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1 2019 Course #1 Self-Study Course Contact Us: Phone Toll Free Fax Web dentistry.osu.edu/sms Course Instructions: Read and review the course materials. Complete the 12 question test. A total of 9 questions must be answered correctly for credit. Submit your answers online at: Check your for your CE certification of completion (please check your junk/spam folder as well). About SMS CE courses: TWO CREDIT HOURS are issued for successful completion of this self-study course for the OSDB biennium totals. CERTIFICATE of COMPLETION is used to document your CE credit and is ed to each course participant. ALLOW 2 WEEKS for processing of your certificate. Frequently Asked Questions: Q: Who can earn FREE CE credits? A: EVERYONE - All dental professionals in your office may earn free CE credits. Each person must read the course materials and submit an online answer form independently. Q: Where can I find my SMS number? A: Your SMS number can be found in the upper right hand corner of your monthly reports, or, imprinted on the back of your test envelopes. The SMS number is the account number for your office only, and is the same for everyone in the office. Q: How often are these courses available? A: Four times per year (8 CE credits). The Ohio State University College of Dentistry 305 W. 12th Avenue Columbus, OH The Ohio State University College of Dentistry is a recognized provider for ADA CERP credit. ADA CERP is a service of the American Dental Association to assist dental professionals in identifying quality providers of continuing dental education. ADA CERP does not approve or endorse individual courses or instructors, nor does it imply acceptance of credit hours by boards of dentistry. Concerns or complaints about a CE provider may be directed to the provider or to the Commission for Continuing Education Provider Recognition at The Ohio State University College of Dentistry is approved by the Ohio State Dental Board as a permanent sponsor of continuing dental education. This continuing education activity has been planned and implemented in accordance with the standards of the ADA Continuing Education Recognition Program (ADA CERP) through joint efforts between The Ohio State University College of Dentistry Office of Continuing Dental Education and the Sterilization Monitoring Service (SMS).

2 2019 Course #1 HIV and Periodontitis This is an OSDB Category B: Supervised self-instruction course About the Author Najla Kasabreh, DDS Written by: Najla Kasabreh, DDS Edited by: Sydney Fisher, MPH Nick Kotlar, BS Release Date: February 25, :30am EST Last Day to Take Course Free of Charge: March 27, :30pm EST Dr Kasabreh obtained her D.D.S from the university of Jordan in She then worked as a research and teaching assistant in the Periodontology department in the same school. During that time she gained experience in Periodontology, oral medicine and oral surgery. She is currently a third year periodontology resident at the Ohio State University. She has one case report published in the field of oral medicine." Dr. Kasabreh can be reached at kasabreh.1@buckey .osu.edu Neither I nor my immediate family have any financial interests that would create a conflict of interest or restrict my judgement with regard to the content of this course. Introduction HIV is a viral infection that affects an individual s immune system making him/her prone to opportunistic infections. These infections will affect any part of the body including the oral cavity. In fact, oral manifestation might be the first sign of the disease. In order to keep a healthy periodontium, a well-balanced immune system is important, which is lacking in the case of HIV-positive individuals. The knowledge of the expected periodontal manifestation is very important to any clinician since he/she is responsible for suspecting the presence of any oral abnormal findings, reaching a diagnosis, and treating the patient accordingly. This CE course will discuss HIV in detail, including definitions, prevalence, 2 pathogenesis, and treatment options.

3 Definition of HIV/AIDS Patients with AIDS have been reported as early as the early 1980s. Initially, it was observed in the homosexual community and later in drug users, as well as patients receiving blood transfusions. The condition then became rapidly an epidemic. The virus responsible for this infection was isolated in Human immunodeficiency virus, or more commonly known as HIV, is a retrovirus. Both types of the virus, HIV 1 and HIV 2, attack the body s defense cells, specifically the CD4 cells. CD4 cell is a T cell or a T-lymphocyte cell, which is a white blood cell, and thus a part of the natural defense system. The virus successfully injects its DNA into the CD4 cells. Once this happens, a person will be HIV-positive. AIDS or Acquired Immune Deficiency Syndrome is the state where the patient has symptoms due to significant depletion of the immune system and inability to fight other bacteria, virus or fungi, thus leaving the individual susceptible to infections. Prevalence and Important Statistics With the advocation of treatment, 28,500 new cases of HIV were diagnosed in 2015 in the United States (68% among gay and bisexual men, 23% among heterosexual and 9 % among people who inject drugs). There was a decline of 8% from 2010 ( Figure 1). 1 Figure 1 Globally, there were around 36.9 million people living with HIV/AIDS in Since 1996, new infections were reduced by 47%. 2 Out of the 36.9 million, 21.7 million were receiving antiviral treatment. Estimated new HIV infections in the United states by transmission category

4 Figure 2 Estimated number of people living with HIV in 2017 (Adopted from WHO). 2 Table 2: Prevalence of HIV among people aged 15 to 49 years by region (adopted from WHO). 3 Africa Americas WHO region % [ ] 0.5 % [ ] South- East Asia Europe Eastern Mediterranean Western pacific WHO Global 0.3 % [ ] 0.4 % [ ] 0.1 % [< ] 0.1 % [< ] 0.8 % [ ]

5 Table 3: Distribution of people living with HIV, according to gender and age. 4 Category People living with HIV in 2017 Adults 35.1 million [29.6 million 41.7 million] women Men Children (younger than 15 years) 18.2 million [15.6 million 21.4 million] 16.8 million [13.9 million 20.4 million] 1.8 million [ 1.3 million 2.4 million] In 2000, there were 1.5 million HIV-related deaths. This number has decreased in 2017 to 0.9 million (Figure 3). 5 Figure 3: Number of HIV related deaths. 5

6 Immunopathogenesis of HIV As mentioned earlier, HIV is a retrovirus that targets CD4+ cells. This includes (T lymphocytes, mononuclear phagocytes, and dendritic cells). HIV carries RNA, as opposed to DNA that humans carry. HIV enters the cells via a viral envelope glycoprotein (gp120env). With a huge effort in research, it was discovered that chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5) are the receptors of HIV on CD4 cells. 67 Once the virus attaches itself to the receptors, a conformational change takes place allowing the virus to get access into the T cell. The double stranded Viral DNA synthesis starts in the cellular cytoplasm and is completed in the nucleus. Once the viral DNA synthesis is completed it becomes integrated into the host DNA. Moving forward, now HIV RNA will be transcribed via the cellular RNA polymerase II which leads to the synthesis of the viral proteins. The next step will be the assembly of these proteins to form new mature viruses that are ready to invade other cells. It should be mentioned, however, that once integration is complete, the infection may become latent for several months/ years. Once the virus is activated, the CD4 cell dies. The virus then buds from its plasma membrane, fuses with nearby uninfected T cells and forms multinucleated giant cells, continuing the death and cytolysis of the other cells which may or may not be infected. HIV replication and pathogenesis occur primarily in the lymphoid organs. 8 Gut-associated lymphoid tissue (GALT) is believed to be the primary site of infection. 9 The next target of HIV after systemic infection is the central nervous system (CNS), which can be targeted by the virus or by previously infected host cells. 10 There are 3 possible modalities that have been proposed for HIV entry to CNS : through diffusion from blood through the blood-brain barrier (BBB), by transcytosis 11 or via HIV-infected leukocytes. 12 This will give rise to a number of neurologic symptoms later on.

7 Figure 4 Life cycle of HIV in a CD4+ cell. 13 HIV binds to the receptor on the CD4 cell leading to fusion with the cell membrane and the virus. The capsid of the virus is then uncoated, and RNA and proteins are released into the cytoplasm. Next, HIV RNA is transcribed to DNA via reverse transcription, forming the pre integration complex (PIC); that subsequently enters into the nucleus. In the nucleus, the viral DNA is integrated into the host DNA to be transcribed and translated later on to form new viral RNA and proteins. The new viral products then assemble into new virus that buds off the cell surface. The virus continues to mature and become infectious virions.

8 Stages of HIV infection: According to the Centers for Disease Control and prevention; HIV has 3 stages. The person can progress to all of these stages if he/she doesn t receive the proper treatment: Stage 1: Acute HIV infection Usually flu-like symptoms develop within 2-4 weeks after infection with HIV. These symptoms may last for a few weeks. Since this stage has flu-like symptoms; people are often unaware that they have been infected. This stage is considered very contagious. In this stage, there is no opportunistic illness. Stage 2: Clinical latency (HIV inactivity or dormancy) In this stage, HIV is active, but the numbers of the virus are very low. The person infected may not develop any symptoms and this stage can last for decades. Stage 3: Acquired immunodeficiency syndrome (AIDS) This stage starts when the person s CD4 count drops and the HIV load increases. In this stage, person can get infections very easily, since their immune defense system is severely compromised. Common symptoms of AIDS include chills, fever, sweats, swollen lymph glands, weakness, and weight loss. CD4+ Count and Viral Load As mentioned earlier, CD4+ cells are white blood cells that are targeted by the HIV virus. In a healthy individual, the CD4 count ranges from cells/mm 3. A diagnosis of AIDS is made when the CD4 count is < 200 cells/mm 3.

9 Routes of Infections A person can get infected by a variety of routes. The virus can be transmitted via certain body fluids, including blood, semen, rectal fluids, vaginal fluids and breast milk. The T cells can be attacked when the virus comes in contact with a mucous membrane or an open wound. 13,14 The following are examples of HIV infection routes: 1. Sexual transmission 2. Shared needles (used for drugs, tattooing, piercing etc.) 3. Vertical transmission or during breastfeeding 4. Shared personal items 5. Occupational exposure Classification Redfield et al. in 1986 suggested the Walter Reed classification. The aim of this classification was to unify clinical evaluation of the disease presentation and response to treatment with antiviral medications. 15 As can be noticed in this classification system, a smaller stage number represents a simpler form of the disease clinical presentation. For example, WR1 represents an asymptomatic HIV-positive HIV-positive individual with T cell counts > 400 cells/mm 3. Whereas WR6 represents a patient with HIVrelated infections (AIDS). In addition to the stage, some letters are used to designate a symptom, a disease or an infection. For example, letter K is added to the stage once Kaposi's sarcoma is diagnosed. Other neoplasms are designated by the letter N. CNS is added to the stage once the patient presents with neurologic disease such as demyelinating disease, encephalopathy, or neuropathy. Letter B is added to any stage when symptoms are present. Symptoms include: 1. Temperature greater than 38 C for 3 weeks 2. Unexplained loss of > 10% of body weight within three months 3. Night sweats for 3 weeks 4. Diarrhea for more than 1 month

10 Table 4: The Walter Reed Staging Classification for Human T-cell Lymphotropic Virus Type III (HTLV-III). 15 Stage Seropositiv ity CL WR0 - - WR1 + - WR2 + + WR3 + -/+ WR4 + -/+ WR5 + -/+ T cells (cells/mm 3 ) > 400 cells/mm 3 ) > 400 cells/mm 3 ) >400 cells/mm 3 ) < 400 cells/mm 3 ) < 400 cells/mm 3 ) < 400 cells/mm 3 ) IDH O/P C OOI Normal - - Normal - - Normal - - Normal - - Partial - - Complete and/or oral/oropharynge al candidiasis - WR6 + -/+ < 400 cells/mm 3 ) Partial/complete -/+ + CL: Chronic l chronic lymphadenopathy IDH: Impaired delayed hypersensitivity O/P C: Oral/Pharyngeal candidiasis OOI: Other opportunistic infections In an attempt to correlate the WR classification to the oral manifestation, Thompson et al. examined 390 HIV-positive individuals. 16 Oral disease was absent in most of the patients with stage WR1, WR2, and present in almost all the patients with stage WR6. The most prevalent finding was supraclavicular chronic lymphadenopathy with a prevalence of 59.2%. The onset of chronic lymphadenopathy correlated with staging level of WR1 through WR3, indicating that chronic lymphadenopathy has a tendency to occur early in the WR staging scheme. Oral hairy leukoplakia was also prevalent in 36.4% individuals with most of the lesions occurring on the lateral aspect of the tongue. The occurrence of oral hairy leukoplakia was significantly correlated to T cell counts but it showed weak correlation to WR staging scheme. Oral candidiasis was present in 10.2% of the patients.

11 Treatment of HIV Azidothymidine (a.k.a. AZT or zidovudine), an anti-cancer medication, was the first medication used to treat HIV. It was reported that AZT decreased mortality and opportunistic infections. 17 Resistance to AZT soon progressed, rendering the need to develop new medications. It was fruitful to develop other treatment options alongside the advances in technology and knowledge of the virus life cycle. Protease inhibitors, nucleoside reverse transcriptase inhibitors is a combination antiretroviral therapy that was shown to reduce morbidity and mortality among HIV patients. 18 Some other strategies include stem cell transplantation and vaccines. Figure 5 The antiretroviral drugs commonly used are indicated in the figure in the green box: Fusion inhibitors, Entry inhibitors, NRTI; nucleoside reverse transcriptase inhibitors, NNRTIs; non nucleoside reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors. 13

12 Highly active antiretroviral therapies, or HAART, is a combination of reverse transcriptase inhibitors and protease inhibitors. This regimen was found to be successful in reducing the HIV virus to undetectable levels. With the use of HAART, a drop in the mortality rate was seen in some countries. With the introduction of protease inhibitors, it was found that oral opportunistic infections have changed. 19 Changes in prevalence of oral candidiasis, aphthous ulcers, oral warts, herpes simplex virus lesions and Kaposi s sarcoma were not statistically significant. However, the prevalence of hairy leukoplakia and necrotizing periodontal diseases has decreased, whereas HIV salivary gland disease has increased. Protease inhibitors inhibit the maturation of the virus thus are effective in reducing viral replication, which in turn results in increased CD4 counts. This mechanism may explain the differences seen in oral opportunistic infections. The decrease in hairy leukoplakia prevalence from 26% to 11% may be attributed to the viral load reduction. The reduction in necrotizing periodontal diseases prevalence from 5% to 1.7% may be attributed to the protease inhibitors mediated increase in the neutrophil counts. On the other hand, the HIV salivary gland disease has increased from 1.8% to 5%. This is mainly due to increase in CD8 cells infiltrating the salivary glands, a phenomenon known as diffuse infiltrative lymphocytosis syndrome. HIV-positive Individuals in a Dental Setting Other than periodontal dental disease treatment, which will be discussed later, a dentist should be prepared to address other dental concerns. The dentist and the dental team should perform the cross-infection protocol. To date, there is only one documented case of HIV transmission from a dentist to patient and 63 HIV infected health care personnel to patients. In The Ohio State University safety and infection prevention manual, if there is an exposure of the skin by a contaminated instrument the following should be done: 1. Immediately isolate the involved instrument or needle 2. Wash the affected area with soap and water (do not apply alcohol) and cover with a bandage. 3. Notify supervising faculty member or supervisor 4. With a faculty member present, inform the patient that an exposure occurred

13 5. Make a notation in patient s record 6. Request that the patient consent to allow a sample of blood to be analyzed for possible infectious agents. Another aspect to be aware of when treating HIV-positive individuals is the rate of wound healing. Wound healing is usually delayed in HIV-positive individuals due to deterioration in their immune system. Impaired wound healing was experienced by 4 patients with average CD4+ /CD8-r cell ratio of 0.4 after extractions of impacted teeth although antibiotics were prescribed. 20 Also, those patients experienced severe and prolonged pain. Wound healing was complete in 4-6 weeks. However, these patients were under extensive local and systemic treatment. Periodontal Disease Periodontitis is a microbially driven inflammation of tooth supporting structures. The presence of bacterial biofilm targets the initiation of hostmediated inflammation, which will cause gingival inflammation/ gingivitis. Periodontitis as a separate disease entity results from microbial dysbiosis that itself happens due to changes in the host s defense system; inflammatory products and tissue breakdown by-products. However, periodontitis is believed to be a multifactorial disease, for which oral mycobiome, genetics and environmental factor all play a part in the disease initiation and progression, and thus its response to different therapeutic modalities. It is of utmost importance for the dental clinician to know the oral manifestations of HIV infection. More often, these oral manifestations are the first clinically noticeable expression of the infection. 21 HIV infection has been associated with attachment loss (percent of more than one site with attachment loss >= 4 mm was 60%), pocketing (percent of more than one site with probing depth >= 4 mm was 51%), bleeding on probing (97%), ulceration (3%), red banding (12%) and erythema (12%). 22 This association was independent of other known risk factors for periodontal diseases, such as age, gender, subgingival biofilm, and smoking.

14 In 1994, a group of dentists acquired a set of diagnostic criteria to help diagnose periodontal conditions associated with HIV infection. 23 The diagnostic criteria were first designed to be used for epidemiologic studies but can also be used in clinical situations. These diagnostic criteria help the researcher or the clinician to distinguish up to 8 conditions that may be seen on HIV infected individuals. Table 5: Diagnostic criteria for HIV-associated periodontal conditions. Adopted from Robinson et al. 23 Chronic Marginal Gingivitis (Conventional gingivitis) To be defined by the presence of erythema, glazing, or swelling of the free gingival margin. With no recession except at the midbuccal surfaces and no pocketing greater than 3 mm. Necrotizing Ulcerative Gingivitis (acute) To be defined by the presence of conventional gingivitis and both of the following: a. Gingival ulceration radiating from one or more interdental papilla tips. b. Inflammation limited to the marginal gingiva. HIV-Associated Gingivitis To be defined by the presence of gingival erythema manifested by one of the following: A. Punctate erythema of the attached gingiva. B Diffuse erythema of the attached gingiva, ignoring lesions which are largely limited to the marginal gingiva. One possible way to recognize such lesions would be to assess whether the mucogingival junction is ill-defined. C. A well- defined red band along the free gingival margin which does not bleed in 50% or more sites on probing.

15 Ulcerative HIV-Associated Gingivitis To be defined by the presence of HIV-associated gingivitis and one of the following: a. Ulceration of the free gingiva. b. spontaneous bleeding. It is assumed that spontaneous bleeding is a sign of micro-ulceration. Chronic Adult Periodontitis To be defined by the presence of gingivitis and attachment loss manifested by one of the following: a. Recession exposing the cementoenamel junction (excluding the mid-buccal surfaces). b. Pocketing greater than 4 mm in two or more sites, excluding pseudo-pockets, third molars, and teeth undergoing orthodontic treatment. Ulcerative HIV-Associated Periodontitis To be defined by the presence of HIV-associated gingivitis and attachment loss where the recession is greater than or equal to 2 X the probing depth (excluding the mid-buccal surfaces) and one of the following: a. Presence of exposed bone. b. Ulceration/necrosis of the attached gingiva. c. Patient complaint of severe, "deep," or "bone" pain. Non-Ulcerative HIV-Associated Periodontitis To be defined by the presence of HIV-associated gingivitis and attachment loss where the recession is greater than or equal to 2 X the probing depth (excluding the mid-buccal surfaces) in one of two forms: a. Reverse architecture; i.e., a depression in place of an inter-dental papilla b. Cratering; i.e., a deepening of the inter-dental col where the buccal and palatal/lingual gingivae remain.

16 Necrotizing Periodontitis To be defined by the presence of ulceration/necrosis of the attached gingiva and mucosa and/or bone 10 mm from the cementoenamel junction or beyond the muco-gingival junction, whichever is nearer. Although this definition is arbitrary, it is objective. The term necrotizing Periodontitis is used to distinguish this type of lesion from necrotizing stomatitis lesions not originating in the periodontium. Attachment loss can be recorded in two forms, with or without gingivitis. The presence of attachment loss in the absence of gingivitis is not intended to imply active disease but is included to allow collection of data on as many situations as possible. Generalized attachment loss with marginal gingivitis will be assumed to be chronic adult Periodontitis. Attachment Loss with Reverse Architecture or Inter-Dental Cratering To be defined by the presence of attachment loss greater than or equal to 4 mm and where the recession is equal to or greater than 2X the probing depth (excluding the mid-buccal surfaces) in one of two forms: a. Reverse architecture; i.e., a depression in place of an inter-dental papilla. b. Cratering; i.e., a deepening of the inter-dental col where the buccal and palatal/lingual gingivae remain. Generalized Attachment Loss To be defined by the presence of attachment loss great than or equal to 4 mm (excluding the mid-buccal surfaces) without reverse architecture and or cratering.

17 Common Periodontal Diseases in HIV-positive Patients Gingivitis Atypical gingivitis in homosexual men was reported first by Peter Robinson et al. in The distinguishing features were a red linear border in the attached gingiva and red petechia like patches on both the attached and unattached gingiva. As more cases were reported in the literature, it was revealed that gingivitis in HIV individuals may have the conventional gingivitis form or erythematous band shaped gingivitis. For more characteristics of each form, reader should refer to Diagnostic criteria for HIV associated criteria mentioned above. It was suggested that there is no direct relationship between periodontal status and HIV progression; the total numbers of CD4 positive cells or the type of retroviral therapy used. 24 The prevalence of gingivitis varied among studies from different countries; 19% HIV-positive individuals in North America, including 28.5% with AIDS, had chronic gingivitis. 24 Severe non-specific gingivitis was seen in 9% of British HIVpositive individuals, out of which 9% has AIDS. 25 Conventional gingivitis was diagnosed in 3.6% German HlV positive individuals. 20 Yet other studies had shown good periodontal status among HIV-positive individuals. HIV-associated gingivitis was seen in 9% of women and 15% of men in a study done in the states in heterosexual men and women having AIDS and in 4 % HIV-positive Greek individuals. 26,27 The microbiota present in the plaque in HIV-positive individuals having gingivitis were comparable to HIV-negative individuals. 28 Candida albicans, Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum and Campylobacter rectus were the most commonly found microbes in extensive studies done by Murray et al. from 1988 to ,29 These studies also revealed that C. albicans was found in 50% of HIV associated gingivitis sites, 26% of unaffected sites of HIVpositive individuals and 3% of healthy sites of HIV-negative individuals, indicating a significant presence of C. albicans. Treatment of gingivitis in HIV-positive individuals is the same as treatment for non-hiv-positive individuals. However, due to its atypical presentation, adjunctive measures might be deemed important in order to improve the clinical presentation. Rinsing with 0.12% chlorhexidine gluconate twice daily has shown significant improvement after 3 months. 30

18 The use of 10% povidone- iodine irrigation 3 to 5 time daily did not improve the clinical features in three months, but it did reduce the pain that is usually present. 21 It should be remembered that C. albicans is frequently present. Treatment of Candida infection thus might also be added to the treatment regimen for successful outcomes. Murray et al. stated that HIV-associated gingivitis may be a precursor to HIVassociated periodontitis. This means that early identification and treatment may prevent the disease progression. 28 Acute Necrotizing Ulcerative Gingivitis In 1984, Stevens et al. determined that necrotizing ulcerative gingivitis (NUG) has 3 criteria that should be present for diagnostic purposes. 31 These criteria are: (1) acute necrosis and ulceration of interproximal papillae, (2) pain, and (3) bleeding. NUG has also other signs and symptoms but these are the 3 main ones. Other clinical features include: pseudoinembrane formation, lymphadenopathy, excessive salivation, fetid odor and abnormal sensations of the teeth. NUG is most commonly seen in smokers, in patients undergoing stressful events, patients suffering from malnutrition and HIV-positive individuals. In HIV-infected individuals, the condition can be described as a fiery red and swollen gingiva with yellowish-gray marginal areas of necrosis with loss of interdental papillae. 32 The prevalence of NUG in HIV-positive individuals is almost consistent in most of the studies with 5% of seropositive men from the United States, 5.5% in a German population based study 5% among 75 Dutch patients, and 11% of the patients from the Greek study. 20, 27, 33, 34 Microbiological studies revealed the presence of Borrelia (gram positive cocci), ß-hemolytic streptococci and C albicans in the lesions. 20 This chart, adopted from Randal W. Rowland demonstrates the necrotizing ulcerative gingivitis and its possible etiology. It also shows how HIV infection with or without candidal infection, can lead to Necrotizing ulcerative periodontitis, which may eventually develop into necrotizing stomatitis. 35

19 Figure 6: Possible etiology of necrotizing ulcerative gingivitis. 35 Necrotizing Ulcerative Periodontitis Necrotizing periodontal gingivitis (NUG), necrotizing ulcerative periodontitis (NUP), and necrotizing stomatitis (NS), can be collectively termed necrotizing gingivostomatitis (NG). Clinically, NUG can be described as necrosis of only the tip of or the entire interdental papilla, NUP can be described as necrosis of the entire papilla, involving the marginal gingiva, with necrosis extending also into attached gingiva and involving bone. NS can be described as necrosis extending into buccal or labial mucosa, and exposing alveolar bone in some cases. When the necrosis perforates the skin of the cheek, the clinical presentation is called noma or cancrumoris.

20 Per the American Academy of Periodontology (AAP) world workshop for periodontal disease classification in 2017, necrotizing periodontal disease is now classified into necrotizing periodontal diseases in chronically, severely compromised patients and necrotizing periodontal diseases in temporarily and/or moderately compromised patients (previously, in the 1999 classification, necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis). HIV seropositivity/ AIDS with CD4 counts < 200 cells/mm 3 is a predisposing condition to necrotizing periodontal diseases in chronically, severely compromised adult patients. Predisposing factor to NG include history of previous NG, poor oral hygiene, inadequate sleep, unusual psychological stress, poor diet, illness in the previous 3 weeks, social or greater alcohol use, smoking, Caucasian background and age under 21 years 36. This holds true for HIV-negative individuals, but among HIVpositive individuals, the seropositivity overwhelmed all the factors mentioned above. NUP is seen clinically as localized ulcerations and necrosis of gingival tissue, exposure of underlying alveolar bone leading to rapid bone destruction. Spontaneous bleeding and severe pain are also common clinical findings. It was reported that there is a strong correlation between HIV and NUP. 37 The prevalence of NUP was found to be 6.3% in a cohort study comprising 700 individuals with HIV infection. 38 The majority of individuals with NUP were homosexuals. The CD4 cell count ranged between 0 cells/mm 3 to 360 cells/mm 3 with mean count of 53 cells/mm 3. It was also found that the positive predictive value of NUP diagnosis relative to the counts of CD4 cells below 200 cells/mm 3 was 95%. Glick et al. investigated the relationship between NUP and CD4+ cell count below 200 cells/mm 3. It was found that HIV-infected patients with NUP were 21 times as likely to have a CD4+ cell count below 200 cells/mm 3 when compared to HIV-infected individuals without NUP. Another important aspect discussed in the same study is the survival analysis. It was found that the cumulative probability of death was 2.4% after 3 months from NUP diagnosis, 10% after 6 months, 27% after 12 months 73% after 24 months. 38 The proposed treatment for NUP in HIV-positive individuals includes the introduction of antibiotics as an adjunctive treatment to scaling and root planning, and possibly anti-fungal agent.

21 HIV-associated Periodontitis Winkler et al. were the first to describe the appearance periodontal disease in HIV-positive patients and referred to it as AIDS-virus-associated periodontitis (AVAP) or HIV-P. This description included: rapid onset, interproximal soft tissue ulceration, necrosis, ulceration and cratering, marked edema, and intense erythema of the attached and marginal gingivae. Its rapid progression can happen as fast as 3 months. 39 A wide range of clinical features was described for HIV-associated periodontitis. This range comprises adult periodontitis seen in HIV-negative individuals, periodontitis that is rapidly progressing, and periodontitis with soft and hard tissue destruction. Some of these presentations are associated with necrosis and some are not. The tendency for a greater rate of attachment loss in HIV-infected patients increases with pre-existing periodontitis. 40 This was concluded in a study monitoring the periodontal statistics of 30 HIV-positive patients for 18 months and comparing the results to 10 control healthy individuals. This tendency was associated with a drop in CD4 cell counts and an increase in oral manifestations such as hairy leukoplakia, oral candidiasis and Kaposi sarcoma. This increase in attachment loss was not associated with an increase in plaque index or gingival index. The percentage of periodontitis varies in the literature: severe periodontal destruction was reported in 11% of British HIV-positive individuals,19% from the Greek study, and 27% from the American study were diagnosed with moderate periodontitis. The variation between these studies might be related to different criteria in subject s selection and differences in periodontitis definition. 24,25,27 In a southeastern US study, it was found that almost 60% of the study population had probing pocket depths 5 mm, 66 % had an attachment loss of 5mm and 45 % had a recession of 3 mm. 41 They noticed that HIV-associated periodontitis cases were rare and attributed this finding to being under retroviral treatment, those who were under the retroviral treatment were 20% as likely to manifest HIV-associated periodontitis than those who were not under treatment. Interestingly, it was found that HIV-associated periodontitis was more commonly seen in males than females, in black non-hispanic than white non-hispanic, in the age group years of age and in homosexuals.

22 Another study found probing pocket depths of > 5 mm in 2 or more sites in 77% of patient with high viral load. 42 Comparing between HIV-positive and HIVnegative groups at baseline and 3 months later, it was found that the mean attachment loss was greater in HIV-positive group as opposed to HIV negative group. 43 Severe attachment loss was noted in the lower incisors and more suppuration in the HIV-positive group. The finding of HIV-associated periodontitis was not common in the female HIVinfected group and most of the cases with periodontitis had the mild form. 44 In this study there was no evidence relating the presence of periodontal disease to CD4 cells counts. The P. gingivalis and P. intermedia ratio was comparable between HIV-positive and HIV-negative patients. In a male HIV-positive population, subgingival plaque of HIV-positive patients were comparable to HIV negative patients. 45 Differences between the two populations were increased numbers of Clostridia, Candida and C. rectus. 46,47,48 The fact that both HIV-positive and HIV-negative periodontitis subjects share similar subgingival flora was the finding of most microbiological related studies. Sites with periodontitis have higher percentage of Actinobacillus actinomycetemcomitans, Peptostrptococcus micros, Porphyromonas gingivalis and Prevotella intermedia. However, many studies have revealed that, in addition to this similarity, there are others organism that are not usually considered common for periodontitis. B. fragilis, F. necrophorum, F. varium, E. aerofacians, C. albicans, P. aeriginosa, K. oxytoca, E. cloacae, and E. agglomerans were all found in 12 out of 14 HIV-positive periodontitis subjects. 47 Clostridim and Enterococci were uncommon organisms found in homosexual AIDS patients. 48 In another study including 39 HIV-positive subjects, 17 of which had periodontitis (the rest having gingivitis), it was concluded that the microflora is similar between HIV-positive periodontitis subjects and HIV-negative periodontitis subjects, with the exception of Mycoplasma salivarium which was significantly higher in HIVpositive subjects. 46 CD4/CD8 ratio is usually compromised in HIV patient. It is compromised even more in HIV-positive individuals with periodontitis to nearly a complete absence of T-cells. The CD4/CD8 ratio in the peripheral blood analysis of HIV-negative individual with periodontitis was found to be 2.07 ± as opposed to 0.58 ± 0.26 for the HIV-positive individuals with periodontitis.

23 It was soon noticed that HIV-associated periodontitis is different than chronic periodontitis. In HIV-associated periodontitis there is severe pain which is not the case in chronic periodontitis. In addition to pain, extensive soft tissue necrosis, bleeding that is spontaneous, and rapid loss of alveolar bone were other disease characteristics that made it distinguishable from chronic periodontitis. 49 These characteristics can be localized to a small area wherein the adjacent tissues are healthy or generalized with chronic periodontitis. With periodontitis, an individual will be more susceptible to infections, such as periodontal disease. Periodontitis may progress episodically depending on the host and bacterial relationship. In case of HIV patients, the host defense, including local cytokines, is altered, which can be manifested as exacerbation of periodontal disease. The treatment of periodontal disease in HIV-positive individuals involves gross scaling to remove plaque, soft debris and necrotic tissue if present. Povidone iodine irrigation is recommended during the gross scaling procedure as it has an esthetic and antiseptic effects. Follow-up visits are recommended and should be frequent to remove the remaining plaque, and calculus. Oral hygiene instruction should also be given to the patient as well. Individuals with necrotizing periodontal disease will benefit from an approach consisting of debridement and irrigation with a 0.2% chlorhexidine gluconate mouth rinse and a 3-day course of systemic metronidazole. 50 In cases of necrotizing periodontal disease, it is very important to start the treatment regimen as soon as possible as there is a tendency for necrotizing periodontal disease to develop into Noma (cancrum oris) if left untreated. As mentioned earlier, Candidal infection is very common and sometimes may develop after use of some antibiotic agents. Therefore, the use of topical or systemic antifungal is recommended, especially when such an infection is suspected, the patient is not responsive to conventional therapies, and in severely immunocompromised patients. There are doubts with regard to bacteremia occurring after debridement and its effect in HIV-positive individuals. However, one study observed transient bacteremia in HIV-positive individuals where the bacterial levels returned to normal within 30 minutes of debridement. 51

24 Other Oral Manifestations of HIV Oral manifestations in HIV-positive individuals are often first sign of the disease. 52 There are other oral infections/conditions that have also been noticed to be present or increased in HIV/AIDS patients. In addition to HIV gingivitis, HIV periodontitis and necrotizing disease group, oral candidiasis (i.e. pseudomembranous, erythematous, angular cheilitis), herpetic ulcers, oral ulcers, xerostomia, salivary gland disease, hairy leukoplakia (OHL), thrombocytopenia purpura, lymphomas, squamous cell carcinomas and Kaposi s sarcoma were all reported in the literature. From a population consisting of 606 individuals who are HIV-positive, an attempt was made to reveal the prevalence of opportunistic infections. 53 It was found that lesions with moderate-to-high Positive predictive values (PPV) for CD4 levels of <200 cells/mm 3 were as follows: Kaposi s sarcoma (PPV = 100%), pseudomembranous candidiasis ((PPV = 82.2%), linear gingival erythema (PPV = 70.0%), hairy leukoplakia (PPV = 66.3%), angular cheilitis (PPV = 60.0%), and erythematous candidiasis (PPV = 58.3%). The PPV of Necrotizing ulcerative periodontal diseases, HIV salivary gland disease, oral ulcers, and oral warts was below 50%. A 2 year longitudinal study, found that one or more oral lesions, were observed in 36% of the HIV-infected subjects, as opposed to 0% in non-infected subjects, with an odds ratio of 6 times for those who had CD4 cell counts between cells/mm 4 and 23 times for those with CD4 cell counts less than 200 cells/mm 3 when compared to those who had CD4 cell counts of 400 cells/mm 3 or greater. 54 Of the fungal infections, oral candidiasis is the most commonly seen. The pseudomembranous form is associated with severe immunosuppression status than the erythematous or hyperplastic variants. 55 Oral candidiasis has been reported in patients with CD4 count between cells/mm 3. Candida infection was seen in > 50% of patients in a study assessing the HIV viral load and oral diseases. 42 There was a strong association between fungal cultures and viral load especially for those who had a high viral load (>10,000 copies/ml). Only some of these patients showed clinical signs of fungal infection. Other viral infections might also be present in HIV-positive individuals such as herpes simplex virus (HSV) (causing primary herpetic gingivostomatitis, recurrent herpes labialis or intra oral herpes) or herpes zoster virus (HZV) infection.

25 Although HZV infections rarely occur in association with HIV infection, its presence indicates a poorer prognosis. Oral hairy leukoplakia (OHL) is one of the most common oral lesions that is seen in HIV infections, although it may also be seen in non-hiv patients (i.e. organ transplant recipients taking immunosuppressive oncologic therapies, patients diagnosed with acute leukemia, patients with autoimmune diseases under corticosteroids treatment and smokers). Clinically, OHL is presented as flat or raised white lesion with striations. It is most commonly seen in the tongue, but can be seen on the buccal mucosa and the gingiva, necessitating the importance of the full knowledge and awareness of the general dentist and the periodontist in regard to different manifestations and possible locations of the lesion. OHL is associated with Epstein-Barr viral infection. Oral pigmentation is also another manifestation that was seen in HIV+ individuals. 55,56 39% of HIV-positive individuals screened in India presented with oral pigmentation and the CD4 count for these individuals was between cells/mm 3. These lesions should be distinguished from physiologic pigmentation. 56 Kaposi sarcoma is a multifocal malignant tumor that is considered the most commonly diagnosed malignant lesion in AIDS individuals. As any other malignant tumor, Kaposi sarcoma is presented as red to bluish patch that grows into a nodule and finally to a mass. Normal oral mucosal color Kaposi sarcoma has also been described in the literature. The palate is the most common site for Kaposi sarcoma, but gingival involvement has also been reported. Non-Hodgkin's lymphoma (NHL) is another malignant tumor that can be seen among HIV-positive individuals. It is second to Kaposi sarcoma in prevalence, most commonly affecting the gingiva as a rapidly progressing growth that is usually ulcerated. Opportunistic infections HIV-positive subjects are also susceptible to opportunistic infections which include Pneumocystis carinii pneumonia, central nervous system or disseminated toxoplasmosis, chronic cryptosporidiosis, candida esophagitis, disseminated histoplasmosis, central nervous system or disseminated cryptococcosis, disseminated atypical mycobacterial disease, extrapulmonary tuberculosis, disseminated nocardiosis, disseminated cytomegalovirus, and chronic mucocutaneous herpes simplex.

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