1. Department of Epidemiology
Recurrence of detectable herpetic genital lesions in HIV-serodiscordant couples, Lusaka, Zambia
Kristin M. Wall, PhD
Department of Epidemiology
Emory University
Atlanta, GA, USA

2. Conflict of interest
The authors have no conflicts of interest due to financial or personal relationships that might be perceived to cause bias.

3. Background
HSV-2 and herpetic ulcers are risk factors for HIV acquisition
and transmission in several studies
In a Zambian heterosexual HIV serodiscordant couple cohort ( ):
Risk of HIV in women increases when
Women have herpetic ulcers (aHR* = 1.9, p=0.02)
Men partners have herpetic ulcers (aHR* = 1.6, p=0.03)
Risk of HIV in men increases when
Men have herpetic ulcers (aHR* = 3.0, p<0.001)
Baseline HSV-2 positivity was not predictive of HIV risk
*Controlling for age, viral load, duration of follow-up, male circumcision, and self-reported/biological markers of condomless sex
Acquisition 1-3, transmission 19,20

4. HSV-2 baseline prevalence:
Though HSV-2 is common, detectable herpetic genital lesions are relatively rare
HSV-2 baseline prevalence:
Study intervals positive for detectable herpetic (RPR-negative) ulcers:
HIV+
HIV-
P-value
Men (N=1731)
81%
57%
<0.001
Women (N=1891)
90%
82%
62% of couples were concordant positive and 30% discordant for HSV-2
7% of individuals experienced an incident RPR- genital lesion; their median no. recurrences was 2 (IQR=3) for men and 2 (IQR=2) for women.
% study intervals
Men 9%
Women 5%

5. Detectable herpetic genital ulcer
HSV-2
(68-87% baseline prevalence) +
Associated factors
Detectable herpetic genital ulcer
(5-9% of intervals)
HIV risk
aHR=
Studies have evaluated risk factors for incident HSV-2 infection among high-risk individuals 51
Little is known about factors associated with primary and recurrent herpetic genital lesions
This limits prevention, early identification, and treatment to potentially reduce HIV incidence

6. Factors associated with time-to-recurrent detectable RPR- ulcers
MEN
aHRs*
Man HSV-2 baseline positive
1.8
Man’s age (per year increase)
0.98
Increasing HIV stage in men (versus M-)
Incident gonorrhea/chlamydia in men
2.8
Uncircumcised with foreskin smegma (versus circumcised)
WOMEN
aHRs*
Increasing HIV stage in women (versus F-)
Incident gonorrhea/chlamydia in women
1.8
Incident non-STI genital inflammation, discharge, BV, candida
1.7
Incident non-STI genital inflammation in man
2.0
Incident RPR- ulcer in male partner
1.5
*p<0.005
Associated factors were similar when stratifying by baseline HSV-2 and HIV status

7. Detectable herpetic genital ulcer
HSV-2
(68-87% baseline prevalence) +
Associated factors
Detectable herpetic genital ulcer
(5-9% of intervals)
HIV risk
aHR=
HIV positivity and stage
STI and non-STI inflammation
Male circumcision/ hygiene
Implications
Periodic screening for lesions in HIV discordant couples may improve lesion identification and management via counseling, episodic treatment, and possibly suppressive therapy in PLHIV (especially those with higher HIV stage).
Screening and treating for causes of genital inflammation, including non-STI causes, and encouraging male circumcision/hygiene may decrease genital lesion recurrence.
Detectable RPR-negative herpetic ulcers were drivers of HIV acquisition in women and men.
Most individuals never had a detectable herpetic ulcer, regardless of baseline HSV-2 or HIV status.

8. Acknowledgements Rwanda Zambia HIV Research Group (RZHRG) Contributors
William Kilembe
Bellington Vwalika
Lisa Haddad
Shabir Lakhi
Htee Khu Naw
Ilene Brill
Roy Chavuma
Cheswa Vwalika
Lawrence Mwananyanda
Elwyn Chomba
Joseph Mulenga
Amanda Tichacek
Susan Allen
Zambian Ministry of Health & District Health Management Team
Study Participants & Clinic Staff

9. Funding
National Institutes of Child Health and Development (NICHD R01 HD40125)
National Institute of Mental Health (NIMH R )
AIDS International Training and Research Program Fogarty International Center (D43 TW001042)
Emory Center for AIDS Research (P30 AI050409)
National Institute of Allergy and Infectious Diseases (NIAID R01 AI51231; NIAID R01 AI040951; NIAID R01 AI023980; NIAID R01 AI64060; NIAID R37 AI51231)
US Centers for Disease Control and Prevention (5U2GPS000758)
International AIDS Vaccine Initiative
Arise—Enhancing HIV Prevention Programs for At-Risk Populations, through financial support provided by the Canadian Government through Foreign Affairs, Trade and Development Canada (DFATD, formerly CIDA) with technical support from PATH (CID SUB). Arise implements innovative HIV prevention initiatives for vulnerable communities, with a focus on determining cost-effectiveness through rigorous evaluations.
UK Department for International Development (DFID) UK
This study was made possible by the generous support of the American people through the United States Agency for International Development (USAID). The contents are the responsibility of the International AIDS Vaccine Initiative and do not necessarily reflect the views of USAID or the United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

10. Incident HIV in women (N = 1384 M+F- couples)
Cox Models
aHR*
95%CI
P-value
Incident HIV in women (N = 1384 M+F- couples)
Women’s RPR- ulcer
1.9
1.1
3.3
0.024
Men’s RPR- ulcer
1.6
2.4
0.028
Incident HIV in men (N = 1601 M-F+ couples)
3.0
1.7
5.3
<.0001

11. Rates of incident detectable RPR- genital ulcers
MEN
Rate/100PY
95%CI
log rank p-value
HIV+/HSV2+
65.5
61.1
70.0
<0.001
HIV+/HSV2-
29.2
23.2
36.4
HIV-/HSV2+
18.4
15.9
21.3
HIV-/HSV2-
15.0
12.5
17.9
WOMEN
Rate/100PY
95%CI
log rank p-value
HIV+/HSV2+
30.8
28.4
33.3
<0.001
HIV+/HSV2-
26.6
19.8
34.9
HIV-/HSV2+
13.9
11.9
16.0
HIV-/HSV2-
21.4
16.2
27.8