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Overview of HIV Disease
Dr. Marianne Harris
AIDS Research
Program
St. Paul’s Hospital
Adults and Children Estimated to
Be Living With HIV, 2008
North America
1.2 million
Caribbean
230,000
Latin America
1.7 million
Eastern Europe and
Western/
Central Asia
Central Europe
1.5 million East Asia
730,000
North Africa and Middle East
380,000
Sub-Saharan Africa
22 million
UNAIDS, 2008. Available at: http://www.unaids.org.
740,000
Southern and
Southeast Asia
4.2 million
Oceania
74,000
Total: 33 (31-36) million
3
Estimated Adult and Child Deaths from
AIDS: 2007
4
5
Life Expectancy Five African
Countries: 1970 - 2010
Canada life expectancy (2006 estimate): 80.22 years
6
HIV natural history
Development of AIDS is like an
impending train wreck where:
Viral Load = Speed of the train
CD4 count = Distance from site of doom
HIV
infection
J. Coffin, XI International AIDS Conf., Vancouver, 1996
HIV Natural History
• 8 to 10 years of symptom-free living
after initial infection with the virus
• As CD4 count drops, the potential for
opportunistic infections (OIs) increases
• AIDS is defined by certain OIs and
cancers
Oropharyngeal Candidiasis
• White patches in mouth (thrush)
• Pain/burning with eating
• Can spread to esophagus  painful
swallowing, burning in chest
• Cause of weight loss, wasting
Pneumocystis carinii
pneumonia (PCP)
• New name: Pneumocystis jiroveci
• Symptoms include dry cough, shortness of
breath and fever
• Possibly anorexia and/or fatigue
• Insidious as compared to bacterial pneumonia
• CXR nonspecific
• Diagnosed with bronchoscopy/biopsy
Pneumocystis carinii
pneumonia
Toxoplasmosis
• Seizures, motor disturbances or altered
mental status
• Space-occupying lesion in the brain
• Diagnosed with serum serology and a
CT or MRI scan
• Differential diagnosis: CNS lymphoma
Toxoplasmosis
Kaposi’s Sarcoma
• Pink, red or violet lesions which generally begin on
the skin or the mouth
• Can be in GI or respiratory tract
• As lesions enlarge, they darken and coalesce to form
raised plaques or tumours
• Diagnosed with a biopsy of lesions
• Any CD4, AIDS-defining
• Caused by Human Herpes Virus 8 (HHV-8)
• Treated with radiation/chemotherapy (ARVs)
Targets for HIV Inhibition
Protease
Inhibitors
Entry
Inhibitors
Reverse
Transcriptase
Inhibitors
Maturation
Inhibitors
Integrase
Inhibitors
ARV-induced pVL changes are associated
with a change in the rate of CD4 decline
CD4
Low pVL
Hi pVL
Time, years
Goals of therapy
• Maximal and durable suppression of
viral load to <50 copies/mL
• Restore/preserve immune function
• Improve quality of life
• Reduce HIV-related morbidity/mortality
What are the risks?
• Poor compliance  resistance 
limitations on future treatment options
• Short- and long-term side effects
HIV Drug Resistance
• Reduced susceptibility of virus to one or
more ARV drugs
• Patient has many strains of virus; may
harbour sensitive and resistant strains
at the same time
• Testing picks up the predominant viral
populations
• Minority populations don’t go away
Why does it happen ?
Lots of viruses are
made every day;
there is a natural
variation of drug
sensitivity
Why does it happen ?
Lots of viruses are
made every day;
there is a natural
variation of drug
sensitivity
Why does it happen ?
If replication is not
completely stopped, those
which are less susceptible
can eventually escape
Resistant
Virus
Implications of Resistance
• Resistance can develop to any/all drugs
• Resistance to 1 drug in a class often means
resistance to others (cross resistance)
• Sometimes the resistant virus is passed from person
to person: “Primary resistance” (5-10% )
• Resistance will not go away when drug is removed
(even if main virus reverts to “wild type”) - resistant
viruses are archived
• Develops when virus is allowed to reproduce when
antivirals are around (i.e. suboptimal levels of drug
which do not suppress virus completely)
100.0
80.0
86% (2007)
60.0
?100%
(2010)
65% (2000)
40.0
2009
2007
2005
2003
0.0
2001
20.0
1999
Percentage of Patients with pVL <50 copies
BC Data: Viral load <50 copies/mL over time
(N approx. 7400 in DTP)
Year
V Lima, et al., CROI 2008;Poster #895
600
Rates of New Resistance in BC
500
3TC
nRTI
400
Number
of New
Cases of 300
Resistance
detected 200
PI
Any
100
Year
2008
2006
2004
2002
2000
1998
1996
0
V Lima, et al., CROI 2008;Poster #895
Viral Load Stratified by Adherence level
Percent of Participants With pVL<500
Copies At Least Twice
(first 12 months of therapy)
100%
84%
75%
Mantel-Haenszel
Mantel-Haenszel
trend
test p = 0.001
Trend test p = 0.001
50%
64%
47%
24%
25%
12%
0%
<70%
70% - <80% 80% - <90% 90% - <95%
Adherence Level
95% - 100%
Low-Beer et al. JAIDS 2000.
What are the risks?
• Poor compliance  resistance 
limitations on future treatment options
• Short- and long-term side effects
Buffalo hump
Lipodystrophy: abdominal
obesity
Lipodystrophy: facial fat loss
Incidence of MI by ART duration
Relative rate per additional year
of exposure to ART*: 1.17
(95% CI: 1.08-1.26), p<0.0001
8
6
4
2
0
HAART Exposure (yrs) None
No. of MIs
Patient years
14
10,103
<1
1-2
2-3
3-4
4-5
5-6
>6
16
22
34
56
55
39
41
277
6,324
8,165
10,846
13,060
12,254
9,073
6,751
76,577
El-Sadr et al, CROI 2005: Oral session #10
HAART=combination antiretroviral therapy
*Adjusted for conventional risk factors not influenced by HAART
HIV+ with CD4 count > 350/mm3
84% on ART, 16% off ART
Randomized
n = 2752
n = 2720
Continuous ART
Intermittent ART
• Stop or defer when CD4 > 350
• Restart/start if CD4 < 250
Follow-up
94% on ART
99% CD4 > 200
33% on ART
96% CD4 > 200
N Engl J Med 2006
1200
1000
Continuous vs Intermittent
HAART
Cont CD4, cells/mm3
Cont pVL, Kcopies/mL
800
Cont
Int
600
PVL
U/D
Int
400
CD4
High
OK
200
Cost
+++
+
Deaths
0
0
OI/Ca
0
0
NonADI
Events
+++
Toxicit
y
+
QoL
+
+++
0
1200
1000
Int CD4, CD4, cells/mm3
Time
Int pVL, Kcopies/mL
800
600
400
200
0
Time
Endpoints of the SMART study, including
cardiovascular disease
N Engl J Med 2006
SMART: Risk of serious non-AIDS events
Number of events
Intermittent Continuous
ART
ART
113
73
27
24
Renal
9
2
CVD
48
31
Liver
10
7
Other non-AIDS death
30
16
All serious non-AIDS
Non-AIDS malignancy
Of the 85 deaths that occurred in SMART,
only 7 (8%) were from AIDS diseases
0.5
1 2 3 5 10
Hazard ratio
Intermittent ART vs. Continuous ART
SMART, NEJM 2006 & Neaton et al, Current Opinion in HIV/AIDS 2008
Summary of SMART Study
- HIV is a chronic inflammatory disease
- Inflammation: important driver of non-AIDS events
- heart, liver, kidney, etc
- malignancies
- Inflammation: important driver of CD4 decline
- ADIs at a late stage of the disease
B.C. CENTRE FOR
EXCELLENCE IN HIV/AIDS
http://www.cfenet.ubc.ca
HIV Prevention
Dr. Marianne Harris
AIDS Research Program
St. Paul’s Hospital
Estimated Number of People Newly Infected
with HIV: 2007
48
Estimated New HIV Infections:
Canada 1981 - 2005
Source: CCDR. August 2006.
49
Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.
50
Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.
51
Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.
52
Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.
53
HIV Rates BC: 1995-2005
Total BC vs Aboriginal BC
Source: STI/HIV Prevention and Control, BCCDC. 2005 Annual Report.
54
People Living with HIV in Canada: 2005
An estimated 27%
(15,660) of the 58,000
individuals living with
HIV are unaware of their
HIV infection
2005
MSM
MSM-IDU
IDU
Heterosexual:
Non-endemic
Heterosexual:
Endemic
Other
Total
1,100-2,000
70-150
350-650
550-950
400-700
< 20
2,300-4,500
Source: CCDR. August 2006.
55
Awareness of Serostatus Among People
with HIV and Estimates of Transmission
~25%
unaware
of infection
~55% of
new infections
~75%
aware
of infection
~45% of
new infections
PLWHA
New infections each year
56
Testing and
treatment of
genital infections
(STIs)
Voluntary
Counselling and
Testing (VCT)
Microbicides
HIV
PREVENTION
Behavioural
Intervention
(ABC)
Immunisation:
Vaccines
HSV-2
Suppressive
therapy
Cervical Barriers:
vaginal
diaphragms
Male
circumcision
Exposure prophylaxis
MTCT
PEP
PrEP
Source: IAC. 2006.
57
Estimated 10-year Infection Rates
for Various HIV Prevention
Methods
Source: Cates W. HIV/AIDS Annual Updates. 2006.
58
Consistently high uptake of services at
Vancouver’s Supervised Injection Facility
Mark Tyndall, E. Wood, C. Buchner,
J. Montaner, R. Zhang, T. Kerr
University of British Columbia
BC Centre for Excellence in HIV/AIDS
CAHR - Montreal, April 2008
OVERVIEW



North America’s first sanctioned
supervised injection site (SIS) was a
response to the public health impact of
injection drug use
BC Centre for Excellence is conducting a
comprehensive evaluation of the SIS
Characteristics and drug use patterns of
those using the SIS
Health Related Consequences of illicit drug use






HIV/HCV infections
Drug overdoses
Injection-related infections
Injuries due to accidents
and violence
Emergency room visits and
acute bed use
Public disorder
North America’s First Supervised Injection Facility

Injections in a controlled setting

Provision of sterile injecting equipment

Information on safe injecting practices

Counselling and primary medical care

Referral to detox and other services
SIS Evaluation Structure
InSite
database
Cohort of
SIS users
CHASE
VIDUS
External
activities
Program Evaluation
Uptake,
overdoses
referrals,
drug use,
Survey,
HIV/HepC,
risk behavior
Linkages,
treatment,
service use
Control group, Ethnography,
Pre-SIS
community
behavioral
attitudes,
& HIV/HepC
crime
InSite Database
A comprehensive database has been set up
at Insite
 This includes a sign-in record, demographic
information, drugs used, and nursing
interventions
 Nursing / Counseling screens record
specific supports given and referrals made
 Monthly data transfers are made for
further analysis

2004
max
2005
mean
2006
min
2007
2008
Mar
Feb
Jan
Dec
Nov
Oct
S ep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
S ep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
S ep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
S ep
Aug
Jul
Jun
May
Apr
Mar
Daily Visits to Insite
Number of DailyVisits byMonth
1200
1000
800
600
400
200
0
Number of Visits by Month
25000
20000
15000
10000
5000
0
Mar
Apr
May
Jun
Jul
Aug
2004
Sep
Oct
Nov
Dec
Jan
Feb
Mar
2005
Apr
Number of Participants by Month per month
Number of participants
25002500
2000
1500
1000
500
0
Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2004
2004
2005
2006
Number of Participants Number of New Comers
2007
2008
Age Group by Gender
1400
1200
1000
800
600
400
200
0
0-19
20-29
30-39
40-49
Male
Mean ages:
Male 40.0
Female 36.0
50-59
Female
60-69
70-99
Gender and Ethnicity
Ethnicity (Fe ma le )
N=1215 (27%)
0% 2%
1%1%
25%
47%
Caucasian
Abor iginal
Asian
Black
Hispanic
Ethnicity (Male)
2%
2%
1%
Other
N=3330 (73%)
2%
10%
60%
Caucasian
Aboriginal
Asian
Black
Hispanic
Other
et
ha
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10
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.
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Drugs used at Insite
% of Substa nce s Use d by Qua rte r
0%
2004 2nd Qtr
5%
2004 3rd Qtr
10%
2004 4th Qtr
15%
20%
2005 1st Qtr
25%
30%
35%
40%
45%
50%
Number of visits to Insite per Month
% of Frequency of Injections by Month
0%
5%
10%
15%
20%
25%
30%
35%
1
2-5
6-25
26-50
51-100
100&up
May-04
Jun-04
Jul-04
Aug-04
Sep-04
Oct-04
Nov -04
Dec-04
Jan-05
Feb-05
Mar -05
Apr -05
Referrals made by the Insite Staff
Referral Programs
1. Addiction Counselling
2. Community Clinics
3. Hospital Emergency
4. Housing
5. Detox
6. Community Serv ices
7. Access One
8. Methadone
9. Recovery
10. Outpatient Serv ices
11. Mental health Serv ices
12. Emergency shelters
13. Others
Total:
2nd Qtr
121 27.9%
83 19.1%
62 14.3%
27
6.2%
45 10.4%
33
7.6%
11
2.5%
13
3.0%
17
3.9%
4
0.9%
10
2.3%
0
0.0%
8
1.8%
434
2004
3rd Qtr
126 33.2%
53 14.0%
42 11.1%
36
9.5%
26
6.9%
24
6.3%
32
8.4%
16
4.2%
12
3.2%
0
0.0%
0
0.0%
0
0.0%
12
3.2%
379
4th Qtr
251 45.3%
72 13.0%
60 10.8%
44
7.9%
20
3.6%
26
4.7%
32
5.8%
24
4.3%
14
2.5%
4
0.7%
1
0.2%
0
0.0%
6
1.1%
554
2005
1st Qtr
314
98
68
99
35
39
36
31
9
6
4
2
63
804
39.1%
12.2%
8.5%
12.3%
4.4%
4.9%
4.5%
3.9%
1.1%
0.7%
0.5%
0.2%
7.8%
Overdoses at Insite
40
35
30
25
20
15
10
5
0
M ar
A pr
M ay
J un
J ul
A ug
S ep
N o. o f O D
Overdose based on:
 Breathing slowed/stopped
 Not responding to voice
 Limp / slumped over in chair
 Face pale /cyanotic
 Passed out / seizures
Oct
N ov
D ec
J an- F e b- M a r- A pr05
05
05
05
N o. o f O D P a rtic ipants
Conclusions (1)
Transmission of HIV continues to be high
among illicit drug users in Vancouver
Catastrophic social conditions, failing
prohibition policies, and cocaine use are
the main factors that perpetuate the
HIV epidemic in the DTES
Social improvements and innovative
prevention strategies, like the SIF, need
to be initiated and evaluated.
Conclusions (2)
The first year of Insite data shows the high
uptake of this facility including new participants
each month
Women, Aboriginal people, and cocaine users
appear to be well represented
Referrals to a range of services are being made
consistently and are increasing each quarter
A minority of participants use Insite consistently
Overdoses, although relatively common, are being
managed successfully
Prevention Strategies
- Education
- Change in behaviour
- Harm reduction
-Partly effective, and underused
- New strategies/technology
- Vaccines
-None so far
Effect of HAART on HIV
Transmission
• MTCT
• Discordant Couples
• Ecological Evidence
The Impact of HAART on MTCT
Canada, 1990 - 2004
USA, 1985 - 2000
Role of maternal viral load in HIV transmission established in 1995
Effect of HAART on Heterosexual
Transmission of HIV - Spain
10
9
8
7
6
5
4
3
2
1
0
P = 0.0129 HAART
vs other options
10%
8.6%
0%
No Therapy
Mono or BI
HAART
Therapy
HAART independently associated with 86% reduction in
Castilla, et al. JAIDS 2005; 40:96-101
HIV transmission
Decreased HIV Transmission after a Policy of Providing
Free Access to Highly Active Antiretroviral Therapy in
Taiwan
JID 2004:190 (1 September), 879.
53% reduction in new + HIV tests after introduction of free HAART, with no change in syphilis rates
Rate per 100,000 population
New HIV and Syphilis in BC
25
20
HIV
Syphillis
15
10
5
0
19 19 19 19 19 19 19 19 19 20 20 20 20 20
91 92 93 94 95 96 97 98 99 00 01 02 03 04
M REKART, BC-CDC, 2006
Community plasma HIV RNA among a cohort of
injection drug users in Vancouver
Whiskers represent 95% confidence intervals.
Montaner et al, Late breaker, IAS-IAC, Mexico, August 2008
Community plasma HIV RNA levels and HIV
incidence among two parallel cohorts of IDUs
HIV incidence is expressed as incidence density per 100 person years.
Whiskers represent 95% confidence intervals.
Montaner et al, Late breaker, IAS-IAC, Mexico, August 2008
Cox proportional hazards regression of the time
to HIV infection among 1,048 HIV negative IDUs
followed between M ay 1, 1996 and Dec 31, 2004.
Relative
Hazard
95% Confidence
Interv al
p-v alue
Community Viral Load Per log10 increase
9.40
(4.28 Ğ 20.64)
< 0.001
Unsafe sex
Yes vs No
0.82
(0.56 Ğ 1.21)
0.360
Used syringe borrowing
Yes vs No
1.70
(1.15 Ğ 2.51)
0.008
Ethnicity
White vs Other
0.55
(0.39 Ğ 0.78)
< 0.001
Heroin inj ection
> Dai lyvs < daily
1.19
(0.83 Ğ 1.70)
0.349
Cocaine inj ection
> Dai lyvs < daily
2.88
(1.99 Ğ 4.17)
< 0.001
Unstable housing*
Yes vs No
1.40
(0.98 Ğ 2.02)
0.067
Characteristic
Plasma HIV R NA was time updated based on median value in the BART cohort during the 6 month
à
period prior to each HIV-negative participantÕsfollow-up visits; Defined as insertive or receptive va ginal or
anal intercourse; *Defined as living in a single room occupancy hotel, shelter, recovery or transition house,
jail, on the street, or having no fixed address;
Montaner et al, Late breaker, IAS-IAC, Mexico, August 2008
HIV among Injection Drug Users
BC, 2006 n=4770
* Based on a CD4 Cell count ≤ 200/mm3
A Proposal to Evaluate the Impact of Expanding
HAART on HIV Incidence among Injection Drug
Users in British Columbia
Intervention
3 years
Primary Endpoint
HAART Expansion
HIV Incidence*
within 2008 guidelines
Seconday Endpoints:
mortality and morbidity
HIV-1-RNA Levels
HIV resistance
CD4 cell counts
adverse events and safety labs
hospitalizations
resource utilization
adherence to HAART
* Primary analysis = HIV incidence pre-HAART expansion vs year 3
Expansion of HAART for HIV
Prevention: Challenges
 Untested hypothesis
 Safety/toxicity
 Individual rights
 Resistance
 Hidden epidemics
 Logistics
 Erosion of prevention effort
 Cost
This hypothesis needs to be urgently explored
Expansion of HAART for HIV
Prevention: Challenges
 Untested hypothesis
However, our goal is to
 Safety/toxicity
characterize changes
 Individual rights
in HIV incidence
 Resistance
resulting from
 Hidden epidemics
expanding HAART use
 Logistics
within those in medical
 Erosion of prevention effort
 Cost
need
This hypothesis needs to be urgently explored
Expansion of HAART
• HAART is not a replacement for strengthening
prevention strategies
• Reducing community viral load by widespread use
of HAART should be a part of HIV prevention
• Need to increase case finding
• Aim to increase HAART coverage among those
eligible
• Many challenges to HAART expansion include
addictions and mental illness
Acknowledgements
eSIS staff - Aaron Edie, David Isham, Suze
Coulter, Evelyn King, Megan Olsen, Soni Thindal
Insite staff -Sarah Evans, Jeff West
Health Canada
Vancouver Coastal Health