Severe cutaneous eruptions on telaprevir
Authors: Steven T. Chen, Peggy A. Wu
Journal: Journal of Hepatology (2012)

Since its approval by the Food and Drug Administration in May 2011, telaprevir, a novel serine protease inhibitor, in combination with peginterferon and ribavirin has been increasingly used as an effective treatment for hepatitis C virus (HCV) [[1]Jacobson I.M. McHutchison J.G. Dusheiko G. Di Bisceglie A.M. Reddy K.R. Bzowej N.H. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2163) Google Scholar]. In phase II and III clinical trials involving over 3800 patients, a cutaneous eruption, usually eczematous, occurred in 56% of patients compared to 34% taking peginterferon and ribavirin alone [[2]Transcript for the April 28, 2011 meeting of the antiviral drugs advisory committee. Silver Spring, Maryland: Food and Drug Administration; 2011. Available from: <http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm247236.htm> [Accessed September 14, 2011].Google Scholar]. Furthermore, 3.7% of telaprevir-treated patients developed severe cutaneous adverse events. These events included 11 patients considered to have drug reaction with eosinophilia and systemic symptoms (DRESS), but of these, only one was definite, two were probable, and the remainders were possible, according to diagnostic criteria proposed by Kardaun et al. [2Transcript for the April 28, 2011 meeting of the antiviral drugs advisory committee. Silver Spring, Maryland: Food and Drug Administration; 2011. Available from: <http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm247236.htm> [Accessed September 14, 2011].Google Scholar, 3Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. Herein, we report three patients out of 56 patients at risk (5%) taking telaprevir, peginterferon, and ribavirin at our institution, who developed probable and definite DRESS.Case 1A 60-year-old man with cirrhosis of the liver in week seven of treatment with telaprevir, ribavirin, and peginterferon alfa-2A for chronic HCV was admitted for fever of 39 °C, new shoulder pain, and rash of four-day duration. The patient had previously failed conventional treatment with peginterferon and ribavirin. On telaprevir-based therapy, his HCV viral load (VL) was reduced from >9 million copies IU/ml prior to therapy, to undetectable after four weeks. Partially blanchable, bright, erythematous papules coalescing into larger plaques covered most of the patient’s extremities, chest, abdomen, and back (Fig. 1). The morphology of the rash was consistent with DRESS and involved >50% of his body surface area (BSA). The skin was pruritic but without tenderness, blisters, mucous membrane involvement, facial swelling, nor lymphadenopathy; however, he had left shoulder pain. On laboratory data, he was noted to have an absolute eosinophilia of 805 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 37 K/μl (normal 150–400 K/μl), atypical lymphocytes, and elevations in alanine and asparate aminotransferases to 45 and 74, respectively (normal 0–40 IU/L), thus fulfilling over five diagnostic criteria for a definite case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. All three antiviral therapies were discontinued. A skin biopsy demonstrated eosinophils and was consistent with DRESS. He was managed symptomatically with topical class I corticosteroids and systemic antihistamines. Unfortunately, 2 months after discontinuation of his antivirals, his HCV VL has returned to >5 million IU/ml, and he is being considered for combination therapy with boceprevir, ribavirin and peginterferon.Case 2A 55-year-old female who previously relapsed after peginterferon and ribavirin therapy had a diffuse, pruritic rash, myalgia, fever, and chills for one month prior to admission. She had been taking telaprevir, ribavirin, and peginterferon alfa-2A for chronic HCV with cirrhosis and had an undetectable VL after 8 weeks. One week prior to admission, she finished her 12-week course of telaprevir and remained on ribavirin and peginterferon. Her exam revealed confluent, pink, erythematous plaques with fine scale covering 90% of her BSA and yellow crusts on her lips and chest (Fig. 1). The rash was consistent with an erythrodermic drug eruption. Skin and blood cultures revealed Staphylococcus aureus superinfection and bacteremia. There was no lymphadenopathy, blisters, or mucous membrane involvement. On laboratory data, she had an absolute eosinophilia of 1435 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 93 K/μl (normal 150–400 K/μl), and aspartate aminotransferase of 78 (normal 0–40 IU/L), thus fulfilling over five diagnostic criteria for a definite case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. A skin biopsy showed eosinophils and was consistent with a drug reaction. The remaining antiviral medications were discontinued, and she was managed with antibiotics, topical class I corticosteroids and systemic antihistamines. Two months after completing her 12-week course of telaprevir-based HCV therapy, her VL remained undetectable.Case 3A 56-year-old female, previous non-responder to peginterferon and ribavirin was seen at dermatology clinic for diffuse, indurated, erythematous plaques (Fig. 1) and arthralgias of 10-day duration. She had completed seven weeks of HCV treatment with telaprevir, ribavirin, and peginterferon alfa-2A and her HCV VL was undetectable. She was admitted for fever of 38.5 °C, syncope, and worsening rash, involving 80% of her BSA, morphologically consistent with DRESS. There was no facial swelling, mucous membrane involvement, or blisters. Left inguinal lymphadenopathy of 1 cm was noted. Laboratory data showed an absolute eosinophilia of 1045 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 83 K/μl (normal 150–400 K/μl), atypical lymphocytes, and normal liver function tests. She fulfilled five diagnostic criteria for a probable case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. A skin biopsy was consistent with a drug hypersensitivity reaction. All antiviral therapies were discontinued at initial presentation and class I topical corticosteroids and antihistamines were initiated. Unfortunately, one month after discontinuation of therapy, her HCV VL was again detectable (91,100 IU/ml). A repeat HCV VL was drawn three months after this episode and it was >2 million IU/ml.We present three patients who, after at least seven weeks of telaprevir combined with ribavirin and peginterferon, had severe cutaneous adverse reactions that met criteria for probable and definite DRESS necessitating discontinuation of therapy (see Addendum). Typical of DRESS, these patients developed symptoms many weeks later in the treatment course than is observed with other drug reactions. These three patients presented within a month of each other and represent a higher rate of DRESS following combined telaprevir therapy than previously reported. DRESS is a potentially life threatening syndrome with a reported mortality of up to 10% [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar]. It has the potential to affect visceral organs, most commonly liver, kidney, lung [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar], and new reports have also highlighted a DRESS-related myocarditis [[6]Bourgeois G.P. Cafardi J.A. Groysman V. Hughey L.C. A review of DRESS-associated myocarditis.J Am Acad Dermatol. 2011; 89 ([epub])Google Scholar]. The pathophysiologic mechanism of DRESS is not completely understood; however, current theory ascribes immunologic activation due to drug metabolite formation as the main mechanism [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar]. DRESS is treated with withdrawal of the offending medication, symptomatic management, and potential systemic immunosuppression [[7]James W.D. Berger T.G. Elston D. Andrews’ diseases of the skin: clinical dermatology. 11th ed. WB Sanders, Philadelphia2011Google Scholar]. In order to avoid concerns regarding the suppression of antiviral response, however, systemic immunosuppression was avoided. When compared to the study population in previous reports, our sample size is markedly smaller, and the higher incidence rate may be an anomaly; however, we feel with increasing use of telaprevir, further monitoring of severe adverse event incidence will be critical in determining true risk for potential patients. While the majority of patients treated with telaprevir develop benign drug eruptions [[8]Cacoub P. Bourlière M. Lübbe J. Dupin N. Buggisch P. Dusheiko G. et al.Dermatological side effects of hepatitis c and its treatment: patient management in the era of direct-acting antivirals.J Hepatol. 2012; 56: 455-463Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar], these three cases of DRESS emphasize that with the increasing use of telaprevir, clinicians need to be aware of potentially life-threatening reactions.AddendumSome experts may require more stringent criteria for liver involvement (elevated alanine aminotransferase twice the upper limit of normal on at least two occasions) and lymph node involvement (lymphadenopathy greater than 1 cm for two anatomic sites). By those criteria our series would be considered two probable and one possible case of DRESS [[4]Roujeau J, personal communication, Oct.31, 2011.Google Scholar].Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Since its approval by the Food and Drug Administration in May 2011, telaprevir, a novel serine protease inhibitor, in combination with peginterferon and ribavirin has been increasingly used as an effective treatment for hepatitis C virus (HCV) [[1]Jacobson I.M. McHutchison J.G. Dusheiko G. Di Bisceglie A.M. Reddy K.R. Bzowej N.H. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2163) Google Scholar]. In phase II and III clinical trials involving over 3800 patients, a cutaneous eruption, usually eczematous, occurred in 56% of patients compared to 34% taking peginterferon and ribavirin alone [[2]Transcript for the April 28, 2011 meeting of the antiviral drugs advisory committee. Silver Spring, Maryland: Food and Drug Administration; 2011. Available from: <http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm247236.htm> [Accessed September 14, 2011].Google Scholar]. Furthermore, 3.7% of telaprevir-treated patients developed severe cutaneous adverse events. These events included 11 patients considered to have drug reaction with eosinophilia and systemic symptoms (DRESS), but of these, only one was definite, two were probable, and the remainders were possible, according to diagnostic criteria proposed by Kardaun et al. [2Transcript for the April 28, 2011 meeting of the antiviral drugs advisory committee. Silver Spring, Maryland: Food and Drug Administration; 2011. Available from: <http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm247236.htm> [Accessed September 14, 2011].Google Scholar, 3Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. Herein, we report three patients out of 56 patients at risk (5%) taking telaprevir, peginterferon, and ribavirin at our institution, who developed probable and definite DRESS. Case 1A 60-year-old man with cirrhosis of the liver in week seven of treatment with telaprevir, ribavirin, and peginterferon alfa-2A for chronic HCV was admitted for fever of 39 °C, new shoulder pain, and rash of four-day duration. The patient had previously failed conventional treatment with peginterferon and ribavirin. On telaprevir-based therapy, his HCV viral load (VL) was reduced from >9 million copies IU/ml prior to therapy, to undetectable after four weeks. Partially blanchable, bright, erythematous papules coalescing into larger plaques covered most of the patient’s extremities, chest, abdomen, and back (Fig. 1). The morphology of the rash was consistent with DRESS and involved >50% of his body surface area (BSA). The skin was pruritic but without tenderness, blisters, mucous membrane involvement, facial swelling, nor lymphadenopathy; however, he had left shoulder pain. On laboratory data, he was noted to have an absolute eosinophilia of 805 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 37 K/μl (normal 150–400 K/μl), atypical lymphocytes, and elevations in alanine and asparate aminotransferases to 45 and 74, respectively (normal 0–40 IU/L), thus fulfilling over five diagnostic criteria for a definite case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. All three antiviral therapies were discontinued. A skin biopsy demonstrated eosinophils and was consistent with DRESS. He was managed symptomatically with topical class I corticosteroids and systemic antihistamines. Unfortunately, 2 months after discontinuation of his antivirals, his HCV VL has returned to >5 million IU/ml, and he is being considered for combination therapy with boceprevir, ribavirin and peginterferon. A 60-year-old man with cirrhosis of the liver in week seven of treatment with telaprevir, ribavirin, and peginterferon alfa-2A for chronic HCV was admitted for fever of 39 °C, new shoulder pain, and rash of four-day duration. The patient had previously failed conventional treatment with peginterferon and ribavirin. On telaprevir-based therapy, his HCV viral load (VL) was reduced from >9 million copies IU/ml prior to therapy, to undetectable after four weeks. Partially blanchable, bright, erythematous papules coalescing into larger plaques covered most of the patient’s extremities, chest, abdomen, and back (Fig. 1). The morphology of the rash was consistent with DRESS and involved >50% of his body surface area (BSA). The skin was pruritic but without tenderness, blisters, mucous membrane involvement, facial swelling, nor lymphadenopathy; however, he had left shoulder pain. On laboratory data, he was noted to have an absolute eosinophilia of 805 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 37 K/μl (normal 150–400 K/μl), atypical lymphocytes, and elevations in alanine and asparate aminotransferases to 45 and 74, respectively (normal 0–40 IU/L), thus fulfilling over five diagnostic criteria for a definite case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. All three antiviral therapies were discontinued. A skin biopsy demonstrated eosinophils and was consistent with DRESS. He was managed symptomatically with topical class I corticosteroids and systemic antihistamines. Unfortunately, 2 months after discontinuation of his antivirals, his HCV VL has returned to >5 million IU/ml, and he is being considered for combination therapy with boceprevir, ribavirin and peginterferon. Case 2A 55-year-old female who previously relapsed after peginterferon and ribavirin therapy had a diffuse, pruritic rash, myalgia, fever, and chills for one month prior to admission. She had been taking telaprevir, ribavirin, and peginterferon alfa-2A for chronic HCV with cirrhosis and had an undetectable VL after 8 weeks. One week prior to admission, she finished her 12-week course of telaprevir and remained on ribavirin and peginterferon. Her exam revealed confluent, pink, erythematous plaques with fine scale covering 90% of her BSA and yellow crusts on her lips and chest (Fig. 1). The rash was consistent with an erythrodermic drug eruption. Skin and blood cultures revealed Staphylococcus aureus superinfection and bacteremia. There was no lymphadenopathy, blisters, or mucous membrane involvement. On laboratory data, she had an absolute eosinophilia of 1435 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 93 K/μl (normal 150–400 K/μl), and aspartate aminotransferase of 78 (normal 0–40 IU/L), thus fulfilling over five diagnostic criteria for a definite case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. A skin biopsy showed eosinophils and was consistent with a drug reaction. The remaining antiviral medications were discontinued, and she was managed with antibiotics, topical class I corticosteroids and systemic antihistamines. Two months after completing her 12-week course of telaprevir-based HCV therapy, her VL remained undetectable. A 55-year-old female who previously relapsed after peginterferon and ribavirin therapy had a diffuse, pruritic rash, myalgia, fever, and chills for one month prior to admission. She had been taking telaprevir, ribavirin, and peginterferon alfa-2A for chronic HCV with cirrhosis and had an undetectable VL after 8 weeks. One week prior to admission, she finished her 12-week course of telaprevir and remained on ribavirin and peginterferon. Her exam revealed confluent, pink, erythematous plaques with fine scale covering 90% of her BSA and yellow crusts on her lips and chest (Fig. 1). The rash was consistent with an erythrodermic drug eruption. Skin and blood cultures revealed Staphylococcus aureus superinfection and bacteremia. There was no lymphadenopathy, blisters, or mucous membrane involvement. On laboratory data, she had an absolute eosinophilia of 1435 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 93 K/μl (normal 150–400 K/μl), and aspartate aminotransferase of 78 (normal 0–40 IU/L), thus fulfilling over five diagnostic criteria for a definite case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. A skin biopsy showed eosinophils and was consistent with a drug reaction. The remaining antiviral medications were discontinued, and she was managed with antibiotics, topical class I corticosteroids and systemic antihistamines. Two months after completing her 12-week course of telaprevir-based HCV therapy, her VL remained undetectable. Case 3A 56-year-old female, previous non-responder to peginterferon and ribavirin was seen at dermatology clinic for diffuse, indurated, erythematous plaques (Fig. 1) and arthralgias of 10-day duration. She had completed seven weeks of HCV treatment with telaprevir, ribavirin, and peginterferon alfa-2A and her HCV VL was undetectable. She was admitted for fever of 38.5 °C, syncope, and worsening rash, involving 80% of her BSA, morphologically consistent with DRESS. There was no facial swelling, mucous membrane involvement, or blisters. Left inguinal lymphadenopathy of 1 cm was noted. Laboratory data showed an absolute eosinophilia of 1045 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 83 K/μl (normal 150–400 K/μl), atypical lymphocytes, and normal liver function tests. She fulfilled five diagnostic criteria for a probable case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. A skin biopsy was consistent with a drug hypersensitivity reaction. All antiviral therapies were discontinued at initial presentation and class I topical corticosteroids and antihistamines were initiated. Unfortunately, one month after discontinuation of therapy, her HCV VL was again detectable (91,100 IU/ml). A repeat HCV VL was drawn three months after this episode and it was >2 million IU/ml.We present three patients who, after at least seven weeks of telaprevir combined with ribavirin and peginterferon, had severe cutaneous adverse reactions that met criteria for probable and definite DRESS necessitating discontinuation of therapy (see Addendum). Typical of DRESS, these patients developed symptoms many weeks later in the treatment course than is observed with other drug reactions. These three patients presented within a month of each other and represent a higher rate of DRESS following combined telaprevir therapy than previously reported. DRESS is a potentially life threatening syndrome with a reported mortality of up to 10% [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar]. It has the potential to affect visceral organs, most commonly liver, kidney, lung [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar], and new reports have also highlighted a DRESS-related myocarditis [[6]Bourgeois G.P. Cafardi J.A. Groysman V. Hughey L.C. A review of DRESS-associated myocarditis.J Am Acad Dermatol. 2011; 89 ([epub])Google Scholar]. The pathophysiologic mechanism of DRESS is not completely understood; however, current theory ascribes immunologic activation due to drug metabolite formation as the main mechanism [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar]. DRESS is treated with withdrawal of the offending medication, symptomatic management, and potential systemic immunosuppression [[7]James W.D. Berger T.G. Elston D. Andrews’ diseases of the skin: clinical dermatology. 11th ed. WB Sanders, Philadelphia2011Google Scholar]. In order to avoid concerns regarding the suppression of antiviral response, however, systemic immunosuppression was avoided. When compared to the study population in previous reports, our sample size is markedly smaller, and the higher incidence rate may be an anomaly; however, we feel with increasing use of telaprevir, further monitoring of severe adverse event incidence will be critical in determining true risk for potential patients. While the majority of patients treated with telaprevir develop benign drug eruptions [[8]Cacoub P. Bourlière M. Lübbe J. Dupin N. Buggisch P. Dusheiko G. et al.Dermatological side effects of hepatitis c and its treatment: patient management in the era of direct-acting antivirals.J Hepatol. 2012; 56: 455-463Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar], these three cases of DRESS emphasize that with the increasing use of telaprevir, clinicians need to be aware of potentially life-threatening reactions. A 56-year-old female, previous non-responder to peginterferon and ribavirin was seen at dermatology clinic for diffuse, indurated, erythematous plaques (Fig. 1) and arthralgias of 10-day duration. She had completed seven weeks of HCV treatment with telaprevir, ribavirin, and peginterferon alfa-2A and her HCV VL was undetectable. She was admitted for fever of 38.5 °C, syncope, and worsening rash, involving 80% of her BSA, morphologically consistent with DRESS. There was no facial swelling, mucous membrane involvement, or blisters. Left inguinal lymphadenopathy of 1 cm was noted. Laboratory data showed an absolute eosinophilia of 1045 cells/μl (normal 0–500 cells/μl), thrombocytopenia of 83 K/μl (normal 150–400 K/μl), atypical lymphocytes, and normal liver function tests. She fulfilled five diagnostic criteria for a probable case of DRESS [[3]Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. Halevy S. Davidovici B.B. Mockenhaupt M. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (713) Google Scholar]. A skin biopsy was consistent with a drug hypersensitivity reaction. All antiviral therapies were discontinued at initial presentation and class I topical corticosteroids and antihistamines were initiated. Unfortunately, one month after discontinuation of therapy, her HCV VL was again detectable (91,100 IU/ml). A repeat HCV VL was drawn three months after this episode and it was >2 million IU/ml. We present three patients who, after at least seven weeks of telaprevir combined with ribavirin and peginterferon, had severe cutaneous adverse reactions that met criteria for probable and definite DRESS necessitating discontinuation of therapy (see Addendum). Typical of DRESS, these patients developed symptoms many weeks later in the treatment course than is observed with other drug reactions. These three patients presented within a month of each other and represent a higher rate of DRESS following combined telaprevir therapy than previously reported. DRESS is a potentially life threatening syndrome with a reported mortality of up to 10% [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar]. It has the potential to affect visceral organs, most commonly liver, kidney, lung [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar], and new reports have also highlighted a DRESS-related myocarditis [[6]Bourgeois G.P. Cafardi J.A. Groysman V. Hughey L.C. A review of DRESS-associated myocarditis.J Am Acad Dermatol. 2011; 89 ([epub])Google Scholar]. The pathophysiologic mechanism of DRESS is not completely understood; however, current theory ascribes immunologic activation due to drug metabolite formation as the main mechanism [[5]Cacoub P. Musette P. Descamps V. Meyer O. Speirs C. Finzi L. et al.The DRESS syndrome: a literature review.Am J Med. 2011 Jul; 124: 588-597Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar]. DRESS is treated with withdrawal of the offending medication, symptomatic management, and potential systemic immunosuppression [[7]James W.D. Berger T.G. Elston D. Andrews’ diseases of the skin: clinical dermatology. 11th ed. WB Sanders, Philadelphia2011Google Scholar]. In order to avoid concerns regarding the suppression of antiviral response, however, systemic immunosuppression was avoided. When compared to the study population in previous reports, our sample size is markedly smaller, and the higher incidence rate may be an anomaly; however, we feel with increasing use of telaprevir, further monitoring of severe adverse event incidence will be critical in determining true risk for potential patients. While the majority of patients treated with telaprevir develop benign drug eruptions [[8]Cacoub P. Bourlière M. Lübbe J. Dupin N. Buggisch P. Dusheiko G. et al.Dermatological side effects of hepatitis c and its treatment: patient management in the era of direct-acting antivirals.J Hepatol. 2012; 56: 455-463Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar], these three cases of DRESS emphasize that with the increasing use of telaprevir, clinicians need to be aware of potentially life-threatening reactions. AddendumSome experts may require more stringent criteria for liver involvement (elevated alanine aminotransferase twice the upper limit of normal on at least two occasions) and lymph node involvement (lymphadenopathy greater than 1 cm for two anatomic sites). By those criteria our series would be considered two probable and one possible case of DRESS [[4]Roujeau J, personal communication, Oct.31, 2011.Google Scholar]. Some experts may require more stringent criteria for liver involvement (elevated alanine aminotransferase twice the upper limit of normal on at least two occasions) and lymph node involvement (lymphadenopathy greater than 1 cm for two anatomic sites). By those criteria our series would be considered two probable and one possible case of DRESS [[4]Roujeau J, personal communication, Oct.31, 2011.Google Scholar]. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors wish to thank Dr. Michael Curry for his clinical expertise and patient care.