Rapporteurs Summaries

Daily Highlights

Lead rapporteurs and their team of junior rapporteurs will provide daily scientific overviews and will publish conference summary paper manuscript after the conference in an open-access, peer-reviewed journal. 

Daily summaries will be posted below as they become available.

Monday 22 October 2018

Team A

The rapporteur Team A welcomes you to this series of short reports summarizing relevant data on vaccine approaches and antibody infusion presented at the HIVR4P 2018 Conference. On Monday, 22 October we had the opportunity to join an excellent Opening Session with two stimulating talks describing the past and future of HIV vaccines and antibody-based therapies.

First, Linda-Gail Bekker, who received the 2018 HIVR4P “Desmond Tutu Award for HIV Prevention Research and Human Rights” presented on where we are in the quest to find an HIV vaccine, with a positive message: “A journey of hope”.

She pointed out that to reach the 2020 global HIV target, there is still a large amount of work to do as the prevention gap still exist around the world (from Eastern Europe to Africa). There is no need to keep reminding ourselves how important it is to find a vaccine because a vaccine is the key to prevent and reduce the burden of HIV and to overcome stigma in communities.

She then emphasized on the well-known challenges of making a vaccine (genetic viral diversity, lack of natural sterilizing immunity, imperfect animal models, and the difficulty to engage the private sector). In the case of HIV these challenges apply to both cellular and humoral immunity. Although, Linda elaborated on the two ways antibodies can prevent HIV, either elicited by vaccination or by passive infusion.

Dr Bekker pointed out how the partial protective effect observed in the RV144 trial, an ALVAC and AIDSVAX prime boost trial, was instrumental in designing new vaccinations approaches. Some examples are the HVTN 100, a phase 1/2 trial in low risk HIV-uninfected, South African adults combining ALVAC-HIV (VCP2438) and subtype C gp120/MF59. This controlled, randomized, double-blind study, sponsored by National Institute of Allergy and Infectious Diseases (NIAID), HIV Vaccine Trials Network, Bill and Melinda Gates Foundation, Medical Research Council, Sanofi Pasteur and Novartis Vaccines, was used a go/no go criteria to start the bigger trial HVTN702 (UHAMBO). Early data of HVTN 100 trial paved the way for HVTN 702 study, although latest data contributed to amend the new study for an additional vaccination at month 18. HVTN 702 is a Phase 2 trial built on the RV144 and HVTN 100 trials and optimized for prevention of clade C infections; 80% of the 5400 participants have been recruited.

In addition, Johnson and Johnson research program is starting the Phase 2b HVTN705 study (IMBOKODO) in 2600 participants using Ad26.Mos4.HIV mosaic antigens combined with trimeric Clade C gp140 protein. This strategy has been proven to be immunogenic in humans and has shown 67% protection in macaques. The pipeline of new immunogens is also fed by new approaches from IAVI (G001 and W001) to test novel vaccine candidates (eOD-GT8 60mer and BG505. GT1.1 gp140) designed to stimulate the immune system to initiate a key first step in the generation of broadly neutralizing antibodies (bNAbs).

Finally, Dr Bekker described the ongoing AMP studies testing the efficacy of the bNAb VRC01 administered by infusion to non-infected individuals. In this regard, a new study from SANOFI testing a tri-specific antibody infusion in non human primates has been published recently, paving the way to human trials.

To conclude, she emphasized on the need of a global involvement and the use of multiple approaches (vaccine-based or not) to defeat HIV.

The second talk on vaccine approaches was presented by Anthony Fauci, MD, Director of NIAID. In his nicely structured talk, Dr Fauci described several concepts relevant to the design of a strategy against HIV. Dr Fauci defined three levels of pandemics control, to help to understand what actually HIV prevention means. The top level, Eradication, it is something that could be designate only to small pox; a second level, Elimination, is associated with Polio and Malaria (in some countries). However, the only realistic level that we could achieve for HIV with a global and combined effort is a third level, the Control.

To achieve this control, the preventing path towards ending the HIV/AIDS pandemic can be envisaged as the convergence of two roads defined by non-vaccine and vaccine prevention strategies. Non-vaccine prevention is a combination of multiple strategies, from condom use, prevention of mother-to-child transmission, voluntary medical circumcision and treatment as prevention (TasP) or Pre-Exposure Prophylaxis (PrEP). Dr Fauci focused on the latter approaches, showing for TasP a large volume of evidence (HPTN 052 or PARTNER studies) indicating that undetectability means untransmittability. Regarding PrEP, different prophylactic approaches were reviewed, systemic or topical ART, long acting drugs, either ART or antibodies that can could support a 6-month dosage. While PrEP has shown a high efficacy, antibodies (currently tested in the MP study) can be largely improved for prophylactic usage, by modulating their interaction with neonatal Fc receptors, by vector based delivery (AAV-based strategies), by combining antibodies with different specificities and finally by generating synthetic bi- or tri-specific antibodies.

A second relevant concept raised by Dr. Fauci was the definition of incidence hotspots, which can be geographic (some areas of Africa but also some areas of the US) and/or demographic (populations at risk). Identifying and specifically acting on these incidence hotspots should be a priority in HIV prevention.

Going back to vaccine approaches, Dr Fauci described two main paths to a vaccine. The first one is a classical approach, in which the candidate is empirically designed and tested to find correlates of protection. This is the case of the different approaches seeking to amplify signals achieved in the RV144 trial, by enhancing the breadth, strength and durability of immune responses elicited by the existing immunogens. The second assumes a correlate (generation of bnAbs, in the case of HIV) and designs a vaccine to achieve protective levels of that correlate. This second approach is actively explored by several laboratories either by designing immunogens based on known vulnerability Env epitopes, or by designing a collection of immunogens that guide germline B-cells towards a the development of bnABs (Epitope- versus B-cell linage-based immunogen design, respectively). Importantly, both approaches are reaching human trials. Before concluding his talk, Dr Fauci raised a relevant question on what we expect from a HIV vaccine, in terms of effectiveness. He reasoned that a 95-100% is unlikely, and that at least 50-60% effectiveness through vaccine could be good enough for HIV prevention. Recent data on animal models and improved vaccination strategies and immunogen design, make this figure achievable.

Both plenary talks in the Opening Session concurred in the description of most relevant approaches to control HIV pandemics and allowed us to visit all HIV vaccine trials, from early gp120-based approaches to the newest immunogen designs, including trimeric forms of HIV Env entering in human trials. We have learned from both speakers that vaccine and non-vaccine approaches (PrEP, condoms, treatment as prevention,…) will be required to control (probably not to eradicate) HIV pandemics. Finally, different strategies of vaccine design can be helpful to reach a 50-60 % efficacy, a figure that could be defined as the lowest acceptable value for a vaccine candidate to be used in combination with other prevention strategies.

Team B

In the opening plenary session, Sheena McCormack discussed the use of novel clinical trial designs to more efficiently assess the efficacy of new HIV prevention products in the current environment of highly effective TDF/FTC as PrEP.

One challenge is that alternative PrEP agents such as long-acting injectable PrEP are being compared to oral TDF/FTC as the new standard of care. Such non-inferiority designs require a significantly larger sample size and longer duration of follow-up due to the high efficacy of the comparison TDF/FTC regimen. A novel approach to overcome this challenge is to concurrently measure the background HIV incidence in the source population as an estimate for what the incidence would be in a hypothetical placebo group. This ‘placebo’ incidence rate can then be incorporated into a novel measure of effectiveness known as the averted infections ratio (AIR), which compares the proportion of infections averted by the new drug to that averted by TDF/FTC.

Similar challenges pertaining to high TDF/FTC efficacy may limit the efficiency of using standard randomized controlled trials to evaluate the efficacy of immunotherapies and vaccine candidates. McCormack described the use of a multi-arm, multi-stage (MAMS) platform trial design which may offer several key beneficial features in this context: multiple arms of different agents (e.g., vaccine, bNAb) are compared to one placebo group in the same trial, reducing the number allocated to placebo; combination interventions can be assessed (e.g., vaccine+bNAb), resulting in a higher target effectiveness and smaller sample size needed; and interim analyses indicating early lack of benefit can lead to discontinuation of ineffective agents without stopping the entire trial.

 

Tuesday 23 October 2018

Team A

The agenda of the second day of the HIVR4P meeting proposed a wide and dense amount of new data on recombinant antibodies (used in treatment or prevention strategies) and on vaccine approaches, including i) those following the RV144 trial (induction of durable ADCC promoting antibodies); ii) those aimed to elicit bnAbs (either by mimicking Env vulnerability sites or by driving immune responses from gremlin B-cells); and those aiming to elicit robust CTL responses.

Regarding the use of antibodies as treatment, Pilar Mendoza (0A08.01) from M Nussenzweig’s lab presented recently published data on treatment of HIV infected individuals interrupting ART with anti-CD4bs 3BNC117 and anti-V3 glycan supersite 10-1074 antibodies. The combination was sufficient to maintain viral suppression in individuals with a sensitive reservoir without developing double resistant viruses. Those Individuals remained suppressed as long as plasma concentration of Abs was higher than 10 μg/ml and median time to rebound was 21 weeks, significantly higher when compared to untreated or single antibody treated individuals. However, reservoir size was not significantly impacted, raising the question whether prolonged treatment would have an impact in the reservoir (a crucial question in cure strategies).

An alternative to the combination of antibodies is the development of bifunctional antibodies carrying multiple Env binding sites in a single molecule. An example was presented by Zhiwei Chen (Sy01.01) describing the molecule BiIA-SG, a bispecific anti gp120 and anti CD4 engineered antibody able to protect humanized mice from HIV acquisition. The combination of BiIA-SG with strategies aimed to improve CD8 T cells is a priority of Dr. Chen team. A new example of antibody mimetics was presented by Mathias Glögl in a poster session (PD01.01), describing anti-V3 DARPins (an acronym for designed ankyrin repeat proteins), which are genetically engineered antibody mimetic proteins.

The role of antibodies in prevention was developed by Lynn Morris (SY01.02) presenting technical data on the AMP study. A presentation complemented by a series of data that improved our knowledge on pharmacokinetics and tissue distribution of antibodies in vivo. In particular, the pharmacokinetics of the anti CD4bs Ab VRC01 and the VRC01LS (a Fc mutant showing higher affinity fot FcRn receptors and showing extended plasma half-life) was discussed at the Oral Abstracts Session 08. Madhu Prabhakaran (OA08.04) and Coleen Cunningham (OA08.05) presented data at mucosal sites in adults and plasma PK in infants, respectively. In the same session Ann M Carias nicely demonstrated that LS mutations introduced in VRC01 not only modified half-life but also tissue distribution in treated NHP (OA08.06).

Research on vaccines aimed at eliciting protective anti HIV antibodies was well represented by the different human trials aimed at amplifying the signal of the RV144 study, or aimed at developing bnAb-based strategies. The talk by Xioying Shen (OA02.03) was about the HVTN 100 trial, a Phase 1/2 C ALVAC-HIV and bivalent subtype C gp120 adjuvanted with MF59 in South Africa. The study aims to improve RV144 efficacy result using vaccine constructs adapted for the subtype C epidemic. Although HVTN 100 elicited anti-V1V2 binding antibody responses, with lower magnitude and breadth compared to the B/E vaccine in RV144 and HVTN 097, the elicited antibodies in HVTN 100 were capable of mediating phagocytosis and ADCC. At the same session, Zoe Moodie’s presentation (OA02.04) compared the humoral response elicited by DNA prime compared to ALVAC prime. In HVTN 111 and HVTN 100. Higher anti-V1V2 IgG and CD4+ T cell response, nAb Titers were obtained with DNA prime than with ALVAC. Her data, combined with the improved manufacturing and cost effectiveness of DNA, support further evaluation DNA in prime-boost regimens with Env proteins.

Different approaches to a bnAb-based HIV vaccine were presented in different sessions. Peter Kwong presented a fusion peptide immunization followed Env trimer that able to elicit neutralizing antibodies in animal models (OA03.01). See Basic Science Report). However, more advanced and sophisticated designs were presented at the Symposium SY01. Polyvalency of Env presentation and mobilization of B-cell lineages promoting bnAbs were recurrent issues in this session, with groups presenting Env on the surface of virus-like particles (VLPs) or ferritin nanoparticles (E Yuste SY01.03 and K. Saunders SY01.04, respectively). Interestingly, the last approach used recombinant HIV-1 envelope protein with V1 glycans removed that could bind to precursors of a V3 glycan bnAb B cell lineage. Immunization of DH270 UCA knockin mice with trimers and ferritin nanoparticles elicited antibodies capable of binding and neutralizing tier 2 HIV-1 viruses with V1 Env glycans present.

However the most advanced work was presented by Bill Schief (SY01.05), developing immunogens specifically designed to prime germline precursors. He described the eOD-GT8, a protein that shows high binding affinity for VRC01-class inferred-germline Abs, and when presented as 60-mer can prime VRC01-class responses in the VH1-2 mouse, a stringent model system. A Phase I trial (G001) in humans has started in 2018 to test safety of two different doses of AS01B adjuvanted eOD-GT8 60-mer. The exhaustive immunological follow up G001 participants will reveal whether the proposed mechanism is also functional in humans and then be extended to other bnABs. However, precursor priming for other bnAb classes will be more difficult than for VRC01-class bnAbs. Nearly all other classes of bnAbs are HCDR3-dependent, have lower precursor frequencies and higher levels of precursor diversity. New methods will be needed to design germline-targeting priming immunogens for HCDR3-dependent bnAbs.

Finally, regarding CTL- based vaccines, the issue of immune-dominant domains within HIV-1 T-cell vaccines was addressed with the focus on shifting the immune responses to potentially protective but subdominant epitopes. The success of these strategies was highlighted in the most advanced effort (N Frahm, OA07.01) where mosaic Env sequences were designed to include sequence diversity in T-cell epitopes. In NHP, bi-valent and trivalent mosaic vaccines increased epitope recognition compared to consensus vaccines. A trivalent group M T-cell mosaic DNA vaccine was then compared to T/F clade B transmitted-founder B.1059 or ConS DNA vaccines all boosted with a non-matching MVA gp150 Gag/Pol in phase I trial HVTN106. The magnitude of Env specific CD4+ T-cells responses was higher in the mosaic Env DNA vaccine compared to T/F DNA vaccines. Furthermore, overall breadth to both vaccine matched and heterologous peptides was significantly higher in the group primed with mosaic DNA. In another study (B Felber, OA07.02), vaccines expressing Conserved Elements (CE) of p24 Gag and Env associated with virus control were successful in inducing cytotoxic immune responses to subdominant epitopes and increasing breadth and magnitude cellular immunity in NHPs. Further approaches to predict protective CD8+ T cell epitopes across HLAs were outlined in computational machine learning tools and structure based network analysis. It will be interesting to see if these strategies are able to enhance cellular immunity in vivo as well.

Team B

Oral abstract (OA01): Location, Location, Location: Mucosal Mediators of Risk

This session addressed the importance of understanding the role of the mucosal female genital tract (FGT) in the risk of HIV acquisition and the efficacy of PrEP.

Mucosal inflammation for example can increase the risk of HIV infection by recruiting and activating immune target cells in the FGT. Fowke and colleagues presented data showing that when daily low dose acetylsalicylic acid (ASA) is administered to HIV-negative low risk women, there was a 35% and 28% reduction, respectively, in CCR5+ CD4+ T cells and Th17 cells in the FGT. They concluded that daily use of ASA could be a novel approach that, when combined other methods of prevention, might reduce the risk of HIV infection.

Hormonal contraception (HC) is among strategies used to prevent unwanted pregnancies, however, HC may affect HIV-1 risk through changes in FGT microbiota. Balle et al. examined the impact of three HC methods on the adolescent FGT microbiota and related mucosal cytokine levels in a randomized, crossover trial. Adolescent girls (n=131), aged 15 to 19 were enrolled and randomized into three study arms: 1. injectable norethisterone enanthate (NET-EN), 2. combined oral contraceptives (COCs) or 3. combined contraceptive vaginal ring (CCVR) for 16 weeks. Participants were then switched to a second HC for four months. Use of COCs was found to be associated with lower microbial diversity and decreased abundance of bacterial vaginosis (BV)-associated bacteria in the vagina correlating with lower inflammation and potentially a lower HIV risk.

Pre-exposure prophylaxis (PrEP) in women has been found to have highly variable efficacy which has recently been associated with dysbiotic vaginal microbiota. Cheu et al. investigated the mechanism(s) underlying how vaginal bacteria might alter PrEP drug levels through bacteria-mediated metabolism. By co-culturing Jurkat cells (HIV targets) with PrEP drugs (tenofovir [TFV], tenofovir alafenamide [TAF], and dapirivine [DPV]) the investigators found that vaginal dysbiosis can metabolize PrEP drugs including TFV and DPV. This highlights the role that the microbiome can play in drug uptake to target sites and systemic availability and how this may affect virus transmission and treatment for prevention. Thus, understanding the vaginal microbiome and prevention of BV are critical for improving HIV prevention strategies.

Oral abstract (OA04): Entry into the PrEP Continuum

In the oral abstract session, “Entry into the PrEP Continuum,” speakers highlighted the critical roles of monitoring PrEP outcomes and determining individuals’ motivations for initiating PrEP with respect to promoting PrEP scale-up among key populations globally.

Laura Fitch presented data from AVAC’s Global PrEP tracker (available at PrEPWatch.org) that includes a comprehensive database of information ongoing and planned demonstration projects, implementation initiatives, and national programs worldwide. Data from the first quarter of 2018 indicate that 309,525 people have been initiated on PrEP globally. North America and Sub-Saharan Africa currently have the highest overall number of initiations, accounting for 71% and 15% of the total number of users respectively. In the US, the majority of users are men who have sex with men (MSM), while the majority of users in sub-Saharan Africa are adolescent girls and young women (AGYW).

Kristi Gamarel and Nicholas Thuo both discussed important findings regarding individual motivations to use PrEP. Gameral provided information collected from MSM in New York, in primary partnerships. She found that those who had sexual goals congruent with those of their partner were 2-times more likely to initiate PrEP. Among young women in Kenya, Thuo et al. found, through qualitative interviews with PrEP initiators, that young women were self-aware and able to accurately identify risk in their relationships and interactions. The primary factors influencing their uptake of PrEP included a fear of acquiring HIV, their own perceived risk of HIV, and PrEP recommendations from health care workers and trusted peers.

Rosemary Delabre provided data on risk, risk-reduction behaviors and interest in using PrEP among transgender persons participating in a community-based, online survey in Europe. Among 245 transgender respondents (145 identifying as transgender women [TW] and 100 identifying as transgender men [TM] ); more than half of TW (n=74, 54.4%) and almost one-third of TM (n=28, 28.9%) reported interest in using PrEP. She emphasized the importance of engaging transgender persons in research and in tailored PrEP programs. From a local perspective, Albert Liu provided data from two population-based studies of HIV-uninfected TW and MSM conducted in San Francisco. Using this data, 97% of MSM and 79% of TGW in San Francisco were aware of PrEP, yet only 40% of MSM and 15% of TGW had used PrEP despite high levels of health insurance coverage and engagement in health care.

Symposium (SY04): ARVs for Prevention: Extrapolating from Data to Clinical Practice

The first presentation in the session by Marta Boffito highlighted the importance of both pharmacokinetic and pharmacodynamic studies in the evaluation of novel PrEP agents. She highlighted the important role of animal models, as well as Phase 1, 2 and 3 studies in providing data to guide dosing strategies but stressed the importance of understanding cellular pharmacology considerations for these drugs, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender and appropriate dosing strategies based on pharmacokinetic principles. Further, she highlighted, that while drug concentrations in animal models and in vivo human tissues may correlate well with efficacy (e.g. for TDF/FTC), some drugs do not always show optimal tissue exposure (e.g. Cabotegravir LA), thus understanding what and how new PrEP agents may be effective extends beyond just tissue concentrations.

Charles Dobard of the Centers for Disease Control and Prevention (CDC) discussed the use of animal models in preclinical studies of ARVs for PrEP. These models, particularly humanized mouse models and nonhuman primate models using macaques, allow for the assessment of biological efficacy of PrEP under highly controlled conditions, thus playing a key role in defining relationships between pharmacokinetics and pharmacodynamics of experimental agents. Dobard highlighted recent exciting advances including the elucidation of a Rhesus macaque model of penile SHIV transmission as well as animal model studies showing high efficacy against rectal, vaginal and penile SHIV using both Tenofovir Alafenamide (TAF) and long-acting cabotegravir regimens.

The second two presentations of the session focused on practical aspects of PrEP implementation. Irene Mukui, systematically described the impressive progress and lessons learned from the national roll-out of a PrEP program in Kenya. In May of 2017, 1425 Kenyans were currently on PrEP compared to 17,466 in August 2018. She described how this has been achieved through the coordinated effort of multiple national and international stakeholders, integration into existing systems (e.g. Existing ARV supply chains) as well as through community involvement and demand creation. Efficient, strategic information systems and epidemiologic mapping enabled focusing on specific geographic areas (high incidence clusters) and populations.

The last presentation from civil society activist Emily Bass reviewed the interplay between advocacy and implementation. She opted for a “power-point-less” presentation, but providing, nonetheless, a well-articulated, self-reflective examination of PrEP roll-out throughout most of SSA and the current and future role of advocates/activists in this. Bass and colleagues also described the importance of ensuring that demand creation for PrEP and other novel prevention methods was undertaken creatively, meaningfully and with intent.

Poster Discussion (PD04): PrEP: Doing It Right at Delivery

Hyman Scott from the San Francisco Department of Public Health presented on PrEP use and interest among MSM (n=1,088) recruited on a gay social networking app from six cities across the United States. PrEP use was high, with 44% reporting current PrEP use. An encouraging 63% of non-users expressed interest in using PrEP, with higher interest among younger MSM and those reporting more condomless anal intercourse. Alex Carballo-Diéguez from Columbia University and NY State Psychiatric University reported on the high acceptability and likelihood of use of a rectal microbicide douche among MSM and transgender women who engage in anal intercourse in the United States. A national internet-based survey (n=4,751) found that the majority of this population currently used a douche before anal intercourse. Almost all (98%) of those who reported a recent history of rectal douching and 94% of those who did not douche stated that they would likely use a rectal microbicide douche to prevent HIV, and 95% of those who reported only insertive anal intercourse stated that they would support a partner's use of an HIV-preventive douche. Additionally, qualitative interviews conducted with participants (n=12) after completion of a phase 1 rectal microbicide douche trial reported high acceptability and high likelihood of use. A key quote from a participant that highlights the behavioral congruence of this strategy is as follows “I douche anyway, so it’s part of our routine…It’s like washing my hands before I eat”

Jayne Osindo from the African Population and Health Research Center reported on community and implementer perceptions of the girl-focused DREAMS programme in two Nairobi slums. While adolescent boys and young men also benefited from the programme, there were concerns from both the boys themselves as well as community members that they were missing out on social protection interventions and HIV prevention information. Fernandos Ongolly from the Kenya Medical Research Institute reported on the broadly positive experiences of serodiscordant couples accessing PrEP in public HIV clinics in Kenya, with particular benefits of shared decision-making regarding PrEP initiation.

Team C

Opening Plenary: PL02

Thomas Hope presented an exciting overview of the use of novel imaging approaches to answer questions about early HIV transmission, mucosal reservoirs during ART, antibody distribution, and PrEP efficacy in an in vivo non-human primate model. This group has been at the forefront of developing new imaging technologies to localize and quantify viral reservoirs, particularly within mucosal tissues.

Thumbi Ndung'u reviewed data from the FRESH (Females Rising through Education, Support, and Health) cohort of young women from South Africa. This study provides guidance and life skills to high-risk women, as well as longitudinal follow-up and treatment to those who become HIV-1 positive. Early ART prevented seroconversion, preserved functionality of HIV-1 specific CD8 T cells and proliferation capacities of CD4+ T cells. However, in terms of HIV-1 reservoir size, early ART did not significantly affect amounts of total HIV DNA or even detection of HIV in lymphoid tissue sanctuaries.  Finally, treatment interruption in early treated FRESH women led to rapid viral rebound, suggesting that additional strategies are needed to achieve functional cure. Future studies will include TLR ligands in combination with bNAbs and cART prior to treatment interruption.

Oral Abstract (OA03): Structure and Maturation of bNAbs

This session presented several new insights and technical advances in our understanding of bNAb structure and maturation. Peter Kwong described an approach to improve vaccine-elicited broadly neutralizing antibodies targeting the fusion peptide N-terminus. Rhesus macaques were immunized with residues 512-519 of the fusion peptide coupled to KLH and/or with soluble DS-SOSIP-stabilized Env trimers. Increasing the number of FP-KLH primes increased the frequency of broadly neutralizing responses. Mohammed Sajadi characterized novel bNAbs from an elite neutralizer (N49). These bNAbs were found to target a new form of the very highly conserved inner domain/CD4 binding site epitope (iCD4BS); this epitope could serve as a new target for vaccine design.  Marie Pancera described advances in eliciting VRC01-class bNAbs through immunization. These bNAbs target conserved regions of the CD4-binding site. Induction of such responses by vaccination is challenging, as they are highly mutated, and germline VRC01 bNAbs do not bind Env immunogens due to steric hindrance. Structural characterization of germline VRC01 revealed important features that will improve further immunogen design, potentially by removing glycans surrounding the CD4bs while retaining the short glycan at position N276. Elise Landais reported on longitudinal development of VRC01-class antibodies from a subtype C-infected broad neutralizer in IAVI Protocol C. Antibody development was traced from unmutated common ancestor to affinity-mature bnAbs, providing new insights on development of this lineage over time. David Sacks compared broadly neutralizing and “off track” antibodies that share high sequence identity, showing that as few as 3 mutations can result in the off-track phenotype; therefore, extensive hypermutation does not necessarily result in breadth. Finally, Hui Li presented a new strategy for constructing SHIVs encoding primary or transmitted/founder HIV Envs.  Of 98 macaques infected, 16 developed bNAbs; these were mainly directed to V2 and V3 glycan epitopes, and strongly recapitulated bNAb responses in humans. This suggests macaques can be a robust model for bNAb development and HIV-1 Env immunogen design.

Oral Abstract (OA06): Mucosal Models of Prevention

Highlights from this session included the role of mucin-IgG complexes at the mucosal surface presented by Arangassery Rosemary Bastian. Binding affinity between HIV-specific IgG antibodies and MUC5AC and MUC2 correlated with in vitro enhancement of neutralization potency, with the best example being VRC01-MUC5AC complexes that included around 8 IgG molecules per mucin monomer bound with high affinity. In contrast, PG16 was a weak binder and its neutralization potency was not as enhanced when complexed with MUC5AC. Interestingly, IgG complexing with mucin hindered virus mobility. Marta Rodríguez-García showed how neutrophils from the female genital tract capture HIV through release of neutrophil extracellular traps, which contain extracellular DNA and granular proteins including molecules with antiviral activity such as a-defensin-1-3. Jake Rhodes presented the role of a new epidermal cell type, CD11c+ mononuclear phagocytes, which express high CD45 and CD33 and low langerin levels. These cells capture HIV with higher affinity than Langerhans cells and within 30 minutes post-viral exposure. These cells were only isolated when mucosal tissue was digested with collagenase type IV. Kadryn Kadasia described patterns of expression of Fc receptor and Ig levels in the genital tract. IgG was abundant in basal and apical epithelial layers and IgA in suprabasal and apical layers. In parallel, FcgRII and FcgRIII expression seemed to be restricted to epithelium and lamina propria layers of vaginal and foreskin tissue, FcRn was found in the basal side of epithelial layer, and interestingly, FcaRI was detected in suprabasal epithelial cells. 

Symposium (SY02): Early Invaders: Establishment of HIV Infection

In this fascinating session on viral transmission, 3 important advances were reported: new cell populations actively targeted by HIV-1 at the mucosa; the role of glycosylation in mucosal selection; and the impact of early ART on mucosal immune responses. Manish Sagar identified a vaginal resident CD1a+ classical DC (cDC) population able to support CCR5-tropic but not CXCR4-tropic HIV-1 replication in vitro, in contrast to vaginal Langerhans cells (LC), suggesting that these cDC might play an active role in the selection of transmitted viral variants during sexual HIV acquisition.  Andrew Harman provided evidence of CD11c+ cDCs highly susceptibility to CCR5-tropic HIV-1 in male and female genital mucosa. Intriguingly, data from Eric Arts also supported a role of migrating DC selecting and disseminating virus from mucosal sites. He also provided evidence for selection of specific patterns of glycosylated viruses raising the question of whether active recruitment/infection of Lectin-expressing DC could be a mechanism for preferential transmission of viral variants. Finally, Alexandra Schuetz provided new data on the impact of early treatment on mucosal T cell populations and HIV replication in an acute HIV infection cohort from Thailand. Patients treated in Fiebig I had lower levels of immune activation, but interruption of ART led to viral rebound in patients treated at all stages. However, the combination of early ART and bnAb could represent a more promising strategy for future studies.

Poster Discussion (PD05): Microbiome: When Microorganisms and the Immune System Meet

The effects of Bacterial vaginosis (BV), chlamydial infection and trichomonas vaginalis (TV) infection on inflammatory markers and immune cell distribution were discussed during the microbiome poster session. Smritee Dabee reported high prevalence of BV in a cohort of adolescent and young women in South Africa. High inflammation was linked to BV, with upregulation of cytokines but mixed profile in chemokines. Particularly, IP-10 and MIG were downregulated. Interestingly, geographical differences were found in the response to BV in cytokines and chemokines, although general trends of inflammation and increased frequencies of activated CCR5+ CD4+ T cells were maintained. Using the VK2 epithelial cell line, Monalisa Manhanzva showed that Lactobacilli species isolated from women with BV induced more inflammation that Lactobacilli isolated from women without BV. In addition, isolated Lactobacilli were able to suppress inflammatory responses to G. vaginalis. Seth Bloom compared CD4+ T cells subsets in women from the FRESH cohort that were infected with Chlamydia to identify potential mechanisms for increased HIV risk. Chlamydial infection increased frequencies of activated CCR5+ CD4+ T cells, but no changes were found in Th17 cells, suggesting that increased risk for HIV acquisition is not due to Th17 cell expansion. Interestingly, they found an increase in regulatory T cells in women infected with chlamydia. Yashini Govender demonstrated that after TV exposure, PBMCs release exosomes with specific proteomic profiles, including proteins that interact with HIV or have anti-HIV activity. Finally, James Kublin reported interesting data on the effects of the gut microbiome on vaccine responses.

Team D

Untangling Hormonal Impacts on the Vaginal Microbiome and HIV Acquisition Risk

Mucosal microbiomes across the body influence susceptibility to disease and response to treatment. There is strong evidence that vaginal dysbiosis increases risk for HIV acquisition. Specifically, an acidic, healthy, lactobacilli-dominant vaginal environment decreases risk of HIV and other sexually transmitted infections (STIs), whereas a dysbiotic one increases HIV and STI risk. The relationship between hormonal contraception and HIV susceptibility is less clear. Studies of multiple contraception methods have found that hormonal contraception optimizes vaginal bacteria over time (as measured by decreased Nugent score). Dr. Achilles argued that these findings rule out dysbiosis as a pathway for hormonal contraception to increase HIV risk. Two possible mechanisms for an increase in HIV risk following initiation of hormonal contraception are changes in bleeding patterns and decreased condom use after starting hormonal contraception.

For the vaginal ring (NuvaRing), three months of available data demonstrated a decrease in dysbiosis, though accumulation of biomass on the ring was positively associated with dysbiosis. Considering these findings, Dr. Achilles identified several additional priority research questions: What happens to the vaginal microbiome when women have more bleeding, even if it is light spotting (as occurs in some women after starting hormonal contraception)? What happens to microbiome with vaginally delivered drugs? What are the longitudinal impacts of intrauterine devices (IUD) or implants on the vaginal microbiome, and how does the microbiome alter the metabolism and efficacy of these devices?

In a symposium titled "Beyond Placebo: Designing and Implementing Next Generation HIV prevention HIV prevention Trials", presentations provided regulatory, statistical, ethical, and community perspectives on the current dilemma in designing new randomised clinical trials (RCTs) in the era of highly effective FTC/TDF as standard of care. From the regulatory perspective, Jeffrey Murray from the US FDA noted that non-inferiority trials may not be possible in women due to absence of a consistent historical comparison. New non-inferiority trials may be possible in MSM, but because the interpretation of non-inferiority trials depends on infection rates, as adherence increases the rate of new infections decrease (meaning it will require trials with potentially unfeasible large sample sizes or very long follow up.) From the statistical perspective, Deborah Donnell noted that potential solutions for future designs may include: refining the statistical approaches by changing the measurement scale (e.g. use of relative difference, restricted mean survival time, or averted infection ratio); increasing the operational efficiency of RCTs (for example using multi-arm trials or multi-arm multi-stage designs); or modifying the population enrolled in the trial based on participant unmet needs or willingness to use current standard (FTC/TDF).

HIV prevention is all about choice, but if one chooses HPTN-077, a study by HIV Prevention Trials Network sought to test acceptability of long acting injectable Cabotegravir (CAB LA) in HIV uninfected, low-risk men and women in the U.S., Brazil, South Africa and Malawi. It was observed that here was a strong preference for a LAI PrEP at both baseline and follow-up, with product attributes being moderately to highly acceptable to most of the participants in both cohorts. Furthermore, participants from non-U.S. versus U.S. sites were found to be more interested in future use of an injectable PrEP. However, given the large differences between geographic regions, introduction strategies will likely require tailoring.

A discrete choice experiment conducted by the Research Tringle Institute International on attribute preferences for long-acting PrEP among South African youth found that each attribute evaluated influenced preferences of the youth, but duration of effectiveness exerted the strongest influence on preferences. Location of where to obtain the product was more influential, overall, for females than males, with females preferring to access method at a health care facility.

Quatro, a study among young women in Zimbabwe and South Africa tested the acceptability of four vaginal delivery forms (vaginal gel, films, rings and insert) for preventing HIV. The findings from adherence marker evaluation confirmed that most women did use the product, at least two times during the month of use, over half of the women who chose an on-demand product used it with sex and older women were more adherent to product. Interestingly, most of the women using the IVR, used it for the full 30 days. The findings from preferences study highlighted that users desired multiple prevention options hence women should be given various options to choose from.

Another study, ‘Influencers of Use and Attitudes Towards the Dapivirine Vaginal Ring’ it was found that partners were the main influencers of ring use, however, partner support was largely obtained after vaginal ring information provision. The study concluded that partner engagement is important for support of products that might impact on sexual relationships and recommends community, partner and individual level messaging on ring use and side effects to improve adherent ring use.

It is all about choice, the uChoose study data suggest that long acting injectable PrEP would be a method of choice for prevention in adolescents.

The MEN-ding the Gaps session started off with a poster discussion exploring barriers to HCT in men. Barriers included fear of knowing HIV status, the assumption that acquiring HIV is seen as inevitable in this setting, use of female partner’s HIV status as proxy for male HIV testing, social status, stigmatisation and masculinity. Introduction of the proposed technology and HIV self-testing (HIVST), was looked upon favourably as HIVST allows for privacy and linkage to care via mobile phones has potential to overcome barriers to HIV testing and linkage to care in men. A study describing awareness, willingness and barriers to HIVST use among 4136 MSM in Brazil who use a gay social networking app revealed that 22% never tested for HIV. Main reasons were fear of a positive result (39%), shame (24%) and lack of perceived HIV risk (12%). Awareness and willingness to use HIVST were low (32% and 44% respectively) among the MSM analysed. Factors associated with HIVST willingness included income, schooling, intention to use condoms, PrEP willingness, trust in HIVST in comparison to conventional tests and pre-test counselling and decreased marijuana use. A study conducted by CDC Zambia sought to profile demographic characteristics of uncircumcised males to help address gaps in increasing circumcision coverage in Zambia. It concluded that circumcision programs need to focus on provinces with the highest HIV rates and be tailored to increase circumcision uptake among young, unmarried Zambian males with some education, who are more likely to reside in rural areas and likely to have had recent unprotected sex with a non-marital partner.

 

Wednesday 24 October 2018

Team A

The third day of the HIVR4P meeting started with a plenary session by R Sandiers on the pipeline novel HIV-1 envelope proteins to induce neutralizing antibodies, then the focus moved to a large but balanced volume of information on B and T cell approaches to vaccine and therapy.

Plenary session highlighted the need for novel Env immunogens designs and summarized 4 hypotheses and examples that have recently or will soon be entered into clinical trials. For the first hypothesis, bnAbs are going to be induced by stable native-like Env trimer as non-native Env species fail to induce high levels of bnAbs. With phase I clinical trials planned for immunogens BG505 SOSIP.664 (W001), ConM SOSIP.v7 and ConS SOSLUFO. In the second hypothesis, bnAbs are induced from lineage Env immunogens from individuals developing broadly neutralizing antibodies in order to as broadly neutralizing antibodies do not emerge instantly in response to just one antigen in HIV-1 infected individuals. With CH505 gp120 series (HVTN115B), CH505 SOSIP series and Env SOSIP trimers from acute neutralizers soon entering clinical trials. Engagement of germline precursors by specific germline targeting Env immunogens was proposed in hypothesis 3 and for this approach eOD-GT8 60mer, 426 cTM and BG505 GT1.1 are the first immunogens to be tested in clinical trials in the next year. In the final hypothesis, bnAbs are to be induced by epitope focusing to circumvent potential immune-dominant non-neutralizing epitopes within the Env sequence. With the Fusion-peptide targeting immunogen FP8_v1-rTTHC and MPER liposomes entering clinical trials in 2019. This shows that the current pipeline for HIV-1 Vaccine 2.0 is well developed and should provide information on the success of the different strategies within the next two years. Importantly, none of these strategies are mutually exclusive, rather its different combinations will open promising avenues towards an HIV-1 vaccine that induces broadly neutralizing antibodies. The figure of 60% protection is not so far.

Regarding the use of antibodies as treatment, M Blasi and JM Martínez-Navío described gene (0A13.04 and 05). Maria Blasi highlighted the challenges of using passive infusion to deliver antibodies and in her study she used a double approach to eliminate the virus in monkeys, she combined the IDLV-CMV-SIV-gag and IDLV-CMV-PGT121 to activate CTL responses and virus neutralization simultaneously. While IDLV-SIV-gag was successful in enhancing the magnitude and functionality of CD8+ cell response, IDLV-PGT121 did not induced sufficient plasma levels of PGT121 to demonstrate activity. Martínez-Navío, on the other hand, used a different approach to deliver bNAbs. He used AAV1 and AAV8 to deliver potent bnAbs in monkeys and data showed that uninfected monkeys could protect from HIV acquisition, while infected monkeys could be suppress viremia. The results were exciting; however, one big concern was the production of anti-drug antibodies (ADA), which was associated with low plasma bnAb levels and high viral load in some monkeys. His study also suggested that monkeys were functionally cured, but the virus was not completely eradicated, despite having an undetected viral load.

The role of antibodies in prevention was nicely described by A Hessel (OA13.06) in the context of mother to child transmission. Her data clearly demonstrated that passive infusion of bnAbs is able to protect newborn macaques from HIV acquisition. However this process is both time- and dose dependent. So, hit early, hit hard. It is relevant to remember that a human trial, the P1112 study is currently ongoing to evaluate the safety and PK analysis of the antibody VRC01 in HIV-exposed newborns.

Besides the plenary session on vaccine development, further vaccine approaches have been discussed, in both the T- and the B-cell sides, through the different sessions.

Session OA11 summarized various innovative vaccine strategies, including DNA approaches presented by R Shattock (OA11.01) and S Edupuganti (OA11.06LB). R Shattock presented a combined Intradermal and intramuscular DNA prime that provided enhanced humoral response to an HIV-1 Clade C Envelope Vaccine, showing that DNA priming phase induced 100% seroconversion. The group with combined Intradermal and intramuscular injection showed enhancement in binding antibody response after protein boost. Hence, the author concluded that DNA prime-protein boost approach to be a potential approach in candidate HIV-1 vaccines evaluation. Another highlighted talk of the session was Y C Wong’s presentation (OA11.04) on PD-1/Gag based vaccine that provided Immune Control of SHIV Infection in Rhesus Macaques. The authors designed a novel vaccine by fusing an antigen of interest to a soluble programmed death-1 molecule (PD-1). The results confirm that vaccine induced long-lasting effector memory CD4+ and CD8+ T cell responses against the selected antigen (Gag-p27) in rhesus macaques. Furthermore, the vaccine induced protection against simian-human immunodeficiency virus (SHIV162P3) challenge. In vaccinated animals, viral loads correlated with CD8+T cell responses and viral load rebounded when CD8+T were depleted in vivo, indicating that the vaccine-induced protection is mediated through CD8+ T cells. A third significant highlight of the session was the presentation of RT Wyatt (OA11.05) who showed identification of two rabbit antibodies 1C2 and E70 targeted towards gp120-gp41 interphase and CD4 binding site respectively. Those antibodies have been isolated from animal vaccinated with a strategy based on the sequential exposure of the CD4 binding site modulated by removal of surrounding glycosylation sites.

Sequential immunization and the analysis of the path followed by bnAbs was the main topic of Poster Discussion 10.  The session was excellent and included 5 cutting edge presentations focused on the analysis of different ways for the elicitation of bNAbs by various vaccine approaches. One of the highlights of the session was the study conducted by T Zhou (PD10.04), from Dr. Mascola and Dr. Kwong’s lab. The authors further developed the above mentioned targeted deglycosylation strategy, with iterative boosts involving Env trimers with restored glycans as a way to elicit broadly neutralizing responses against the conserved CD4BS site of vulnerability. The other impressive work presented in this session is the one by Mattia Bonsignori (PD10.05), from B. Haynes group. The authors were reconstructed the VRC01 lineage from the unmutated common ancestor (UCA) and identified multiple solutions adopted by the evolving B cells to overcome the N276 glycan barrier. As different paths led to highly or moderate neutralization breadth, the selection of immunogens that guide immune responses through the good path would be crucial for the success of a vaccine. Molecular data presented yesterday will be of key relevance.

The role of T cells and CTL-based vaccines was deeply discussed in the afternoon Symposium ‘Let's Talk T Cells!’. Two major talks given by WA Burgers (SY06-02) and C Brander (SY06.03) reviewed the knowledge as well as the limitations on measuring and understanding CD8 T cells responses in HIV infection. Particularly interesting was the discussion on the definition of the quality of T cell responses. The session also focused on the role of T cells on pediatric HIV infection (SY06.01) and the lessons that we can learn from this particular setting. Finally, in a more mechanistic presentation AD Kelleher (SY06.04) outlined an interesting new technique in which biopsies were successfully taken from the axillary lymph nodes using an ultrasound-guided fine needle method. In this pilot study, CD4 T cells, CD8 T cells and B cells were present in these biopsies and increased TFh responses were observed after inoculation with an influenza vaccine. An exciting discussion developed around the timing of sampling for this TFh response with regard to an HIV-1 vaccine and it was suggested that for example the HPV vaccine program could be used for this purpose (as flu vaccines are probably not mimicking a true primary response).

Team B

Plenary: PL03.01 - Beyond TDF/FTC: The Future of Systemic Pre-exposure Prophylaxis

Raphael Landovitz provided an excellent overview of past, current, and anticipated future work to identify new systemic PrEP products. In doing so, he provided hope that the future of biomedical HIV prevention is ripe with the possibility of CHOICE. Next generation systemic PrEP candidates include oral TAF/FTC, injectable cabotegravir, broadly neutralizing antibodies (bnAbs), the dapivirine vaginal ring, and even implantable devices and microneedle array patches.

In the DISCOVER trial, the safety and efficacy of daily oral TAF/FTC is currently being evaluated against daily oral TDF/FTC among 5,000 cisgender men and transgender women who have sex with men. Already approved for HIV treatment, TAF/FTC may have less renal and bone toxicity than TDF/FTC.

Trials are also underway to evaluate the safety and efficacy of long-acting injectable cabotegravir, which is administered as a single 600-mg intramuscular injection every 8 weeks after a 4-week loading dose. In HPTN 083 and HPTN 084, long-acting cabotegravir is being compared to daily oral TDF/FTC among a target of 7,700 persons.

In the Antibody Mediated Prevention (AMP) trials, the safety and efficacy of two doses of the passively infused VRC01 monoclonal antibody, administered every 8 weeks, are being compared to placebo among 2,700 men and transgender persons who have sex with men and 1,900 cisgender women. It is expected that combination bnAbs, analogous to combination antiretroviral therapy, will be investigated in future trials.

The ASPIRE and Ring trials previously demonstrated an approximately 30%-reduced risk of HIV infection conferred by the dapivirine vaginal ring. Subsequent open-label studies pointed to a larger, approximately 50%-reduced risk. This product is currently under regulatory evaluation.

Landovitz concluded by presenting some innovative work using microneedle patches, which work by puncturing the stratum corneum to allow delivery of drug to dermal layers. Studies exploring cabotegravir dissolving microneedle patches are underway.

Plenary: PL03.02 - On-demand Topical Agents for HIV Pre-exposure Prophylaxis

Craig Hendrix from Johns Hopkins gave an overview of the product pipeline for on-demand topical PrEP. He summarized the evidence that on-demand products can work, and that topical PrEP can protect against HIV infection, and argued that having a range of CHOICES of prevention options is important, drawing parallels with contraception, where increased choice of contraceptive options  leads to increased uptake. He outlined the different vaginal and anal microbicide formulations in development, beginning with Pod-IVR, a vaginal ring that can deliver multiple ARVs simultaneously – this could provide better anal as well as vaginal protection for women, as some drugs (FTC and MVC) are able to achieve protective levels in the rectum when delivered through a vaginal ring. Other formulations included fast-dissolving vaginal films, vaginal and rectal inserts, and a number of multipurpose prevention formulations, which provide additional protection against other STIs or contraceptives. A number of phase 1 trials of rectal microbicides have recently or will soon be conducted, several of which are aiming to be behaviorally congruent, i.e. adding PrEP to a product people already commonly use as part of their sexual routine, in this case lubricants and douches, already used by >85% and >75% of MSM, respectively. Studies have shown promising results for the feasibility and acceptability of a rectal microbicide douche for MSM. Professor Hendrix finished with a call to ensure that microbicide development continues to be a priority, to ensure as wide a range of HIV prevention choices as possible.

Symposium (SY11): ARVs for Prevention in Women of Childbearing Age

Anne Lyerly (appearing from North Carolina via webcam) explored ethical considerations around conducting HIV prevention studies in women of childbearing age. Starting with the statement that ‘women deserve safe and effective medication over the course of their lifespan, including during pregnancy, and deserve an evidence base adequate to that fact’, she showed how the exclusion of pregnant women from research means that knowledge about the pharmacodynamics and safety in pregnancy of medications used for HIV treatment and prevention lags many years behind drug approval. These delays may prevent the ethical conduct of RCTs among pregnant women. Limited data makes it harder for providers and patients to make informed choices about the relative risks and benefits of PrEP use during periconception and pregnancy.

Elaine Abrams (Columbia University) discussed recent findings from the Tsepamo study that Dolutegravir (DTG) use at conception may increase the risk of neural tube defects, leading to WHO treatment guidelines restricting DTG use among women of childbearing age to those using reliable contraception. She drew parallels with historical restrictions on the use of Efavirenz by women of childbearing age, based upon small numbers of cases of neural tube defects, which hampered treatment rollout. In her “Tale of Two ARVs”, Abrams discussed how  small number of cases of neural tube defects associated with early ARV exposure have once again impacted treatment guidelines and particularly treatment options for women – delaying, hopefully temporarily, access to DTG. After more than two decades, she noted, the alternative, EFV, appears to be safe and is not associated with neural tube defects.

Sharon Hillier (University of Pittsburgh) started her talk by asking the audience “How much do any of us really understand about risk?” She provided examples, from breast cancer, that understanding health risk is even more complicated. She highlighted that while overall there had been a balanced and fair response to warnings regarding DTG use among women of childbearing age, there are lessons that can be learned. She discussed that following WHO warnings about DTG use in pregnancy, the HPTN 084 study, examining the efficacy of long-acting cabotegravir – structurally related to DTG – among women aged 18-45 has required its participants to use long-acting contraception, meaning that there will be data gaps on the safety of yet another PrEP drug in pregnancy and periconception.

Oral abstract (OA15): New ARVs for Prevention

The moderators began this session by addressing the importance of new ARVs to tackle non-adherence issues observed in treatment and prevention strategies. Following that, many novel antiretroviral compounds and delivery platforms were discussed.

James Cummins provided data on the pharmacokinetic-pharmacodynamic (PK-PD) properties of drug-containing intravaginal rings (IVRs) containing the antiretroviral compound MK-2048 (a second generation integrase inhibitor) alone or in combination with vicriviroc inserted and retained in the Rhesus macaque (RM) for 14 days. Results indicated the utility of the RM model for evaluating the PK of MK-2048 and confirming its antiviral activity in vaginal tissues.

Jill L. Schwartz and colleagues at CONRAD provided data on the safety and PK of TAF-based oral PrEP regimens. Women (n=75) at 3 clinical sites in the US and Dominican Republic, were randomized 1:1:1 to: F/TAF 200/10mg,  F/TAF 200/25mg, or F/TDF 200/300mg and assessed at baseline, after a single dose and after 14 days of use.  The team found that F/TAF had fewer side effects, lower plasma TFV, and higher PBMC TFV-DP concentrations providing evidence for a safer and more potent oral PrEP regimen for HIV prevention in women.

Two studies further advanced our knowledge of the PKs of Long-acting (LA) Cabotegravir (CAB). Susan Ford, presented a CAB Population Pharmacokinetics model that included intrinsic and extrinsic factors, developed with data from Phase 1/2 studies and simulations that can be used to inform PrEP Ph3 dosing strategies. Results revealed that LA CAB absorption rate differs between males and females and also provided information that can be used to develop recommendations for re-initiation strategies for those with prolonged interruptions in dosing.

Finally, Landovitz and colleagues provided results from HPTN 077 evaluating tail-phase safety, tolerability and pharmacokinetics of LA injectable CAB in HIV-uninfected individuals. The t1/2app of CAB LA for females was significantly increased compared to males, and was also influenced by BMI. The median time to the Lower Limit of Quantification (LLOQ) was 66.3 weeks for females and 42.7 weeks for males. 76 weeks after the final injection, 58% of females and 87% of males had levels < LLOQ.

Symposium (SY07): Optimizing PrEP Delivery for PrEP Users

The “Optimizing PrEP delivery” symposium started with a presentation by Dr. Rene Heffron, who provided an excellent overview of the innovations in integrating PrEP into programs addressing each stage of women’s reproductive health continuum. For those who desire pregnancy, PrEP can be provided efficiently through safer conception programs as demonstrated by Schwartz et al in South Africa and Heffron et al in Kenya. Additional opportunities include integration of HIV prevention into antenatal care and PMTCT or family planning clinics or other places where emergency contraception or abortion care is provided. Some challenges to integration were discussed including low funding levels, nonsupportive policies and low provider comfort.

Dr. Nittaya Phanuphak, of the Thai Red Cross, presented on the successes of key-populations-led programs in Thailand. The impressive scale-up from 0 in 2014 to 5000 persons on PrEP to date, has been achieved primarily due to community involvement in program planning and implementation.

The audience, however, was truly captivated by a passionate and provocative talk delivered by Dr. Sarit Golub from Hunter College in New York who challenged traditional approaches to risk assessment as a means to determine PrEP eligibility and increase clients’ motivation to use this prevention modality. Dr. Golub presented the audience with four (data-driven) statements that she believes are currently contributing to gaps in PrEP optimization: 1) Risk assessment tools are not always predictive at the patient level; 2) Risk perception is rarely an intervenable factor; 3) Current constructions of risk are stigmatizing and alienating to potential PrEP users; and 4) The concept risk compensation directly impedes and fuels disparities in PrEP access. Originating from paternalistic attitudes of the past, risk compensation arguments seek to reassert control over sexual expression by substituting fear of STI epidemics in place of fear of HIV. She described an alternative approach to discussing prevention, through Sexual Health and HIV Prevention Options Counseling, in which clients and providers would work collaboratively to understand and address client’s personal health priorities, thereby focusing on reasons why people might want to take PrEP other than because they are “high risk”, e.g. to reduce anxiety, take control over their sexual health, increase their sexual satisfaction and intimacy, among others.

Poster Discussion (PD09): Long-Acting Prevention Agents in Experimental Models

Long-acting injectables ARVs represent a promising alternative to daily ARVs, however, their safety, toxicity, and loading capacities still require additional investigation. While introducing the session, Stephanie Barret focused her discussion on the importance of LA ARVs for both HIV treatment and prevention.

Benhabour and colleagues investigated the safety of Long-acting (LA) injectable formulations of antiretrovirals (ARVs) in mice and macaques.  They developed a polymer-based in-situ forming implant (ISFI) that can incorporate several different ARVs, provide ultra-long-acting (ULA) release of drugs for up to one year, and be removed easily. Their finding suggest that Long-acting injectable formulations are a safe and promising strategy for HIV treatment and prevention.

Using the functional role of blocking the HIV attachment to its coreceptor CCR5, John McBride and colleagues designed a 5P12-RANTES based microbicides incorporated in a novel ring that has controlled release of these microbicides. Such a ring could be could be loaded with broader range of active molecules and applied to both anal and vagina for the prevention of HIV transmission.

Both vaginal and oral formulations of tenofovir (TFV) haven shown to be effective in HIV-1 prevention. However, tenofovir alafenamide (TAF) seems to be safer and more potent. In this presentation, Gunawardana and colleagues provided data on an in vivo evaluation of subdermal implants for delivering TAF in mice, dogs and sheep. Overall, the devices were well-tolerated, but a drug-related local toxicity was observed in dogs at high TAF release rates.

Team C

Oral Abstract (OA09): Translating Immunity From Pre-clinical Animal Models to Humans

Jason Gorman reported on the crystal structure of the first SIVmac239 fully neutralizing Abs in complex with rhesus CD4 and SIVmac239 gp120. The Ab, designated ITS90.03, targets a glycan hole at residue 238. The SIVmac gp120 core was found to align well with HIV-1 and -2 gp120, with divergence in the alpha 0 region and V4 loop. Further similarities were observed between rhCD4 recognition of SIVmac239 and huCD4 interaction with HIV-1; and between the glycan shields. Overall this work revealed similar sites of vulnerability between HIV-1 and SIV Env. Ann Hessell reported that native HIV-1 Env could elicit Tier 2 heterologous neutralizing MAbs in nonhuman primates. Greater clonal expansion was observed for strongly neutralizing Abs. All the NHP mAbs generated were able to mediate ADCP; however, although macaque serum exhibited ADCC against SHIV SF162P3, no mAbs to date demonstrated ADCC activity. Wilton Bryan Williams showed that SHIV-C CH848 infection of two macaques elicited 2G12-like NAbs. Next generation sequencing revealed pre-infection clonally related IgM heavy chain genes in blood that were somatically mutated. Results suggest that this lineage may have been initiated by high mannose glycan-bearing environmental antigens. Miroslaw Gorny evaluated the efficacy of a DNA/protein vaccine in rhesus macaques. Five of 9 immunized macaques exhibited strong control of SHIV-BaLP4 challenge. The ID50of plasma Abs directed towards V2 peptide 230 was higher in controllers compared to non-controllers, and 3 of 5 controllers developed V1V2 Abs in vaginal secretions. Jeffrey Schneider addressed the question of biodistribution of VRC01 following intravenous injection. Light Sheet microscopy data revealed a gradual buildup of CY5-labeled VRC01 in rhesus macaques, peaking at 72h post-inoculation. This suggests that challenge sites are not fully protected by 24h post-injection, with important implications for future challenge studies.  Similar distribution of VRC01 was observed in vaginal and rectal epithelium, although with apparently different delivery mechanisms. Finally, Ying Huang reported a meta-analysis of 12 single-mAb NHP SHIV challenge studies performed over 2001-2017, plus over 30 unpublished studies. She concluded that for all specificities of Ab (CD4 binding site, V1V2, V3 glycan, MPER), serum ID50 correlated inversely with protection.

Oral Abstract (OA14): Antibody Functions Beyond Neutralization

James Arthos described how gp120 V2 mimics MAdCAM in the way that it binds to a4b7 integrin. Antibodies specific to the alpha-helical conformation of V2 inhibit binding to a4b7. In addition, MAdCAM can deliver costimulatory signals through a4b7 to CD4+ T-cells. In vitro,the combination of MAdCAM and retinoic acid (unique to gut inductive tissues in vivo) induced CCR5 and promoted viral replication in recently activated naïve CD4+ T-cells. Simone Richardson reported on functions associated with the Fc region of CAP256 antibody variants. IgG3 forms of these antibodies had increased neutralization potency and enhanced effector functions (both phagocytosis and trogocytosis) as compared to IgG1 variants. Studies implicated the increased hinge length of IgG3 variants compared to IgG1, as responsible for the enhanced functionality. A structural biologist, William Tolbert characterized the Fc domains of IgG1-4 in rhesus macaques and determined the differences between human and macaque Fc-mediated effector functions. Macaque IgG1 Fc is the most similar to human IgG3 and IgG1, and has the highest affinity to macaque receptors. Matthew Worley argued that neutrophils are an ideal cell to prevent HIV transmission due to their diverse FcR profiles, rapid effector functions, rapid migration and their effectiveness at mucosal sites, despite a short half-life. He showed that viremic controllers induced more IgG-mediated HIV specific neutrophil phagocytosis than non-controllers. Furthermore, removal of IgA from plasma increased phagocytic responses in both viremic controllers and progressors. Svenja Weiss described the first study using an RV144-like immunization regimen with a SHIV challenge in rhesus macaques. Five of 9 animals showed tight control of SHIV-BaL infection. V2p antibodies, which bind to the a-helix conformation of the C-strand of V2, were associated with control. It was noted that the outcome of this study was control of infection, rather than complete protection.

Symposium (SY05): Close Encounters of the Third Kind: Innate and Adaptive Immune Responses in HIV Dissemination

Anthony Cunningham reviewed the role of type I interferons in acute and chronic HIV infection. He highlighted the dichotomous role of plasmacytoid DCs, which serve both as the major source of Type I IFNs and as cells capable of triggering inflammation and recruiting CD4+ T-cells to mucosal sites. Myeloid DCs serve as HIV target cells and also transfer virus efficiently to CD4+ T-cells. HIV modulates gene expression in DCs and macrophages, and blocks interferon induction in these cells by dysregulation of TBK1; this effect is mediated by the HIV accessory protein Vpr. HIV directly induces over 20 ISGs in macrophages, DCs and CD4+ T-cells.

Mary Carrington reviewed HLA Class I alleles that impact HIV infection. While HLA B*57 is highly enriched in “elite controllers”, in fact most subjects with B*57 fail to control HIV in the absence of therapy. This indicated the presence of distinct modifiers of B*57. Recently, a single variant (rs643347A/G) encoding an Ile to Val substitution at position 47 of KIR3DL was identified as having a protective effect in individuals with B*57:01, but not B*57:03. KIR3DL1 an NK receptor that binds HLA-B*57:01. Also, elevated HLA-A mRNA expression was recently associated with lower CD4 counts over time. Elevated HLA-A expression also associates with higher HLA-E, greater NKG2A-mediated inhibition of NK cell function, and therefore weaker HIV control.

Zaza Ndhlovu presented recent data on HIV persistence in lymph nodes from women in ART in the FRESH cohort. Even with very early treatment, T follicular helper cells were expanded, germinal centers formed and Gag p24 was detected within the germinal centers. HIV RNA was also visualized and quantified. Ongoing viral replication was likely, as suggested by changes in viral sequences from lymph nodes obtained after ~1 year on ART. HIV RNA was found to accumulate in lymph node CXCR3+ Tfh cells.

Keith Reeves presented recent advances in the characterization of memory NK cells.He described four types of NK cell “memory”:  cytokine-induced memory; adaptive evolved memory; antigen-specific memory; and “memory-like” NK cells.  NK cells are multifunctional, induce robust responses in HIV infection and vaccination and NK cell memory (Type 3) is partially dependent on NKG2c and NKp44. Type 4 “Memory-like” NK cells are epigenetically modified following initial antigen exposure and can be rapidly mobilized after subsequent exposure. They are massively expanded by CMV and preferentially accumulate in the gut.

Poster Discussion (PD06): Mechanisms of Natural Control

Jeromine Klingler and Nuria Gonzalez provided evidence that Antibodies (Ab) from HIV-1 controllers can target specific regions of HIV-1. Interestingly Dr. Klingler also found that frequencies of IgG3 are enriched in plasma from controllers compared to progressors and that ADCC activity is stronger in Abs isolated from controllers expressing protective HLA-B57 alleles. Consistently, Dr. Gonzalez also found preferential targeting of HIV-1 specific Abs against V3 regions in controllers.  In addition to humoral immune responses, Enrique Martin-Gayo presented novel data identifying enhanced abilities of primary dendritic cells from HIV controllers to respond to HIV-1 dsDNA, through a mechanism that involved RNA polymerase III (RNApol III) which allows synergy of DNA and RNA sensing pathways. Specific polymorphisms in RNApol III could be involved in enhanced sensing of HIV-1 in DC from controllers. Elina El-Badry provided evidence of different patterns of CD8 and CD4 T cell activation in HIV infected women and men from Zambia, which could have an impact on differential disease progression between men and women. Olivier Lucar presented exciting data on the characterization of a new population of CD57+ NKG2C+ HIV antigen-specific NK cells that were cloned from the blood of HIV+ subjects. These cells have the ability to potently lyse K562 and autologous B cells loaded with HIV.

Team D

Roundtable (RT01): Accelerating Product Introduction for Impact
World over, challenging governments and sexual stigma present barriers to prevention programs. Three themes emerged in a discussion of lessons from implementing products (e.g., PrEP, contraceptives, HPV vaccine, Ebola vaccine).  

1)    Choice, choice, choice. Choice!  includes layering prevention methods, having different options (especially “fit and forget” technologies), and making products responsive to people’s concerns. Speakers emphasized the need to maintain successful interventions – e.g., VMMC, delaying sexual debut, fewer partners – amid new technologies. New technologies must be complementary to, and not displace or replace the existing successful technologies.

2)    Context means tailoring interventions to locations, in terms of sexual practices, states, and society. Dr. Alex Coutinho asked, can we de-medicalize biomedical HIV prevention, the way we have with VMMC? Otherwise, clinic-delivered biomedical technologies will flounder in countries lacking strong health systems unless they adapt to the system. Dr. Swati Gupta highlighted how HIV vaccine efforts can learn from the Gardasil HPV vaccine, which despite being inexpensive (20 cents/dose) and efficacious (100% against HPV-16 and -18 related precancers), has low uptake in low income countries, where most cervical cancer deaths occur. In South Africa, a national HPV vaccination campaign that delinked the vaccine from sex led to high coverage in adolescents, Dr. Hasina Subedar explained.

3)    Community involvement means that community members, scientists, activists must work together before, during, and after research. Maria del Rosario León pointed out that while PrEP trials were conducted in Peru, and guidelines were published, PrEP is still not available in the public health system. This underlines the need for countries that participate in research to then be able to provide the resulting developments to their people.

Oral abstract (OA12): Contraception and HIV Risk: Still Between a Rock and a Hard Place
Understanding the biological mechanisms through which hormonal contraception methods like injectable Depot Medroxyprogesterone Acetate (MPA) and norethisterone enanthate (NET-EN) may mediate HIV acquisition risk is critical.

Bick and Maritz presented data indicating that potential MPA biological effects on HIV acquisition risk are mediated through a different mechanism from that of NET-EN, showing that MPA, but not NET-EN, increased activation of CCR5 and CD4+ T-cells in various biologic matrices (cervical explants, PBMC, TZM-bl cells), likely mediated through the glucocorticoid receptor. Similarly, Matubu reported that DMPA but not NET-EN, decreased T cell activation to polyclonal stimulation as shown by low CTLA-4 expression but did not increase T-cell expression of PD-1. A phase I pharmacokinetic study of dapivirine (DPV) and levonorgestrel (LNG) vaginal ring for combined prevention of HIV and pregnancy risk (Achilles et al) showed that the ring was safe and well-tolerated and resulted in sufficient DPV and LNG exposure. From the MTN-020/ASPIRE study cohort (Baeten et al), a surprisingly high HIV incidence was observed in women using the NET-EN contraception (6.22 per 100 years), although there were no significant differences in HIV risk across the four contraception methods (DMPA, NET-EN, implant, and cIUD). Lastly, Renee Heffron reported a pilot study of safer contraception, demonstrating no HIV transmissions in the context of high pregnancy rates among HIV serodiscordant couples using various combinations of safer contraception strategies like ART, PrEP, VMMC, or timed condomless sex acts.

Poster Discussion (PD08): Trials and Tribulations in Roll Out
Adherence to the vaginal ring is an issue. A study by RTI international on what women prefer in an HIV prevention product recruited woman from South Africa and Zimbabwe using a discrete choice experiment design. The study explored the preference of users in terms of 6 key attributes: HIV prevention efficacy, pregnancy prevention, dosage, mode of insertion, causes wetness and partner awareness.

Another poster discussed identifying in whom and when to test for renal insufficiency during PrEP use can aid scale up. A longitudinal study among PrEP users, older than 18 years ,at Washington University in St. Louis ID Clinic was conducted from 2014-2017. The study found that renal function among PrEP users in the analysis demonstrated a small and clinically insignificant decrease in eGFR. Hence, to hasten PrEP implementation by reducing costs and procedures the evidence supports less frequent renal monitoring may be required in low-risk PrEP users.

The 4th poster assessed PrEP side effects and discontinuation in pregnant and non-pregnant women. PrEP initiation is sometimes accompanied by gastrointestinal side effects, mostly soon after initiation and often resolving with continued care. The study determined the frequency of side effects and their influence on PrEP continuation. Women who experienced side-effects were more likely to discontinue PrEP, especially during pregnancy. Special considerations may be needed to address side-effects among pregnant women and to support PrEP use during pregnancy.

A pilot study of video-based counseling and home-based HIV testing for transgender youth

had success with diversified recruitment strategy and found no technical or logistical barriers to delivering the intervention. The study participants reported high levels of satisfaction and willingness to repeat intervention.

Oral abstract (OA10): Key to the Response: Populations, Partners and Prevention
One study examined context-specific data on characteristics, HIV risk and health-seeking behaviours of male partners of AGYW in in 2 informal settlements in Durban, where DREAMS was being implemented. Findings showed that most men had multiple AGYW partners and their experience of violence, depression and alcohol abuse was common and strongly associated with HIV risk behaviours.  

Sheila Harvey reported on help seeking behaviours of women experiencing intimate partner violence (IPV) in Mwanza, Tanzania and its implications for HIV. Women’s disclosure of IPV was high (73%) however less than 1 in 5 (19%) women sought help outside the family (majority went to local and religious leaders) as a number of barriers exist for women seeking help for IPV. Next steps include development of strategies to identify women experiencing IPV to enable linkage to care as well as exploring availability and quality of formal services that address violence against women.

The third study showed that women joined sex work at an early age mostly due to poverty and influence from friends who are already in sex work. Targeted interventions [economic empowerment programs, interventions targeting both FSWs and MCs at venues where sex work occurs (e.g. lubricant and condom promotion) and structural interventions to address MC and police violence] are needed to reduce the risk of HIV acquisition among FSW and onward transmission to male clients and eventually to their female partners.  

HPTN-075 study showed that HIV incidence among MSM and TGW is alarmingly high (incidence varied per study site).  The most critical factor is having a rectal STI at enrolment.  HIV prevention efforts addressing the needs of MSM and TGW should be intensified and optimized and structural barriers to preventative behaviour (including access to appropriate medical care) should be removed.

Discussions also revealed that young transwomen in Brazil have high HIV risk and low prevention use; as well as a higher rate of HIV compared to other populations of trans youth around the world.  Interventions are needed that bring young transwomen into the health care system to increase HIV testing, PEP awareness and PrEP use. Findings from HPTN-074 showed that scalable, integrated HIV intervention for PWID that combined systems navigation and psychosocial counselling had a strong impact on mortality with over 50% all-cause reduction among HIV infected persons.  This can be explained by increased antiretroviral therapy (ART) uptake and medication-assisted treatment (MAT).

 

Thursday 25 October 2018

Team A

The last day of the HIVR4P meeting we travelled from the basic molecular mechanisms controlling Env Ab interactions and evolution (OA16 and OA22) to the translation of knowledge to optimize information from trials testing vaccine candidates (SY08). Advances in both fields will be necessary to walk the path forward for HIV vaccines, as Dr J Mascola emphasized in the closing plenary session (PL04.04).

OA16 and OA22 included excellent works defining the moves of the endless tango between Env and Antibodies. This is a two-way dance, in which first Env drives antibody evolution from germline precursor B cells, and then mature antibodies drive Env evolution to escape immune pressure.

Several strategies were presented to tickle the germline at OA16. First, a tool called Armadillo was presented by K Wiehe (OA16.01) to identify improbable mutations critical for broadly neutralizing activity. If validated, this tool will help future sequential immunogen design allowing for a truly predictable directional antibody selection. R Pantophlet (OA16.02) explored whether carbohydrate mimicry of mammalian oligomannose might more readily elicit the bnAbs. Synthetic glycan derivatives can be designed to bind V3/glycan PGT bnAbs and germline precursors. Proof of concept immunogenicity experiments in transgenic mice are planned. X Chen (OA16.03), from Mascola’s lab, showed a sequential immunization in a knock-in mouse model expressing a repertoire of VRC01-class precursors with diverse CDRH3s. This approach elicited neutralizing VRC01-class Ab able to neutralize N276 glycan-containing viruses. This work provides proof of concept that even highly somatic mutated bnAbs like the VRC01-class Abs can be elicited through rationally designed sequential immunization. Similarly, R Andrabi (OA16.06), from Burton’s lab, presented on a novel immunogen and vaccine strategy that successfully induced an immunofocused V2-specific cross-clade tier-2 neutralizing response in Knock-in mouse. All approaches will be enriched by the analysis of natural infection, a nice example is the in-depth analysis of The CAP256 patient (CAPRISA002 cohort, South Africa) presented by L Reh (OA16.05), from A Trokla’s lab.

OA22 explored antibody development and Env escape. In a nicely designed work, C Deal (OA22.06) infected humanized mice with different HIV isolates and While for some bnAbs after four weeks treated animals with AAV vectors coding for different bnABs. Some animals showed long-lasting viremia control, being the percentage of non responder animals was highly dependent of the combination bnAb/virus. The authors demonstrated generation of resistant viruses; however, he mechanism of escape, and hence the location and number of mutations was strongly dependent on the Env/antibody pairing. A complex landscape is anticipated and the data suggested that bnAb combinations will be mandatory for therapeutic interventions. An alternative to the combination of antibodies is the development of bifunctional antibodies carrying multiple Env binding sites in a single molecule. Another example was also presented in this session by C Fellinger (OA22.05). The eCD4Ig protein is a modified CD4-IgG fusion protein that interacts with the CD4 and the coreceptor binding sites of HIV Env. Interestingly, in vivo (AAV treated NHP) and in vitro data suggest that the generation of eCD4Ig-resistant viruses is difficult and seems to have a higher fitness cost, thus increasing the therapeutic potential of this molecule.

The symposium 08 offered new data on different NHP immunizations. G Franchini (SY08.03) reproduced the RV144 based immunization schedule, improving protection by using DNA prime. Her data showed that titers of V2 targeting antibodies and monocyte activation were positively associated with protection in Rhesus macaques, while elicitation of V1 antibodies were associated with poor protection. To explore the role of V1 loop, the authors designed two versions of a V1-loop-deleted Env, which showed better binding to anti-V2 antibodies and to sCD4. However, when immunogenicity and efficacy were tested at suboptimal doses in NHP, data were not conclusive. Further studies will be needed to understand the role of anti-V1 antibodies. The last speaker of this session, SP. Kasturi (SY08.05) explored the role of adjuvants in durability of plasma antibodies elicited by Env immunization. Besides Allum, the authors tested TLR4/7/8 agonists PLGA, MPLA and the hydrophobic R848 derivative 3M-052) alone or in combination. Data showed that 3M-052 had impressive effects on titer and durability, therefore seems to be a critical component of a vaccine. He further showed that the route of vaccination matter as subcutaneous gave better results than intramuscular injection. Human trials will start soon to definitively delineate dose and safety of this new adjuvant. Implementation of clinical trials also requires reliable platforms to rapidly generate and analyze data. Two of those platform were presented. G Ferrari (SY08.02) described the reliable ADCC assays that has been and will be used in several human trials to be used for human trials, including the gp120 coated target cells or the infected cells. He showed that ADCC responses directed against HIV-1-infected cells are more difficult to detect. M Gale (SY08.04) showed transcriptome data on the Picker’s RhCMV/SIV vaccine. He showed that clear segregation of protected and unprotected animals could already be seen after three days vaccination in both subcutaneous and oral immunizations. This signature involves myeloid cells, TLR activation, non canonical T cells signature, trafficking and IL-15 as described also by M Muller (SY08.01). In summary, several presentations concurred in the relevance and the complexity of myeloid cell-T cell cross talk in immunogenicity and the potential beneficial role of IL-15 (OA22.01, 03 and 04). Probably, the different platforms (ADCC, transcriptomics, and adjuvant analysis) will help to understand and then manipulate this complex cross-talk.

To close the meeting, the very last plenary talk by J Mascola (PL04.04) started profiling the vaccine that we want: it should protect >60% of individuals; be administered in 3 immunizations, and boosted at least every 10 years, showing a wide coverage of viral clades in both men and women.

To reach these objectives, there are 4 main tasks ahead: i) to further develop the RV144 study (this is currently ongoing in HVTN 702 and HVTN705 studies); ii) to understand previous failures (this is also an ongoing task, focused on understanding how nature makes bnAbs); iii) using antibodies as protection (AMP study) and iv)  explore new B and T cell targeted immunogens. For T cells, Dr Mascola highlighted the adaptation to humans of CMV-based vaccines, while for B cells different approaches are worth to be developed, the epitope based design (always in prime boost strategies with Env trimmers at the end), the germline or lineage-based immunogens and the native trimer.

The field is in general optimistic, the data generated over the last ten years and the newest antigens, vaccine platforms, vectors and adjuvants as well clinical trial structures are good reasons for that. Tens of new products have entered o will enter in 2019 in Phase I trials in humans. The data generated will be relevant to improve a final design closing the iterative vaccine circle. “The path will not be short, it will probably be bumpy, but reaching the final goal is likely” said J Mascola.

Team B

Oral abstract (OA19): Stay With Me: Retention on PrEP

Matthew Spinelli from the University of California presented an analysis of PrEP discontinuation among PrEP users in the San Francisco Primary Care Clinics safety-net network.  Among 411 PrEP users (36% White, 26% Latino, and 13% Black, with a median age of 35), 24% had a PrEP interruption. His analysis found that, among those on PrEP for at least 90 days, the strongest predictor of discontinuation was missing a PrEP visit in the previous quarter. Where reasons for discontinuation were known, these were most frequently structural issues, including problems with cost and insurance or difficulty attending visits or completing laboratory testing. Retention on PrEP had declined in this cohort in recent years, possibly because more recent PrEP initiations were driven more by provider recommendation rather than patient request.

Kenneth Mugwanya from the University of Washington reported on progress in the Partners Scale Up project, which has integrated PrEP into Public Health HIV clinics in Kenya, where 65% of those initiating PrEP have returned for at least one PrEP refill within 3 months of starting. An impressive 3600-plus PrEP initiations have occurred over the past 18 months (53% Female, 46% <30 years old; 85% reporting an HIV+ partner). In contrast to the SF findings, in this group, retention improved with more recent PrEP initiators, possibly reflecting both growing health provider comfort with delivery as well as the gradual increase in PrEP awareness in the communities.

Michel Alary from Université Laval presented results from a PrEP/TasP demonstration project among female sex workers (FSWs) in Cotonou, Benin, where high levels of mobility led to low retention in the PrEP program (48%), despite very high initial uptake levels (88% of those eligible); in contrast, Sue Napierala (RTI International) reported that uptake of PrEP among FSWs in Zimbabwe in the intervention arm of the SAPPH-Ire trial was relatively low (38% of those eligible), but 81% returned for at least one refill. This highlights the importance of collecting and analyzing local data to inform further PrEP scale-up and optimization.

Oral abstract (OA23): Great Expectations: The Impact of PrEP

Jared Baeten began the session by presenting the pooled analysis of HIV incidence outcomes from 46 PrEP demonstration projects.  In the combined sample size of 10,609 people, the overall incidence rate was 0.64% per year, with relatively higher level among women (0.81%), especially in Africa (1.42%), and in transgender women (1.62%). However, it should be noted that the numbers of transgender women included in these studies was quite small. These results compare favorably to HIV incidence results found in PrEP clinical trials, confirming the high effectiveness of oral TDF/FTC in “real-world” settings.

The next presentation by Urvi Parikh reported on resistance testing results from the MTN-020 (ASPIRE) trial, comparing the Dapavirine (DPV) vaginal ring to placebo. Resistance was evaluated by two methods – standard genotyping and next generation sequencing. The frequency of NNRTI mutations was low and did not differ by arm, indicating that NNRTI resistance was likely transmitted and not selected by DPV ring use.

Roundtable (RT02): Getting to U: Undetectable = Untransmittable

U=U: If you're on suppressive ART, you are sexually noninfectious. The risk is zero.

Dr. Judy Auerbach, co-moderator of the roundtable began by outlining the main goals of the overall session which were to discuss: 1) challenges of staying on ARVs for the “long haul”; 2) the scientific evidence that informs guidance around treatment as prevention; 3) what U=U means for non-sexual transmission of HIV; 4) understanding of the meaning of undetectable; and 5) the challenges and successes of U=U as a movement, including providers resistance to discussing it.

Nelly Mugo reviewed the scientific study data from more than 7 trials that show conclusively that, in terms of sexual transmission, U does equal U. However, in the context of breastfeeding, Lena

Serghides provided data that U may not be =U due to the fact that transmission of HIV through breast milk is different than other modes of transmission, and current ART therapy is not sufficient to eliminate the cell-associated virus that is present.

Bob Remien provided an overview of the history of initiation and adherence to ARVs, including facilitators and barriers to adherence. He provided some insight into what U=U might mean in terms of providing new motivations for getting and staying on ART, including reductions in stigma, renewed hope and possible improvements in mental health and well-being? A particular poignant quote from an HIV-positive person participating in one of his studies captures this when he said, “U=U has given me my life back.”

Bruce Richman, from the Prevention Access Campaign,  the “father” of U=U, closed the session with a passionate presentation of why  U=U is a real game changer. This reality transforms social, sexual and reproductive lives, helps to dismantle HIV stigma, and encourages engagement at all stages of the care continuum.

Plenary (PL04) PL04.01 - Combination prevention: What will it take to make it work?

In the closing plenary session, Diane Havlir provided a convincing argument that innovative multi-disease approaches to combination HIV prevention will be needed to dramatically reduce the gap between the proven efficacy of HIV prevention interventions and their effectiveness in real-world settings. Combination prevention approaches such as treatment as prevention, PrEP, PEP, condoms, behavioral interventions, voluntary male medication circumcision, and needle exchange will have the greatest impact when integrated with other key services that collectively reflect the major health and life priorities of individuals and their communities.

As a primary example of the powerful impact that integration of HIV and other health services can have on community-level HIV outcomes, Havlir presented results from the SEARCH (Sustainable East Africa Research in Community Health) study, which tested a community-level intervention integrating delivery of HIV and other health services in rural Kenya and Uganda. The intervention involved a multi-disease-focused health campaign and health fairs that implemented a test-and-treat strategy for HIV while also providing services for other health priorities including diabetes, hypertension, deworming, bed nets, cervical cancer screening, dermatology, vision, maternal and child health, and men’s health. In the first phase of this study, approximately 1,000 people visited these health fairs each day. Remarkably, this intervention resulted in a large increase in the proportions of persons in those communities who knew their HIV status (53% to 91%) and who had viral suppression among those with HIV (42% to 79%). This community-level intervention was also associated with a 21%-reduction in mortality.

Havlir ended the session with an example of how integrative service provision could also be used among men who have sex with men in San Francisco. As part of the Magnet Express program, men can walk in without an appointment and receive a host of sexual health services including testing for HIV, gonorrhea, chlamydia, syphilis, and hepatitis C, counseling, PrEP, or PEP.

Team C

Oral Abstract (OA17): Factors Influencing Viral Transmission and Spread

Analysis of the impact of pre-adapted polymorphisms in HIV Gag on early virus control and disease progression by Daniela Monaco revealed a low rate of reversion and increased viral adaptation during the first two years. Disease progression (CD4 decline to 350) was more rapid in individuals with highly pre-adapted virus than in those in whom adaptation increased over the course of infection. Reporting on Lake Victoria fishing communities with a high prevalence of both HIV and Schistosoma mansoni, Rupert Kaul showed that Schistosome treatment with Praziquantel reduced HIV entry into cervical and blood CD4 T-cells, inducing a transient increase in mucosal activation and alpha4beta7 expression in blood T cells. Mucosal and systemic IFN2a expression was increased post-Sm treatment, which was linked to decreased viral entry in CD4 cells. Morgane Rolland used phylodynamic analysis and modeling of viral growth rates to more accurately assess the duration of the eclipse phase of HIV infection. In the RV217 HIV-1 acute infection cohort, the eclipse phase was estimated to last 6 days for infections by single founders, with no obvious effect linked to virus subtype or gender.  Although different estimation methods gave varying results, the most accurate method (“BEAST”) concluded a median of 6 days, with no difference between infections established by single versus multiple founder viruses. Gladys Macharia showed that rectal multivariant infection was associated with depletion of effector memory CD4 T cells and reduced CD8 T cell proliferation in the acute stage; and with disease progression and higher peak viral load in the long term. In oral transmission studies using the SIVmac251 model to model neonatal transmission in rhesus macaques, Roslyn A. Taylor found that the entire digestive tract is highly susceptible to replicative viral infection and that the majority of infected cells are T cells. Finally, Nicole Naiman presented data from 72 mother-infant pairs collected in Nairobi during the 1990s in a breastfeeding study; 21 infants became infected. Data analysis revealed that IgG binding to the gp41 ectodomain was associated with increased risk of mother-to-child transmission.

Oral Abstract (OA21): Linking Arms in Defense: Innate, Cellular and Humoral

The session opened with Monica Vaccari describing a non-human primate vaccine study in which animals were primed with either ALVAC-SIV, a DNA-SIV, or an Ad26-SIV vaccine, followed by two ALVAC-SIV + gp120 boosts and mucosal SIVmac251 challenge. They found that non-classical monocytes (CD16+) were associated with increased acquisition while decreased risk was associated with classical monocytes (CD16-CD14+), NLP3, IL-1b, gut homing CCR5 and GATA3. Discussing an analytic treatment interruption study, RV411, Bonnie Slike reported that out of 76 markers measured, expression of APRIL, a protein important for B-cell development, was most strongly associated with a shorter time to rebound after treatment interruption. Following up on lessons learned from RV144, Sampa Santra’s laboratory compared three different priming vectors (DNA, MVA and VSV) in an attempt to find the one most effective at priming both cellular and humoral responses. She found that the recombinant MVA prime elicited higher binding and neutralizing antibody responses, led to higher germinal centre activity and superior antigen-specific B-cell responses. Jerôme Kervevan showed that targeting HIV antigens to human Langerhans cells (LCs) promotes differentiation of Tfh from naïve CD4 T-cells, using anti-Langerin antibody fused with HIV-Env gp140. He also found that targeting LCs enhanced IgG secretion by B-cells. Julia Roider characterized the differences in neutralizing antibody production between infected children and adults. She showed that both progressing and non-progressing children had higher levels of broad and potent neutralizing antibodies, as well as higher frequencies of tonsillar Tfh cells, compared to adults. The differences in Tfh frequencies, functionality and regulation might explain the superior neutralization breadth in children compared to adults. In the final talk of the session, Kathryn Foulds used computational approaches to show that virus evolution in breakthrough infections was due to de novo point mutations, recombination, and population replacement. She also reported on the ability of CTL and humoral responses to induce vaccine-mediated immune pressure.

Symposium (SY10): Mucosal Environment: Barriers and Facilitators of Transmission

Microbial diversity is believed to be associated with increased HIV risk, although the exact mechanisms are still unclear. Heather Jaspan gave a comprehensive talk covering different tissue sites and their associated microbiota, including the female and male genital tracts, and the infant gut microbiota during breastfeeding. At all different sites, higher microbial diversity was consistently associated with increased HIV risk. She mentioned other HIV risk factors such as higher inflammation levels and the recruitment of target cells to the mucosa. Encouragingly, certain bacterial taxa associated with immune quiescence are already involved in probiotic development. Connie Celum reported on the increasing rates of C. trachomatis and N. gonorrhoea infection in North America, especially in MSM. She emphasized the pressing need for more innovative ways to tackle this problem, eg. the use of doxycycline as post-exposure prophylaxis as it has good tolerability, bioavailability and half-life. She emphasized that reducing STI rates “isn’t all about STI diagnoses”, but that clinics must also be accessible to high risk groups, encouraging testing and improving their location in the community, as well as branding and outreach. Colleen Kelley described the antomic features of the rectal mucosa and how it is immunologically distinct from both the FGT and the penis. She reported findings from the RM-MSM and the PrEP-Lube studies, where an enrichment for Prevotellaceae over Bacteroidaceae and an increase in Shannon diversity were found. In RM-MSM, increased HIV risk could be also be due to the distribution of cells in the rectal mucosa, with increased IL-17+ and FoxP3+ cells at the lumen. Cara Wilson reported on efforts to model the complex interactions that occur between immune cells, HIV, and intestinal microbiota using in vitro systems. During HIV infection, her group found that the abundance of Firmicutes decreased while Proteobacteria frequencies and the Prevotella to Bacteroides ratio increased. Interestingly, mucosa-associated butyrate-producing bacteria were associated with reduced CD4 T-cell proliferation and activation, and butyrate itself had dose-dependent effects on HIV infection.

Team D

Oral abstract (OA18): In Opinion 360: Meaningful Engagement From Research to Roll Out, speakers discussed examples of how prevention projects can represent community interests at every stage. Dr. Rita Nakalega detailed how community engagement activities were key to getting community support to allow the MTN-034/REACH study to proceed in Uganda. Study leaders solicited input from adolescent girls and their mothers about ethical considerations, from parental consent and disclosure to who should be recruited. Ultimately, it was decided that only adolescent girls at high risk would be enrolled. For recruitment, Gail Broder discussed how successful recruitment of participants in the AMP studies required different methods in different regions. Notably, while nearly half of participants enrolled in the Americas and Switzerland were recruited online, two-thirds of participants enrolled at the African sites were recruited through face-to-face interactions with study staff. On the implementation side, Key Populations-Led Health Services helped grow PrEP services in Thailand. Dr. Nittaya Phanuphak explained how the Princess PrEP Project set up client-centered, one-stop services clinics run by MSM, transgender women, and members of other key populations. Dr. Jeremy Sugarman described how an international trial of HIV prevention for people who inject drugs provided not only direct benefits to participants who received the intervention, but also benefits to participants receiving standard of care, and social benefits to participants and their partners. Studying these benefits, while continuing to focus on ethics, safety, and minimizing risk, can guide how to design studies that really serve the people they are meant to benefit.

Plenary (PL04) PL04.02 - Implementing a Multi-Disciplinary Prevention Revolution
In a passionate presentation Maureen Luba, an advocate from Malawi reiterated a key theme out the HIVR4P 2018 that its only through integration that we will achieve epidemic control and that choice of prevention options needs to central to that effort. Throughout the meeting, speakers repeated the importance of multiple prevention options to reduce new infections. The voices of young women and other advocates were heard just before the closing ceremony (and also during the opening session – see picture below). The take home message was - having a choice of prevention options is critical to keep in the pipeline.  

Plenary (PL04) PL04.03 - The Impact of Prevention Strategies on HIV Incidence in a Community Center

Work from BCN Checkpoint, a community-based detection center of HIV and other STIs, demonstrated dramatic decrease in HIV incidence in their cohort with the delivery of integrated HIV prevention strategies which include HIV testing, STI screening and treatment, ART for HIV infected, and PrEP for HIV uninfected. There was concern about the EU’s delay for approval of PrEP.

Oral abstract (OA20): Into the Future With Delivery Technologies
Studies have found that though microbicides have interesting properties they also have several limitations. A study by Institute for Research and Innovation in Health (i3S), University of Porto, Portugal and Institute of Biomedical Engineering, University of Porto,

Portugal, INEB developed a thermosensitive enema as a vehicle for nanoparticles to assess the ability to distribute and retain in mice using IVIS. The study established that thermosensitive enemas are interesting vehicles for nanoparticles, ensuring proper distribution, with enhanced retention.

Another study by Population Council USA, presented findings from successful development of a topically applied Griffithsin (GRFT)/ Carrageenan (CG) fast dissolving inserts (FDI) for prevention of HIV, HSV-2, and HPV. The FDIs. The findings highlighted good handling properties and stability of FDI under accelerated temperature and humidity conditions. Further, a.) they disintegrated completely in the macaque vaginal lumen, b) are safe (no pH changes or inflammation), c) rapidly deliver therapeutic levels of GRFT and CC,  and d) lastly, significantly protected animals from SHIV, HSV-2, and HPV infections.

 

Rapporteur Teams

Team A

LEAD
Julià Blanco, IrsiCaixa, Spain

Nigel Aminake Makoah, National Institute for Communicable Diseases, South Africa
Maria Luisa Rodríguez, IrsiCaixa, Spain
Tripti Shrivastava, Translational Health Science and Technology Institute, India
Michiel Van Diepen, University of Cape Town, South Africa

Team B

LEAD
Lisa Hightow-Weidman, University of North Carolina at Chapel Hill, United States

Mamadou Diallo, Université Laval, Canada
Kostyantyn Dumchev, Ukrainian Institute on Public Health Policy, Ukraine
Matthew E. Levy, George Washington University Milken Institute School of Public Health, United States
Kate Mitchell, Imperial College London, United Kingdom

Team C

LEAD
Barbara Shacklett, University of California, Davis, United States

Smritee Dabee, University of Cape Town, South Africa
Carolina Herrera, Imperial College London, United Kingdom
Enrique Martín Gayo, Hospital La Princesa, Universidad Autónoma de
Madrid Spain, Spain
Marta Rodriguez-Garcia, Dartmouth Medical School, United States

Team D

LEAD
Nyaradzo Mgodi, University of Zimbabwe, Zimbabwe

Kenneth K. Mugwanya, University of Washington, United States
Krishnaveni Reddy, Wits Reproductive Health and HIV Institute, South Africa
Chelsea L. Shover, Stanford University, United States
Monika Walia, Population Council, India

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