HIV

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 PATHOGENESIS

Stages of HIV infection

Advanced stage

Opportunistic infectionsCD4 < 50

CMVMAC

Natural History of HIV Disease

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