce-previr discontinued the treatment because of skin eruption. Themedian time to appearance of rash or dry skin is not mentionedin these studies. No major cutaneous side effect as DRESS andStevens–Johnson syndrome (SJS) was reported with boceprevir.However, cases of SJS and DRESS have been described in thePhase III telaprevir trials, the other specific inhibitor of HCV ser-ine protease 3 [5,6]. Boceprevir has a high efficacy and is one ofthe major treatments for HCV [5,6]. It provides frequentcutaneous side effect even including DRESS. This highlights theimportance of cooperation between dermatologists and hepato-gastroenterologists.

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Conflict of interest

The authors who have taken part in this study declared that theydo not have anything to disclose regarding funding or conflict ofinterest with respect to this manuscript.

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