Expedited Partner Therapy (EPT) for
Gonorrhea & Chlamydial Infection
Matthew R. Golden MD, MPH
Center for AIDS & STD, University of WA
Public Health – Seattle & King County
Overview
• Background on development of EPT
• Overview of data from randomized trials
• Barriers to EPT
• Community-level scale-up
Gonorrhea — Rates: United States, 1941–2006
and the Healthy People 2010 target
Rate (per 100,000 population)
500
Gonorrhea
2010 Target
400
300
200
100
0
1941
46
51
56
61
66
71
76
81
86
91
96
Note: The Healthy People 2010 target for gonorrhea is 19.0 cases per 100,000 population.
2001
06
Chlamydia — Rates: Total and by sex: United States,
1987–2006
Rate (per 100,000 population)
600
Men
Women
Total
480
360
240
120
0
1987
89
91
93
95
97
99
2001
03
Note: As of January 2000, all 50 states and the District of Columbia had regulations
requiring the reporting of chlamydia cases.
05
Chlamydia in Minnesota
Rate per 100,000 by Year of Diagnosis, 1992-2007
300
Rate of Chlamydia per 100,000 .
275
250
225
200
273 per 100,000
175
150
125
100
75
50
115 per 100,000
25
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Year
Figure 35. Nonspecific urethritis — Initial visits to physicians’
offices by men: United States, 1966–2000
160
Adjusted chlamydia
prevalence
Gonorrhea incidence
0.14
0.12
140
120
0.1
100
0.08
80
0.06
60
0.04
40
0.02
R2=0.95
0
20
0
GC cases per 100,000 women
0.16
19
88
19
90
19
92
19
94
19
96
19
98
20
00
20
02
20
04
Proportion of positive chlamydia
tests
Adjusted chlamydia prevalence in Infertility Prevention Project
(IPP) clinics & gonorrhea incidence, 1988-2005
Chlamydia — Positivity Rates by Age and Gender
MIPP† Clinics, 2002-2007
20%
Males, 15-19
Females, 15-19
Males, 20-24
Females, 20-24
Percent Positive
(No. positive / No. of tests)
16%
12%
8%
4%
0%
2002
2003
2004
2005
2006
2007
Year
† The Minnesota Infertility Prevention Project (MIPP) is a project funded by the CDC to provide STD testing and treatment to uninsured men and women ages 15-24.
Participating clinics include STD, family planning, adolescent, and community clinics.
Pelvic inflammatory disease — Hospitalizations of women
15 to 44 years of age: United States, 1980–2003
Hospitalizations (in thousands)
200
Acute, Unspec.
Chronic
160
120
80
40
0
1980
82
84
86
88
90
92
94
96
98
2000
02
Pelvic inflammatory disease — Initial visits to physicians’ offices
by women 15 to 44 years of age: United States, 1980–2004
Visits (in thousands)
500
400
300
200
100
0
1980
82
84
86
88
90
92
94
96
98
Note: The relative standard error for these estimates ranges from 19% to 30%.
SOURCE: National Disease and Therapeutic Index (IMS Health)
2000
02
04
Ectopic pregnancy — Hospitalizations of women 15 to
44 years of age: United States, 1980–2003
Hospitalizations (in thousands)
100
80
60
40
20
0
1980
82
84
86
88
90
92
94
96
98
2000
02
16
Racial Disparities in a Probability Sample of
American Adolescents
14
14
13.3
12
White
Black
Latino
Asian
Native American
10
8
6
4
4.4
2.5
3.3
1.9
2
0.13
0.13
0
Risk
Ratio
Chlamydia
1.0 5.5 1.8 1.3 5.3
Gonorrhea
1.0 14.6 1.0
JAMA
2004:291:2229
Gonorrhea Rates by Race/Ethnicity
Minnesota, 1997-2007
White
American Indian
Hispanic*
1200
Rate per 100,000 persons .
1000
Black
Asian/PI
800
600
400
200
0
1997
1998
1999
* Persons of Hispanic ethnicity can be of any race.
2000
2001
2002
Year
2003
2004
2005
2006
2007
Gonorrhea & Chlamydia in the U.S.
Circa 2008
• Gonorrhea rates are very low relative to the 1970-80s
• Chlamydia probably dropped with the introduction of
screening
• Major morbidity from gonorrhea and chlamydia is way
down
• Burden of disease is now probably roughly stable
• Dramatic racial disparities persist
• Additional progress will require new approaches
Strategies to Improve the Control of Bacterial STD
• Primary prevention – behavior change
• Primary & secondary prevention - Case-finding & treatment
• Increase screening
• Rescreening – retest those with an STD at 3 months
• Improve partner treatment
Partner Notification
• Process of notifying the sex partners of persons with an
STD and assuring their treatment
• Public health authorities developed partner notification
programs in the 1940s for syphilis
• Public health advisors interview people with STD and
notify their partners
• Growth in the 1960s and 70s and assumed some
responsibility for gonorrhea
• Contraction in the 1980s – tentative response to HIV, no
response to chlamydia
PN: Data from mathematical models
Source: Am J Epi 2001;153:90
Percent Interviewed for PN
Percentage of Cases of STD/HIV Interviewed for PN in
High STD/HIV Morbidity Areas of U.S., 1999-01 & 2006
100
80
1999-2001
2006
10
12
89 87
60
52
40
32
20
17
6
0
Syphilis
HIV
Gonorrhea
Sources: STD 2003:30:490, STD 2004;31:709, unpublished
Chlamydia
Could We Provide DIS Services To
Everyone with a Reportable STD?
• ~ 1.5 million cases of HIV, syphilis, gonorrhea,
and chlamydia reported annually in U.S.
• ~2800 Disease Intervention Specialists (DIS) to
provide services to 75% of cases
• ~ $200 million annually for DIS
• CDC STD budget = $108 million in 2007
Chlamydia partner notification practices among private sector
providers in King County (n=150)
100
Percent
80
90
60
40
20
17
0
Source: STD
1999;26:543-7.
Told
patient to
notify
partners
Knows all
partners
treated
4
Gave
patient
medication
for partners
Outcomes of partner notification for gonorrhea and
chlamydial infection by patient referral
Number
STD
% partners
evaluated
Colorado 1977
93
GC
51%
Colorado 1985
3368
GC
62%
Canada 1992
37
CT
68%
London 1994
254
CT
53%
Amsterdam 1997
440
GC/CT
40%
Seattle 2001
698
GC/CT
51%
Indianapolis 2002
241
GC/CT/NGU/TV
65%
France 2002
145
Any STD
49%
City (yr)
Expedited Partner Therapy (EPT)
• Global term for process of treating partners without
their mandatory prior examination
• Patient delivered partner therapy (PDPT) – index
patient gives meds to partners
• Most common form of EPT
Proportion of women “reinfected” with Chlamydia
trachomatis based on partner notification practices:
Swedish observational data
15
10
10.2
8.4
5
0
4.8
1.8
No PN
Source: Int. J STD & AIDS 1991;2:116
Pt.
referral
Conditional
referral
Pt delivered
prescription
Proportion of patients with chlamydial infection to
whom physicians give medications for their sex
partners
60
50
40
44
Chlamydia
50
30
Gonorrhea
34
31
20
10
0
8
Never
N=2,538 CT N=1,873 GC
Sometimes
7
Half
9 7
6 4
Usually
Always
Source: Sex Trans Dis 2005;32:101
3 RCTs of Expedited Partner Therapy (EPT)
Study
Multi-city CT
in ♀1
Population
1787 Women
screened CT+
– mostly FP
clinics
Intervention
Patient-delivered partner
therapy (PDPT)
Seattle
CT/GC2
Populationbased
All offered assistance
1) PDPT
2) Partners contacted
by hlth. dept. offered
direct Rx
2751 Men &
Women
Outcome
- Partner
treated*
- Infection at 1&
4 months
- Partner
treated*
- Infection at 34 months
Follow-up
90% 1 month
55% 3-4
months
68% at 10-18
weeks
New Orleans
urethritis3
977 STD clinic
patients
2 Interventions
1) Informational booklet
2) PDPT
- Partner
treated*
- Infection at 12 months
85% Interview
30%
specimen
Scotland CT
303 Women in
STD, FP and
Abortion clinics
2 Interventions
1) PDPT
2) Mailed specimen
-Partner treated
- Infection w/in
12 months
65%
* Partner treatment per participant report in all studies except Scotland
Sources: Schillinger et al Sex Transm Dis 2003;30:491, Golden et al NEJM 1992;352:6762, Kissinger et al
Clin Inf Dis 2005;41:6233, Cameron ST et al, Num Reprod 20094
Partner treatment per index patient report
100
Percent
80
Standard
Expedited
P<.0001
83
82
P<.0001
61
60
57
65
50
40
P=.001
20
11
6
0
Talked to
partner about
STD
Partner "very
likely" treated
All partners
treated
Sex untreated
partner
Source: NEJM 2005;352:676
Percent
Infection during follow-up among 1860 persons
completing the randomized trial
16
14
12
10
8
6
4
2
0
Standard care
Expedited care
P=.02
P=.17
13.2
13
10.8
10.6
P=.04
9.9
3.4
Gonorrhea
Chlamydia
N=358
N=1595
Source: NEJM 2005;352:676
Gonorrhea or
Chlamydia
N=1860
Impact of PDPT on Index Patient GC/CT Reinfection
in 4 Randomized Controlled Trials
CT in women (CDC multi city trial)
GC or CT in men or women (Seattle)
Urethritis in men (New Orleans)
0.19
0.8
0.62
0.59
0.76
0.38
0.74
0.54
CT in women (Scotland)
0.1
1.05
0.98
1.32
1
Log Odds Ratio
3.56
10
Impact of PDPT on Index Patient Report that Partner
was Treated in 4 Randomized Controlled Trials
Study
Multi-city CT in ♀
Seattle CT/GC
New Orleans
urethritis
Scottish CT in ♀*
PDPT
Control P-value
86%
57%
0.001
64%
52%
0.001
56%
34%
0.001
94%
78%
0.02
* Outcome is all partners contacted, not treated
Subgroup Analysis: Reinfection Partner Study
12
10
EPT
Standard
11.2
10.5
Percent
9.6
8
9.4
9.1
7.4
6
8
7.8
6.6
6.2
6.2
5.1
4
7.4 7.4
7.2
4.2
2
0
Age
<=20
Age
>20
White African
Am
1 sex >1 sex
partner partner
Relative risks associated with receipt of standard care 1-2-1.8
Sources: Golden et al NEJM 1992;352:6762 (unpublished data)
Male
Female
Subgroup Analysis: Percentage of Partners Treated
100
EPT
Standard
80
Percent
77
60
67
63
53
76
65
56
55
48
40
66
66
63
50
56
47
37
20
0
Age
<=20
Age >20
1 sex
partner
>1 sex
partner
Relative risks associated with receipt of EPT 1-2-1.3
Sources: Golden et al NEJM 1992;352:6762 (unpublished data)
Male
Female
Casual
partner
Not
Casual
CDC & Professional Activities Related to EPT
CDC Dear Colleague Letter
Date
5/05
Expedited Partner Therapy Review & Guidance
Document
2/06
American Medical Assoc. Statement on EPT
6/06
Legal Status EPT Evaluation
6/06
STD Treatment Guidelines
8/06
CDC EPT Website
10/6
New Partner Notification Guidelines
2008
Am. Acad. Pediatrics Supports EPT
2008
Barriers
• Is this legal, and what is my liability?
• Is this an acceptable standard of medical
care?
• Will EPT promote antimicrobial
resistance?
• Is this ethical?
Legal Status of EPT in the United States
WA
ME
ND
MT
OR
ID
MN
NY
WI
SD
MI
WY
PA
IA
NE
NV
IL
UT
CO
CA
KS
OH
IN
WV
VA
MO
KY
NC
TN
OK
AZ
SC
AR
NM
MS
AL
TX
GA
LA
FL
AK
HI
Source: Adapted from Hodge
JG. AJPH 2008;98:236
EPT Permissible
EPT newly legal
EPT Prohibited
EPT legal status uncertain EPT under consideration
Legal Issues in MN
• “Nothing in this chapter prohibits a licensed practitioner
from issuing a prescription or dispensing a legend drug
in accordance with the Expedited Partner Therapy in the
Management of STD guidance document issued by the
US CDC.”
• CDC recommends that EPT when other management
options are impractical or unsuccessful
http://www.cdc.gov/std/treatment/EPTFinalReport2006.pdf
Legal Issues
Information to provide with
EPT
• Name of original patient
sufficient in MN
• Information about
medications & STD
• Advice about
complications and need
for care (e.g. PID)
• Where to seek care
Information in MN
• MN Dept Health has
information sheets on their
website that can be
distributed with medications
http://www.health.state.mn.us/divs/idepc/dtopics/stds/ept/ctinstructions.pdf
Liability
• You can always be sued
• Are you acting in a manner that is consistent
with standards of care in your community?
• Can you be sued for not providing EPT?
Is EPT a Good Standard of Care?
• A complete evaluation of all partners would
be best
• Are we missing concurrent diagnoses?
• Are we placing partners at significant risk of
adverse drug reactions?
STD diagnoses in persons presenting as contacts to
gonorrhea, chlamydia or NGU/MPC
Seattle, Baltimore, Birmingham and Denver
Women
(n=2507)
Gonorrhea*
3.9%
PID
3.7%
Heterosexual Men Men who Have
Sex with Men
(n=3511)
(n=460)
3.1%
6.1%
NA
NA
New HIV
0
0.2%
5.5%
Early Syphilis
<0.1%
0
0.4%
* GC excludes contacts to GC.
Source: CID 2005;40:787
Adverse Drug Reactions
• Anaphylaxis to macrolides is very rare
• PCN
– Anaphylaxis with cephalosporins is rare (0.10.0001%)
– ~10% of people report having a PCN allergy
– Cross reactivity to 3rd gen cephalosporins 1-3%
– Only avertable reactions are those occurring in
persons with a known allergy who take meds
despite written warnings
• No cases anaphylaxis to date in CA and WA
Antimicrobial Resistance
• No known chlamydial resistance to azithro
• Cephalosporin resistant GC very uncommon is U.S.
– Some evidence rising MICs in Japan
• Standard of care is to treat contacts to GC &
chlamydia without awaiting test results
– EPT primarily increases antimicrobial use by
increasing appropriate treatment of partners
• In 2005, 55 million prescriptions for Azithro; 3 million
cases of chlamydia in U.S.
Ethics
Respect for Patient Autonomy
Beneficence
Nonmaleficence
Justice
• Insofar as RCTs show decreased reinfection in
index cases given EPT, EPT is a superior standard of
care
• Is EPT better for the partner? Can partners make
an informed decision?
EPT Guidelines
CDC
CA
MN
WA
Heterosexual “Can be used as
GC & CT
an option when
other management
strategies are
impractical or
unsuccessful.”
Partners who are
“unable or
unlikely to seek
timely treatment”
Most
appropriate for
partners who
are unable or
unlikely to seek
prompt clinical
services.
Give if
partner
treatment
“not
otherwise
assured”
MSM
GC & CT
Should not be
considered a
routine partner
management
strategy
No different
recommendation
– acknowledges
potential risk
Not
recommended
as routine
MSM should
be referred to
health Dept.
Trichomonas
Not recommended
as routine
Not addressed
Not
recommended
as routine
Not
addressed
California State EPT Program
• Guidelines promulgated and published
(Sex Transm Dis 2007, epub)
• Paying for EPT
• Medicare waiver to pay for PDPT denied
• State bulk purchasing medication for PDPT for
Infertility Prevention Program clinics
• CDC funded evaluation in family planning clinics
CA Family Planning Clinic Evaluation: Association of Treatment
Outcome with Management Strategy by Relationship Type
Partner Notification Method
Employed
Patient Referral
Bring Partner to Clinic (BYOP)
PDPT
None
Percentage Partners Treated, by
Index Case Report
100
80
79
10
77
60
20
54
40
40
20
14
12
0
Source: Yu. 2007 CDC STD Prevention Conference
Patient
Referral
BYOP
PDPT
None
Association of Treatment Outcome with
Management Strategy by Relationship Type
Partner
Management
Strategy
Steady Partner
(n=551)
Non-steady Partner
(n=404)
OR (95%)*
OR (95%CI)*
BYOP
3.6 (1.8-7.4)
3.5 (1.7-7.0)
PDPT
2.8 (1.4-5.4)
6.0 (3.3-10.8)
Patient referral
1.4 (0.7-2.6)
2.0 (1.2-3.3)
1.0
1.0
None
*OR adjusted for patient’s age and race/ethnicity
Source: Yu. 2007 CDC STD Prevention Conference
Steps in Developing and Implementing A New Public Health Intervention
Evaluate Existing System & Literature on Alternatives
Design Intervention
Consider Feasibility for Wide-Spread Implementation
Individual Level Randomized Controlled Trials
Cost-Effectiveness Analysis (relative CEA)
Re-Design Intervention for Scale-up
Model Population-Level Impact
Community-Level RCT
Scheme of PN Barriers & Interventions
Index patient
diagnosed &
treated
Partner Notified
BARRIERS Doesn’t know partner(s)
Doesn’t like partner(s)
Can’t reach partner(s)
Afraid of partner(s)
INTERVENTION
DIS
Partner Treated
Access to care
(clinic hrs, transportation)
Partner asymptomatic - not
concerned
Pt Delivered Rx
Proportion of Patients with Untreated Partners at Time of
Study Interview
100
80
60
40
20
+ Risk Factor
No Risk Factor
0
0
2
4
6
8
10
12
14
Days Between Treatment & Interview
Risk factors: > 1 sex partner 60 days or pt does not anticipate sex with partner in future
Source: STD
2001;28:658
PN CT & GC: where do we go from here?
Association of PN Plan on Case Report Form with PN Outcomes
All partners already treated
Provider to assure PN
Health dept. assistance requested
100
80
60
78
40
20
0
47
42
32
40
6
30
39
16 22
13 11
% Given PDPT by % with Untreated
Given PDPT by
Increase in
Clinician Before
Partners
Health Dept.
Partner
Health Dept.
Treatment*
contact
Source: Golden et al. Sex
* Limited to persons contacted >7 days after treatment
Transm Dis 2007;epub
Percentage of Persons with Gonorrhea or Chlamydia in King
County Given PDPT by Their Diagnosing Provider
50
40
30
20
10
16
5
0
1998-2002
2004-2005
Use of PDPT remained significantly greater in the 2004-05 (OR 3.2, 95% CI 2.5- 4.1)
compared to 1998-2002 after adjusting for diagnosing site, gender, GC vs. CT, and the
presence of case report risk factors for PN failure
Estimated Percentage of Persons Assuring the Treatment of
All of their Sex Partners Among All Cases* of Gonorrhea or
Chlamydial Infection in King County
100
80
Percent
64
58
60
40
39
20
0
* Nonincarcerated
heterosexuals
No
Intervention
Intervention
without Direct
Public Health
Assistance
Intervention Including
Direct Public Health
Intervention
Assessment of Community-Wide EPT:
Simulation Model
50% → 60% partners treated
Ct prevalence in women (%)
5
4
3
2
1
0
-2
0
2
4
6
8
Years since PDPT introduction
15 realisations, thick line is median.
Includes annual Ct screening of 25% of women aged <26.
10% increase in partner treatment results in a ~25% reduction in
CT prevalence at 2 years, and a ~50% reduction in 4 years
10
Percent infected
Chlamydia Positivity in Women Tested in IPP Clinics in King
County and WA State Outside of King County, 1998-2007
9
8
7
5.8
5.5
6
5
5.4
4.9
4
3
EPT
2
RCT
Begins
1
0
1998
6.3
5.5
6.2
5.7
6.9
6
7.3
5.7
PHSKC
Recommends
EPT
2000
2002
Time
7.5
5.9
7.1
7.1 7.7
5.9 5.6
PHSKC Institutes Free
EPT and Case-Report
Based Partner
Notification Triage
2004
2006
5.9
WA State EPT Community-Level Randomized Trial
• Stepped-wedge community-level randomized trial
• Unit of randomization = health jurisdiction (n=24)
• Timing of program institution is randomly assigned as “steps”
• Every ~6 months - 1st step 9/07, 2nd step 5/08, 3rd step 12/08
• Intervention
• Case-report based triage of cases for assisted partner notification
• Free PDPT distributed via large clinics & commercial pharmacies
• Case report form has prescriptions preprinted for faxing
• Outcome = Prevalence of chlamydia in sentinel clinics (IPP), reported
incidence of gonorrhea in women
Cases with at Least One Partner Treated via EPT from the Diagnosing
Provider, WA State EPT Community-Level Trial Waves 1 and 2
Wave 1
40
Wave 2 Intervention Begins
Wave 1 Intervention
Begins
30
20
10
0
Ju
n07
Ju
l -0
7
A
ug
-0
7
Se
p07
O
ct
-0
7
N
ov
-0
7
D
ec
-0
7
Ja
n08
Fe
b08
M
ar
-0
8
A
pr
-0
8
M
ay
-0
8
Ju
n08
Ju
l -0
8
A
ug
-0
8
Percent
50
Wave 2
Preliminary Outcomes: Wave 1 Communities, WA State EPT,
Proportion of Partners Notified and Treated
Prior Intervention
Intervention Period - Prior DIS Interviews
Intervention Period - Post DIS Interviews
100
80
73
60
P<.0001
71
40
47
55
38
20
50
0
Notified
Treated
Outcomes restricted to persons interviewed >7 days post treatment. Adjusted for
demographic factors.
Conclusions
• Expedited partner therapy (EPT) decreases
reinfection rates and increases the proportion of
partners treated per index patient report
• EPT is legal in MN, but requires that you dispense
information for partners
• EPT can be introduced into a diverse large
communities and appears to have a population-level
effect on the proportion of all partners treated
• The population-level of effect of EPT on the
occurrence of STD or STD associated morbidity,
like that of other STD interventions, has yet to be
proven