Evolution of HIV Diagnostics andand

Goals for the 2010 Conference

Bernard M. Branson, M.D.

Associate Director for Laboratory DiagnosticsAssociate Director for Laboratory Diagnostics

CDC Division of HIV/AIDS Prevention

l iEvolution…

or other influences – like Creationism?…or other influences like Creationism?

FDAAPHL

C

CLSIIndustry

CLIA CDC

Consumer

CLIA CDC

Medical Practitioners

Intellectual Property Rightsg

1987 1992 1987 Vironostika HIV-1 EIA

1992 Fluorognost

IFA

1985 Abbott

HIV 1 EIA

1991 Cambridge

Western blotHIV-1 EIA Western blot

i i Al i h Diagnostic Algorithm: 1989

The Public Health Service recommends that no positive test results be given to clients/patients until a screening test has been repeatedly reactive(i.e., greater than or equal to two tests) on the same specimen and a supplemental more specific testspecimen and a supplemental, more specific testsuch as the Western blot has been used to validate those results validate those results

1989 Almanac

Berlin Wall dismantled

Tiananmen Square

Exxon Valdez

U.S. invades Panama

1987 1994 1992

1987 Vironostika HIV-1 EIA

Vironostika Oral fluid

EIA

Abbott HIV-1/HIV-2

EIA

1985 Abbott

HIV 1 EIA

1992 Murex SUDS

1994 Orasure

Specimen HIV-1 EIA SUDS Specimen Collection

Device

1995 Human Retrovirus Testing Conference:1995 Human Retrovirus Testing Conference:Provide results from rapid tests?

1987 1994 1996 1996 1992

Abb tt 1987 Vironostika

EIA

1994 Vironostika

Oral fluid EIA

Abbott p24 Donor Screen

Calypte HIV-1

Urine EIA

Abbott HIV-1/HIV-2

EIA

1985 Abbott

HIV-1 EIA

1992 Murex SUDS

1994 Orasure

Specimen

1996 Coulter p24

D

1996 HomeAccess HIV 1 Home Collection

DeviceDonor Screen

HIV-1 Home Test System

Alternative specimens Alternative specimens

p24 Antigen testing p24 Antigen testing

Clinical applications Clinical applications of PCR

Home collection Home collection: impact on public healthhealth

HIV-1 viral load HIV-1 viral load assays

Mfg demos: RT PCR RT PCRUrine kitOral fluid deviceHome collection

d i d iNew Recommendation …and a Promise Health-care providers should provide preliminary Health care providers should provide preliminary

positive test results before confirmatory results are available in situations where tested persons benefit.

When additional rapid tests become available for puse in the United States, the PHS will re-evaluate algorithms using specific combinations of two or

id f i d fi i HIV more rapid tests for screening and confirming HIV infection.

Rapid Testing E l ti Evaluation Applications

Challenges to the Testing Algorithm:Testing Algorithm: Repeat sampleOral fluidO u Nucleic Acid

Testing Strategies R id EIA Rapid EIADouble EIAWestern blotWestern blot

New Testing Strategy: New Testing Strategy: detecting early HIV infection for prevention and for estimating incidence

2000 Genetic Systems

1996 1992

Genetic Systems HIV-1/HIV-2 Peptide EIA

1987 Vironostika

EIA

1994 Vironostika

Oral fluid EIA

1996 Abbott p24

Donor Screen

1992 Abbott

HIV-1/HIV-2 EIA

1985 Abbott

HIV-1 EIA

1992 Murex SUDS

1994 Orasure

Specimen

1996 Coulter p24 Donor

SSUDS Specimen Collection

Device

Screen

1999 Roche

Amplicor Amplicor HIV-1

Monitor

Preliminary Preliminary evaluation of avidity index to distinguish index to distinguish incident vs prevalent infection

Evaluation of the Inno-LIA in a testing algorithm for li i ti f th elimination of the

Western blot

2000 2000

COBAS 2002

P l i 2003

GS HIV 1

1992

Genetic Systems HIV-1/HIV-2 Peptide EIA

COBAS Ampliscreen

HIV-1

Procleix HIV-1/HCV

NAT

GS HIV-1 HIV-2 Plus O

EIA

1987 Vironostika

EIA

1992 Abbott

HIV-1/HIV-2 EIA

1985 Abbott

HIV-1 EIA

1992 Murex SUDSSUDS

1999 Roche

Amplicor

2002 OraQuick

HIV 1/HIV 2

2004 Multispot

HIV 1/HIV 2 HIV-1 Monitor

HIV-1/HIV-2 Rapid Test

HIV-1/HIV-2 Rapid Test

Approved package insert:

Intended Use Biological Principles Restrictions Restrictions Warnings Directions for Use I t t ti Interpretation Limitations Performance Characteristics

Ch i Change in Language

“This test is suitable for use in multi-test algorithms designed for statistical validation of rapid HIV test results. When multiple rapid HIV tests are available, this test should be used in appropriate multi test algorithms ”multi-test algorithms.

Comparing new EIAs Comparing new EIAs with old stand-bys

NAAT testing for acute infectionacute infection

Roll-out of rapid Roll out of rapid testing

Options for confirmatory testingy g

2000 2002

Procleix 2003 2006

1992

Genetic Systems HIV-1/HIV-2 Peptide EIA

ProcleixHIV-1/ HCV NAT

GS HIV-1 HIV-2 Plus

O EIA

Procleix Ultrio HIV/HCV/HBV

1987 Vironostika

EIA

1992 Abbott

HIV-1/HIV-2 EIA

2006 Advia

Centaur

1985 Abbott

HIV-1 EIA

1992 Murex SUDS

1/O/2 CIA

SUDS

1999 Roche

Amplicor

2002 OraQuick

HIV-1/HIV-2 id

2004 Multispot

HIV-1/HIV-2 id

2006 Aptima

Qualitative

2008 Ortho Vitros

HIV 1+2 HIV-1 Monitor

Rapid Test Rapid Test Qualitative RNA

HIV 1+2 CIA

Random Access EIAs Random Access EIAs

Acute HIV screening Acute HIV screening

Ch ll ith th Challenges with the current algorithm

Alternatives to the current algorithmcurrent algorithm

Sequence of Test Positivity Relative to WB50 % Positive Cumulative Frequency

natio

n*

PTIM

A

A+O

bC

ombi

n

HIV

-1/2

PA

K

pos

itive

ocle

ix/ A

P

ott r

DN

ARa

d 1/

2+

vlti-S

pot

veal

G2

onos

tka

aQui

ckig

old

Ind

ott A

g/Ab

CO

MPL

ETE

V-1/

2 ST

AT-P

WB

Pro

Abb

Bio- rLav

MulRev

Viro

Ora

Uni

WB

Abb C

HIV

Days before WB positive

25 20 10 5 -2015

Modified from Owen et al J Clin Micro 2008

* = not currently FDA approved

Al i h fi i iAlgorithm: Definition

Overall sensitivity or specificity may be improved by using test combinations under one of two decision rules for resolving discordant results. Assumes that errors in the tests are random and

independent but errors can be systematic as with falseindependent, but errors can be systematic, as with false-negative results in early infection.

Few testing strategies involve only a single test, but the g g y gcosts of “confirmation” can be prohibitive.

i i i f h C Al i hLimitations of the Current Algorithm

Antibody tests do not detect infection in ~ 10% of Antibody tests do not detect infection in ~ 10% of infected persons at highest risk of transmission

Western blot confirmation is less sensitive during early infection than many widely used screening early infection than many widely used screening tests

Delays inherent with centralized screening reduce the “effective sensitivity” because infected persons y pdo not learn their test results

i i i f d Al i hLimitations of Proposed Algorithms

Most look like the traditional algorithm Most look like the traditional algorithm Include Western blot Additional (more expensive) tests if WB is negative Additional (more expensive) tests if WB is negative

Logistics of multiple POC tests can be daunting Cost and space requirements of multiple Cost and space requirements of multiple

laboratory platforms is prohibitive Tests are usually repeated at care site anyway, with ests a e usua y epeated at ca e s te a y ay, t

additional tests (e.g., viral load) for clinical staging and management

Problems with Regulatory ConstraintsProblems with Regulatory Constraints

Not responsive to clinical needs:p Preliminary results from rapid tests but not EIAsUse of rapid tests on potentially exposed infants is

drestricted Not feasible to accumulate sufficient numbers for

required validationsrequired validations

Delays the availability (and improvement) of state-of-the-art technologygy

Cost discourages innovation

Goals for 2010 ConferenceGoals for 2010 Conference

Recommend New Algorithms

Goals for 2010 ConferenceGoals for 2010 Conference

Review the available evidence

Identify the needs of different stakeholdersy

Develop a menu for specific applicationsp p pp

Begin consensus process for updating testing

Agree on a new Algorithm

Begin consensus process for updating testing recommendations

Change

The only people who like change…

The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of

the Centers for Disease Control and Prevention