International Epidemiologic Databases to Evaluate AIDS East Africa IeDEA Executive Committee meeting May 4-5, 2010 Zanzibar Patient retention and losses

International Epidemiologic Databases to Evaluate AIDS

East Africa IeDEA Executive Committee meetingMay 4-5, 2010

Zanzibar

Patient retention and losses to follow-up

Cumulative mortality & ascertainment bias

6.4%124 deaths 2236 PY

2.3%41 deaths in 1508 PY

1.8%414 deaths in 20532 PY

P Braitstein, M Brinkhof, et al. The Lancet 367(9513): 817-824. 2006

Outline

1. LTFU in HIV-infected adults1. Men vs. Women

2. LTFU in HIV-infected and HIV-exposed children1. Outcomes of children LTFU

2. Implications for mortality estimates

3. Impact of outreach strategies on retention

The USAID-AMPATH Partnership

• 25 parent clinics• 23 satellites

• ~110,000 patients enrolled• Enrolling1200/mth • > 66,000 active patients

• 21% <14 years• 56% on cART•Active Outreach Program using peer phone calls and home visits

Cumulative Patients Enrolled: Nov ’01 – Feb ‘09

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INFLUENCE OF GENDER ON LOSS TO FOLLOW-UP IN A LARGE HIV TREATMENT PROGRAMME IN WESTERN KENYA

VO Ochieng , D Ochieng, J Sidle, M Holdsworth, AM Siika, M Owiti, S Kimaiyo, KK Wools-Kaloustian, C Yiannoutsos , and P Braitstein.

Bulletin of the WHO (epub 16 April, 2010)

Methods 1

• Patient inclusion:– aged ≥14 years– enrolled between Nov 2001 and Nov 2007

• LTFU defined:– being absent from the clinic for >3 months if on cART – being absent from the clinic for >6 months if not on

cART

Methods 2

• Incidence rates: – With and without at least 1 day of follow-up– From date of enrolment into the program

• Overall• Pre-cART (censored at date of cART initiation)

– From date of cART initiation– Presented per 100 person-years

• Analysis– Kaplan-Meier & Cox Regression methods

– Event date: date of last visit if definition of LTFU met by close of database

– Censor date: date of death or last visit

Events & Person-Years

Number of LTFU events

Person-years of follow-up

From enrolmentincluding those with

zero days of follow-up

12,935 51,574

From enrolment ≥ 1 day of follow-up

10,744 51,574

Pre-cART (≥ 1 day of follow-up)

5497 20,214

Post-cART (≥ 1 day of follow-up)

4382 31,383

Incidence Rates (IR) per 100 py

IR (95% CI)

Overall

IR (95% CI)

Men

IR (95% CI)

WomenFrom enrolment

including those with zero days of follow-up

25.1(24.7 – 25.5)

28.1(27.3 – 29.0)

23.8(23.3 – 24.3)


27.2(26.5 – 27.9)

32.7(31.2 – 34.2)

25.2(24.4 – 26.0)


14.0(13.6 - 14.4)

15.0(14.3 – 15.8)

13.5 (13.0 – 14.0)

IR (95% CI)

Overall

IR (95% CI)

Men

IR (95% CI)

WomenFrom enrolment


25.1(24.7 – 25.5)

28.1(27.3 – 29.0)

23.8(23.3 – 24.3)


27.2(26.5 – 27.9)

32.7(31.2 – 34.2)

25.2(24.4 – 26.0)


14.0(13.6 - 14.4)

15.0(14.3 – 15.8)

13.5 (13.0 – 14.0)

Incidence Rates (IR)

IR (95% CI)

Overall

IR (95% CI)

Men

IR (95% CI)

WomenFrom enrolment


25.1(24.7 – 25.5)

28.1(27.3 – 29.0)

23.8(23.3 – 24.3)


27.2(26.5 – 27.9)

32.7(31.2 – 34.2)

25.2(24.4 – 26.0)


14.0(13.6 - 14.4)

15.0(14.3 – 15.8)

13.5 (13.0 – 14.0)


IR (95% CI)

Overall

IR (95% CI)

Men

IR (95% CI)

WomenFrom enrolment


25.1(24.7 – 25.5)

28.1(27.3 – 29.0)

23.8(23.3 – 24.3)


27.2(26.5 – 27.9)

32.7(31.2 – 34.2)

25.2(24.4 – 26.0)


14.0(13.6 - 14.4)

15.0(14.3 – 15.8)

13.5 (13.0 – 14.0)


Predictors of Loss to Follow-up

Zero days of FUP AOR (95% CI)

N=29.376

Pre-cART AHR (95%CI)

N=42,903

Post-cART AHR (95% CI)

N=20,329

Men vs. Women 1.42 (1.19-1.70)

1.27 (1.19-1.36)

1.24 (1.15-1.33)



N=29.376


N=42,903

Post- cART AHR (95% CI)

N=20,329

Men vs. Women 1.42 (1.19-1.70)

1.27 (1.19-1.36)

1.24 (1.15-1.33)

Age (≥36.2 y vs. <36.2)

0.46 (0.39-0.55)

0.64 (0.60-0.68)

0.59 (0.55-0.64)


N=29.376


N=42,903


N=20,329

Men vs. Women 1.42 (1.19-1.70)

1.27 (1.19-1.36)

1.24 (1.15-1.33)

Age (≥36.2 y vs. <36.2)

0.46 (0.39-0.55)

0.64 (0.60-0.68)

0.59 (0.55-0.64)

Disclosure (yes vs. no)

0.61 (0.52-0.72)

0.81 (0.77-0.87)

0.91 (0.85-0.98)



N=29.376


N=42,903


N=20,329

Men vs. Women 1.42 (1.19-1.70)

1.27 (1.19-1.36)

1.24 (1.15-1.33)

Age (≥36.2 y vs. <36.2)

0.46 (0.39-0.55)

0.64 (0.60-0.68)

0.59 (0.55-0.64)


0.61 (0.52-0.72)

0.81 (0.77-0.87)

0.91 (0.85-0.98)

Travel ≥1 hr to clinic (yes vs. no)

1.04 (0.88-1.23)

1.06 (0.99-1.13)

1.11 (1.04-1.19)



N=29.376


N=42,903


N=20,329

Men vs. Women 1.42 (1.19-1.70)

1.27 (1.19-1.36)

1.24 (1.15-1.33)

Age (≥36.2 y vs. <36.2)

0.46 (0.39-0.55)

0.64 (0.60-0.68)

0.59 (0.55-0.64)


0.61 (0.52-0.72)

0.81 (0.77-0.87)

0.91 (0.85-0.98)


1.04 (0.88-1.23)

1.06 (0.99-1.13)

1.11 (1.04-1.19)

Ever received cART (yes vs. no)

0.07 (0.06-0.09)

- -



N=29.376


N=42,903


N=20,329

Men vs. Women 1.42 (1.19-1.70)

1.27 (1.19-1.36)

1.24 (1.15-1.33)

Age (≥36.2 y vs. <36.2)

0.46 (0.39-0.55)

0.64 (0.60-0.68)

0.59 (0.55-0.64)


0.61 (0.52-0.72)

0.81 (0.77-0.87)

0.91 (0.85-0.98)


1.04 (0.88-1.23)

1.06 (0.99-1.13)

1.11 (1.04-1.19)

Ever received cART (yes vs. no)

0.07 (0.06-0.09)

- -

Urban clinic attendance (yes vs. no)

0.63 (0.53-0.74)

0.82 (0.77-0.88)

0.97 (0.90-1.04)



N=29.376


N=42,903


N=20,329

CD4 count at enrolment (≥200 vs. <200 cells/ml3)

3.49 (2.61-4.68)

1.31 (1.21-1.41)

0.98(0.91-1.06)



N=29.376


N=42,903


N=20,329

CD4 count at enrolment (≥200 vs. <200 cells/ml3)

3.49 (2.61-4.68)

1.31 (1.21-1.41)

0.98(0.91-1.06)

WHO stage III/IV (vs. I/II)

2.67 (2.25-3.17)

1.54 (1.44-1.65)

1.30 (1.21-1.40)


Implications

• High rates of LTFU especially:– pre-ART among adults– after enrolment visit– among HIV-exposed children

• Different mechanisms at play– Among the very sick and the relatively healthy

• Potential interventions to improve retention:– Weekend, evening, and family clinics (accommodate

men and women’s different needs)– Disclosure counseling– Support programs (e.g. food supplementation)

J Mamlin, T. Petersen, P. Braitstein et al. AJPH 2008

RETENTION OF HIV-INFECTED AND HIV-EXPOSED CHILDREN IN A COMPREHENSIVE CLINICAL CARE PROGRAM IN WESTERN KENYA

P Braitstein, A Katschke, C Shen, et al. Invited manuscript Tropical Medicine & International Health (in press)

Background

• Of the 2.1 million children aged ≤15 years living with HIV/AIDS end of 2008: (WHO AIDS EpiUpdate 2009)

• Only 38% of those in need receiving cART (given old treatment guidelines) (UNAIDS Towards Universal Access 2009)

• Mortality after 2 years among children receiving cART is approximately 7% – 2-year risk of LTFU approximately 10% (KIDS ART-LINC JAIDS 2008; Bolton-

Moore et al. JAMA 2007; Ellis et al. Ann Trop Paediatr 2007; George et al. JID 2007)

• Among HIV-infected children not on cART, and children whose last known serostatus was HIV-exposed, rates of LTFU are reported to be much higher (30%-40%)

• LTFU may be an even greater threat for children than adults:

– HIV-infected children will need care and treatment for longer.

– Vulnerable to and dependent upon their caregivers.

• Ascertainment issues are critical:– Survival

– HIV transmission

• Issues surrounding pediatric LTFU are not yet well characterized

– Rates in HIV-exposed, HIV-positive pre-ART

– Impact of rapid and massive scale-up of programs

– Risk and protective factors: opportunities to increase retention

– Outcomes of those LTFU & impact on mortality estimates

Study Objectives

1. Calculate the incidence of LTFU among HIV-exposed and HIV-infected children, the latter both pre- and post-cART initiation

2. Identify baseline and time-varying risk factors for LTFU for both HIV-exposed and HIV-infected children– Manuscript in press at TMIH

3. Identify outcomes of a random sample of HIV-positive and HIV-exposed children from an urban and a rural setting– Pedi-Up (Pediatric Losses to Follow-up) Study on-going

Retrospective Analysis

• N=13,510– 3106 HIV-infected at enrolment– 10,404 HIV-exposed at enrolment

• HIV status = at enrolment – up to 1st 3 clinic visits

• Fixed covariates: • Gender, orphan status (at enrolment), clinic location at enrolment

(urban vs. rural), enrolment period (<2005, 2005-2006, ≥2007), and receiving food supplementation (ever vs. never)

• Time varying covariates: – Age, antiretroviral use, HIV status, immune status (CD4% per age

specific categories), CDC clinical stage, weight for height (Epi-Info Z scores)

Analysis Methods

• LTFU: absent from clinic for >3 months if last on cART and >6 months if not on cART with no information as to vital status

• Incidence rates– Point estimates – Confidence intervals constructed using exact binomial limits. – Presented per 100 child-years of follow-up

• Time-dependent proportional hazard regression models were used – For missing time-dependent covariates, we searched within a 3-

month window and imputed the closest observed value.

• Included all LTFU events for each subject– Accounted for intra-patient clustering with sandwich estimator of

the standard errors of the regression coefficients

Incidence Rates of LTFU (per 100 CY)

• Overall: 18.4 (17.8-18.9)

• HIV-exposed at enrolment: 20.1 (19.4-20.7)

• HIV-infected at enrolment: 14.2 (13.3-15.1)

• HIV-infected pre-cART: 15.2 (13.8-16.7)

• HIV-infected on cART: 14.1 (13.1-15.8)


• Overall: 18.4 (17.8-18.9)






• Overall: 18.4 (17.8-18.9)





Risk & Protective Factors: HIV-exposedUnadjusted HR

(95% CI)Adjusted HR

(95% CI)

Male gender 1.00 (0.89-1.12) -

Orphan 0.31 (0.26-0.37) 1.57 (1.23-1.64)

Urban clinic 1.24 (1.11-1.39) 0.93 (0.83-1.04)

Age (per year increase) 0.87 (0.85-0.89) 0.98 (0.82-1.18)

Severely immune suppressed

1.35 (1.04-1.76) -

Severely low weight for height

2.10 (1.68-2.61) 1.69 (1.25-2.28)

Advanced clinical disease 0.59 (0.56-0.70) 1.41 (1.14-1.74)

Received food 0.52 (0.37-0.72) 0.58 (0.32-1.04)

Became HIV-infected 0.22 (0.19-0.25) 0.26 (0.21-0.32)

On cART 0.47 (0.41-0.55) 1.56 (1.23-1.99)


(95% CI)Adjusted HR

(95% CI)

Male gender 1.00 (0.89-1.12) -

Orphan 0.31 (0.26-0.37) 1.57 (1.23-1.64)

Urban clinic 1.24 (1.11-1.39) 0.93 (0.83-1.04)



1.35 (1.04-1.76) -


2.10 (1.68-2.61) 1.69 (1.25-2.28)


Received food 0.52 (0.37-0.72) 0.58 (0.32-1.04)


On cART 0.47 (0.41-0.55) 1.56 (1.23-1.99)


(95% CI)Adjusted HR

(95% CI)

Male gender 1.00 (0.89-1.12) -

Orphan 0.31 (0.26-0.37) 1.57 (1.23-1.64)

Urban clinic 1.24 (1.11-1.39) 0.93 (0.83-1.04)



1.35 (1.04-1.76) -


2.10 (1.68-2.61) 1.69 (1.25-2.28)


Received food 0.52 (0.37-0.72) 0.58 (0.32-1.04)


On cART 0.47 (0.41-0.55) 1.56 (1.23-1.99)

Risk & Protective Factors: HIV-infectedUnadjusted HR

(95% CI)Adjusted HR

(95% CI)

Male gender 1.10 (0.95-1.26) -

Orphan 0.83 (0.70-0.98) 1.09 (0.75-1.60)

Urban clinic 1.06 (0.92-1.22) -



1.83 (1.46-2.30) 2.17 (1.51-3.12)


3.82 (2.74-5.32) 1.61 (0.66-3.93)

Advanced clinical disease

1.21 (1.02-1.43) 0.85 (0.59-1.23)

Received food 0.09 (0.02-0.38) -

On cART 0.94 (0.81-1.08) -

Risk & Protective Factors: HIV-infectedUnadjusted HR

(95% CI)Adjusted HR

(95% CI)

Male gender 1.10 (0.95-1.26) -

Orphan 0.83 (0.70-0.98) 1.09 (0.75-1.60)

Urban clinic 1.06 (0.92-1.22) -



1.83 (1.46-2.30) 2.17 (1.51-3.12)


3.82 (2.74-5.32) 1.61 (0.66-3.93)

Advanced clinical disease

1.21 (1.02-1.43) 0.85 (0.59-1.23)

Received food 0.09 (0.02-0.38) -

On cART 0.94 (0.81-1.08) -

Implications

• High rates of LTFU– In comparison to other published rates, our LTFU

among HIV-infected is higher– Decreasing with time, in spite of massive scale-up

since 2005• AMPATH specific because of outreach program?

– Irrespective of pre- or post-cART among HIV-infected

• Both HIV-exposed and HIV-infected children more likely to become LTFU if sick, HIV-exposed if malnourished– High probability of mortality

Implications (2)

• Opportunities for intervention:– Strengthen care for HIV-exposed (link more strongly

to mother’s care?)– Food supplementation– Consider earlier use of cART to preserve immunity

and health

“PEDI-UP”: PROSPECTIVE EVALUATION OF THE OUTCOMES OF CHILDREN LOST TO FOLLOW-UP FROM A COMPREHENSIVE HIV CLINICAL CARE PROGRAM IN WESTERN KENYA (ON-GOING STUDY)

Methods

• Randomly selected 30% of children who became LTFU from 1 of 2 clinics (1 urban, 1 rural)

• Defined as LTFU within prior 6 months from October 2009

• Same definition of LTFU (absence >3 months if last known to be on cART, absence >6 months if last known not to be on cART)

• HIV-infected, HIV-exposed, or HIV status missing at last visit (determined using a combination of time-updated clinician documentation and laboratory results).

• Community health workers recruited and trained• Each assigned up to 3 children

• Using locator information on file with Outreach Program as starting point

• ‘Primary reason’ for LTFU determined by 2 independent reviewers

Preliminary Results• 100 children identified LTFU: 67 found (67%)

– 44 HIV-infected• 28 found so far (64%)

– 20 found alive– 7 (25%) found deceased

• 9 have poor or missing locator information– Innovative strategies being employed to improve chances of finding them

– 48 HIV-exposed children identified as LTFU• 34 found so far (71%)

– 33 found alive– 1 (3%) found deceased

– 8 HIV serostatus missing/unknown • 5 found so far (63%)• 2 found deceased (40%)

Caregiver Reported Reasons for LTFU (other than death)

• HIV-infected children (n=20):– 6 stated lack of transport or other financial difficulties– 4 transferred to another clinic – 4 displaced (from post-election violence)– 1 the caregiver refused care for the child

• Child healed by faith– 2 indicated disclosure issues– 2 no easily identifiable single cause– 1 stated child was HIV-negative (to be confirmed by charts)

Caregiver Reported Reasons for LTFU (other than death)

• HIV-exposed children (n=30):– 6 not a single identifiable cause

– 6 indicated disclosure issues (family or community)

– 5 the caregiver refused care for the child (child healed by faith, using herbs/traditional medicine, family or community discrimination)

– 4 the caregiver said child is HIV-negative

– 3 said doctor told them child was HIV-negative and not to return (needs verification from chart)

– 2 were displaced (post-election violence)

– 1 had transferred to another AMPATH clinic

– 2 child apparently didn’t miss appointment (needs verification from chart)

– 1 caregiver died (not disclosing child’s status to others)

Initial Thoughts• Next step:

– Mortality estimates among HIV-infected children in AMPATH will need to be revised given these data

– Data not necessarily generalizeable to other programs because of decentralization of AMPATH clinics and active outreach program

• Programs like AMPATH need to improve documentation of mortality and HIV-status

• Creative and rigorous education and sensitization initiatives are required to

– Decrease HIV stigma

– Improve caregivers understanding about HIV in children

• Advocacy for children’s human rights

DESCRIPTION OF OUTREACH STRATEGIES IN HIV PROGRAMS IN EAST AFRICA AND THEIR CORRESPONDING RATES OF LOSSES TO FOLLOW-UP

East Africa Site Assessments

• Module 2, Section 4 (Follow-up and Death Ascertainment)– Is there an active system of follow-up?– Which patients trigger an outreach visit?– What is the main trigger (e.g. 1 missed appointment

vs. defined as lost)– Do you staff dedicated?– What cadre are they?– What methods are used for home visits?– What is the major reason for LTFU?

Key Outreach Model Characteristics

• Personnel: Use of dedicated peers vs. dedicated professionals vs. a mix vs. no dedicated staff (or use of other NGO staff)

• Patients: ART only vs. geographic radius vs. all• ART patients: geographic radius ART vs. ART all• How: Telephone only vs. home visits only vs. mix vs.

nothing specific• When: After 1 missed visit vs. after LTFU vs.

inconsistent• How: Car only vs. bike/foot/public transit vs. all available

means vs. telephone only

Documents

International Epidemiologic Databases to Evaluate AIDS East Africa IeDEA Executive Committee meeting May 4-5, 2010 Zanzibar Patient retention and losses