CD4 Assays Are No Longer Needed for Care of Children in Low-resource Countries. The case against Di Gibb

Transcription

1 CD4 Assays Are No Longer Needed for Care of Children in Low-resource Countries The case against Di Gibb

2 The value of CD4 Pre-ART CD4 CD4 monitoring on ART

3 Pre-ART CD4 for linkage to care & clinical management 1. Prioritise urgency of linkage to care & ART start Most deaths occur before ART in those with lowest CD4 2. Investigate/manage OIs and prevent death soon after starting ART in children with low CD4 TB, bacterial infections, cryptococcal disease Potential interventions (REALITY Trial - children >5yrs) a. Extra Nutrition b. More potent ART (also in the ARROW Trial) c. Immediate OI prophylaxis 3. Inform short-term follow-up in those at high risk

4 HPPMCS: ~4000 children, ~7000 years follow-up; ~1000 AIDS & 568 deaths Longitudinal model: CD4, viral load, age CD4 & Viral load are independent predictors of mortality. but only weakly associated BUT CD4 is a much stronger predictor of disease progression and death;

5 Early mortality on ART predicted by pre-art CD4: Evidence from DART and ARROW trials Mortality among HIV-infected African adults and children with CD4 <100c/ml at ART start is 3X higher than would be expected in similar patients in high-income settings

6 Pre-ART CD4 for followup, retention & HIV program management 4. Educate children, carers, pregnant adolescents about HIV Promote adherence, follow-up & retention 5. Inform optimal program management a. Guide drug use during stock-outs b. Triage of stable patients (could and should take account of baseline CD4) c. Prioritise follow-up of defaulters to prevent treatment interruptions

7 Enabling ART Rollout Stock-outs in the 3 months prior to survey by country and facility level: Highest for paediatric formulations

8 Children interrupting ART in PENTA 11 Trial Restarted ART* N=19 Off for 48 wks** N=32 P-value Age started ART 3.3 years 1.3 years 0.01 CD4 pre-art 13% 23% <0.001 % CDC B/C 47% 47% 1.0 Time on ART 5.4 years 5.9 years 0.8 CD4 at interruption 34% 37% 0.04 Lowest CD4 off ART 14% 23% <0.001 *most restarted early for falling CD4 11 restarted within 10 weeks ~75% had nadir CD4 <15% ** restarted as per protocol at 48 weeks ~20% had CD4 nadir <15% Only nadir CD4 (p=0.007) & age at ART (0.07) predicted staying off ART AIDS 2010, 24:

9 CD4 percent Log viral load cd4pct Log VL Months from starting triple therapy Treatment Interruption: CD4 falls rapidly to pre-art levels 1

10 HOW BIG IS THE PROBLEM? One in 4 patients starting ART in Africa had CD4 <100cells/mm3 across all regions (WHO: global update 2013) As pmtct scales up, an increasing proportion of children will present to care outside pmtct; Many will have low CD4 counts

11 POSTER P43 Lablite Project to Q >1000 children presenting to District Hospitals and Primary Care facilities in Zimbabwe, Malawi & Uganda ~2/3 aged >2 years >1/3 aged >5 years 43% those >5 years in Zimbabwe had CD4 <100

12 The value of CD4 Pre-ART CD4 CD4 monitoring on ART

13 Who 2013 Guidelines

14 Viral load as predictor of disease progression on ART Current CD4 is the better predictor of immediate morbidity/mortality on ART; viral load adds little further prognostic information RCTs measuring the Impact of laboratory monitoring on important clinical outcomes have failed to find added advantage from viral load over and above CD4 HBAC trial (Uganda; BMJ 2011) PHPT3 trial (Thailand; Plos Medicine 2013) Zambian Cluster randomised trial Penpact1 trial showed no difference in clinical, VL or CD4 outcomes between switch at VL 1,000 vs 30,000 in children over 4 years DART and ARROW trials found SAME retrospective VL response in Clinical vs CD4 monitoring arms

15 Alive (%) Clinical vs CD4 Monitoring in ARROW 1206 Children did extremely well on treatment: no advantage of laboratory monitoring for toxicity Small significant benefit from routine CD4 monitoring after the first year on ART Deaths Deaths Rate 2 0.1/100 CY /100 CY 96% 95% 29 deaths Lab: 1.3/100 CY Clin: 1.1/100 CY 25 deaths Years from treatment initiation

16 Causal Modelling of effect of frequency of CD4 monitoring 1 Survival from week 48 1 Modelled survival based on DART weekly CD4s weekly CD4s 24-weekly CD4s 48-weekly CD4s No CD4 monitoring No CD4 monitoring Weeks since 48 weeks on first-line ART Weeks since 48 weeks on first-line ART Ford D et al Am J Epidemiology 2015

17 Viral Load Failure & Switch to Second-line ART >10,000 children in Trials/Cohorts starting ART Trials Cohorts ARROW Trial CHAPAS 3 Trial CHER Trial IeDEA S Africa PHPT Thailand Penpact1 Trial EPPICC Infants CHIPS UK/ Ireland Number Monitoring strategy % VL failure >400c/ml at 2-5 yrs Clinical or CD4 3m Clinical & CD4 3m CD4 3m VL 12m CD4 6m VL 12m CD4 6m VL 6m CD4/VL 3m VL 1000 VL 30,000 CD4/VL 3m 15% 15% 16% 19% 23% 17% 23% CD4/VL 3m 18% (rebound) % switch at 3-6 yrs 5% 5% 2% 6.3% 17.8% 23% 17% 48% (rebound) Sources: ARROW, Lancet 2013; CHAPAS 3 Musiime, Melbourne 2014; CHER, Lancet 2013; Davies, JAIDS 2011; Collins, JAIDS 2013; Penpact1, Lancet ID 2009; Judd A, EPPICC, AIDS 2011; Childs T, Lancet HIV in press

18 POINT of CARE CD4

19 Nurses in Primary Health Clinics Can Accurately Perform CD4 counts Using Point- Of-Care Devices Alere PIMA (Lab Techs) vs. BD FACSCalibur Alere PIMA (Nurses) vs. BD FACSCalibur Limits of Agreement -314 to +257 Limits of Agreement -249 to +148 Jani et al. (2011); AIDS

20 Point-Of-Care CD4 Counting Reduces Pre- Treatment Loss-To-Follow-Up Percent Of Patients Receiving CD4 Test Results Percent Of Patients Returning After Initial CD4

21 Point-of-care (POC) CD4 Mobile HCT program (Johannesburg: ACCESS VCT) integration of POC CD4 testing to improve linkage to HIV care POC CD4 technology Pima Analyzer

22 Point-of-care (POC) CD4 Mobile HCT program (Johannesburg: ACCESS VCT) integration of POC CD4 testing to improve linkage to HIV care POC CD4 technology Pima Analyzer Zyomyx, Inc Daktari Burnett Omega

23 Health centre IV Uganda

24 CD4 measurements at Health centre IV Uganda

25 CD4 measurements at Health centre IV Uganda

26 Conclusion Pre-ART CD4: Very valuable for prioritising ART and medical management for individuals and programmes Timely and cost effective linkage to care (particularly POC ) Longterm follow-up and retention in care of the most vulnerable CD4 Monitoring on ART Adds value to clinical monitoring only May add value in prioritising timing of switching even if you have VL could be done 12 monthly on ART Furthermore.. CD4 has already been used for years; If its not broke, why throw it? CD4 can be used BOTH pre-art and on ART VL is mostly not scaled up, is costly, there is no POC; where available, VL appears often not being used for switching anyway