# Presentation: 672671

## Clinical Experience withApproved Rapid HIV Tests

- Associate Director for Laboratory Diagnostics
- Divisions of HIV/AIDS Prevention
- National Center for HIV, STD, and TB Prevention
- Centers for Disease Control and Prevention

- Clinical Experience withApproved Rapid HIV Tests

- FDA Blood Products Advisory Committee Meeting
- March 10, 2006

**Notes:**

	Good morning/afternoon.

	My name is ______ and I am __________ from  ___________ in the Division of HIV/AIDS Prevention at the CDC. 

	Thank you for inviting me to talk with you today about CDC’s new Advancing HIV Prevention initiative, which we refer to as AHP.

## Outline

- Background: preliminary results and PPV
- Counseling message: Preliminary positive test
- Post-marketing surveillance: rapid HIV tests
- Rapid HIV test experience in urban programs
- Investigation of false-positive oral fluid tests

- The findings and conclusions in this presentation are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention

## 1989 USPHS Recommendation

*“**The Public Health Service recommends that no positive test results be given to clients/patients until a screening test has been repeatedly reactive on the same specimen and a supplemental, more specific test such as the Western blot has been used to validate those results.”*

*- Interpretation and Use of the Western Blot Assay for Serodiagnosis of HIV-1 Infections.  MMWR R&R 1989; 38(S-7) *

## Slide 4

## SUDS Evaluation: STD Clinic

- Total Tests

- HIV Positive

- Received Results

-     HIV negative

-     HIV positive

-       Returned

-       Required outreach

**Conventional**** **

- Protocol

**n (%)**

- 1,160

-    29 (2.5)

- 337 **(30)**

-   23 **(79)**

-   13 **(45)**

-   10 **(34)**

- Rapid

- Protocol

**n (%)**

- 1,493

-      32 (2.1)

- 1,361 **(93)**

-      31 **(97)**

-      30 **(94)**

-        1   (3)

**%**

**Change**

-   29

-  -16

- 210

-   23

- 109

-  -91

## SUDS Evaluation: STD Clinic

- Total Tests

- HIV Positive

- Received Results

-     HIV negative

-     HIV positive

-       Returned

-       Required outreach

**Conventional**** **

- Protocol

**n (%)**

- 1,160

-    29 (2.5)

- 337 **(30)**

-   23 **(79)**

-   13 **(45)**

-   10 (34)

- Rapid

- Protocol

**n (%)**

- 1,493

-      32 (2.1)

- 1,361 **(93)**

-      31 **(97)**

-      30 **(94)**

-        1   (3)

**%**

**Change**

-   29

-  -16

- 210

-   23

- 109

-  -91

## What if rapid HIV tests were used in public testing sites?

**Source:**  CDC Client Record Database, 1995

## Rapid Tests at All Public Sites

- Learn HIV+

- Learn HIV-

- False + screen

- 36,082

- 2,074,454

- 8,301

- 27,912

- 1,385,129

-   +8,170 (29%)

- +689,325 (50%)

-     8,301

- Outcome

- Rapid Test

- Algorithm

- Current

- Algorithm

- Difference

**Total tests: 2,112,270    Prevalence: 1.6%**

*- Update:  HIV Counseling and Testing Using Rapid Tests—United States, 1995.  MMWR 1998; 47:211-215.*

## 1998: PHS Recommendation Changed

- “Provide preliminary positive HIV test results before confirmatory results are available in situations where tested persons benefit.”

## Positive Predictive Value of a Single Test Depends on Specificity & Varies with Prevalence

**Test Specificity**

- _HIV Prevalence_

- _Predictive Value, Positive Test_

-   10%

-   99%

-   98%

-   92%

-     5%

-   98%

-   96%

-   85%

-     2%

-   95%

-   91%

-   69%

-     1%

-   91%

-   83%

-   53%

-  0.5%

-   83%

-   71%

- 36%

-  0.3%

-   75%

- 60%

-   25%

-  0.1%

-  50%

-   33%

-   10%

**OraQuick**

**Single EIA**

**Reveal **

**99.9%**

**99.8%**

**99.1%**

-   97%

-   95%

-   87%

-   77%

- 63%

-   50%

-   25%

**Uni-Gold**

**99.7%**

*(Calculated based on point-estimates in mfg package insert)*

## Negative Predictive Value of a Single Test Depends on Sensitivity & Varies with Prevalence

**Test Sensitivity**

- _HIV Prevalence_

- _Predictive Value, Negative Test_

-   10%

-   99.96%

-   100%

-   99.98%

-     5%

-   99.98%

-   100%

-   99.99%

-     2%

-   99.99%

-   100%

-   100%

-     1%

-   100%

- 100%

-   100%

-  0.5%

-   100%

-   100%

- 100%

-  0.3%

-   100%

- 100%

-   100%

-  0.1%

- 100%

-   100%

-   100%

**OraQuick**

**Single EIA**

**Reveal**

**99.6%**

**100%**

**99.8%**

-   100%

-   100%

-   100%

-   100%

- 100%

-   100%

-   100%

**Uni-Gold**

**100%**

*(Calculated based on point-estimates in mfg package insert)*

## Qualitative Interpretation of Quantitative Probabilistic Expressions

- Based on positive predictive value:
- “Very likely” you are infected
- “Somewhat likely...”
- “Possible...”
- “There’s a chance...”

## CDC’s Recommended Counseling Message

- “Your preliminary test result is positive, but we won’t know for sure if you are infected with HIV until we get the results from your confirmatory test. In the meantime, you should take precautions to avoid transmitting the virus.”

*-HIV Counseling with Rapid Tests. http://www.cdc.gov/hiv/pubs/rt-counseling.htm*

## Background

- Oraquick Rapid HIV-1 Antibody Test
- Approved  for use with whole blood November 2002
- CLIA-waived February 2003
- Approved for use with oral fluid March 2004
- Approved for HIV-2 detection and name changed to “OraQuick Advance” June 2004
- CDC initiated post-marketing surveillance in 2003

## Postmarketing Surveillance:  Aug 2004-June 2005

|  |  | Seropositivity
Median % (range) |  | Observed Specificity
Median % (range) |
| --- | --- | --- | --- | --- |
| Whole blood
  (n=135,724) 
Oral fluid
  (n=26,066)  | 0.83 (0.08 - 2.60)

1.00 (0 - 4.02)   |  |  | 99.98 (99.73 - 100) 

 99.89 (99.44 -100)  |
|  |  |  |  |  |

- Median seropositivity and specificity** **for 17 project areas

**Notes:**
This slide depicts the observed project area specific median seropositivity and specificity as well as the package insert specificity by Oraquick specimen type.    
There were over 134k whole blood Oraquicks performed.  Median seropositivity was 1.09%, specificity was 99.98% which is consistent with the package insert.  
There were over 25k Oraquicks performed on oral fluid.  3/17 project areas did not conduct OraQuicks on oral fluid during the surveillance period.     The median seropositivity was 0.86%.  Median specificity was 99.90% which is also consistent with the package insert:      
Extra: The whole blood median PPV was 99.24%.
The oral fluid median PPV was 91.09% 

## Postmarketing Surveillance:  Aug 2004-June 2005 Specificity and Positive Predictive Value

|  | Total Tests | True Positive | False Positive | 
Specificity | 
PPV |
| --- | --- | --- | --- | --- | --- |
| Chicago
Whole blood
Oral fluid | 
3,687
2,018 | 
55 (1.5%)
15 (0.7%) | 
1
2 | 
99.97%
99.90% | 
98%
88% |
| Indiana
Whole blood
Oral fluid | 
4,868
593 | 
37 (0.8%)
1 (0.2%) | 
1
1 | 
99.98%
99.83% | 
97%
50% |
| New York City
Whole blood
Oral fluid | 
13,673
8,248 | 
199 (1.4%)
92 (1.1%) | 
7
11 | 
99.95%
99.87% | 
97%
89% |

## Rapid Test Implementation: Chicago1/1/05 – 12/31/05

- 14 Community-Based Partners
- Clinics, community centers, outreach, mobile units
- 4861 tests
- 78  (1.6%) confirmed positive
- 7 Chicago Dept of Public Health Clinics
- Clinics, special testing events, outreach, jail
- 3244 tests
- 52 (1.6%) confirmed positive

## Rapid Test Implementation: Chicago

- Receipt of HIV-positive test results
- 64% in 2004 with conventional testing
- 94% in 2005 with rapid testing
- False-positives:
- 7 (0.056%) of 12,395 rapid tests in 2004-2005
- Rapid testing now offered at all CDPH HIV/STD sites

## Rapid Test Implementation: San Francisco January – September 2005

_**January – September 2005**_

| 
Test | 
# of Tests | 
% of Tests | Confirmed Positives | Positivity Rate |
| --- | --- | --- | --- | --- |
| Rapid Oral | 5741 | 35% | 137 | 2.4% |
| Rapid Finger stick | 1796 | 11% | 45 | 2.5% |
| Conventional  | 9032 | 54% | 311 | 3.4% |

-   As of the third quarter in 2005, 46% of HIV tests were conducted using oral/fingerstick rapid tests.

- *Note that positivity rate is higher for conventional testing, but known positives are sometimes retested to screen for access into care.

## Rapid Test Implementation: Los Angeles1/1/05 – 2/9/06

|  | # of Tests | Invalid | Prelim Positive | Confirmed Positive | False Positive | Incon-clusive | Pending |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Rapid | 9,922 | 9 | 137* | 131 (1.3%) | 3 (.03%) | 2 | 1 |
| Conventional | 11,274 |  |  | 182 (1.6%) |  | 12 | 51 |
| Total | 21,196 |  |  |  |  |  |  |

**Preliminary data.  Data on confirmatory testing were not recorded for an additional 51 preliminary positive rapid tests that are being investigated*

## Rapid Test Implementation: Houston1/1/05 – 11/04/05

|   |   | % | PTC % | New (+) | New (+) PTC |
| --- | --- | --- | --- | --- | --- |
| Total Tests | 19,729 |   | 73.44% | 328 (1.7%) | 178 (54%) |
| Conventional | 9,984 | 50.61% | 48.70% | 262 (2.6%) | 112 (43%) |
| Rapid | 9,745 | 49.39% | 98.78% | 66 (0.7%) | 66 (100%) |

- Note:
-  Conventional testing is performed in Houston Dept of Health clinics
-  Rapid testing is performed in community-based organizations

## Investigation of False-Positive Oral Fluid Rapid Tests

- Press reports of false-positives:
- SF Clinics Getting High False-Positive Rate on Oral HIV Test                 - *San Francisco Chronicle 12/10/05*
- False Positives from HIV Test          *- NY Times 12/11/05*
- Facility Halts Use of Oral HIV Test  *– LA Times 12/16/05*
- More Sites Drop Oral HIV Test       *- LA Times 12/20/05*

## Sources of Data

- 4 prospective studies with parallel testing of whole blood & oral fluid OraQuick, EIA, & Western blot, 2000 - 05
- Outlier analysis, 41 sites in 3 states Sept –Nov 05
- Recent testing data, NY City STD clinics, Dec 05 – Jan 06

## Combined Results:  4 Prospective Studies

|  | Reference Negative | False Positive | 
Specificity |
| --- | --- | --- | --- |
| OraQuick Whole blood | 12,010 | 12 | 99.9% |
| OraQuick Oral Fluid | 12,010 | 54 | 99.6% |
| Serum EIA | 12,010 | 35 | 99.7% |

## Individual Study Results

|  | Reference Negative | False Positive | 
Specificity (95% CI) |
| --- | --- | --- | --- |
| Los Angeles | 5,327 |  |  |
|     Whole blood |  | 4 | 99.9%  (99.8-100.0)  |
|     Oral fluid |  | 21 | 99.6%  (99.4-99.8)  |
|     EIA |  | 23 | 99.6%  (99.4-99.7) |
| MIRIAD | 2,278 |  |  |
|     Whole blood |  | 2 | 99.9%  (99.8-100.0)  |
|     Oral fluid |  | 5 | 99.6%  (99.4-99.8)  |
|     EIA |  | 7 | 99.6%  (99.4-99.7) |

## Individual Study Results

|  | Reference Negative | False Positive | 
Specificity (95% CI) |
| --- | --- | --- | --- |
| Phoenix | 2,000 |  |  |
|     Whole blood |  | 3 | 99.9%  (99.6-100.0)  |
|     Oral fluid |  | 5 | 99.8%  (99.4-99.9)   |
|     EIA |  | 0 | 100%   (99.9-100.0)  |
| Minnesota | 2,405 |  |  |
|     Whole blood |  | 2 | 99.9%  (99.6-100.0)  |
|     Oral fluid |  | 23 | 99.0%  (98.6-99.4)  |
|     EIA |  | 5 | 99.8%  (99.5-99.9)  |

## Minnesota Cluster, Oral Fluid False Positives - 2004

- March 2002 – March 2004:
- 7 false positives, 2017 tests (Specificity 99.7%)
- April 2004 – August 2004:
- 16 false positives, 407 tests (Specificity 96.1%)
- Follow-up study, Feb-May 2005, 9 sites in 3 states:
- 0 false positives, 2,314 tests (Specificity 100%)
- Case-control study could not proceed

## Outlier Analysis, 41 Sites in 3 Jurisdictions: False-positive Oral Fluid tests, Sept-Nov 2005

- Outlier Analysis, 41 Sites in 3 Jurisdictions: False-positive Oral Fluid tests, Sept-Nov 2005

**New York City**

**New Jersey**

**San Francisco**

## New York City: Sept – Nov 2005

|  | NYC - 3 sites with excess FP |  |  |  | NYC -7 sites without excess FP |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | # tests | # false pos | Specificity | # tests | # false pos | Specificity |
| Sept |  | 1662 | 4 | 99.8% | 2316 | 2 | 99.9% |
| Oct |  | 1762 | 10 | 99.4% | 2279 | 1 | 99.9% |
| Nov |  | 1581 | 32 | 98.0% | 2164 | 3 | 99.9% |

## San Francisco: Sept – Nov 2005

|  | SF - 1 site with excess FP |  |  |  | SF -11 sites without excess FP |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | # tests | # false pos | Specificity | # tests | # false pos | Specificity |
| Sept |  | 232 | 8 | 96.5% | 472 | 1 | 99.8% |
| Oct |  | 262 | 9 | 96.5% | 587 | 3 | 99.5% |
| Nov |  | 160 | 6 | 96.3% | 551 | 5 | 99.1% |

## New York City STD Clinics

| Month | # False Positive | # of Tests | Specificity |
| --- | --- | --- | --- |
| August | 5 | 3786 | 99.87 |
| September | 6 | 3978 | 99.85 |
| October | 11 | 4043 | 99.73 |
| November | 35 | 3754 | 99.07 |
| 12/6-21/05 |                Fingerstick testing only |  |  |
| 12/22/05 – 1/17/06 | 31 | 4807 | 99.35 |

## Interim Algorithm, NYC & San Francisco: Finger-stick after Reactive Oral Fluid Test  

- Both rapid tests we ran today were preliminary positive.  It is likely that you have HIV.  To make absolutely sure, we are going to draw blood and send it to our lab so they can run confirmatory testing. The results of those tests will be ready in 1 week.  In the meantime, you should assume that you are infected with HIV, and take all necessary precautions to protect your partners.

**OraQuick Advance Reactive with oral fluid**

**Conduct OraQuick Advance Fingerstick**

**Fingerstick Negative**

**Fingerstick Reactive**

**Counseling Message:**
- Although the oral rapid test we ran today was preliminary positive, the fingerstick test was negative. Because the fingerstick test is a more accurate test, it’s likely that you don’t have HIV.  In order to know for sure, we need to draw blood and send it to our lab for confirmation.  The results of those tests will be ready in 1 week.  In the meantime, you should assume that you _may_ be infected with HIV, and take all necessary precautions to protect your partners.

**Lab runs EIA, IFA/WB**

- Interim Algorithm, NYC & San Francisco: Finger-stick after Reactive Oral Fluid Test

## Positive Oral Fluid Tests with Reflex to Finger-stick, New York City STD Clinics

| Oral Fluid | Finger-Stick | Western blot |
| --- | --- | --- |
| 69 reactive | 32 reactive | 31 positive
1 pending |
|  | 6 refused | 6 positive |
|  | 31 negative | 29 negative
2 indeterminate |
|  |  |  |

**December 22, 2005 – January 27, 2006**

## Conclusions

- Rapid HIV tests demonstrate high specificity, but as with all screening tests, false-positive tests will occur and should be expected.  Confirmatory testing after a reactive test must always be performed.
- More persons learn their HIV status when they receive timely results from rapid tests than with conventional HIV testing.
- OraQuick specificity is slightly lower with oral fluid than with whole blood, but well above FDA’s minimum threshold (98%) with both specimen types.
- Excess false-positive oral fluid tests occurred at a limited number of sites and appear to be related to unidentified site- or host-specific factors.

## Acknowledgements

- Susan Banks (NYC)
- Bob Bolan (LA)
- Evan Cadoff (NJ)
- Jim Dilley (SF)
- Stephen Dziuban
- Shelley Facente (SF)
- Gloria Ferko (OTI)
- Ann Gardner (AZ)
- Keith Kardos (OTI)
- Peter Kerndt (LA)

- Kathleen Krchnavek (WI)
- Patrick Keenan (MN)
- Krishna Jafa (CDC)
- Sindy Paul (NJ)
- Steve Rubin (NYC)
- Ellen Rudy (LA)
- Tracey Sides (MN)
- Patrick Sullivan (CDC)
- Apurva Uniyal (LA)
- Laura Wesolowski (CDC)