EACS 2023: HIV cure-related research
1 December 2023. Related: Conference reports, Cure-related research, EACS 19 Warsaw 2023.
Kirk Taylor, HIV i-Base
EACS 2023 included a lively oral symposium on HIV cure-related research with two comprehensive summary reviews and four oral abstracts. [1-6]
Data included updates on broadly neutralising antibody (bNAb) research, with some cases of ART-free virologic control for up to 24 weeks. [1]
The second update covered promising results on cellular therapies, similar to those used to target cancers, and how these may be adapted to combat HIV. [2]
New data from the INACTION cohort showed that earlier ART is linked to a smaller reservoir and reduced inflammation. [4]
Finally, early data on the use of PD-1 inhibitors to perhaps enable ART-free viral suppression. [5]
Treatment interruption studies
Professor Sarah Fidler from Imperial College London presented an update on treatment interruption studies. [1]
This included a survey of attitudes to participation in treatment interruption studies which showed that 39% of respondents were keen to join, citing altruism as a primary reason (89%). However, 9/10 people were concerned about HIV transmission when off ART and weekly viral load testing was preferred by 35%. [3]
A useful meta-analysis has also reported viral re-suppression rates for people restarting ART following a treatment interruption. Within three months of re-starting ART, 96% of participants achieved virologic control. Viral re-suppression rates were higher for people who had first started ART during the early vs chronic phase of HIV (13% vs 4%).
Recent bNAb data has reported cases of viral suppression out to 24 weeks. The ongoing UK RIO study using the same bNAbs is using a single infusion of 3BNC-117-LS plus 10-1074-LS to aim for viral suppression for up to 20 weeks.
Romidepsin has also been combined with bNAbs to target the viral reservoir. This approach decreased proviral RNA, enhanced T-cell responses, and delayed time to viral rebound. Similar data have been reported with an alternative strategy using TLR9 agonists plus bNAbs in the phase 2a TITAN study. The AMFAR study combining bNAbs, TLR9 agonist and a DNA/MVA vaccine reported a median time to viral rebound of 15 weeks.
Novel approaches to HIV cure-related research
Dr Asier Sáez-Cirión of the Pasteur Institute discussed progress of cure studies and approaches in the pipeline. [2]
Successful cure strategies will require combined approaches to reduce viral reservoir and reinforce immune barriers. Treatment interruption studies show that greater success is achieved if ART was initiated soon after HIV transmission. Currently, 82 cure-related trials have been registered that involve bNAbs (n=18), gene editing (n=14), vaccines (n=13) and ART-based (n=11) approaches.
The reservoir is being targeted through multiple strategies that include latency reversal agents, HIV replication-induced death, targeting specific cellular characteristics, repressing proviral replication with transcription inhibitors and removal of proviral DNA through gene editing.
Approaches to boost immune defences include the induction of intrinsic resistance, therapeutic vaccines, use of immune modulators and adoptive therapies using cells from elite controllers. Research into mechanisms to eliminate HIV-containing reservoir cells is ongoing.
Cell therapies are being developed with the aim to replicate the immune responses seen in elite controllers who retain high CD4 counts and very low viral load without using ART. This is being studied using vaccines to induce immune responses against HIV and reprogramming of CD8 T-cells. This approach can also be adapted to utilise natural killer cell responses against HIV. This has shown promise in the arena of cancer research, raising hopes for development of IV cure strategies.
Early ART reduces inflammatory response and viral reservoir
Dr Valeria Bono of the University of Milan presented results from the INACTION cohort study on the effect of early initiation of ART on inflammation markers and reservoir size. [4]
Responses were compared between participants with primary HIV (PH; n=55) or chronic HIV (CH; n=18). Both groups were predominantly male (96% for PH and 89% for CH) and median (IQR) age was 34 years (27 to 45) and 31 years (26 to 46) for the PH and CH groups, respectively. Higher baseline viral load and lower CD4 count was reported for the PH group.
Baseline levels of HIV DNA were similar for both groups, however the relative decrease following initiation of ART was greater for those in the PH group at week 48. Inflammatory markers reduced in both groups but there was no difference between PH and CH. People with primary HIV infection had lower levels of plasma CD14 and E-cadherin. The authors suggest that treatment during the primary phase reduces the size of the reservoir and inflammatory markers.
Phase 1b studies of budigalimab, a PD-1 inhibitor, for HIV viral control off-ART
Dr Routy of McGill University Health Centre discussed ongoing trials on the use of a PD-1 inhibitor budigalimab for HIV cure. [5]
PD-1-expressing CD4 cells that have a high content of proviral HIV DNA and are a key target for HIV cure strategies. Randomised double-blind phase 1b studies (M19-939 and M19-972) are using low-dose (≤20 mg) budigalimab for people living with HIV and an international phase 2 study in 140 participants is due to enrol shortly.
The drug was well-tolerated with no serious treatment-related adverse events reported.
PD-1 receptor saturation was achieved for 10 weeks post treatment interruption. Biweekly budigalimab administration delayed viral rebound and/or enabled ART-free viral suppression for 6/9 participants but only by about a week, with only two participants having a response out to week 24.
PD-1 CAR T cells in a macaque model: caution for lymphoma
Dr Eichholz of the Fred Hutchinson Cancer Centre discussed their development of a CAR T cell approach to eradicate the HIV reservoir. [6]
Transfusion of PD-1 CAR T cells led to successful replication within macaques and destruction of HIV-containing follicular helper cells in lymph nodes.
However, this approach also resulted in serious complications, with two cases of immunodeficiency-related B cell lymphoma.
Further safety and specificity measures are being explored to enable further development of this model.
References
Unless stated otherwise, all references are to the programme and abstract of the 19th EACS, 18–21 October 2023, Warsaw, Poland.
https://eacs2023.abstractserver.com/program/#/program/1/horizontal
- Fidler S. Update on treatment interruption trials. 19th EACS, 18–21 October 2023, Warsaw, Poland. Oral Presentation PS10 HIV Cure intervention – new approaches.
https://eacs2023.abstractserver.com/program/#/details/sessions/58 (Programme link)
https://live.allintheloop.net/Agenda/EACS/EACS2023/greenLiveStream/444784/2 (webcast with login) - Lee MJ. Attitudes towards participation in HIV cure trials which include a treatment interruption amongst participants in an observational study. 19th EACS, 18–21 October 2023, Warsaw, Poland. Poster abstract ePA061.
https://live.allintheloop.net/Cms/EACS/EACS2023/View/19317 (Abstract, page 123)
https://eposters-eacs2023.medicalcongress.online/mediatheque/media.aspx?mediaId=180800&channel=109239 (e-poster with log-in) - Sáez-Cirión A. Novel approaches in the pipeline towards HIV cure. 19th EACS, 18–21 October 2023, Warsaw, Poland. Oral Presentation PS10 HIV Cure intervention – new approaches.
https://eacs2023.abstractserver.com/program/#/details/sessions/58 (Programme link)
https://live.allintheloop.net/Agenda/EACS/EACS2023/greenLiveStream/444784/2 (webcast with login) - Bono V. Gut barrier damage and reservoirs, yet not peripheral inflammation, are contained in PHI-treated PLWH. 19th EACS, 18–21 October 2023, Warsaw, Poland. Oral Presentation PS10.O1.
https://eacs2023.abstractserver.com/program/#/details/presentations/934 (abstract)
https://live.allintheloop.net/Agenda/EACS/EACS2023/greenLiveStream/444784/2 (webcast with login) - Routy JP. Safety, pharmacokinetics, and exploratory efficacy of the PD-1 inhibitor budigalimab in antiretroviral treatment-suppressed people living with HIV-1: Preliminary analysis of 2 phase 1b studies including an analytical treatment interruption. 19th EACS, 18–21 October 2023, Warsaw, Poland.Oral Presentation PS10.O3.
https://eacs2023.abstractserver.com/program/#/details/presentations/1116 (abstract)
https://live.allintheloop.net/Agenda/EACS/EACS2023/greenLiveStream/444784/2 (webcast with login) - Eichholz K. Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centres of rhesus macaques. 19th EACS, 18–21 October 2023, Warsaw, Poland.. Oral Presentation PS10.O2.
https://eacs2023.abstractserver.com/program/#/details/presentations/773 (abstract)
https://live.allintheloop.net/Agenda/EACS/EACS2023/greenLiveStream/444784/2 (webcast with login)