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HIV PATHOGENESIS
Retrovirus HIV-1 HIV-2Binds to CD4 receptor Fusion with lipid layer
Enters host CD4 cell: reverse transcriptase → DNAViral DNA integrated into host DNA
Proviral DNA → viral proteinsProteaseAssembly and budding of new viral particle
HIV PATHOGENESIS
Stages of HIV infection
Acute infection
50% develop febrile, flu-like illness1 – 6 weeks after exposureadenopathypharyngitisrashheadache/aseptic meningitisdiarrhea
HIV PATHOGENESIS
Stages of HIV infection
Acute infection
HIV test (antibody) may be negativeantibodies: 4 – 6 weeksHIV RNA PCR + (needs confirmation)
HIV PATHOGENESIS
Stages of HIV infection
Acute infection
very high levels of HIVHIV disseminates to sanctuary sites (lymphatic/CNS)viral levels decrease over 4 months to set point
HIV PATHOGENESIS
Stages of HIV infection
Intermediate stage
T cell destructiongradual decline in immune function 8 – 10 yearsduration depends on initial set point
HIV PATHOGENESIS
Persistent cellular activation
hypergammaglobulinemiaincreased secretion of cytokinesincreased CD4 activation: enhance HIV replication
activation increased by infection byCMV, HSV, EBV, TB: enhance HIV replication
apoptosis↑
HIV PATHOGENESIS
Evasion of immune system
continuing mutations evade cytolytic T cells, Igdownregulation of HLA class 1 on infected cellssequestration in immune privileged sites (CNS)
latently infected resting CD4 cells
HIV PATHOGENESIS
Stages of HIV infection
Advanced stage
Opportunistic infectionsCD4 200 – 500
pneumococcal pneumoniaTBherpes zosterthrushoral leukoplakia
HIV PATHOGENESIS
Stages of HIV infection
Advanced stage
Opportunistic infectionsCD4 < 200
pneumocystis carinii pneumoniacandida esophagitistoxoplasmosisPMLTB
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
HIV EPIDEMIOLOGY
Transmission
Sexual transmission
HIV virus in seminal fluid (cells and free)male to female transmission 8x more effectiveanal intercourse increases transmissiongenital ulcers increases transmissionSTDs increases transmission
HIV EPIDEMIOLOGY
Transmission
Blood and blood products
risk < 1:800,000 blood donationsHIV RNA may not be detected first 1 -2 weeks
HIV EPIDEMIOLOGY
Transmission
Maternal-fetal/infant transmission
most in the perinatal periodprobability 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%
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
HIV EPIDEMIOLOGY
Transmission
Transmission by other body fluids
no convincing evidence that saliva transmits HIVby 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
HIV AND RESPIRATORY TRACT
Sinusitis: could be mucormycosis in low CD4Pneumonia: x 6 risk of pneumococcal pneumonia
→ vaccine PCP may be indolent
may cavitate in treated patientsrequires prophylaxis (CD4 < 200) (TMP-sulfa)
TB HIV increases risk of TB x 100risk in tuberculin + = 10% per year
HIV AND RESPIRATORY TRACT
TB dissemination more in low CD4treatment as non-HIVall patient with HIV should have PPDprophylaxis if PPD 5 mm or any + if high risk
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
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
HIV AND GENITOURINARY TRACT
UTI (same management)HIV nephropathy (proteinuria)drugs: nephrolithiasis (indinavir)
HIV AND HEMATOPOIETIC SYSTEM
Lymphadenopathypersistent generalized: HIV earlyddx: lymphoma TB Kaposi atypical mycobacteriae toxoplasmosis
Thrombocytopeniafrequent (3%), platelet specific antibodiesresponds to anti-retroviral Rx
HIV AND NEUROLOGICAL SYSTEM
Opportunistic infectionsToxoplasmosis
late with CD4 < 200presents with headache and focal signsMRI: usually multiple enhancing lesionsdx: treatment first 2 – 4 weeks, bx if no
response
Cryptococcosissubacute meningoencephalitisCSF: cryptococcal antigen +, often few WBC
HIV AND NEUROLOGICAL SYSTEM
HIV encephalopathyCSF is abnormal in 90% of HIV patientsencephalopathy: dementiacerebral atrophy on MRI
otherslymphomaPMLperipheral neuropathymyelopathymyopathy
HIV AND NEOPLASTIC DISEASES
Lymphoma (non-Hodgkin’s)6% of all AIDS patientslate (<200 CD4)
immunoblastic:often GI tract: dysphagia, abdominal painmarrow, liver, lungs
Burkitt’s:less frequent EBV-positive
HIV AND NEOPLASTIC DISEASES
Lymphoma
Primary CNS lymphoma:EBV-positiveheadache, seizure, focal deficitfew lesions on MRI, deep, some enhanceddx: toxoplasmosis (treat first)
HIV TREATMENT
Deferring therapyBenefits: quality of life (side-effects)
preserve drug options delay resistance
Risks: deterioration immune system increased transmission
HIV TREATMENT
Clinical CD4 Viral load Decision
AIDS
Symptoms
Treat
AIDS
Assympt
< 200 Treat
Assympt > 200
< 350
Offer
Assympt > 350 > 100,000 May defer
Assympt > 350 < 100,000 Defer
HIV TREATMENT
HAARTInitial treatment (example of preferred regimen)
NNRTI-basedefavirenz + AZT + 3TC
Protease inhibitor-basedlopinavir/ritonovir + AZT + 3TC
HIV TREATMENT
Adverse effects
NRTIall: lipodystrophydidanosine: pancreatitis, neuropathystavudine: pancreatitisAZT: headache, GI intolerance, marrow
NNRTInevirapine: hepatic necrosisefavirenz: neuropsychiatric, teratogenic
HIV TREATMENT
Adverse effects
PIdiabeteslipodystrophydrug interactionindinavir: nephrolithiasisnelfinavir: diarrhearitonovir: GI intolerance, hepatitis
OCCUPATIONAL EXPOSURE
Risk of transmission after percutaneous exposure
Source Risk
HBV eAg + 22 – 30 % eAg - 1 – 6 %
HCV 1.8 %
HIV 0.3 %
OCCUPATIONAL EXPOSURE
Wound careclean with soap and waterflush mucous membrane with wateravoid bleach or agents caustic to skin
Assessment of infection risktype of exposurebody substancesource
No testing of needles or sharp instruments
OCCUPATIONAL EXPOSURE
Risk of HIV transmission by exposure route
percutaneous 0.3%mucous membrane 0.09%non-intact skin 0.1%
OCCUPATIONAL EXPOSURE
Evidence for HIV PEP
AZT associated with 81% decrease of transmissionAZT during pregnancy ↓perinatal transmission by 67%
OCCUPATIONAL EXPOSURE
Baseline testing of exposed + sourcePEP to start within hoursDecision re: starting PEP days after can be considered
OCCUPATIONAL EXPOSURE
HIV PEP Basic RegimenAZT: 300 mg bid3TC: 150 mg bid
Expanded regimenbasic regimen plus one:Nelfinavir: 1250 mg bidEfavirenz: 600 mg dailyIndinavir 800 mg q8h
OCCUPATIONAL EXPOSURE
PEP for percutaneous injuries
Exposure type HIV class 1 HIV class 2 Unknown statusUnknown source
Less severe basic PEP expanded generally no PEP*More severe expanded expanded generally no PEP*
*consider basic PEP if risks for HIV
OCCUPATIONAL EXPOSURE
PEP for mucous membrane or non-intact skin exposure
Exposure type HIV class 1 HIV class 2 Unknown statusUnknown source
Small cons basic PEP basic PEP generally no PEPLarge basic PEP expanded generally no PEP
*consider basic PEP if risks for HIV
OCCUPATIONAL EXPOSURE
PEP rarely if ever warranted in:
intact skin with blood or infectious body fluidunknown source in population with low HIV prevalencelow risk exposure to unknown source
OCCUPATIONAL EXPOSURE
PEP in pregnancy
Not a contraindication to PEPlong term effect on fetus unknownmost data on AZT
efavirenz contraindicatedd4t and ddI: lactic acidosisindinavir: hyperbilirubinemia pre termnevirapine: liver failure
OCCUPATIONAL EXPOSURE
Follow-up testing of exposed person
test at 6 weeks, 3 months, 6 monthslonger (12 months) if co-infection with HCV
OCCUPATIONAL EXPOSURE
Post exposure recommendations
PEP side effectssigns and symptoms of acute HIVprevention of transmission: condom
no blood donation
References
Guidelines for the use of antiretroviral agents in HIV-1-infectedadults 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