Track B report by Annie LUETKEMEYER
Rapporteur Summary of THBS03, Understanding HIV transmission Mechanisms: Microbicides and PrEP (7.22.10)
THBS0302 Characteristics of transmitted viruses in acute and early HIV infection (Presenter: E Hunter)
The explanation for the “genetic bottleneck” seen at time of acute HIV infection does not appear to derive from limited viral diversity in donor genetic tract nor be due to a strictly stochastic event. HIV viruses most able to establish successfully transmitted infection are characterized by highly CCR5 and CD4+ receptor dependence and less N-linked glycosylation.
THBS0303 Oral PrEP during mucosal SHIV infection reduces viremia, preserves CD4+ counts and raises potent T cell responses (Presenter: E. Kersh)
Rhesus macaques were infected via repeated low dose rectal exposure to SHIV, with and withoug PreP (either once weekly Truvada or an oral pro-drug of tenofovir) or without PrEP. SHIV infection despite PrEP (n=6) was associated in lower viremia (5.5 vs 7.5 log10 copies/ml) at week 6, 5 fold higher CD4+ cell at peak viremia, and a more robust SHIV-specific T cell response, compared to non-PrEP exposed controls (n=5). An attenuated disease course and improved immune preservation may potential benefits of PrEP, despite failure to prevent HIV infection.
THBS0304 Understanding mucosal immunity and HIV transmission: the way to new prevention technologies (Presenter: R.Shattuck)
Further development of microbicides as PrEP will require better understanding of required drug dosing, optimal timing in relationship to HIV exposure, new formulations to maximize adherence, and investigation of ART agents that act at differing parts of the HIV lifecycle. PK/PD assessment at the mucosal surface will be essential to understand if drug is at the right site and at the right concentration to prevent infection. Vaccines and mucosal PrEP may work together to optimally reduce HIV transmission.
THBS0305 Exposure of extracellular and intracellular tenofovir and emtricitabine in mucosal tissues after a single fixed dose TDF/FTC: Implications for pre-exposure HIV prophylaxis (PrEP) (Presenter: K Patterson)
In 15 HIV uninfected men and women receiving one dose of Truvada, tenofovir and emtricitabine were detected for up to 14 days and preferentially penetrated the genital and rectal drug compartment, compared with plasma. Combination therapy may be attractive to ensure adequate drug levels at all genital sites during intermittent PrEP .
THBS0306 Current and planned HIV prevention trial: microbicides and PrEP (S. Abdool Karim)
Five PrEP trials are currently underway evaluating both tenofovir gel and oral formulations in diverse populations including women, serodiscordant couples, MSM and IDU in different parts of the world. Future PrEP trials are planned to evaluate a vaginal ART containing ring and to confirm the results seen with vaginal tenofovir gel in CAPRISA 004. As ART as PrEP is further explored, remaining issues must be addressed including safety of ART use in healthy patients, impact on HIV resistance, adherence, affordability, PrEP effect on behavioral disinhibition, and choice of medication(s).
THBS0306 Prevention research advocacy: Community Preparedness in HIV prevetion trials and use of existing prevention methodologies (Presenter: F. Temu on behalf of C. Shagi )
Shagi and colleagues explored how effective use of a participatory community liason system (CLS) facilitated communication between investigators, stakeholders, community and potential participants microbicide trial and promoting adherence and retention in the MDP 301 PRO2000.
Track A report by Takafira MDULUZA
The session was dedicate to the understanding of the determinants of HIV transmission, and to the development of microbicides and Pre-exposure Prophyilaxis (PreP).
Eric Hunter (USA) discussed the characteristics of transmitted viruses in acute and early HIV infection highlighting the genetic bottlenecks in the transmission of the virus and their origin. The envelope (Env) glycoproteins of the founder viruses in the recipient host (i.e. the virus that succeeds out of the swarm of quasispecies present in the transmitter) showed a high dependency on CD4 rather than CCR5 for mediating entry into cells expressing different levels of these receptors, consistently with efficient replication in mucosal T cells and not in tissue macrophages. The differences in glycosylation and V1-V4 lengths may reflect tropism for determinants such as α4b7 (as earlier discussed by Anthony S. Fauci) binding or a requirement for dendritic cell (DC) interactions that are currently being investigated. Hunter hypothesized that Env of these viruses might better bind CD4 than CCR5.
Hunter’s hypothesis was further discussed by Robin Shattock (U.K.) who underscored the importance of understanding mucosal immunity and HIV transmission and the way to improve new prevention technologies. He pointed out that the time to act against the virus is short and the success for any prevention technology will depend on maintaining protective inhibitor concentrations at the mucosal portals of entry. More than 20 studies were listed that demonstrated biological plausibility of Tenofovir gel which is now a benchmark for mucosal surface control (as illustrated by the success of the CAPRISA 004 trial – see early reports). Combined microbicides or PreP with vaccines have the potential of delivering a better protection that could possibly reverse the HIV pandemic. Vaccine induced immunity may cover intermittent compliance, breakthrough viruses and prevent resistance evolution.
Further, Ellen Kersh (USA) discussed oral PrEP during mucosal SHIV infection that reduced viremia, preserved CD4+ T cell counts, and raised potent T cell responses. The discussion gave vivid potential benefits for PrEP even when it fails to give protection by possibly attenuating disease course that could potentially mean longer disease-free life, reduced need for anti-retrovirals and fewer chances of virus transmission.
Kristine Patterson (USA) discussed implications for oral PrEP by extracellular and intracellular Tenofovir and Emtricitabine (TFV/FTC) in multiple biological compartments. The penetration of TFV/FTC reported in their study supported the use of other anti-retroviral agents in all mucosal tissues as part of early development strategies for oral PrEP. A differential drug terminal elimination emphasizes consideration for combination therapy.
A concluding remark on microbicides and PrEP trials was delivered by Salim Abdool Karim (South Africa). Oral and topical PrEP are promising, but there is a dilemma on current trials on the use of Tenofovir gel/pill and Truvada pill in injecting drug users, discordant couples, young women and men having sex with men. If effective, the implementation of the programs will require extensive community education to promote PrEP with integrated use of other prevention strategies, including long term follow-up and surveillance in sentinel groups to monitor adverse events, adherence, drug resistance, impact on later therapeutic regimens and behavioral disinhibition.
The last report of the session was by Florence Temu (Tanzania) who discussed after showing a recorded video on Community Liaison System for prevention research advocacy. Examples were given from their participation in the Microbiocide Development Programme (MDP) known as MDP 301, a multi-centre, randomised, double blind, placebo controlled phase-III trial that took place from 2005 to 2009 and preceded by a 2-year feasibility study. Community Liaison System remains a very crucial component in clinical trials, promotes study adherence and preparations for study outcome. Last but not least, study participants are proud of being part of the research.