Tests for Recent Infectionand

CDC’s Plans for the Detuned IND

Bernard M. Branson, M.D.Centers for Disease Control and

Prevention

Less Sensitive EIA Strategy

Principle: As seroconversion progresses

–Antibody titers increase–Antibody “affinity” increases

Window Period and STARHS

HIV

An

tib

od

y

Infection Time 1

Sensitive

EIA

Time 2

LessSensitive

EIA

Window Period

Vironostika:Mean 170 days (95% CI=162, 183)

0

0.5

1

1.5

2

2.5

3

3.5

0 200 400 600 800 1000 1200

Window Period Estimates: Incidence

Days

SO

D

Mean

Mis-classifi

edLong-standi

ng

Misclassified recent

170 days (95% CI=162, 183)

Cutoff

STARHS for Individual Results

Two factors: Variability in different seroconverters Variability in the less-sensitive assay

itself

Distribution of Individual Window Periods

200 400 600 800

days since seroconversion

0.5

1.0

1.5

2.0

SO

D

Proportion of persons with time from seroconversionto test longer than mean window

period

days since seroconversion

200 400 600 800

0.5

2.0

Each line is someone’s optical density curve.The windows with SOD cut off 1.0 end at the horizontal line.

The red curve is the probability density of the windows.The vertical line is at the mean window period.

183

SO

D

1.0

1.5

Proportion of individuals with time fromseroconversion to test greater than 1 year

Each line is someone’s optical density curve.The windows with SOD cut off 1.0 end at the horizontal line.

The red curve is the probability density of the windows.The vertical line is at one year from seroconversion.

days since seroconversion

SO

D

200 400 600 800

0.5

1 .0

1.5

2.0

365

0

100

200

300

400

500

600

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

SOD

Da

ys

Upper 95% CI Mean Lower 95% CI

365

183

Simulated 95% Confidence Interval for the window period (in days) of one personselected from a population, by standardized optical density (SOD)

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

Interpretation of Results

170-day window period is used in formulas to calculate incidence from aggregate data

For individuals: SOD < 1.0: probably seroconverted within 1

year SOD 1.0 or greater: may or may not have

seroconverted > 1 year ago.

Incidence Assays on the Horizon

HIV-1 Plus O, successor to Vironostika

BED antibody capture assay Avidity index IgG subclass assay

IgG Capture BED Assay

Uses synthetic peptide that represents multiple subtypes (B, E, and D)

Captures both HIV antibody and IgG antibodies

Measures increase in proportion of HIV-IgG as infection progresses

Avoids problem of very large dilution step

BED: Changes in OD-n after seroconversion

0

0.5

1

1.5

2

2.5

3

3.5

4

0 200 400 600 800 1000

Days Since Seroconversion

OD

-n

Cutoff 1.0/window 160 days

BED Label Indication

“For surveillance use only. Not for in vitro diagnostic use.”

For CDC’s National Incidence Surveillance: No IDE required No informed consent required No IRB review required

CDC’s IND for the “Detuned Assay”

Began with Abbott 3A11; amended to use Vironostika

BED has utility for both B and non-B subtypes

CDC does not plan to continue or amend the IND because the BED accomplishes CDC’s objective of HIV incidence surveillance.

FDA: General Principles

1. If research (with intention to produce generalizable knowledge) is done with either an unapproved product or off-label use of an approved product, and it involves clinical management in any way (including diagnosis, prognosis, treatment decisions, eligibility for clinical trials, counseling, notification of partners, etc.) then an IND or IDE is required.

FDA: General Principles

2. For clinical lab testing, if done under CLIA as a laboratory practice (subject to CLIA-required validation) and does not violate FDA’s analyte-specific labeling, or as part of the practice of medicine for the management of individual patients, off-label use does not require an IND or IDE. The regulations do not allow this to be a subterfuge for a study; if the purpose is an organized effort to produce generalizable information, users cannot pretend it is clinical use.

FDA: General Principles

3. Accountability. The law prohibits distribution of medical products that are unapproved or used off-label for the purposes of an investigation. The sponsor that provides the material is accountable to ensure that is not misused. If a product is used in a study in a way that is not consistent with its label indication, either the distributor or end-user must apply for an IND/IDE. Proper protocols are required, and FDA has enforcement authority within the U.S. The laws mostly regulate the product, and enforcement falls upon the distributor.

FDA: General Principles

4. An IND is required for biologics (in the case of HIV tests, those approved for screening blood products; an IDE is required for other in vitro diagnostics. (This would apply to either the Vironostika Plus O or the BED.)

Q and A

Is off-label use of the Vironostika Plus O (with the LS procedure), under IRB protocol with informed consent possible without IND?

An IDE is required because this use is part of an investigation.

Q and A

How should CDC manage requests for "Surveillance Use" of the BED in surveillance activities other than CDC's national incidence surveillance;  e.g., might off-label use of Vironostika offer an alternative for this in unlinked surveys with subtype-B specimens?

As long as the use is non-clinical, no IDE is required. There can be linkages between the assay results and identifiers, but only in such a way that it is not possible for the information to get to individuals or practitioners.

Q and A

Want about use of the BED assay outside the U.S.?

If the product is used for clinical purposes outside the U.S., the manufacturer needs to apply to FDA for approval for export. The assay can be used (and distributed outside the U.S.) without export approval if used under the exemption (i.e., non-clinical use such as surveillance.)