TAG HIV Basic Science, Vaccines, and Cure Project Blog

By Richard Jefferys, Project Director at Treatment Action Group (TAG).

recent posts

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the March 2023 Update

    March tends to be the busiest month for updates to TAG’s HIV cure-related clinical research listing because of results being presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI). Today’s update includes links to 30 abstracts from CROI 2023; posters can be downloaded from the abstract pages, but webcasts of oral presentations won’t be publicly accessible until around March 24 (one month after CROI ended). More detailed coverage of the study results presented at CROI will be posted to the blog when all presentations become freely available, hopefully next week.

    Three new HIV cure-related studies were added to registries over the past month, one interventional and two observational:

    The US Military HIV Research Program continues a longstanding collaboration with the Thai Red Cross AIDS Research Centre in Bangkok, launching a multi-pronged combination trial in people who started antiretroviral therapy (ART) during acute HIV infection. The experimental therapies that will be administered are two long-acting broadly neutralizing antibodies (bNAbs) — VRC07-523LS and PGDM1400LS — a souped-up version of the cytokine IL-15 named N-803, and three different therapeutic HIV vaccine products: an adenovirus serotype 26 vector and a modified Vaccinia Ankara strain vector encoding HIV antigens (Ad26.Mos4.HIV and MVA-BN-HIV) plus a gp120 protein boost with ALFQ adjuvant (A244d11gp120/ALFQ). Participants need to have been on ART for at least 48 weeks with viral loads suppressed to less than 50 copies/ml, have HIV that’s sensitive to the bNAbs in laboratory tests, and lack genetic traits (HLA types) that have been associated with immune control of HIV replication. The study involves an analytical treatment interruption (ATI) and will measure the time to sustained viral rebound (defined as ≥1000 copies/ml for four consecutive weeks, without a decline by >0.2 logs from the previous measurement). Recruitment has not yet begun.

    APRIL (Analysis of the Persistence, Reservoir and HIV Latency) is a pending new observational study being conducted at the University Hospital, Strasbourg, France which involves collection of blood samples from people on ART to analyze the HIV reservoir. In the Netherlands, researchers at the Universiteit van Amsterdam have opened NOVA, an observational investigation into the properties of the HIV reservoir and HIV-specific immune response that may be associated with the capacity for post-treatment control of viral load. The registry description of NOVA suggests that it may eventually involve an ATI, but this does not appear to be required as of yet.

    Researchers in Zurich have been conducting a cohort study of people with acute HIV infection for two decades. We’ve added to the listing this month because cure-related results were presented at CROI 2023, describing predictors of time to HIV viral load rebound after ATI.

    Two trials have shifted to the “completed” table:

    • TITAN, which investigated the combination of a toll-like receptor 9 agonist, lefitolimod, with two bNAbs (3BNC117 and 10-1074).
    • AELIX-003, a trial testing two therapeutic HIV vaccines (MVA.HTI and ChAdOx1.HTI) combined with the toll-like receptor 7 agonist vesatolimod.

    Results from both studies were reported at CROI 2023 (see abstracts 136 and 443) and will be included in our forthcoming coverage of the conference.

    Also added to the completed table is ATN 137, a study of youth initiating ART during either acute or chronic HIV infection sponsored by the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN). The addition was prompted by the reporting of results related to the HIV reservoir and immune responses at CROI 2023.

    The company Immunocore has sponsored a phase I trial of a novel approach that aims to redirect the attentions of T cells targeting other antigens toward the elimination of HIV-infected cells (T-cell receptor-based bispecifics). The trial does not appear to have been entered in online registries but has now been added to the completed table because results were presented at CROI 2023. A larger, registered trial is ongoing.

    Disappointingly — and like too many other CROI 2023 abstracts — the Immunocore report refers to study participants as “subjects” and provides no demographic information whatsoever. TAG has previously collaborated with AIDS Action Baltimore, AVAC, NASTAD, and the Federal AIDS Policy Partnership Research Working Group to write to CROI about the lack of reporting of participant demographic information, and it’s frustrating to see the problem continue. A broader community sign-on letter to CROI is now being planned.

  • Mosaico HIV Vaccine Trial Results Presented at CROI 2023

    The early termination of the Mosaico HIV vaccine trial due to lack of efficacy was announced a little over a month ago, on January 18. Yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, preliminary details of the results were disclosed in a short presentation by Susan Buchbinder.

    As outlined at the time of the original announcement, the Mosaico trial enrolled cisgender men and transgender people who have sex with cisgender men and/or transgender people at sites in Argentina, Brazil, Italy, Mexico, Peru, Poland, Puerto Rico, Spain, and the USA. Most participants (91.5%) identified as male, but the researchers were able to enroll a high proportion of transgender women (5%) in addition to transgender men, gender queer, and gender variant or non-conforming participants. The breakdown by race showed that white (44.5%), multiple races (41.8%), Black or African American (7.7%), and American Indian or Alaska Native (3.1%) were most frequently represented with the majority (86.6%) of participants of Hispanic or Latino ethnicity.  

    The Mosaico study employed a novel design that enrolled people at high risk for HIV infection who'd chosen not to use oral pre-exposure prophylaxis (PrEP). Counseling about PrEP continued throughout the trial, and participants could change their minds and initiate PrEP without being disenrolled. Buchbinder showed that PrEP uptake increased over time, from 1.8% during months 1-3 to 10% by months 18-21.

    The vaccine regimen administered in Mosaico proved safe, with the most common side effect being the typical local and systemic reactogenicity that accompanies the mounting of an immune response. There were no thrombotic events with concurrent thrombocytopenia, which have been reported for a COVID-19 vaccine that uses a similar adenovirus serotype 26 vector. There were eight deaths unrelated to trial participation (five in the placebo and three in the vaccine arm) which may be an indication of the vulnerability of the study population. Causes were not provided so it’s not known yet if COVID-19 was a contributor (the pandemic emerged around the same time as Mosaico opened, causing some delays to enrollment).

    The incidence of HIV infection among vaccine and placebo recipients was indistinguishable: there were 113 cases of HIV acquisition in each group, which included 1938 and 1940 evaluable participants, respectively. This equated to an HIV incidence of 4.1 per 100 person-years in both arms of the trial.

    The highest rates of HIV acquisition were in the 411 participants aged between 18 and 20; the incidence in this group was over 5 per 100 person-years. Most enrollees were in Latin America (3218 out of 3887 participants in total), which had the highest geographic HIV incidence of 4.7 per 100 person-years in the placebo arm and 4.8 per 100 person-years in the vaccinees (214 HIV seroconversions in total). Buchbinder noted that these are interim results, and the final numbers may change somewhat.

    The countries with the largest number of participants were Peru (1615, 41.5% of the total) and Brazil (852, 21.9%). A country-by-country breakdown of HIV acquisition events wasn’t provided but the results may echo a recently published report from the ImPrEP implementation study, which stated that: “Participants from Peru, transgender women, younger participants (aged 18–24 years), and individuals who were not White had greater HIV incidence, as well as increased odds of early loss to follow-up and lower odds of PrEP adherence and long-term PrEP engagement.” Taken together, both sets of results emphasize the urgent need to improve support for locally tailored HIV risk reduction approaches including PrEP access, in addition to advocating to ensure that long-acting injectable PrEP is rapidly made available. The most recent oral PrEP uptake figures on AVAC’s PrEPWatch website are 2,931 in Peru and 89,410 in Brazil.

    Buchbinder’s presentation was followed by a talk from Larry Corey, Co-Principal Investigator of the HIV Vaccine Trials Network (HVTN), who emphasized the unique challenges HIV poses for vaccine development. The vaccine regimen in Mosaico was considered the most promising approach for inducing potentially protective non-neutralizing immune responses based on animal models, but the preponderance of evidence now indicates that it’s unlikely that this type of response can achieve efficacy.

    As explained in our previous Mosaico post, the HIV vaccine field is now working to solve the complex challenge of inducing broadly neutralizing antibodies (bNAbs), which have demonstrated protective efficacy in a subset of participants in the Antibody-Mediated Prevention (AMP) studies (which delivered the bNAb VRC01 directly via infusion). There have been signs of progress and several trials are now underway to assess if it’s possible to nudge human B cells down the tricky pathway toward bNAb production. Corey noted that the proteins being delivered in these studies are best described as “reagents” rather than vaccines because the necessary components for a complete bNAb-inducing vaccine regimen have yet to be identified. Vaccines that induce other types of immunity, particularly T cell responses, are still under investigation, but Corey suggested they will almost certainly need to be part of a combination approach that includes bNAbs.

    *Disclosure: Treatment Action Group receives funding from the HIV Vaccine Trials Network to support community engagement efforts related to biomedical HIV prevention research.

  • The Düsseldorf Patient HIV Cure Case Published in Nature Medicine

    The news today is awash with stories about the Düsseldorf Patient, one of five people considered likely cured of HIV after receipt of a stem cell transplant to treat a life-threatening cancer diagnosis. As with all five reported cases to date, the stem cell donor was homozygous for the CCR5Δ32 mutation, which renders immune cells resistant to most HIV variants. The media coverage has been prompted by the publication of a detailed report in the journal Nature Medicine by Björn-Erik Ole Jensen and colleagues.

    The individual, who identified himself as Marc in an interview with a Dutch news outlet in 2021, has now been off antiretroviral therapy (ART) for four years with no sign of HIV viral load rebound. His current health is reported to be good, although the paper makes clear his journey has been difficult having experienced two relapses of acute myeloid leukemia and reactivation of multiple chronic viral infections (cytomegalovirus, herpes simplex virus 2, human herpesvirus 8 and Epstein–Barr virus). Mild chronic graft-versus-host disease of the eyes with bilateral keratoconjunctivitis sicca (dry eye syndrome) developed after the stem cell transplant and is still present.

    The news headlines are potentially confusing because some state Marc is the third case to reflect the chronological sequence (after Timothy Ray Brown and Adam Castillejo) while others designate him the fifth to reflect the total number of cases described to date, which include two more recent examples in New York City and at the City of Hope in Los Angeles.

    The first scientific description of the Düsseldorf Patient was in a poster presentation at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI), prior to interruption of ART. Two post-interruption follow up posters were presented at CROI in 2019 and 2020. The HIV cure research field has thus been aware of the case for a long time, and there was frustration and confusion last year when the announcement of a fifth similar possible HIV cure at the City of Hope mistakenly referred to it as the fourth based on the unnecessarily prim rationale that information on the Düsseldorf Patient hadn’t yet been published in a journal. Today’s publication will hopefully put any uncertainty to rest.

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the February 2023 Update

    The February 15, 2023 update to TAG’s HIV cure-related clinical research listing includes three newly registered studies:

    The AIDS Clinical Trials Group (ACTG) is initiating a study of two long-acting broadly neutralizing antibodies (bNAbs) named VRC07-523LS and PGT121.414.LS combined with antiretroviral therapy (ART) in people with acute (recently acquired) HIV infection. The trial has yet to begin recruiting but will take place at multiple sites in the United States, Brazil and Peru. The primary goals of the research are to evaluate the safety of the bNAbs, assess whether they can delay the rebound of HIV viral load after an analytical treatment interruption (ATI), and measure any effects on the HIV reservoir and/or HIV-specific immune responses. The registry entry lacks information on how long participants will be treated prior to the ATI. The hope is to build on preliminary evidence that bNAbs may be able to slightly reduce the size of the intact HIV reservoir, enhance HIV-specific immunity, and promote enhanced control of HIV viral load after ART interruption in some recipients.

    Researchers at the Masonic Cancer Center, University of Minnesota are conducting a trial that will administer a natural killer (NK) cell product, FT538, either alone or in combination with vorinostat, an HDAC inhibitor and candidate HIV latency-reversing agent. NK cells are a subset of immune system cells that can potentially kill virus-infected targets such as CD4 T cells harboring HIV. A prior study in people with HIV has investigated adoptive transfer of NK cells — which involves extracting them from the blood of matched donors, expanding them in the laboratory and then infusing them into study participants — but results have not yet been presented to our knowledge. FT538 takes a different off-the-shelf approach that generates the NK cells in the lab from specially engineered “mother” cells called induced pluripotent stem cells (iPSC). The company developing FT538 is Fate Therapeutics and there are several other ongoing trials in people with cancers. The HIV study will investigate the safety of intravenous dosing of FT538 and look for evidence of a reduction in the low amounts of HIV RNA that can be generated by the HIV reservoir in people on ART. If FT538 proves safe, vorinostat will be administered to attempt to reactivate latent HIV and make additional HIV-containing cells vulnerable to destruction by the NK cells. Recruitment for the trial has not yet begun.

    A new trial sponsored by the Hospital Universitari Vall d'Hebron Research Institute in Barcelona, Spain will test the effects of lauric acid, a dietary fatty acid, on the HIV reservoir. At the XII Congreso Nacional GeSIDA in 2021, the researchers conducting the study presented laboratory evidence that lauric acid can promote activation of latent HIV without negatively effecting CD8 T cell responses (a problem that has been reported with other candidate latency-reversing agents). The conference abstract is appended below. The clinical trial is open for enrollment.

    The other updates to the listing this month are the addition of links to newly published results from the Early Infant Treatment (EIT) trial in Botswana and the ACTG HIV reservoirs cohort study (A5321). The latter publication describes a careful evaluation of the levels of intact HIV in people on ART during long-term follow up.

    Lastly, there’s bad news about the EHVA T02 trial that intended to evaluate a combination of a therapeutic vaccine (MVA HIV-B) and the anti-α4β7 integrin antibody vedolizumab in people with HIV. The clinicaltrials.gov entry has not yet been updated, but the research had to be stopped due to slow enrollment and an imminent expiration date for the MVA HIV-B vaccine, which made it logistically impossible to complete the study as planned.

    XII Congreso Nacional GeSIDA y XIV Reunión Docente de la Red de Investigación de Sida (RIS) November 2021

    CO-16. LAURIC ACID, A NATURAL SATURATED FATTY ACID, INDUCES THE METABOLIC REPROGRAMING OF T CELLS AND REACTIVATES LATENT HIV, WHEREAS PRESERVES CD8 T CELL RESPONSES

    Grau Expósito1, A. Rull2, J.N. Howard3, J. Burgos4, J. Navarro4, A. Curran4, B. Planas1, V. Falcó4, M. Genescà1, A. Bosque3, F. Vidal2 and M.J. Buzon1

    1 Vall d’Hebron Institut de Recerca, Barcelona.

    2 Institut d’Investigació Sanitària Pere Virgili, Tarragona.

    3 George Washington University School of Medicine and Health Sciences, Washington D.C.

    4 Hospital Universitari Vall d’Hebron, Barcelona.

    Introduction:

    Elimination of the latent HIV reservoir that persists in antiretroviral treated (ART) HIV-infected individuals is recognized as the main barrier to cure HIV. Current latency reversal agents (LRA) do not impact the reservoir in vivo and are relatively toxic compounds, precluding their prolonged clinical use. Here, we study the effect of Lauric Acid (LA), a natural non-toxic compound, on the HIV reservoir and cytotoxic CD8+ T cell responses.

    Methods:

    HIV reactivation assays were performed in latency models (cellular and tissue models) and in primary CD4+ T cells obtained from ART-suppressed HIV-infected individuals. Using different techniques, as qPCR and flow cytometry, we assessed the capacity of LA to promote HIV viral transcription and p24 protein production in vitro. Functional assays were also performed to determine the effect of LA on CD8+ T cell cytotoxic activity. Moreover, metabolomic, proteomic and lipidomic analyses were performed to elucidate the impact of LA on CD4+ and CD8+T cells.

    Results:

    Lauric acid was able to promote a significant increase in the viral transcription and protein production in both latency models and in primary cells from HIV-infected individuals, with reduced cell-associated toxicity (p<0.001 and FC=2.6). Functional assays demonstrated that LA did not induce a global activation of CD8+ T cells, nor precluded their cytotoxic function. Moreover, lipidomic assays of CD4+ T cells suggested that LA modifies the composition of the lipid content upregulating diacylglycerols and producing de novo phosphatidylcholines, which are necessary for viral protein production during HIV transcription. Furthermore, LA impacted the metabolism of CD8+ T cells with a significant upregulation of the β-oxidation pathway and the proteasome activity, reprogramming cells to obtain energy not only from glycolysis but also from fatty acids.

    Conclusions:

    Using different models of HIV latency, including human lymphoid tissues and cells from ART-treated individuals, we prove the ability of LA to reprogram cell metabolism and serve as a potent natural LRA. Thus, the capacity of LA to reactivate the latent virus and preserve immune responses, together with the low toxicity found in human studies and its low cost, shapes LA as an excellent candidate for a cost-effective therapeutic strategy directed to impact the HIV reservoir.

  • Interim Analysis of Mosaico HIV Vaccine Efficacy Trial Results Prompts Discontinuation

    Disappointing news was announced today about the HIV vaccine efficacy trial, Mosaico (also codenamed HVTN 706/HPX3002). A scheduled interim analysis of the results by the Data Safety Monitoring Board (DSMB) found that the vaccines were safe but there was no prospect of demonstrating protective efficacy against acquisition of HIV infection in the study population, prompting discontinuation.

    No details are yet available but press releases were issued by AVAC, the HIV Vaccine Trials Network (HVTN), and the vaccine manufacturer Janssen. HVTN and AVAC will host a global webinar next Wednesday, January 25, to provide additional information.

    Mosaico had successfully recruited around 3,900 cisgender men and transgender people who have sex with cisgender men and/or transgender people at sites in Argentina, Brazil, Italy, Mexico, Peru, Poland, Puerto Rico, Spain, and the USA. There has been widespread praise for the scale and diligence of consultations with participating communities, which contributed significantly to the design and conduct of the study.

    Of particular importance, Mosaico pioneered a new approach to HIV vaccine trials by recruiting people at risk of HIV acquisition who’d chosen not to use pre-exposure prophylaxis (PrEP). Flexibility was built into the design to ensure any participants who later decided to start PrEP were provided access and allowed to continue in the study. This represents one potential strategy for addressing the ethical conundrum of recruiting people into efficacy trials of novel biomedical preventions when highly effective PrEP is increasingly available (e.g. Truvada daily pills and more recently the long-acting injectable drug cabotegravir).

    The lack of efficacy is somewhat bleak news for HIV vaccine research, at least in the near term. The vaccine regimen tested in Mosaico is a prime-boost combination of viral vectors (adenovirus serotype 26) and proteins designed to induce immune responses to diverse HIV variants. The trial’s name derived from the components included in the vaccines, which were mosaics mimicking elements of HIV from multiple different global clades of the virus.

    The vaccine was generally considered to represent the most promising candidate that could be created with available technology. Studies in the macaque model of infection with SIV (HIV’s simian counterpart) had demonstrated efficacy, which suggests that the relevance of such models will need to be reevaluated.

    Today’s news was not entirely surprising given that a very similar vaccine regimen made by Janssen also failed to demonstrate significant efficacy in Imbokodo, a smaller trial conducted among cisgender women on the African continent (see TAG’s report from September 2021).

    For both trials, the lack of efficacy does not preclude the possibility of important information emerging from analyses of the data that have been collected; as such, the research cannot be considered a failure. The contributions of the volunteers and the many people involved in executing these logistically daunting studies weren’t for naught, because it’s crucial to know what doesn’t work even though the hope is always for success.

    While there may understandably be some frustration regarding how long and difficult the road to an effective HIV vaccine is proving to be, it’s important to appreciate that this reflects the novel challenges posed by the virus.

    Two features in particular stand out: one is the fact that HIV infects and disrupts CD4 T cells, which would normally serve the function of coordinating the immune system’s response to a virus or other pathogen. In other words, once HIV enters the body it immediately starts to directly undermine the immune mechanisms that might otherwise be able to clear or control it. Secondly, HIV’s outer envelope has evolved a cloud of sugary decoy molecules that serve to block inhibition by most antibodies.

    The potentially good news is that in recent years, an increasing number of unusual antibodies have been identified that can strongly inhibit many different HIV variants. Work is now well underway to design HIV vaccine candidates that may be able to induce this type of broadly neutralizing antibody (bNAb).

    Challenges remain however, because tricky and complex vaccine approaches will be needed to induce the immune system to make antibodies with the unusual structural features of bNAbs that convey strong anti-HIV effects. It appears unlikely that an HIV vaccine candidate capable of inducing bNAbs will be developed and ready for efficacy testing within the next few years.

    In the interim, scientists are testing options for delivering bNAbs directly into the body (the scientific term is passive immunization). The first trials assessing the efficacy a bNAb delivered by intravenous infusion did not show a reduction in HIV acquisition overall, however there was evidence of a protective effect in a subset of participants. The bNAb used in the trials, VRC01, was among the first to be discovered and there are hopes that combinations of more recently discovered bNAbs with increased potency can do better.

    While it’s unclear whether passive immunization with bNAbs can become a practical and accessible HIV prevention option, these studies can also provide important information to guide the development of bNAb-inducing HIV vaccines.

    As articulated very clearly in AVAC’s statement today, the uncertain timeline for an HIV vaccine underscores the importance of ensuring that currently available biomedical prevention options are made affordable and accessible for everyone in the world who needs them. Furthermore, an effective HIV vaccine remains a vital goal and continued investment is essential despite the challenges and setbacks.  

    TAG will provide a more detailed update on the current state of HIV vaccine and passive immunization research in our annual Pipeline Report in late July.

    *Disclosure: Treatment Action Group receives funding from the HIV Vaccine Trials Network to support community engagement efforts related to biomedical HIV prevention research.

  • TAG’s HIV Cure-Related Clinical Research Listing: January 2023 Update

    Since 2014, TAG has maintained an online listing of HIV cure-related clinical trials and observational studies, drawing information primarily from the clinicaltrials.gov registry. The listing is updated monthly. Studies are included based on the registry descriptions and the outcomes being assessed (study endpoints), with measurements of the HIV reservoir representing the most common reason for inclusion.

    The listing contains a large amount of information and can be difficult to follow if you’re not familiar with the field of HIV cure research. To help provide some context, TAG creates an annual summary and explainer in the form of our Research Toward a Cure and Immune-Based Therapies Pipeline Report. Starting this year, we’re aiming to supplement this coverage by providing background information on each monthly update to the listing via this blog.

    The January 17, 2023, update includes two newly registered cure-related studies.

    The first is an interventional trial in which participants on antiretroviral therapy will receive venetoclax, a drug that is approved for the treatment of blood cell cancers. Venetoclax inhibits or antagonizes BCL-2, a protein involved in promoting the survival of white blood cells by inhibiting apoptosis (a mechanism of cell death).

    The rationale for the study is based on evidence from laboratory and animal studies indicating that CD4 T cells containing integrated HIV—the cells that constitute the main HIV reservoir that persists despite ART—have high levels of the BCL-2 protein and are resistant to apoptosis. In both the laboratory dish and the humanized mouse model, venetoclax has been shown to promote the death of HIV-infected CD4 T cells, when HIV is actively making viral proteins.

    The human trial is being led by Thomas Rasmussen from Aarhus University in Denmark in collaboration with Sharon Lewin from the Doherty Institute at the University of Melbourne in Australia. The plan is to recruit participants in both locations. Venetoclax will be given daily in 14-day cycles of escalating doses (200mg, 400mg, 800 mg), with each dose increase only proceeding if safety is established at the lower dose.

    The primary goal is to evaluate the safety of venetoclax in people with HIV on ART because the drug can cause a range of side effects. Secondary outcome measures include the size of the HIV reservoir and any effects of venetoclax on cell pathways involved in promoting apoptosis.

    If the results support further research in people with HIV, the researchers will consider investigating venetoclax in combination with latency-reversing agents. This plan is based on the evidence that venetoclax’s ability to promote the death of HIV-infected cells requires the virus to be actively making viral proteins. Current information on the HIV reservoir in people on ART suggests that some cells actively make viral proteins (at least intermittently) whereas others contain HIV that is completely latent (inactive). The researchers believe that in this latter group of reservoir cells, HIV may need to be awakened by a latency-reversing agent to enable venetoclax to promote cell death.

    The second new entry in the listing is an observational study, in which researchers led by Barbara Ensoli at the Istituto Superiore di Sanità in Italy are conducting long-term follow-up of people with HIV who received an experimental therapeutic HIV vaccine in a completed trial conducted in South Africa. The primary aim is to assess the persistence of immune responses against the HIV Tat protein contained in the vaccine more than 10 years after administration. Secondary measures include CD4 T cell counts, HIV viral load, and HIV reservoir size.

    An ongoing trial of the anti-cytomegalovirus (CMV) drug letermovir (trade name Prevymis) sponsored by the ACTG has temporarily suspended recruitment – this is not due to any problem but reflects a planned pause to evaluate the effects of the drug on inflammatory markers among the first 40 participants before deciding whether to continue enrollment.

    Additional updates to the listing include links to a newly published scientific paper describing the ongoing 2000HIV observational study. Led by researchers at Radboud University in the Netherlands, the study represents an ambitious effort to use the latest multi-omics tools to “comprehensively identify environmental, host genetic and non-genetic pathways and mechanisms that impact HIV-related comorbidities and the size of the viral reservoir.”

    Lastly in the January 2023 update, three studies shift into the table for research that has been completed or ended:

    • An investigation of the effect of N-803, an enhanced version of the cytokine IL-15, on lymph node B cell follicles in people with HIV on ART. Conducted by Timothy Schacker and colleagues at the University of Minnesota, results are pending.
    • A French observational study exploring whether a cell surface protein, CD32a, may help identify CD4 T cells containing HIV has been terminated. The reason cited in the registry entry is: “no interesting results.” The original research suggesting CD32a as a potential marker of the HIV reservoir was controversial, and the premature end of this study may suggest that this line of investigation has not panned out.
    • A small Canadian study of cannabinoid capsules in people with HIV has published initial results, reporting mostly good tolerability but safety concerns in two participants. Measures of the HIV reservoir were included in the trial but will be reported in future papers. A larger ongoing study in France is currently investigating the effects of cannabidiol administration on the HIV reservoir, inflammation, and autophagy (a complex mechanism involved in cell survival).

  • AIDS 2022: Another Possible HIV Cure Case After Stem Cell Transplantation for Cancer; Example of Extended Post-Treatment Control in Spain

    The 24th International AIDS Conference (AIDS 2022) officially opens on Friday in Montreal, but a Zoom press conference today shared news of results from several studies, including two case reports relevant to HIV cure research.

    Jana Dickter from the City of Hope hospital in Los Angeles described another instance of “prolonged HIV-1 remission” after receipt of a stem cell transplant required to treat a life-threatening cancer, this time in a 66-year-old man. The stem cell donor was homozygous for the CCR5Δ32 mutation, which causes immune cells to be resistant to most HIV variants. Dickter emphasized the unique aspects compared to previously reported cases:

    • The person was older (63 at the time of the transplant procedure, 66 now)
    • Has been living with HIV longer (over 31 years)
    • Received a less immunosuppressive regimen during transplantation and a chemotherapy regimen that is better tolerated by older people

    As explained in a press release from the City of Hope, the stem cell transplant was administered in early 2019 after a diagnosis of acute myelogenous leukemia (AML). Antiretroviral therapy (ART) was stopped in March 2021 and the man has now been followed for over 17 months with no HIV viral load rebound or HIV DNA detected. Antibody responses against HIV have waned and virus-specific T-cell responses are no longer detectable. The AML is in remission. Regrettably, the details of these results won’t become available until Dickter presents at the conference on Monday August 1 (the abstract text is unavailable until tomorrow).

    Dickter noted that the particular protocol employed at City of Hope is likely better suited to older people with HIV who require stem cell transplants to treat cancers, and may offer additional opportunities to attempt cures if appropriate CCR5Δ32 homozygote donors can be identified.

    As with the New York City woman reported at CROI earlier this year, the researchers are being cautious and using the term “remission” to describe the case rather than cure, due to limited follow-up. It would be helpful for the HIV cure research field to come to consensus on how best to define “cure” in such cases, because news coverage tends not to adhere to these distinctions in terminology.

    There’s also an urgent need for consensus on how many cases of HIV cure/remission have been achieved by stem cell transplants from CCR5Δ32 homozygote donors: both the International AIDS Society and City of Hope press releases erroneously state that this represents the “fourth” such case but in fact, as reported for NBC News by Benjamin Ryan, there are five in total:

    • Timothy Ray Brown (aka The Berlin Patient)
    • Adam Castillejo (aka The London Patient)
    • The Düsseldorf Patient
    • The New York Patient
    • The City of Hope Patient

    Details on each of the prior cases is included in TAG’s latest Research Toward a Cure and Immune-Based Therapies Pipeline Report.

    Dr. Núria Climent delivered the second report, about a case of “exceptional post-treatment control” in a woman with HIV who’d participated in a clinical trial in Barcelona. The Hospital Clínic-IDIBAPS have issued a press release about the findings. If I’m understanding correctly, it also involves an older individual: the woman was 59 at the time of study enrollment and so is in her 70s now.

    The study was complicated, beginning by randomizing people with recent HIV infection to receive either ART or ART plus the immunosuppressant drug cyclosporine. There were a total of 20 participants, 19 cisgender men and the one cisgender woman (who was assigned to receive ART plus cyclosporine). Results from this initial part of the study were published in 2016.

    The woman was then rolled over into another protocol that involved an analytical treatment interruption (ATI). A short course of GM-CSF and pegylated alpha interferon was given during the ATI, followed by another period of ART plus subcutaneous low-dose IL-2 before  treatment was interrupted completely. 

    The crux of today’s report is that the participant has now maintained an undetectable HIV viral load for more than 15 years off ART and has displayed a progressive decline in measures of the HIV reservoir during that time. HIV that’s capable of replicating can still be detected at low levels, however, suggesting that control is being actively maintained by the immune system. In laboratory tests, the researchers identified “memory-like” natural killer cells and gamma-delta CD8 T cells as contributors to suppressing HIV replication (these represent relatively small subsets of immune system cells whose potential role in suppressing HIV hasn’t received much attention historically).

    The woman does not have any genetic factors that have been associated with immunological control of HIV infection, and Climent explained that she experienced quite severe symptoms during primary infection (which was diagnosed at Feibig stage 5).

    In response to questions, Climent noted that the woman was the only study participant who experienced post-treatment control, so the role (if any) of the immune-based interventions that were given is unclear. The researchers have also not tested for the presence of antiretrovirals in blood samples, which is necessary to confirm that the viral load control has occurred post-treatment. The formal presentation at the conference will occur on Sunday July 31.

    There’s been at least one other report of extended post-treatment control in a person who received ART plus cyclosporine during early HIV infection; in that case it was a man described as “the Lausanne Patient” by researcher Guiseppe Pantaleo, who’d been off ART for over eight years at the time of the report back in 2009. HIV cure research might potentially benefit from compiling all the historical reports of post-treatment control and assessing their current status (if the information is available); so far the phenomenon appears rare but it has the potential to offer clues to help develop curative interventions.

    AIDS 2022 will feature several sessions including HIV cure research in the coming days, listed below.

    Thursday July 28

    Pre-conference symposium: Pathways to an HIV cure: Research and advocacy priorities

    Friday July 29

    Satellite: Africa HIV cure research: Strengthening industry-community engagement in clinical research

    Saturday July 30

    The view from the bench: Advances in HIV basic and translational research

    Late Breaker Track A

    Global Village: On the road to HIV cure gene therapy: Who can learn from whom?

    Novel insights into the nature of the HIV reservoir and mechanisms of persistence

    Sunday July 31

    Approaches for HIV cure and vaccine research

    Combining immunotherapeutic agents to achieve ARV-free remission of HIV

    Responding to the virus: Advances in HIV immunology

    Monday August 1

    Late Breaker Track B

    Finding the needle in the haystack: Progress in understanding the HIV reservoir

    Tuesday August 2

    Shake and bake: Promising strategies for HIV cure

  • CROI 2022: Genomic Entrapment of HIV in People on Long-Term Antiretroviral Therapy, Chimeric Antigen Receptor T Cells and More on bNAbs

    This year’s virtual Conference on Retroviruses and Opportunistic Infections (CROI) ended on February 24th. Abstracts from the meeting are now available publicly in an abstract book and searchable database. Webcasts of all the presentations are due to become available around March 25th. Several presenters reported potentially encouraging developments in HIV cure research, in addition to those covered on the blog previously.

    Genomic Entrapment of HIV in People on Long-Term Antiretroviral Therapy

    Kyra Seiger from the Ragon Institute of MGH, MIT and Harvard described results demonstrating that the makeup of the HIV reservoir shifts over time in people on long-term antiretroviral therapy (ART). The key finding is that a substantial proportion of the intact HIV that persists after long-term ART appears to be entrapped in the genetic code of remaining infected cells, and likely unable to emerge and replicate.

    The finding relates to how HIV integrates its genetic code—in the form of HIV DNA—into the human DNA (known as the genome) of the cells that it infects.  

    As a loose analogy, if you think of a cell’s genome as a factory for producing all the proteins the cell needs to go about its daily business, HIV DNA tends to integrate in machinery that gets switched on regularly. This gives the virus opportunities to hijack that machinery to make more HIV proteins (and potentially more copies of infectious HIV).

    But HIV DNA can also land in the genomic equivalent of a darkened factory storage room nobody goes into (sometimes referred to as a “gene desert”)—in that case, the virus can become trapped and unable to reactivate.

    The importance of where HIV DNA integrates into a cell’s genome was first highlighted by studies of elite controllers, which provided evidence that their immune responses can clear cells containing more active HIV, leaving behind only those cells containing HIV integrated in places in the genome from which it can’t reactivate. Essentially, the intact HIV that remains in their bodies appears entrapped, and unable to replicate or cause harm.

    In two widely publicized cases involving elite controllers—Loreen Willenberg and the Esperanza Patient—this phenomenon may have resulted in a natural cure of HIV.

    More recently, a small study published by the laboratory of Xu Yu at the Ragon Institute has offered a hint that something similar may be occurring in people on long-term ART.

    Seiger’s CROI presentation built on this work, analyzing the location of integrated HIV in eight people who’ve been on ART for an average of around 20 years (the range was 17-23 years). In this group, approximately 84% of the intact HIV that could be detected was in locations in the genome that are unfavorable to reactivation. In contrast, only 31% of intact HIV in a cohort of 43 people on ART for a shorter duration (1-13 years) was in similar locations.

    Seiger noted that this offers evidence that cells containing HIV capable of reactivating are preferentially eliminated over time in people on long-term ART—likely because the activity of HIV can generate viral proteins that flag the cells for destruction by the immune system.

    Additional evidence supporting this scenario is that non-intact, defective integrated HIV DNA doesn’t show a similar pattern. When Seiger analyzed defective integrated HIV DNA in the group on long-term ART, there was no evidence for preferential elimination of defective HIV DNA located in more active regions of the genome.

    The results are encouraging because they suggest that, over time, HIV-specific immune responses in people on ART can contribute to reducing the reservoir of intact HIV.

    As reported by Jon Cohen for Science Magazine in January, the next step for this research is to conduct careful analytical treatment interruptions (ATIs) in people who’ve been on long-term ART and whose remaining intact HIV DNA is integrated into apparent gene deserts. The hope is that the only intact HIV left in their bodies may be inert and incapable of causing viral load rebound. The researchers stress, however, that only individuals with a particular HIV reservoir profile will be eligible for these studies, and people on long-term ART shouldn’t attempt ATIs on their own.

    The evidence that HIV-specific immune responses can reduce the intact viral reservoir in people on ART also provides a fillip for efforts to bolster these responses with immune-based therapies, such as CAR T cells, broadly neutralizing antibodies and therapeutic vaccines.

    Chimeric Antigen Receptor (CAR) T Cells 

    During an interactive session on chimeric antigen receptor (CAR) T cells, Jim Riley from the University of Pennsylvania revealed preliminary results from an ongoing clinical trial in people with HIV. The CAR approach involves genetic modification of T cells to equip them with receptors that enable better recognition and killing of specific targets. CAR T cell candidates designed to recognize and kill cancerous cells have shown efficacy in clinical trials and several are now licensed as cancer treatments.

    Riley’s study administered CAR T cells designed to target HIV-infected cells, in combination with CD4 T cells that have been genetically modified to block expression of the CCR5 receptor (which HIV uses to enter cells). The latter strategy was developed by Sangamo Therapeutics. Each study participant had their cells sampled, expanded and modified in the laboratory, and then reinfused.

    Riley was able to share data from eight participants. Four started an ATI the day after receiving the cell infusions and four waited eight weeks after the infusion before undergoing ATI. All participants in the first group experienced viral load rebounds over 100,000 copies/ml, which necessitated restarting ART before the end of the planned 16-week ATI. In contrast, the second group were able to complete the ATI with viral loads mostly in the low thousands.

    One participant maintained a very low viral load and didn’t restart ART after 16 weeks. This individual has now been followed for around 16 months off ART and the most recent viral load was 37 copies/ml.

    Riley noted that this person had participated in previous Sangamo trials and had received two infusions of CD4 T cells genetically modified to block expression of the CCR5 receptor. While this single case of extended viral load control off ART is an outlier in the context of the trial, the outcome suggests that strategies aiming to bolster the number of gene-modified cells are worth pursuing.

    Riley’s research group already has a potentially enhanced CAR T cell design that they intend to move into trials. This newer CAR T cell includes the co-stimulatory molecules 4-1BB and CD28 and, in animal models, showed increased proliferative potential and activity.

    More on Broadly Neutralizing Antibodies (bNAbs)

    The day after Ole Søgaard debuted the primary results from the eCLEAR study (see prior blog post), Míriam Rosás-Umbert from Aarhus University provided additional details on the immune-enhancing effects of the bNAb 3BNC117.

    Rosás-Umbert explained that bNAbs can bind to HIV and chaperone the virus into cell pathways that promote antigen presentation (in other words, help make HIV visible to other components of the immune system, including T cells). Evidence for bNAbs boosting virus-specific CD8 T cell responses has been previously reported in both macaque and human studies.  

    Among eCLEAR study participants with HIV that was sensitive to 3BNC117, Rosás-Umbert found that CD8 T cell responses targeting HIV Gag and Pol proteins were significantly higher at months three and 12 of follow up compared to other participants.

    The ability of T cells to produce the cytokine interferon gamma in response to HIV Gag was also significantly greater in participants with HIV that was sensitive to 3BNC117, and this capacity was associated with maintenance of viral load below 5,000 copies/ml during an ATI (in one case, HIV viral load has remained undetectable for 3.7 years off ART).

    A poster presentation by Christian Gaebler from Rockefeller University debuted results from a trial combining two bNAbs, 3BNC117 and 10-1074, in people with HIV on ART. As in previously published studies from the same group, the bNAbs showed strong anti-HIV activity.

    The most intriguing finding was that two participants were able to maintain HIV viral load suppression without ART for an extended period after bNAb administration. One of the individuals has since been lost to follow up, but the other is approaching three years off ART with no viral load rebound. Similarly prolonged post-treatment control of viral load was observed for two participants in a prior trial of this bNAb combination.

    Taken together, these results strongly support the idea that bNAbs can have a vaccine-like effect that improves the immune response to HIV. The challenge now is to increase the proportion of people able to control viral load after an ATI. Multiple trials of bNAb combinations are ongoing (see TAG's Research Toward a Cure Trials listing) and many more are planned.

  • CROI 2022 Update: A New Potential HIV Cure Case; Broadly Neutralizing Antibody Enhances Post-Treatment Control

    The Conference on Retroviruses and Opportunistic Infections (CROI) is taking place virtually again this year, running from February 12th to February 24th. In a session today on HIV cure research, Yvonne Bryson and colleagues from the IMPAACT research network presented important news about another potential example of an HIV cure achieved by stem cell transplantation.

    The case involves a woman living with HIV who was diagnosed with acute myelogenous leukemia (AML), a life-threatening cancer, in 2017. The researchers sourced cord blood stem cells from a donor homozygous for the CCR5Δ32 mutation that prevents expression of the CCR5 co-receptor that most HIV strains use as an entryway into cells. The aim was to treat the cancer while also generating a new immune system made up of HIV-resistant cells, following the model that has produced three other known cases of likely HIV cures in men (Timothy Ray Brown, Adam Castillejo and the Düsseldorf patient).

    A difference with prior cases is that stem cells from umbilical cord blood are less efficient at generating a new immune system after transplantation, so the woman also received stem cells from the peripheral blood of an adult relative who lacked the CCR5Δ32 mutation. Shortly after the transplant, most of the immune cells that could be detected were derived from the adult blood stem cells, but over time the proportion of cells derived from the cord blood transplant increased. From day 100 of follow-up, all T cells and myeloid cells (monocyte/macrophages) were progeny of the cord blood transplant and therefore possessed the CCR5Δ32 mutation. As reported at the Annual Meeting of the American Society for Hematology in 2018, remission of AML was achieved and the woman initially continued on antiretroviral therapy (ART) with HIV viral load remaining suppressed.

    At CROI today, Yvonne Bryson reported that ART was interrupted three years after the transplant with no HIV viral load rebound. The woman, who’s described as middle aged and of mixed race, has now been off ART for more than 14 months with persistently undetectable HIV viral load (during this time they’ve received COVID-19 vaccination without any untoward effect).

    Tests for HIV DNA, a surrogate measure of the HIV reservoir, have also been negative except one detection of trace amounts at an early timepoint after ART cessation. Antibody and T cell responses against HIV are no longer detectable. The absence of ART has been confirmed by measuring drug levels in blood. The researchers have tested the woman’s cells in the laboratory and found them to be resistant to HIV.

    The case bolsters the evidence that an HIV cure is achievable and demonstrates that, for people with HIV and certain life-threatening cancers, stem cell transplantation from donors homozygous for the CCR5Δ32 mutation can work in women as well as men.

    Bryson pointed out that cord blood stem cell banks can be tested for the presence of the CCR5Δ32 mutation, and the approach used in this case could increase the chances of identifying CCR5-negative donors for people with HIV who require stem cell transplants for cancers (cord blood stem cells have less stringent requirements for matching the genetics of recipients). Background on the use of cord blood stem cell transplants in HIV cure research and the possibilities of identifying matches for people of different races can be found in an overview article published in 2015 by Lawrence Petz and colleagues.

    During the same CROI session on HIV cure research, Ole Søgaard provided additional encouragement with a presentation on results from the “eCLEAR” trial, which investigated the broadly neutralizing antibody 3BNC117 and a candidate latency-reversing agent, romidepsin.

    The study enrolled 60 participants, approximately half with recent HIV infection (less than 6 months), and randomly assigned them to one of four groups:

    • ART alone
    • ART plus 3BNC117 at day 7 and 21 after ART initiation
    • ART plus romidepsin at day 10, 17 and 24
    • ART plus 3BNC117 and romidepsin (administered at the same times listed above)

    The primary aim was to assess if administering these interventions around the time of ART initiation could accelerate clearance of the HIV reservoir and promote control of HIV viral load after an analytical treatment interruption (ATI). The rationale derived from a study demonstrating that the persistent HIV reservoir is formed close to the time of ART initiation in a substantial proportion of people with HIV.

    Participants were followed for a year and then given the option of undergoing a 12-week analytical treatment interruption (ATI) at day 400 of follow up. The majority of participants were white men; a total of five women were enrolled but none were randomized to receive 3BNC117.

    Receipt of 3BNC117 was associated with greater declines in levels of cells expressing HIV RNA and the HIV p24 protein, as well as increases in HIV-specific CD8 T cell responses. Furthermore, four out of the five participants whose pre-ART HIV samples were fully sensitive to 3BNC117 (i.e. no evidence of resistance to the anti-HIV effects of the antibody) maintained HIV viral load below 5,000 copies/ml throughout the 12-week ATI, compared to three of 15 participants who had pre-ART evidence of HIV resistance to 3BNC117 or did not receive the antibody. These effects appeared independent of receipt of romidepsin.

    One participant from the 3BNC117 and romidepsin group remains off ART and has maintained undetectable HIV viral load for 3.7 years and counting. In the Q&A session after his talk, Søgaard noted that the HIV reservoir in this individual (as measured by an intact proviral DNA assay) is continuing to shrink in size over time.

    Additional information on the association between 3BNC117 and improved CD8 T cell responses will be presented at CROI tomorrow by Míriam Rosás-Umbert (this presentation remains embargoed).

    The results indicate that broadly neutralizing antibodies (bNAbs) like 3BNC117 may have the potential to enhance clearance of the HIV reservoir and promote containment of viral load after treatment interruption. Additional ongoing studies involving combinations of bNAbs and ATIs, such as the RIO trial, should shed further light on the efficacy of the approach. Combinations of bNAbs may be necessary to circumvent the problem of baseline HIV resistance to individual antibodies.

    Links to the relevant CROI abstracts are below – presentation webcasts will become available on these pages in around 30 days (at the current time access is restricted to conference registrants).

    HIV-1 Remission with CCR5Δ32Δ32 Haplo-Cord Transplant in a U.S. Woman: IMPAACT P1107 (abstract 65)
    JingMei Hsu, Koen Van Besien, Marshall J. Glesby, Anne Coletti, Savita G. Pahwa, Meredith Warshaw, Amanda Golner, Frederic Bone, Nicole Tobin, Marcie Riches, John W. Mellors, Renee Browning, Deborah Persaud, Yvonne Bryson

    The Impact of 3BNC117 and Romidepsin Treatment at ART Initiation on HIV-1 Persistence (abstract 62)
    Jesper D. Gunst, Marie H. Pahus, Míriam Rosás-Umbert, Thomas Benfield, Henrik Nielsen, Isik S. Johansen, Rajesh Mohey, Lars Østergaard, Mariane H. Schleimann, Martin Tolstrup, Julie Fox, Michel Nussenzweig, Marina Caskey, Sarah Fidler, Ole Søgaard

    Administration of 3BNC117 at ART Initiation Induces Long-Term HIV CD8 T-Cell Immunity (abstract 122)
    Míriam Rosás-Umbert, Jesper D. Gunst, Rikke Olesen, Marina Caskey, Michel Nussenzweig, Martin Tolstrup, Ole Søgaard

    Helpful media articles on the possible new HIV cure case:

    A Woman Is Cured of H.I.V. Using a Novel Treatment – Apoorva Mandavilli, New York Times

    Scientists have possibly cured HIV in a woman for the first time – Benjamin Ryan, NBC News

  • Post-Treatment Control of HIV: Potentially Differing Mechanisms and Issues for Clinical Trials

    A paper published in Nature Medicine on October 28th describes two cases of extended post-treatment control of HIV. The research was led by Jana Blazkova from the laboratory of Tae-Wook Chun at the National Institute of Allergy and Infectious Diseases (NIAID) and an accompanying press release generated several media stories. The two people with HIV were participants in a therapeutic HIV vaccine trial conducted at the National Institutes of Health Clinical Center in Bethesda, Maryland.

    Both individuals had initiated antiretroviral therapy (ART) during acute HIV infection and were randomized to the placebo arm of the trial. The protocol included an analytical treatment interruption (ATI), and at the time ART was stopped they had been receiving treatment for 6.7 and 6.5 years, respectively.

    One person, referred to as Participant 04 in the paper, experienced an initial viral load rebound to 26,967 copies/ml about two months into the ATI before controlling to undetectable levels for a little over 1.5 years. There were subsequent transient viral load blips to 778 and 1,784 copies/ml after 581 and 875 days, respectively, but control was then maintained for approximately an additional two years.

    The researchers analyzed the genetic sequences of the viruses that became detectable during the blips and found that mutations were accumulating over time, indicating ongoing low-level HIV replication. There was also evidence that CD8 T cells targeting HIV had induced escape mutations (the immunological equivalent of drug resistance mutations), suggesting these immune responses were playing a role in the observed post-treatment control of viral load.  

    Screening for the presence of ART in blood samples was conducted regularly on both participants, and around day 1250 (nearly 3.5 years after ATI) these tests showed that Participant 04 had initiated a suboptimal ART regimen without letting the researchers know. The paper provides no information on whether there was a subsequent switch to effective ART.

    Viral load in the second participant (#30) remained almost completely undetectable until after almost four years of follow up (there were only four detectable readings during this period, all at the borderline of the 20 copies/ml detection limit of the test). A significant viral load rebound was detected at day 1,424 and detailed analyses of the virus sequences indicated that superinfection with a different HIV variant had occurred. The participant reportedly confirmed that a potential exposure to HIV had preceded the rise in viral load.

    In the case of Participant 30, post-treatment control was associated with potent antibody-mediated neutralization activity against HIV isolates sampled prior to the time of viral load rebound. In contrast, the activity of the antibody response was weak against the emerging HIV variant ascribed to superinfection.

    The researchers note that this is an unusual observation, as past reports have primarily linked the phenomenon of post-treatment control to HIV-specific T cell responses. They write that the results “suggest that one of the potential mechanisms by which Participant 30 achieved near complete virologic suppression in vivo, before superinfection, might have involved neutralizing antibodies against HIV.”

    In addition to providing clues about possible mechanisms of post-treatment control, the findings potentially raise issues for the conduct of HIV cure research. Firstly, it will be important to try to better understand the reasons why study participants might feel reluctant to disclose the use of ART to researchers. This may be an area where social science can contribute insights to help lessen the risk of the issue arising in future studies.  

    Secondly, discussions of the potential for HIV transmission during ATI have largely focused on risk to HIV-negative partners of trial participants, but this report emphasizes that the risk of superinfection also needs to be considered and included in the informed consent and counseling process for trials involving ATIs.