1. STI Update Peter A. Leone,MD Associate Professor of Medicine
University of North Carolina
Medical Director
North Carolina HIV/STD Prevention and Care Branch

2. North Carolina HIV Disease Reports

3. North Carolina HIV ~32,000 living with HIV
~ 18,000 aware of HIV infection
~12,000-13,000 in care
~30-40% unaware of HIV status

4. Awareness of Serostatus Among People with HIV and Estimates of Transmission
new infections
~45% of
~25%
unaware
of infection
~75%
aware
PLWHA
New infections each year 4

5. Identification of HIV Status to Reduce Transmission
Goal of new CDC recommendations to increase number who know HIV+ status
People do not perceive risk
Clinicians do not offer test
Stigma of identified risk and of testing
Knowing HIV+ status can reduce transmission by: Behavior change
- HAART reducing viral load
MMWR 55:1-7, 2006
Inungu J. AIDS atient Care STDs 16:293, 2002

6. Knowledge of HIV Infection and Behaviour
Results: The analysis integrating all 11 findings indicated that the prevalence of UAV with any partner was an average of 53% (95% confidence interval [CI]: 45%–60%) lower in HIV+ persons aware of their status relative to HIV+ persons unaware of their status. There was a 68% reduction (95% CI: 59%–76%) after adjusting the data of the primary studies to focus on UAV with partners who were not already HIV+. The reductions were larger in between-group comparisons than in within-subject comparisons. Findings for men and women were highly similar.
Reduction in unprotected anal or vaginal intercourse with HIV
Negative partners - HIV positive aware vs HIV positive unaware:
68% (95% CI: 59%–76%)
Source: Marks G, et al. Meta-analysis of high risk sexual behavior, aware vs unaware. JAIDS. 2005 6

7. Source of HIV tests and Positive Tests
38-44% of adults yrs. have been tested
16-22 million aged yrs. tested/yr in U.S.
HIV Tests HIV+ Tests
Private MD/HMO % %
Hospital/ED/Outpt % %
Public clinics % %
HIV C&T % %
Drug treatment % %
Correctional facility % %
STD clinics % %
National Health Interview Survey,2002; Suppl; to HIV/AIDS surveillance,

8. New CDC Recommendations for Screening for HIV infection:
In all health care settings, screening for HIV infection should be routinely performed for all patients age 13-64
Providers should initiate screening unless HIV prevalence has been documented to be <0.1%.
All patients initiating treatment for TB should be routinely screened for HIV infection
All patients seeking treatment for STDs, including all patients attending STD clinics, should be routinely screened for HIV during each visit for a new complaint, regardless of patient specific behavioral risks for HIV infection.

9. Further Modification to “Routinize” HIV testing in Medical Care Settings
"Testing for HIV may be offered as part of routine laboratory testing panels using a general consent which is obtained from the patient for treatment and routine laboratory testing,so long as the patient is notified that they are being tested for HIV and given the opportunity to refuse testing."

10. Changes to NC Administrative Code Nov. 1, 2007
Providers and Laboratories to report HIV/AIDS from 7 days to 24 hrs
HIV testing can be a part of a panel of tests without a standalone written consent just for HIV testing as long as the consent for testing specifies that HIV testing is included.

11. Changes to NC Administrative Code Nov. 1, 2007
Opt-out HIV screening in medical settings and for prenatal and STD visits
Pretest counseling not required
Post-test counseling required only for positives
HIV tests at first prenatal visit and 3rd trimester
Mandatory HIV test at L&D for all women for whom HIV status is unknown and in infant if test not obtained from mother

12. General Consent Form
I hereby voluntarily consent to medical and/or dental examinations, treatments and procedures which are deemed necessary in the opinion of my physician and health care providers, including HIV tests, laboratory tests and x-rays. I understand that my medical information is strictly confidential and is protected by North Carolina General Statute 130A-143 and no guarantees or warrantees have been made to me concerning the results of the examinations, treatments or procedures. My signature acknowledges that I have been given the opportunity to ask questions about this consent form and the opportunity to refuse services.
Client Signature _____________ Date_____________

13. HIV Required Reporting in NC Confirmed HIV infection is defined as: - a positive virus culture - repeatedly reactive EIA antibody test confirmed by WB or indirect immunofluorescent antibody test; - positive polymerase chain reaction (PCR) test; or other confirmed testing method approved by the Director of the State Public Health Laboratory

14. HIV/STD Rule Changes (STD)
Branch Overview
Current Initiatives

15. UNC Hospitals Rules Changes
UNC Health Care System has required a written consent from patients for HIV tests. The HIV testing rules have been revised and, as a result, after January 1, 2008, a separate written consent for HIV testing will not be required. Our General Consent for Treatment contains a consent for routine laboratory testing that encompasses HIV testing.

16. Rules Changes
NOTE: Patients must still be notified in advance that the test will be performed and, with exceptions below, patients must still consent to the testing. This notification and consent may be done orally, but the physician must document in the patient’s medical record.
Pre-test counseling is no longer required for HIV testing.

17. Window Periods for HIV Tests
Stekler J. et al CID 2007

18. HIV viremia during early infection
Peak viremia: gEq/mL
HIV RNA (plasma)
Ramp-up viremia
DT = 21.5 hrs
HIV Antibody
HIV p24 Ag
p24 Ag EIA -
Viral set-point: gEq/mL
HIV MP-NAT -
1st gen
HIV ID-NAT -
2nd gen
4th gen
3rd gen
“blip” viremia 11 16 22 10 20 30 40 50 60 70 80 90
100

19. 3rd Generation HIV assays
Moving the window to the “left”
Increase in ELISA + and WB – or WB+/-
Think AHI but recognize may have false positive

20. Non-specific Mononucleosis-like Signs and Symptoms
Fever
Rash
Oral ulcer
Weight loss
Loss of appetite
Headache
Fatigue
Adenopathy
Sore throat/ pharyngitis
Muscle and/or joint pain
Diarrhea
GI upset/nausea/
vomiting

21. Common Signs & Symptoms
Study of 160 patients with primary HIV infection in 3 countries
% of patients
Vanhems P et al. AIDS 2000; 14:  

22. Role of Rapid Antibody Testing
Makes testing feasible in non-traditional settings
Highly effective for outreach situations (needle exchange, bathhouse testing, “street-corner” outreach)
Increases receipt of positive HIV test results
Where HIV results notification (PCRS) not in place
Might increase requests for HIV testing
Is not preferred in many established testing settings
Cost 2-3x ELISA Ab tests
May defer resource allocation to HIV negatives
May miss AHI

23. PCR Testing of Pooled Sera to Identify Acute HIV Infection (seronegative, PCR positive)
Source: ISSTDR, 2007 23

24. Typical Course of Primary HIV
1 mil
100,000
10,000
1,000
100
HIV RNA
HIV RNA
HIV-1 Antibodies Ab
P24 +
Typical Sequence of Events in Primary HIV Event
Infection 0
Entry of virus into bloodstream 3-7
Detectable HIV-1 RNA 7-14
Detectable p24 antigen
Onset of symptoms (Lindbach)
Peak viremia 21 days, initial doubling time 10 hours (Little, J Exp Med 1999)
Antibody seroconversion 24 days (Lindbach)
Even following the introduction of MP-NAT, a preseroconversion donation with a viral load of ≤ 150 copies of RNA/ml went undetected and resulted in an HIV transmission. (Delwart et al, Vox Sanguis, 2004; 86:171-1.) + _
Exposure
Symptoms 10 3 14 21 28 35
Days
Source: Hecht. Primary HIV. 24

25. Efforts to date to detect and follow up with newly acquired HIV/HCV infections have attempted to highlight the signs and symptoms of a seroconversion illness.
However, despite infection of nearly 60 million individuals worldwide with HIV, fewer than 1,000 cases have been diagnosed in the first month of infection, primarily because of a lack of a specific and recognizable acute retroviral syndrome.
Since acute retroviral syndromes mimic many common febrile illnesses, the true diagnosis (acute HIV) is rarely considered at an initial patient encounter. 25

26. SPREAD THE WORD - NOT HIV
ACUTE
HIV
SYNDROME
If you have an STD, Get Tested for HIV.
Early Detection is Best!
Learn to Recognize IT. Tell a Friend.
Acute HIV is Easily Misdiagnosed.
IT CAN BE MISTAKEN FOR COMMON ILLNESSES
Common Symptoms of Acute HIV:
High Fever
Rash
Fatigue
Swollen Glands
Sore Throat
Nausea/Vomiting
Night Sweats
Symptoms usually appear about
2 weeks after exposure
What Puts You At Risk?
Unprotected Sex
Sharing Needles
The Acute HIV Program
If you suspect you may have Acute HIV, get tested at your Local Health Department or at your doctor’s office.
FREE Screening for acute HIV is done on all HIV tests done through the NC Health Departments
Screening for acute HIV can be done at your doctor’s office – ask for an HIV RNA test in addition to the standard HIV antibody test.
SPREAD THE WORD - NOT HIV

27. Acute HIV and North Carolina STAT27

28. Wesolowski et al, PLoS 2008

29. Discordant results 167,371 rapid HIV ELISA 2589 (1.6%) HIV +
2417 (93%) WB/IFA +
172 (7%) WB/IFA - or +/-
89/182 (52%) repeat confirmatory test
17 (19%) were HIV+ (3 WB +/- and NAAT+)
72/89 (81%) were uninfected (12 repeat WB +/-)
Discordants:
~50% repeat + for which 20% were HIV+ (3 AHI)
Wesolowski et al, PLoS 2008

30. Discordant results EIA / ELISA + require confirmatory test WB +
WB – WB or +/-
NAAT ++
NAAT +
NAAT -
NAAT+/-
AHI
HIV+
AHI
HIV-
Repeat test
Probable -

31. HIV Testing Goals Universal testing of individuals 13-64 yr
Opt-out testing in STD/ Prenatal/Prison settings
Allow uncoupling of pre- and post-test counseling from HIV testing itself
Think and test for AHI ( RNA) with “mono-like” illness in sexually active adult……. Fast Track

32. GC

33. Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseria gonorrhoeae isolates with resistance or intermediate resistance to ciprofloxacin, 1990–2004
Note: Resistant isolates have ciprofloxacin MICs ≥ 1 µg/ml. Isolates with intermediate resistance have ciprofloxacin MICs of µg/ml. Susceptibility to ciprofloxacin was first measured in GISP in 1990.

34. Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseria gonorrhoeae isolates with resistance to ciprofloxacin by sexual behavior, 2001–2004

35. Gonorrhea
Do not use quinolones (cipro, oflox, levo)

36. Previous Recommendations 2006 NC STD Treatment Guidelines Uncomplicated Gonorrhea
Cefpodoxime 400 mg PO x 1 or
Ceftriaxone 125mg IM
Alternatives: Gentimicin 240 mg IM ( not for oral pharyngeal)- do test of cure
Quinolones: Do test of cure
Ciprofloxacin 500mg PO
Ofloxacin 400mg PO
Levofloxacin 250mg PO
Azithromycin 2.0 g PO ( expensive, nausea and vomiting)
Add co-treatment for Ct if not treating with Azithromycin
Plus, Azithromycin 1g PO or Doxycycline 100mg po BID x 7d

37. 2008 NC STD Treatment Guidelines Uncomplicated Gonorrhea
Cefixime 400 mg PO x 1 or
Ceftriaxone 125mg IM
Alternatives: Gentimicin 240 mg IM ( not for oral pharyngeal)- do test of cure
Quinolones: Do test of cure
Ciprofloxacin 500mg PO
Ofloxacin 400mg PO
Levofloxacin 250mg PO
Azithromycin 2.0 g PO ( expensive, nausea and vomiting)
Add co-treatment for Ct if not treating with Azithromycin
Plus, Azithromycin 1g PO or Doxycycline 100mg po BID x 7d

39. 2006 CDC STD Treatment Guidelines Uncomplicated Gonorrhea
Alternatives:
Spectinomycin 2g IM
Oral Alternatives:
Cefpodoxime (Vantin®) 400mg PO single dose OR
Cefuroxime (Ceftin®) 500mg PO single dose

40. Fung et al. National STD Prevention Conference. 2006

41. Urethritis Management
2006 CDC STD Guidelines:
If Chlamydia or Gonorrhea positive, some experts suggest repeat Chlamydia or Gonorrhea Testing in About 3 Months

42. Treponema pallidum

43. The Course of Untreated Syphilis
6 weeks to
6 months
Approx.
18 months
Many years
to a lifetime
Infection
Primary
(Chancre)
Secondary
(Rash)
Latent Syphilis
(No signs of disease)
Tertiary
Benign gummatous
Cardio-vascular syphilis
Neurosyphilis
Incubation period
9 – 90 days
Many years
to a lifetime
Late Syphilis
1-2 years
Early Syphilis

44. Primary and Secondary Syphilis – United States

45. Diagnosis of Syphilis Darkfield microscopy Direct immunofluorescence
Polymerase chain reaction (PCR)
Serology
Nonspecific (Cardiolipin-based)
Specific (Treponemal)

46. Serological Tests for Syphilis
Non-treponemal (reagin) tests
Complement Fixation Test
Wasserman reaction
Flocculation Reactions
Rapid plasma reagin (RPR) test
VDRL
TRUST
Treponemal (specific) tests
TPI
FTA-ABS
TPHA
TPPA
ELISA (EIA)
Automated chemiluminescence platforms
Current Chromatographic (POC) Tests

47. Principle of the
Rapid Plasma Reagin
Test

48. RPR Rotator

49. Qualitative RPR Test

50. Quantitative RPR Test
End-Point Titer
(1:64)

51. Reactivity of Non-treponemal Serological Tests by Stage of Syphilis
and Influence of Successful Treatment

52. Serologic Tests for Syphilis
Test Sensitivity by stage of untreated syphilis Specificity
Primary Secondary Latent Late
VDRL % % % 37-94% %
RPR % 100% % 73% %
TRUST % % % %
MHA-TP % % % 94% %
FTA-ABS % 100% % %
Sensitivity increases with duration of lesion in primary syphilis (serology becomes positive when chancre has been present for avg. of 14 days).
Expect titer of nontreponemal test to be >1:16 in secondary syphilis.
Prozone phenomenon, a rough or weakly reactive appearance seen when there is excess antigen in the serum, occurs in 1-2% of secondary syphilis.
Variation of plus or minus one dilution is expected; an increase of one dilution then may be due to the variability in the test, but increase of two dilutions cannot be attributed to this and suggests treatment failure or reinfection.
MHA-TP a little more specific than FTA-ABS.

53. Principle of
FTA-ABS
Test

54. Fluorescent Treponemal Antibody Test

55. Principle of Treponema pallidum Haemagglutination Assay

56. Treponema pallidum Haemagglutination Assay

57. Treponema pallidum Passive Particle Agglutination Assay (TPPA)
Interpretation of Results
Positive Control Dilution(++)(+)(+)(+/-)(-)(-)

58. ELISA Test

59. DiaSorin Liaison Treponemal Chemiluminescence Assay

60. DiaSorin Liaison Treponemal Chemiluminescence Assay – Principle of Test

61. Reactivity of Treponemal Serological Tests by Stage of Syphilis
and Influence of Successful Treatment

62. Use of Treponemal and Non-treponemal Tests to Monitor Impact of Specific Interventions for Syphilis Among STD Patients
Treponemal 15
% Seropositive 10
Non-treponemal 5 1 2 4 5
Time (Years)

63. Interpretation of Serological Tests for Syphilis
RPR+ve, FTA-ABS-ve
False positive RPR screening test
RPR+ve, FTA-ABS+ve
Untreated syphilis
Previously treated late syphilis
RPR-ve, FTA-ABS+ve
Very early untreated syphilis
Previously treated early syphilis
RPR-ve, FTA-ABS-ve
Not syphilis
Incubating syphilis
Very late syphilis
Syphilis with concomitant HIV infection
Note: These possible interpretations do not necessarily have equal weight

64. Syphilis Serology – Conventional Wisdom
Screen with a Non-treponemal test (eg. an RPR, VDRL Test)
(ie. an inexpensive test with high sensitivity, but which may lack some specificity)
Confirm with a Treponemal test (eg. FTA-Abs, TP-PA, etc.)
(ie. a relatively expensive test which is highly specific, but which may lack some sensitivity)

65. Changing Times in Syphilis Serology
Prevalence of syphilis is extremely low in many industrialized countries
Labor costs have increased
Introduction of treponemal tests which can be fully automated

66. Syphilis Serology – An Alternative Approach in Low Prevalence Settings
Screen with a Treponemal test (eg. TP-PA, EIA, Automated or POC test.)
Confirm with a Non-treponemal test (eg. an RPR, VDRL Test)
It is important that all specimens that test positive with the initial treponemal test be retested with a non-treponemal test to give a better indication of disease that requires therapy.

69. What should we do with discordant treponemal/ non-treponemal results?
For the first time we will detect treponemal Ab- positive, non-treponemal Ab-negative specimens during screening.
This situation has resulted in considerable confusion among both laboratorians and clinicians

70. Suggested Algorithm for Serological Screening for Syphilis
Treponemal Test
RPR - +
(Syphilis, old and new. Treatment usually indicated unless previously treated. Retreat if titer has increased > 4 fold)
(No syphilis diagnosis. Recent infection cannot be ruled out )
(Probably old treated syphilis. Treatment may be indicated if not previously treated)
If false-positive screening treponemal test suspected, or if not previously treated,, retest with a different treponemal test.
If second test is positive then treat unless there is a history of treatment
If second treponemal test is negative, a third treponemal test could be used to resolve the discrepancy between the two treponemal tests.

71. Syphilis Serology The Conventional Wisdom Should Prevail in High Prevalence Settings
It is more important to differentiate between active and previously- treated disease, otherwise overtreatment rates would be unacceptably high
Labor costs largely remain low in comparison to the cost of test kits
The capital and maintenance costs of automated systems may be prohibitive

72. Conclusions
Treponemal screening alone has profound implications for both treatment of individuals and also disease control activities.
There are clearly problems associated with screening with treponemal tests and reporting these results without also performing and reporting a ‘confirmatory’ non-treponemal test result.
CDC is planning a consultation, with APHL, later this year to formulate recommendations regarding laboratory diagnostic testing for STDs including serological testing for syphilis. These guidelines will act as a companion document to the CDC STD Treatment Guidelines.

73. Protocol for Tp +
Tp + and RPR + : untreated syphilis unless R/O by Rx history
Tp + and >4x titer RPR : new infection
Tp + but RPR – :
Hx of previous Rx no further F/U
No Hx of Rx:
Obtain different 2nd Tp
If 2nd Tp + then discuss with patient

74. 2nd Tp Test Obtain different 2nd Tp (probably Tp WB):
If 2nd Tp + then discuss with patient
Unlikely infectious; treat for LLS
If 2nd Tp – then discuss with patient
No further F/U
Atkas et al;Int J STD AIDS 2007
MMWR Aug. 15, 2008

75. 2006 CDC STD Treatment Guidelines Syphilis and PCN Allergy
Primary, Secondary, and Early Latent
Doxy 100mg po bid or tetracycline 500mg qid x 2 wks OR
Azithromycin 2 G po single dose OR
Ceftriaxone 1 g IM/IV daily x 8-10d
Late Latent Syphilis or Unknown Duration
Doxy 100mg po bid or tetracycline 500mg qid x 4 wks
Ceftriaxone?
Neurosyphilis
Ceftriaxone 2 g IM/IV daily for 10-14d as an alternative in neurosyphilis

76. Treatment of Partners, Suspect and Associates
Screen:
If < 90 Days : Rx if + or –
If > 90 Days: Rx if +
No Rx if -

77. Policy for Billing
"All local health departments will offer HIV and STD services at no cost to the client regardless of county of residence.
Exceptions include:
a) asymptomatic clients who request screening for non-reportable STDs (e.g. herpes serology, Hep C)
b) clients who receive follow-up treatment of warts after the diagnosis is established
c) clients who request testing not offered by the state.
These clients may be billed for testing and screening according to local billing policy". Thus, those asymptomatic males who request and are willing to pay for a chlamydia test can be billed for the chlamydia test. Your protocol should include a stat gram stain for symptomatic males to rule out GC. If the gram stain is negative, the client should be treated in accordance with the NGU protocol whether or not the chlamydia test is done

78. HSV Diagnosis Provided by the State lab Culture
Not Provided by the State Lab
PCR (Not FDA approved for genital site)
Western blot
FDA Approved IgG type specific tests include:
HerpeSelect® ELISA HSV-2 or HSV-1
HerpeSelect® Immunoblot for HSV-2 and HSV-1
Biokit HSV-2 Rapid Test
SureVue HSV-2
Detection of HSV-2 Antibody Using Type Specific Serology
When no lesion is available to culture or the lesion has started healing, consider type specific serology. There are several accurate type specific serology tests available.
Western Blot is the gold standard test for HSV-2, developed by Dr. Rhoda Ashley Morrow at the University of Washington. It is not commercially available, however the lab does accept shipments from offices. Call for information. Cost to the patient is approx. $ Results are available in 4-6 days.
There are FDA Approved IgG type specific serology tests available. There are also many non-type specific tests on the market so it’s important to know which test your lab runs.
The sensitivity and specificity for the HSV-2 tests are listed below:*
Sensitivity Specificity
Western Blot HSV
HerpeSelect ELISA
HerpeSelect Immunoblot HSV
biokitHSV-2 only
Surevue HSV-2
* Test results should be correlated to clinical history and epidemiologic data, as the likelihood of a false-positive result increases with decreasing underlying prevalence of HSV-2.
GSK does not warrant the accuracy of any diagnostic tests. Please consult the manufacturers for further information about these products.
HerpeSelect is a registered trademark of Focus Diagnostics, Inc. GSK has no financial interest in Focus Diagnostics.
biokitHSV-2 Rapid Test is owned by biokit. GSK has no financial interest in biokit.
Captia is a trademark of Trinity Biotech. GSK has no financial interest in Trinity.
References:
1. HerpeSelect Product Information. Focus Diagnostics, Oct. 15, 2004.
2. biokit Package Insert. July 16, 2004.

79. When should type-specific serology be performed?
Recurrent genital symptoms or atypical symptoms with negative HSV cultures
Clinical diagnosis of HSV without lab confirmation
Partner with genital herpes
? patients with multiple sexual partners, HIV+ patients and MSM

80. Genital Herpes – Episodic Treatment
HIV-negative
Acyclovir 400 mg TID or 800 mg BID x 5d or 800mg TID x 2d
Famciclovir 125 mg BID x 5d or 1000mg BID x 1d
Valacyclovir 500 mg BID x 3d or 1 g qd x 5 d
HIV-positive
Acyclovir 400 mg TID x 5-10 d
Famciclovir 500 mg bid x 5-10 d
Valacyclovir 1 G bid x 5-10 d

81. Genital Herpes – Suppressive Therapy
HIV-
Acyclovir 400mg po BID
Famciclovir 250mg po BID
Valacyclovir 500mg po qd
Valacyclovir 1g po qd
HIV+
Acyclovir mg po BID-TID
Famciclovir 500mg po BID
Valacyclovir 500mg po BID
HIV+ persons are likely to be more contagious for HSV. The extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. Some specialists suggest routine suppression of HSV-2+ HIV+ individuals, even if they are asymptomatic

82. HSV and Pregnancy
To date, no increased risk of birth defects in women treated with acyclovir during 1st trimester
More limited data for valacyclovir and famciclovir
Many specialists recommend HSV suppression during third trimester in order to prevent C-section