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HIV

HIV. HIV PATHOGENESIS. Retrovirus HIV-1 HIV-2 Binds to CD4 receptor Fusion with lipid layer Enters host CD4 cell: reverse transcriptase → DNA Viral DNA integrated into host DNA Proviral DNA → viral proteins Protease Assembly and budding of new viral particle. HIV PATHOGENESIS.

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HIV

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  1. HIV

  2. HIV PATHOGENESIS Retrovirus HIV-1 HIV-2 Binds to CD4 receptor Fusion with lipid layer Enters host CD4 cell: reverse transcriptase → DNA Viral DNA integrated into host DNA Proviral DNA → viral proteins Protease Assembly and budding of new viral particle

  3. HIV PATHOGENESIS Stages of HIV infection Acute infection 50% develop febrile, flu-like illness 1 – 6 weeks after exposure adenopathy pharyngitis rash headache/aseptic meningitis diarrhea

  4. HIV PATHOGENESIS Stages of HIV infection Acute infection HIV test (antibody) may be negative antibodies: 4 – 6 weeks HIV RNA PCR + (needs confirmation)

  5. HIV PATHOGENESIS Stages of HIV infection Acute infection very high levels of HIV HIV disseminates to sanctuary sites (lymphatic/CNS) viral levels decrease over 4 months to set point

  6. HIV PATHOGENESIS Stages of HIV infection Intermediate stage T cell destruction gradual decline in immune function 8 – 10 years duration depends on initial set point

  7. HIV PATHOGENESIS Persistent cellular activation hypergammaglobulinemia increased secretion of cytokines increased CD4 activation: enhance HIV replication activation increased by infection by CMV, HSV, EBV, TB: enhance HIV replication apoptosis↑

  8. HIV PATHOGENESIS Evasion of immune system continuing mutations evade cytolytic T cells, Ig downregulation of HLA class 1 on infected cells sequestration in immune privileged sites (CNS) latently infected resting CD4 cells

  9. HIV PATHOGENESIS Stages of HIV infection Advanced stage Opportunistic infections CD4 200 – 500 pneumococcal pneumonia TB herpes zoster thrush oral leukoplakia

  10. HIV PATHOGENESIS Stages of HIV infection Advanced stage Opportunistic infections CD4 < 200 pneumocystis carinii pneumonia candida esophagitis toxoplasmosis PML TB

  11. HIV PATHOGENESIS Stages of HIV infection Advanced stage Opportunistic infections CD4 < 50 CMV MAC

  12. Natural History of HIV Disease

  13. HIV EPIDEMIOLOGY Worldwide estimate: 37 millions Two-thirds in sub-Saharan Africa In US: prevalence ~ 0.3% overall 40,000 new infections / year (stable) In Canada: prevalence 56,000 cases in 2002 11,000 IVDU and 10,000 heterosexuals 2800 – 5200 new infections / year

  14. HIV EPIDEMIOLOGY Transmission Sexual transmission HIV virus in seminal fluid (cells and free) male to female transmission 8x more effective anal intercourse increases transmission genital ulcers increases transmission STDs increases transmission

  15. HIV EPIDEMIOLOGY Transmission Blood and blood products risk < 1:800,000 blood donations HIV RNA may not be detected first 1 -2 weeks

  16. HIV EPIDEMIOLOGY Transmission Maternal-fetal/infant transmission most in the perinatal period probability of transmission: 15 – 35% correlation with maternal level of viremia < 1000 copies HIV 0% 1000-10000 17% 10000-50000 21% 50000-100000 30% > 100000 40%

  17. HIV EPIDEMIOLOGY Transmission Maternal-fetal/infant transmission AZT second trimester + to infant 6 weeks: decreases transmission 23% to < 5% → cesarian delivery + Rx mother transmission can occur via breast-feeding

  18. HIV EPIDEMIOLOGY Transmission Transmission by other body fluids no convincing evidence that saliva transmits HIV by kissing or other exposure (saliva contains HIV IgA, leukocyte protease inhibitor) 4 cases of transmission through bites no evidence of transmission from tears, sweat, urine

  19. HIV AND RESPIRATORY TRACT Sinusitis: could be mucormycosis in low CD4 Pneumonia: x 6 risk of pneumococcal pneumonia → vaccine PCP may be indolent may cavitate in treated patients requires prophylaxis (CD4 < 200) (TMP-sulfa) TB HIV increases risk of TB x 100 risk in tuberculin + = 10% per year

  20. HIV AND RESPIRATORY TRACT TB dissemination more in low CD4 treatment as non-HIV all patient with HIV should have PPD prophylaxis if PPD 5 mm or any + if high risk

  21. HIV AND GASTROINTESTINAL TRACT Esophagitis: CMV (large ulcer) HSV (multiple small ulcers) Candida Secondary infections: Salmonella, Campylobacter Cryptosporidia (Rx supportive) Isospora (Rx with TMP-sulfa) Colitis: CMV

  22. HIV AND GASTROINTESTINAL TRACT Hepatobiliary: co-infection with HBV and HCV granulomatous hepatitis (TB, histoplasmosis) cholangitis (CMV, Kaposi) drug: nucleoside analogs (steatosis, lactic acidosis) nevirapine: fulminant hepatitis

  23. HIV AND GENITOURINARY TRACT UTI (same management) HIV nephropathy (proteinuria) drugs: nephrolithiasis (indinavir)

  24. HIV AND HEMATOPOIETIC SYSTEM Lymphadenopathy persistent generalized: HIV early ddx: lymphoma TB Kaposi atypical mycobacteriae toxoplasmosis Thrombocytopenia frequent (3%), platelet specific antibodies responds to anti-retroviral Rx

  25. HIV AND NEUROLOGICAL SYSTEM Opportunistic infections Toxoplasmosis late with CD4 < 200 presents with headache and focal signs MRI: usually multiple enhancing lesions dx: treatment first 2 – 4 weeks, bx if no response Cryptococcosis subacute meningoencephalitis CSF: cryptococcal antigen +, often few WBC

  26. HIV AND NEUROLOGICAL SYSTEM HIV encephalopathy CSF is abnormal in 90% of HIV patients encephalopathy: dementia cerebral atrophy on MRI others lymphoma PML peripheral neuropathy myelopathy myopathy

  27. HIV AND NEOPLASTIC DISEASES Lymphoma (non-Hodgkin’s) 6% of all AIDS patients late (<200 CD4) immunoblastic: often GI tract: dysphagia, abdominal pain marrow, liver, lungs Burkitt’s: less frequent EBV-positive

  28. HIV AND NEOPLASTIC DISEASES Lymphoma Primary CNS lymphoma: EBV-positive headache, seizure, focal deficit few lesions on MRI, deep, some enhance ddx: toxoplasmosis (treat first)

  29. HIV TREATMENT Deferring therapy Benefits: quality of life (side-effects) preserve drug options delay resistance Risks: deterioration immune system increased transmission

  30. HIV TREATMENT

  31. HIV TREATMENT HAART Initial treatment (example of preferred regimen) NNRTI-based efavirenz + AZT + 3TC Protease inhibitor-based lopinavir/ritonovir + AZT + 3TC

  32. HIV TREATMENT Adverse effects NRTI all: lipodystrophy didanosine: pancreatitis, neuropathy stavudine: pancreatitis AZT: headache, GI intolerance, marrow NNRTI nevirapine: hepatic necrosis efavirenz: neuropsychiatric, teratogenic

  33. HIV TREATMENT Adverse effects PI diabetes lipodystrophy drug interaction indinavir: nephrolithiasis nelfinavir: diarrhea ritonovir: GI intolerance, hepatitis

  34. OCCUPATIONAL EXPOSURE Risk of transmission after percutaneous exposure SourceRisk HBV eAg + 22 – 30 % eAg - 1 – 6 % HCV 1.8 % HIV 0.3 %

  35. OCCUPATIONAL EXPOSURE Wound care clean with soap and water flush mucous membrane with water avoid bleach or agents caustic to skin Assessment of infection risk type of exposure body substance source No testing of needles or sharp instruments

  36. OCCUPATIONAL EXPOSURE Risk of HIV transmission by exposure route percutaneous 0.3% mucous membrane 0.09% non-intact skin 0.1%

  37. OCCUPATIONAL EXPOSURE Evidence for HIV PEP AZT associated with 81% decrease of transmission AZT during pregnancy ↓perinatal transmission by 67%

  38. OCCUPATIONAL EXPOSURE Baseline testing of exposed + source PEP to start within hours Decision re: starting PEP days after can be considered

  39. OCCUPATIONAL EXPOSURE HIV PEP Basic Regimen AZT: 300 mg bid 3TC: 150 mg bid Expanded regimen basic regimen plus one: Nelfinavir: 1250 mg bid Efavirenz: 600 mg daily Indinavir 800 mg q8h

  40. OCCUPATIONAL EXPOSURE PEP for percutaneous injuries Exposure type HIV class 1 HIV class 2 Unknown status Unknown source Less severe basic PEP expanded generally no PEP* More severe expanded expanded generally no PEP* *consider basic PEP if risks for HIV

  41. OCCUPATIONAL EXPOSURE PEP for mucous membrane or non-intact skin exposure Exposure type HIV class 1 HIV class 2 Unknown status Unknown source Small cons basic PEP basic PEP generally no PEP Large basic PEP expanded generally no PEP *consider basic PEP if risks for HIV

  42. OCCUPATIONAL EXPOSURE PEP rarely if ever warranted in: intact skin with blood or infectious body fluid unknown source in population with low HIV prevalence low risk exposure to unknown source

  43. OCCUPATIONAL EXPOSURE PEP in pregnancy Not a contraindication to PEP long term effect on fetus unknown most data on AZT efavirenz contraindicated d4t and ddI: lactic acidosis indinavir: hyperbilirubinemia pre term nevirapine: liver failure

  44. OCCUPATIONAL EXPOSURE Follow-up testing of exposed person test at 6 weeks, 3 months, 6 months longer (12 months) if co-infection with HCV

  45. OCCUPATIONAL EXPOSURE Post exposure recommendations PEP side effects signs and symptoms of acute HIV prevention of transmission: condom no blood donation

  46. References Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2005. DHHS www.AIDSinfo.nih.gov Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. www.cdc.gov/hiv/pubs/guidelines/htm Harrison’s Principle of Internal Medicine 16th Ed 2005 p 1076- 1139

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