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 Africa and Middle East380,000

Sub-Saharan Africa22 million

Eastern Europe and Central Asia 1.5 million

Oceania74,000

Caribbean230,000

Southern and Southeast Asia

4.2 millionLatin America

1.7 million

UNAIDS, 2008. Available at: http://www.unaids.org.

East Asia740,000

North America1.2 million

Western/Central Europe

730,000

Total: 33 (31-36) million

3

4

Estimated Adult and Child Deaths from AIDS: 2007

5

6

Life Expectancy Five African Countries: 1970 - 2010

Canada life expectancy (2006 estimate): 80.22 years

HIV natural history

J. Coffin, XI International AIDS Conf., Vancouver, 1996

Development of Development of AIDSAIDS is like an is like an impending train wreck where: impending train wreck where: Viral Load = Viral Load = Speed of the train Speed of the train CD4 count = CD4 count = Distance from site of doomDistance from site of doom

HIVinfection

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)

Reverse Transcriptase

Inhibitors

Protease Inhibitors

Integrase Inhibitors

EntryInhibitors

Targets for HIV Inhibition

Maturation Inhibitors

ARV-induced pVL changes are associated ARV-induced pVL changes are associated with a change in the rate of CD4 declinewith a change in the rate of CD4 decline

Time, yearsTime, years

CD4CD4Low pVLLow pVL

Hi pVLHi pVL

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)

0.0

20.0

40.0

60.0

80.0

100.019

99

2001

2003

2005

2007

2009

Perc

enta

ge o

f Pa

tien

ts w

ith

pVL

<50

cop

ies

Year

V Lima, et al., CROI 2008;Poster #895

BC Data: Viral load <50 copies/mL over time(N approx. 7400 in DTP)

65% (2000)

86% (2007)

?100%(2010)

Number of New Cases of Resistance detected

0

100

200

300

400

500

600

1996

1998

2000

2002

2004

2006

2008

3TC

nRTI

PI

Any

YearV Lima, et al., CROI 2008;Poster #895

Rates of New Resistance in BC

Mantel-Haenszel trend test p = 0.001

12%

24%

47%

64%

84%

0%

25%

50%

75%

100%

<70% 70% - <80% 80% - <90% 90% - <95% 95% - 100%

Pe

rce

nt

of

Pa

rtic

ipa

nts

Wit

h p

VL

<50

0

Co

pie

s A

t L

eas

t T

wic

e

Viral Load Stratified by Adherence level

(first 12 months of therapy)

Adherence Level

Mantel-Haenszel

Trend test p = 0.001

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

Inci

den c

e /

1000

PY

/ 95

% C

I

No. of MIsPatient years

14 16 22 34 56 55 39 41 277 10,103 6,324 8,165 10,846 13,060 12,254 9,073 6,751 76,57776,577

HAART Exposure (yrs)

0

2

4

6

8

None <1 1-2 2-3 3-4 4-5 5-6 >6

El-Sadr et al, CROI 2005: Oral session #10HAART=combination antiretroviral therapy

*Adjusted for conventional risk factors not influenced by HAART

Relative rate per additional year of exposure to ART*: 1.17

(95% CI: 1.08-1.26), p<0.0001

N Engl J Med 2006

Intermittent ART

• Stop or defer when CD4 > 350 • Restart/start if CD4 < 250

Continuous ART

HIV+ with CD4 count > 350/mm3

n = 2720 n = 2752

Randomized

94% on ART 99% CD4 > 200

33% on ART96% CD4 > 200

Follow-up

84% on ART, 16% off ART

Continuous vs Intermittent HAART

0

200

400

600

800

1000

1200 Int CD4, CD4, cells/mm3

Int pVL, Kcopies/mL

0

200

400

600

800

1000

1200 Cont CD4, cells/mm3

Cont pVL, Kcopies/mL

Time

Time

Cont Int

PVL U/D Int

CD4 High OK

Cost +++ +

Deaths 0 0

OI/Ca 0 0

Non-ADI

Events

+++

Toxicity

+

QoL + +++

Endpoints of the SMART study, including cardiovascular disease

N Engl J Med 2006

SMART: Risk of serious non-AIDS events

Renal 9 2

Liver 10 7

All serious non-AIDS

CVD 48 31

Non-AIDS malignancy 27 24

Other non-AIDS death 30 16

Number of events

Intermittent Continuous ART ART

113 73

Of the 85 deaths that occurred in SMART, only 7 (8%) were from AIDS diseases

1 20.5 Hazard ratio Intermittent ART vs. Continuous ART

3 5 10

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

48

Estimated Number of People Newly Infected with HIV: 2007

49

Estimated New HIV Infections: Canada 1981 - 2005

Source: CCDR. August 2006.

50Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.

51Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.

52Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.

53Source: STI/HIV Prevention and Control, BCCDC. 2006 Annual Report.

54

HIV Rates BC: 1995-2005Total BC vs Aboriginal BC

Source: STI/HIV Prevention and Control, BCCDC. 2005 Annual Report.

55

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

  MSM MSM-IDU IDU Heterosexual:Non-endemic

Heterosexual:Endemic

Other  Total

2005 1,100-2,000 70-150 350-650 550-950 400-700 < 20 2,300-4,500

Source: CCDR. August 2006.

56

Awareness of Serostatus Among People with HIV and Estimates of Transmission

~55% of new infections

~45% of new infections

~25%unawareof infection

~75%awareof infection

PLWHA New infections each year

57

HSV-2 Suppressive

therapy

Testing and treatment of

genital infections (STIs)

Cervical Barriers: vaginal

diaphragms

Male circumcision

Exposure prophylaxis MTCT

PEPPrEP

Immunisation: Vaccines

Voluntary Counselling and Testing

(VCT)

Behavioural Intervention

(ABC)

HIV PREVENTIO

N

Microbicides

Source: IAC. 2006.

58

Estimated 10-year Infection Rates for Various HIV Prevention

Methods

Source: Cates W. HIV/AIDS Annual Updates. 2006.

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 ColumbiaBC Centre for Excellence in HIV/AIDS

CAHR - Montreal, April 2008CAHR - 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 infectionsHIV/HCV infections Drug overdosesDrug overdoses Injection-related infectionsInjection-related infections Injuries due to accidents Injuries due to accidents

and violenceand violence Emergency room visits Emergency room visits

and acute bed useand acute bed use Public disorderPublic disorder

North America’s First Supervised Injection North America’s First Supervised Injection FacilityFacility

Injections in a controlled settingInjections in a controlled setting

Provision of sterile injecting Provision of sterile injecting equipmentequipment Information on safe injecting Information on safe injecting practicespractices

Counselling and primary medical careCounselling and primary medical care

Referral to detox and other servicesReferral to detox and other services

SIS Evaluation StructureSIS Evaluation StructureInSite InSite

databasedatabase

Uptake,Uptake,overdoses overdoses referrals, referrals, drug use, drug use,

Cohort of Cohort of SIS usersSIS users

Survey,Survey,HIV/HepC,HIV/HepC,

risk behaviorrisk behavior

CHASECHASE

Linkages,Linkages,treatment,treatment,service useservice use

VIDUS VIDUS

Control group,Control group,Pre-SIS Pre-SIS

behavioralbehavioral& HIV/HepC& HIV/HepC

ExternalExternalactivitiesactivities

Ethnography,Ethnography,communitycommunityattitudes,attitudes,

crimecrime

Program EvaluationProgram Evaluation

InSite Database

A comprehensive database has been set A comprehensive database has been set up at Insiteup at Insite This includes a sign-in record, This includes a sign-in record, demographic information, drugs used, demographic information, drugs used, and nursing interventionsand nursing interventions Nursing / Counseling screens record Nursing / Counseling screens record specific supports given and referrals specific supports given and referrals mademade Monthly data transfers are made for Monthly data transfers are made for further analysisfurther analysis

Daily Visits to InsiteDaily Visits to Insite

Number of Daily Visits by Month

0

200

400

600

800

1000

1200

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 2005 2006 2007 2008

max mean min

Number of Visits by Month

0

5000

10000

15000

20000

25000

Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr

2004 2005

Number of Participants by Month

0

500

1000

1500

2000

2500

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 2005 2006 2007 2008

Number of Participants Number of New Comers

25002500

Number of participants per month

2004

Age Group by Gender

0

200

400

600

800

1000

1200

1400

0-19 20-29 30-39 40-49 50-59 60-69 70-99

Male Female

Mean ages:Mean ages:Male 40.0 Female 36.0Male 40.0 Female 36.0

Ethnicity (Female)

47%

25%

1%1%0%2%

Caucasian Aboriginal Asian Black Hispanic Other

Ethnicity (Male)

60%

10%

2% 2% 1% 2%

Caucasian Aboriginal Asian Black Hispanic Other

N=1215 (27%)N=1215 (27%)

N=3330 (73%)N=3330 (73%)

Gender and EthnicityGender and Ethnicity

Drugs used at InsiteDrugs used at Insite

% of Substances Used by Quarter

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50%

2004 2nd Qtr 2004 3rd Qtr 2004 4th Qtr 2005 1st Qtr

Number of visits to Insite per MonthNumber 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 StaffReferrals made by the Insite Staff

Referral Programs1. Addiction Counselling 121 27.9% 126 33.2% 251 45.3% 314 39.1%

2. Community Clinics 83 19.1% 53 14.0% 72 13.0% 98 12.2%

3. Hospital Emergency 62 14.3% 42 11.1% 60 10.8% 68 8.5%

4. Housing 27 6.2% 36 9.5% 44 7.9% 99 12.3%

5. Detox 45 10.4% 26 6.9% 20 3.6% 35 4.4%

6. Community Services 33 7.6% 24 6.3% 26 4.7% 39 4.9%

7. Access One 11 2.5% 32 8.4% 32 5.8% 36 4.5%8. Methadone 13 3.0% 16 4.2% 24 4.3% 31 3.9%

9. Recovery 17 3.9% 12 3.2% 14 2.5% 9 1.1%

10. Outpatient Services 4 0.9% 0 0.0% 4 0.7% 6 0.7%

11. Mental health Services 10 2.3% 0 0.0% 1 0.2% 4 0.5%

12. Emergency shelters 0 0.0% 0 0.0% 0 0.0% 2 0.2%

13. Others 8 1.8% 12 3.2% 6 1.1% 63 7.8%

Total: 434 379 554 804

2004 20052nd Qtr 3rd Qtr 4th Qtr 1st Qtr

Overdoses at Insite

0

5

10

15

20

25

30

35

40

Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan-05

Feb-05

Mar-05

Apr-05

No. of OD No. of OD Participants

Overdose based on:Overdose based on: Breathing slowed/stoppedBreathing slowed/stopped Not responding to voiceNot responding to voice Limp / slumped over in chairLimp / slumped over in chair Face pale /cyanoticFace pale /cyanotic Passed out / seizuresPassed out / seizures

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 Conclusions (1)(1)

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

Conclusions Conclusions (2)(2)

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

USA, 1985 - 2000

Canada, 1990 - 2004

Role of maternal viral load in HIV transmission established in 1995

Castilla, et al. JAIDS 2005; 40:96-101

Effect of HAART on Heterosexual Transmission of HIV - Spain

8.6%

10%

0%0123456789

10

No Therapy Mono or BITherapy

HAART

P = 0.0129 HAART vs other options

HAART independently associated with 86% reduction in 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

New HIV and Syphilis in BC

0

5

10

15

20

25

HIV

Syphillis

Rat

e p

er 1

00,0

00 p

op

ula

tio

n

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 May 1, 1996 and Dec 31, 2004.

Characteristic Relative Hazard

95% Confidence Interval

p-value

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 injection > Daily vs < daily 1.19 (0.83 Ğ 1.70) 0.349

Cocaine injection > Daily vs < daily 2.88 (1.99 Ğ 4.17) < 0.001

Unstable housing* Yes vs No 1.40 (0.98 Ğ 2.02) 0.067

  Plasma HIV R NA was time updated based on median value in the BART cohort during the 6 month period prior to each HIV-negative participantÕs follow-up visits;

àDefined as insertive or receptive vaginal 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 UsersBC, 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 hypothesisSafety/toxicity Individual rights ResistanceHidden epidemics LogisticsErosion of prevention effortCost

This hypothesis needs to be urgently explored

Expansion of HAART for HIV Prevention: Challenges

Untested hypothesisSafety/toxicity Individual rights ResistanceHidden epidemics LogisticsErosion of prevention effortCost

This hypothesis needs to be urgently explored

However, our goal is to characterize changes in HIV

incidence resulting from expanding

HAART use within those in medical need

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

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

AcknowledgementsAcknowledgements