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HIV: what, target
- causative agent for AIDS, HTLV Family, Retrovirus class (lentivirus subclass)
- T4 lymphocytes: helper T-cell; helps both T and B cell functions; destroyed by HIV, resulting in immunodeficiency and ultimate demise due to bacterial or viral infections.
- CD4 receptor; Ig like structure; binds MHC2 complement on the surface of antigen presenting cell
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HIV anatomy
- lipid bilayer membrane
- glycoprotein - gp41, gp120, ...
- inside
- proteins: p17, p24
- two copies of RNA and reverse transcriptase
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Binding of HIV to T4 via
gp120 to CD4 and CCR5 (chemokine receptor), which allow the entry
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HIV Life Cycle
- vRNA + tRNA primer + viral reverse transcriptase + human nucleotides -> vDNA
- RNA-vDNA + RT + viral RNase H -> dsDNA (proviral)
- dsDNA integrated into host DNA
- proviral DNA -> mRNA -> Protein + RNA -> new viruses -> leaves the cell and affect other healthy cells
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viral RNase H only works with ____
RNA-DNA hybrid
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HIV Genome
- Diploid genome (2 RNA copies/ virus particle)
- RNA physically linked as a dimer by hydrogen bonds; Harbors tRNAlys (using its CCA end as the primer) for initiating reverse transcription
- RNA is single-stranded, positive sense, composed of 9749 nucleotides w/ 5' cap and 3' poly-(A) tail
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HIV Genome and major gene products
- HIV genome encodes nine open reading frames, 15 proteins
- LTR: long terminal repeat sequences at the 5' and 3' ends; 5' one has transcription promoter sites, or transcription factor binding sites; Attracts transcription machinery
- GAG: a group antigen including MA, CA, NC proteins; Nucleocapsid, core protein (matrix), P-6
- POL: for proteins inside the membrane; spliced into three parts: PR (protease; self-splices itself out first
- ), RT, and IN
- ENV: Gp160; cleaved to Gp120 and Gp41
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Small sequences/proteins
- make the virus infectious
- regulatory functions; +/- virus production
- REV: negative control
- TAT: transcription stimulator
- NEF: negative regulator, slows down transcription
- That’s why sometimes you have viral infection and sometimes it’s quiet
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Host receptors
- CD4 antigen: primary receptors, binds HIV gp120
- Chemokine receptors: essential co-receptors, seven transmembrane GPCR, tropism
- -CCR5: employed by macrophage-tropic HIV strains involved in critical early stages of infection, CCR5 receptor gene was mapped to human chromosome 3p21 only 18 kb away from CCR2B receptor gene
- -CXCR4: ligand is a B cell stimulatory factor called fusin, promotes infection /fusion of CD4+ T cells
- -CCR2: recently identified co-receptor
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Nucleoside Class inhibitors: _______ inhibitors, bind to _____, DNA chain terminators. These drugs are phosphorylated to ______ by host cell enzymes before being incorporated into the growing DNA chain and inhibiting further elongation. Eg. ______ etc.
- competitive
- the enzyme's active site
- the triphosphate form
- AZT (azidothymidine),
- DDI (didanosine),
- 3TC (Lamivudine)
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Non-Nucleoside Class: these drugs do not need to be phosphorylated to be active, bind elsewhere other than the enzyme’s active site and function in a _______ fashion. These drugs work _____ with nucleoside analogs, exhibit high therapeutic index and good bio-availablity. Eg. ______ etc.
- noncompetitive
- synergistically
- Nevirapine,
- delavirdine,
- efavirenz
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Every step of the viral life cycle is a potential target
- Binding: stop w/ antibody; Risky can affect CD4
- Fusion: antibody
- Most popular target is reverse transcription, modify nucleotides/sides, eg AZT
- Interfere with integration - dsDNA cannot go to nucleus
- Integrase inhibitor
- Translation - NO; would be lethal to us, too
- transcription - NO; same
- Polyprotein can be produced and its cleavage is dependent on protease, which is virally coded.
- blocking the viral protease will not allow the polyproteins to form single proteins
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Pol (Rt) :
- AZT/dideoxy nucleosides/
- non-nucleoside inhibitors, e.g. Nevirapine
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Protease:
- Peptide mimicking compounds that are transition state analogs. They bind the enzyme much more tightly than the natural substrate and function as competitive enzyme inhibitors.
- saquinavir, indinavir etc.
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Integrase:
Issentress (Merck)
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Entry Site (CCR-5):
Maraviroc
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Fusion Inhibition:
Enfuvirtide (EFV)
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HAART: Highly Active Anti-Retroviral Therapy
- Combination therapy of multiple anti-HIV drugs
- the most effective means of controlling HIV-1 infection.
- Typically, combines one protease inhibitor with two reverse transcriptase inhibitors
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Attempts of anti-HIV vaccines
- Nothing yet
- Therapeutic vaccines: boost the immune system of an already-infected person
- Protective/Prophylactic vaccines: to prevent HIV infection in uninfected population
- Perinatal vaccines: prevent mother-to-child transmission
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Viruses cannot reproduce or express their genes without the help of a living cell – not alive but not quite dead
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Three levels of defense
- Innate immunity: barriers
- Innate immunity: cells and fluids; rapid; no memory; all you need for dental infections
- Adaptive immunity: Where the CD4 cells are
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For the HIV patient, antibiotics usually ______ as in any other patient (even if CD4 count is low)
not needed unless already has dental infection
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Adaptive immunity
- Along came viruses, fungi and cancer
- •We needed a system to fight these attackers
- •We needed a system with memory and a rapid response to fight these invaders
- •The body developed B-lymphocytes which make antibodies and…
- •The body developed T-lymphocytes to coordinate the attack and kill the invaders
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CD-4
- The “coach” that helps the system function but does not kill – the cell that the HIV virus attacks.
- Secretes chemicals (cytokines) to guide rest of immune resp
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CD-8
The killers that directly attack invaders
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Theories on CD4 Cell Death
- Suicide (apoptosis)?– Holes in membrane from release of new virions? –
- A newer theory - it is a victim of the chronic inflammatory process: In an area of inflammation (like HIV infection) pro-inflammatory signals released by death of cells attract more cells (CD4) into the infected tissue to die and, in turn, produce more inflammation.
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HIV – drug/vaccine resistance
Multiple mutations interrupt the efforts to interrupt HIV life-cycle!
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HIV -> AIDS
- CD4<200
- if rises >200, still considered that patient has AIDS
- The immune system weakens
- The illnesses become more severe leading to an AIDS diagnosis
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What is an opportunistic infection?
- -An infection caused by a pathogen that usually does not cause disease in a healthy host, i.e. one with a healthy immune system
- - A compromised immune system, however, presents an "opportunity" for a resident pathogen to cause an infection and/or a cancer to develop. Commonly occurring opportunistic infections in the oral cavity of HIV infected patients are:
- Candidiasis (fungus)
- Herpes (virus) – the “cold sore” (HSV-1)
- Kaposi’s Sarcoma (cancer) from the HHV-8 (herpes virus)
- Tuberculosis - Quantiferon (IGRA) Test
- Evaluates for latent TB, measures interferons
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Prolonged life-span with use of HAART has increased:
- the numbers of HIV patients that present for dental treatment
- the challenges related to restorative considerations that may increase with time
- medical complexity considerations due to prolonged lifespan with co-morbid conditions (other disease, cognitive decline)
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Dental Care for Patients with HIV (PHIV) - Overall Considerations
- no more complex than for any other patient with a significant medical history
- Risk of transmission to the dental team is negligible if appropriate infection control procedures are followed
- Standard medical assessment with additional considerations specific for HIV
- Hemostasis, infection risk, drug actions/interactions, ability to tolerate treatment, co-morbidities
- HIPAA considerations as for any other patient
- Signed consent for medical info. sharing (?)
- TB – no risk unless patient presents with productive cough
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Patients with HIV - Health History – Specific Issues
- The privacy setting
- Confidentiality with pediatric patients
- Risk factors – mode of transmission, if disclosed, may have implications for dental treatment
- Co-morbidities
- Patient is compliant with medications (?)
- Patient is following up with MD?
- Last CD4 count, viral load - If CD4 down and viral load up, you may have soft tissue risk
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HIV – Medications and Drug Interactions
- Current medications – HAART or for other comorbidity
- Not taking HAART – why? - Physician care? Non-compliance?
- GI upset may be from the use of multiple Rx, not GI disease – avoid NSAIDs (?)
- Drug-drug interactions with HAART medications from commonly dentist-prescribed medications are usually not a significant issue
- HAART medications may affect blood cell counts (may be from the virus)
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HIV Patient –Labs. for Dental Care
- medical in nature, not specifically focused on HIV (CBC/D, complete metabolic panel, coagulation studies)
- Altered blood cell counts – reduced red cells, white cells, platelets
- CD4 count / viral load should be known so as to create an awareness of the potential for oral lesions or other systemic problems
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Reduce or Eliminate Risks for Acquiring HIV Infection in the Dental Office
- Infection control practices
- Blood and body fluid precautions
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HIV – Clinician Guidelines for General Dental Care Treatment Planning
- Patient assessment and management for general dental procedures are based upon patient’s medical status, not the HIV status
- Thorough oral soft tissue examination – screening for opportunistic disease and/or cancer (Kaposi’s Sarcoma)
- Other patient medical issues, whether or not HIV related, can influence planning and management
- Life-style factors may be issues of concern in dental treatment planning
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Antibiotics
- For the HIV patient with no active oral infection, there is no data to support the need for antibiotic coverage based on a patient’s CD4 count
- Antibiotics should be used if the absolute neutrophil is low (<500 mm3) or segmented neutrophil count is low as with any other non-HIV patient
- Other medical issues may require antibiotic use
- Patients may be on other antibiotics for prevention of opportunistic infections. However, standard dental management protocols are still used (infection, cardiac prophylaxis)
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HIV – Clinician Guidelines for General Dental Care
- Overall, HIV patients do not exhibit dental disease characteristics different from the nonafflicted population
- Xerostomia from medications can be a common complicating factor
- As with any medical illness, degree of impairment, care setting and personal hygiene characteristics will strongly influence planning, treatment, follow-up maintenance and prognosis
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Oral Surgery: Clinician Guidelines
- Communicate with patient – pre- and post-op instructions
- Incidence of post-procedural complications is no greater than in other populations
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Noted periodontal manifestations:
- Linear Gingival Erythema
- Necrotizing Ulcerative Gingivitis (NUG)
- Necrotizing Ulcerative Periodontitis (NUP)
- These periodontal manifestations may occur in non-HIV individuals such as immunocompromised patients
- NUP may be a marker of immune decline from HIV to AIDS
- These entities may be superimposed on conventional periodontitis
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Linear Gingival Erythema (LGE)
- Erythematous band along the gingival margin, not always associated with bleeding or discomfort
- Can present on nonattached gingival tissues as petechiae
- Not necessarily related to plaque accumulation; may be due to subgingival candida colonization
- Debridement, chlorhexidine gluconate
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Endodontic (Root Canal) Considerations
- Endodontic treatment appears to offer many benefits and few drawbacks for HIV patients
- Reduced infection risk
- Reduced need for extraction
- Improved ability to chew
- Improved self-esteem
- Restorative and maintenance prognosis as with any patient
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Special concern should be given to Prosthodontic treatment:
- overall medical status
- candidiasis
- xerostomia
- wasting syndrome
- maintenance potential
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HIV and Dental Implants
- Surgical risks should be part of assessment (bleeding, infection)
- Other life-style factors relating to the illness may be a consideration (illicit drugs, hygiene)
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Xerostomia
- Impacts on hard and soft tissue
- Impacts on quality of life
- Treatments choices
- Over-the-counter products
- Prescription medications
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Patients may be on other antibiotics for prevention of opportunistic infections. However, standard dental management protocols are still used (infection, cardiac, other)
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There is no evidence to support alterations in oral health care solely based on HIV status.
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Rapid HIV Antibody Combo. Test
- Tests for p24 antigen / HIV antibodies
- One drop of blood
- Results in 20 minutes
- FDA Approved
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