morbidity and mortality in the haart era andrew phillips royal free & university college medical...
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Morbidity and Mortality in the HAART era
Andrew PhillipsRoyal Free & University College Medical SchoolLondon
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Death in the HAART era: rates and reasons
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Trends in death rate: HOPS
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Trends in death rate over calendar time in UK
Source: HPA
0
2
4
6
8
10
Number of deaths in year Number seen for care in year
1481 749 514 472 484 477 520 572 495 539 497Deaths
Seen for care(thousands,rounded)
15 16 18 20 22 26 32 36 41 46 52
96 97 98 99 00 01 02 03 04 05 06
Year
Rate per100 people
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Breakdown of causes of death: France 2005
Lewden et al, CROI 2007
0 5 10 15 20 25 30 35 40
AIDS Cancer Hepatitis C CVD Suicide Non-AIDS infection Accident Hepatitis B Liver disease OD / drug abuse neurologic renal pulmonary digestive iatrogenic metabolic psychiatric other unknown
Percent
N = 937 deaths
ANRS EN19 Mortalité 2005
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Audit of 397 deaths in UK 2005: Scenario leading to AIDS-related deaths
BHIVA Audit – Johnson et al 2006
Scenario % of AIDS deaths
Diagnosed too late for effective treatment 40%
Under care, but with untreatable complication 29%
Treatment ineffective due to poor adherence 12%
Chose not to receive treatment 8%
Known HIV, not under regular care, 6%re-presented too late
MDR HIV, ran out of options 5%
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Incidence of non-AIDS death 1994-2004
0
1
2
3
4
5
6
7
8
9
10Rate per 100 personyears
Year
Test for trend: p < 0.0001
(excluding death from unknown causes)
95 96 97 98 99 00 01 02 03 04
EuroSIDA; Mocroft, Lundgren et al, personal communication
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Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?
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Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?
Incidence of, and death from:
- Non-AIDS malignancies
- End stage renal disease
- Cardiovascular events
- Liver cirrhosis
- Deaths from other non-AIDS causes
- Not focussing on adverse effects of ART
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Possible mechanisms: General
- Very early loss of CD4 T cells in gastrointestinal tract
- Loss of immunological and epithelial integrity of the mucosal barrier – leading to microbial translocation
- Generalized immune activation
- Fibrosis of lymphatic tissue
Veazey et al, Science 1998 Brenchley et al, Nature Med 2006Brenchley, J Exp Med 2004 Schacker et al, Clin Vacc Immunol 2006
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Possible mechanisms: Non-AIDS malignancies
Immunodeficiency, leading to:
- reduced control of oncogenic pathogens
- damage due to infections and resulting chronic inflammation
- loss of ability to identify transformed cells
Littman et al. Cancer Epidemiol Biomarkers Prev 2005
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Possible mechanisms:Kidney disease- HIV associated nephropathy (HIVAN) (viral nephritis reversed by ART)
- Link with other kidney pathologies (e.g. immune complex glomerulonephritis)
- High prevalence of proteinuria, associated with HIV RNA level and CD4 count
- HIV RNA and CD4 count predict raised creatinine levels
- proteinurea & elevated creatinine associated with all cause mortality in HIV patients
Szczech et al, Kidney International 2002 Lucas et al, AIDS 2004Szczech et al, Kidney International 2004 Kimmel et al, Ann Intern Med 2003
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Possible mechanisms:Cardiovascular diseaseAssociation of HIV-infection with adverse changes in known or potential biomarkers forCVD.
- HDL-cholesterol depletion
- Inflammation (raised IL-6, C-reactive protein)
- Endothelial activation/dysfunction (VCAM, ICAM)
- Activation of coagulation (D-dimer)
Several of the changes appear to be at least partially reversed by ART
Riddler JAMA 2003 de Larranaga et al, Blood Coag. & Fibrinolys 2003Lau et al, Arch Intern Med 2006 Wolf et al, J Infect Dis 2002
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Possible mechanisms:Liver disease
- immunodeficiency linked to more rapid progression of liver fibrosis in HBV and HCV infected people - affect CD4+ and CD8+ response to HBV / HCV
- alter HBV / HCV quasi-species
- increased hepatocyte apoptosis
Tan et al, Current HIV research 2006 Thio et al, Lancet 2002Eyster et al, JAIDS 1993 Soto et al, J Hepatol 1997
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Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?
Types of evidence
comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected people
studies of the association between CD4 count
(and HIV RNA) and risk of serious non-AIDS events
randomized trials of the impact on serious non- AIDS events of reduction in HIV RNA level and increase in CD4 count with ART
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Comparison of risk of events between HIV-infected and HIV-uninfected people: limitations
- HIV -ve comparison group will differ from HIV-infected group in more ways than just the HIV infection (eg smoking)
Adjustment for such confounding bias may not be possible.
Each non-AIDS condition has its own set of risk factors which could act differently in HIV-infected people.
- HIV infected subjects often mixture of those on ART and ART-naïve, so not possible in all studies to distinguish effect of HIV from effect of ART.
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For 20 / 28 cancers examined there was significantly increased incidencein both groups – strongly suggesting a link with immunodeficiency
Standardized Incidence Ratio
HIV/AIDS Transplant
Lung 2.7 2.2Leukaemia 3.2 2.4Kidney 1.5 6.8Oesophagus 1.6 3.1Stomach 1.9 2.0
Meta-analysis: 444,172 people with HIV, 31,977 transplant patients
Grulich et al, Lancet 2007
HIV and risk of non-AIDS malignancies
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CID 2007
AIDS 2007
HIV and risk of lung cancer, independent of smoking
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Hazard ratio for End Stage Renal Disease
# people # ESRD Hazard ratio*
White HIV -ve 1,201,870 3991 1.0 HIV +ve 6,139 13 0.8 (0.5 – 1.3)
Black HIV -ve 206,636 1425 2.0 (1.9 – 2.2) HIV +ve 6,816 129 4.6 (3.4 – 6.1)
*Adjusted for age, sex, baseline eGFR category, CAD, HTN, heart failure, COPD, PVD, HCV infection, cerebrovascular disease, and SES.
Little effect of HIV in diabetics
Choi et al J Am Soc Nephr 2007
U.S. Veterans without diabetes
HIV and risk of End Stage Renal disease
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HIV and Cardiovascular Disease
Subject source N CVD Risk in HIV +cases in vs. HIV –ve HIV +
Klein Administrative & 72 Increasedclinical managementdatabase
Mary-Krause HIV cohort / 60 Increased in thosegeneral population with > 18 m PI use
Currier Adminstrative 1360 Increased atdatabase younger ages
Triant Patient Data 189 IncreasedRegistry
Klein et al, JAIDS 2002 Mary-Krause et al, AIDS 2003Currier et al, JAIDS 2003 Triant et al, J Clin Endocrin Metab 2007
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HIV (and haemophilia) status 25 year cumulative risk
of liver death
Severe haemophilia, not HIV 1.4 (0.7 – 3.0)
Moderate / mild haemophilia, not HIV 1.2 (0.5 – 2.6)
HIV-infected (all haemophilia severities) 6.5 (4.5 – 9.5)
HIV and Liver disease
4865 men and boys with haemophilia (and probable HCV infection),of whom 1218 HIV-infected
Darby et al, Lancet 1997Similarly for HBV in MACS – Thio et al, Lancet 2002
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All cause death rates in ART-naïve patients with CD4 count > 350 /mm3, compared with the general population
Abstract N-264 Wednesday 10.30 - Lodwick et al
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Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?
Types of evidence
comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected
people
studies of the association between CD4 count
(and HIV RNA) and risk of serious non-AIDS events
randomized trials of the impact on serious non- AIDS events of reduction in HIV RNA level and increase in CD4 count with ART
![Page 24: Morbidity and Mortality in the HAART era Andrew Phillips Royal Free & University College Medical School London](https://reader030.vdocuments.us/reader030/viewer/2022032800/56649d2a5503460f949fef10/html5/thumbnails/24.jpg)
CD4 count and risk of death: DAD and CASCADE
200 – 350 – > 500 349 499
CD4 count (/mm3)
DAD
Rate
/ 100 personyears
95% CI
Non-AIDS causes All causes
CASCADE(ART-naïve)
Weber at al Marin et al
0.0
0.4
0.8
1.2
1.6
0.0
0.4
0.8
1.2
1.6
200 – 350 – > 500 349 499
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Bonnet et al, HIV Medicine 2007
Number of hospitalizations Number (mean per patient) during 2000-2004
CD4 count of patients
> 500 2442 16 (0.01) 335 (0.14) 351 (0.14)
200-499 2922 60 (0.02) 581 (0.20) 641 (0.22)
< 200 1229 260 (0.21) 439 (0.36) 699 (0.57)
Hospitalization events according to cause and CD4 count: Aquitaine cohort, 2000-2004
3863 patients
AIDS non-AIDS All
p < 0.001 p < 0.001
ANRS C03 Aquitaine Cohort
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1.0 1.5
Renal
Liver
All serious non-AIDS
HIV RNA and risk of serious non-AIDS events: SMART
CVD
Non-AIDS malignancy
Other non-AIDS death
Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count
0.50.2
SMART, unpublished
Adjusted hazard ratio < 400 vs. > 400 copies/mL
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Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?
Types of evidence
comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected
people
studies of the association between CD4 count
(and HIV RNA) and risk of serious non-AIDS events
randomized trials of the impact on serious non- AIDS events of reduction in HIV RNA level and increase in CD4 count with ART
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Intermittent ART
Stop or defer ART whenCD4 count > 350, restart or start ART when CD4 count < 250
Continuous ART
Participants with CD4 count > 350
n = 2720 n = 2752
N Engl J Med 2006
Randomization
94% on ART 99% CD4 > 200
33% on ART96% CD4 > 200
Follow-up
84% on ART, 16% off ART
SMART Study
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Risk of serious non-AIDS events in SMART
SMART Study Group, NEJM 2006 & Neaton et al, Current Opinion in HIV/AIDS 2008
1 2
Renal 9 2
Liver 10 7
All serious non-AIDS
CVD 48 31
Non-AIDS malignancy 27 24
Other non-AIDS death 30 16
0.5 Hazard ratio Intermittent ART vs. Continuous ART
Number of events
Intermittent Continuous ART ART
3 5 10
113 73
Of the 85 deaths that occurred in SMART, only 7 (8%) were from AIDS diseases
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Number of events Hazard ratio Deferred vs.Deferred Immediate Immediate ARTART ART (95% CI) p-value
12 2 7.02 (1.57 – 31.4) 0.01
N = 477 patients
Risk of serious non-AIDS events in SMART: patients ART naïve or off ART for > 6 months
Emery et al, JID (in press)
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Inflammatory and coagulation markers in SMART
Abstract D-60 Wednesday 10.00 – Kuller et al
- Illustrates value of biomarker studies based on stored samples from a randomized trial with clinical endpoints
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Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?
Summary
- On balance, evidence suggests HIV may well play a role in several serious non-AIDS defining events.
- In the upper CD4 count range, while overall risk of any disease is relatively low, non-AIDS events are much more common than AIDS events. - Given the associations with latest level of CD4 count / HIV RNA and the results from SMART use of ART may well reduce risk of some serious non-AIDS events.
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What steps can we take towards further reduction in morbidity and
mortality ?
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What steps can we take towards further reduction in morbidity and mortality ?
- Continued efforts to diagnose HIV as early as possible
- Research into prediction of non-AIDS events in context of HIV
- ART-naïve and ART-treated - standardize diagnostic criteria and data collection methods
- Trial of ART initiation in people with CD4 count > 500 /mm3
- non-AIDS diseases relatively common at higher CD4 count - SMART suggests risk / benefits of ART favour benefit - durable virological benefit of current ART - cost-effectiveness / reduction in transmission risk - basis for identifying biomarkers that mediate raised risk, providing insights into mechanisms (also beyond HIV)
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Conclusions
- The study of serious non-AIDS conditions is an important emerging area for HIV research
- Research is needed to provide a basis for defining models of care for people with HIV which take into account the risk of all serious conditions - Research into mechanisms by which HIV affects risk of non- AIDS conditions is needed, and it may help us understand more about the causes of such conditions outside HIV
- The possibility that ART should be initiated much earlier should be investigated in a randomized trial. Such a trial will form a key resource for this new research area.
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Acknowledgements
Jens Lundgren, Jim Neaton
HIV Epidemiology & Biostatistics Group, Royal Free, UCLCaroline Sabin, Amanda Mocroft, Fiona Lampe, Alessandro Cozz-Lepri, Colette Smith, Zoe Fox, Wendy Bannister, Loveleen Bansi, Rebecca Lodwick, Joanne Reekie
DAD (Aquitaine, Nice, CPCRA, EuroSIDA, ICONA,SHCS, Brussels, BASS, AHOD, ATHENA, HivBivus)EuroSIDASMART FIRSTCASCADEHOPS
Extra analyses: Jacquie Neuhaus (SMART), Grace Peng, Jason Baker (FIRST), Benoit Marin, Genevieve Chene, Abdel Babiker (CASCADE), Colette Smith, Caroline Sabin (DAD), Amanda Mocroft (EuroSIDA)