Point of Care diagnostics: South Africa’s experience Lesley Scott Department of Molecular Medicine and Haematology University of the Witwatersrand, and the National Priority Program, NHLS Johannesburg, South Africa POC WHO, IAS satellite 30th June 2013

A perspective on South Africa’s Testing volumes Total Population over 50 Million at last census Estimated 5.7 million HIV infected individuals of which 1.9 million are receiving ARV therapy. HIV continues to drive these testing needs. Currently Conduct approximately ~ 4 million CD4 tests annually, 2 million viral loads and currently 360 000 EID assays 3rd highest TB cases, 20% worlds reported HIV‐associated TB cases and 4th largest reported numbers of MDR. over 1.4 million GeneXpert tests (2012), smear microscopy load ~5 million smears in 2012, 1.2 million TB cultures in 2012 30-40% of all public health sector laboratory expenditure for HIV and TB 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 The NSP has five goals: „  halving the number of new HIV infections „  ensuringthatatleast80%ofpeoplewhoareeligiblefortreatmentfor HIV are receiving it (at least 70% should be alive and still on treatment after five years) „  halving the number of new TB infections and deaths from TB „  ensuring that the rights of people living with HIV are protected „  halving the stigma related to HIV and TB. NSP, 2012 http://www.doh.gov.za/docs/stratdocs/2012/NSPsum.pdf

NDOH Healthcare Facilities 256 NHLS labs ~80% population (public sector) NDOH Healthcare Facilities Over 7636 health facilities 54 different categories of facility 45% urban, 45% rural, 0.7% peri-urban Over 3515 ARV clinics New guidelines: On ART: CD4 only at 12 months Pre-ART: CD4 every 6 months 2013/2014: 14 million HCT – 2,166 855 (14%) expected HIV positive and require CD4. Target to initiate 500 000, 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 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

Evaluations of POC CD4 Count Within Comprehensive Interventions: linkage to care!! Recently completed pilot evaluations (no comparison arms): HBCT-Plus (Home based counseling and testing, POC CD4 count, facilitated referrals, and follow up home visits) 86% initiated ART ≤ 3months in rural KZN [16] RAP (“Rapid Initiation of Antiretroviral Therapy in Pregnancy”) 97% initiated ART (91% on same day) in Cape Town [17] Randomized controlled trials now underway Grand Challenges Canada RCT (“Investigating the feasibility of implementation of multi-disciplinary point-of-care testing in an HIV treatment clinic using a randomised controlled trial”) RapIT (“Rapid Initiation of Antiretroviral Therapy to Promote Early HIV/AIDS Treatment in South Africa”) Others? Courtesy Syndey Rosen, NDoH/NHLS POC workshop Pretoria, 24-15th June 2013

Grand Challenges Canada (POC implementation award, 2011-2014) Feasibility of implementing multi-disciplinary point-of care (POC) testing in an active HIV treatment clinic ( PI: Wendy Stevens ) CD4, Creatinine, ALT, Hb, TB (VL, CryAG) Develop a “POCT package” Perform randomized controlled trial (POC vs SOC “2010 guidelines”) Determine costing Recommend policy

Findings Clinic space to perform “multiple POCT” is variable and limited. POCT requires its own checklist within quality ISO, CLSI and SANAS guidelines : pre-analytical, analytical and post analytical; equipment, safety, storage, waste, test QC, EQA, operator certification, training. SOP’s to include quick reference charts. Training both central and “on-site” test witnessing: more emphasis placed on computer literacy (GeneXpert experience) A “starter kit” (measuring cylinder, squeegee bottle, spill kit, order charts etc to introduce GCLP into clinics. Health system strengthening required for daily clinic workflow issues 69% HIV patients require multiple POCT (>3/visit).

Nurses perform multiple POC, daily QC and EQA as accurately as laboratory testing. Multiple POC’s (CD4, Hb, ALT, Creat) could be performed accurately on 1 finger stick (8% required >1 finger stick). 100% of patients said they prefer either one (65.5%) or two finger sticks (34.5%) over a venepuncture specimen. 68.8% would be willing to have up to 3 finger sticks before having a blood draw. Earliest time a POCT performed was 09:30, (median11:00 and the latest 12:24). Median time taken from the time the nurse started the first POCT to the time taken to start the last POCT varied depending on the number and type of tests requested. When CD4 requested, tests took ~1hr47min, No CD4 requested, ~6min - 14minutes. These time measurements did not include acting on result or any connectivity.

+ Human resources CLINIC DUTIES Patient registration History taking POC DUTIES (pre-analytical, analytical, post-analytical) Additional finger prick/venepuncture Sample labelling Instrument QC testing Instrument maintenance Testing: ALT, Creat, lactacte, Hb: <2minutes PIMA = 20 minutes Xpert MTB/RIF =2 hours Result recording/printing/reporting External quality assessment (EQA) Infection control Spill cleaning Waste disposal Additional skills: Phlebotomy Testing performed from blood tubes (pipetting skills) Additional duties: Operator certification and on-going monitoring Managing test failures, instrument downtime Stock control Specimen storage Human resources CLINIC DUTIES Patient registration History taking Physical exam Counselling Rapid testing (HIV, pregnancy) Phlebotomy – lab tests Treatment Return visit booking + Who will perform POCT? Task Shifting – management of task shifting from lab staff to clinical staff Regulation and certification around scope of work?

TB screening (questionnaire) RCT at 3 remote PHC N=3000 HCT/PICT HIV Positive HIV Negative PIMA CD4> 350 CD4< 350 ALT TB screening (questionnaire) Hemoglobin Negative Positive GeneXpert Creatinine SOC participants Consent and Finger-stick x1 Venipuncture: HIV test confirmation +PIMA in POC Use stored blood from tests above Sputum POC participants Adherence counseling ART start (same day) Venipuncture TB screening Return in one week CD4<350 1-4 weeks later Follow up for 6 or 12 months N=1000 N=480 N=316 N=50 N= 288 CD4>350

Outcome measures Primary: Proportion of patients retained in care at 6/12 and 12/12 Secondary: Time taken from HCT to initiation of ART in both arms Proportion of patients in each arm experiencing an OI (including TB) in the follow-up period Proportion of patients experiencing treatment interruptions in each group Determine cost effectiveness of POC testing vs Standard of Care (SOC) Preliminary results before study end (dedicated staff) GCC RB Osih Category POC SOC P-value Initiation 112 74 0.01 Mean CD4 values if less than 350 194.6 cells/mm3 166.4 cells/mm3 TB symptoms present 132 (52.4%) 123 (55.9%) Time to initiation (Mean) 4.1 days 16.9 days Time to initiation (Median) 1 day 20 days As per 2010 guidelines

TAT: 3 clinics North West Province 75% of specimens are collected (once/day courier) from the clinic and received at laboratory within one day; Patient initiated SOC 85% lab tests completed by lab within one day; 72% printed results stamped in the clinic within one day. Without connectivity in clinics, POCT will lose National data TAT: 3 clinics North West Province Patient initiated day 1 with POC , same day 72% lab results returned to clinic POC placement with staff versus treatment guideline timeline change to initiate day 1 or day 7 to compliment clinic work flow.

Beyond the LIS: Our experience at POC: Laboratory information system (LIS): instant data stream to central “powerhouse data repository” Result reporting Billing Program M&E Central data warehouse National data Beyond the LIS: Our experience at POC: Manual entry transcription errors Both clinic sites had transcription errors (1%; n=5/480): Incorrect assay result recorded Assay result recorded under incorrect test.

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

Centralised data for decentralised testing POC Device #1 POC Device #2 POC Device #3 POC Device #4 Host LIS/HIS Universal POC Devices Interface Program / Data Management System HL7/ASTM /POCT1-A Bi-directional Communication POCT1-A ASTM HL7 Proprietary

Feasibility of multi-disciplinary Point-of-Care Testing

Available Options for Connectivity Product Instrument Interfacing Training and Certification QC and instr. Management Patient History Result Management Clinical Information Visit Management AegisPOC Extensive Yes No POCcelerator Cobas IT Limited Identicare Development Therapy Edge None eKAPA Instrument and Data Management Patient Management

Dashboard Middleware PIMA connectivity: PIMA modem required for FTP-PUSH LIS mechanism can be developed to interface results from CSV file Two components: Dashboard and Middleware Solutions Dashboard contains a small subset of the full features of the middleware solutions Dashboard is unlinked from patient information Dashboards are instrument / manufacturer specific Middleware solutions are vendor & instrument neutral. PIMA connectivity:

Cepheid/NHLS Remote Monitoring Operational dashboard for real-time monitoring of results, errors, resistance and positivity rates Pre-configured on all newly installed GeneXperts Compare results per country, province, district, sub-district, laboratory. Break down of error rates per error code and % increase / decrease over a time period. User Workshop held 5-9th November to improve usability and facilitate design changes, Johannesburg

Current GeneXpert Placements National policy Roll out March 2011, testing at smear microscopy labs >1mil tests to date. Gx at POC: NTCM=too costly, 2 ½ staff required for 15 patients same day treatment Phase 2 Phase 3 Testing centres: 175 Analysers: 242 Clinic placements: 20 Gx4: 77 Gx16-8: 1 Gx16: 162 GX48: 1 GX80-48: 1

POCT not an easy decision for South Africa Both a national policy and legal framework required. NDoH/NHLS combined POCT workshop (24-25th June 2013): output to form a national advisory body to focus on POCT. POCT “an extension of the lab tiered network” Focus on CD4, Cryptococcal antigen testing <100CD4 cells/ul Investigate POCT for NCD’s Determine the place of VL Address lack of regulation issues Address connectivity as a critical component for quality POCT Combine efforts on modeling the place and cost for POCT. Address gaps in research – especially linkage to care (HIV and TB) and improve health systems.

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

In the interim: 62 CD4 labs – current footprint Proposed CD4 service delivery model NHLS CD4 testing laboratories (Red), Proposed community laboratories (Green), POC/mini-lab sites (Yellow) in reference to the NDOH clinics (blue)

Is South Africa ready for (multiple) POCT? Clinic space is varied and limited Nurses can perform multiple POCT duties but time is limited. Need a new cadre of POCT staff More studies needed: Full economic costing Cost-effectiveness (incl. multiple POCT) Cost of deployment and logistics Cost of quality assurance Address economic scale and new guidelines: Hb, ALT, cr, CD4 at once for 7 day initiation Same day initiation impact (HCT + adherence + LTH + HIV resistance) yet unknown: takes more than a rapid CD4 count

Acknowledgments National Department of Health NHLS National Priority Program staff (led by Prof Wendy Stevens and Dr. Leigh Berrie NHLS POCT working group GCC team and clinical partners Funders: Clinton Foundation, CDC, PEPFAR, Grand Challenges Canada Professor Scott and R&D Development team South African Cryptococcal Screening Programme: Nelesh Govender HERO: Professor Sydney Rosen, Dr. Lawrence Long, Kate Schnippel Connectivity working group (Brad Cunningham) CD4 working team (Prof. Debbie Glencross), viral load (Dr. Sergio. carmona) Special thanks to Trevor Peter, Maurine Murtagh, Rosanna Peeling, Tim Tucker, Ilesh Jani. Mozambique program