Download HIV for the oral surgeon

HIV/AIDS
Edsel Salvaña, MD, DTM&H
Associate Professor
Infectious Diseases Section
Department of Medicine, UP-PGH
Research Faculty
National Institutes of Health
Learning Objectives
 To learn about HIV pathogenesis
 To learn about the impact of
antiretroviral therapy on the
epidemiology and prognosis of persons
living with HIV/AIDS
 To discuss the preventive measures
and prospects for a vaccine and cure
HIV
 Human Immunodeficiency Virus
 Causative agent of Acquired Immune
Deficiency Syndrome
 RNA virus – retrovirus, uses reverse
transcriptase enzyme
Natural history
 Acute HIV infection is characterized by
a flu-like illness with lymphadenopathy,
fever and malaise
 Self-limited and patient usually recovers
 Takes 8 to 10 years to develop AIDS
AIDS
 Defined either by laboratory parameters
in an asymptomatic patient, or by an
AIDS-defining illness, usually an
opportunistic infection
 CD4 < 200 is AIDS
 Opportunistic infections: PCP, MAC,
cryptococcus meningitis, Kaposi’s
sarcoma, CNS lymphoma, esophageal
thrush etc. = AIDS at ANY CD4 count
Johnston and Fauci. NEJM 359 (9): 888, Figure 1
Origin of HIV
 traced to a simian virus, SIVcpz from
chimpanzees
 likely bloodborne transmission to
human hunters
 Phylogenetic analysis points to at least
three different independent transmission
events in the 20th century
 major (M, between 1915 and 1941),
outlier (O), and nonmajor and nonoutlier
(N)
 earliest documented case of HIV-1
infection (with group M strain) blood
sample from 1959 in Kinshasa, Zaire
 Some evidence that O may be from
gorillas
Selective Timeline of
HIV/AIDS
 1981 – 1st cases of PCP, KS reported
 1983 – Retrovirus isolated and identified
 1985 – Blood supply testing began (EIA)
 1987 – Azidothymidine (ZDV) approved
 1987-1995 – Dual-NRTI regimens
 1992 – PCP Prophylaxis: better outcomes1
 1995 – CCR5 identified as 1° receptor
 1996 –HAART era began: Introduction of PIs
1Chaisson
RE et al. Arch Intern Med. 1992 Oct; 152(10):2009-13.
http://hiv.buffalo.edu/images/hiv_virus_in_action.jpg
CD4 + cell
 Mostly T-helper cells, also found in
some histiocytes including Langhans
cells and reticuloendothelial cells which
serve as reservoir sites
 CD4+ T-cell is the lynchpin of cellularmediated immune system
CCR5 and CXCR4
 Primary receptor of HIV found to be
CCR5, and not CD4
 Δ32 mutation confer high level
protection against infection with CCR5
virus
 CCR5 and CXCR4 are chemokine
receptors, R4 is essential to life
 Emergence of R4 viruses might be a
late phenomonon in disease
How does HIV cause AIDS?
 Early infection depletes most gut
associated CD4 cells
 During the latent phase, viremia is at a
low level, but there is evidence that
ongoing viral replication causes
unregulated immune stimulation
 Constant immune stimulation eventually
leads to immune dysregulation and
destruction of CD4 cells
In early HIV Infection, gut CD4 T cells are
profoundly depleted
Brenchley et al Nat Immunol ‘06
Plasma LPS levels are
increased in chronic HIV
infection
Brenchley et al, Nat Med 06
%CD38+ CD4 T cells
Levels of circulating microbial products
correlate with indices of immune activation
Plasma 16s DNA (copies/ul)
Brenchley et al Nat Med ‘06
Jiang et al J Inf Dis ‘09
How do these microbial products drive
immune activation? (that’s their job!)
Kanzler et al Nat Med ‘07
Immune
Deficiency
HIV replication
Immune
Activation
Microbial
Translocation
Gut
Mucosal damage
Natural History of HIV Disease
1200
 Acute HIV syndrome
wide dissemination of virus
seeding of lymphoid organs
Death
Opportunistic
diseases
Clinical latency
800
1/512
1/256
1/128
Constitutional
symptoms
600
1/64
1/32
400
1/16
1/8
200
1/4
0
1/2
0
0 3 6 9 12
Weeks
1
2
3
4
5 6 7
Years
8
9
Plasma Viremia (Dilutional Titer)
CD4+ T-cells, cells/L
1000
Primary
infection
10 11+
From Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann
Intern Med. 1996 Apr 1;124(7):654-63.
Diagnosis
 HIV ELISA detects HIV antibody –
screening test, highly sensitive (>99%),
can sometimes have false positive
 Western Blot is confirmatory test
 Window period of 3 to 6 weeks from
acute infection to development of
antibodies
 HIV PCR can detect virus around 5
days from infection
HIV Testing
 Must be with full consent
 Confidential
 Can opt to use an alias
 If result is negative, can report to
patient, if positive, WAIT FOR
CONFIRMATORY TEST
 Never assume that patient’s
companions know his/her status
Transmission
 Blood-borne
 Sexual transmission
 Vertical transmission
 Theoretical risk with saliva to open
wound, or human bite but no
documented cases, one case of
infection from deep kissing
 No risk from urine, feces, sweat or tears
Epidemiology
 33.4 million people worldwide are
currently infected with HIV
 28 million deaths so far
 2.7 million new cases in 2008
 2 million deaths reported
 number of new cases has declined by
17% since 2001
 number of deaths has decreased by 10%
since 2001
Philippine HIV/AIDS situation
 Traditionally low prevalence area
 Only 4,567 confirmed case since 1984
 Estimated to have around 12,000 cases
in 2005 (UNAIDS)
THE LANCET Infectious
Diseases Vol 3 June 2003
http://infection.thelancet.com
HIV and AIDS Cases, 1984 - 2009
(Source: AIDS Registry, NEC)
Transmission
 Blood-borne
 Sexual transmission
 Vertical transmission
 Theoretical risk with saliva to open
wound, or human bite but no
documented cases, one case of
infection from deep kissing
 No risk from urine, feces, sweat or tears
Modes of Transmission
(Source: AIDS Registry, NEC 84-08)
Nedlestick
injury
<1% IDU
No data
9%
<1%
Perinatal
1%
Blood/Blood
Products
1%
National AIDS/STI
Prevention and
Control Program
Infectious Disease
Office
Sexual
Contact
89%
New Cases From 20012008
17
%
WORLD
334%
PHILIPPINES
Treatment
 Consists of combination anti-virals
 Uses at least two classes of drugs and
at least three active drugs
 ARV – antiretrovirals
 HAART – Highly Active Antiretroviral
treatment
 Rationale is to prevent resistance
mutations
From death sentence to chronic
disease
 After an unprecedented global effort in
research and aid, effective medication
was discovered
 Turning point came with discovery of
protease inhibitors, and use of HAART
The Fundamental Questions
 Why treat?
 When to start HAART?
 What are the best drugs to use?
 How to follow a patient on HAART?
 When to switch regimens?
 NOTE: IF YOU DON’T DO THIS FOR A
LIVING, REFER TO SOMEONE WHO
DOES – OUTCOMES ARE BETTER
HAART Improves Outcomes1
1Palella
FJ et al. N Engl J Med 1998 March; 338:853-60.
Predictors of Virological
Success
 Potency of ARV regimen
 Adherence
 Lower baseline viremia
 Higher baseline CD4 cell counts
 Rapid reduction of viremia in response
to treatment
FDA-Approved Antiretrovirals
Class
Generic
name
Symbo
l
Brand
name
Class
Generic
name
Symbol
Brand name
Zidovudine
ZDV, AZT
Retrovir®
Saquinavir
SQV
Invirase®/Fortovase®
Lamivudine
3TC
Epivir®
Ritonavir
RTV
Norvir®
Stavudine
d4T
Zerit®
Indinavir
IDV
Crixivan®
Zalcitabine
ddC
Hivid®
Nelfinavir
NFV
Viracept®
Didanosine
ddI
Videx®
Lopinavir
LPV/r
Kaletra®
Abacavir
ABC
Ziagen®
Fosamprenavir
fAPV/FPV
Lexiva®
Tenofovir
TDF
Viread®
Atazanavir
ATV
Reyataz®
Emtricitabine
FTC
Emtriva®
Tipranavir
TPV
Aptivus®
Delavirdine
DLV
Rescriptor®
Darunavir
TMC114
Prezista ®
Nevirapine
NVP
Viramune®
FI
Enfuvirtide
ENF, T-20
Fuzeon®
Efavirenz
EFV
Sustiva®
EI
Maraviroc
MVC
Celsentri®
Etravirine
ETR
Intelence®
InI
Raltegravir
RGV
Isentress®
NRTI
NNRTI
PI
Selecting a Regimen
 Potency
 Tolerability
 Drug-drug interactions
 Co-morbidities
 Lifestyle (dosing convenience, etc)
 Adherence
 Pre-treatment CD4 cell count
 Gender
Other Concepts
 Resistance Mutations
 Altered drug susceptibilities
 Viral Fitness and Replicative Capacity
 M184V/I
 “Boosting”
 Ritonavir (atazanavir, delavirdine)
 Pharmacologic manipulation
 Increase dosing intervals, reduce dose
  threshold for developing drug resistance
OI prophylaxis
 PCP (CD4<200) – Cotrimoxazole
 Toxoplasma (CD4<100) –
Cotrimoxazole
 MAC (CD4<50) – Azithromycin
 Other OI’s: CNS lymphoma, KS,
Giardia, Cryptococcus, CMV, PML,
Cryptosporidium, Thrush, Bacterial
Pneumonia x 3, Cervical Cancer
Prevention
 Use prophylactics
 Monogamy
 Circumcision
 Do not recap needles
 Post-exposure Prophylaxis
 Blood screening
 ?Microbicides
 ?Vaccines
Risk from occupational exposure to
patient with known disease
 HIV 0.3%
 HBV: HbSAg+ HbEAg+ 22-31%
HbSAg+ HbEAg- 1-6%
 HCV 1.8%
Factors that affect transmission
 Type of exposure
 Amount of blood or body fluid
transferred
 Size of needle, hollow bore
 Patient on antiretrovirals
 Current viral load
Precautions
 Assume all patients are potentially
infected
 Universal precautions: glove (can
double-glove for known positives),
gown, face mask and eye protection
 Never recap needles, uses needleless
systems when possible
 Dispose of sharps properly
When to give prophylaxis?
 Risk stratify patient: known history of
HIV, recent testing, occupation, sexual
history, high risk exposures
 Risk stratify injury: large hollow bore
needles, bleeding profusely etc.
 If low risk, no need for prophylaxis
 If high risk, need to start prophylaxis
within 72 hours of injury, otherwise no
benefit
Microbicides
 Topically applied prior to sexual
intercourse
 Mechanically or chemically blocks entry
of the virus into target cells
 Resuts disappointing so far
Vaccines
 Traditional approaches to producing
broadly neutralizing antibody have failed
 T-cell vaccines underwent trials, failed
with evidence of possible harm
Selected Obstacles to HIV-Vaccine
Development and Their Implications.
 The window of opportunity for the immune system to
clear the initial infection is narrow, since HIV
integrates and establishes latent infection within days
or weeks.
 Destruction of CD4+ T cells begins early after
infection.
 Enormous genetic diversity and mutations that occur
with replication enable HIV to avoid immune
surveillance.
 Conserved antibody targets on the outer envelope
protein are "hidden" from immune recognition.
Johnston MI, Fauci AS. An HIV Vaccine — Challenges and Prospects. NEJM
2008;359:888-890
Implications
 Rational, empirical approaches to
vaccine development have not been
successful to date.
 Fundamental questions regarding HIV
disease and the host response to the
virus need to be answered.
 Fresh new ideas beyond the scope of
classic vaccinology are urgently
needed.
Johnston MI, Fauci AS. An HIV Vaccine — Challenges and Prospects. NEJM
2008;359:888-890
THANK YOU!