Population attributable fraction of genital inflammation and ulceration in HIV risk among discordant couples, Zambia,

Transcription

1 Population attributable fraction of genital inflammation and ulceration in HIV risk among discordant couples, Zambia, th International Workshop on HIV Transmission Kristin M. Wall, PhD Department of Epidemiology Rwanda Zambia HIV Research Group Emory University, Atlanta, GA, USA

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

3 Study population HIV serodiscordant heterosexual couples (M+F- & M-F+) Identified from couples voluntary HIV counseling and testing services (CVCT) in Lusaka, Zambia from Baseline & 3-monthly follow-up Baseline and time-varying demographic, behavioural, family planning, and clinical exposures measured Free outpatient care including routine genital exams and risk reduction counseling provided HIV+ partners referred to antiretroviral treatment (ART)

4 Outcome of interest Incident HIV infection genetically linked to the study partner HIV-negative partners retested 3-monthly using rapid serologic tests Linkage established by comparing conserved PCRamplified nucleotide sequences

5 Exposures of interest: time-varying GUIs Composite variable of genital inflammation (GI) Cervical or vaginal inflammation in women (physical exam) Discharge (physical exam, self-report) Inguinal adenopathy (physical exam) Trichomoniasis, gonorrhea, chlamydia, candida, or bacterial vaginosis (lab diagnosis or sign/symptom-based treatment)

6 Exposures of interest: time-varying GUIs Composite variable of genital ulceration (GU) Chronic or acute genital or perianal ulcers (diagnosed/treated at the research clinic or selfreport) Erosion or friability of the cervix or vagina (physical exam) Treatment of chancroid or HSV Rapid plasma reagin (RPR) serology for syphilis

7 Analysis methods Multivariable Cox models Censoring: ART initiation of HIV+ partners, death/separation within the couple Adjusted hazard ratios (ahrs) and 95%CIs reported Population attributable fractions (PAFs) for GUIs PAF: the population-level reduction in the incidence of a disease that would occur if exposure to a risk factor were removed [(ahr - 1)/aHR] * the proportion of cases exposed

8 Results: HIV incidence N = 1349 M+F- couples 207 incident infections in women 2,848 couple-years (CY) 7.3/100 CY (95%CI: ) N = 1601 M-F+ couples 171 incident infections in men 3,367 CY 5.1/100 CY (95%CI: )

9 Results: couple GUI characteristics M+F- couples (% intervals) Linked transmission p-value M-F+ couples (% intervals) Nontransmitting Nontransmitting Linked transmission p-value WOMAN Inflammation 17% 41% < % 44% <.0001 Ulcer 5% 17% < % 18% 0.06 MAN Inflammation 28% 52% < % 36% <.0001 Ulcer 15% 25% % 23% <.0001

10 Results: couple GUI characteristics M+F- couples (% intervals) Linked transmission p-value M-F+ couples (% intervals) Nontransmitting Nontransmitting Linked transmission p-value WOMAN Inflammation 17% 41% < % 44% <.0001 Ulcer 5% 17% < % 18% 0.06 MAN Inflammation 28% 52% < % 36% <.0001 Ulcer 15% 25% % 23% <.0001 GUIs more common prior to transmission events versus non-transmitting intervals

11 Results: couple GUI characteristics M+F- couples (% intervals) Linked transmission p-value M-F+ couples (% intervals) Nontransmitting Nontransmitting Linked transmission p-value WOMAN Inflammation 17% 41% < % 44% <.0001 Ulcer 5% 17% < % 18% 0.06 MAN Inflammation 28% 52% < % 36% <.0001 Ulcer 15% 25% % 23% <.0001 Inflammation more common than ulceration overall

12 Results: Cox models (M+F-) ahr* 95%CI p-value PAF WOMAN Inflammation < % Ulcer < % MAN Inflammation < % *Controlling for first interval since enrollment, age, and man s viral load

13 Results: Cox models (M+F-) ahr* 95%CI p-value PAF WOMAN Inflammation < % Ulcer < % MAN Inflammation < % *Controlling for first interval since enrollment, age, and man s viral load Inflammation predictive in recipient and donor

14 Results: Cox models (M+F-) ahr* 95%CI p-value PAF WOMAN Inflammation < % Ulcer < % MAN Inflammation < % *Controlling for first interval since enrollment, age, and man s viral load Ulceration only predictive in recipient

15 Results: Cox models (M+F-) ahr* 95%CI p-value PAF WOMAN Inflammation < % Ulcer < % MAN Inflammation < % *Controlling for first interval since enrollment, age, and man s viral load Highest PAF from donor s inflammation

16 Results: Cox models (M-F+) ahr* 95%CI p-value PAF WOMAN Inflammation < % MAN Inflammation < % Ulcer < % *Controlling for the first interval since enrollment, age, woman s viral load, man s circumcision status, and self-reported unprotected sex

17 Results: Cox models (M-F+) ahr* 95%CI p-value PAF WOMAN Inflammation < % MAN Inflammation < % Ulcer < % *Controlling for the first interval since enrollment, age, woman s viral load, man s circumcision status, and self-reported unprotected sex Inflammation predictive in recipient and donor

18 Results: Cox models (M-F+) ahr* 95%CI p-value PAF WOMAN Inflammation < % MAN Inflammation < % Ulcer < % *Controlling for the first interval since enrollment, age, woman s viral load, man s circumcision status, and self-reported unprotected sex Ulceration only predictive in recipient

19 Results: Cox models (M-F+) ahr* 95%CI p-value PAF WOMAN Inflammation < % MAN Inflammation < % Ulcer < % *Controlling for the first interval since enrollment, age, woman s viral load, man s circumcision status, and self-reported unprotected sex Highest PAF from donor s inflammation

20 Conclusions and recommendations: genital inflammation High PAF (23-35%) for GI of donor and recipient Many common GI abnormalities were not STIs (discharge, BV, candida, IA), trich was the only common GI cause Many asymptomatic IAs more common in uncircumcised men and men with white matter accumulation under foreskin Educational, screening, and low-cost treatment Education to increase awareness of abnormal discharges or discomfort Home remedies/hygienic practices are suggested, debated Access to inexpensive antifungals and antibiotics as well as further evaluation of probiotics in the maintenance of healthy vaginal flora

21 Conclusions and recommendations: genital ulceration Relatively high PAF (10-14%) for GU of recipient only Active ulcers (syphilis & HSV) associated with HIV acquisition Many asymptomatic Educational, screening, and low-cost treatment Testing effectiveness of educational interventions about signs/symptoms of active ulcers Routine screening for active ulcers in high-risk HIVpersons Testing effectiveness of treating active ulcers with reinforced condom counseling until the ulcer is healed

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

23 Funding National Institutes of Child Health and Development (NICHD RO1 HD40125) National Institute of Mental Health (NIMH R01 66,767) 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 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.

24 Other covariates of interest Baseline Age, years cohabiting, income, literacy, previous/current pregnancy, fertility intentions, HIV stage and VL of the HIV-positive partner, male circumcision status Time-varying Self-reported protected and unprotected sex acts, sperm presence on vaginal swab wet mount, method of contraception, pregnancy

25 Results: couple characteristics Men 35yo and women 29yo on average Income of $95/month on average Unprotected sex reported in 30% of study intervals 8% HIV+ men and 17% HIV- men circumcised

26 Results Composite GI decomposition: Discharge, BV, candida, trichomonas common (5-16% of intervals) in women Most (50-85%) of the latter 3 were asymptomatic for discharge IA common women (10-39%) and men (37-80% of intervals) IAs more common in uncircumcised men (p<0.05) and men with white matter accumulation under foreskin (p<0.001) Composite GU decomposition: Active ulcers (syphilis and HSV) common in HIV- men (5-18% of intervals) Cervical erosion/friability (4-10% of intervals) common in HIV- women Other multivariable model findings: Couple age disparity, hormonal contraception, and pregnancy were not predictive of HIV infection Uncircumcised HIV-negative men were at increased risk of infection (ahr=2.5; 95%CI: )

27 GI Mechanisms Alteration of the mucosal barrier in the genital tract Recruitment of immune cells which function as HIV-target cells in the HIVnegative partner Increased production of pro-inflammatory cytokines and recruitment of HIVinfected lymphocytes to the genitalia in HIV-positive individuals Increased viral shedding in HIV+ individuals The nature of co-infections and intravaginal practices are highly relevant in this multifactorial process [15-19]. GU Breaks in the genital mucosa with recruitment of lymphocyte HIV target cells thus target cells are exposed If ulceration in the HIV-positive donor is actually not a significant part of the transmission mechanism, this could explain the lack of success of acyclovir treatment among HSV-2 positive/hiv-positive persons to reduce risk of HIV transmission in a RCT conducted in 14 African sites [30]. Even if ulceration in the HIV-positive partner is a risk factor for transmission, only a minority of persons with HSV-2 antibodies actually develop recurrent ulcers [31] (active ulcer being the mechanism). It is not surprising that HSV-2 positivity did not predict seroconversion in our study. GU bleeding during intercourse