HIV AIDS and Oral complications of HIV disease

HIV infection

Human influenza virus (HIV) , the cause of the acquired immune deficiency syndrome (AIDS), continues to spread, being described as a global health emergency by the World Health Organization (WHO) in 2003.

Infection transmitted via,

• Semen
• Cervical secretions
• Blood

routes of transmission-

• Sexual intercourse (vaginal and anal)
• Contaminated blood, blood products and organ donations
• contaminated needles ( intravenous drug abuse, injection, needle tract injury )
• Vertical transmission (parentally, perinatally, breast-feeding)

The virus

HIV belongs to the lentivirus group of the retrovirus family. There are at least two types, HIV-1 and HIV-2.

Retroviruses are characterized by the possession of the enzyme reverse transcriptase, which allows viral RNA to be transcribed into DNA, and then incorporated into the host cell genome. Reverse transcription is an error-prone process with a significant rate of misincorporation of bases. This, combined with a high rate of viral turnover, leads to considerable genetic variation and a diversity of viral subtypes.

Life cycle

1.       Entry and integration-

                                  Infection of a CD4+ cell occurs via a direct interaction between the gp120 envelope proteins and a conserved CD4 binding site. Binding of CD4 to gp120 is not sufficient for cell entry, and a family of co-receptors has been identifi ed, the normal function of which is to bind small chemotactic peptides termed ‘chemokines’. The ability of HIV to infect different cell types depends on the ability of gp120 to bind differentially to these different chemokine receptors.

• viruses with gp120 that preferentially binds the CCR5 chemokine receptor found on cells of the monocyte/ macrophage series (macrophage tropic)

• viruses that bind preferentially to the CXCR4 chemokine receptor found predominantly on lymphocytes (tropic for lymphocyte cell lines).

Binding of the virus through these molecules triggers a conformational change in the envelope and and fusion with cell mebrane occurs, releasing the virus capsid into the cell cytoplasm. Here, reverse transcriptase inside the capsid structure initi- ates the conversion of the diploid RNA genome into dsDNA. At the same time, the genome is transported into the nucleus.

2.       Transcription and translation-

                                                           Once the virus is integrated, it is treated as a normal cellular gene and the polymerase en- zymes that transcribe cellular genes produce viral mRNA transcripts. The virus can become transcriptionally silent and enter a latent state which may be reactivated at a later time.

3.       Budding:

                   The envelope glycoproteins are translated on the rough endoplasmic reticulum and processed by the Golgi apparatus. They are then transported to the cell surface, where they encounter Gag proteins that have been translated on free ribosomes in the cytoplasm. A capsid structure assembles, incorporating two RNA molecules, and the virus buds from the cell, taking with it its envelope containing envelope glyco- proteins, structural Gag proteins, replicative enzymes and certain viral accessory proteins.

Pathogenesis

The pathogenesis of HIV is still poorly understood. Several viral proteins have been shown to affect cellular func- tion in a manner that might contribute to a cytopathic effect, and it is likely that the progressive depletion of the CD4 lymphocyte population results from a combination of virus- mediated cell killing and clearance of virus-infected cells by the immune system. Thus, by a process of gradual attrition, the CD4 lymphocyte count decreases and immunological de- ficiency eventually results, rendering the patient vulnerable to opportunistic infections and malignancies.

In the earlier stages of disease, abnormal immunological function can be detected. Cells of the monocyte/macrophage series (e.g. dendritic cells) infected with HIV show an im- paired ability to initiate immune responses, possibly as a result of defective presentation of antigen to lymphocytes.

Progression within human body

Incubation

The 2-4 weeks immediately following infection are usually silent both clinically and serologically.

Seroconversion/primary illness

The majority of HIV seroconversions are also clinically silent. In a proportion, a self-limiting

non-specific illness occurs 6-8 weeks after exposure. Symptoms include fever, arthralgia, myalgia, lethargy, lymphadenopathy, sore throat, mucosal ulcers and occasionally a transient faint pink maculopapular rash. Neurological symptoms are common, including headache, photophobia, myelopathy, neuropathy and in rare cases encephalopathy. The illness lasts up to 3 weeks and recovery is usually complete.

Clinical latency

The majority of people with HIV infection are asymptomatic for a substantial but variable length of time. However, the virus continues to replicate and the person is infectious. Studies suggest a median time of 10 years from infection to development of AIDS, although some patients progress much more rapidly and others have remained symptom-free for up to 15 years.

Symptomatic HIV infection

As HIV infection progresses the viral load rises, the CD4 count falls, and the patient develops an array of symptoms and signs. The clinical picture is the result of direct HIV effects and of the associated immunosuppression.

In an individual patient the clinical consequences of HIV-related immune dysfunction will depend on at least three factors:

·        The microbial exposure of the patient throughout life

·        The pathogenicity of organisms encountered

The degree of immunosuppression of the host

Oral Manifestations of HIV Disease

HIV-related oral abnormalities are present in 30% to 80% of HIV-infected individuals, and these abnormalities are often inaccurately described in medical care and frequently are misdiagnosed or inadequately treated. Oral lesions are among the early signs of HIV infection and can predict its progression to AIDS. Factors that predispose to HIV-related oral conditions include CD4+ cell count of less than 200/µL, plasma HIVRNA levels greater than 3000 copies/mL, xerostomia, poor oral hygiene, and smoking. For individuals with unknown HIV status, oral manifestations may suggest possible HIV infection, although they are not diagnostic of infection. At present three groups of oral manifestations of AIDS are defined based on their intensity and features.

GROUP 1(lesions strongly associated with HIV infection)

Seven cardinal features

• Oral candidiasis- erythematous, pseudomembranous
• Hairy leukoplakia
• Kaposi’s sarcoma
• Linear gingival erythema
• Necrotizing ulcerative gingivitis
• Necrotizing ulcerative periodontitis
• Non- Hodgkin’s lymphoma

GROUP 2 (lesions less commonly associated with HIV infection)

• Bacterial infections-mycobacterium avium intracellulare

                                            Mycobacterium tuberculosis

• Melanotic hyperpigmentation
• Necrotizing ulcerative stomatitis
• Salivary gland diseases
• Thrombocytopenic purpura
• Viral infections-herpes simplex virus

                                   Human papilloma virus lesions

                                   Varicella zoster virus

GROUP 3 (lesions may be seen in HIV infection)

• Bacterial infections- actinomyces israelii

                                    Escherichia coli

                                    Klebsiella pneumonia

• Cat-scratch disease
• Drug reactions-erythema muliforme

                                  Lichenoid reactions

                                  Ulcerative

• Fungal infections other than candida- histoplasmosis, Crytococcus, neoformans Aspergillosis

• Neurological disturbances
• Viral infections- CMV

Oral Candidiasis

The 3 common presentations of oral candidiasis are angular cheilitis, erythematous candidiasis, and pseudomembranous candidiasis. Angular cheilitis presents as erythema or fissuring of the corners of the mouth. It can occur with or without erythematous or pseudomembranous candidiasis, and can persist for an extensive period of time if left untreated. Erythematous candidiasis may be the most under diagnosed and misdiagnosed oral manifestation of HIV disease. The condition presents as a red, flat, subtle lesion on the dorsal surface of the tongue or on the hard or soft palates. It may present as a “kissing” lesion—if a lesion is present on the tongue, the palate should be examined for a matching lesion, and vice versa. The condition tends to be symptomatic, with patients complaining of oral burning, most frequently while eating salty or spicy foods or drinking acidic beverages. Clinical diagnosis is based on appearance, as well as on the patient’s medical history and virologic status. The presence of fungal hyphae or, more likely, blastospores can be confirmed by performing a potassium hydroxide (KOH) preparation.



Erythematous candidosis



Pseudomembranous candidiasis (or thrush) appears as creamy, white, curdlike plaques on the buccal mucosa, tongue, and other oral mucosal surfaces. The plaques can be wiped away, typically leaving a red or bleeding underlying surface.



Pseudomembraneous candidiasis



Oral thrush on soft palate



The most common organism involved is Candida albicans; however, there are increasing reports of involvement of non-albicans species. As with erythematous candidiasis, diagnosis is based on appearance.

Oral Hairy Leukoplakia



Hairy leukoplakia on lateral border of the tongue



The natural history of hairy leukoplakia is variable. Lesions may frequently appear and disappear spontaneously. Hairy leukoplakia is often asymptomatic, and many patients are unaware of its presence. Some patients with hairy leukoplakia do experience symptoms including mild pain, dysesthesia, alteration of taste, and the psychological impact of its unsightly cosmetic appearance. There has been a marked decrease in the incidence of oral hairy leukoplakia in the potent antiretroviral era. However, it is important to note that the condition is observed with immune deterioration and that patients presenting with it while on antiretroviral therapy may thus be experiencing failure of their current regimen.

Kaposi’s Sarcoma

Kaposi’s sarcoma (KS) was described initially in 1872 by a Hungarian dermatologist, Moritz Kaposi. Kaposi sarcoma is a spindle-cell tumor thought to be derived from endothelial cell lineage. Kaposi sarcoma can be primarily categorized into four types: epidemic of AIDS-related, immuno-compromised, classic or sporadic, and endemic (African).

Epidemic AIDS-related Kaposi’s sarcoma is still the most frequent HIV-associated oral malignancy, although its incidence has dramatically decreased in the potent antiretroviral therapy era. This entity occurs in patients with advanced HIV infection and is the most common presentation of Kaposi's sarcoma. Kaposi’s sarcoma associated herpesvirus (KSHV) HHV-8 has been identified as the etiologic agent. This condition carries a variable clinical course ranging from minimal mucocutaneous disease to extensive organ involvement.



Kaposi's sarcoma on hard palate



Kaposi's sarcoma on skin



Kaposi’s sarcoma can be macular, nodular, or raised and ulcerated, with color ranging from red to purple early lesions tend to be flat, red, and asymptomatic, with the color becoming darker as the lesion ages. AIDS-related Kaposi sarcoma is the most clinically aggressive form of Kaposi sarcoma. Diagnosis is frequently missed in African-American patients due to lesion coloration. Progressing lesions can interfere with the normal functions of the oral cavity and become symptomatic secondary to trauma or infection. Definitive diagnosis requires biopsy. In the United States, Kaposi sarcoma serves as an AIDS-defining illness in 2-3% of HIV-infected homosexual men. In the mid 1990s, it was the initial presentation in approximately 15% of homosexual men. In Africa and developing regions, epidemic AIDS-related Kaposi sarcoma is common in heterosexual adults and occurs less often in children. Visceral involvement is widespread.

Linear gingival erythema

This entity, previously known as HIV associated gingivitis, is characterized by an erythematous band that follows the contour of the free gingiva with a typical chevron appearance. The attached gingiva is the site of an inflammatory reaction composed of petechia-like macules also having a reddish hue. Spontaneous bleeding is a frequent finding. It is seen most frequently in association with anterior teeth, but commonly extends to the posterior teeth.



Linear gigival erythema



The erythematous inflammatory band is obviously the result of bacterial proliferation in the gingival sulcus. The most frequently found microorganisms in this lesion are: Bacteroides gingivalis, Bacteroides intermedius, Actinomyces viscosus, Fusobacterium nucleatum and Actinobacillus actinomycetemcomitants, among others. Some data indicate a relationship between sub-gingival colonization of Candida species and HIV related periodontal conditions including linear gingival erythema (LGE). However, antifungals typically are not needed for treatment. LGE is seen in patients with increased immuno suppression and as a rule is not associated with pain but it is considered a potential precursor of necrotizing ulcerative periodontitis. LGE does not respond to the usual therapeutic methods utilized to treat other types of gingivitis not associated to HIV infection.  Treatment includes debridement by a dental professional, twice daily rinses with a 0.12% chlorhexidine gluconate suspension for 2 weeks, and improved home oral hygiene. If the lesion persists in spite of the local therapy, systemic antibiotics can be prescribed.

Necrotizing Ulcerative gingivitis and periodontitis

This particular type of gingivitis is generally seen in AIDS patients with advanced immune suppression, that is with CD4+ cell counts below 100 cell per mm3. Although necrotizing gingivitis and necrotizing periodontitis may reflect the same disease entity, they are differentiated by the rapid destruction of soft tissue in the former condition and hard tissue in the latter.



Necrotizing ulcerative periodontitis



Necrotizing ulcerative periodontitis is a marker of severe immune suppression. The condition is characterized by severe pain, loosening of teeth, bleeding, fetid odor, ulcerated gingival papillae, and rapid loss of bone and soft tissue. Patients often refer to the pain as “deep jaw pain.” Treatment includes removal of dental plaque, calculus, and necrotic soft tissues utilizing a 0.12% chlorhexidine gluconate or 10% povidone-iodine lavage, and institution of antibiotic therapy. Pain management is crucial, as is attention to nutrition in these patients. Timely referral to primary care is indicated to rule out other systemic opportunistic infections.

Non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma is cancer of the lymphoid tissue, which includes the lymph nodes, spleen, and other organs of the immune system. Non-Hodgkin’s lymphoma is an AIDS-defining cancer. A lymphoma is the name given to a tumour (or growth) of lymphocytes (white blood cells). Non-Hodgkin’s lymphoma (NHL) is caused by the unregulated production of B-cells, and is sometimes called B-cell lymphoma.

B-cells are one of the two main classes of lymphocytes, (the other being the T-cells). They are produced in the bone marrow and spleen and are involved in the production of antibodies. In HIV infection, B-cells typically become ‘over-active’. People who are infected with Epstein-Barr virus (which also causes glandular fever), may develop a generalised increase in B-cell reproduction. In some people, particularly if the immune system is suppressed, the continuous replication of B-cells may cause lymphoma.



Non-hodgkin's lymphoma on soft palate



NHL may occur in the lymph nodes (glands), spleen, digestive system, liver, kidney or in a particular form seen in immuno-suppressed people – in the brain, where it often occurs without any further spread and is called primary CNS (central nervous system) lymphoma.

Although lymphoma can occur at any CD4 count, they are more common in people with very low counts. NHL in people with HIV is more aggressive and responds less well to treatment than in HIV-negative people.

With the advent of modern HIV treatment many AIDS-related illnesses have become less common and NHL is now less commonly seen in people with HIV. Neurological problems seen in primary CNS lymphoma can include headaches, confusion, memory loss, lethargy, partial paralysis, loss of speech and seizures. Common symptoms of systemic lymphoma include fevers, swollen lymph nodes and spleen, weight loss and drenching night sweats.



Patients affected with non-hodgkin's lymphoma



Other symptoms may also be present, depending on the parts of the body affected. NHL can be diagnosed from a sample of bone marrow, lymph node or other affected body tissue. A computerised scan of the head and torso will usually also be performed to measure how far the tumour has spread. If there are symptoms in the digestive system, an endoscopy might also be performed (using a flexible instrument which allows the inside of the body to be seen). Blood tests may also reveal unusually high levels of lactase dehydrogenase (LDH) or of uric acid. Standard treatment for primary CNS lymphoma is radiotherapy of the brain which may improve symptoms, though the outlook is often poor. This is usually accompanied by a short course of steroids, e.g. dexamethasone, to shrink both the tumour and swelling due to accumulated fluid. Most people continue or start HIV treatment if they have developed a lymphoma, as this boosts the immune system and improves the chances of treatment working.