STIs and susceptibility to HIV infection R. Scott McClelland, MD, MPH University of Washington

Conflict of Interest Research funding, paid to the University of Washington, from Hologic Corporation Research funding, paid to the University of Washington, for collaboration on NIH UH2/UH3 grant with Becton Dickinson

Outline Summarize (very briefly) the first 30 years of research into STIs and susceptibility to HIV Emphasize conditions with greatest potential impact on HIV susceptibility in populations Highlight opportunities & challenges in future research on STIs and HIV susceptibility In the interest of time, will focus on susceptibility, rather than infectivity. Also, infectivity may be less of an issue in the era of test and treat all, as effective combination ART appears to be effective at prevention transmission even when people living with HIV have coinfection with other STIs.

“Epidemiological Synergy” Wasserheit JN. Sex Transm Dis 1992

RCTs of STI Interventions Hayes et al. AIDS 2010

Why did most interventions fail to reduce STI incidence? STIs do not increase HIV susceptibility? Inadequate interventions? Effective control conditions? Study power? Behavior change? Epidemic stage?

Why did most interventions fail to reduce STI incidence? STIs do not increase HIV susceptibility? Inadequate interventions? Effective control conditions? Study power? Behavior change? Epidemic stage?

Why did most interventions fail to reduce STI incidence? STIs do not increase HIV susceptibility? Inadequate interventions? Effective control conditions? Study power? Behavior change? Epidemic stage?

Why did most interventions fail to reduce STI incidence? STIs do not increase HIV susceptibility? Inadequate interventions? Effective control conditions? Study power? Behavior change? Epidemic stage? Study power: estimation of rate of treatable STIs, estimation of expected HIV incidence, between cluster variability, retention, adherence

Why did most interventions fail to reduce STI incidence? STIs do not increase HIV susceptibility? Inadequate interventions? Effective control conditions? Study power? Behavior change? Epidemic stage?

Why did most interventions fail to reduce STI incidence? STIs do not increase HIV susceptibility? Inadequate interventions? Effective control conditions? Study power? Behavior change? Epidemic stage?

70 Changes in the contribution of genital tract infections to HIV acquisition among Kenyan high-risk women from 1993-2012 Masese AIDS 2015; 29:1077-85 PAF 52.8% 60 50 PAF 22.6% 40 30 20 In this recent publication by Linnet Masese, working with data from the Mombasa Sex worker cohort, the color coding shows 5 year periods spanning from 1993 through 2012. What we see is that HSV-2 (including both prevalent and incident infections), contributes about 53%, while BV/intermediate contribute about 23% to the PAF for HIV acquisition. These PAF for both BV and HSV-2 are very similar to those of Zimbabwean and Ugandan women in a paper published by Janneke van de Wijgert in STD in 2009. In contrast, with the exception of vaginal yeast, most other genital conditions (TV, GC, nonspecific cervicitis, GUD, and genital warts) contribute 1% or less to PAR for HIV. Why does this matter, and how should it shape our approach moving forward? Interventions that address genital conditions with the greatest contribution to PAR would be expected to have the greatest potential impact on population HIV incidence. 10 VVC INTERM BV TRICH GC NON- PREV INCI- GUD GEN- VAG SPEC. HSV-2 DENT ITAL MICRO CX HSV-2 WARTS

HPV and susceptibility to HIV The other condition contributing a high PAF is HPV. Again, as with HSV-2 and vaginal dysbiosis, persistence/chronicity is a factor. Lissouba et al. Sex Transm Infect 2013

Conditions with greatest contribution to PAF of HIV acquisition Vaginal Dysbiosis PAF 23-29% HSV-2 PAF 53-58% HPV PAF 21-37% HSV – but RCTs of suppression have not worked, and recent HSV vaccine trials have not demonstrated efficacy Vaginal dysbiosis – but mechanism not completely understood and interventions may not be sufficient HPV – but epidemiological data are weaker. vaccine an attractive intervention, and but is 9-valent sufficient?

Tightening the link between genital infections and HIV susceptibility Demonstrating the mechanisms through which genital infections increase susceptibility to infection with HIV Providing experimental evidence that genital infections increase HIV susceptibility Feasibile in the era of effective combination HIV prevention?

Understanding mechanisms Laboratory proof Probable Possible Understanding mechanisms

HSV-2 and HIV

CD4 and CD8 cells are present at the site of HSV-2 reactivation for at least 20 weeks, regardless of ACV treatment. They bear HIV co-receptors CCR5 and CXCR4, interact closely with DC. And finally, ex vivo experiments showed that skin biopsies from healed genital herpes lesions supported a substantially greater amount of HIV replication than did skin biopsies from unaffected control areas (2 subjects). Short: High numbers of CD4/CCR5 cells are present at the sites of HSV-2 lesions for at least 20 weeks with or without ACV, they are closely assoc with DC, and in ex-vivo experiments, there is higher HIV replication in specimens from HSV lesion sites compared to control sites. Zhu et al. Nature Med 2009

Vaginal Dysbiosis and HIV

Gosmann et al. Immunity 2017

HPV and HIV

HPV-negative male Male with cleared HPV Tobian et al. J Infect Dis 2013

Experimental and quasi-experimental evidence that STIs increase HIV risk Cartoon credit, Gary Larson

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Randomized trial Strongest evidence, but many obstacles in era of effective combination HIV prevention Low HIV incidence with PrEP and TasP Provide PrEP or just counsel and refer? Adherence to PrEP and new intervention related? Ethical to randomize intervention (eg. HPV vaccine)? Are current interventions adequate? High cost Does the answer to second question differ if intervention is unproven (e.g. vaginal health) vs. proven for another indication (HPV vaccination)

Stepped-wedge cluster RCT Hemming BMJ 2015

Stepped-wedge cluster RCT Experimental design providing strong evidence for causal association, but with some limitations Shares many possible of the possible pitfalls of RCT Variability between clusters Logistically complex to implement Bias due to changing HIV incidence over time May be well-suited to proven intervention with plan to scale up (e.g. HPV vaccination)

Stepped-wedge cluster RCT Experimental design providing strong evidence for causal association, but with some limitations Shares many possible of the possible pitfalls of RCT Variability between clusters Logistically complex to implement Bias due to changing HIV incidence over time May be well-suited to proven intervention with plan to scale up (e.g. HPV vaccination)

Stepped-wedge cluster RCT Experimental design providing strong evidence for causal association, but with some limitations Shares many possible of the possible pitfalls of RCT Variability between clusters Logistically complex to implement Bias due to changing HIV incidence over time May be well-suited to proven intervention with plan to scale up (e.g. HPV vaccination)

Stepped-wedge cluster RCT Experimental design providing strong evidence for causal association, but with some limitations Shares many possible of the possible pitfalls of RCT Variability between clusters Logistically complex to implement Bias due to changing HIV incidence over time May be well-suited to proven intervention with plan to scale up (e.g. HPV vaccination)

Stepped-wedge cluster RCT Experimental design providing strong evidence for causal association, but with some limitations Shares many possible of the possible pitfalls of RCT Variability between clusters Logistically complex to implement Bias due to changing HIV incidence over time May be well-suited to proven intervention with plan to scale up (e.g. HPV vaccination)

Stepped-wedge cluster RCT Experimental design providing strong evidence for causal association, but with some limitations Shares many possible of the possible pitfalls of RCT Variability between clusters Logistically complex to implement Bias due to changing HIV incidence over time May be well-suited to proven intervention with plan to scale up (e.g. HPV vaccination)

Pre-post intervention Lower cost, sidesteps some of the ethics issues, and could be used alongside intervention rollout (e.g. HPV vaccine), but… Non-randomized – might be best suited to generating, rather than proving hypotheses

Conclusion Genital infections with high PAF may be best targets to reduce HIV susceptibility HSV, vaginal dysbiosis, and HPV Important to avoid moving to large and costly trials without understanding the impact of interventions on the mechanistic intermediates Trials to prove causal associations will require thoughtful design to address new challenges in the era of effective combination HIV prevention

Acknowledgements Thanks to Judy Wasserheit for her contributions to this presentation.