improving adherence and survival in antiretroviral therapy programs

Improving adherence and survival in antiretroviral therapy programs

Andrew BoulleInfectious Disease Epidemiology Unit

School of Public Health and Family MedicineUniversity of Cape Town

5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009 2

Drivers of mortality on ART

Lawn. AIDS 2008

IntroductionImproving survival

Improving adherenceSummary

Determinants of on-ART mortalityExcess on-ART mortality in resource-limited settingsRelationship between programme mortality and access to careEvidence for improved survival with increased access to ARTClinical challenges associated with averting on-ART mortality


Distribution of excess mortality in population on ART - SSA

Brinkhof. PLoS Med 2009





Clinical outcomes on ART in Switzerland and South Africa

Keiser, PLoS Medicine 2008





Clinical outcomes on ART in Switzerland and South Africa

Adjusted HR for mortalityMonths 1-3: 5.9 (1.8-19.2)Months 4-24: 1.8 (0.9 – 3.5)

Keiser, PLoS Medicine 2008




South Africa

Switzerland


Possible explanations for adjusted mortality differences on ART

• Host and agent– Patients from sub-Saharan Africa treated in France

and Switzerland have equivalent survival after adjustment for later initiation of ART*

• Environment– Access to ART– Access to health care– Co-morbidities

* Breton, HIV Med, 2007; Staehelin, AIDS, 2003.





Later access to ART could result in selection bias0

510

1520

05

1015

20

0 200 400 600 800

Khayelitsha 2001 - 2005

Switzerland* 2001 - 2007

Per

cent

Baseline CD4 count (cells/µl) at ART initiation

CD4 = 200 cells/µl

* Source: Matthias Egger for the SHCS





0 50 100 150 200

2500

20

40

60

80

100

120

140

160

Med

ian

CD

4 co

unt

at s

tart

of

AR

T

0

20

40

60

80

100

120

140

160

Mea

n #

adul

ts s

tart

ed o

n A

RT

per

mon

th

2001/2 2003/4 2005/6 2007+

2001/2 12 66 23 57

2003/4 60 93 42 61

2005/6 144 110 52 85

2007+ 130 130 96 93

New adults/monthMedian baseline

CD4 - all patients

Oesophageal

candidiasis

Extra-pulmonary

tuberculosis

Adjustment for clinical severity by WHO stage may be incomplete





Important not to lose sight of pre-ART mortality

Pre-ART ART

• Raise eligibility threshold• Expand VCT • Improve wellness programmes• Improve referral systems E

nrol

men

t

Pre-Care

Enr

olm

ent





0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

months

Initial CD4<=200, No HAART Initial CD4<=200, HAART

CD4>200, No HAART CD4>200, HAART

87% of patients who died never received ART

Source: Fairall, Arch Intern Med, 2008

Mortality in HIV patients in care in the Free State Province

See update LBPED05. (Margaret May)

• 80% of deaths still pre-ART

• 12% in waiting times if CD4<25 vs. 100-200 cells/µl





Does increased enrolment reduce on-ART mortality?

n 80 248 524 4041 7694

CD4 < 50 cells/µl 51.3% 50.4% 36.8% 24.4% 19.7%

95% CI (39.8 - 62.6) (44.0 - 56.8) (32.7 - 41.1) (23.1 - 25.8) (18.8 - 20.6)

Mortality 13.1% 11.1% 8.9% 6.1% 6.3%

95% CI (6.7 - 22.2) (7.6 - 15.3) (6.7 - 11.6) (5.5 - 6.9) (5.6 - 7.1)

Loss to follow-up 0.0% 0.4% 1.8% 3.9% 4.3%95% CI (0.0 - 4.3) (0.0 - 2.0) (0.9 - 3.3) (3.4 - 4.5) (3.7 - 5.0)

0%

5%

10%

15%

20%

25%

2001 2002 2003 2004 2005

Year starting ART

Pro

po

rtio

n d

ied

or

lost

to

fo

llow

up

at

6 m

on

ths

Deaths

Losses to follow-up

Boulle, B-WHO, 2008





Mortality by year of starting ART post-linkage

logrank p=0.014

N (events)276 (40) 233 (7) 2212001/2365 (52) 307 (10) 2872003985 (95) 858 (24) 80420041557 (127) 1349 (33) 57620051969 (127) 920 (6)2006921 (32)2007

0.00

0.05

0.10

0.15

0.20

Cum

ulat

ive

mor

talit

y -

corr

ecte

d

0 1 2Duration on ART in years

2001/220032004200520062007

Corrected mortality by year, Khayelitsha cohort

2001-2007Enrolment: from <100 to 2000 adults/yearMedian baseline CD4: 43 to 131 cells/µlStage IV at start of ART: 55% to 29%




WEPED211


Clinical factors related to context• Tuberculosis

– TB treatment when starting ART is not an independent risk for higher mortality• Lawn CROI 2007; Zachariah AIDS 2006; Stringer JAMA 2006; Boulle JAMA 2008

– But, undiagnosed TB a likely contributor based on pre-ART autopsy studies. – Effective TB screening pre-ART and on ART could dramatically reduce new TB

disease early on ART (Gideon, TUPEB154)

– Presumptive treatment where strongly suspected? (Saranchuk, SAMJ 2007)

– IPT on HAART as well?– Undiagnosed drug resistance in hospitalised patients is an important

consideration in patients deteriorating on TB treatment (Pepper,PLoS One 2009)

• Kaposi’s sarcoma– 35% mortality and 25% loss to follow-up in a cohort of patients with KS starting

ART (Chu, CROI 2009, R-138)

• Cryptococcal meningitis– Cryptococcal antigen screening pre-ART in patients with low CD4 counts

identifies those at risk for incident disease on ART (Jarvis CID 2009)

• See editorial review (Lawn, Harries et al, AIDS 2008)





Programme outcomes where routine viral load is available

Excellent outcomes require a targeted approachWho to target / what to measurePragmatism



Boulle, B-WHO, 2008


Meta-analysis of DOT as an adherence intervention




Ford et al., 2009review of studies until April 2009


How do we identify who needs an intervention above

In care

Appointments on time

All doses and doses on time

Viral load suppressed

Pharmacy recall(Bisson PLoS Med 2009, Nachega Ann Intern Med 2007)

Self-report Pill counts

Electronic medication monitoring

Viral load





Conserving first line therapy




Orrell, Antivir Ther, 2007


Missed opportunities to do the sensible things

Policy– Clinical guidelines and regimen choice

• Adequate data on pill burden and toxicity therefore we need new regimens– Drug procurement and distribution

• Unprecedented leverage due to volume• Incomprehensible that we do not have 28 day packs, blistered to obviate the need for

pillboxes• Distribution chain already assured, why not use for adherence promotion material

– Health systems• Primary care location of treatment (Bedelu JAIDS 2007)

Target interventions– Seek to identify patients with early viraemia– At-risk populations

• Pregnant women (Kaplan, AIDS 2008)• Young adults and adolescents• Substance abuse / depression / marginalised groups• Men?





• Expanded access to ART the single most important factor in reducing ART programme mortality

• Targeting both clinical and adherence interventions is required given the scale of the service, and the excellent clinical and adherence outcomes in the majority of patients.

• Adequate technologies are required such as expanded access to viral load measures and improved tuberculosis diagnostics

• There are aspects to ART delivery which are likely to promote adherence and retention in care and which do not further burden the health services



Summary


Acknowledgements

Gary MaartensMatthias EggerNathan FordEric GoemaereGraeme MeintjesGilles Van CutsemDavid CoetzeeKatherine HilderbrandMeg OslerLouise KnightKathryn StinsonChris KenyonRobert WilkinsonMolebogeng Rangaka


Questions?

improving adherence and survival in antiretroviral therapy programs

Documents

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