Robert G. Gish MD UC San Diego

Transcription

1 Robert G. Gish MD UC San Diego

2 The Pipeline of HIV-Related Point-Of- Care Tests is Growing Viral detection Examples: CD4 test Examples:

3 Evidence of the Impact of Some Point-Of- Care Tests in Pilot Studies is Also Mounting Source: Jani et al (2011)

4 There is a Need for Normative Guidance for New Point-Of-Care Testing Point-of-care test deployment at full scale will take significant investment Public health benefits may be reduced if implementation is not well planned and executed Policies and guidelines for new POC test adoption and implementation need to be developed from a health system perspective Challenges: Multiple new products and regulatory weaknesses Increased decentralization of testing and care into community and informal settings Appropriate usage of test results and linkage into care

5 Some Examples of Previous HIV Testing Guidance

6 1 2 Extensive Guidance May Be Needed to Ensure Optimal Deployment for Viral Hepatitis Defining Point Of Care : Where, How, By Whom, For Whom? Evaluating and Selecting New POC Technologies 3 Cost-effectiveness of POC Testing in Different Settings 4 Integrating POC into Lab Networks and Clinic Operations 5 Clinical Interpretation/New Patient Management Algorithms

7 What Is Required to Develop Normative Guidance on Point-Of-Care Testing? Consensus-based analysis of product utility Technical performance studies, clinical trials, implementation pilots, operational research and costeffectiveness studies Evaluate different patient populations, test operators, clinical settings and deployment approaches Use evidence-based criteria Health system perspective Strengthening of regulatory frameworks on diagnostics

8 WHO Working Group The WHO has convened a Working Group to develop short and medium term product development priorities for HIVrelated diagnostics The Group met in October 2011 and May 2012 There is a need with the global hepatitis initiative for POC testing guidelines as part of country regional and global efforts

9 WHO Working Group Collated expert consensus on ideal current platforms for: o Serological testing for HIV infection o Early diagnosis of HIV infection in infants o CD4 cell counting o HIV viral load testing o HIV drug resistance testing ohepatitis B and C testing o Multiplex platforms (HIV + TB, syphilis, hepatitis) o Improvements in logistics (results transfer and sample collection) o Rapid diagnostic test readers

10 WHO Working Group Needs of patient care considered at five levels of health service delivery : o Community outreach setting o Primary care setting o District o Regional or provincial o National Priorities for generalized and concentrated epidemic settings considered separately 2 Meeting Reports Development of additional WHO guidance to be informed by relevant operational research

11 Conclusions Operational research is key to development of guidance Health system perspective is critical if deployment is to generate meaningful impact Efficiency of research needs to be maximized by data sharing, prevention of research duplication and strengthening of regulatory framework WHO Working Group will play an important role in the development of further guidance

12 MBio Diagnostics SnapEsi Serologic Device SnapCount CD4 T-cell Counter

13 Multi-Mode Planar Waveguide Fluorescence Reader System

14 Waveguide Optics HIV Antigen Spot

15 First Generation Cartridge ARRAY FEATURES: 1. Stain Control / Alignment human IgG 2. POSITIVE CTRL Goat anti-human IgG 3. POSITIVE CTRL Goat anti-human IgG 4. NEGATIVE CTRL Bovine serum albumin 5. NEGATIVE CTRL Bovine serum albumin 6. Stain Control / Alignment human IgG 7. HCV core antigen 8. HCV core antigen 9. HCV non-structural protein NS3 (c33c) 10. HCV non-structural protein NS3 (c33c) 11. Stain Control / Alignment human IgG 12. HIV gp41 antigen 13. HIV gp41 antigen 14. HIV gp120 antigen 15. HIV gp120 antigen 16. Stain Control / Alignment human IgG

16 SnapEsi Serodiagnostic Assay Low density microarray printed to the waveguide Passive flow driven by both capillary action and hydrostatic pressure

17 Preliminary Serology Data (as of March 2, 2012) HCV (core, NS3, NS4 and NS5) HIV (gp 41, p24) T.Pallidum (p17, p47) Sensitivity 96% (100%)* 100% 92.7% (96.1%)* Specificity 98.7% (96.9%)* 100% 94.4% (92.7%)* True Positives True Negatives False Positives False Negatives Indeterminant Invalid Total *retroactive analysis with adjusted CO values

18 Next Steps: 2013 and Beyond Nucleic acid detection Respiratory virus diagnosis (underway with ongoing NIAID support) Additional syndromic multiplex panels Blood transfusion for RLS HIV, HTLV, T. pallidum, Plasmodium sp, HBV, HCV, HHV-8 Hepatitis screening in resourced settings HBsAg, HBcAb, HBsAb, HCV, ALT, AST Custom configurations for field epidemiology

19 WHO Goals for 2020

20 Integrated POC Testing: Broader Implications Medical Management Ministry of Health Real time monitoring of utilization Real time surveillance of co-infections

21 HBV POC test kit from Korea 1 US $ for kit 20 min of medical assistant time

22 HBsAg variant (diluted 1/100) sd144e sg145r sp120t st123s IU/ml sk122r si126t sy134n sn133l

23 HBV genotype A dilution series 49,780 IU/ml 4,978 IU/ml 498 IU/ml 50 IU/ml 5 IU/ml

24 HBV Genotype Last dilution detected by POC strip HBsAg titre (IU/ml) at final dilution A 1/ B 1/ C 1/ D 1/ E 1/ F 1/ G 1/100 77

25 A Simple Test Procedure Utilizing All Sample Types COLLECT TEST Oral Fluid 99.6% 100.0% Venipuncture Whole Blood MIX Serum / Plasma Fingerstick Whole Blood 25

26 Hepatitis C Virus (HCV) Infection Testing Algorithm ANTI-HCV Point-of-care immunoassay (Rapid Test) or Bench immunoassay (EIA, CIA, MEIA, CMIA) REACTIVE (+) NEGATIVE (-)* NAT for HCV RNA NEGATIVE (-)** STOP POSITIVE (+) Active / Current HCV infection Refer to Care and Treatment # If immunocompromized status or acute infection is suspected, then test for HCV RNA. # # If ongoing risk factors (e.g.. injecting drug use or other recent exposures) repeat anti-hcv testing >6 months after most recent exposure

27 OraQuick HCV Test- Interpretation Non-reactive: Single line appears at the C (control) triangle A negative result indicates the absence of HCV antibodies in the sample Reactive for anti-hcv: Two lines appear One at the C (control) triangle and the other at the T (test) triangle Indicates the presence of HCV antibodies in the sample. 27

28 Sensitivity and Specificity of a Rapid HCV Test Matrix Specificity (n=450) Sensitivity (n=122) Oral Fluid 100% ( %) 99.2% ( %) Venous Whole Blood 100% ( %) 100% ( %) Fingerstick Blood 100% ( %) 100% ( %) Plasma 99.8% ( %) 100% ( %) Serum 99.8% ( %) 100% ( %) Lee SR, et al J. Clin Virol. (2010) 48:

29 Sensitivities and Specificities in Each Specimen Type for the OraQuick HCV Rapid Antibody Test- CE Approved Claims Matrix Sensitivity a Specificity a TP Proportion (95% CI b ) TN Proportion (95% CI b ) Serum 756/ % (99.3%, 100.0%) 1422/ % (99.6%, 100.0%) Plasma 755/ % (99.3%, 100.0%) 1420/ % (99.5%, 100.0%) Venipuncture 753/ % (99.9%, 100.0%) 1421/ % (99.5%, 100.0%) Fingerstick 752/ % (99.0%, 100.0%) 1421/ % (99.6%, 100.0%) Oral Fluid 739/ %* (96.9%, 99.0%) 1418/ % (99.2%, 99.9%) Abbreviations: TP = true positive; TN = true negative; CI = confidence interval a. Sensitivity and specificity are calculated based on the HCV-infected or not HCV-infected samples with valid OraQuick Rapid HCV Antibody Test result. b The two-sided 95% exact CI of sensitivity is calculated using the exact method (Clopper-Pearson) by PROC FREQ with options BINOMIAL, EXACT, and ALPHA=0.05. *Of the 12 specimens that were FN in oral fluid alone, only 4 (0.5%) were PCR positive Lee SR et al. Jnl. Virol. Methods (2011) 172:

30 Detection by OraQuick Analytical Sensitivity of a Rapid HCV Test Compared to Laboratory EIA Below EIA Cutoff of 1.0 Limit of Detection (LoD*) of OraQuick HCV = 0.75 S/C in laboratory EIA *LoD determined as the lowest level of antibody (EIA S/C) which the OraQuick test could detect 95% of the time. Testing conducted using multiple lots, across multiple days and operators 30 American Society for Microbiology Meeting 2010

31 Seroconversion Sensitivity of a Rapid HCV Test Compared to Laboratory EIA OraQuick HCV seroconversion results compared to FDA-approved EIA were as follows: OraQuick HCV Rapid Antibody Test Time to Detection Days to Evidence of HCV Infection FDA-Approved anti-hcv EIA Time to Detection Average Difference (OraQuick- EIA) -3.6 (-5.9 to -1.2) OraQuick HCV was able to detect antibodies earlier than the approved EIA in 9 of 18 seroconversion panels and by an overall average of 3.6 days (CIs = 1.2 to 5.9 days earlier). Source: OraQuick HCV Rapid Antibody Test Package Insert 31

32 Positive and Negative Agreement in Fingerstick Whole Blood-FDA Approved Claims Of 1660 symptomatic or at-risk subjects, 719 were HCV infected, 926 were HCV negative and in 15 cases, FDA approved lab tests could not determine HCV status OraQuick HCV Rapid Antibody Test Results Positive Subject HCV Infected Status Negative Unable to Determine Infected Status Positive Negative 11* Invalid % (708/719) 99.7% (923/926) *Six (6) of the eleven (11) were negative for HCV RNA by PCR. 32

33 Positive Predictive Value: Fingerstick Whole Blood The following were the supplemental test results when subjects that were reactive by OraQuick HCV in fingerstick whole blood were tested by RIBA Number of OraQuick Reactive Results RIBA Results Positive Indeterminate Negative 722^ * 2 * Eighteen (18) of the RIBA indeterminate were positive for HCV RNA when tested by PCR. ^ One (1) subject reactive by OraQuick did not have RIBA or PCR completed. These data indicate that the positive predictive value of OraQuick HCV in this high prevalence (43%) population was 98% (708/722) 33

34 Combined serologic testing: role of anti-hbc

35 Costs POC per patient total costs for fingerstick and oral swab HCV tests for public screening program 30$ Kit and min of patient and/or medical assistant time Costs per patient for standard general screening in a public setting 200$ Costs include: Space fees, centrifuge, consents, database set up and maintenance, furniture, office space, call back, shipping, laboratory fees, insurance, legal costs

36 Low-Cost, Speedy Liver Test in Development Third World nations would benefit from the paper-based system, researchers say WEDNESDAY, Sept. 19 (HealthDay News) -- A new test could provide a simple, inexpensive and reliable way to check for liver damage, researchers report. They said the postage-stamp-sized paper-based device shows promise for use in developing countries and as a way to reduce health care costs in the United States. The test was developed by researchers at Beth Israel Deaconess Medical Center in Boston and Diagnostics for All, a nonprofit based in Cambridge, Mass., dedicated to improving the health of people in developing nations. "Our device is designed to use a droplet of blood from a finger prick to deliver results in 15 minutes," research co-lead author Dr. Nira Pollock, an infectious diseases doctor at the medical center and the associate director of the Infectious Diseases Diagnostic Laboratory at Boston Children's Hospital, said in a Beth Israel news release. The test paper changes color in response to increasing levels of liver enzymes. "It could have significant implications around the world, particularly in developing nations where blood tests can be prohibitively expensive and the results can sometimes take weeks to return," Pollock added. Clinical tests showed that the paper-based test was more than 90 percent accurate compared with the gold-standard automated platform test. The test's development is detailed in an article in the Sept. 19 issue of the journal Science Translational Medicine. The next stage is to conduct a field study of the test, which will involve 600 people in Ho Chi Minh City, Vietnam.

37 Summary and conclusions The time is (almost) here for rapid tests = POC testing Provide CEA analyses Define operational details to enhance implementation Need to finalize, in resource poor countries, the acceptance of regulatory authorities High reproducibility Low demands for technical training Consistency across various test settings