Download Natural History of HIV Disease

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
Stages of HIV infection
Acute infection
50% develop febrile, flu-like illness
1 – 6 weeks after exposure
adenopathy
pharyngitis
rash
headache/aseptic meningitis
diarrhea
HIV PATHOGENESIS
Stages of HIV infection
Acute infection
HIV test (antibody) may be negative
antibodies: 4 – 6 weeks
HIV RNA PCR + (needs confirmation)
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
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
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↑
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
HIV PATHOGENESIS
Stages of HIV infection
Advanced stage
Opportunistic infections
CD4 200 – 500
pneumococcal pneumonia
TB
herpes zoster
thrush
oral leukoplakia
HIV PATHOGENESIS
Stages of HIV infection
Advanced stage
Opportunistic infections
CD4 < 200
pneumocystis carinii pneumonia
candida esophagitis
toxoplasmosis
PML
TB
HIV PATHOGENESIS
Stages of HIV infection
Advanced stage
Opportunistic infections
CD4 < 50
CMV
MAC
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 effective
anal intercourse increases transmission
genital ulcers increases transmission
STDs increases transmission
HIV EPIDEMIOLOGY
Transmission
Blood and blood products
risk < 1:800,000 blood donations
HIV RNA may not be detected first 1 -2 weeks
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%
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 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
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
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
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
Lymphadenopathy
persistent generalized: HIV early
ddx: lymphoma
TB
Kaposi
atypical mycobacteriae
toxoplasmosis
Thrombocytopenia
frequent (3%), platelet specific antibodies
responds to anti-retroviral Rx
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
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
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
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)
HIV TREATMENT
Deferring therapy
Benefits: 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
HAART
Initial treatment (example of preferred regimen)
NNRTI-based
efavirenz + AZT + 3TC
Protease inhibitor-based
lopinavir/ritonovir + AZT + 3TC
HIV TREATMENT
Adverse effects
NRTI
all: lipodystrophy
didanosine: pancreatitis, neuropathy
stavudine: pancreatitis
AZT: headache, GI intolerance, marrow
NNRTI
nevirapine: hepatic necrosis
efavirenz: neuropsychiatric, teratogenic
HIV TREATMENT
Adverse effects
PI
diabetes
lipodystrophy
drug interaction
indinavir: nephrolithiasis
nelfinavir: diarrhea
ritonovir: GI intolerance, hepatitis
OCCUPATIONAL EXPOSURE
Risk of transmission after percutaneous exposure
Source
Risk
HBV eAg +
eAg -
22 – 30 %
1– 6%
HCV
1.8 %
HIV
0.3 %
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
OCCUPATIONAL EXPOSURE
Risk of HIV transmission by exposure route
percutaneous
mucous membrane
non-intact skin
0.3%
0.09%
0.1%
OCCUPATIONAL EXPOSURE
Evidence for HIV PEP
AZT associated with 81% decrease of transmission
AZT during pregnancy ↓perinatal transmission by 67%
OCCUPATIONAL EXPOSURE
Baseline testing of exposed + source
PEP to start within hours
Decision re: starting PEP days after can be considered
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
OCCUPATIONAL EXPOSURE
PEP for percutaneous injuries
Exposure type HIV class 1
HIV class 2
Unknown status
Unknown source
Less severe
More severe
expanded
expanded
generally no PEP*
generally no PEP*
basic PEP
expanded
*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 status
Unknown source
Small
Large
basic PEP
expanded
generally no PEP
generally no PEP
cons basic PEP
basic PEP
*consider basic PEP if risks for HIV
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
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
OCCUPATIONAL EXPOSURE
Follow-up testing of exposed person
test at 6 weeks, 3 months, 6 months
longer (12 months) if co-infection with HCV
OCCUPATIONAL EXPOSURE
Post exposure recommendations
PEP side effects
signs and symptoms of acute HIV
prevention of transmission: condom
no blood donation
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 10761139