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Oral lesions: A true clinical indicator in human immunodeficiency virus

From the onset of the human immunodeficiency virus (HIV) epidemic over 20 years ago (since the appearance of the first cases of contamination by the HIV virus in the 1980s), more than 60 million people have become infected and more than 20 million people have died. An estimated 15,000 new infections occur each day, with more than 95% of these in developing countries. The distinctive characteristic in the pathogenesis of HIV/acquired immunodeficiency syndrome is that the primary target cell for HIV is immune cells bearing the CD4 marker at their surface, and the CD4 cell count and viral load have been used lately as the most important laboratory parameters to evaluate the evolution of the disease. Oral lesions are common (30–80%) in patients infected by the HIV virus and may indicate an impairment in the patient's general health status and, consequently, a poor prognosis. Oral manifestations can suggest decreased cluster-differentiated (CD4+) T cell count and increased viral load, which might also aid in diagnosis, progression, and prognosis of the disease. At the tertiary level of oral care, a dentist should be available to make definitive diagnoses of oral lesions and provide professional oral services such as prophylaxis, restorations, biopsies, and the prescription of appropriate medication.


HIV: Prevalence and epidemiology
Human immunodeficiency virus (HIV) causes progressive mutilation of the body's cellular immune system, leading to augmented susceptibility to tumors and fatal conditions such as acquired immunodeficiency syndrome (AIDS). The emergence and pandemic spread of AIDS constitute the greatest challenge to the public in modern times. [1] From the onset of the HIV epidemic over 20 years ago (since the appearance of the first cases of contamination by the HIV virus in the 1980s), more than 60 million people have become infected and more than 20 million people have died. More than 20 years into this HIV-AIDS pandemic, it has stuck almost all the countries and populations in many ways. No disease has struck with such serious consequences as AIDS. It has devastating social, psychological, and financial ramifications. Currently, it is the fourth-leading cause of mortality worldwide. [2] AIDS, caused by HIV, is presently considered as one of the most dreadful diseases affecting human kind. An estimated 15,000 new infections occur each day, with more than 95% of these in developing countries. Sub-Saharan Africa currently bears the greatest burden worldwide, with 28.5 million (70%) individuals infected. In South Africa, 5.2 million of the population was estimated to be infected with HIV/AIDS. HIV is transmitted by sexual means, through the exchange of body fluids (especially infected semen during intercourse); by non-sexual means, via the parenteral transfer of infected blood; or through vertical transmission to infants born of infected mothers. The only fluids that have been demonstrated to be associated with transmission of the virus are blood, semen, breast milk, and vaginal secretions. Casual contact (shaking hands, hugging, casual kissing, etc.) has not been shown to transmit HIV. The United Nations Programme on HIV/AIDS estimates that over 40 million people are living with HIV/AIDS globally. An estimated 15,000 new infections occur each day, with more than 95% of these in developing countries. Sub-Saharan Africa currently bears the greatest burden worldwide, with 28.5 million (70%) individuals infected. In South Africa, 5.2 million of the population was estimated to be infected with HIV/AIDS. Between 60% and 90% of the people with HIV infection will have at least one oral manifestation at some time during the course of their disease. Oral lesions cause significant discomfort and have a major impact on the quality of life. Recognition and management of these oral conditions is therefore important for the health and quality of life of the individual with HIV/AIDS. Despite the increasing number of reports on the prevalence of oral manifestations in HIV-positive/AIDS patients, there is limited information about the impact of these lesions on the quality of life in these patients.

Structure of human immunodeficiency virus
The HIVs are members of the retrovirus family of viruses. The retrovirus family is composed of three subfamilies: oncoviruses, spumaviruses and lentiviruses. Based on the structure, biologic properties, and protein and nucleic acid sequence homology, HIV is classified as lentivirus. A mature extracellular particle of HIV is characteristically 90-130 ηm in diameter. HIV has a cylindrical eccentric nucleoid, or core. The nucleoid contains the HIV genome, which is diploid (i.e., composed of two identical singlestranded RNAs). Encoded in the RNA genome are the entire complements of genes of the virus. These genes code for the structural proteins that are used to assemble the virus particles and the regulatory proteins involved in the regulation of viral gene expression. The HIV RNA genome is associated with a basic nucleic acid-binding protein p9 and the reverse transcriptase (RT). The core or capsid antigen p24 encloses the nucleoid components, completing the nucleocapsid structure. The matrix antigen p17 encircles the viral core and lines the inner surface of the envelope of the virus. The surface of the HIV manifests external knob-like structures formed by the envelope glycoprotein gp120. The transmembrane protein (TMP) gp41 spans the viral membrane and has both external and internal domains. The TMP anchors the external gp 120 to the viral envelope. The membrane lipid bilayer is derived from the host cell plasma membrane. [3] Human immunodeficiency virus and immune system: CD4 target The distinctive characteristic in the pathogenesis of HIV/AIDS is that the primary target cell for HIV is immune cells bearing the CD4 marker at their surface. With the infection of HIV, there will be gradual decrease of human immune cells bearing CD4 antigen receptor, the most important being T helper cells (CD4 T cells), B lymphocytes, macrophages, and natural killer cells. The CD4 cells coordinate a number of immunological functions, and as these cells are decrease the risk and severity of opportunistic infections (OI) increasing the death of the patients. It is stated that the absolute number of CD4 lymphocytes fall from a normal level of 800-900 cu/mm to 60-100 per year. [4] Because the loss of immune containment is associated with declining CD4 counts, the Centre for Disease Classification (CDC) stratifies patients with HIV infection into three categories on the basis of CD4 counts: CD4 counts ≥500 cells/mm 3 , 200-499 cells/ mm 3 and <200 cells/mm 3 . A CD4 count <200 cells/mm 3 is associated with severe immune suppression, and the CDC in 1993 included all HIV-infected persons with such a count as fulfilling an AIDS-defining diagnosis. [5] The amount of CD4 lymphocyte cells per milliliter and/or the quantity of RNA-HIV-1 copies per milliliter (viral load) are surrogate markers of HIV disease progression. It is known that HIVpositive patients with CD4 lymphocyte cells counts less than 200 per milliliter are severely immune depressed and HIV-positive patients with a viral load greater than 10,000 copies per milliliter show an active viremia. [6,7] The CD4 cell count and viral load have been used lately as the most important laboratory parameters to evaluate the evolution of the disease. [8] Although there have been reports of delayed antibody response to HIV1 infection, 95% or more of the infected persons develop detectable antibodies to HIV1 within 3-6 months. The interval between infection and seroconversion or detection of antibodies has been called the window period. The standard screening test for HIV infection is elaborated in Table 1.

Human immunodeficiency virus: Clinical presentation
Symptoms of HIV disease can appear at any time during the course of HIV infection. The spectrum of illness changes as the CD4+ T cell count declines. The more severe and life-threatening complications of HIV infection occur in patients with a CD4+ T cell count <200/μL. A diagnosis of AIDS is made in anyone with HIV infection and a CD4+ T cell count <200/μL and in anyone with HIV infection who develops one of the HIV-associated diseases considered to be indicative of a severe defect in cell-mediated immunity. While the causative agents of the secondary infections are characteristically opportunistic organisms such as P. carinii, atypical mycobacteria, cytomegalo virus (CMV), and other organisms that do not ordinarily cause disease in the absence of a compromised immune system, they also include common bacterial and mycobacterial pathogens. Approximately 60% of the deaths among AIDS patients are as a direct result of an infection other than HIV, with P. carinii, viral hepatitis, and non-AIDS defining bacterial infections heading the list. Following the widespread use of combination antiretroviral therapy and implementation of guidelines for the prevention of OIs, the incidence of secondary infections has decreased dramatically. Overall, the clinical spectrum of HIV disease is constantly changing as patients live longer and new and better approaches to treatment and prophylaxis are developed. In general, it should be stressed that a key element of the treatment of symptomatic complications of HIV disease, whether they are primary or secondary, is achieving good control of HIV replication through the use of combination antiretroviral therapy and instituting primary and secondary prophylaxis as indicated. [2] Without treatment, HIV-infected patients will progress through the stages described in Table 2.

Oral lesion in human immunodeficiency virus
Oral lesions are common (30-80%) in patients infected by the HIV virus and may indicate an impairment in the patient's general health status and, consequently, a poor prognosis. Many of these HIV-positive patients present manifestations involving the maxillofacial region in all stages of the disease, and, in some cases, the oral lesions are the first signs of infection. [9,10] With disease progression, the deleterious effect of HIV on the immune system results in an escalating incidence of widely recognized and extensively described OIs and diseases, among which are the oral manifestations of HIV and, since the onset of the HIV pandemic, oral lesions have been well documented as early markers of HIV infection and as predictors of HIV disease progression. [11,12] Oral manifestations can suggest decreased cluster-differentiated 4 (CD4+) T cell count and increased viral load, which might also aid in the diagnosis, progression, and prognosis of the disease. [13][14][15] The risk of oral complication increases with immunologic deterioration. Oral examination is therefore useful for the early diagnosis, which can prolong the asymptomatic period, delay disease progression, and prevent OIs with proper education and   bacterial, and neoplastic infections. These lesions are often the first clinical symptoms of HIV infection and their diagnosis is an auxiliary method to raise early suspicion of AIDS. [16] The various commonly associated oral lesions with HIV are illustrated in Table 3. Clinical stages of oral lesions associated with HIV with respect to its occurrence are illustrated in Table 4.

Effect of antiretroviral therapy on oral lesions
In the recent years, the management of HIV-positive individuals has been based on highly active antiretroviral therapy (HAART), comprising a combination of nucleoside analogue RT inhibitors and at least one protease inhibitor and/or one non-nucleoside analogue RT inhibitor. HAART induces a marked reduction of viral replication and increases the CD4+ cell count. Since the introduction of HAART in the mid-1990s, it has been accompanied by a reduction in the frequency of many of the secondary events caused by HIV infection, including some oral lesions. [17] Since the advent of HAART, studies had shown a decline in the prevalence of oral lesions associated with HIV/AIDS. These lesions include: oral candidiasis, hairy leukoplakia, Kaposi's sarcoma, herpes simplex labiali, and periodontal disease. [18] CONCLUSION The World Health Organization (WHO) Global Oral Health Program recently formulated policies for the prevention of oral manifestations in HIV/AIDS. [19] Prevention of HIV/AIDS-related oral disease is based on the involvement of primary healthcare workers as well as oral health professionals in the early detection and screening, on the integration of oral disease prevention and oral health promotion into community and national HIV/ AIDS programmes, and on the WHO technical support to build capacity in countries. By using a systematic approach and giving the patient a complete oral examination, the dentist will be able to diagnose oral lesions in patients with HIV disease. Rather than trying to guess the correct diagnosis, a good diagnostician should obtain the history of the lesion, should evaluate signs and symptoms, and should determine the possible etiology. Important factors to be considered in the differential diagnosis are the history of the lesions, the clinical appearance, location, and symptoms like pain, burning sensation, and discomfort upon deglutition. It is also important to consider the nature of the lesion. An oral mucosal lesion can be reactive, inflammatory, infectious, or malignant. It can be a localized process or part of a systemic disease. From the analysis of the data collected during clinical examination, the dentist can construct a list of differential diagnoses, listing the most probable disease that could cause that particular lesion. This procedure should lead to the final diagnosis of the disease and indicate the most appropriate treatment. Not uncommonly, oral lesions in HIV patients can cause severe impairment of oral functions as well as pain and discomfort and, in addition, they are a manifestation of opportunistic diseases secondary to systemic immunosuppressant. Therefore, from the oral cavity, they may disseminate systemically and cause a much more dangerous threat to the patient's health. Some of the lesions may be transmissible and patients must be counseled on the prevention of transmission (e.g., Herpes, syphilis, tuberculosis). HIV-related oral abnormalities are present in 30-80% of the HIV-infected individuals, and these abnormalities are often inaccurately described in medical care. Dental expertise is necessary for the proper management of oral complications in HIV infection or AIDS. Medical clinicians should be able to recognize HIV-associated oral disease and to provide appropriate care and referral. At the tertiary level of oral care, a dentist should be available to make definitive diagnoses of oral lesions and provide professional oral services such as prophylaxis, restorations, biopsies, and the prescription of appropriate medication. There is a need for dentists to be involved throughout the management of HIV patients and not only at the tertiary level of care. There is also a need for training and retraining of medical personnel in the diagnosis and management of HIV-associated oral lesions and appropriate patient referral.