South Africa’s experiences and future plans for CD4 and viral load implementation Lesley Scott Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa On behalf of the NHLS National Priority Program: Wendy Stevens, Sergio Carmona, Debbie Glencross

NDoH Healthcare Facilities Over 7636 health facilities 54 different categories of facility 45% urban, 45% rural, 0.7% peri-urban Over 3515 ARV clinics 265 NHLS labs ~80% population (public sector) National Department of Health manages health across all 9 provinces; provinces have significant autonomy National Health Laboratory Service managed from a single headquarters in Johannesburg but services all 9 provinces: Services >80% of total public sector population Responsible for teaching and research in pathology disciplines National Footprint of 265 laboratories Strong private sector with at least 5 major players services the insured population: knowledge base weak at a NDoH level on private sector activities Universal testing for HIV and screening for TB – the primary objectives being to ensure that all citizens know their HIV and TB status, and to prevent new HIV and TB infections (NSP: 2012-2017): massive increase in testing requirements

Scaling up Lab Capacity HIV Specific Testing Volumes within the NHLS since 2006 has supported the growth # of patients on ART Scaling up Lab Capacity Forward planning with suppliers and funders Pre-site assessments Assess centralisation of lab services where possible Pre-installation staff training (centralised) on both technical and Good Lab Practice On site continued training ID super users for on site troubleshooting Distribution nationally of a prequalification panel and continued EQA programme (NHLS-QCMD partnership) Vendor-Client monthly review committee to assess progress and preventative management

Laboratory services in South Africa Total Population >50 Million: ~5.7Million HIV infected individuals. 20% worlds reported HIV‐associated TB cases and 4th largest reported numbers of MDR. April 2012-April 2013: CD4 = 3,813 812 tests performed; VL = 1,994 220 tests, 360 000 EID assays. Changes to treatment guidelines Once patient’s on ART, CD4 only performed at 12 months. Pre-ART: CD4 every 6 months? (wellness clinic testing). Estimated CD4 for 2013/2014: 14 million HCT – 2,166 855 (14%) expected HIV positive and require a CD4. Target to initiate 500 000 on ART, thus 1 CD4 at 12 months. Residual 1,666 855 with CD4 >350c/ul will be monitored 6 monthly (ie 3,333 711 CD4 tests). Total CD4 for 2013/14 = 6,000 566: significant scale up Universal testing for HIV and screening for TB – the primary objectives being to ensure that all citizens know their HIV and TB status, and to prevent new HIV and TB infections (NSP: 2012/2013-2016/2017) . Increase testing requirements NSP, 2012 http://www.doh.gov.za/docs/stratdocs/2012/NSPsum.pdf

NHLS consumes a large portion of the global HIV VL diagnostic supply, to minimize risks, 2 platforms are used for HIV viral load tesitng Currently 17 functioning laboratories 8 sites using the Abbott m2000 system 9 sites using the Roche Cobas Ampliprep/ Cobas TaqMan system Current instrument capacity (8 hour shift) 6888 samples per day = 151,536 per month = 1,818,432 per annum Currently 2 HIV viral load systems as per tender agreement: Abbott m2000 and Roche Cobas Ampliprep/Cobas TaqMan

Assay verification performed, internal and external Quality Control frequently lacking South Africa’s NHLS rapid implementation/technology switch to the two testing platforms in 17 laboratories occurred within 8 months required: Industry partner’s collaboration, Training programs, Method verification with a VL prequalification panel. Material used to prepare the verification panels was a combination of known HIV-positive and -negative plasma packs (200 ml) obtained from the South African National Blood Services (SANBS): 42-member verification panel of 500 copies/ml, 2.7log copies/ml; 1,000 copies/ml, 3.0 log copies/ml; 5,000 copies/ml,3.7 log copies/ml; 50,000 copies/ml, 4.7 log copies/ml; and100,000 copies/ml, 5.0 log copies/ml). The percentage similarity CV was useful as an overall measure of variability. Across platform acceptable variability = 2.9% percentage similarity CV

Next Generation high throughput analysers: 2014: 3x current testing capacity Modular with Medium to XL throughput Continues sample loading Random access Increase testing menu: wider virology cover, microbiology and haem-onc On board reagents (refrigerated >2wks) reducing hands on Simple to run, one operator per 8 hr Reduction of testing time 2-3hrs ~ 1000 HIV VL / 8hrs ? Cartridge based Illustrative Only

Extending services: What can DBS provide? With the improved universal access to ART, this would require adequate monitoring Dry Blood Spots (DBS) Provide a convenient alternative for specimen collection Transport logistics are simpler, with demonstrated stability vs blood tubes Collection of specimens may not require venisection but rather capillary blood Decentralisation of sample collection DBS may be used for infant diagnosis, VL monitoring and drug resistance testing Can be performed on several existing platforms, unclear on precision at critical range

Extending services: Plasma Preparation Tubes Transport of blood samples without loss of RNA integrity PPT centrifuged to separate cellular components from RNA. The mean difference between EDTA and PPT prepared samples (n = 261) was acceptable (log 0.04 copies/ml, percentage similarity CV 3.53%). PPT can be used for viral load testing on the CAP/CTM HIV-1 v2.0. Modificiations required for Abbott HIV-1 RT But at an added cost!

The NHLS enumerates CD4 for the public sector at 62 labs – current footprint for >3.8m test Red- NHLS CD4 lab Blue- DoH clinic

Connectivity: interfaced to LIS Real time continuous (currently 2 systems) Real time continuous monitoring through middleware solutions

Centralised testing allows for central monitoring of operational aspects of VL, EID and CD4 testing: Dashboards *connectivity of POC devices to a CDW imperative

Centralised testing allows for central data management and comprehensive M&E reporting: NDoH province, district….drill down *connectivity of POC devices to a CDW imperative

Increasing access to results: SMS printers SMS printers to improve turn-around-time of results back to facilities from the labs Beneficial in remote, far-reaching areas where no internet access is available SMS is automatically generated from the lab’s LIS Result printed on paper and to be stored in patient’s file Initial roll-out in 2009: Currently 1990 SMS printers in the field nationwide (~4500 DoH facilities) Services available for: CD4 Count, HIV VL, EID, GeneXpert TB and TB Microscopy. Dashboard

Totally Centralised model (4hr) Models for POC implementation Solution: 15 Labs No POC Decentralised model (1hr) Solution: 127 Labs 190 POC © Selective Analytics 2012 www.mapplace.co.uk

Proposed CD4 service delivery model to improve coverage NHLS CD4 testing laboratories (Red), Proposed community laboratories (Green), POC/mini-lab sites (Yellow) in reference to the NDOH clinics (blue) Beckman Coulter, SP PLG incl. internal QC using bead flow rate.

Tiered CD4 service delivery plan within quality system (EQA) True POC <10 samples/day NHLS Community laboratories (outside of 200 km radius of NHLS district laboratory) Low Volume CD4 Instruments >11<=100 samples/day District laboratories >100 <=300 samples per day Centralized Testing Laboratories >300 samples/day Rural clinic , no ART Testing for screening only : not for monitoring. Patients go CD4 in hand to nearest HCT clinic. LIS connectivity needed to ensure data captured for patient follow-up and epidemiological review. District HCT clinic Possible enrolment onto ART or refer to nearest treatment facility (locations identified by mapping District HCT, ARV Referral Centres and NHLS Community laboratories). Instruments with higher precision/accuracy (>90%) Connected to LIS. Do CD4 at baseline and for monitoring. Increasing requirements for numbers of CD4 tests / day All ARV treatment centers Direct access to HCT Referred patients Screening and Monitoring All ARV treatment centers Direct access to HCT Referred patients Screening and Monitoring

Conclusions The purpose of global ART: effective long-term treatment for all chronic patients (including paediatrics). VL testing becoming more important for detecting VL failure and a move towards routine VL testing. Level of access required for VL testing is most likely mixed model: Centralised (super labs): easier to manage but requires good efficient logistics around specimen transport (ppt, DBS) and result reporting (sms printers) Decentralized (POC): increase access, manage LTFU, consider: demand/ location/ throughput/ operator, must have connectivity Implementation: Clinical & Lab Service mapping including volumes critical Equipment standardisation for costing Pre-analytical and post-analytical remain problematic for different reasons Careful costing, modelling, monitoring and evaluation of impact needed Connectivity for national reporting critical

Acknowledgments National Department of Health NHLS National Priority Program (Wendy Stevens, Sergio Carmona, Debbie Glencross, Leigh Berrie, ) NHLS – CDW (Sue Candy) NHLS POCT working group Funders: Clinton Foundation, CDC, PEPFAR, Grand Challenges Canada, USAID R&D Development team HERO: Professor Sydney Rosen, Dr. Lawrence Long, Kate Schnippel, Bill Macleod Connectivity working group (Brad Cunningham)