Manifestations of Acute Herpetic Gingivostomatitis in Human Immunodeficiency Virus: Positive Patients S K Narendra 1, N C Sahani 2, D N Moharana 3

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1 Received: 16 th October 2015 Accepted: 13 th January 2016 Conflict of Interest: None Source of Support: Nil Original Research Doi: /jioh Manifestations of Acute Herpetic Gingivostomatitis in Human Immunodeficiency Virus: Positive Patients S K Narendra 1, N C Sahani 2, D N Moharana 3 Contributors: 1 Professor and Head, Department of Periodontology, SCB Dental College, Cuttack, Odisha, India; 2 Associate Professor, Department of Community Medicine, SCB Medical College, Cuttack, Odisha, India; 3 Professor, Department of Medicine, SCB Medical College, Cuttack, Odisha, India. Correspondence: S K Narendra. Department of Periodontology, SCB Dental College, Cuttack, Odisha, India. suryakantanarendra@yahoo.com How to cite the article: Narendra SK, Sahani NC, Moharana DN. Manifestations of acute herpetic gingivostomatitis in human immunodeficiency virus: Positive patients. J Int Oral Health 2016;8(4): Abstract: Background: Acute herpetic gingivostomatitis causing pain and discomfort to the patients in human immunodeficiency virus (HIV) positive individuals and in patients suffering from acquired immunodeficiency syndrome (AIDS) represents one association of different disease entity. The purpose of this study was to characterize the clinical features of oral ulcers associated with herpes simplex virus (HSV) infection in AIDS. Materials and Methods: 135 patients infected with HIV developing oral ulcers were included in this study. Immunohistochemical staining is done to detect herpes simplex viral infections associated with this manifestation. The mucositis is taken for quantitative analysis of oral ulceration. Qualitative analysis of the association of acute febrile condition is done. CD4 T-cell count was done for these patients. Here, analysis is done to detect if there is any correlation extensiveness and aggressiveness of acute herpetic gingivostomatitis lesions and CD4 T-cell count. Results: Association of herpes simplex viral infections is found in 36 out of 135 cases. In HIV + patients with CD4 count <500, the lesions due to HSV infection reaches a significant level within remains more or less unchanged in the oral cavity up to 3 months. Mucosal ulcers due to acute herpetic gingivostomatitis in HIV + patients with adequate immune status get manifestated for a period of 1-week with spontaneous remission within 2 weeks. Conclusion: Persistent oropharyngeal mucosal ulcers along with acute febrile condition in AIDS are found to be associated with HSV infection in patients with low CD4 T-cell count. Key Words: Herpetic gingivostomatitis, herpes simplex infections, human immunodeficiency virus infections Introduction Manifestations of viral infections of the oral cavity in human immunodeficiency virus (HIV) infected patients are common. These concurrent infections served as the clinical criteria for determining the disease progression. 1 Epstein-Barr virus, herpes virus Type 1 and rarely Type 2, Cytomegalovirus (CMV), and human papillomavirus are the common viral manifestations found in HIV-infected patients. 1 Oral viral lesions are one of the classified oral manifestations of HIV-associated infection declared by the WHO Collaborative Centre. Out of them, 23% of oral lesions are viral in origin, distributed in the lip, buccal mucosa, tongue, and palate. 2 Ulcers in oral mucosa persisting for a longer time in acquired immunodeficiency syndrome (AIDS) represent one associated disease entities caused by several factors. 3 Persistent mucosal ulcers in patients suffering from AIDS are found to be associated with herpes simplex virus (HSV). 3 These viral lesions are difficult to differentiate from ulcerogenic diseases such as aphthous major and necrotizing stomatitis. 3 Oral ulcerative lesion in patients with AIDS is associated with concurrent oral HSV and CMV infection. 4 Recurrent oral HSV lesions are common in both immunocompetent and immunocompromised persons. 4 Oral ulcers caused by co-infection of HSV and CMV presented persistent oral pain with non-healing tendency on the palate, retromolar pad, tongue, lip, with non-specific clinical appearance. 5 features of intraoral HSV infection varies from single ulcers to multiple lesions; ulcers occurred on keratinized surfaces or non-keratinized mucosa of the oral cavity with history of recurrences. 6 Oral lesions associated with CMV infection in HIV-infected patients is also manifested with oral ulcerations. 7 Extensive oral ulcerations are also found to be associated with simultaneous concurrent infections with oral HSV, CMV, and histoplasmosis in HIV-infected person. 8 Advances in the development and application of antiviral drugs have brought additional improvement in quality of life for the HIV-infected individual. Acyclovir is the drug of choice for treatment of both varicella zoster virus (VZV) and HSV infections. Ganciclovir or foscarnet is other groups of drugs can be used for viral infection of HIV-Infected patients. 9 With this background of information, we have planned this study to characterize clinical features of oral ulcers associated with HSV infection in AIDS. Materials and Methods 135 patients infected with HIV developing oral ulcers were included in this study. Immunohistochemical staining is done to detect herpes simplex viral infections associated with this manifestation. The mucositis is taken for quantitative analysis of oral ulceration to quantitate the manifestation of herpetic gingivostomatitis. 10 Spijkervet s mucositis is displayed in Table 1. Qualitative analysis of the association of 460

2 acute febrile condition is done. CD4 T-cell count was done for these patients. The patients are divided into 2 groups; Group 1 with CD4 count <500 and Group 2 with CD4 count 500. In Group 1, degree of mucosal ulceration is monitored for a period of 3 months at 1 week, 1 month, 2 months and 3 months of follow-up or until the reversal of the lesions. In Group 2, degree of mucosal ulceration is monitored until the reversal of the lesions. Results Out of 135 HIV-positive patients with oral ulcers, herpetic gingivostomatitis presents as ulcers and vesicles on the gingiva as well as elsewhere on the oral mucosa in 36 patients displayed in Table 2. Herpes simplex lesions appear as small vesicles that rupture, ulcerate, and then form a crust, confined to the keratinized mucosa. In the Group 1: With CD4 count 500, mucositis score in patients suffering from herpes simplex are analyzed from 1 st week up to 3 months in T ables 3-6. In Table 3, it is shown that changes in increase in degree of mucosal involvement in Group 1 base and 1 week is significant. In Table 4, it is shown that changes in increase in degree of mucosal involvement in Group 1 1 month Table 1: (Spijkervet s mucositis ). Local sign Score of local sign Length (cm) Score of length No mucositis 0 White discoloration Erythema Pseudomembrane Ulceration An area (The i th area=1.n) might include several sub areas. n: Number of areas, K: Sign, E: Length Table 2: Profile of baseline characteristics. Characteristics Numbers Number of patients enrolled 135 Number of patients treated 135 Number of patients followed up 135 Sex wise distribution of the sample Female 15 Male 120 Age wise distribution of the sample (years) Number of patients HIV+with oral ulcers 135 Number of patients HSV+/others 36/99 Group 1: Number of HIV+patients with HSV+and 15 CD4 T cell count <500 Group 1: Number of HIV+patients with HSV+and 21 CD4 T cell count 500 HIV: Human immunodeficiency virus, In Table 5, it is shown that changes in increase in degree of mucosal involvement in Group 1 2 months In Table 6, it is shown that changes in increase in degree of mucosal involvement in Group 1 3 months To summarize it can be stated that, In HIV + patients with CD4 <200, the lesions due to HSV infection reach a significant level within remain more or less unchanged in the oral cavity up to 3 months. This is the reason they are called resistant ulcers due to compromised healing capacity of immune compromised patients. Table 3: Degree of mucosal manifestation of HSV infection in Group 1 base and 1 week. P 1 week Difference B and 1 week (D1) 0.34± ± ±0.28 t=4.24, df=14 P<0.001 Table 4: Degree of mucosal manifestation of HSV infection in Group 1 1 month. P 1 week 1 month Difference 1 month (D1) 0.34± ± ± ±0.22 t=0.4, df=14 Table 5: Degree of mucosal manifestation of HSV infection in Group 1 2 months. P 1 week 2 months Difference 2 months (D1) 0.34± ± ± ±0.18 t=0.46, df=14 Table 6: Degree of mucosal manifestation of HSV infection in Group 1 3 months. P 1 week 3 months Difference 3 months (D1) 0.34± ± ± ±0.10 t=0.3, df=14 461

3 In the Group 2: With CD4 count >500, mucositis score showing mucosal manifestation in patients suffering from herpes simplex are analyzed from 1 st week up to 2 nd week or until the remission of the lesions displayed in the Tables 7 and 8. In Table 7, it is shown that changes in degree of mucosal involvement in Group 2, the base and 1 week are significant. In Table 8, it is shown that changes in degree of mucosal involvement, the base and 2 nd week, are not significant. Thus, it can be stated that mucosal ulcers due to acute herpetic gingivostomatitis in HIV + patients with adequate immune status get manifestated for a period of 1-week with spontaneous remission within 2 weeks. Association of symptoms such as dysphagia and other febrile conditions, anorexia, and malaise is found for a period of 1-week in patients of Group 2 and for a period of more than a month in patients of Group 1 displayed in Table 9. Discussion Manifestations of concurrent viral infections of the oral cavity in HIV-positive patients served as the clinical criteria Table 7: Degree of mucosal manifestation of HSV infection in Group 2 (CD4 count 500) base and 1 week. 1 week Difference B and 1 week (D1) P 0.34± ± ±0.28 t=4.33, df=20 P<0.001 Table 8: Degree of mucosal manifestation of HSV infection in Group 2 (CD4 count 500) base and 2 nd week. 2 weeks Difference B and 2 nd week (D1) P 0.34± ± ±0.28 t=0.075, df=20 Table 9: Statements of HSV positive HIV patients (n=36) for Qualitative analysis : Number of patients who responded agree getting the symptoms. symptoms Group 1 (n=15) with 1 month symptoms Group 2 (n=21) with 1 week symptoms Dysphagia Febrile symptoms including anorexia /malaise for determining the disease progression. During the study of oral manifestations of AIDs patients, it is found that 23% of oral lesions are viral in origin, distributed in the lip, buccal mucosa, tongue, and palate. Herpes group viruses are common opportunistic pathogens in HIV-infected individuals. Persistent mucosal ulcers caused by herpes simplex infection are difficult to differentiate from ulcerogenic diseases such as aphthous major and necrotizing stomatitis. Persistent oral pain with non-healing tendency is the characteristic clinical features of intraoral HSV infection. Extensive oral ulcerations are also found to be associated with simultaneous concurrent infections with oral HSV, CMV, and histoplasmosis in HIV-infected person. Application of antiviral drugs such as acyclovir, ganciclovir, or foscarnet has brought additional improvement in quality of life for the HIV-infected Individual. 1-9 In both developing and developed countries, HIV infection is a major global health problem. Reports of oral lesions in HIV infection are well-documented in developed countries, but reports from developing countries on oral lesions are neither well-documented nor adequate. Oral health measures are to be effectively formulated for the HIV-infected individuals with the help of these reports. 11 This present discussion in the Indian context has its own significance, as the seroprevalence of HSV-infection being inversely related to socioeconomic background. Primary HSV-1 infections are usually asymptomatic but give rise to mucocutaneous vesicular eruptions following an incubation period. The lips, gingiva, buccal mucosa, tongue, the hard and soft palate are the primary areas affected by herpetic gingivostomatitis. 12 Diagnostic culture for HSV for all oral ulcers should be recommended regardless of their location in immunocompromised patients. Early diagnosis and treatment with acyclovir are readily effective and reduces patient morbidity. 13 Success and clinical outcome of antiretroviral therapy (ART) are measured by the CD4 + T-cell count. In addition to that, a good immunological response, which is an integral part of the success of ART, is also determined by CD4 + T-cell count and plasma viral load. 14 Ability of the HSV to establish latency and undergo subsequent recurrence, make it one ubiquitous infectious agent for which a complete cure is far from reality. This infection is a matter of concern for the immunocompromised patient, as it is associated with increased morbidity and mortality. In immunocompromised patients, antiviral drug regimens may reduce the morbidity and potential mortality caused especially by the HSV. 15 Standard topical therapy and systemic antiviral therapy have been widely accepted as an effective treatment protocol for primary herpetic gingivostomatitis. Acyclovir (ACV) 5% cream and penciclovir 1% cream are both effective, well-tolerated, and accepted for herpes labialis. Systemic acyclovir and famciclovir may be effective in the acute treatment of severe HSV-1 disease in immunocompromised patients reducing the duration and 462

4 recurrence of HSV-1 infection. The optimal timing and dose of the treatment are uncertain and variable according to different situation. 16 Data from developing countries regarding oral lesions associated with adult HIV infection are inadequate to bring any alteration in 1993 ECC/WHO classification of oral lesions associated with adult HIV infection. 17 Patients are more frequently dependent on dentists for diagnosis and treatment of recurrent herpetic infections. During treatment on patients, the dental office should use management strategies for prevention of the spread of this infection and ensuring adequate nutrition and maintenance of proper oral hygiene practices. 18 It is always difficult to distinguish the precipitating factors of oral mucosal ulcerations one from the other which leads to inappropriate therapeutic intervention. Treatment strategies within the general practice setting can be improved by better understanding of the virologic and local immunologic alterations within the oral mucosa. 19 Health care workers together with nurses and community health workers are in need for comprehensive training with regards to diagnosis and management of oral lesions of HIV as the prevalence of specific oral mucosal lesions in order of occurrence was as follows: Pseudomembranous candidiasis 27%, erythematous candidiasis 26%, angular cheilitis 14%, hairy leukoplakia 12%, ulcerations 12%, necrotizing gingivitis 5%, linear gingival erythema 3%, and non-hodgkin s lymphoma and Kaposi s sarcoma <1%. 20,21 Profound immune deficiency, which develops in HIV/AIDS infected patients, leads to the development of opportunistic infection constituting the clinical features of HIV/AIDS. Increased risk of autoimmune disease with development of opportunistic infection and malignancy results from the destruction of the immune system by the virus. Mononucleosis syndrome, the clinical symptoms found to be manifested as primary illness within weeks after first exposure to HIV in about half of the total cases. The patients with intact immunity, i.e., when CD4 T-cell counts is >500 cells/mm 3 ), rarely develops HIV-related complications. When CD4 counts drop below 200 cells/mm 3, progressive risk of developing opportunistic infections such as recurrent mucocutaneous HSV, herpes zoster (VZV), oral candidiasis and oral hairy leukoplakia, and malignancies increases, which is a typical clinical feature of AIDS. 22 Treatment for suppression of mucocutaneous HSV lesions in HIV patient was shown to be effectively controlled by application of drugs such as famciclovir, acyclovir, and valaciclovir in randomized, double-blind trials. Early HIV testing and timely initiation of ART is critical for the improved quality of life. 23,24 The primary form of herpetic gingivostomatitis, which is common among children and young adults is also seen in other age group with HIV infection as revealed in this study. In HIV + patients with CD4 <500, the lesions due to HSV infection reaches a significant level within remains more or less unchanged in the oral cavity up to 3 months. This is the reason they are called resistant ulcers due to compromised immune status and healing capacity of patients. Mucosal ulcers due to acute herpetic gingivostomatitis in HIV + patients with adequate immune status get manifestated for a period of 1-week with spontaneous remission within 2 weeks. The clinical manifestations of herpetic gingivostomatitis include vesicles, ulcers, and associated with symptoms of febrile conditions. These lesions start as small crops of vesicles that progress and rupture to produce small, painful, coalescing ulcers. As these lesions are usually confined to the keratinized mucosa, the lateral border of the tongue and buccal mucosa are rarely involved. The unexplored major percentage of these cases is might be due to other ulcerogenic diseases such as aphthous major, necrotizing stomatitis, and ulcerations with other viral infection. Oral lesions that are associated with this disease are important since they affect the quality of life of the patient and are useful markers of disease progression and immunosuppression. Oral infection caused by the HSV represents one of the more common conditions in HIV + patients; the dental practitioner will be called on to manage. Conclusion Oral infection caused by the HSV represents one of the more common conditions the dental practitioners/periodontists will be called on to manage in patients suffering from AIDS. Oral ulcers caused by co-infection of HSV presented persistent oral pain with non-healing tendency in HIV + patients with low CD4 T-cell count. Oral lesions that are associated with this disease are important since they affect the quality of life of the patient and are useful markers of disease progression and immune suppression. In normal condition, unique in its ability to establish latency and undergo subsequent recurrence, herpes simplex viral infection is considered as one ubiquitous infectious condition for which a cure does not exist. References 1. Itin PH, Lautenschlager S. Viral lesions of the mouth in HIV-infected patients. Dermatology 1997;194(1): Tukutuku K, Muyembe-Tamfum L, Kayembe K, Odio W, Kandi K, Ntumba M. Oral manifestations of AIDS in a heterosexual population in a Zaire hospital. J Oral Pathol Med 1990;19(5): Flaitz CM, Nichols CM, Hicks MJ. Herpesviridaeassociated persistent mucocutaneous ulcers in acquired immunodeficiency syndrome. A clinicopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81(4): Heinic GS, Northfelt DW, Greenspan JS, MacPhail LA, Greenspan D. 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5 herpes simplex virus infection in association with HIV infection. A case report. Oral Surg Oral Med Oral Pathol 1993;75(5): Regezi JA, Eversole LR, Barker BF, Rick GM, Silverman S Jr. Herpes simplex and cytomegalovirus coinfected oral ulcers in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81(1): Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86(4): Firth NA, Rich AM, Reade PC. Oral mucosal ulceration due to cytomegalovirus associated with human immunodeficiency virus infection. Case report and brief review. Aust Dent J 1994;39(5): Jones AC, Migliorati CA, Baughman RA. The simultaneous occurrence of oral herpes simplex virus, cytomegalovirus, and histoplasmosis in an HIV-infected patient. Oral Surg Oral Med Oral Pathol 1992;74(3): Fletcher CV. Treatment of herpesvirus infections in HIV-infected individuals. Ann Pharmacother 1992;26(7-8): Spijkervet FK, van Saene HK, Panders AK, Vermey A, Mehta DM. Scoring irradiation mucositis in head and neck cancer patients. J Oral Pathol Med 1989;18(3): Ranganathan K, Hemalatha R. Oral lesions in HIV infection in developing countries: An overview. Adv Dent Res 2006;19(1): Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: Overview on relevant clinico-pathological features. J Oral Pathol Med 2008;37(2): Woo SB, Lee SF. Oral recrudescent herpes simplex virus infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83(2): Pasternak AO, de Bruin M, Bakker M, Berkhout B, Prins JM. High Current CD4 T Cell Count Predicts Suboptimal Adherence to Antiretroviral Therapy. PLoS One 2015;10(10):e Huber MA. Herpes simplex type-1 virus infection. Quintessence Int 2003;34(6): Arduino PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: Review of its management. Oral Dis 2006;12(3): Patton LL, Phelan JA, Ramos-Gomez FJ, Nittayananta W, Shiboski CH, Mbuguye TL. Prevalence and classification of HIV-associated oral lesions. Oral Dis 2002;8 Suppl 2: Siegel MA. Diagnosis and management of recurrent herpes simplex infections. Oral Dis 2002;8 Suppl 2: Sciubba JJ. Herpes simplex and aphthous ulcerations: Presentation, diagnosis and management An update. Gen Dent 2003;51(6): Ramphoma KJ, Naidoo S. Knowledge, attitudes and practices of oral health care workers in Lesotho regarding the management of patients with oral manifestations of HIV/AIDS. SADJ 2014;69(10):446, Kamiru HN, Naidoo S. Oral HIV lesions and oral health behaviour of HIV-positive patients attending the Queen Elizabeth II Hospital, Maseru, Lesotho. SADJ 2002;57(11): Lloyd A. HIV infection and AIDS. P N G Med J 1996;39(3): Baccaglini L, Atkinson JC, Patton LL, Glick M, Ficarra G, Peterson DE. Management of oral lesions in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103 Suppl: S50.e Beyene MB, Beyene HB. Predictors of late HIV diagnosis among adult people living with HIV/AIDS who undertake an initial CD4 T cell evaluation, Northern Ethiopia: A Case-control study. PLoS One 2015;10(10):e

Oral Health & HIV. Professor Sudeshni Naidoo Department of Community Dentistry University of the Western Cape

Oral Health & HIV. Professor Sudeshni Naidoo Department of Community Dentistry University of the Western Cape Oral Health & HIV Professor Sudeshni Naidoo Department of Community Dentistry University of the Western Cape Importance & relevance of Oral HIV Lesions >70% of HIV+ve patients present with oral manifestations