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HIV/AIDS
2009
Overview
 Etiology
 Pathology
 Epidemiology
 Clinical
presentation
 Clinical course
 Diagnosis
 Therapy
 Health maintenance/education
Etiology
 The
virus
 HIV
causes AIDS
Etiology
 RNA
virus
 Retrovirus, subfamily lentivirus
 Cytopathic – kills cells
 HIV 1 most common
 HIV 2 found in West Africa – less aggressive
disease, less vertical transmission
 CD4 + lymphocyte is primary target but
monocyte/macrohages also express CD4 and
become infected
Pathology
 Modes
of transmission
 Sexual
 Vertical
– mother to child, perinatal
 Parenteral – injection drug users
 Transfusion
 Nosocomial
Pathology
Transmission
 Transfusion
 Highest
incidence during late 1970’s
 Routine testing donors 1985
 Pooled coagulation factors highest risk
 8000 persons with hemophilia infected prior
to 1985
 Current risk estimates 1 in 38,000 to 1 in
300,000 units of blood
Pathology
CD4 + lymphocyte depletion
 Direct
cytopathic effects
 Membrane
effects, accumulation of virus,
disruption of cellular RNA and protein
processing
 Bystander
 Syncytia
 Failure
 Bone
formation
to regenerate cells
marrow infection, thymus infection
 Autoimmunity
Pathology
Other Mechanisms
 CD4
cell impairment
 CD8 cell alterations
 Monocyte/macrophage functional
abnormalities
 B cell abnormalities
 Cytokines
 Natural killer cells
Epidemiology
History
 Early
1980’s
 Outbreak of previously unknown illness
among MSM
 Virus identified in 1983
 Antibody testing of blood supply 1985
Epidemiology
Global
 40
million living with HIV or AIDS
 3.5 million deaths in 2001
 4.3 million newly infected 2006 (est.)
 20 million deaths due to AIDS since
beginning of epidemic
Epidemiology
United States
 40,000
infected each year in U.S.
 One half of new infections in ages 13-24
 17,011 deaths in 2005; 550,394 total
 U.S. HIV prevalence 1.2 million
 New York state has most cases
 172,377
 District
 128.4
(18%)
of Columbia has highest rate
per 100,000 (U.S. rate 14/100,000)
Epidemiology
United States
1
million infections
 25% don’t know they are infected; in
some areas 75% MSM don’t know they are
infected
 AIDS is reportable in all states
 CDC recommends reporting of HIV; 38
states currently mandate reporting
Epidemiology
Maine
 1,256
cases since 1982
 555 AIDS related deaths
 71
deaths in 1993
 13 deaths in 2001
 HIV
prevalence in Maine ~ 1,500 - 2,000
 One
third don’t know status
 MSM - 50% of cases
 IDU - 20%
 Heterosexual - 20%
Clinical Presentations of HIV
Established Infection
 Generalized
lymphadenopathy
 Unexplained thrush
 New severe psoriasis, skin disorder
 Unexplained weight loss
 Unexplained thrombocytopenia, etc
 Neurologic disease (CNS/peripheral)
 Recurrent bacterial pneumonia
 Chronic diarrhea
Clinical Presentations of HIV
Acute HIV Syndrome
 Fever
 Sore
throat
 Swollen lymph nodes
 Headache
 Arthralgias/myalgias
 Lethargy/malaise
 Anorexia/weight loss
 Nausea/vomiting/diarrhea
Clinical Manifestations
AIDS – Defining Conditions
 CD4
count < 200, or < 15%
 Candidiasis (not thrush or vaginal)
 Invasive cervical cancer
 CMV retinitis
 HIV encephalopathy
 Kaposi sarcoma
 Mycobacterium
 Pneumocystis
 Progressive
avium, M. tuberculosis
pneumonia
multifocal leucoencephaolopathy
Diagnosis
 Antibody
testing
 ELISA/Western
Blot antibody test
 Rapid blood/oral test
 Home HIV test kit
 Viral
detection
 Culture
 RNA
PCR (viral load)
 DNA PCR
Maine HIV Testing 2007
 Changes
 No
in state law
pre-test counseling required
 No written informed consent
 Required
 ‘A
patient must be informed orally or in writing that
an HIV test will be performed unless (they) decline’
 ‘Information must include an explanation of what an
HIV infection involves, and the meaning of positive
and negative test results’
 ‘If a test is positive, post-test counseling must be
provided’
Diagnosis
Indications for Testing
 Behavioral
risk factors
 Conditions associated with infection
 Recipients of blood or blood products between
1978 and 1985
 Persons with other STDs
 Pregnant women
 Children born to infected women or women at
increased risk of infection
 Occupational or non-occupational exposure
New Recommendations
 HIV
testing included in the routine panel of
prenatal screening for all pregnant women
 Repeat
screen in the third trimester in areas
with elevated rates of HIV among pregnant
women
Home Test Kits
 Collect
 Send
 Call
specimen at home
to lab
for result/counseling
Key Lab Values
 CD4
+ Lymphocyte count
 CD4 + Lymphocyte percent
 HIV RNA Viral Load
Viral Load
 Highest
in initial infection
 Key to monitoring effectiveness of
antiviral therapies
 Patient’s ‘set point’ determines risks/rate
of progression of infection
 Determines risk for maternal-fetal
infection
 Determines risk of occupational exposure
infection
Screening Tests
 CBC
 Pap
 Chemistries
 PPD
 G6PD
 Urine
 Fasting
lipids
 Fasting
glucose
 CXR
Smear
GC/Chlamydia
 Serologies
 CMV
 Hepatitis
A, B, C
 Syphilis
 Toxoplasma
Antiretroviral Therapy
Sites of Action
Antiretroviral Drugs

Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
Zidovudine AZT (Retrovir)
Didanosine ddI (Videx)
Zalcitabine ddC (Hivid)
Lamivudine 3TC (Epivir)
Stavudine
d4T (Zerit)
Abacavir (Ziagen)
Tenofovir (Viread)
Emtricitabine (Emtriva)
Antiretrovirals cont’d
 NonNucleoside
RTI’s (NNRTI’s):
Efavirenz (Sustiva)
Neviripine (Viramune)
Delavirdine (Rescriptor)
 Etravirine
(TMC-125)- ??? January 2008
Antiretrovirals cont’d
 Protease
Inhibitors (PI’s):
Saquinavir (Fortovase, Invirase)
Indinavir (Crixivan)
Ritonavir (Norvir)
Amprenavir (Agenerase)
Nelfinavir (Viracept)
Lopinavir/ritonavir (Kaletra)
Fos-amprenavir (Lexiva)
Atazanavir (Reyataz)
Tipranavir (Aptivus)
Darunavir (Prezista)
Antiretrovirals con’t

Fusion Inhibitor
Enfuvirtide (T20, Fuzeon)
New Classes of Antiretrovirals
 HIV
integrase inhibitors
 HIV
maturation inhibitor (PA-457)
 Co-receptor
blockers (CCR5 antagonists)
CCR-5 Co-Receptor Antagonist
 Maraviroc
 Patients
– August 2007
with prior experience
 Only CCR5-tropic HIV-1
 Not dual/mixed CXCR4-tropic virus
Integrase Inhibitor
 Raltegravir
 Integrase
– October 2007
strand transfer inhibitor
Treatment Guidelines
JAMA 2004;292:251-265 (July 14, 2004)
Treatment for Adult HIV Infection
2004 Recommendations of the
International AIDS Society-USA Panel
Treatment Guidelines
 Recommendations
When
What
When
What
for 4 key issues
to start
drugs to start with
to change
to change to
Special Circumstances
Postexposure Prophylaxis
 Occupational
 Updated
U.S. public health service guidelines for the
management of occupational exposures to HBV,
HCV, and HIV and recommendations for
postexposure prophylaxis. MMWR 2001;50(RR11)1-67.
 Nonoccupational
 New
guidelines: Antiretroviral Postexposure
Prophylaxis After Sexual, Injection-Drug Use, or
Other Nonoccupational Exposure to HIV in the United
States. MMWR 2005;54(RR-02)1-20.
Concept of HIV PEP
 Prevention
of initial local infection and
propagation of virus with antiretrovirals
 Data from animal studies indicate that infection
can be prevented if antiretrovirals given within
72 hours of exposure
 Data from perinatal studies show efficacy even
if only infant treated after birth
Nonoccupational HIV PEP
Issues to Consider







Risk of transmission
Medication adverse events
Medication non-compliance
Loss to follow up
Cost
Possible increase in high risk behaviors
Possible medication resistance
Baseline and Follow-Up Testing
Baseline
HIV, pregnancy test, GC, Chlamydia, CBC, LFTs,
chemistries
Follow-up
4 weeks HIV test
3 months HIV test, Hep B and C
6 months HIV, Hep B and C
12 months HIV
Need to monitor CBC, LFTs, chemistries if on PEP
Recommended Medications
 NNRTI
– based
 Efavirenz
PLUS
 Lamivudine or emtricitabine PLUS
 Zidovudine or tenofovir
 Protease
inhibitor – based
 Lopinavir/ritonavir
PLUS
 Lamivudine or emtricitabine PLUS
 Zidovudine
Special Circumstances
Pregnancy
 Antiretroviral
medications for the health of the
mother and to prevent perinatal transmission
 ACTG 076 Trial – AZT for mother and infant
 Recommendations based on treatment status of
mother prior to pregnancy – continue meds if
on, try to include AZT if possible
 HIV
Antiretroviral Pregnancy Registry
www.apregistry.com
Immune Reconstitution
Inflammatory Syndrome
 Atypical
inflammatory reactions that occur after
initiation of effective antiretroviral therapy due
to immune recognition of opportunistic
infection antigens
 Usually occur few weeks to several months
after initiation of therapy
 Usually self-limited, but manifestations may be
severe
(Medicine 2002;81:213-227)
Monitoring Antiviral Therapy
 Adherence
 CD4
and Viral Load
 Baseline
 3-4
wks after start therapy
 Every
4-8 weeks until undetectable
 Every
3 months after stabilization
 Drug
Resistance Testing
 Treatment
 Before
failure
treatment initiation
What Is ‘Non-Adherence’
 Failure
to take medications
 Taking meds in unprescribed doses
 Missing doses frequently
 Taking meds off prescribed schedule
 Failure to match med/dose with food as
directed
 Selectively eliminating 1 of meds from regimen
 Sharing/selling meds
 Hoarding meds for future use
HIV Resistance to Drugs

Viral conditions that lead to development
of resistance:
 High
replication rate
 High mutation rate
 Selective pressure of drugs favors mutant
strains over wild type; increasingly resistant
strains over time
Antiretrovirals: The Downside
Serious acute toxicity/allergy
 Common side effects (medication
specific)
 Metabolic effects
 Mitochondrial toxicity
 Reconstitution syndromes
 Drug interactions

Prophylaxis
PCP
CD4 < 200, prior dz TMP/SMX
Tuberculosis
PPD > 5mm
INH
MAI
CD4 < 50
Azithro, Clarithro
Toxoplasmosis
CD4 < 100, +serol
TMP/SMX
Pneumococcus
all
vaccine
Hepatitis B
all non-immune
vaccine
Influenza
all
vaccine
Health Maintenance
 Importance
of primary care provider
 Routine screening tests
 Nutrition and exercise
 Medication adherence
 Prevention of transmission
 Testing for other chronic infections with
similar routes of transmission (i.e., viral
hepatitis)
Health Maintenance
 Immunizations
 Annual
influenza, pneumococcal, tetanus,
hepatitis A and B
 STD
testing
 ?frequency
 PAP
smears
 Tuberculin skin test
Challenges in HIV Care
 Recognition
of acute/primary HIV
 Recognition
of chronic HIV
 Determine
 Tailor
timing of treatment
HAART to individual patients
 Support
“Near Perfect” adherence
Challenges

Anticipate drug toxicities, interactions

Recognize and treat co-existent psychiatric illness
or substance abuse

Look for coexistent Hep B, Hep C, STDs

Attention to associated risks (cervical, anal CA)

Identify high risk behaviors to prevent transmission

Simplify treatment regimens when appropriate
Resources
 Treatment
for Adult HIV Infection:
2004 Recommendations of the International
AIDS Society-USA Panel. JAMA 2004;292:251265.
 2007
Medical Management of HIV Infection
John G. Bartlett, M.D. and Joel E. Gallant,
M.D., M.P.H. www.hopkins-hivguide.org
 www.cdc.gov
 www.aidsinfo.nih.gov