AIDS RESEARCH AND HUMAN RETROVIRUSES CONFERENCE SUMMARY Volume 35, Number 7, 2019 Mary Ann Liebert, Inc. DOI: 10.1089/aid.2019.0074 HIV Research for Prevention 2018: From Research to Impact Conference Summary and Highlights Barbara L. Shacklett,1 Julià Blanco,2,3 Lisa Hightow-Weidman,4 Nyaradzo Mgodi,5 José Alcamı́,6 Susan Buchbinder,7 Mike Chirenje,5 Smritee Dabee,8 Mamadou Diallo,9 Kostyantyn Dumchev,10 Carolina Herrera,11 Matthew E. Levy,12 Enrique Martin Gayo,13 Nigel Aminake Makoah,14 Kate M. Mitchell,15,16 Kenneth Mugwanya,17 Krishnaveni Reddy,18 Maria Luisa Rodrı́guez,2 Marta Rodriguez-Garcia,19 Chelsea L. Shover,20 Tripti Shrivastava,21 Georgia Tomaras,22 Michiel Van Diepen,8 Monika Walia,23 Mitchell Warren,24 Amapola Manrique,25 Bargavi Thyagarajan,25 and Tamara Torri26 Abstract The HIV Research for Prevention (HIVR4P) conference is dedicated to advancing HIV prevention research, responding to a growing consensus that effective and durable prevention will require a combination of approaches as well as unprecedented collaboration among scientists, practitioners, and community workers from different fields and geographic areas. The conference theme in 2018, ‘‘From Research to Impact,’’ acknowledged an increasing focus on translation of promising research findings into practical, accessible, and affordable HIV prevention options for those who need them worldwide. HIVR4P 2018 was held in Madrid, Spain, on 21–25 October, with >1,400 participants from 52 countries around the globe, representing all aspects of HIV prevention research and implementation. The program included 137 oral and 610 poster presentations. This article presents a brief summary of highlights from the conference. More detailed information, complete abstracts as well as webcasts and daily Rapporteur summaries may be found on the conference website. 1 Medical Microbiology and Immunology, University of California, Davis, Davis, California. 2 IrsiCaixa, IGTP, Barcelona, Spain. 3 Chair in AIDS and Related Illnesses, Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic-UCC, Barcelona, Spain. 4 Division of Infectious Diseases, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina. 5 University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. 6 AIDS Immunopathology Unit, Instituto de Salud Carlos III, Madrid, Spain. 7 San Francisco Department of Public Health, San Francisco, California. 8 Division of Medical Virology, University of Cape Town, Cape Town, South Africa. 9 Department of Social and Preventive Medicine, University Laval, Quebec, Canada. 10 Research, Ukrainian Institute on Public Health Policy, Kyiv, Ukraine. 11 Faculty of Medicine, Department of Medicine, Imperial College London, London, United Kingdom. 12 Department of Epidemiology and Biostatistics, The George Washington University, Washington, District of Columbia. 13 Immunology Department, Hospital Universitario La Princesa, Universidad Autónoma de Madrid, Madrid, Spain. 14 Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa. 15 MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom. 16 HPTN Modelling Centre, Imperial College London, London, United Kingdom. 17 Department of Epidemiology, University of Washington, Seattle, Washington. 18 Wits Reproductive Health and HIV Institute, University of the Witwatersrand, School of Clinical Medicine, Johannesburg, South Africa. 19 Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. 20 Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California. 21 Department of Infection and Immunology, Translational Health Science and Technology Institute, Faridabad, India. 22 Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. 23 Population Council, New York, New York. 24 AVAC, New York, New York. 25 Global HIV Vaccine Enterprise, New York, New York. 26 International AIDS Society, Geneva, Switzerland. ª Barbara L. Shacklett, et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 598 CONFERENCE SUMMARY AND HIGHLIGHTS 599 Keywords: clinical trial, bNAbs, HIVR4P, immunogens, TasP, Env Introduction RV144 has led to several subsequent vaccine trials. RV144 remains the only vaccine trial to demonstrate efficacy against O pening plenary talks, delivered by Linda-Gail Bekker (Abstract PL01.01)1 (recipient of the 2018 Desmond Tutu Award for HIV Prevention Research and HIV acquisition, with antibodies directed against the V1V2 region of gp120 and ADCC-mediating antibodies correlating with lower acquisition rates, and plasma envelope (Env)- Human Rights), Anthony Fauci (Abstract PL01.03),1 and specific IgA antibodies correlating with risk.3,4 HVTN 100 Sheena McCormack (Abstract PL01.02),1 provided impor- was a phase 1/2 study in low-risk, HIV-uninfected South tant perspectives on the major challenges facing the HIV Africans combining ALVAC-HIV and subtype C gp120 ad- prevention field. Presenting his long-term vision for control juvanted with MF59. As reported by Xiaoying Shen (Ab- of the pandemic, Dr. Fauci introduced the image of two roads stract OA02.03),1 HVTN 100 elicited anti-V1V2 binding converging toward eventual control. The two roads represent antibody responses and antibodies capable of mediating vaccine-based and nonvaccine-based strategies, with the latter phagocytosis and ADCC; however, V1V2 antibody magni- group including condom use, voluntary medical male cir- tude and breadth were lower than those reported in RV144 cumcision (VMMC), prevention of mother-to-child trans- and HVTN 097. A comparison of HVTN 100 and HVTN 111, mission, treatment as prevention (TasP), and pre-exposure presented by Zoe Moodie (Abstract OA02.04LB),1 revealed prophylaxis (PrEP). He emphasized that control of the pan- induction of higher anti-V1V2 IgG titers, NAb titers, and demic appears to be a more realistic goal at this time, rather CD4+ T-cell responses with DNA prime compared with AL- than complete eradication, and that a vaccine capable of VAC prime, supporting further evaluation of DNA in prime- reaching 50%–60% efficacy, used in combination with other boost regimens with Env proteins. Early data from HVTN 100 prevention and treatment strategies, could help attain this goal. paved the way for HVTN 702 (UHAMBO), a randomized, While the number of new HIV infections is declining globally, double-blind study that is currently recruiting participants, and key populations such as adolescent girls and young women in will test immunogens optimized for prevention of Clade C southern Africa, female sex workers, men who have sex with infections. men (MSM), the Lesbian Gay Bisexual Transgender Queer community and people who inject drugs are still dispropor- tionately affected by the epidemic.2 These plenary talks set the Novel immunogen design stage for the remainder of the conference, which also focused In a comprehensive overview, Rogier Sanders (Abstract on vaccine-based and nonvaccine-based strategies for HIV PL03.03)1 summarized current immunogen design efforts, prevention. A list of HIV prevention clinical trials discussed outlining four hypotheses driving these efforts. The ‘‘native at HIV Research for Prevention (HIVR4P) 2018 is presented trimer’’ hypothesis predicts that a stable structural and antigenic in Table 1. mimic of the native, cleaved Env trimer will induce neutralizing antibodies. This is being tested with a third-generation native- More Signposts on the Road to HIV Vaccines like trimer, BG505 SOSIP.664, in the vaccine trial designated The journey of discovery toward an effective HIV vaccine as W001. The second or ‘‘lineage immunogen’’ hypothesis is may be longer than many imagined, but the consensus from based on the observation that bNAbs do not emerge immedi- this conference was that there are now more signposts than ately in response to one antigen, but instead require coevolution ever to guide the way. HIVR4P included a wealth of presenta- of the virus and the antibody response. Therefore, sequential tions exploring our growing knowledge of immune responses, immunization with a series of Envs mimicking those longitu- updates from studies currently underway, views of strategies to dinally produced in individuals who develop bNAbs over time improve the results of RV144, and an examination of the may induce similar antibodies. This is being tested by CHAVI- growing pipeline of vaccine approaches. These include broadly ID using sequential immunogens derived from CH505 gp120 neutralizing antibodies (bNAbs) and CD8+ T-cell pathways to a and SOSIP trimers. vaccine, and DNA, RNA, and mosaic strategies. As concluded In a related approach, José Alcami, Eloisa Yuste, and by John Mascola (Abstract PL04.04)1 in his final plenary talk, colleagues (Abstract SY01.03)1 have synthesized Env tri- ‘‘The path [to vaccine development] will not be short, it will mers from very rare ‘‘acute neutralizers’’; these will be tested probably be bumpy, but reaching the final goal is likely.’’ in a European trial beginning in 2019 within the EAVI2020 Current vaccine studies fall into three broad categories: (i) project. The third or ‘‘germline-targeting’’ hypothesis pre- those following the RV144 trial and aimed at induction of du- dicts that Env immunogens engineered to target germline rable antibody-dependent cell-mediated cytotoxicity (ADCC)- precursors will effectively prime bNAbs. Leading immuno- promoting antibodies; (ii) those aimed at eliciting bNAbs, either gens in this category are the eOD-GT8 60-mer described by by mimicking Env vulnerability sites or by driving immune Bill Schief (Abstract SY01.05),1 426cTM, and BG505 responses from germline B-cells; and (iii) those aiming to elicit GT1.1, all of which are planned for upcoming clinical trials. robust T-cell responses, including those directed toward po- The fourth or ‘‘epitope-focusing’’ hypothesis reviewed by tentially protective but subdominant epitopes. Dr. Sanders reasons that Env vaccines contain many poten- tially distracting epitopes; accordingly, priming with a highly focused immunogen might produce a more focused response. RV144 follow-up The leading immunogen in this category, the fusion peptide- As described by Linda-Gail Bekker (Abstract PL01.01)1 based immunogen FP8_v1-rTTHC, will begin clinical trials in an Opening Plenary talk, the partial protection observed in in 2019 led by the NIH VRC. Table 1. HIV Prevention Clinical Trials that are Described in this Conference Summary Trial Intervention Phase Strategy Trial sites Population Status AMP STUDY Antibody infusion 2b Intravenous infusion of human Botswana, Kenya, Malawi, Women, ages 18–50 Ongoing HVTN 703/HPTN 081 mAb, VRC01 Mozambique, South Africa, Tanzania, Zimbabwe AMP STUDY Antibody infusion 2b Intravenous infusion of human Brazil, Peru, Switzerland, United Men (MSM) and Ongoing HVTN 704/HPTN 085 mAb, VRC01 States transgender persons, ages 18–50 ASPIRE (MTN 020) Vaginal ring 3 DPV ring Malawi, South Africa, Uganda, Women, ages 18–45 June 2015 Zimbabwe CHAPS PrEP 2 On-demand oral TAF/FTC South Africa, Uganda, Zimbabwe Men, ages 13–24 Ongoing compared with TDF (TDF/FTC) for insertive sex DISCOVER PrEP 3 Daily, oral TAF/FTC compared Austria, Canada, Denmark, France, Men (MSM) and TGW, Ongoing with TDF (TDF/FTC) Germany, Ireland, Italy, The ages ‡18 Netherlands, Spain, United Kingdom, United States ECHO (Evidence for Hormonal DMPA, LNG South Africa, Kenya, Swaziland, Women, ages 16–35 Ongoing Contraceptive contraceptives Zambia Options and HIV and HIV Outcomes) study HPTN 046 TasP 3 Oral Nevirapine South Africa, Tanzania, Uganda, Pregnant women ‡18 Completed Zimbabwe and their infants November 600 2011 HPTN 077 PrEP 2a Long-acting, injectable cabotegravir Brazil, Malawi, South Africa, Men and women, ages Completed United States 18–65 July 2018 HPTN 083 PrEP 3 Injectable cabotegravir LA for PrEP Argentina, Brazil, India, Peru, Men (MSM) and TGW, Ongoing South Africa, Thailand, Vietnam, ages ‡18 United States HPTN 084 PrEP 3 Long-acting injectable cabotegravir Botswana, Kenya, South Africa, Women, ages 18–45 Ongoing compared with daily oral Uganda, Zimbabwe TDF/FTC HVTN 097 Vaccine 1b ALVAC and AIDSVAX B/E, South Africa Women and men, ages Completed tetanus toxoid vaccine and 18–40 February hepatitis B vaccine 2015 HVTN 100 Vaccine 1/2 ALVAC prime and bivalent subtype South Africa Men and women, ages Completed C gp120/MF59 boost 18–40 August 2018 HVTN 106 Vaccine 1 Nat-B/CON-S/Mosaic Env DNA Switzerland, United States Women and men, ages Ongoing prime, MVA-CDMR boost 18–50 HVTN 111 Vaccine 1 Subtype C DNA prime and subtype South Africa, Tanzania, Zambia Men and women, ages Ongoing C gp120/MF59 boost 18–40 HVTN 702 Vaccine 2b/3 ALVAC prime and bivalent subtype South Africa Men and women, ages Ongoing C gp120/MF59 boost 18–35 (continued) Table 1. (Continued) Trial Intervention Phase Strategy Trial sites Population Status HVTN 705 Vaccine 2b Ad26.Mos4.HIV prime, Clade C Malawi, Mozambique, South Women, ages 18–35 Ongoing gp140 boost Africa, Zambia, Zimbabwe MTN 030/IPM 041 Microbicides 1 DPV/LNG vaginal rings United States Women, ages 18–45 Completed August 2017 Promise study TasP 3 Oral ZDV, Nevirapine Truvada, India, Malawi, South Africa, Pregnant, postpartum Completed Lamivudine-ZDV, Lopinavir- Tanzania, Uganda, Zambia, women and their September ritonavir Zimbabwe children 2016 Quatro study Vaginal delivery Placebo delivery through South Africa, Zimbabwe Women, ages 18–30 Completed forms—gel, hydroxyethyl cellulose gel, September insert, film, vaginal insert, film, or IVR 2017 or IVR RING STUDY IPM Microbicides 3 DPV vaginal ring South Africa, Uganda Women, ages 18–45 Completed 027 December 2016 601 RV144 Vaccine 3 ALVAC prime and VaxGen gp120 Thailand Men and women, ages Completed B/E boost 18–30 June 2009 RV217 Early Capture HIV Prospective natural history study Kenya, Tanzania, Thailand, Uganda Men and women, ages Completed Cohort Study following high-risk volunteers 18–50, at high risk of September (ECHO) HIV-1 infection 2018 Tsepamo study TasP 3 DTG, FTC/TAF or DTG, FTC/TDF Botswana Pregnant women, ages Ongoing or efavirenz/FTC/TDF ‡18 and their infants UChoose Contraceptive Injectable Nur-Isterate, intravaginal South Africa Women, ages 16–17 Ongoing methods as Nuvaring and daily, oral proxy for HIV Triphasil tablet prevention methods W001 Vaccine 1 Recombinant BG505 SOSIP gp140 Kenya, United States Men and women, ages Ongoing protein trimer 18–50 DMPA, depot medroxyprogesterone acetate; DPV, dapivirine; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; IVR, intravaginal ring; LNG, levonorgestrel; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; TAF, tenofovir alafenamide; TasP, treatment as prevention; TDF, tenofovir disoproxil fumarate; TGW, transgender women. 602 SHACKLETT ET AL. Mosaic immunogen approaches those relying on vector-based delivery, such as adeno- and T-cell-based vaccines associated virus-based strategies presented by José Martı́nez- In HVTN 106, a phase 1 study reported by Nicole Frahm Navı́o (Abstract OA13.05)1; or those modulating antibody (Abstract OA07.01),1 a trivalent group M T-cell mosaic DNA interaction with neonatal Fc receptors to increase plasma vaccine was compared with DNA sequences from transmit- half-life; antibody combinations with different specificities; ted/founder clade B.1059, or group M centralized sequences and synthetic bi- or trispecific antibodies. The latter ap- (ConS). The magnitude of Env-specific CD4+ T-cell responses proach was exemplified by antibody mimetics such as newly was higher in the group receiving the mosaic vaccine, and designed ankyrin repeat proteins (DARPins) presented by response breadth was also greater in the group primed with Matthias Glögl (Abstract PD01.01)1 and a new engineered mosaic DNA. Current and future studies utilizing mosaic bispecific antibody, which successfully protected human- immunogens include the phase 2b HVTN 705 study (IM- ized mice from HIV acquisition. These antibodies, devel- BOKODO), which will utilize Ad26.Mos4.HIV mosaic an- oped by Zhiwei Chen (Abstract SY01.01),1 recognize both tigens combined with trimeric Clade C gp140 protein. This gp120 and CD4. strategy has shown significant protection in nonhuman pri- mates and is demonstrably immunogenic in humans. Talks Advances in Basic Science by Wendy Burgers (Abstract SY06.02)1 and Christian Brander (Abstract SY06.03)1 reviewed the role of T-cells HIV transmission and dissemination in vaccine-mediated protection. Studies to date suggest a role for CD4+ T-cells in supporting effective antibody de- New findings presented at HIVR4P focused on aspects of velopment, and work from Louis Picker’s laboratory on the mucosal HIV transmission and early dissemination. Thomas cytomegalovirus-vectored simian immune deficiency vac- Hope (Abstract PL02.01)1 described the use of novel imag- cine in rhesus macaques indicates a critical role for vaccine- ing approaches to answer questions about early HIV trans- induced, nonclassical CD8+ T-cell responses, restricted by mission, mucosal reservoirs during antiretroviral therapy Major Histocompatibility Complex class II and class I histo- (ART), antibody distribution, and PrEP efficacy in an in vivo compatibility antigen, alpha chain E. There remain gaps in our nonhuman primate model. His group has been at the forefront understanding of the role of T-cells in protection from and/or of developing and applying new technologies to localize and clearance of infection, as well as of how best to measure T-cell quantify viral reservoirs, particularly within mucosal tissues. responses, and what tissues should be sampled. Michael Gale In a session focused on Mucosal Models of Prevention, Ro- (Abstract SY08.04)1 presented transcriptome data from ani- semary Bastian (Abstract OA06.01)1 showed that binding mals in the RhCMV/SIV vaccine study, showing clear segre- affinity between HIV-specific IgG antibodies and various gation between protected and unprotected animals by 3 days mucins correlated with in vitro enhancement of neutralization postvaccination. potency. Marta Rodriguez-Garcia (Abstract OA06.02)1 ex- plored how neutrophils from the female genital tract capture HIV through release of extracellular traps. Antibody-Mediated Prevention Manish Sagar (Abstract SY02.01)1 identified a vaginal Recombinant forms of bNAbs are known to be safe when resident CD1a+ classical dendritic cell (DC) population able to administered by infusion to uninfected individuals, also support CCR5-tropic but not CXCR4-tropic HIV-1 replication known as passive immunization. Lynn Morris (Abstract in vitro, suggesting that these cells might play an active role in SY01.02)1 provided an overview of ongoing and planned the selection of transmitted viral variants during sexual HIV antibody-mediated prevention (AMP) studies. Two studies acquisition. Andrew Harman (Abstract SY02.02)1 provided are currently underway to evaluate the efficacy of the VRC01 evidence of CD11c+ DCs highly susceptible to CCR5-tropic bNAb: HVTN 704/HPTN 085, which focuses on MSM and HIV-1 in male and female genital mucosa. Data from Eric Arts transgender individuals in the Americas, and HVTN 703/ (Abstract SY02.03)1 supported a role of migrating DC select- HPTN 081, which enrolled women in sub-Saharan Africa. As ing and disseminating virus from mucosal sites. He also pro- mentioned previously, there is also a pipeline of double and vided evidence for selection of specific patterns of glycosylated triple bNAb combinations, with improved breadth and po- viruses, raising the question of whether active recruitment/ tency toward acute-early Clade C viruses, which will be infection of lectin-expressing DC could be a mechanism for tested in future trials. The current AMP studies are seen as preferential transmission of viral variants. Finally, Alexandra pivotal proof-of-concept trials; if successful, results of these Schuetz (Abstract SY02.04)1 provided new data on the impact trials will strengthen the rationale for bNAb-based vaccines, of early treatment on HIV replication and mucosal T-cells in an and pave the way for improved prevention trials with passive acute infection cohort from Thailand. Patients treated begin- administration of bNAbs. ning at Fiebig stage I had lower levels of immune activation, Importantly, AMP strategies can also be used to pre- but interruption of ART led to viral rebound in patients treated vent mother-to-child transmission. Ann Hessell (Abstract at all stages. OA13.06LB)1 extended her earlier findings that postexposure Reporting on Lake Victoria fishing communities with a high prophylaxis with passive infusion of bNAbs is able to protect prevalence of both HIV and Schistosoma mansoni, Rupert newborn macaques from oral exposure to SHIV. Protection is Kaul (Abstract OA17.02LB)1 showed that schistosome treat- time- and dose dependent, and is most effective when the ment with Praziquantel reduced HIV entry into cervical and bNAbs are present before the virus is widely disseminated blood CD4+ T-cells. Morgane Rolland (Abstract OA17.03)1 throughout the body. used phylodynamic analysis and modeling of viral growth New data presented at HIVR4P described different im- rates to more accurately assess the duration of the eclipse phase proved AMP strategies currently under development, including of HIV infection. In the RV217 HIV-1 acute infection cohort, CONFERENCE SUMMARY AND HIGHLIGHTS 603 the eclipse phase was estimated to last 6 days for infections by HIV-1 infection of peripheral blood mononuclear cell and single founders, with no obvious effect linked to virus subtype TZM-bl cells in the laboratory. In the case of MPA, the or gender. In oral transmission studies using SIVmac251 to mechanism involved increased activation of CD4+ T-cells model neonatal transmission in rhesus macaques, Roslyn and increased expression of CCR5, mediated through the Taylor (Abstract OA17.05)1 found that the entire digestive glucocorticoid receptor. In a related study, Taguma Matubu tract is susceptible to replicative viral infection, and that the (Abstract OA12.04)1 reported that DMPA, but not NET-EN, majority of infected cells are T-cells. Nicole Naiman (Abstract decreased T-cell activation in response to polyclonal stimu- OA17.06)1 presented data from mother–infant pairs collected lation, suggesting a possible window of immune suppression in Nairobi during the 1990s in a breastfeeding study. IgG at peak MPA levels. This ‘‘window’’ could translate to binding to the gp41 ectodomain was associated with increased heightened susceptibility to HIV infection. The ongoing risk of mother-to-child transmission. ECHO trial of DMPA, the Jadelle implant, and the copper IUD to evaluate whether any of the three methods might actually increase the risk of HIV acquisition was described at A role for the microbiome in HIV susceptibility? the conference, and results are expected in mid-2019. Finally, several speakers discussed the role of microbial A phase 1 pharmacokinetic (PK) study of a dapivirine (DPV) diversity in HIV susceptibility. Heather Jaspan (Abstract and levonorgestrel (LNG) vaginal ring for combined pre- SY10.01)1 reported that higher diversity was consistently vention of HIV and pregnancy risk [MTN-030/IPM 041, associated with increased HIV risk, as were inflammation and presented by Sharon Achilles (Abstract OA12.02LB)1] recruitment of target cells to the mucosa. Connie Celum demonstrated that this ring was safe, well tolerated, and re- (Abstract SY10.02)1 reported on increasing rates of other sulted in adequate DPV and LNG exposure. sexually transmitted pathogens, notably Chlamydia tracho- Focusing on ‘‘safe conception’’ strategies for couples matis and Neisseria gonorrhoeae infection in North America, living with HIV, Renee Heffron (Abstract OA12.05)1 re- especially in MSM, and emphasized the need for more in- ported on a pilot study of HIV prevention in the context of novative ways to address this problem. Cara Wilson (Ab- pregnancy optimization for HIV serodiscordant couples in stract SY10.04)1 reported on the use of in vitro systems to Kenya. Couples utilized a variety of safe sex strategies, in- model the complex interactions between immune cells, HIV, cluding ART, PrEP, VMMC, or timed condomless sex acts. and intestinal microbiota. Her group found that mucosal Encouragingly, the study detected no new HIV infections butyrate-producing bacteria were associated with reduced among the 74 couples enrolled. CD4+ T-cell proliferation and activation. Mucosal microbiomes influence susceptibility to disease PrEP Comes of Age and response to treatment. There is strong evidence that vaginal dysbiosis increases risk of HIV acquisition. How- PrEP impact, PrEP access, and the possibility that PrEP ever, the relationship between hormonal contraception and works differently for different people were running themes HIV susceptibility is less clear. Studies of multiple con- throughout HIVR4P 2018. Conference sessions and presen- traception methods have found that hormonal contra- tations looked at the current and potential future impact of ception optimizes vaginal bacteria over time (as measured PrEP, scale-up options, and opportunities and challenges of by decreased Nugent score). Sharon Achilles (Abstract building social, political, and financial support to make PrEP PL02.03)1 argued that these findings rule out dysbiosis as a available for those who could benefit most. Abstracts focused pathway for hormonal contraception to increase HIV risk. on PrEP acceptability, mathematical modeling of PrEP tar- Two other possible mechanisms are changes in bleeding geting, costs and benefits, and a host of presentations on patterns and decreased condom use. For the vaginal ring emerging PrEP drugs and delivery options that could greatly (NuvaRing), 3 months of data demonstrated a decrease in increase the future impact of PrEP were also discussed. dysbiosis, though accumulation of biomass on the ring was Jared Baeten (Abstract OA23.01)1 reported on HIV in- positively associated with dysbiosis. Considering these cidence in persons using Truvada [emtricitabine (FTC)/ findings, Dr. Achilles identified priority research questions: tenofovir disoproxil fumarate (TDF)] in a total of 46 PrEP What happens to the vaginal microbiome when women have demonstration projects worldwide, involving >10,000 par- more bleeding, even if it is light spotting (as occurs in ticipants. Encouragingly, only 91 incident infections were some women after starting hormonal contraception)? What detected, of which 27 occurred >30 days after the final dose of happens to microbiome with vaginally delivered drugs? Truvada was taken and 17 occurred within the first 3 months What are the longitudinal impacts of intrauterine devices of initiating PrEP, thus may have resulted from an earlier (IUDs) or implants on the vaginal microbiome, and how exposure. This translates to an incidence rate of <1% per year. does the microbiome alter the metabolism and efficacy of These findings emphasize that PrEP adherence is critical for these devices? success. Contraception, pregnancy and HIV risk Who is using PrEP? Hormonal contraception products such as injectable depot Laura Fitch (Abstract OA04.01)1 presented data from medroxyprogesterone acetate (DMPA) and norethisterone AVAC’s Global PrEP tracker (PrEPWatch.org). Data from enanthate (NET-EN) may modulate HIV acquisition risk; the first quarter of 2018 indicated that 309,525 people have however, the biological mechanisms at play remain incom- initiated PrEP globally, with the highest numbers in North pletely understood. Chanel Avenant (Abstract OA12.01)1 America (71%) and sub-Saharan Africa (15%). In North showed that both MPA and luteal phase hormones increased America, the majority of users are MSM, while the majority 604 SHACKLETT ET AL. of users in sub-Saharan Africa are adolescent girls and young doses of bimonthly passively infused VRC01 bNAb are being women. Significant challenges to PrEP uptake and continu- compared with placebo. The ASPIRE and Ring trials previ- ation remain, even in areas of relatively high current usage. ously demonstrated an *30% risk reduction conferred by the Albert Liu (Abstract OA04.06)1 reported on PrEP awareness DPV vaginal ring; subsequent open-label studies pointed to among HIV-uninfected MSM and transgender women greater, *50%, risk reduction. This product is currently (TGW) in San Francisco. In this study, 97% of MSM and under regulatory evaluation. Finally, other novel approaches 79% of TGW were aware of PrEP, yet only 40% of MSM and under development include implants and microneedles, 15% of TGW had used PrEP despite high levels of health which puncture the stratum corneum of the skin, allowing insurance coverage and engagement in health care. Irene direct delivery of drug into underlying tissues. These can take Mukui (Abstract SY04.03)1 described progress and lessons several forms, including dissolving patches applied to the learned from the national rollout of PrEP in Kenya. As of skin. The range of products currently under development May 2017, only 1,425 Kenyans were taking PrEP com- provides hope that the future of biomedical HIV prevention pared with 17,466 in August 2018. This impressive increase will involve user-empowering choices. was achieved through coordinated efforts of national and In an oral abstract session focused on the development of international stakeholders, community members, and a new ARVs, James Cummins (Abstract OA15.01)1 provided focus on specific geographic areas with high incidence data on the PK-pharmacodynamic (PK-PD) properties of clusters. drug-containing intravaginal rings (IVRs) containing the second-generation integrase inhibitor MK-2048 alone or in combination with vicriviroc, inserted and retained for 14 days Optimizing PrEP delivery in Rhesus macaques. Results indicated the utility of the Renee Heffron (Abstract SY07.01)1 provided an over- macaque model for evaluating PK of MK-2048 and con- view of programs that incorporate oral PrEP into programs firming its antiviral activity in vaginal tissues. addressing each stage of women’s reproductive health. For those who desire pregnancy, PrEP can be provided efficiently through safer conception programs. Additional opportunities Treatment as Prevention include integration of HIV prevention into antenatal care and Undetectable equals untransmittable prevention of mother-to-child transmission, family planning clinics and other places where emergency contraception or Nelly Mugo (Abstract RT02.02)1 reviewed the science of abortion care is provided. Challenges to integration were ‘‘undetectable = untransmittable’’ (U = U), the observation discussed, including low funding levels, nonsupportive pol- that suppressive ART has been convincingly and repeatedly icies, and low provider comfort. Nittaya Phanuphak (Ab- demonstrated to prevent sexual transmission of HIV. Based stract SY07.04)1 described the successes of PrEP programs upon multiple published studies, the World Health Organi- led by key populations in Thailand. An impressive scale-up to zation now states that there is scientific ‘‘consensus that 5,000 persons currently on PrEP, up from zero in 2014, was people who have achieved and maintained an undetectable achieved primarily due to community involvement in pro- viral load cannot transmit HIV sexually to their HIV negative gram planning and implementation. partners.’’ This is true irrespective of sexual practices (anal, In a captivating presentation, Sarit Golub (Abstract vaginal, and penile condomless penetrative sex), and within SY07.03)1 identified flaws in current risk-assessment the context of high transmission rates of other sexually practices that contribute to stigma and alienation of potential transmitted infection. However, she also stressed that com- PrEP users. She described an alternative approach to dis- munity trials with weak linkage to ART treatment after a HIV cussing prevention, sexual health and HIV prevention op- diagnosis have failed to produce similar reductions in HIV tions, counseling, in which clients and providers work incidence. Bruce Richman (Abstract RT02.05)1 emphasized collaboratively to understand and address individual clients’ the transformative nature of U = U in dismantling HIV stigma personal health priorities. This approach focuses on reasons and providing a strong argument for universal health care why people might want to take PrEP rather than focusing on access. He emphasized that this message is difficult to com- ‘‘risk,’’ thereby reducing anxiety, increasing sexual satis- municate to the public at large, because ‘‘science doesn’t faction, and improving the sense of control over one’s own have a publicist,’’ and there are many layers of long-standing sexual health. stigma to overcome. New ARVs and combination products for prevention Breastfeeding is an exception 1 Raphael Landovitz (Abstract PL03.01) provided a Lena Serghides (Abstract RT02.03)1 reported that mother- comprehensive overview of work to identify new systemic to-child transmission through breastfeeding appears to be an PrEP products, including oral tenofovir alafenamide (TAF)/ exception to the rule of U = U. In the PROMISE trial of FTC, injectable cabotegravir, bNAbs, the DPV vaginal ring, >2,000 infants and their mothers, transmission rates of 0.6% implantable devices, and microneedle array patches. In the and 0.9% were seen within 12 and 24 months of breastfeed- DISCOVER trial, the safety and efficacy of daily oral ing, respectively. Two of eight women who transmitted the TAF/FTC are being compared with TDF/FTC. Trials are also virus to their infants had confirmed undetectable plasma viral underway to evaluate the safety and efficacy of long-acting load. Similarly, in the HPTN 046 trial, transmission among injectable cabotegravir, which is being compared with daily women on ART was 0.5% at 18 months. Although cell-free oral TDF/FTC in HPTN 083 and 084. In AMP trials, dis- virus is largely eliminated by ART, latently infected CD4+ cussed elsewhere, the safety and efficacy of two different T-cells harboring cell-associated HIV DNA are not. Given CONFERENCE SUMMARY AND HIGHLIGHTS 605 the large amount of breastmilk consumed over a 6-month Elaine Abrams (Abstract SY11.02)1 discussed recent period, infants may be exposed to many latently infected findings from the Tsepamo study that Dolutegravir (DTG) CD4+ T-cells. Furthermore, some women have detectable use at conception may increase the risk of neural tube defects, HIV RNA in breastmilk despite undetectable levels in plas- leading to WHO guidelines restricting DTG use among wo- ma. Thus, unfortunately U does not equal U in the context of men of childbearing age to those using reliable contraception. mother-to-child transmission. That said, breastfeeding deci- She drew parallels with historical restrictions on the use of sions in resource-poor settings must also weigh the impor- Efavirenz (EFV) by women of childbearing age, based upon tance of preventing malnutrition and diarrheal/pneumonia small numbers of cases of neural tube defects, which ham- diseases against the relatively low risk of HIV transmission pered treatment rollout. After more than two decades, she for women on suppressive cART. noted, EFV appears to be safe and is not associated with neural tube defects. Sharon Hillier (Abstract SY11.04)1 The Future of Prevention Research asked ‘‘How much do any of us really understand about risk?’’ She highlighted that while overall there had been a If a single sentiment permeated this third biennial HIVR4P balanced response to warnings regarding DTG use among meeting, it may have been the sense of excitement at women of childbearing age, there are lessons that can be the richness of the prevention pipeline, and the variety of learned. She discussed that after WHO warnings about DTG new prevention approaches and products in development. use in pregnancy, the HPTN 084 study, examining the effi- Presentations on new prevention drugs and delivery sys- cacy of long-acting cabotegravir (CAB LA)—structurally tems—including inserts, implantables, gels, biodegradable related to DTG—among women aged 18–45 has required its polymers, refillable reservoirs, osmotic pumps, and more— participants to use long-acting contraception, meaning that drew crowds in Madrid. So did discussions about the op- there will be data gaps on the safety of yet another PrEP drug portunities and obstacles created by the increasing number of in pregnancy and periconception. prevention options available and in development. Among these are the challenges of evolving trial design, the need to Choice in Prevention Options understand user preference and evaluate health system ca- pacity, managing product introduction and, of course, main- ‘‘Show Me The Ring’’ taining financial and political support for biomedical HIV The themes of user choice and the need for more and better prevention. user-controlled prevention options, including options that can protect women without their partner’s knowledge, reso- Trial design in the PrEP era nated throughout the conference. Interest was high in the A major challenge for clinical trial design in the PrEP era is status of the DPV ring, as well as in new rings and other that alternative PrEP agents are being compared with oral female-controlled products in development. Updates on TDF/FTC as the current standard of care. Sheena McCormack vaginal and rectal microbicides also filled conference rooms (Abstract PL01.02)1 discussed novel trial designs to assess the in Madrid, with delegates anxious to learn the latest on these efficacy of new HIV prevention products in this environment. long-sought-after forms of prevention. Noninferiority studies require a larger sample size and longer Craig Hendrix (Abstract PL03.02)1 reviewed the pipeline follow-up than traditional studies due to the high efficacy of for on-demand, topical (vaginal/rectal) PrEP. He summarized the TDF/FTC regimen. To overcome this challenge, back- evidence that such products can be effective, arguing that ground HIV incidence in the source population may be used as choice from among a range of prevention options leads to an estimate of what incidence would be in a hypothetical increased uptake, drawing parallels with contraception. He placebo group. This can be incorporated into a novel measure described vaginal and anal microbicides in development, of effectiveness, termed the averted infections ratio, which beginning with the Pod-IVR, a vaginal ring that can deliver compares the proportion of infections averted by the new drug flexible drug combinations. Studies published in 2018 re- with that averted by TDF/FTC. Another approach, also ad- vealed that some drugs (FTC and MVC) can achieve pro- dressed by Deborah Donnell (Abstract SY03.02),1 uses a tective levels in the rectum when delivered through pod multiarm, multistage trial design, allowing multiple agents vaginal rings. Other novel products included fast-dissolving and/or interventions to be compared with a single placebo vaginal films, vaginal and rectal inserts, and numerous mul- group, thereby reducing the number allocated to placebo. tipurpose formulations that provide protection against other From the regulatory perspective, Jeffrey Murray (US FDA) STIs and/or deliver contraceptive agents. At least eight phase (Abstract SY03.01)1 noted that noninferiority trials in women 1 trials of rectal microbicides have been or will soon be may be difficult due to the absence of consistent historical conducted. Several of these are aiming to be behaviorally comparison data. congruent; that is, by adding PrEP to a product that people already use as part of their sexual routine, in this case lubri- cants and douches used by >85% and >75% of MSM, re- HIV prevention in women of childbearing age spectively. Studies have shown promising feasibility and Anne Lyerly (Abstract SY11.01)1 explored ethical con- acceptability of a rectal microbicide douche for MSM. Dr. siderations regarding HIV prevention trials in women of Hendrix finished with a call to ensure that microbicide de- childbearing age. She showed how exclusion of pregnant velopment continues to be a priority, to provide as wide a women from research studies means that knowledge about range of HIV prevention choices as possible. the PDs and safety in pregnancy of medications used for Presented by Elizabeth Montgomery (Abstract OA04.04),1 HIV treatment and prevention lags many years behind drug the Quatro study of 200 young women in Zimbabwe and South approval. Africa tested the acceptability of four vaginal placebo delivery 606 SHACKLETT ET AL. modalities: monthly rings and precoital films, inserts and New strategies of vaccine design are following several gels. The findings from adherence marker evaluation con- well-defined routes to reach 50%–60% efficacy, suggested as firmed that most women did use the products, over half of the the lowest acceptable threshold for a vaccine candidate to be women who chose an on-demand product used them with used in combination with other prevention strategies. In sex, and older women were more adherent. Findings from the parallel, bNAbs are emerging as important new tools in the study highlighted that users desired multiple prevention op- repertoire of feasible prevention strategies. For both these tions; accordingly, women should be given various options to approaches, data from ongoing studies will be eagerly choose from. awaited at the next HIVR4P meeting. Adolescents in South Africa account for 40% of new in- Condom use, VMMC, prevention of mother-to-child fections, yet little is known about preferred prevention mo- transmission, TasP, and PrEP have also made significant dalities in this group. Findings from UChoose, a study of strides as nonvaccine-based strategies for HIV prevention. prevention choices in adolescent women ages 15–19, were Multipurpose products, providing protection against HIV and presented by Katherine Gill (Abstract OA05.06LB).1 This pregnancy, will provide exciting new options for women. open-label, randomized crossover study used licensed con- It was clear from discussions in the meeting rooms, poster traceptive modalities (monthly vaginal rings; injectables; sessions, and hallways that hope persists that the future of oral contraceptives) to assess acceptability and preferences. biomedical HIV prevention will include a wide array of Results suggested that long-acting injectable PrEP would prevention modalities. Behavioral research has demonstrated have the highest acceptability, followed by vaginal rings, and that preferences for specific modalities vary greatly, and the finally, oral pills. availability of multiple options may help us to develop a wider range of implementation strategies to reach more men and women worldwide. Ensuring that scientific advances ‘‘Give Me Prevention That Lasts’’ progress from the laboratory to clinical trials to the com- Continuing with the theme of choice in prevention, those munity remains a challenge that HIVR4P participants are seeking news on systemic prevention approaches encoun- poised to address. tered an expanding universe of data on long-acting PrEP at The next HIVR4P conference will be held in Cape Town, HIVR4P, including the first tail-phase data on long-acting South Africa, in October 2020. injectable cabotegravir in women. Reported by Elizabeth Tolley (Abstract OA05.01),1 A Acknowledgments phase 2 study by the HIV Prevention Trials Network, HPTN The authors acknowledge the conference participants who 077, sought to test acceptability of CAB LA in HIV unin- agreed to release the contents of their presentations. They fected, low-risk men and women in Brazil, Malawi, South apologize to all those whose important work could not be Africa, and the United States. There was a strong preference cited in this review due to space limitations. Conference Co- for long-acting injectable PrEP at both baseline and follow- Chairs for HIVR4P 2018 were José Alcamı́ of the Instituto de up, particularly from participants outside the United States. Salud Carlos III, Spain; Susan Buchbinder of the San Fran- Susan Ford (Abstract OA15.05)1 presented a CAB Po- cisco Department of Public Health, United States; Mike pulation PKs model that included intrinsic and extrinsic Chirenje of the University of Zimbabwe College of Health factors, developed with data from phase 1/2 studies and Sciences, Zimbabwe; and Georgia Tomaras of Duke Uni- simulations that can be used to inform PrEP phase 3 dosing versity, United States. Conference partners for HIVR4P 2018 strategies. Results revealed that the CAB LA absorption rate included the French National Agency for Research on AIDS differs between males and females, and provided informa- and Viral Hepatitis (ANRS); Bill and Melinda Gates Foun- tion that can be used to develop recommendations for re- dation; Gilead Sciences*; Glaxo-SmithKline (GSK); Gov- initiation strategies for those with prolonged interruptions in ernment of Spain (Gobierno de España, Ministerio de Ciencia, dosing. Innovación y Universidades); Instituto de Salud Carlos III; the Finally, Raphael Landovitz (Abstract OA15.06LB)1 and International AIDS Vaccine Initiative (IAVI); International colleagues provided results from HPTN 077 evaluating tail- Partnership for Microbicides (IPM); Janssen; Merck Sharp and phase safety, tolerability, and PKs of long-acting injectable Dohme AG (MSD); South African Medical Research Council; CAB in HIV-uninfected individuals. The apparent half-life of United States National Institutes of Health (NIH) and United CAB LA for females was significantly longer compared with States Department of Health and Human Services (HHS){; and males, and was also influenced by body mass index. The ViiV Healthcare. The views expressed herein do not neces- median time to the lower limit of quantification (LLOQ) was sarily reflect the official views or policies of partners. 66.3 weeks for females and 42.7 weeks for males. At 76 weeks after the final injection, 58% of females and 87% of males had levels below the LLOQ. *Supported by Gilead who provided funding. Gilead has had no input into the content of the materials used at this meeting/confer- Concluding Messages ence. No other pharmaceutical company has had input into the content of the materials used at this conference. In the two years since the HIVR4P 2016 conference, { HIVR4P 2018 was made possible in part by 1 R13 AI136762-01 consistent progress has been made toward improving and from the National Institute of Allergy and Infectious Diseases expanding HIV prevention strategies. As prevention science (NIAID). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily advances, however, the challenges of maintaining the polit- reflect the official policies of the Department of Health and Human ical will and funding to support a global movement to end the Services; nor does mention of trade names, commercial practices, or AIDS epidemic come into even sharper focus. organizations imply endorsement by the U.S. Government. CONFERENCE SUMMARY AND HIGHLIGHTS 607 Author Disclosure Statement against HIV-1 acquisition. Sci Transl Med 2015;7: 310rv317. No competing financial interests exist. 4. Kim JH, Excler JL, Michael NL: Lessons from the RV144 Thai phase III HIV-1 vaccine trial and the search for References correlates of protection. Annu Rev Med 2015;66:423–437. 1. Abstracts of the HIV Research for Prevention Meeting, HIVR4P, 21–25 October, 2018, Madrid. AIDS Res Hum Address correspondence to: Retroviruses 2018;34(S1):1–408. Tamara Torri, MA 2. UNAIDS: Fact Sheet—World AIDS Day 2018, 2017 Global International AIDS Society HIV Statistics. 6 pp. Available at www.unaids.org/sites/ 23, Avenue de France default/files/media_asset/UNAIDS_FactSheet_en.pdf (2018), CH-1202 Geneva accessed March 12, 2019. Switzerland 3. Corey L, Gilbert PB, Tomaras GD, Haynes BF, Pantaleo G, Fauci AS: Immune correlates of vaccine protection E-mail: tamara.torri@iasociety.org