Skin Disorders in HIV-infected Patients from West Java

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1 ORIGINAL ARTICLE Skin Disorders in HIV-infected Patients from West Java Reiva Farah Dwiyana, Rasmia Rowawi, Mery Lestari, Bachti Alisjahbana, A.J.A.M van der Ven, Tony S. Djajakusumah Department of Dermato-Venereology, Padjadjaran University/Hasan Sadikin Hospital. Jl. Pasirkaliki no. 9, Bandung 5, Indonesia, Health Research Unit, Faculty of Medicine, Department of Internal Medicine, Faculty of Medicine Padjadjaran University/Hasan Sadikin Hospital Bandung, Indonesia, Department of General Internal Medicine, Division of Infectious Diseases, Radboud University Nijmegen Medical Centre, The Netherlands. Corresondence mail to: ABSTRACT Aim: to describe the spectrum of HIV-related skin disorders as well as their prevalence and relation to CD- cell counts among HIV-seropositive patients from West Java, Indonesia. Methods: all HIV-positive patients presenting in 8 at the HIV-clinic, Hasan Sadikin Hospital, were included in a cross-sectional study. Patients who had a skin complaint were examined by a dermatologist. Skin diseases were classified based on ICD. Results: among 83 patients, (.%) had a skin complaint, consisting of skin manifestations (73.3%), drug eruptions (3.5%), and sexually transmitted infections (5.7%), some of them had more than one diseases. The most common skin manifestations were drug eruptions, pruritic papular eruptions, seborrhoeic dermatitis, herpes zoster, dermatophytosis, and bacterial skin infections. Among patients who started nevirapine, 6.% (95%CI: 3.9% - 8.9%) developed any kind of drug eruption, and.% (95%CI.%-.6%) developed a severe drug eruption. No cases of Kaposi sarcoma, penicilliosis, eosinophilic folliculitis were seen, however one case of histoplasmosis was diagnosed. Conclusion: this is the first report describing the prevalence and characteristic of skin manifestation in HIVpositive in Indonesia. Indonesian physicians should be alert about HIV when patient presents with certain skin manifestations. The rate of severe drug eruptions following treatment with nevirapine is a cause of concern that needs further study. Key words: skin disorders, HIV patients. INTRODUCTION Human immunodeficiency virus (HIV) infection is a worldwide problem today, and also South-East Asia is increasingly affected. Heterosexual transmission is mostly driving the HIV epidemic but injecting drug use (IDU) is in some areas the most important route of transmission. The latter is especially true for large parts of Indonesia, where the number of injecting drug users has greatly increased recently. As a consequence of this, growing numbers of HIV-infected subjects with a history of IDU, present themselves to health care facilities. Many of these patients come with late stage disease and symptoms related to HIV/AIDS. Skin disorders are common manifestations of HIV disease, affecting nearly every patient during the course of the infection. These disorders develop as the result of the acquired immunodeficiency but may also be the effect of treatment. 3 The clinical spectrum of HIVrelated skin disorders varies widely from mild conditions, i.e. xerosis cutis to life threatening disease such as Stevens- Johnson syndrome. The clinical manifestations of HIV-related skin disorders depend on the level of immunodeficiency but may also vary from region to region. -8 For instance, Kaposi sarcoma is an important HIV-related skin disorder in Sub-Sahara Africa due to the high prevalence of HHV-8, 6 while HHV-8 and Kaposi prevalence is very low in South-East Asia. 9 On the other hand, penicilliosis is a common HIV-related skin disorder mostly described in patients from Thailand and not from Sub-Sahara Africa. 6,8 Apart from regional differences, certain skin disorders also related to patients risk behavior. Mollusca contagiosa and condylomata accuminata are sexually transmitted and not related to injecting drug use. In the present study, oral disorders were, however, not included in the analysis. 8

2 Vol Supplement July 9 Dermatological Manifestations of HIV-infected Patients from West-Java In South East Asia, the prevalence of HIV-related skin disorders that have been reported from Singapore, Thailand, and Malaysia, were 86.5%, 8%, 7.7%, respectively.,8, From Indonesia, no data were reported so far. The spectrum of disease from Java may differ from other areas in South East Asia, while injecting drug users comprise a much larger proportion of the HIVinfected patients. The present study aimed, therefore, to describe the spectrum of HIV-related skin disorders as well as their prevalence and relation to CD-cell counts among HIV-seropositive patients from West Java, Indonesia. METHODS This is a cross-sectional descriptive study carried out during a period of months (January December 8) in Teratai Clinic, Hasan Sadikin Hospital, Bandung, Indonesia. Teratai is the main referral clinic for treatment and care of HIV-infected patients in West Java, Indonesia. The clinic is operated by general physicians or residents of internal medicine and supervised by infectious diseases specialists. First-line antiretroviral treatment (ART) consists of a combination of zidovudine, lamivudine and nevirapine, whereby nevirapine is dosed mg once daily for the first two weeks and mg twice daily thereafter. Efavirenz 6 mg once daily is replacing nevirapine in case of concurrent anti-tuberculous treatment. Cotrimoxazole prophylaxis is given if CD-cell count is below /ml or in case of an AIDS defining diagnosis. All HIV-seropositive patients that presented to Teratai clinic in 8 were asked to participate in the study. After informed consent, information was collected using structured forms that included data on socio-demography, risk behavior, physical complaints, medical examination, treatment history, and CD-cell counts. All the patients with a skin complaint and/or abnormal skin examination were referred to a dermatologist for specific examination. The diagnosis of doubtful skin conditions was supported by skin biopsy, Gram staining, KOH preparation, culture, and serologic examination. Skin diseases were divided into the following categories: non-infectious cutaneous inflammation, infection, drug eruption, malignancy, and others. For the specific classification of the diseases, the International Classification of Diseases of WHO was used. Cases of oropharyngeal candidiasis are not included in this study, since this illnesses is not referred to the dermatologist but treated by the physicians of Teratai. In case of a drug eruption, the causative agent was determined by a dermatologist and two infectious disease specialist and the criteria for the diagnosis were set as follows:. The clinical manifestation of the suspected drug is in line with what can be expected,. Timing was as expected for adverse reaction of the suspected drug, 3. Improvement of eruption after discontinuation of suspected drug,. No good alternative diagnosis. In case of severe drug eruption, patients were admitted in the hospital and treated with dexamethasone and supportive care. Ethical clearance was obtained from the institutional review board of Ethical Committee Hasan Sadikin General Hospital. Statistical analysis was performed using SPSS 3.. Prevalence and proportion of the diagnosis were calculated. Chi-square test was used to evaluate significant differences of proportion and Student T-Test or Mann-Whitney was used to measure differences in continuous variable. CD cell counts of patients with and without a specific skin disease were compared. RESULTS Nine hundred and nineteen HIV-seropositive patients were included in the study but 83 could be analyzed because of incomplete data (58), death or transferred outside West Java (8). A total of (.%) persons were referred to a dermatologist. Median age of the patients with a skin disorder was 8 (- 5) years, most were males (7.3%) and a history of injecting drug use was notified in 76.6% of the cases. Some patients had more than one skin conditions and in total 7 diagnoses were made. Eighty-one (7.7%) of the dermatological patients presented with CD below cell/ml. The mean and median CD-cell counts were /ml and 5/ml (IQR 6-3) and the median CD-cell count in the dermatological patients was significantly lower (p<.5) compared to the median CD-cell count of 7/ml (IQR 53-38) of the patients without skin manifestations. Antiretroviral treatment was used by 55/73 (6.3%) of the patients without skin manifestations, while by / 3 (88.5%, p<.5) of the patients with skin manifestations. A wide spectrum of skin manifestations was noticed as can be seen in table. Non-infectious cutaneous inflammation was diagnosed 66 times and is thereby the most common group of skin disease, followed by infections, 37 drug eruptions, sexually transmitted infections, and 3 other kinds of skin diseases. No malignancy cases were seen. The two most common specific diseases were pruritic eosinophilic eruption (n=35) and drug eruption (36), followed by seborrhoeic dermatitis (). Herpes zoster developed in 6 patients 9

3 Reiva Farah Dwiyana Acta Med Indones-Indones J Intern Med Tabel. Prevalence of Skin Manifestations and Its Relation to CD Count Total CD count median (range) No skin disease complaints 76 6 ( 39) Non-infectious cutaneus inflammation PPE Seborrhoeic dermatitis Irritant contact dermatitis Neurodermatitis Unclassified dermatosis in IRIS Psoriasis vulgaris Infections Herpes zoster Dermatophytosis Bacterial skin infection Scabies Verucca vulgaris Varicella Histoplasmosis cutis Verucca plana Drug eruption Drug eruption Steven Johnson syndrome Acneiform eruption Erythroderma (3 383) 6 (9 78) 59 (333 87) 6 (3-9) (3 65) 7 (6 5) (8 73) ( - ) 58 (75 58) 63 ( 6) 33 and in 6 of those, this skin disorder developed -6 months after initiation of antiretroviral treatment. Table also shows the median CD-cell counts associated with the different diseases. The prevalence of drug eruptions in the present study was high and involved 3.7% of the patients with skin manifestations (Table ). Nevirapine was the most common etiological agent and caused a drug eruption in 6.% (95% CI: 3.9% - 8.9%) of the patients in whom this drug was administered. Severe drug eruptions (Steven Johnson syndrome and erythroderma) were noticed in 5 patients and developed in.% (95%CI.%-.6%) of the patients treated with nevirapine ( 59) 8 (5 59) ( 37) 3 Malignancy Kaposi sarcoma - Sexually transmitted infection Condilomata accuminata Latent syphilis Vulvovaginal candidiasis Herpes genitalis Proctitis gonorrhoeae Fluor albus Urethritis gonorrhoeae Cervitis gonorrhoeae Others Xerosis cutis Post-inflammation hyperpigmented macule Insect bite Acne vulgaris Ptyriasis alba Urticaria Twenty nails distrophy ( - ) (58 36) 39 (33 ) ( - 3) 9 (5 333) (3-9) 8 (5-69) 3 6 (3-87) 58 (5-8) 5 p value <.5, p value <.5 compared to patient without skin disease complaints; PPE=pruritic popular eruption, IRIS=immune reconstitution inflammatory syndrome. Severe drug eruptions mostly occurred in patients with low CD-cell counts as can be seen in table 3. Median CD-cell counts of patients with a nevirapine related drug eruption were 5/ml (IQR 5-6) while CD-cell counts of patients that were administered nevirapine and did not developed a drug eruption were 5/ml (IQR 5-38), this difference was significant. Table. Drug Eruptions Related to ARV Treatment and Suspected Drugs Suspected drugs NVP EFV ATD CMX Others Unknown Total drug eruption (n=37) 3 (6.) (.8) 3 (8.) 3 (5.) (5.) (5.) Severe drug eruption (n=7) 5 (7.) (.3) (.3) No rash (N=86) Total patients (N=83) no data on the total patient receiving this drugs NVP= nevirapine, EFV=efavirenz, ATD=antituberculous drugs, CMX=co-trimoxazole Relative risk (RR) NVP versus CMX for total drug eruption: 8.; CI:.-6.8 RR EFV versus CMX for total drug eruption:,6; CI:.6-.8 RR ATD versus CMX for total drug eruption.; CI: RR NVP versus EFV for total drug eruption: 3.; CI:.-8.7 RR NVP versus EFV for severe drug eruption:.6; CI:.3-.5 Table 3. Drug Eruption of Patient Receiving ARV Treatment Related to CD Count Drug Eruption n CD Median (IQR) No drug eruption Mild-moderate drug eruption Severe drug eruption Significances: (6; 39) 9 (; 95) (; 3) No drug eruption mild-moderate drug eruption: p<.5 Mild-moderate drug eruption severe drug eruption: p=.69 No drug eruption severe drug eruption: p<.5 DISCUSSION The present study shows that skin disorders are common (.%) among a large group of HIV-infected subjects from West Java. The prevalence in our study is, however, lower compared to what has been reported from other countries, including those from South East Asia.,8, Oral candidiasis, however, was not included in our analysis, unlike in the other reports. In addition to that, high CD-cell counts could also possibly explain the lower prevalence of skin conditions in our study but we found, on the contrary, that our patients presented with lower CD-cell counts and started HAART later were compared to other reports. 3, Most of our study patients consisted of males, in their third decade, and with a history of injecting drug use. Our population is, therefore, different from other studies

4 Vol Supplement July 9 Dermatological Manifestations of HIV-infected Patients from West-Java from Western countries that mostly include homosexual subjects, 7 and from reports from Singapore, India, and Thailand, that consist mostly of patients, whereby heterosexual transmission is common.,5,8 Despite the difference in study population, the general pattern of HIVrelated skin disorders in our population was, however, in line with the findings of the other reports. The most common skin manifestations in our study population were pruritic papular eruption (PPE), drug eruption, seborrhoeic dermatitis, and herpes zoster. These disorders were mostly seen in patients with low CD- cell counts. Dermatophytosis and bacterial skin infection were also common but found in patients with higher CD-cell numbers. Interestingly, we confirmed one case of histoplasmosis (see picture). Although histoplasmosis, as well as penicilliosis, has been repeatedly described from neighboring countries such as Thailand. 8,5 only one Indonesian patient with histoplasmosis has been described before. 6 Also peniciliosis as well as eosinophilic folliculitis and bacillary angiomatosis were not diagnosed in our population. Figure. A 37-year-old man with histoplasmosis and CD was Figure. A 7-year-old man with Steven Johnson syndrome caused by nevirapine No Kaposi sarcoma was diagnosed in our study. Human herpesvirus 8 (HHV-8), also known as Kaposi s sarcoma-associated herpesvirus, is etiologically associated with Kaposi s sarcoma and other lymphoproliferative diseases. 7,8 HHV-8 prevalence exhibits considerable variation in different geographic regions and populations. HHV-8 prevalence is very high in Sub-Sahara Africa but generally low in South East Asia. 6,9 Kaposi sarcoma is, therefore, only sporadically reported from South East Asia. 9, To the best of our knowledge, no data on HHV-8 are available from Indonesia. HHV-8 is, however, transmitted by injecting drug use, and our group is, therefore, planning to determine HHV-8 prevalence among HIV-infected patients in West Java. Herpes zoster is another common HIV-related skin disorder but this condition developed in 6 of the 5 patients to 6 months after initiation of ART. The development of Zoster after initiation of ART may be due to the restored ability to mount an inflammatory response, or the immune reconstitution inflammatory syndrome (IRIS). For Zoster, this usually occurs within the first 6 months. Apart from IRIS, ART and especially nevirapine may also cause drug eruptions. In the present study, 6.% of the patients that were administered nevirapine, developed a rash. This finding is in line with reports from others. A retrospective study from Thailand found a cumulative incidence of 8.5% of nevirapine related skin rashes in subjects with CD-cell counts < 5/ml, while a prospective study from Spain reported nevirapine rash in 6.5% of patients with CD >5/ml and in 5% of subjects with CD < 5/ml. 3 Steven Johnson syndrome developed in.% of the patients, in whom nevirapine was administrated, but none of the patients with a severe drug eruption died. CD-cell counts were low in patients with a rash and even very low in subjects with a severe drug eruption, while usually high CD cell counts are reported as a risk factor for drug eruptions. We have no explanation for this discrepancy. CONCLUSION This is the first report describing the prevalence and characteristic of skin disorders in HIV-seropositive patients in West Java, Indonesia. We hope that our description of dermatological manifestation among HIV patients will help Indonesian s physicians to diagnose HIV earlier. Drug eruptions following treatment with nevirapine, other ARTs, and cotrimoxazole need careful attention and severe cases need to be managed in the hospital.

5 Reiva Farah Dwiyana Acta Med Indones-Indones J Intern Med ACKNOWLEDGEMENT This study can only be conducted with the support of the Head of Hasan Sadikin Hospital, Prof.Dr.dr. Cissy R.S. Prawira and the HIV team. We thank dr. Nirmala Kesuma, dr. Rudi Wisaksana, dr. Laila Mahmudah, dr. Astrid Danarastri, Prima, and all the clinical staff of the Teratai Clinic Hasan Sadikin Hospital for establishing the cohort of HIV-positive patients. Support is available through the Integrated Management for Prevention, and Control and Treatment of HIV-AIDS (IMPACT) program with funding from the European commission. REFERENCES. National AIDS Commision RoI. Country report on the follow up to the Declaration of Commitment on HIV/AIDS, Reporting Period 6-7, (UNGASS). Jakarta; 8 Contract No.: Document Number.. Ministry of Health RoI, Directorate General CDC & EH. Cases of HIV/AIDS in Indonesia, Reported thru December 8. Jakarta; 9 [updated 9; cited 9, April, 6]; Available from: 3. Saavedra A JR. Cutaneous manifestations of human immunodeficiency virus disease. In: Wolff K GL, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds. New York: McGraw Hill; 8.. Goh BK, Chan RK, Sen P, Theng CT, Tan HH, Wu YJ, et al. Spectrum of skin disorders in human immunodeficiency virusinfected patients in Singapore and the relationship to CD lymphocyte counts. Int J Dermatol. 7 Jul;6(7): Kumarasamy N, Solomon S, Madhivanan P, Ravikumar B, Thyagarajan SP, Yesudian P. Dermatologic manifestations among human immunodeficiency virus patients in south India. Int J Dermatol. Mar;39(3): Mbuagbaw J ei, Alemnji G, Mpoudi N, Same-Ekobo A. Patterns of skin manifestations and their relationships with CD counts among HIV/AIDS patients in Cameroon. Int Soc Dermatol. 6;5: Uthayakumar S, Nandwani R, Drinkwater T, Nayagam AT, Darley CR. The prevalence of skin disease in HIV infection and its relationship to the degree of immunosuppression. Br J Dermatol. 997 Oct;37(): Wiwanitkit V. Prevalence of dermatological disorders in Thai HIV-infected patients correlated with different CD lymphocyte count statuses: a note on cases. Int J Dermatol. ;3(): Chen N, Nelson KE, Jenkins FJ, Suriyanon V, Duerr A, Costello C, et al. Seroprevalence of human herpesvirus 8 infection in Notherm Thailand. Clin Inf Dis. ;39:5-8.. Jing W, Ismail R. Mucocutaneus manifestations of HIV infection: a retrospective analysis of 5 cases in a Chinese population in Malaysia. Int J Dermatol. 999;38: Chaovavanich A. Skin manifestations in HIV/AIDS. Bangkok: Bamrasnaradura Infectious Disease Institute; 6.. World Health Organization. International Classification of Diseases- (ICD-); Castelnuovo B, Byakwaga H, et al. Can response of a pruritic papular eruption to antiretroviral therapy be used as a clinical parameter to monitor virological outcome? AIDS. 8;: Costner M, Cockerell CJ. The changing spectrum of the cutaneous manifestations of HIV disease. Arch Dermatol. 998;3: Khuanchai S. Penicilliosis marneffei in Thailand. J Japan Ass Inf Dis. 6;8: Grosse G HW, Staib F. Histoplasmosis of the skin as an initial opportunistic infection. Dtsch Med Wochenschr. 993;8: Ablashi D, Chatlynne L. Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa. Br J Cancer. 999;8: Babal P, Pec J. Kaposi s sarcoma - still an enigma. J Eur Acad Dermatol Venereol. 3;7: Schwartz RA, Micali G, Nasca MR, Scuderi L. Kaposi sarcoma: A continuing conundrum. J Am Acad Dermatol. 8;59: Munoz-Perez MA, Rodriguez-Pichardo A, Camacho F, Colmenero MA. Dermatological findings correlated with CD lymphocyte counts in a prospective 3 year study of 6 patients with human immunodeficiency virus disease predominantly acquired through intravenous drug abuse. Br J Dermatol. 998;39: Lehloenya R, Meintjes G. Dermatologic manifestations of the immune reconstitution inflammatory syndrome. Dermatol Clin. 6;: Ananworanich J, Moor Z, Siangphoe U, Chan J, Cardiello P, Duncombe C. Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine, efavirenz or both drugs. AIDS. 5;9: Anton P, Soriano V, Jimenez-Nacher I, Rodriguez-Rosado R, Dona MC, Barreiro PM, et al. Incidence of rash and discontinuation of nevirapine using two different escalating initial doses. AIDS. 999;3:5-5.