Oral manifestations of HIV/AIDS in Asia: Systematic review and future research guidelines

Objectives The authors have conducted a systematic review of oral manifestations of HIV from studies conducted in Asia to establish the characteristics and prevalence of individual oral manifestations in Asia, and to assess the direction of future research studies on oral manifestations of HIV in Asia. Material and Methods The electronic retrieval systems and databases searched for relevant articles were PubMed [MEDLINE], EBSCO, and EMBASE. The search was for limited articles published in English or with an English abstract and articles published during the period January 1995 to August 2014. The authors reached a final overall sample of 39 studies that were conducted in Asia. Results The median population size among all studies was 312.7 patients. Oral candidiasis [OC] was the most common oral manifestation [37.7%] in studies conducted in Asia. The overall prevalence of oral hairy leukoplakia and melanotic hyperpigmentation was computed to be 10.1% and 22.8% respectively. Thailand and India are primarily countries with maximum research on oral manifestations. Conclusions The research on oral manifestations of HIV in Asia has to upgrade to more interventional and therapeutic studies rather than the contemporary cross- sectional epidemiological descriptive studies. The authors have given suggestions and future directions for the implementation of clinical research of oral manifestations in HIV patients. Key words:Oral manifestations, HIV/AIDS, Asia, Systematic review.


Introduction
Human Immunodeficiency Virus [HIV] is a massive and byzantine challenge for the public health system. The spread of HIV infection in Asian countries is a major concern that is still showing a rising trend (1). Despite a 26% reduction in HIV infections since 2001, the pandemic still outpaces the response and half of the people [49%] in Asia pacific region are unable to access the anti-retroviral therapy. The overall national prevalence in Asian countries is low, a misleading true statistic, that tends to camouflage the real pandemic threat. The huge volume of Asian population ensures that even a low prevalence transmutes into a colossal HIV infected population in numbers. HIV infection is of portentous significance as majority of the patients belong to economically and reproductively active group within their communities which can have a devastating effect on the socio-economic status of nation. Oral manifestations in HIV infection have been well documented as early markers of HIV infection and progression (2). Oral manifestations of HIV/AIDS [Acquired immunodeficiency syndrome] are significant as they may affect the patients' quality of life and can be used to assess the status of immunosuppression and determine the prognosis of the disease (3). Early diagnosis and appropriate treatment of oral lesions have great influence on patients' general health and can reduce the mortality rate of the disease. Thus it becomes imperative for all health care workers to be equipped with the necessary knowledge and expertise to manage oral manifestations of HIV infection. There are considerable regional variations in the oral manifestations of HIV infection, depending both on the populations studied and on the clinical heterogeneity (3). The oral manifestations in Asian countries as compared to western countries and other developing nations in Africa and Latin Americas are relatively different (2). The constraint of resources in Asian countries hinders the possibility of providing an effective health care system. Though many studies have been conducted on oral manifestations in HIV, the research in Asia is currently at a pivotal juncture as the existing research is getting repetitive. Currently, Asian studies predominantly focus on prevalence of oral manifestations and assess their association with parameters of HIV infection, sociodemographic data and deleterious habits. An oral lesion index is required that can assist health care workers to identify the oral manifestations and thus evaluate the predictability of the immune status in HIV patients especially in a resource constrained settings. The authors have hereby conducted a systematic review of oral manifestations of studies conducted in Asia to establish the characteristics and prevalence of individual oral manifestations in Asia, and to assess the direction of future research studies on oral manifestations of HIV in Asia. The author's primary aim is to provide a computed prevalence of the oral manifestations of HIV/AIDS in Asia that would help in the possibility of formulation of oral lesion index in the foreseeable future.

Material and Methods
The systematic review was based on the ongoing research on oral manifestations of HIV/AIDS. The geographical region of Asia was considered primarily as the maximum number of HIV patients is currently present in Asia. The PubMed interface of MEDLINE was interrogated by MeSH and free-text words. A comprehensive literature search was executed till August 2014. The MeSH was ''oral, lesions'', "oral manifestations", HIV", "AIDS".
The electronic retrieval systems and databases searched for relevant articles were PubMed [MEDLINE], EBS-CO, and EMBASE. The search was for limited articles published in English or with an English abstract and articles published during the period January 1995 to August 2014. Each country located within Asia [countries were included according to United Nations website code 142] was individually typed in concurrence with the above mentioned Mesh words. Only oral epidemiological studies related to oral manifestations of HIV were included. All the studies that had followed presumptive criteria of EEC clearinghouse classification [1993] were included. Articles were manually retrieved from National Medical Library, New Delhi. Relevant cross references of the articles were also retrieved manually or electronically. The shortlisted studies were screened and independently categorized by all the authors. Any disagreement between the authors regarding article and data extraction was sorted. In reading the articles, the reference lists were checked to identify any other articles that may have been relevant to the research question or provided additional information. Individual prevalence rates were observed and were computed manually wherever it was required. The exclusion criteria to ensure uniformity of the studies were: 1. Studies on oral manifestations done outside Asia were excluded. Russia was excluded due to geographical overlap with Europe. 2. Exclusive HIV paediatric studies were excluded. 3. Interventional studies for oral manifestations in HIV patients were not included. 4. Individual case reports were excluded. The authors reached a final overall sample of 39 studies (4-42) that were conducted in Asia after applying the exclusion criteria (Methodology described in Table 1).

Results
Tabulation of the research studies (4-42) conducted on oral manifestations in Asia was done (  (38). The median population size among all studies was 312.7 patients. The primary mode of transmission of HIV in studies conducted in Asia is predominantly heterosexual route [overall 76.5%]. Males were more affected with HIV than females in almost all the studies except in a recent study (41) where all the 292 patients were HIV infected pregnant women. Anti-retro viral therapy [ART]'s usage was documented in twenty one studies [21/39; 53.8%]. ART was observed in these studies with varying percentages and the combined prevalence of patients on ART in Asian studies was observed to be only 35.7%.

Literature search strategy
Key word-"HIV", "AIDS", "Oral Manifestations", "Asia", "Names of all the Asian countries individually such as china, Pakistan, Singapore, Jordan, etc" Tsang and samranayake (1999) Japan Khongkunthi an et al.    Asian studies has been found to be very low as compared to developed countries (15).NHL was however observed with a prevalence of 4% in a study conducted by Nittayananta et al. (6) (14) whereas an Indian study (9) had observed a very low prevalence of 0.9% HSV infection.
-Miscellaneous oral manifestations No oral warts were observed or reported from studies in Asian countries (31). Histoplasmosis and penicilliosis caused by Penicillium marneffei were observed in studies conducted in Thailand and were found to be associated with severe immunosuppression (13,15,28). However, reports of penicilliosis were not documented in other Asian studies. Oral submucous fibrosis and homogenous leukoplakia were more frequently found in studies conducted in south India by Ranganathan et al. (16). Reports of exfoliative cheilitis were scarce in Asian studies (11). Bodhade et al. (29) had however observed nine cases of mollascum contagiosum in their study from India.

Discussion
The  (38). In Asian studies predominantly heterosexual population studies have been documented and the possibility of reduced frequency of orogenital contact [as documented in most of studies], could possibly explain the absence of oral warts (21). Studies need to be conducted measuring the stimulated and unstimulated salivary flow in a longitudinal cohort of HIV positive patients initially before HAART has begun and later at six months interval to accurately measure the impact of HAART on xerostomia. No reports of CMV sialadenitis were observed that could possibly be attributed to lack of resources to isolate the virus. The most common oral manifestation expectedly was OC [with no predominant subtype prevalence]. The difference in prevalence range of OC can be due to differences in the prescribed medications, the stages of the disease or the route of transmission of the infection, and the longevity of HIV infection. Melanotic hyperpigmentation was found with a greater frequency [22.8%] as compared to OHL [10.1%]. This can be attributed to a relatively greater usage of ART that tends to suppress OHL and promotes melanosis (27). An important aspect of this review was the absence of cases of Kaposi's sarcoma in Asia, the malignant neoplasia most frequently associated with HIV /AIDS patients. The prevalence of Kaposi's sarcoma has been found to be higher in Africa and developed world. Shiboski et al. (44) had recently postulated that, though oral squamous cell carcinoma [SQCC] has not yet been shown to be associated with HIV ⁄ AIDS in studies, in the era of HAART, patients with HIV disease would live longer and would be more likely to have carcinoma. Factors like greater availability of HAART, high prevalence of oral HPV infection and association of higher usage of tobacco either in smokeless or smoking may combine for a greater risk of developing oral SQCC in Asian countries (45). A recent review of malignancies of Head and neck region revealed 14 cases of oral SQCC outside Asia and also concluded that the HIV-associated carcinoma would occur at a relatively younger age group (45). NHL is recognized as an AIDS defining condition in HIV-infected individuals and is included among the oral lesions associated with HIV infection. The prevalence of NHL was found to be rare in Asia. Nevertheless, the authors postulate that oral malignancies, especially tobacco related, are likely to be documented more frequently in Asia as due to greater usage of ART in future there would be a likelihood of longer life span for HIV patients and thus these immunocompromised patients would be more exposed to initiating oncogenic factors.  (46). The systematic review conducted on oral manifestations do has some limitations. The computed prevalence of individual oral manifestations is not an exact indication as the clinical heterogeneity in race, habits, level of immunosuppression and gender prevalence in each study can make the comparison of studies very difficult. The ethnic diversities among the Asian population can create a variance of clinical presentation and there is a possibility of inter-examiner variability also. Moreover the different medications of ART do have some variations on the immunity thus influencing the oral cavity. The absolute CD4 counts were not considered by the authors as the data was not universal and standardized in respective countries. The effect of the systemic medication also plays a role in the variations of the oral manifestations. The formulation of an oral lesion index in the future would be an exciting and major breakthrough in the field of oral epidemiology in HIV/AIDS (31,47). However for the oral lesion index a combined prevalence of the oral manifestations in a given region is required and thus authors have conducted the review for the initial progress for the formulation of an oral lesion index. The authors suggest that the data derived in this review can subsequently be utilized in ensuing research studies further to create a record for further help in analysis of oral e426 manifestations and the predictability of immune status from oral manifestations. The research on oral manifestations in Asia has to upgrade to more interventional and therapeutic studies rather than the contemporary cross-sectional epidemiological descriptive studies. The only predicament for ensuing stage of research is "If not now, then when"? The authors have given suggestions and future directions for the implementation of clinical research of oral manifestations in HIV patients. 1. The quantity of conducted studies on oral manifestations from Asia is sufficient but there is unequal distribution with most of studies in India and Thailand. Moreover, the data on oral manifestations in HIV/AIDS infected population is limited from Middle East countries, China and Japan. Research studies need to be conducted in these regions. ] for conducting research especially on clinical trials for management or oral lesions and thus making it more organized and treatment-centric. This would serve a dual purpose of saving resources as well as prevention of duplication of same study. 5. Studies need to be longitudinal and multicentric to exactly ascertain the prevalence of individual oral manifestations. Focus should also be on microbiological aspects of the studies like detection of strains of candida species as they are being conducted in developed nations (43). However, recently few studies in Asia have measured the stimulated and unstimulated salivary flow (48). 6. Two examiners should preferably do the intraoral examination with blinding of HIV status to exactly ascertain the prevalence of individual oral manifestation as a single examiner might be influenced by HIV status and there is always a risk of bias for over diagnosis of HIV related lesions especially OHL.