Toronto I-II 4:00 pm The use and misuse of cohort studies in guiding care
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Transcript of Toronto I-II 4:00 pm The use and misuse of cohort studies in guiding care
Toronto I-II 4:00 pm
The use and misuse of cohort studies in guiding care
Jens LundgrenProfessor in the Department of International Health, Immunology and Microbiology at the University of Copenhagen and coordinator of theDAD study (Data Collection on Adverse Events of Anti-HIV Drugs)
Moderator: Colin KovaksAssistant Professor, Department of Medicine, University of Toronto, and a primary care physician currently practicing at the Maple Leaf Medical Clinic in Toronto
Use (and misuse) of cohort studies to inform treatment decisions
OHTN Research Conference 2013, Toronto17th November 2013
Professor Jens D. Lundgren MD DMScCopenhagen HIV Programme
Department of Infectious Diseases, Rigshospitalet, University of Copenhagen
Denmark
We all know !
• Zidovudine monotherapy should be used in early HIV• ART should be deferred to CD4 < 200 cells/µL• ART interruptions are healthy• d4T + ddI is a atoxic combination of ARV’s• IL-2 should be provided to well suppressed pts
remaining with a low CD4 count• Tenofovir does not adversely affect kidney function• Atazanavir/r causes no other adverse drug reaction
that increased levels of bilirubin
Expert opinion is a hall-mark of HIV medicine !Error rectified by continued research
HIV epidemic in eastern Europe and central Asia the fastest growing in the world:
Estimated number of people living with HIV in WHO-EURO Region, 1990-2011
Source: UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2012.
0.0200,000.0400,000.0600,000.0800,000.0
1,000,000.01,200,000.01,400,000.01,600,000.01,800,000.02,000,000.02,200,000.02,400,000.02,600,000.02,800,000.03,000,000.0
WHO European Region (total estimated)2.4 million
Eastern Europe and central Asia1.5 million
Western and central Europe860 000
The number of new cases of HIV infection in Russian citizens, 1987 -
2009
UNAIDS Country Report
*
*: numbers continue to increase in 2010/11 (app 70,000)20-25 million HIV tests per year – www. hivrussia.org
Infection increasing faster than treatment:
WHO European Region, 1985–2011
0200400600800
1 0001 2001 4001 6001 800
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
HIVAIDSAIDS deathsPeople on ART
Sources: ECDC/WHO. HIV/AIDS surveillance in Europe 2011. Stockholm: ECDC; 2012; Federal Scientific and Methodological Center for the Prevention and Control of AIDS, Russian Federation; Ukrainian AIDS Centre,
Ukraine; WHO/UNICEF/UNAIDS monitoring and reporting on the Health Sector Response to HIV/AIDS.
(diagnosed)
Treatment cascade in Europe
Infect
ed
Diagno
sed
In car
e*
On ART
Fully
suppre
ssed
0102030405060708090
100
All EuropeWestern EEastern E
% o
f all
infe
cted
*: incomplete data on number of persons in care in Eastern Europe
Durability of HIV suppression*: the key indicator to benchmark for good
ART care
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110.0
20.0
40.0
60.0
80.0
100.0South Central West NorthCentral East East
Prop
ortio
n of
FU
whe
re >
90%
FU
has
VL
< 50
0
*: % of follow-up (FU) on ART where >90% FU has VL < 500 EuroSIDA (unpublished)
Late presentation by year of presentation
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010/11
0
25
50
75
100
0
100
200
300
400
LPadvanced immunode-ficiencyAIDS
LP : CD4 < 350/AIDS; advanced immunodeficiency : CD4 < 200/AIDSN 7367 7404 8046 7756 8591 8663 8251 8618 9057 7548 3223
Year of presentation
Prop
ortio
n
Med
ian
CD4
at p
rese
ntat
ion
Crude odds ratio 0.96 (0.95 – 0.97) per calendar yearCrude odds ratio 0.95 (0.94 – 0.96) per calendar yearCrude odds ratio 0.94 (0.93 – 0.95) per calendar yearCrude 4.4 (3.8 – 5.0/mm3) per year increase in CD4 at presentation
COHERE: Mocroft et al, PLoS Med 2013
Testing strategies
• Existing approach• Self referral• Selected clinics in health system (ID, STD)
• Future approach• Community testing (ensure transferral to
care)• Provider-initiated testing
• Indicator conditions (in any clinic or general practitioner seeing persons with such conditions)
– Mononucleose-like illness, TB, viral hepatitis, STD, psoriasis, cervical dysplasia, esophageal candidiasis, malignant lymphoma, etc
Focus to get general practitioners
to test persons presenting with indicators
routinely
Guidelines Changebut not in Synchrony
De Cock & El-Sadr, NEJM 20132013
When to START ART ?
Benefit toIndividual vs
individuals sexual partner vs
societal benefit
Use of ART to reduce transmission:
CD4 threshold vs coverage• Main determinant is coverage• If all infected on ART - very few transmissions• Realistic goal: rate of reproduction should be
below 1• Required coverage remains to be defined• If most transmissions occur prior to diagnosis,
elevating CD4 count for when to start ART will not be effective• Testing strategies are critical• If source of infection is often very recently infected
persons, not even the best testing strategy will work
Potential impact of cART on epidemic
Granich RM et al. Lancet 2009
Potential impact of cART on epidemic
Granich RM et al. Lancet 2009;373:48-57; Montaner JS. TasP-Workshop, Vancouver 2012.
Early vs delayed* ART of HIV+ persons living in sexual relationship with HIV-
person: HPTN 052
*: Early = CD4 350-550 cells/µL; delayed = CD4 < 250 cells/µL Cohen et al, NEJM 2011
Risk of HIV infection for HIV neg
In 28 of 38 infections, virus wasgenetically linked to virus from HIV+
HR=0.11 (0.04-0.33)Most :HeterosexualReported use of condoms
Uknowns from study: IDU ?No condoms ?MSM ? Population benefit ?
HIV among MSM in the UK – increasing incidence despite extensive ART coverage
• Observed increases in HIV incidence in last 10 years despite gradual larger ART coverage
• More condom-less sexual behaviour
Phillips et al. PLoS One 2013
00.20.40.60.8
11.21.41.61.8
2
1980 1985 1990 1995 2000 2005 2010
Observed
Without condomuse from 2000
Incidence (per 100 person-years)
HIV incidence in the UK among MSM:observed or if condom use ceased in
2000
Phillips et al. PLoS One 2013
Pilcher et al JID 2004; 189:1785–92Weeks after infection
2016 1814121086420
5%
4%
3%
2%
1%
0%
Tran
smis
sion
ris
k pe
r se
xual
act
When does HIV transmission occur?The role of primary HIV Infection
HIV among MSM in the UK – source of most new infections are from undiagnosed men:
more testing = less new infections
• Observed increases in HIV incidence in last 10 years despite gradual larger ART coverage
• More condom-less sexual behaviour• Source of new infections in 2010:
• 82% undiagnosed infection; diagnosed ART naive 10%, diagnosed ART experienced 7%
• If testing frequency increased to 68% of all MSM/yr (compared with currently 25%/yr)• Incidence projected to be reduced by 25%
Phillips et al. PLoS One 2013
CASCADE: Lodi et al; JID 2011
Natural history of HIV: CD4 count distributionaccording to time from infection
First, do no harm
• Primum non nocere• The doctor should not prescribe
medications unless s/he knows that the treatment is unlikely to be harmful
Doctor oath, year 1200
The case why early ART may cause net harm ?
• Low risk of morbidity and mortality in early HIV without ART• In particular among younger persons
• Overrepresented among persons with early HIV
• If ART is of benefit, high NNTB• ART may adversely affect several organ
functions• Risk is low – high NNTH
• If NNTH > NNTB = ART of net harm
• If correct (we will know in next 3-4 yrs) – major implications
HPTN 052 Update: Grinsztejn et al, WAC, July 2012
Non-AIDS events 9 12Diabetes mellitus 5 4Non AIDS malignancy 3 3Cardiovascular/Vascular 1 3Serious liver disease 0 2End stage renal disease 0 0
Number of subjects experiencing >1 eventDelayed Immediate
Any Primary event 77 (9%) 57 (6%)AIDS event 61 40Deaths 15 11Primary event associated 4 1Deaths from other causes 11 10
HR =1.37 ( 0.97 - 1.93 )
ART Initiation in Delayed Arm: 24% - CD4 count 229 (IQR: 197-249)
Do results support initiation of cART at CD4 >350 cells/mm3?
>550 450-559
350-449
250-349
<250
CD4 strata (cells/mm3)
Even
t ra
te
>550 450-559
350-449
250-349
<250
CD4 strata (cells/mm3)
Even
t ra
te
http://www.biomedcentral.com/1741-7015/11/148
It is the deferral strategy that defines the result of
a RCT of WTS ART(not the immediate)
Characteristics at entry and deferral strategies from RCTs
comparing deferred vs. immediate initiation of ART in ART-naive HIV+
persons Study Sample size
Median baseline
CD4 count(cells/ µL)
Deferral Strategy Median CD4 count at ART initiation in
the deferred armSMART 249 437 ART deferred until:
1. CD4 declined to < 250 cells/µL
2. CD4 percentage declined to < 15%
3. Symptoms of HIV disease developed
245
CIPRA HT-001
816 281 ART deferred until:1. CD4 declined to ≤ 200
cells/µL2. AIDS-defining illness
developed
166
HPNT 052
1761 428 ART deferred until:1. CD4 declined to ≤ 250
cells/µL2. AIDS-defining illness
developed
229
When to start ART ?Ability to provide a safe deferral strategy
1 Rosen et al, Plos Med 2011; Severe et al, NEJM 2010
Safe deferral strategy
Unsafe deferral strategy
Retention in care good poorAccess to repeat CD4 counts at sensible intervals
good poor
Diagnosed above CD4 treshold starts ART
As intended Later than intended
Consequences Deferral is possible to when evidence
document that benefits outweights harm from starting
ART
Earlier initiation of AT may outweigh
consequences of this unsafe deferral
strategy
Survival after ART initiated at different CD4 count levels between 200-500: ”causal”
modelling
The HIV-CAUSAL Collaboration, Ann Intern Med 2011
Proportionsurviving
”Use of more stingent criteria [e.g. GRADE], would likely reach the conclusion that evidence
insufficient to make firm recommendations[for starting ART at CD4 of 500 vs deferring to
350 cells/µL].”None of the studies reliable assessed non-fatal
potential harm.
The choice to make for asymptomatic treatment naïve patients
Start ART Start ART Start ART
Prognostic evaluation
Prognostic evaluation
Prognostic evaluation
Talk in 2003
Data Released from WHO-lead meta-analysis
Guideline AIDS or HIV-
Related Symptoms
CD4+ Cell Count
< 200/mm3
CD4+ Cell Count 200-350/mm3
CD4+ Cell Count 350-500/mm3
CD4+ Cell Count > 500
cells/mm3
DHHS-USA, 2013 Yes Yes Yes Yes1 Yes2
International AIDS Society-USA, 2012
Yes Yes Yes Yes1 Yes2
British HIV Association, 2012
Yes Yes Yes Defer 3 Defer3
European AIDS Clinical Society, 2013
Yes Yes Yes Consider3 Consider3
World Health Organization, 2013
Yes Yes Yes Consider4 Defer5(1) Strong strength recommendation based on observational data (A-II)(2) Moderate strength recommendation based on expert opinion (B-III).(3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-AIDS cancers and serodiscordant couples
(4) But treat individuals with CD4 < 350 a priority.(5) But treat all HIV+ pregnant women ,TB co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls
Major Guidelines for ART Initiation
Where is the evidence?
Observational Analyses of Outcome From Deferred vs Immediate ART:
Lack of Consistency
StudyCD4
comparison (cells/mm3)
Relative Hazard (deferred vs. immediate)(95% confidence interval)
AIDS/all-cause mortality
All-cause mortality
NA-ACCORD (NEJM 2009)
<500 vs. >500 n/a 1.94 (1.37, 2.79)<350 vs. 351-
500n/a 1.69 (1.26, 2.26)
When to Start (Lancet 2009)
351-450 vs. 451-550
0.99 (0.76, 1.29) 0.93 (0.60, 1.44)
251-350 vs. 351-450
1.28 (1.04, 1.57) 1.13 (0.80, 1.60)
CASCADE Collaboration (Arch Intern Med 2011)
<500 cs. 500-799 0.91 (0.56, 1.49) 0.98 (0.47, 2.04)<350 vs. 350-
4991.33 (0.88, 2.04) 1.96 (1.25, 3.03)
HIV-CAUSAL (AIM 2011)
<350 vs. 351-500
1.38 (1.23, 1.56) 1.01 (0.84, 1.22)
Transmission on ART – low or zero ?:largely unknown for anal sex
http://www.biomedcentral.com/1741-7015/11/148
Modest evidence to start ART when CD4 < 250/200 cells/µL
D:A:D Lancet 2008
Unanticipated association between abacavir useand raised risk of myocardial infarction
ART exposure and AIDS- and non-AIDS-defining cancer
Adjusted for age, sex, cohort, HIV mode of acquisition, ethnic group, calendar year, body mass index, any prior cancer, prior AIDS diagnosis, prior AIDS cancer, smoking status, HCV and HBV status
AIDS-defining cancer (n = 1,151) Non-AIDS-defining cancer (n = 1,091)
aRR
and
95%
CI
0.8
1.1
1.0
Any cART PI NNRTI0.8
ART exposure (/year)
1.1
1.0
Any cART PI NNRTI0.8
aRR
and
95%
CI
ART exposure (/year)
D:A:D: Bruyand et al CROI 2013 Also Chao et al, AIDS 2012, Piketty et al J Clin Oncol 2012
Acknowledgements
• RFH group: A Phillips, A Mocroft, C Sabin, F Nakagawa, F Lampe, L Shepherd, D Grint, A Schultze, et al
• CHIP: O Kirk, L Peters, L Ryom, J Grarup, D Podlekareva, D Raben, M Mansfield, J Lazarus et al
• WHO-EURO: M Donoghoe, I Eramova, B Drachmann, et al
• J Rockstroh, G Faetkenheuer• EuroSIDA for EuroCoord colleagues last 20 years
What’s next?6:30 p.m. Reception/Networking
(Foyer)