International Epidemiologic Databases to Evaluate AIDS East Africa IeDEA Executive Committee meeting May 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 PY P Braitstein, M Brinkhof, et al. The Lancet 367(9513):

Outline 1.LTFU in HIV-infected adults 1.Men vs. Women 2.LTFU in HIV-infected and HIV-exposed children 1.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

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 enrolment including those with zero days of follow-up 12,93551,574 From enrolment ≥ 1 day of follow-up 10,74451,574 Pre-cART (≥ 1 day of follow-up) ,214 Post-cART (≥ 1 day of follow-up) ,383

Incidence Rates (IR) per 100 py IR (95% CI) Overall IR (95% CI) Men IR (95% CI) Women From 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) Pre-cART (≥ 1 day of follow-up) 27.2 (26.5 – 27.9) 32.7 (31.2 – 34.2) 25.2 (24.4 – 26.0) Post-cART (≥ 1 day of follow-up) 14.0 ( ) 15.0 (14.3 – 15.8) 13.5 (13.0 – 14.0)

IR (95% CI) Overall IR (95% CI) Men IR (95% CI) Women From 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) Pre-cART (≥ 1 day of follow-up) 27.2 (26.5 – 27.9) 32.7 (31.2 – 34.2) 25.2 (24.4 – 26.0) Post-cART (≥ 1 day of follow-up) 14.0 ( ) 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) Women From 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) Pre-cART (≥ 1 day of follow-up) 27.2 (26.5 – 27.9) 32.7 (31.2 – 34.2) 25.2 (24.4 – 26.0) Post-cART (≥ 1 day of follow-up) 14.0 ( ) 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) Women From 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) Pre-cART (≥ 1 day of follow-up) 27.2 (26.5 – 27.9) 32.7 (31.2 – 34.2) 25.2 (24.4 – 26.0) Post-cART (≥ 1 day of follow-up) 14.0 ( ) 15.0 (14.3 – 15.8) 13.5 (13.0 – 14.0) Incidence Rates (IR)

Predictors of Loss to Follow-up Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post-cART AHR (95% CI) N=20,329 Men vs. Women1.42 ( ) 1.27 ( ) 1.24 ( )

Predictors of Loss to Follow-up Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 Men vs. Women 1.42 ( ) 1.27 ( ) 1.24 ( ) Age (≥36.2 y vs. <36.2) 0.46 ( ) 0.64 ( ) 0.59 ( )

Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 Men vs. Women 1.42 ( ) 1.27 ( ) 1.24 ( ) Age (≥36.2 y vs. <36.2) 0.46 ( ) 0.64 ( ) 0.59 ( ) Disclosure (yes vs. no) 0.61 ( ) 0.81 ( ) 0.91 ( ) Predictors of Loss to Follow-up

Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 Men vs. Women 1.42 ( ) 1.27 ( ) 1.24 ( ) Age (≥36.2 y vs. <36.2) 0.46 ( ) 0.64 ( ) 0.59 ( ) Disclosure (yes vs. no) 0.61 ( ) 0.81 ( ) 0.91 ( ) Travel ≥1 hr to clinic (yes vs. no) 1.04 ( ) 1.06 ( ) 1.11 ( ) Predictors of Loss to Follow-up

Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 Men vs. Women 1.42 ( ) 1.27 ( ) 1.24 ( ) Age (≥36.2 y vs. <36.2) 0.46 ( ) 0.64 ( ) 0.59 ( ) Disclosure (yes vs. no) 0.61 ( ) 0.81 ( ) 0.91 ( ) Travel ≥1 hr to clinic (yes vs. no) 1.04 ( ) 1.06 ( ) 1.11 ( ) Ever received cART (yes vs. no) 0.07 ( ) -- Predictors of Loss to Follow-up

Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 Men vs. Women 1.42 ( ) 1.27 ( ) 1.24 ( ) Age (≥36.2 y vs. <36.2) 0.46 ( ) 0.64 ( ) 0.59 ( ) Disclosure (yes vs. no) 0.61 ( ) 0.81 ( ) 0.91 ( ) Travel ≥1 hr to clinic (yes vs. no) 1.04 ( ) 1.06 ( ) 1.11 ( ) Ever received cART (yes vs. no) 0.07 ( ) -- Urban clinic attendance (yes vs. no) 0.63 ( ) 0.82 ( ) 0.97 ( ) Predictors of Loss to Follow-up

Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 CD4 count at enrolment (≥200 vs. <200 cells/ml 3 ) 3.49 ( ) 1.31 ( ) 0.98 ( ) Predictors of Loss to Follow-up

Zero days of FUP AOR (95% CI) N= Pre-cART AHR (95%CI) N=42,903 Post- cART AHR (95% CI) N=20,329 CD4 count at enrolment (≥200 vs. <200 cells/ml 3 ) 3.49 ( ) 1.31 ( ) 0.98 ( ) WHO stage III/IV (vs. I/II) 2.67 ( ) 1.54 ( ) 1.30 ( ) Predictors of Loss to Follow-up

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 1 st 3 clinic visits Fixed covariates: Gender, orphan status (at enrolment), clinic location at enrolment (urban vs. rural), enrolment period (<2005, , ≥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 ( ) HIV-exposed at enrolment: 20.1 ( ) HIV-infected at enrolment: 14.2 ( ) HIV-infected pre-cART: 15.2 ( ) HIV-infected on cART: 14.1 ( )

Incidence Rates of LTFU (per 100 CY) Overall: 18.4 ( ) HIV-exposed at enrolment: 20.1 ( ) HIV-infected at enrolment: 14.2 ( ) HIV-infected pre-cART: 15.2 ( ) HIV-infected on cART: 14.1 ( )

Incidence Rates of LTFU (per 100 CY) Overall: 18.4 ( ) HIV-exposed at enrolment: 20.1 ( ) HIV-infected at enrolment: 14.2 ( ) HIV-infected pre-cART: 15.2 ( ) HIV-infected on cART: 14.1 ( )

Risk & Protective Factors: HIV-exposed Unadjusted HR (95% CI) Adjusted HR (95% CI) Male gender1.00 ( )- Orphan0.31 ( )1.57 ( ) Urban clinic1.24 ( )0.93 ( ) Age (per year increase)0.87 ( )0.98 ( ) Severely immune suppressed 1.35 ( )- Severely low weight for height 2.10 ( ) 1.69 ( ) Advanced clinical disease0.59 ( )1.41 ( ) Received food0.52 ( )0.58 ( ) Became HIV-infected0.22 ( )0.26 ( ) On cART0.47 ( )1.56 ( )

Risk & Protective Factors: HIV-exposed Unadjusted HR (95% CI) Adjusted HR (95% CI) Male gender1.00 ( )- Orphan0.31 ( )1.57 ( ) Urban clinic1.24 ( )0.93 ( ) Age (per year increase)0.87 ( )0.98 ( ) Severely immune suppressed 1.35 ( )- Severely low weight for height 2.10 ( ) 1.69 ( ) Advanced clinical disease0.59 ( )1.41 ( ) Received food0.52 ( )0.58 ( ) Became HIV-infected0.22 ( )0.26 ( ) On cART0.47 ( )1.56 ( )

Risk & Protective Factors: HIV-exposed Unadjusted HR (95% CI) Adjusted HR (95% CI) Male gender1.00 ( )- Orphan0.31 ( )1.57 ( ) Urban clinic1.24 ( )0.93 ( ) Age (per year increase)0.87 ( )0.98 ( ) Severely immune suppressed 1.35 ( )- Severely low weight for height 2.10 ( ) 1.69 ( ) Advanced clinical disease0.59 ( )1.41 ( ) Received food0.52 ( )0.58 ( ) Became HIV-infected0.22 ( )0.26 ( ) On cART0.47 ( )1.56 ( )

Risk & Protective Factors: HIV-infected Unadjusted HR (95% CI) Adjusted HR (95% CI) Male gender1.10 ( )- Orphan0.83 ( )1.09 ( ) Urban clinic1.06 ( )- Age (per year increase)0.96 ( )0.93 ( ) Severely immune suppressed 1.83 ( )2.17 ( ) Severely low weight for height 3.82 ( )1.61 ( ) Advanced clinical disease 1.21 ( )0.85 ( ) Received food0.09 ( )- On cART0.94 ( )-

Risk & Protective Factors: HIV-infected Unadjusted HR (95% CI) Adjusted HR (95% CI) Male gender1.10 ( )- Orphan0.83 ( )1.09 ( ) Urban clinic1.06 ( )- Age (per year increase)0.96 ( )0.93 ( ) Severely immune suppressed 1.83 ( )2.17 ( ) Severely low weight for height 3.82 ( )1.61 ( ) Advanced clinical disease 1.21 ( )0.85 ( ) Received food0.09 ( )- On cART0.94 ( )-

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