Overview of HIV Disease Dr. Marianne Harris AIDS

Overview of HIV Disease Dr. Marianne Harris AIDS

Overview of HIV Disease Dr. Marianne Harris AIDS Research Program St. Pauls 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 Kaposis 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 dont 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 60.0 86% (2007) ?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 Incidence / 1000 PY/ 95% CI 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 +++ Toxicit y + 600 NonADI

Events 400 QoL + +++ 0 1200 1000 Int CD4, CD4, cells/mm3 Time Int pVL, Kcopies/mL

800 200 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. Pauls 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) Behavioural Intervention (ABC) Microbicides HIV PREVENTIO N 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 Vancouvers 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 Americas 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 Americas 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,

Linkages, Control group, Ethnography, Pre-SIS community HIV/HepC, treatment, behavioral attitudes, risk behavior service use & 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 M a r

F e b J a n D e c N o v O c t

S e p A u g J u l J u n M a y

A p r M a r F e b J a n D e c

N o v O c t S e p A u g J u l

J u n M a y A p r M a r F e b

J a n D e c N o v O c t S e p

A u g J u l J u n M a y A p r

M a r F e b J a n D e c N o v

O c t S e p A u g J u l J u n

M a y A p r M a r Daily Visits to Insite Number of Daily Visits by Month 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 50-59 Female Female 36.0

60-69 70-99 Gender and Ethnicity Ethnicity (Female) N=1215 (27%) 0% 2% 1%1% 25% 47% Caucasian Aboriginal Asian

Black Hispanic Ethnicity (Male) 2% 2% 1% Other N=3330 (73%) 2% 10%

60% Caucasian Aboriginal Asian Black Hispanic Other Drugs used at Insite % of Substances Used by Quarter 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 Services 7. Access One 8. Methadone 9. Recovery 10. Outpatient Services 11. Mental health Services 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 53 42 36 26 24 32 16 12 0 0 0 12 379 33.2%

14.0% 11.1% 9.5% 6.9% 6.3% 8.4% 4.2% 3.2% 0.0% 0.0% 0.0% 3.2% 4th Qtr 251 72 60 44 20 26

32 24 14 4 1 0 6 554 45.3% 13.0% 10.8% 7.9% 3.6% 4.7% 5.8% 4.3% 2.5% 0.7% 0.2%

0.0% 1.1% 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 Mar Apr May Jun Jul Aug No. of OD Sep

Oct Nov Dec No. of OD Participants Overdose based on: Breathing slowed/stopped Not responding to voice Limp / slumped over in chair Face pale /cyanotic Passed out / seizures Jan05 Feb05 Mar05

Apr05 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 10% P = 0.0129 HAART vs other options

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 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. Relative Hazard 95% Confidence Interval

p-value Commu nity Viral Load Per log10 increase 9.40 (4.28 20.64) < 0.001 Unsafe sex Yes vs No 0.82 (0.56 1.21) 0.360

Used syringe borrowing Yes vs No 1.70 (1.15 2.51) 0.008 Ethnicity White vs Other 0.55 (0.39 0.78) < 0.001 Heroin injection

> Daily vs < daily 1.19 (0.83 1.70) 0.349 Cocaine injection > Daily vs < daily 2.88 (1.99 4.17) < 0.001 Unstable housing* Yes vs No

1.40 (0.98 2.02) 0.067 Characteristic 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 participantsfollow-up visits; Defined 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 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 HAART Expansion within 2008 guidelines Primary Endpoint HIV Incidence* 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 Safety/toxicity to characterize Individual rights changes in HIV Resistance incidence resulting Hidden epidemics from expanding Logistics Erosion of prevention effortHAART use within Cost those in medical 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

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