Menoufia Medical Journal

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 32  |  Issue : 4  |  Page : 1521--1527

Dermatological adverse effects of new era of direct-acting antivirals in hepatitis C virus treatment


Mohamed A Gaber1, Ahmed E Sallam2, Shaza A. M. Elhamaky3,  
1 Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Tropical Medicine and Hepatology, Ministry of Health, El Mahalla, Gharbia, Egypt
3 Department of Dermatology, Venereology, Ministry of Health, El Mahalla, Gharbia, Egypt

Correspondence Address:
Shaza A. M. Elhamaky
Department of Dermatology, Venereology, Ministry of Health, El Mahalla, Gharbia
Egypt

Abstract

Objective To detect dermatological adverse effects of direct-acting antiviral (DAAs) drugs in treating patients infected with hepatitis C virus (HCV). Background HCV affects more than 200 million people, with an estimated HCV prevalence of 2.2% globally; the highest prevalence (15–20%) has been reported from Egypt. Patients and methods This prospective study was conducted on 108 patients with HCV infection. Patients with any dermatological manifestations before treatment by DAAs were excluded. Patients who came during treatment of HCV or after treatment were examined for dermatological adverse effects that appeared during or after treatment by DAAs. Results The data collected were tabulated and analyzed by Statistical Package for the Social Sciences, version 22.0 on International Business Machines compatible computer. The most common dermatological adverse effects was itching in 36.1% of the cases. In most of the cases (63.9%), the symptoms appeared during the treatment. There was a significant statistical difference between different treatment regimens regarding adverse effects, as itching was more common with regimen 1, dryness was more common in regimen 2, falling of hair was more common in regimen 1, oral ulcer in regimen 4, and photosensitivity was more common with regimen 5. Itching was more common after treatment, whereas pigmentation of skin (hyperpigmentation appeared during treatment versus hypopigmentation appeared both during and after treatment) and photosensitivity appeared during treatment. Conclusion DAAs have dermatological adverse effects. The most common dermatological adverse effects were itching, rash, and photosensitivity. Most of these adverse effects appeared during treatment, in 45.4% of patients.



How to cite this article:
Gaber MA, Sallam AE, Elhamaky SA. Dermatological adverse effects of new era of direct-acting antivirals in hepatitis C virus treatment.Menoufia Med J 2019;32:1521-1527


How to cite this URL:
Gaber MA, Sallam AE, Elhamaky SA. Dermatological adverse effects of new era of direct-acting antivirals in hepatitis C virus treatment. Menoufia Med J [serial online] 2019 [cited 2020 May 31 ];32:1521-1527
Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1521/274280


Full Text



 Introduction



Hepatitis C virus (HCV) affects more than 200 million people, with an estimated HCV prevalence of 2.2% globally [1]. It has been estimated that HCV accounts for 27% of cirrhosis and 25% of hepatocellular carcinoma cases worldwide [2]. Global and region-specific estimates of HCV prevalence vary greatly, but the highest prevalence (15–20%) has been reported from Egypt [3]. The wave of increased HCV-related morbidity and mortality is likely owing to the widespread availability of injectable therapies and the illicit use of injectable drugs [2]. The major known modes of transmission include intrafamilial transmission, direct blood contact, mother to child, organ transplant, injectable treatment for schistosomiasis, needle-stick injuries, medical and dental procedures, injection drug use, and sharing contaminated materials like razors and shaving kits [4]. The knowledge of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors targeting these enzymes [5]. Several findings suggest that HCV modulation of interferon (IFN) induction and signaling attenuates the expression of IFN-stimulated genes, allowing HCV to escape the antiviral actions of the host response [6]. All the major HCV-induced enzymes, namely, nonstructural protein (NS) 2-3 and NS3-4A proteases, NS3 helicase, and NS5B RNA-dependent RNA polymerase, are essential for HCV replication and are potential drug discovery targets. Therefore, direct-acting antiviral (DAA) with different viral targets, such as NS3 protease inhibitors, nucleoside/nucleotide analog, and non-nucleoside inhibitors, and NS5A inhibitors are now available new drugs for HCV [7]. All these new drugs have multiple adverse effects, some of them on the skin, which will be studied in this study and if we can treat them.

This study aimed to detect dermatological adverse effects of the new DAA drugs in treatment of patients infected with HCV.

 Patients and Methods



This prospective study was carried in Mahalla Hepatology Educational Hospital, Gharbia, Egypt. The study was carried on patients with HCV infection (PCR +ve) having dermatological adverse effect attending the HCV follow-up clinic in Mahalla Hepatology Educational Hospital of all patients who came to the clinic for one year from March 2016 till February 2017. Their ages ranged from 18 years old to 75 years old. There were 47 females and 61 males.

The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent, and the Ethics Committee of Faculty of Medicine, Menoufia University, approved the study protocol.

All patients were subjected to written consent before study enrollment, full detailed history taking, presence of any other comorbidity [diabetes mellitus (DM), hypertension (HTN), and cardiac, chest, and rheumatoid disease], if adverse effects appeared during or after treatment, and any treatment taken for these adverse effects.

All patients who came during treatment or after treatment were asked and examined for adverse effects that appeared during or after treatment and underwent examination of skin, scalp, hair, nail, and oral cavity with special attention to scratch marks, pigmentation, hair falling, rash, and photosensitivity.

Exclusion criteria include any patient with dermatological disease before treatment of HCV infection.

Statistical analysis

The data collected were tabulated and analyzed by Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM Corporation, 1133 Westchester Avenue, White Plains, New York) on International Business Machines (IBM) compatible computer.

Two types of statistics were done:

Descriptivestatistics: percentage (%), mean, median, and SDAnalytic statistics:

χ2 was used to study association between qualitative variablesFisher exact test for 2 × 2 tables when expected cell count of more than 25% of cases was less than 5Level of significance was set as P value less than or equal to 0.05.

 Results



The mean value of age was 45.8 ± 11.9 years, and 56.5% of the patients were male. Other comorbidities were present in 37.0% of the cases (11.1, 15.7, 4.6, 2.8, 1.9, and 0.9% of them had HTN, DM, DM and HTN, cardiac disease, chronic obstructive pulmonary disease, and rheumatoid disease, respectively). The most commonly used treatment regimen was regimen 3b (sofosbuvir + daclatasvir + ribavirin) in 45.4% of the patients, and in remaining cases was either regimen 1 (sofosbuvir + IFN + ribavirin) or regimen 2 (sofosbuvir + ribavirin) in 5.6% of the cases, regimen 3a (sofosbuvir + daclatasvir) in 26.9%, regimen 5 (sofosbuvir + simeprevir) in 13%, and regimen 4 (sofosbuvir + ledipasvir + ribavirin) in only 3.7% [Table 1].{Table 1}

Regarding skin manifestations of studied cases, the most common manifestation was itching in 36.1% of the cases, whereas the least common was edema [either lower limb (LL) or breast congestion and edema] and ecchymosis in 0.9%. Other skin manifestations included rash in 17.6% of the cases, either pallor or jaundice in 1.9%, dryness in 8.3%, mouth dryness in 1.9%, either hyperpigmented or hypopigmented area of skin in 4.6 and 1.9%, respectively, falling of hair in 5.6%, oral ulcer in 3.7%, either joint pigmentation or stiffness in 1.9%, photosensitivity in 11.1%, and neuropathy in 8.3% [Table 2].{Table 2}

In most of the cases (63.9%), the symptoms appeared during the treatment versus after treatment (22.2%), whereas in 13.9%, they appeared both during and after treatment. Overall, 45.4% of the patients received medication in the form of antihistaminic (19.4%), antihistaminic and antiedematous (0.9%), diuretics (0.9%), erythropoietin (0.9%), oral anesthetic (0.9%), topical anesthesia (0.9%), topical antibiotics (0.9%), topical corticosteroid (0.9%), topical corticosteroid and emollient (11.1%), ursodeoxycholic acid (1.9%), vitamin B12 (5.5%), and vitamin B12, vitamin C, and folic acid (0.9%) [Table 3].{Table 3}

In this study, there was nonsignificant difference in skin manifestations of the studied cases regarding treatment regimens with respect to rash, color changes, mouth dryness, pigmentation of skin, joint affection, edema, and neuropathy, but there was a significant difference between different treatment regimens regarding itching (0.008), dryness (0.002), falling of hair (<0.001), oral ulcer (0.02), and photosensitivity (<0.001), as itching was more common with regimen 1 (66.7%), dryness was more common in regimen 2 (50%), falling of hair was more common in regimen 1 (50%), oral ulcer was more common in regimen 4 (25%), and photosensitivity was more common with regimen 5 (85.7%) [Table 4].{Table 4}

There was nonsignificant difference in skin manifestations of studied cases regarding time of appearance during or after or both during and after treatment. However, there was a significant difference in itching (95.8% of the cases appeared after treatment, with P < 0.001), pigmentation of skin (hyperpigmentation in 7.2% of cases appeared during treatment versus hypopigmentation in 13.3% of them appeared both during and post treatment, with P = 0.004), edema (both LL edema and breast edema and congestion appeared during and after treatment in 6.7%, with P = 0.01), and photosensitivity (in 17.4% of cases appeared during treatment, with P = 0.02) [Table 5].{Table 5}

 Discussion



Jacobson et al. [8] reported that infection with HCV leads to various clinical manifestations in addition to inflammation and fibrosis of the liver. Cacoub et al. [9] reported that HCV has common adverse effects; among these are systemic disorders and dermatological conditions affecting the skin. Muzaffar et al. [10] reported that in some cases, the only clue to the existence of an underlying HCV infection is cutaneous signs and symptoms.

Silvain [11] stated that treatment of dermatological adverse effects of HCV through eradication of HCV is therefore important in effective patient treatment, although this alone is not a major justification for HCV treatment. Existing and in-development HCV antiviral therapies, however, have a lot of dermatological adverse events associated with these new drugs. We conducted this study to detect dermatological adverse effects of DAAs used in treatment of 108 infected patients with HCV.

In our study, the mean age of the patients was 45.8 ± 11.9 years. However, Raslan et al. [12] from Egypt revealed that the mean age was 46.95 years. Alarmingly, this might indicate that in our region, HCV affects younger individuals. Overall, 56.5% of our cases were males. There was significant difference in skin manifestations of the studied cases with respect to sex, as skin pigmentation (either hyperpigmentation or hypopigmentation) was significant common in male than female (P = 0.02). Neuropathy was significantly more common in female (P = 0.04). In the study by Ali et al. [13], it found that demographic data showed 59% female and 41% male patients. This is in concordance with 57 and 58% females seen in the studies conducted by Asim and Wahid [14] and Soylu et al. [15], respectively. Other comorbidities were present in 37.0% of the cases with was nonsignificant difference in skin manifestations of studied cases regarding to comorbidity (either present or absent). The most commonly used treatment regimen was regimen 3b (sofosbuvir + daclatasvir + ribavirin) in 45.4% of the patients, whereas in the remaining cases was either regimen 1 (sofosbuvir + IFN + ribavirin) or regimen 2 (sofosbuvir + ribavirin) in 5.6% of the cases, regimen 3a (sofosbuvir + daclatasvir) in 26.9%, regimen 5 (sofosbuvir + simeprevir) in 13%, and regimen 4 (sofosbuvir + ledipasvir + ribavirin) in only 3.7%.

Regarding skin manifestations in the studied cases, the most common manifestation was itching in 36.1% of the cases, whereas the least common was edema (either LL or breast congestion and edema) and ecchymosis in 0.9%. Other skin manifestations included rashes in 17.6% of the cases, either pallor or jaundice in 1.9%, dryness in 8.3%, moth dryness in 1.9%, either hyperpigmented or hypopigmented area of skin in 4.6 and 1.9%, respectively, falling of hair in 5.6%, oral ulcer in 3.7%, either joint pigmentation or stiffness in 1.9%, photosensitivity in 11.1%, and neuropathy in 8.3%. Manjón-Haces et al. [16] concerning skin lesions reported results similar to our study, where high frequency of eczema (59%) was seen among patients. Sookoian et al. [17] in their study showed lesser percentages. In most of the cases (63.9%), the symptoms appeared during the treatment versus after treatment (22.2%), whereas in 13.9%, they appeared both during and after treatment. Overall, 45.4% of patients received medication in the form of antihistaminic (19.4%), antihistaminic and antiedematous (0.9%), diuretics (0.9%), erythropoietin (0.9%), oral anesthetic (0.9%), topical anesthetic (0.9%), topical antibiotics (0.9%), topical corticosteroid (0.9%), topical corticosteroid and emollient (11.1%), ursodeoxycholic acid (1.9%), vitamin B12 (5.5%), and vitamin B12, vitamin C, and folic acid (0.9%). Between June 1998 and September 2000, Manjón-Haces et al. [16] studied 210 patients with HCV treatment with IFN-a2b plus ribavirin over a 12-month period. During treatment, most of the patients showed varying degrees of dry skin and pruritus. In 27 cases (13% 24 males, three females; age range 24–54 years), an observed skin lesion began to manifest on average 3.2 months after start of treatment. All patients showed clinical improvement with symptomatic treatment (moisturizing creams, antihistamines, and/or topical cortisone).

In this study, there was nonsignificant difference in skin manifestations of studied cases regarding age groups (either > or et al. [18], the incidence of treatment-related dermatitis was significantly higher (P = 0.03) with age above 45 years, which was against our results. In this study, there was nonsignificant difference in skin manifestations of studied cases regarding time of appearance (during or after or both during and after treatment). However, there was significant difference in itching (95.8% of the cases appeared after treatment; P < 0.001), pigmentation of skin (hyperpigmentation in 7.2% of cases appeared during treatment versus hypopigmentation in 13.3% of them appeared both during and after treatment; P = 0.004), edema (both LL edema and breast edema and congestion appeared during and after treatment in 6.7%; P = 0.01), and photosensitivity (in 17.4% of cases appeared during treatment; P = 0.02). In the study by Teixeira et al. [19], ∼50% of all rash events started during the first 4 weeks of treatment, with the remaining 50% starting until week 12. The median time to onset of rash of any grade was 25 days, supporting that it may occur at any time during treatment.

In this study, there was significant difference between different treatment regimens with respect to itching (0.008), dryness (0.002), falling of hair (<0.001), oral ulcer (0.02), and photosensitivity (<0.001), as itching was more common with regimen 1 (66.7%), dryness was more common in regimen 2 (50%), falling of hair was more common in regimen 1 (50%), oral ulcer in regimen 4 (25%), and photosensitivity was more common with regimen 5 (85.7%). According to Brok et al. [20], there was increased risk of several dermatological adverse reactions with combination therapy (ribavirin + IFN), for example, rash [relative risk (RR) 1.74; 95% confidence interval (CI), 1.17–2.61; 12 trials], pruritus (RR 1.62; 95% CI, 1.29–2.02; 18 trials), dermatitis (RR 1.67; 95% CI, 1.21–2.30; three trials), alopecia (RR 1.10; 95% CI, 0.93–1.30; 10 trail), and dry skin (RR 1.66; 95% CI, 0.83–3.32; three trail).

 Conclusion



DAAs have great effect on eradication of HCV but have dermatological adverse effects. Most of them are treatable and not severe.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Bostan N, Mahmood T. An overview about hepatitis C: a devastating virus. Crit Rev Microbiol 2010; 36:91–133.
2Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007; 13:2436.
3Eassa S, Eissa M, Sharaf SM, Ibrahim MH, Hassanein OM. Prevalence of hepatitis C virus infection and evaluation of a health education program in el-ghar village in Zagazig, Egypt. J Egypt Public Health Assoc 2007; 82:379–404.
4Centers for Disease Control and Prevention. Hepatitis C information for health professionals. Atlanta, GA: CDC; 2011.
5Yao N, Hesson T, Cable M, Hong Z, Kwong AD, Le HV, Weber PC. Structure of the hepatitis C virus RNA helicase domain. Nat Struct Biol 1997; 4:463.
6Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol 1997; 57:1110–1125.
7Asselah T, Bieche I, Narguet S. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in subjects with chronic hepatitis C. Gut 2008; 57:516–524.
8Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010; 8:1017–1029.
9Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC, Saadoun D. Extrahepatic manifestations of chronic hepatitis c virus infection: Therapeutic advances in infectious disease. Ther Adv Infect Dis 2016; 3:3–14.
10Muzaffar F, Hussain I, Haroon TS. Hepatitis C: the dermatologic profile. J Pak Assoc Dermatol 2016; 18:171–181.
11Silvain C. Extrahepatic manifestations of hepatitis c virus infection. Hepatogastro Oncol Dig 2015; 22:649–664.
12Raslan HMZ, Ezzat WM, El Hamid MA, Emam H, Amre KS. Skin manifestations of chronic hepatitis C virus infection in Cairo, Egypt. East Mediter Health J 2009; 15:692–701.
13Ali R, Ashfaq M, Bukhari MA, Shahzad A. Mucocutaneous manifestations in hepatitis C patients. J Pak Assoc Dermatol 2016; 24:40–45.
14Asim SA, Wahid Z. Cutaneous manifestations in hepatitis C virus infection. Pak J Med Sci 2012; 28:891–894.
15Soylu S, Gül Ü, Kiliç A. Cutaneous manifestations in patients positive for anti-hepatitis c virus antibodies. Acta Dermat Venereol 2007; 87:49–53.
16Manjón-Haces JA, Vazquez-Lopez F, Gómez-Díez S, Hidalgo-Garcia A, Pérez-Alvarez R, Soler-Sánchez T, et al. Adverse cutaneous reactions to interferon alfa-2b plus ribavirin therapy in patients with chronic hepatitis c virus. Acta Dermato Venereol 2001; 81:223–223.
17Sookoian S, Neglia V, Castaño G, Frider B, Kien MC, Chouela E. High prevalence of cutaneous reactions to interferon alfa plus ribavirin combination therapy in patients with chronic hepatitis c virus. Arch Dermatol 1999; 135:1000–1001.
18Roujeau JC, Mockenhaupt M, Tahan SR, Henshaw J, Martin EC, Harding M, et al. Telaprevir-related dermatitis. JAMA Dermatol 2013; 149:152–158.
19Teixeira R, de Almeida Nascimento Y, Crespo D. Safety aspects of protease inhibitors for chronic hepatitis c: adverse events and drug-to-drug interactions. Brazil J Infect Dis 2013; 17:194–204.
20Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis c. Cochrane Database Syst Rev 2010; 20:CD005445.