Richard Jefferys, TAG
The first press conference of IAS 2023 meeting was held three days beforehand and featured several cure-related presentations. [1]
Most notably, Asier Sáez-Cirión and Alexandra Calmy described a possible case of an HIV cure (or at least extended remission) in an individual in Geneva who received a stem cell transplant to treat cancer. There are previously reported cases of HIV cures (or likely cures) in people who received stem cell transplants for cancer diagnoses, but all have involved stem cell donors homozygous for the CCR5Δ32 mutation, which makes immune cells resistant to infection by most HIV strains. [2]
In this new case report, the donated stem cells were “wild type,” meaning they lacked this mutation.
A full description of the case won’t occur until the conference track A late breaker session on Monday 24 July. [3]
The study abstract has been shared with journalists and is no longer under embargo, but it’s still unavailable and listed as embargoed for the public on the IAS 2023 website. [4]
The individual is in his early 50s and received the stem cell transplant to treat a biphenotypic sarcoma. Afterward, HIV became undetectable by multiple tests and antiretroviral therapy (ART) was stopped in 2021. After 20 months of subsequent follow up, no viral load rebound has occurred, no HIV-specific T cell responses can be detected, and antibodies against HIV are waning. Sáez-Cirión noted that traces of HIV DNA have been detected at some timepoints, but it didn’t appear to comprise intact, replication-competent virus.
There are similarities to two people with HIV known as the Boston patients who also received wild type stem cell transplants to treat cancers and subsequently stopped ART without a viral load rebound. But in those prior cases, HIV viral load did return after three months and eight months, respectively. [5]
The reasons for the far more extended absence of HIV viral load rebound in the Geneva case are uncertain at this juncture. Speculative possibilities include:
- The effects of graft-versus-host disease (GVHD), which involves the newly transplanted immune cells attacking and clearing the original host immune cells (potentially including CD4 T cells harbouring HIV). GVHD was also reported in the Boston patients.
- The use of the drug ruxolitinib to facilitate the transplant, which wasn’t reported in the Boston patients. Ruxolitinib belongs to a class of compounds called Janus kinase (JAK) inhibitors that have been shown to inhibit HIV infection and the seeding of the reservoir in laboratory studies. [6, 7, 8]
- Ruxolitinib and other JAK inhibitors are being investigated in people with HIV on ART, and on Saturday in Brisbane at the HIV Cure and Immunotherapy pre-meeting Monica Reece is giving a presentation on the effects of ruxolitinib on the HIV reservoir in an AIDS Clinical Trials Group (ACTG) study. [9, 10, 11]
- The occasional use of pre-exposure prophylaxis (PrEP) after stopping his therapeutic ART regimen. This wasn’t discussed during the press conference but is mentioned by Tim Henrich in an excellent, detailed article for POZ Magazine by Liz Highleyman. Henrich suggests that PrEP use might have suppressed any lingering embers of HIV infection and prevented transfer of the virus to the transplanted immune cells. [12]
The hope is that the individual may be cured of HIV infection, but — as has been emphasised in some of the media coverage of the case — this cannot be considered proven. Mathematical modeling work by Alison Hill and colleagues indicates that if HIV has infected a tiny number of the new immune system cells generated by the transplant, viral load rebound could potentially occur after a delay of several years. [13]
The risk is considered higher in this case because the stem cell donor lacked the CCR5Δ32 mutation and hence the newly generated immune system remains vulnerable to HIV infection. Ongoing monitoring will be important and the potential for rebound needs to be borne in mind because, as Gary Steinkohl explained after disclosing his identity as one of the Boston patients, the re-emergence of virus after a long delay can be very traumatic (in his words: “emotionally devastating”). [14]
Another cure-related presentation at the press conference was given by Gabriela Cromhout from the University of KwaZulu-Natal. Cromhout reported the identification five male infants with HIV who experienced apparent control of viral load in the absence of ongoing ART. The cases were identified during a project assessing ART blood levels among infants who acquired HIV via vertical transmission. The testing revealed an absence of sustained ART levels suggestive of non-adherence, but without HIV viral load rebound. Time off-ART was estimated to range from 3-10 months.
One of the infants has never been restarted on ART and has maintained an undetectable viral load after around 19 months of ongoing follow up. The four others have had ART restarted, with three enrolled in a study that plans to eventually undertake an analytical treatment interruption (ATI) to assess if control of viral load will recur.
Cromhout explained that the results may provide evidence of a sex difference in the capacity to control HIV replication among infants, because the cohort comprises 60% females but all the cases were males. In beginning to look for contributing factors, the researchers have noted that when male infants acquire HIV, the virus typically displays sensitivity to the inhibitory effects of the cytokine alpha interferon but a high replication capacity. In females, this is reversed with viruses showing reduced sensitivity to alpha interferon and lower replication capacity.
In the five cases reported by Cromhout, this pattern wasn’t observed – the viruses detectable in the male infants at acquisition were sensitive to alpha interferon and had a low replication capacity.
The detailed presentation of the study will occur on Monday July 24 during a session that starts at 10:30am local time. [15]
As is the case with Sáez-Cirión’s report, the abstract remains embargoed to the public on the IAS Programme website even though the media embargo has been lifted and the abstract shared with journalists. [16, 17]
TAG and many other advocates are calling for a revision of this policy of publicising results ahead of their actual presentation at the conference.
Source
Richard Jefferys, TAG Basic Science Blog (20 July 2023).
https://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2023/07/hiv-cure-research-news-from-the-opening-ias-2023-press-conference.html
References
- IAS 2023. Official Press Conference. Scientific Highlights. (20 July 2023).
https://www.iasociety.org/conferences/ias2023/media/press-conference-programme - Jefferys R. HIV Cure Research Information Sheet. Treatment Action Group. (March 2023).
https://www.treatmentactiongroup.org/publication/hiv-cure-research-information-sheet/ - Ndhlovu L. Track A Rapporteur Summary, IAS 2023. (24 July 2023).
https://programme.ias2023.org/Programme/Session/4398 - Sáez-Cirión A et al. Absence of viral rebound for 18 months without antiretrovirals after allogeneic hematopoietic stem cell transplantation with wild-type CCR5 donor cells to treat a biphenotypic sarcoma. IAS 2023, oral abstract OALBA0504.
https://programme.ias2023.org/Abstract/Abstract/?abstractid=5819 - Henrich T. J. et al. Antiretroviral-Free HIV-1 Remission and Viral Rebound Following Allogeneic Stem Cell Transplantation: A Report of Two Cases. Ann Intern Med; 161(5): 319–327, DOI: 10.7326/M14-1027 (2 September 2014).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236912/ - Reece M. D. et al. Repurposing BCL-2 and Jak 1/2 inhibitors: Cure and treatment of HIV-1 and other viral infections. Frontiers in Immunology, Viral Immunology, volume 13, DOI: 10.3389/fimmu.2022.1033672 (9 December 2022).
https://www.frontiersin.org/articles/10.3389/fimmu.2022.1033672/full - Gavegnano C et al. Ruxolitinib and Tofacitinib Are Potent and Selective Inhibitors of HIV-1 Replication and Virus Reactivation In Vitro. Antimicrobial Agents and Chemotherapy, volume 58, number 4, DOI: 10.1128/aac.02496-13 (18 March 2014).
https://journals.asm.org/doi/10.1128/AAC.02496-13# - Gavegnano C et al. Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. PLOS Pathogens, 13(12): e1006740, DOI: 10.1371/journal.ppat.1006740 (21 December 2017).
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006740 - ClinicalTrial.gov. Phase II study to evaluate the efficacy and safety of baricitinib for reduction of HIV in the central nervous system.
https://clinicaltrials.gov/study/NCT05452564 - IAS 2023. HIV Cure & Immunotherapy Forum (22 July 2023).
https://www.iasociety.org/conferences/ias2023/programme/pre-meetings/hiv-cure-immunotherapy-forum - Marconi V. C. et al. Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus. Clinical Infectious Diseases, volume 74, issue 1, DOI: 10.1093/cid/ciab212 (6 March 2021).
https://academic.oup.com/cid/article/74/1/95/6159796 - Highleyman L. Geneva Man May Be Cured of HIV After Wild-Type Stem Cell Transplant. Poz Magazine (19 July 2023).
https://www.poz.com/article/geneva-man-may-cured-hiv-wildtype-stem-cell-transplant - Hill A. L. et al. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. PNAS, volume 111, number 37, DOI: 10.1073/pnas.140666311 (5 August 2014).
https://www.pnas.org/doi/10.1073/pnas.1406663111 - Halter C. A Tale of Two Diagnoses. Poz Magazine (3 November 2015).
https://www.poz.com/article/boston-patient-q-a-27970-4298 - Co-Chairs’ Choice. IAS 2023, oral abstract session OALBX01 (24 July 2023).
https://programme.ias2023.org/Programme/Session/4566 - Cromhout G et al. Sustained aviraemia in the absence of anti-retroviral therapy in male children following in utero vertical HIV transmission. IAS 2023, oral abstract OALBX0104.
https://programme.ias2023.org/Abstract/Abstract/?abstractid=5727 - IAS 2023. Conference Programme (23–26 July 2023).
https://programme.ias2023.org/