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

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

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 (1994-2012): 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 1-3,37-39 transmission 19,20

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%

Detectable herpetic genital ulcer HSV-2 (68-87% baseline prevalence) + Associated factors Detectable herpetic genital ulcer (5-9% of intervals) HIV risk aHR=1.6-3.0 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

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-) 1.8-3.5 Incident gonorrhea/chlamydia in men 2.8 Uncircumcised with foreskin smegma (versus circumcised) WOMEN aHRs* Increasing HIV stage in women (versus F-) 1.7-2.6 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

Detectable herpetic genital ulcer HSV-2 (68-87% baseline prevalence) + Associated factors Detectable herpetic genital ulcer (5-9% of intervals) HIV risk aHR=1.6-3.0 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.

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

Funding National Institutes of Child Health and Development (NICHD R01 HD40125) National Institute of Mental Health (NIMH R01 66767) 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.1450-08863-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) UK202340-102 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.

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

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