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HIV Update
History


HIV was originally described in 1981
Cluster of cases of Pneumocystis
carinii pneumonia (PCP) and Kaposi's
sarcoma (KS) in previously healthy
males
– Previously very unusual infections in the
U.S.
PCP and KS
History

The virus was first identified in 1983
– Luc Montagnier and Robert Gallo

The first blood test (ELISA) was developed
in 1985
– Screening of blood supply initiated
First HIV-1 Infections

Central Africa
– First human case in 1959

US:
– Haitian connection (UNESCO program to Congo in the 1960s)
– Airline steward helped disseminate HIV in the US and Europe

Worobey’s Study
– Studied genetic relatedness of strains and hypothesized that first
infection occurred in ~1908
– Although HIV may have existed for decades, epidemic began in
the 1950s/1960s

Urbanization, prostitution, needle use, war, and travel/tourism
HIV = Zoonosis
-Cross-species infections
• Sooty Mangabey: HIV-2
• Chimpanzee: HIV-1
-Transmission via exposure to blood,
including for chimps (cuts, ingestion)
-Benign infection in Chimpanzees
• 98% homology with HIV (??
which genes protective)
-Did chimps die off millions of years
ago from SIV?
Did NOT originate from: contaminated vaccines, biologic engineering/
weaponry; cats (feline leukemia virus), etc.
Relationships Among Primate Lentiviruses
HIV-2
B
SIVSTM
100
A
100
HIV-1 group O
100
SIVSM
100
100
100
G
A
CPZANT
100
CPZGB
76
100
96
HIV-1 group N
B
100
.10
100
92
77
99
99
D
100
100
A/E
A/G
H
94
F
JC
HIV-1 group M
HIV-1 Subtypes
HIV Virus
Replication: 10 Billions copies/day
HIV Replication
A global view of HIV infection
33 million people [30–36 million] living with HIV, 2007
Adults and children estimated to be living with HIV, 2007
Western & Eastern Europe
Central Europe & Central Asia
730 000
North America
1.2 million
[760 000 – 2.0 million]
Caribbean
230 000
1.5 million
[580 000 – 1.0 million] [1.1 – 1.9 million] East Asia
Middle East & North
Africa
[210 000 – 270 000]
380 000
[280 000 – 510 000]
Sub-Saharan Africa
Latin America
1.7 million
[1.5 – 2.1 million]
22.0 million
[20.5 – 23.6 million]
740 000
[480 000 – 1.1 million]
South & South-East
Asia
4.2 million
[3.5Oceania
– 5.3 million]
74 000
[66 000 – 93 000]
Total: 33 million (30 – 36 million)
Over 7,400 new HIV infections a day in 2007
•
More than 96% are in low and middle income
countries
•
About 1,000 are in children under 15 years of age
•
About 6,300 are in adults aged 15 years and older
of whom:
— almost 50% are among women
— about 45% are among young people (15-24)
25 years of AIDS
Million
50
45
40
35
30
25
20
15
People
living
with
HIV
1 First cases of unusual immune deficiency are identified
among gay men in USA, and a new deadly disease
noticed
2 Acquired Immune Deficiency Syndrome (AIDS) is
defined for the first time
3 The Human Immune Deficiency Virus (HIV) is
identified as the cause of AIDS
4 In Africa, a heterosexual AIDS epidemic is
revealed
5 The first HIV antibody test becomes
6 available
Global Network of People living with
HIV/AIDS (GNP+) (then International
Steering Committee of People Living
with HIV/AIDS) founded
7 The World Health Organisation
launches the Global Programme on
AIDS
8 The first therapy for AIDS –
zidovudine, or AZT -- is
approved for use in the USA
10
5
1
2
3 4
5
6
9
15
16
14
10 Highly Active Antiretroviral
Treatment launched
11 Scientists develop the first
treatment regimen to reduce motherto-child transmission of HIV
13
11
10
9
12
7 8
In 1991-1993, HIV prevalence in
young pregnant women in Uganda
and in young men in Thailand
begins to decrease, the first major
downturns in the epidemic in
developing countries
Children
orphaned
by AIDS in
subSaharan
Africa
12 UNAIDS is created
13 Brazil becomes the first developing
country to provide antiretroviral
therapy through its public health
system
14 The UN General Assembly Special
Session on HIV/AIDS. Global Fund
to fight AIDS, Tuberculosis and
Malaria launched
15 WHO and UNAIDS launch the "3 x 5"
initiative with the goal of reaching 3
million people in developing world
with ART by 2005
16 Global Coalition on Women and
AIDS launched
0
1980
1985
1990
1995
2000
2005
1.1
Reason for Falling Death
Rates

Impact of HAART
– Highly Active Anti-Retroviral Therapy

Defined as three or more ARV drugs
– Protease inhibitors were approved for use in 1995

Earlier recognition & treatment
– Identifying HIV patients so they could be treated


Still an issue: approximately 250,000 undiagnosed cases in
the U.S.!
Response: CDC recommends testing for all persons
(regardless of risk factors) from ages 13 to 64 years
– Annual testing for high-risk persons

OI prophylaxis, multi-discplinary HIV care, etc.
Current Issues


Continued new infections despite knowledge
of prevention
Lack of safe sex practices
– High rate of STIs (e.g., syphilis)



False sense of security after HAART
availability
Lack of ART availability for the entire world
Long term health effects of chronic HIV
infection as well as long term ART use
How HIV is transmitted

Unprotected Sex
– Anal>vaginal>oral
– Risk is most associated with Viral Load






Increased risk with bleeding or tearing of tissues
Higher risk in the receptive partner
Concurrent STI
Lack of circumcision
Sharing needles or IV drug use
Infected mother to her baby
– While baby is developing in the womb
– During the birthing process
– From breastfeeding (30-40% risk in 6 months)

Blood transfusion (1:1 Million)
How HIV is not
transmitted






Coughing
Sneezing
Shaking hands
Casual kiss
Toilet seats
Bites from mosquitoes or fleas
Transmission

The risk for transmission is highest
during the first year after being
infected
– Viral load is highest during early infection
(and in the late stages)
– Unfortunately, most people do not know
they are infected during this time
Diagnosis

HIV ELISA
– Usually positive within 3-4 weeks, rarely test can
become positive up to 6 months after infection

Confirmatory Western Blot test
– Indeterminate test due to advanced HIV, HIV-2,
autoimmune disease, pregnancy
– Overall, between the two tests it is very accurate

Polymerase Chain Reaction (PCR)
– Positive earlier than ELISA
– Used to test people when we suspect
“Seroconverting Illness”
Stages of HIV Infection


Viral transmission
Primary HIV infection (acute HIV infection or acute
seroconversion syndrome)
– Occurs in approximately 60% of cases

Seroconversion
– ELISA becomes positive due to antibody production

Clinical latent period
– Typically 8-10 years in duration


AIDS
End-Stage/Death
Seroconverting
Symptoms









Fever
Rash
Pharyngitis
Myalgias
Headache
Diarrhea
Abdominal Pain
Arthralgias
Nausea/Vomiting
87%
68%
48%
42%
39%
32%
32%
29%
29%
Seroconverting Rash
Natural History of HIV
Genetics and Disease
Progression
Science; 313:462-6
The Pathogenesis of HIV-1 Infection:
Compartments
Colon, Duodenum and
Rectum Chromaffin Cells
Brain Macrophages
and Glial Cells
Lymphocytes in Blood,
Semen and Vaginal Fluid
Lymph Nodes
Bone Marrow
Skin Langerhans’ Cells
Thymus Gland
Lung Alveolar
Macrophages
AIDS

Defined by CD4 count below 200 (<14%) or an
AIDS-defining condition*
–
–
–
–
–
–
–
–
–
P. carinii/jiroveci pneumonia
Esophageal candidiasis
Wasting
Kaposi's sarcoma
Disseminated M. avium infection (MAC)
Tuberculosis
Cytomegalovirus disease
HIV-associated dementia
And so forth (a total of 26 conditions)
*1993 CDC Surveillance Case Definition
HIV Care in the Military

HIV positive persons may remain on AD status
– Cannot serve overseas (policy being reconsidered)


Must attend 2-week “Initial” evaluation upon diagnosis at one of the
3 Navy HIV Clinics
6-month and annual evaluations thereafter:
– History and Physical
– Laboratory evaluations including CD4 counts and viral load


–
–
–
–
–
–

Initial genotype
Annual syphilis test and PPD and basic lab tests
Initiate ARVs when appropriate
Vaccines
Treat any complications / other medical conditions
Social and mental health support
Education about HIV
Preventive Med sessions/safe sex
Medical Board if diagnosed with AIDS
CD4 Count and Risk for
Opportunistic Diseases



CD4 is the best measure for immune competence
and stage of disease
Basis for treatment initiation
Closely related to risk for an opportunistic
condition:
– <200

PCP
– <100



Toxoplasmosis
Cryptococcal meningitis/disseminated disease
Candidal esophagitis
– <50


MAC
CNS lymphoma
Viral Load
Viral load describes the rate of HIV progression
Higher VLs are usually associated with faster declines in
the CD4 count
Not a primary reason to begin HAART
History of Antiretrovirals
1st Drug: AZT, zidovudine
2nd NRTI: DDI, didanosine
Protease Inhibitors (Saquinavir)
Non-nucleosides (Nevirapine)
4th class: Fusion inhibitors
5th class: CCR5 inhibitors
6th class: Integrase inhibitors
March 1987
October 1991
December 1995
June 1996
March 2003
August 2007
October 2007
Approval of Antiretrovirals
Since ’95, 26 new products were introduced
Combivir
Epivir
Rescriptor
Viramune
Retrovir
Ziagen
Sustiva Trizivir
Videx
Truvada
Epzicom
Viread
Emtriva
Selzentry
Fuzeon
Raltegravir
’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ‘00 ’01 ‘02 ’03 ’04 ’05 ’06 ‘07
NRTI
NNRTI
PI
Viracept Kaletra
Fortovase
Invirase
Agenerase
Zerit
Hivid
Entry inh
CCR5 Inh
Integrase Inh
Norvir Crixivan
Reyataz
Lexiva
Prezista
Aptivus
Atripla
Pros and Cons of Early
Therapy
BENEFITS
 Control of viral
replication easier to
achieve and maintain
 Delay or prevention of
immune system
compromise
 Lower risk of
resistance with
complete viral
suppression
 Decreased risk of HIV
transmission
RISKS
 Drug-related reduction
in quality of life
 Greater cumulative
drug-related adverse
events
 Earlier development of
drug resistance, if viral
suppression is sub
optimal
 Limitation of future
antiretroviral treatment
options
DHHS/USPHS Guidelines
Clinical Category
Symptomatic
(AIDS, severe symptoms)
CD4
Plasma HIV
RNA Recommendation
Any
Asymptomatic
<200/mm3 Any
Asymptomatic
>200/mm3 &
350/mm3
Any
Treat
Treat (14%)
Any
Treat
Asymptomatic
>350
≥100,000
Defer (follow closely)
Asymptomatic
>350
<100,000
Defer therapy
Recommended Regimens
TWO NUCLEOTIDE/NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS “NUKES”
+

NON-NUCLEOSIDE
REVERSE
TRANSCRIPTASE
INHIBITOR
“NON-NUKE”

OR
BOOSTED
PROTEASE
INHIBITOR
“PI”
Nucleoside Reverse
Transcriptase Inhibitors
(NRTIs)
Generic
Name
Abbreviation
Abacavir
ABC
Ziagen®
Didanosine
ddI
Videx®
Emtricitabine
FTC
Lamivudine
Trade Name
Co-Formulation*
Trizivir®
Epzicom®
ABC+3TC+ZDV
ABC+3TC
Emtriva™
Truvada™
FTC+TDF
3TC
Epivir®
Combivir®
Epizicom®
Trizivir®
3TC+ZDV
ABC+3TC
ABC+3TC+ZDV
Stavudine
d4T
Zerit®
Tenofovir
TDF
Viread®
Truvada™
FTC+TDF
Zalcitabine
ddC
Hivid®
Zidovudine
AZT, ZDV
Combivir®
Trizivir®
3TC+ZDV
ABC+3TC+ZDV
Retrovir®
Non-Nucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)
Generic Name
Abbreviation
Trade Name
Efavirenz
EFV
Sustiva®
Nevirapine
NVP
Viramune®
Etravirine
TMC125
Intelence®
Protease Inhibitors (PIs)
Generic Name
Abbreviation
Trade Name
Amprenavir
APV
Agenerase®
Atazanavir
ATV
Reyataz™
Fosamprenavir
Indinavir
F-APV
Lexiva™
IDV
Crixivan®
Lopinavir +
ritonavir
LPV/r
Kaletra®
Nelfinavir
NFV
Viracept®
Darunavir
TMC114
Prezista®
Ritonavir
RTV
Saquinavir hard gel
capsule
Tipranavir
Saquinavir soft gel
capsule
Norvir®
SQV-hgc
Invirase®
TPV
Aptivus®
SQV-sgc
Fortovase®
Recommended Regimens

Two nucleosides:

PI or NNRTI:

Nevirapine (only use if CD4<250 in women or <400
in men)
4 drugs are not better than 3!
– Tenofovir (TDF) & emtricitabine (FTC)
[Truvada]
– Zidovudine (AZT) & lamuvidine (3TC)
[Epzicom]
– Lopinavir/ritonavir
– Atazanavir/ritonavir
– Fosamprenavir/ritonavir
– Efavirenz

Atripla™
*First 1 pill a day for
the complete
treatment of HIV
*July 2006
*Consists of tenofovir,
FTC, and sustiva
*$13,800/year
Medications to Avoid in
Combination






AZT & D4T (antagonism)
D4T & DDI (toxicity)
Tenofovir & DDI (Poor CD4 response)
Tenofovir & abacavir (genetic fragility)
3TC & FTC (same mechanism)
Triple nucleoside regimens (inferiority)
Drug Resistance Testing
If HIV viral load becomes “detectable”
or the patient fails to suppress viral
load, obtain resistance testing to guide
therapy
– Genotype and/or phenotype testing

Other indications for genotypic testing:
– New “initial” patients

Rising rate of primary resistance (10%)
Mutated Position in the
HIV Protease Gene
Mutations Associated
With
PI Resistance
30N
48VM
50V
50L
82ATFS
84VAC
90M
46IL
47A
47V
53L
54VTAS
54ML
23I
24I
32I
73CSTA
76V
88S
88D
10IVFR
20MRIT
NFV
SQV
IDV
RTV
FPV
LPV
x
x
x
x
x
x
36IV
63P
71VTI
77I
Stanford HIV Drug Resistance Database. Available at:
http://hivdb.stanford.edu. Accessed July 24, 2006.
ATV
x
x
High-level resistance
Intermediate resistance
Low-level resistance
Contributes to resistance
No resistance
Hypersusceptibility
Adverse Events
Associated With
• Hepatic events
• Cardiovascular events
• Central nervous system
• Lactic acidosis
• Hyperlipidemia Therapies
events
Antiretroviral
• Hepatic steatosis
• Insulin resistance/diabetes • Fat maldistribution
Serious or Potentially Events With Potential
Life-Threatening
Long-term
Events
Complications
• Pancreatitis
mellitus
• Stevens-Johnson
• Osteonecrosis
syndrome/toxic epidermal
necrosis
• Hypersensitivity reaction
• Bleeding episodes
• Bone marrow suppression
• Nephrolithiasis
• Nephrotoxicity
• Skin rash
Events That May
Compromise
Quality of Life
• Gastrointestinal
intolerance
• Peripheral neuropathy
Fat Distribution Changes
Lipohypertrophy
Fat Distribution Changes
Lipohypertrophy
Fat Distribution Changes
Lipoatrophy of the face
HIV Treatment

New therapies
– Novel locations in the life cycle of HIV to inhibit the virus’
replication (e.g., maturation inhibitors).
– Penetration into HIV reservoirs: brain, genital area/secretions
– Possible inducing latently infected cells into the the active cell
population (Valproic acid)

Vaccines
– No supporting data for good efficacy to date for prevention or for
the treatment of HIV
– HIV has many clades and subtypes to cover; in addition, each
Opportunistic Infections –
Prophylaxis

CD4 count <200: Risk for Pneumocystis carinii pneumonia (PCP)
– Septra 1 tablet daily
– Also reduces risk for toxoplasmosis, diarrhea, respiratory
infections, MRSA, Listeria, Nocardia, etc.

CD4 count <50: Risk for Mycobacterium avium infections
– Azithromycin 5 tablets weekly

Positive TB skin test:
– INH for 9 months

Prevention of infections slows HIV progression and
morbidity/mortality from opportunistic infections!
Life Expectancy

Life expectancy at age 20 years increased from 36
years to 49.4 years (1996 to 2005)
– Women had higher life expectancies
– Patients with transmission via injecting drug use had lower
life expectancies
– Life expectancy was lower in patients with lower baseline
CD4 cell counts than in those with higher baseline counts
(32 years for CD4 cell counts below 100 cells per mL vs.
50 years for counts of >200 cells per mL)1
1: Lancet. 2008 Jul 26;372(9635):293-9
Medical Conditions among
HIV Patients

Leading causes of death:
–
–
–
–
Heart Disease
Liver/cirrhosis
Cancers
Renal dysfunction

Role of chronic HIV/inflammation vs. ARV side effects
– Suicide/trauma/accidents

Similar problems as the general population
Prevention



For every 1 person on HAART,
there are 5 other new infections
Prevention is a MUST!
The idea of combining treatment and
prevention strategies realized
Prevention Strategies
– ABCs



Abstinence
Be faithful
Condoms
– Early HIV testing
– Voluntary counseling and testing (VCT)
– Education

For both young and old
– Partner Notification
Prevention Strategies
–
Male Circumcision


Among men (heterosexual in Africa); still a question
for women or MSM
60% reduction in HIV acquisition
Prevention Strategies
– HAART for patients with HIV

–
–
–
–
–
–
–
Reduces HIV VL and transmission
Microbicides
Vaccine (future)
Universal precautions (PPE)
Screening blood supply/organs
Needle exchange programs
Sperm washing/IVF
STD diagnosis and treatment (e.g. HSV2)
Prevention Strategies Mothers
– MTCT- testing and treatment
– C-section

Especially if VL >1000 copies/ml
– Formula vs. breast milk

Avoid mixing
Post-Exposure
Prophylaxis (PEP)

Treatment of a person recently exposed to
HIV
– Best results within first 48-72 hours
– Validated for needle-stick injuries among
healthcare workers
– Guidelines from CDC regarding sexual exposures
– Typically involves 2-3 HIV drugs for 30 days and
repeated HIV testing up to 6 months
Pre-Exposure Prophylaxis
(PrEP)



Not proven in humans to date
Oral tenofovir protected infant macaques against
SIV infection by oral exposure
Tenofovir vaginal gel
– Safety and tolerability in HIV-infected and HIVuninfected women

Trials under way exploring oral tenofovir (plus
FTC) as pre-exposure prophylaxis against sexual
transmission
– Trials among women in Africa and among MSM in the
developed world underway
Summary


HIV has established itself as the great pandemic
of our time
With advances in HIV care, HIV is now a chronic
disease treated with medications
– Similar to diabetes, heart disease, etc.


“Cocktails” and large number of pills are things
of the past (for the most part)
Future directions
– New medications with less side effects, better
penetration into reservoir sites, etc are needed
– A vaccine would be the best, but no effective vaccine
is in sight for the near future
Questions
?