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

STI Update

Peter A. Leone,MDAssociate Professor of Medicine

University of North CarolinaMedical Director

North Carolina HIV/STD Prevention and Care Branch

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North Carolina HIV Disease Reports

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

Awareness of Serostatus Among People with HIV and Estimates of

Transmission

~55% of new infections

~45% of new infections

~25%unawareof infection

~75%awareof infection

PLWHA New infections each year

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

Knowledge of HIV Infection and Behaviour

Reduction in unprotected anal or vaginal intercourse with HIVNegative 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

Source of HIV tests and Positive Tests

• 38-44% of adults 18-64 yrs. have been tested• 16-22 million aged 18-64 yrs. tested/yr in U.S. HIV Tests HIV+ Tests

• Private MD/HMO 44% 17% • Hospital/ED/Outpt. 22% 27%• Public clinics 9% 21% • HIV C&T 5% 9%• Drug treatment 0.7% 2% • Correctional facility 0.6% 5%• STD clinics 0.1% 6%

National Health Interview Survey,2002; Suppl; to HIV/AIDS surveillance,2000-2003

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.

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."

Changes to NC Administrative CodeNov. 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.

Changes to NC Administrative CodeNov. 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

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_____________

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

HIV/STD Rule Changes (STD)

• http://www.epi.state.nc.us/epi/hiv/

•Branch Overview

•Current Initiatives

UNC Hospitals Rules ChangesUNC Hospitals Rules Changes UNC Health Care System has required a UNC Health Care System has required a

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

Rules ChangesRules Changes

NOTE: NOTE: Patients must still be notifiedPatients must still be notified in in advance that the test will be performed advance that the test will be performed and, with exceptions below, and, with exceptions below, patients must patients must still consentstill consent to the testing. This notification to the testing. This notification and consent may be done orally, but the and consent may be done orally, but the physician must document in the patient’s physician must document in the patient’s medical record. medical record.

Pre-test counseling is no longer required Pre-test counseling is no longer required for HIV testing. for HIV testing.

Window Periods for HIV Tests

Stekler J. et al CID 2007

HIV viremia during early infection

HIV RNA (plasma)HIV Antibody

11

0 10 20 30 40 50 60 70 80 90 100

HIV p24 Ag

16 22

Ramp-up viremia

DT = 21.5 hrs

1st gen2nd gen

3rd gen

p24 Ag EIA -

HIV MP-NAT -

HIV ID-NAT -

Peak viremia: 106-108 gEq/mL

“blip” viremia

Viral set-point: 102 -105 gEq/mL

4th gen

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

Non-specific Mononucleosis-Non-specific Mononucleosis-like Signs and Symptomslike Signs and Symptoms

FeverFever RashRash Oral ulcerOral ulcer Weight lossWeight loss Loss of Loss of

appetiteappetite HeadacheHeadache FatigueFatigue

AdenopathyAdenopathy Sore throat/ Sore throat/

pharyngitispharyngitis Muscle and/or joint Muscle and/or joint

painpain DiarrheaDiarrhea GI upset/nausea/GI upset/nausea/ vomitingvomiting

Common Signs & SymptomsCommon Signs & Symptoms

44

52

55

57

59

74

86

0 10 20 30 40 50 60 70 80 90 100

adenopathy

pharyngitis

headache

rash

myalgias

lethargy

fever

Vanhems P et al. AIDS 2000; 14:0375-0381. 

% of patients

Study of 160 patients with primary HIV infection in 3 countries

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

PCR Testing of Pooled Sera to Identify Acute HIV Infection

(seronegative, PCR positive)Pooled HIV RNA Testing: Yields

15%NYC 3 STD ClinicsNew York City

10%6/1553 (0.39%)STD clinicWashington DC

5%4/2128 (0.19%)STD clinics, community testing and drug treatment

Atlanta

00/15000STD clinicsMaryland (not Baltimore)

7.1%1/1698 (0.06%)Men tested in 3 STD ClinicsLos Angeles

10.5%11/2722 (0.40%)SF STD Clinic PatientsSan Francisco

13.5%21/5995 (0.35%)Men who have sex with men tested through PHSKC

Public-Health Seattle & King County

4%23/109,250 (0.02%)All persons tested for HIV via North Carolina DOH

North Carolina

Increase in Testing Yield

Prevalence HIV RNA+/EIA-

PopulationProgram

Source: ISSTDR, 2007

Typical Course of Primary HIVTypical Course of Primary HIV

1 mil

100,000

10,000

1,000

100

10

HIV

RN

AH

IV-1

An

tibo

die

s

Exposure

P24 +

0 14 21 28 35

Symptoms

Days

HIV RNA

Ab

+

_

3

Source: Hecht. Primary HIV.

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 RashFatigue Swollen GlandsSore Throat Nausea/Vomiting Night Sweats

Symptoms usually appear about2 weeks after exposureWhat Puts You At Risk?Unprotected SexSharing Needles

The Acute HIV Program 919-966-8533

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 DepartmentsScreening 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.

Acute HIV and North CarolinaSTAT

Wesolowski et al, PLoS 2008

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

Discordant results

• EIA / ELISA + require confirmatory test

WB + WB – WB or +/-

NAAT + NAAT -

NAAT+/-

NAAT ++

HIV+ AHI HIV- AHIRepeat test

Probable -

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

GC

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 0.125 - 0.5 µg/ml. Susceptibility to ciprofloxacin was first measured in GISP in 1990.

Percent

Resistance

Intermediate resistance

0.0

2.0

4.0

6.0

8.0

10.0

1990 91 92 93 94 95 96 97 98 99 2000 01 02 03 04

Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseria gonorrhoeae isolates with resistance to

ciprofloxacin by sexual behavior, 2001–2004

Percent Ciprofloxacin Resistant

Heterosexual

Men who have sex with men (MSM)

0

5

10

15

20

25

2001 2002 2003 2004

Gonorrhea

• Do not use quinolones (cipro, oflox, levo) http://www.cdc.gov/std/gisp

Previous Recommendations2006 NC STD Treatment Guidelines

Uncomplicated Gonorrhea

Cefpodoxime 400 mg PO x 1or

Ceftriaxone 125mg IM

Alternatives: Gentimicin 240 mg IM ( not for oral pharyngeal)- do test of cure

Quinolones: Do test of cure Ciprofloxacin 500mg PO

orOfloxacin 400mg PO

orLevofloxacin 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

2008 NC STD Treatment GuidelinesUncomplicated Gonorrhea

Cefixime 400 mg PO x 1or

Ceftriaxone 125mg IM

Alternatives: Gentimicin 240 mg IM ( not for oral pharyngeal)- do test of cure

Quinolones: Do test of cure Ciprofloxacin 500mg PO

orOfloxacin 400mg PO

orLevofloxacin 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

2006 CDC STD Treatment GuidelinesUncomplicated Gonorrhea

Alternatives:• Spectinomycin 2g IM

Oral Alternatives:

• Cefpodoxime (Vantin®) 400mg PO single dose OR

• Cefuroxime (Ceftin®) 500mg PO single dose

Percent of GC Re-infection in Males by Study

7.0

14.8

22.0

5.0

46.0

0.0

5.1

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0

% Re-infection

Golden 2005

Kissinger 2005

Peterman 2005

Sparks 2003

McKee 2000

Gunn 2004

Mehta 2003

Fung et al. National STD Prevention Conference. 2006

Urethritis Management

• 2006 CDC STD Guidelines:

If Chlamydia or Gonorrhea positive, some experts suggest repeat Chlamydia or Gonorrhea Testing in About 3 Months

Treponema pallidum

Primary(Chancre)

Secondary(Rash)

Latent Syphilis(No signs of disease)

Tertiary

The Course of Untreated SyphilisThe Course of Untreated Syphilis

Benign gummatousCardio-vascular syphilisNeurosyphilis

Benign gummatousCardio-vascular syphilisNeurosyphilis

1-2 years

Early Syphilis

1-2 years

Early Syphilis

Many yearsto a lifetime

Late Syphilis

Many yearsto a lifetime

Late Syphilis

6 weeksto

6 months

6 weeksto

6 months

Many yearsto a lifetimeMany yearsto a lifetime

Approx.18 monthsApprox.

18 months

Incubation period9 – 90 days

Incubation period9 – 90 days

Infe

ctio

nIn

fect

ion

Primary and Secondary Syphilis – United States

Diagnosis of Syphilis

• Darkfield microscopy

• Direct immunofluorescence

• Polymerase chain reaction (PCR)

• Serology• Nonspecific (Cardiolipin-based)

• Specific (Treponemal)

Serological Tests for Syphilis

Non-treponemal (reagin) tests

Complement Fixation Test Wasserman reaction

Flocculation Reactions Rapid plasma reagin (RPR) test

VDRLTRUST

Treponemal (specific) tests TPI

FTA-ABSTPHATPPAELISA (EIA)

Automated chemiluminescence platformsCurrent Chromatographic (POC) Tests

Principle of theRapid Plasma Reagin

Test

RPR Rotator

Qualitative RPR Test

Quantitative RPR Test

End-Point Titer(1:64)

Reactivity of Non-treponemal Serological Tests by Stage of Syphilisand Influence of Successful Treatment

Serologic Tests for SyphilisSerologic Tests for Syphilis

Test Sensitivity by stage of untreated syphilis Specificity Primary Secondary Latent Late

VDRL 74-87% 100% 88-100% 37-94% 96-99%

RPR 77-100% 100% 95-100% 73% 93-99%

TRUST 77-86% 100% 95-100% 98-99%

MHA-TP 69-90% 100% 97-100% 94% 98-100%

FTA-ABS 70-100% 100% 97-100% 98-100%

Principle of FTA-ABS

Test

Fluorescent Treponemal Antibody Test

Principle of Treponema pallidum Haemagglutination Assay

Treponema pallidum Haemagglutination Assay

Interpretation of ResultsPositive Control Dilution(++)(+)(+)(+/-)(-)(-)

Treponema pallidum Passive Particle

Agglutination Assay (TPPA)

ELISA Test

DiaSorin Liaison Treponemal Chemiluminescence Assay

DiaSorin Liaison Treponemal Chemiluminescence Assay –

Principle of Test

Reactivity of Treponemal Serological Tests by Stage of Syphilisand Influence of Successful Treatment

Use of Treponemal and Non-treponemal Tests to Monitor Impact of Specific Interventions for

Syphilis Among STD Patients

Non-treponemal

Treponemal

% S

ero

posit

ive

15

10

5

Time (Years)0 21 4 5

Interpretation of Serological Tests for Syphilis

• RPR+ve, FTA-ABS-veFalse positive RPR screening test

• RPR+ve, FTA-ABS+veUntreated syphilisPreviously treated late syphilis

• RPR-ve, FTA-ABS+veVery early untreated syphilisPreviously treated early syphilis

• RPR-ve, FTA-ABS-veNot syphilisIncubating syphilisVery late syphilisSyphilis with concomitant HIV infection

Note: These possible interpretations do not necessarily have equal weight

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)

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

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.

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

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.

Suggested Algorithm for Serological Screening for Syphilis

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

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.

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

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

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

Treatment of Partners, Suspect and Associates

Screen:

If < 90 Days : Rx if + or –

If > 90 Days: Rx if +

No Rx if -

Policy for Billing10. "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

HSV Diagnosis

Provided by the State lab• Culture

Not Provided by the State LabNot 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

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

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

Genital Herpes – Suppressive Therapy

HIV-• Acyclovir 400mg po BID• Famciclovir 250mg po BID• Valacyclovir 500mg po qd• Valacyclovir 1g po qd

HIV+• Acyclovir 400-800mg po BID-TID• Famciclovir 500mg po BID• Valacyclovir 500mg po BID

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