Original Paper Dermatology 2014;228:42–46 DOI: 10.1159/000353160
Received: December 18, 2012 Accepted after revision: May 21, 2013 Published online: January 10, 2014
Cutaneous Reactions in Patients with Chronic Hepatitis C Treated with Peginterferon and Ribavirin Ivana Patrk a Miro Morović b Anamarija Markulin c Jogen Patrk c Departments of a Dermatology, b Infectious Diseases and c Internal Medicine, Zadar General Hospital, Zadar, Croatia
Abstract Background/Objective: Peginterferon alfa and ribavirin could cause various cutaneous reactions. Treatment-related cutaneous reactions are common, and treatable complications can contribute to the treatment discontinuation. Methods: We performed a 6-year prospective study of cutaneous reactions in 271 patients with chronic hepatitis C treated with peginterferon and ribavirin. Results: Cutaneous reactions of mild to moderate degree were seen in 36 (13.3%) patients: localized cutaneous reactions in 7 (2.6%) patients, generalized reactions – pruritus, skin xerosis and eczematous changes – in 28 (10.3%) patients, alopecia in 11 (4.1%) patients; exacerbation of lichen planus was seen in 1 patient. Conclusion: The study showed a relatively low prevalence of cutaneous reactions without the need for discontinuation of any of the drugs used. These reactions correlated only with the age of the patients and treatment duration. This finding is of particular importance with regard to the recently introduced direct-acting antivirals in the treatment of hepatitis C virus infection, which can cause a very severe form of cutaneous reactions. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1018–8665/14/2281–0042$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
The gold standard treatment for chronic hepatitis C, to prevent progression to liver cirrhosis and hepatocellular carcinoma, has been for more than 10 years the combination of pegylated interferon alfa (peginterferon) with ribavirin. Cutaneous reactions occurred in a significant number of the patients, and it is sometimes very difficult to differentiate treatment-related adverse events and the hepatitis C virus (HCV)-related manifestations [1, 2]. The issue is further complicated by the introduction of direct-acting antivirals in the standard treatment protocol recently, which has led to an increase in treatmentrelated reactions as well as an increase in the needs for treatment discontinuation. The aim of this study was to evaluate the incidence and intensity of adverse events in our patients treated with peginterferon alfa-2a and ribavirin, before the introduction of direct-acting antivirals.
Patients and Methods We started a prospective study among 300 patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin from January 2005 to January 2011. Twenty-nine patients were excluded from the study, mostly due to nonresponse to the treatment (absence of early viral response), in a few cases due to significant
Prof. Miro Morović, MD, PhD Zadar General Hospital Department of Infectious Diseases Bože Peričića 5, HR–23000 Zadar (Croatia) E-Mail miro.morovic @ zd.t-com.hr
Downloaded by: University of British Columbia 142.103.160.110 - 7/11/2017 4:28:13 PM
Key Words Cutaneous reactions · Peginterferon · Ribavirin · Chronic hepatitis C
Sex Female Male Total Age, years Genotype 1 2 3 4 Total Cirrhosis No Yes Total Therapy duration 24 weeks 48 weeks Total SVR No Yes Total Skin reaction No Yes Total
62 (22.9) 209 (77.1) 271 (100.0) 35 (31–42) 141 (52.2) 3 (1.1) 110 (40.4) 17 (6.3) 271 (100.0) 178 (65.7) 93 (34.3) 271 (100.0) 182 (67.2) 89 (32.8) 271 (100.0) 79 (29.2) 192 (70.8) 271 (100.0) 235 (86.7) 36 (13.3) 271 (100.0)
Values are numbers with percentages in parentheses or medians with interquartile ranges. SVR = Sustained viral response.
psychiatric disturbances (agitation, depression) and in 2 due to hematologic events. Six of the patients (2%) were coinfected with hepatitis B virus but no additional treatment with nucleoside/nucleotide analogs was used simultaneously. Virologic response and laboratory data during the treatment and follow-up period were collected according to the monitoring chart depending on HCV genotype. The Knodell score was used for fibrosis staging (0–3 without cirrhosis, 4–6 cirrhosis). Cutaneous examination and treatment were provided by experienced dermatologists; dermoscopy (traditional dermatoscope) and biopsy of skin lesions were carried out when needed.
Results
found in 93 (34.3%) patients; sustained viral responses were obtained in 192 (70.8%) of the patients (table 1). Intravenous drug usage, the dominant route of HCV transmission in 244 (90.0%) patients, and 236 (87.1%) patients without any associated diseases (35 patients with associated diseases: diabetes in 3 patients, hypertension in 24, rheumatologic diseases in 5 and psychiatric diseases in 3 patients) were not statistically correlated. Extrahepatic manifestations include hematologic changes – neutropenia (10.6%), thrombocytopenia (10.6%) and anemia (6.4%) –, dysthyroidism (6.4%) and cutaneous reactions (12.0%). Generalized cutaneous reactions – pruritus, xerosis and eczematous changes – were seen in 28 patients (10.3%), alopecia in 11 (4.1%), diffuse alopecia in 7 and alopecia areata in 4 of them; localized reactions were seen in 7 (2.6%), typically as pruritic erythematous patches around injection sites, and in one of them as a sole manifestation. Exacerbation of lichen planus was seen only in 1 case. The univariate and multivariate analyses showed that there was a statistically significant association between the cutaneous reactions and the age of the patients as well as treatment duration. Older patients as well as patients whose therapy lasted 48 weeks are more likely to develop cutaneous reactions. Concentrating on the multivariate analysis, with each additional year in terms of age, the chances for the development of cutaneous reactions increase by 9%, while patients whose therapy lasted 48 weeks have almost 8 times more chances to develop a cutaneous reaction compared to patients whose therapy lasted for 24 weeks. There was no statistically significant correlation between the cutaneous reactions and gender, genotypes, fibrosis stage and sustained viral response (table 2). However, the analysis only of the subgroup with cutaneous reaction (36 patients) showed a statistically significant difference in the prevalence of alopecia between male and female patients (odds ratio = 0.1; 95% confidence interval = 0.0–0.6; p = 0.012). Male participants are 90% more likely to develop alopecia than female patients (table 3).
Discussion
Cutaneous reactions were seen in 36 (13.3%) of 271 patients with chronic hepatitis C treated with peginterferon/ribavirin. The mean age of the patients in the study group was 35 years; there were 209 males and 62 females; more of the patients were infected with genotypes 1 and 4 (58.3%), others with genotypes 2 and 3; cirrhosis was
Our study has shown that cutaneous reactions in patients during the treatment of HCV infection were significantly associated only with the age of the patients and treatment duration. The frequency of the cutaneous reactions among our 271 patients was 13.5%. Other calculations found at least 1 skin manifestation in up to 17% of
Cutaneous Reactions in Patients Treated for Chronic Hepatitis C
Dermatology 2014;228:42–46 DOI: 10.1159/000353160
43
Downloaded by: University of British Columbia 142.103.160.110 - 7/11/2017 4:28:13 PM
Table 1. Patient description
Table 2. Univariate and multivariate analysis of association between age, gender, genotype, cirrhosis, therapy duration, sustained viral response (SVR) and skin reaction
Skin reaction no Gender Female Male Age, years HCV genotype 1, 4 2, 3 Cirrhosis No Yes Therapy duration 24 weeks 48 weeks SVR No Yes
yes
OR
95% CI
p
ORm
95% CIm
pm
total
53 (85.5) 9 (14.5) 182 (87.1) 27 (12.9) 35 (30–40) 43 (37–49)
62 (100.0) 209 (100.0)
– 0.85 1.07
0.38 – 1.94 1.04 – 1.11
0.711
Received: December 18, 2012 Accepted after revision: May 21, 2013 Published online: January 10, 2014
Cutaneous Reactions in Patients with Chronic Hepatitis C Treated with Peginterferon and Ribavirin Ivana Patrk a Miro Morović b Anamarija Markulin c Jogen Patrk c Departments of a Dermatology, b Infectious Diseases and c Internal Medicine, Zadar General Hospital, Zadar, Croatia
Abstract Background/Objective: Peginterferon alfa and ribavirin could cause various cutaneous reactions. Treatment-related cutaneous reactions are common, and treatable complications can contribute to the treatment discontinuation. Methods: We performed a 6-year prospective study of cutaneous reactions in 271 patients with chronic hepatitis C treated with peginterferon and ribavirin. Results: Cutaneous reactions of mild to moderate degree were seen in 36 (13.3%) patients: localized cutaneous reactions in 7 (2.6%) patients, generalized reactions – pruritus, skin xerosis and eczematous changes – in 28 (10.3%) patients, alopecia in 11 (4.1%) patients; exacerbation of lichen planus was seen in 1 patient. Conclusion: The study showed a relatively low prevalence of cutaneous reactions without the need for discontinuation of any of the drugs used. These reactions correlated only with the age of the patients and treatment duration. This finding is of particular importance with regard to the recently introduced direct-acting antivirals in the treatment of hepatitis C virus infection, which can cause a very severe form of cutaneous reactions. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1018–8665/14/2281–0042$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
The gold standard treatment for chronic hepatitis C, to prevent progression to liver cirrhosis and hepatocellular carcinoma, has been for more than 10 years the combination of pegylated interferon alfa (peginterferon) with ribavirin. Cutaneous reactions occurred in a significant number of the patients, and it is sometimes very difficult to differentiate treatment-related adverse events and the hepatitis C virus (HCV)-related manifestations [1, 2]. The issue is further complicated by the introduction of direct-acting antivirals in the standard treatment protocol recently, which has led to an increase in treatmentrelated reactions as well as an increase in the needs for treatment discontinuation. The aim of this study was to evaluate the incidence and intensity of adverse events in our patients treated with peginterferon alfa-2a and ribavirin, before the introduction of direct-acting antivirals.
Patients and Methods We started a prospective study among 300 patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin from January 2005 to January 2011. Twenty-nine patients were excluded from the study, mostly due to nonresponse to the treatment (absence of early viral response), in a few cases due to significant
Prof. Miro Morović, MD, PhD Zadar General Hospital Department of Infectious Diseases Bože Peričića 5, HR–23000 Zadar (Croatia) E-Mail miro.morovic @ zd.t-com.hr
Downloaded by: University of British Columbia 142.103.160.110 - 7/11/2017 4:28:13 PM
Key Words Cutaneous reactions · Peginterferon · Ribavirin · Chronic hepatitis C
Sex Female Male Total Age, years Genotype 1 2 3 4 Total Cirrhosis No Yes Total Therapy duration 24 weeks 48 weeks Total SVR No Yes Total Skin reaction No Yes Total
62 (22.9) 209 (77.1) 271 (100.0) 35 (31–42) 141 (52.2) 3 (1.1) 110 (40.4) 17 (6.3) 271 (100.0) 178 (65.7) 93 (34.3) 271 (100.0) 182 (67.2) 89 (32.8) 271 (100.0) 79 (29.2) 192 (70.8) 271 (100.0) 235 (86.7) 36 (13.3) 271 (100.0)
Values are numbers with percentages in parentheses or medians with interquartile ranges. SVR = Sustained viral response.
psychiatric disturbances (agitation, depression) and in 2 due to hematologic events. Six of the patients (2%) were coinfected with hepatitis B virus but no additional treatment with nucleoside/nucleotide analogs was used simultaneously. Virologic response and laboratory data during the treatment and follow-up period were collected according to the monitoring chart depending on HCV genotype. The Knodell score was used for fibrosis staging (0–3 without cirrhosis, 4–6 cirrhosis). Cutaneous examination and treatment were provided by experienced dermatologists; dermoscopy (traditional dermatoscope) and biopsy of skin lesions were carried out when needed.
Results
found in 93 (34.3%) patients; sustained viral responses were obtained in 192 (70.8%) of the patients (table 1). Intravenous drug usage, the dominant route of HCV transmission in 244 (90.0%) patients, and 236 (87.1%) patients without any associated diseases (35 patients with associated diseases: diabetes in 3 patients, hypertension in 24, rheumatologic diseases in 5 and psychiatric diseases in 3 patients) were not statistically correlated. Extrahepatic manifestations include hematologic changes – neutropenia (10.6%), thrombocytopenia (10.6%) and anemia (6.4%) –, dysthyroidism (6.4%) and cutaneous reactions (12.0%). Generalized cutaneous reactions – pruritus, xerosis and eczematous changes – were seen in 28 patients (10.3%), alopecia in 11 (4.1%), diffuse alopecia in 7 and alopecia areata in 4 of them; localized reactions were seen in 7 (2.6%), typically as pruritic erythematous patches around injection sites, and in one of them as a sole manifestation. Exacerbation of lichen planus was seen only in 1 case. The univariate and multivariate analyses showed that there was a statistically significant association between the cutaneous reactions and the age of the patients as well as treatment duration. Older patients as well as patients whose therapy lasted 48 weeks are more likely to develop cutaneous reactions. Concentrating on the multivariate analysis, with each additional year in terms of age, the chances for the development of cutaneous reactions increase by 9%, while patients whose therapy lasted 48 weeks have almost 8 times more chances to develop a cutaneous reaction compared to patients whose therapy lasted for 24 weeks. There was no statistically significant correlation between the cutaneous reactions and gender, genotypes, fibrosis stage and sustained viral response (table 2). However, the analysis only of the subgroup with cutaneous reaction (36 patients) showed a statistically significant difference in the prevalence of alopecia between male and female patients (odds ratio = 0.1; 95% confidence interval = 0.0–0.6; p = 0.012). Male participants are 90% more likely to develop alopecia than female patients (table 3).
Discussion
Cutaneous reactions were seen in 36 (13.3%) of 271 patients with chronic hepatitis C treated with peginterferon/ribavirin. The mean age of the patients in the study group was 35 years; there were 209 males and 62 females; more of the patients were infected with genotypes 1 and 4 (58.3%), others with genotypes 2 and 3; cirrhosis was
Our study has shown that cutaneous reactions in patients during the treatment of HCV infection were significantly associated only with the age of the patients and treatment duration. The frequency of the cutaneous reactions among our 271 patients was 13.5%. Other calculations found at least 1 skin manifestation in up to 17% of
Cutaneous Reactions in Patients Treated for Chronic Hepatitis C
Dermatology 2014;228:42–46 DOI: 10.1159/000353160
43
Downloaded by: University of British Columbia 142.103.160.110 - 7/11/2017 4:28:13 PM
Table 1. Patient description
Table 2. Univariate and multivariate analysis of association between age, gender, genotype, cirrhosis, therapy duration, sustained viral response (SVR) and skin reaction
Skin reaction no Gender Female Male Age, years HCV genotype 1, 4 2, 3 Cirrhosis No Yes Therapy duration 24 weeks 48 weeks SVR No Yes
yes
OR
95% CI
p
ORm
95% CIm
pm
total
53 (85.5) 9 (14.5) 182 (87.1) 27 (12.9) 35 (30–40) 43 (37–49)
62 (100.0) 209 (100.0)
– 0.85 1.07
0.38 – 1.94 1.04 – 1.11
0.711
