TAG HIV Basic Science, Vaccines, and Cure Project Blog

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

There are twelve updates to the listing this month: four new interventional trials and one observational study have been added (all yet to start recruiting), a planned observational study was withdrawn, a trial of immunomodulators has begun recruiting in China, one trial has shifted to the completed studies table, and links to presentations/publications describing results were added for four studies in the listing.

The ACTG is sponsoring a new placebo-controlled study of a single infusion of each of two long-acting broadly neutralizing antibodies (bNAbs) followed by an analytical treatment interruption (ATI) in people on antiretroviral therapy (ART) at sites in Botswana, Malawi, and South Africa. The bNAbs are 3BNC117-LS-J and 10-1074-LS-J. The plan is to enroll a total of 48 participants, who’ll be randomized to receive the bNAb infusions or placebo versions and start an ATI two days later. The eligibility criteria require that participants have been on a suppressive ART regimen for at least 96 weeks (with some allowance for a short interruption during that period). The researchers will evaluate the capacity of the bNAbs to delay viral load rebound above a threshold of 200 copies/ml (suggesting that an increase of viral load above this level will trigger the restarting of ART). The ACTG is currently in the process of revising their former name AIDS Clinical Trials Group to just the acronym, which has been altered to stand for: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (to reflect the broadening of their mission).

At the Research Institute of the McGill University Health Centre in Canada, Jean-Pierre Routy is initiating a trial that will investigate the safety and effects of fecal microbiota transplantation (FMT) on gut integrity, inflammatory biomarkers, and HIV reservoir measures in people on ART. As outlined in a recent meta-analysis of 10 prior studies, FMT has shown some potential efficacy in restoring healthy gut bacteria and reducing the rate of gastrointestinal infections in PWHIV, with a safety profile similar to that observed in HIV-negative people. Routy’s study will enroll 20 participants with half randomized to receive FMT capsules and half receiving a placebo equivalent. The researchers are limiting the study to people with a CD4:CD8 ratio <1 in order to focus on a population most at risk for persistent inflammation.

The pharmaceutical company AbbVie recently entered the realm of HIV cure research without great fanfare and is now about to launch a combination trial assessing a combination of two antibody-based therapeutics that they’ve previously studied individually in PWHIV (results from those studies have not been publicly presented yet to our knowledge). Budigalimab is an anti-PD-1 antibody that belongs to the class of interventions called immune checkpoint inhibitors (several are licensed for the treatment of cancers), while ABBV-382 is an anti-α4β7 integrin antibody similar to vedolizumab (an antibody approved for ulcerative colitis and Crohn's disease). According to the study record, AbbVie plans to recruit 140 participants at approximately “90 sites worldwide.” The protocol involves an ATI and will evaluate the effect of the antibodies (alone or in combination) compared to placebo on time to viral load rebound greater than 1,000 copies/ml. Based on the company’s website pipeline page, it appears that the ultimate goal may be to combine the two antibodies into a single construct (codenamed ABBV-1882) that can target both PD-1 and the α4β7 integrin. The interventional trial that was completed this month is AbbVie’s phase Ib assessment of ABBV-382 alone — although results don’t appear to be available yet, it seems reasonable to assume that the data supported progressing to the larger combination study.

The last of the new interventional trials is sponsored by the HIV Vaccine Trials Network and aims to test an HIV vaccine construct in PWHIV on ART who will undergo an ATI. The vaccine is part of an effort to develop a “germline targeting” strategy that can eventually lead to the generation of bNAbs. The main goal of the study is to assess how HIV viral load rebound during ATI affects the B cell and antibody responses induced by the vaccine. The rationale is that further stimulation of vaccine-induced B cells by HIV may conceivably drive a process called maturation that can lead to the production of more effective antibody responses, and the researchers plan to study this very carefully. There are also a number of secondary outcome measures focused on the experience and perspectives of the study participants, because while this work may be able to contribute to cure research, the primary focus is on informing the development of an effective preventive HIV vaccine.

The lone new observational study is sponsored by the University Hospital, Ghent and intends to undertake a detailed characterization of the HIV reservoir in individuals who are naturally controlling viral load to low levels in the absence of ART. The observational study that was withdrawn this month was from the same sponsor; the clinicaltrials.gov record notes that it wasn’t able to open because a commercial partner decided not to proceed with the project.

A study of two potential immunomodulators, lenalidomide and adenosylmethionine (added to the listing in November 2022) is now open for enrollment at the First Affiliated Hospital of Zhejiang University School of Medicine in China.

The new links to publications and presentations include:

• Videos of talks at the IAS HIV Cure & Immunotherapy Forum related to the RIO trial and the ICVAX therapeutic vaccine study
• An IAS 2023 abstract reporting a new analysis involving participants in the completed ISALA ATI study in Belgium
• The published results of the completed TITAN trial that combined dual bNAbs with the toll-like receptor 9 agonist lefitolimod (these results were covered in TAG's 2023 Research Toward a Cure and Immune-Based Therapies Pipeline Report)

More on the Links Between the CD4/CD8 Ratio, Immunological Perturbations, and Risk of Illness and Death

Since posting recently about studies investigating the relevance of the CD4/CD8 ratio in the antiretroviral therapy era, several new papers and presentations have provided more information on the topic. Last week in the open access journal PLoS Pathogens, Sergio Serrano-Villar and colleagues reported evidence that a low CD4/CD8 ratio (less than or equal to 0.4)—despite CD4 T cell recovery to a count above 500 on ART—is associated with low naïve CD8 T cells, elevated levels of activated and senescent CD8 T cells, increased innate immune activation, and a greater risk of non-AIDS events. After controlling for age, gender, ART duration and both nadir and proximal CD4 count, each 10% decrease in the CD4/CD8 ratio was associated with 48% higher odds of serious non-AIDS events. In a separate cohort that started ART with advanced disease, a significant correlation between the CD4/CD8 ratio and the risk of mortality was documented. In this analysis, the researchers report that for each 10% increase in the CD4/CD8 ratio on ART there was a 15% decrease in the risk of death. Individuals initiating ART earlier in the course of HIV infection exhibited greater and more rapid improvements in the CD4/CD8 ratio compared to those starting late.

A poster at CROI 2014 presented similar findings. Cristina Mussini and colleagues assessed whether the CD4/CD8 ratio predicted clinical progression in the Icona cohort in Italy. The CD4/CD8 ratio was a significant predictor of the risk of serious non-AIDS events and death, independent of CD4 T cell counts. Normalization of the CD4/CD8 ratio (to greater than or equal to 1) only occurred in a minority of participants, and was more common among younger individuals, those with higher CD4/CD8 ratios at ART initiation, and those starting ART in more recent periods at higher CD4 T cell counts. Another poster at CROI from Talia Sainz et al described the role of CMV infection in lowering CD4/CD8 ratios in HIV-positive people, as is also known to occur in the HIV-negative elderly. Lastly, a recent paper in PLoS One published by Willard Tinago and colleagues from the laboratory of Paddy Mallon in Dublin looked at the links between the CD4/CD8 ratio and other immunological perturbations, with results that appear consistent with those reported by Sergio Serrano-Villar’s group.

The discussion section of the Serrano-Villar paper notes that the data imply that the CD4/CD8 ratio could be useful for monitoring responses to therapies that aim to reduce residual immune activation. Additionally, HIV-positive individuals on suppressive ART who do not experience an increase in the CD4/CD8 ratio “might benefit from screening programs or aggressive management of concomitant risk factors for aging-associated disease.”

PLoS Pathog. 2014 May 15;10(5):e1004078. doi: 10.1371/journal.ppat.1004078. eCollection 2014.

HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality.

Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, Ferre AL, Hayes TL, Somsouk M, Hsue PY, Van Natta ML, Meinert CL, Lederman MM, Hatano H, Jain V, Huang Y, Hecht FM, Martin JN, McCune JM, Moreno S, Deeks SG.

Abstract

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

Cristina Mussini et al. Incidence of CD4/CD8 Ratio Normalization and Its Role in the Onset of Non-AIDS-Related Events. Abstract #753, Conference on Retroviruses and Opportunistic Infections, March 3-6 2014, Boston, MA 

Talia Sainz et al. CMV and HIV: A Double Hit On the CD4/CD8 Ratio. Abstract #243, Conference on Retroviruses and Opportunistic Infections, March 3-6 2014, Boston, MA 

PLoS One. 2014 May 9;9(5):e97011. doi: 10.1371/journal.pone.0097011. eCollection 2014.

Clinical, Immunological and Treatment-Related Factors Associated with Normalised CD4+/CD8+ T-Cell Ratio: Effect of Naïve and Memory T-Cell Subsets.

Tinago W, Coghlan E, Macken A, McAndrews J, Doak B, Prior-Fuller C, Lambert JS, Sheehan GJ, Mallon PW; Mater Immunology Study Group.

Abstract

BACKGROUND: Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.

METHODS: A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.

RESULTS: We recruited 190 subjects, age 42(36-48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6-10.2) years. Nadir and current CD4+ counts were 200(112-309) and 465(335-607) cells/mm3 respectively. Median CD4+/CD8+ ratio was 0.6(0.4-1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3)% were naïve, 36.8(29.0-40.0)% central memory and 27.4(20.0-38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.

CONCLUSIONS: Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.

The Relevance of the CD4/CD8 Ratio in the Antiretroviral Therapy Era

An inversion of the normal ratio between CD4 and CD8 T cells was noted in the very first case reports of individuals with AIDS, before HIV was even identified. Although a number of studies subsequently reported an association between the CD4/CD8 ratio and risk of disease progression, CD4 T cell counts were more extensively researched and became the most commonly used surrogate marker of immune system health in HIV-positive people. In recent years, data has emerged from cohort studies of very elderly HIV-negative people indicating that, in this population, the CD4/CD8 ratio is a strong predictor of the risk of aging-associated diseases and mortality. This new information prompted the research group of Sergio Serrano-Villar at the University Hospital Ramón y Cajal in Madrid to evaluate whether measurement of the CD4/CD8 ratio may provide information about the risk of morbidity and mortality in HIV-positive people in the current era of antiretroviral therapy (ART).

Last year, Serrano-Villar and colleagues published preliminary studies showing associations between the CD4/CD8 ratio and levels of immune activation and markers of immune system aging (immunosenescence) in HIV infection. In two new papers published in HIV Medicine and PLoS One, they now extend these findings and report statistically significant associations between the CD4/CD8 ratio and markers of age-associated disease and the clinical outcomes of non-AIDS-related morbidity and mortality in HIV-positive people. The PLoS One study assesses the link between the CD4/CD8 ratio and several dissimilar non-AIDS diseases in people on ART, and reports a significant association in each case. Separate analyses of participants with low CD4 nadirs (<200 cells) and those with good CD4 recovery on ART (to >350 cells) find that CD4/CD8 ratios remain independently associated with non-AIDS events in each subgroup.

In discussing the implications of their findings, the researchers write: “patients with failure to increase the CD4/CD8 ratio despite achieving full immunovirological response to ART might benefit from screening programs and aggressive management of concomitant risk factors for age-associated disease.” They also note that, since there appears to be a relationship between immune activation and the CD4/CD8 ratio, such individuals may be prime candidates for inclusion in clinical trials of interventions that aim to reduce immune activation and associated adverse clinical outcomes. However, several limitations to the study are acknowledged, and the authors stress that: “before using the CD4/CD8 ratio as a surrogate of serious non-AIDS-related illnesses, these results should be reproduced in larger and prospective studies.”

As it currently stands, there are very few reports of therapies capable of improving low CD4/CD8 ratios in HIV-positive people on ART. IL-7 increases both CD4 and CD8 T cell numbers, and according to a new study published in PLoS Pathogens, may reduce markers of inflammation, but the clinical impact of this cytokine has yet to be evaluated. A further complication is that the company behind IL-7, Cytheris, recently went bankrupt, leaving the rights to its development for HIV in the hands of the French Agence Nationale de Recherche sur le SIDA (ANRS) and a small biotech named Cognate Biosciences. SB-728-T, a gene therapy under development by Sangamo Biosciences, has been reported to significantly improve CD4/CD8 ratios in people on ART, but the duration of the effect is unclear and the company appears uninterested in developing the approach for people with suboptimal immune reconstitution (their focus is on attempting to achieve control of HIV replication after ART interruption). The therapy is also complex to administer because it involves the extraction, expansion and genetic modification of CD4 T cells, followed by reinfusion. A letter from TAG and many other community activists and organizations asking the company to continue to study the potential of SB-728-T to promote immune reconstitution fell on deaf ears.

Although not directly connected to the work of Sergio Serrano-Villar and colleagues, another study on the topic of the CD4/CD8 ratio in HIV infection was published online by the Journal of Immunology this past Monday. Marcus Buggert and a Swedish research team used a bioinformatics approach to explore the connections between several of the laboratory measures used to monitor HIV disease progression (including CD4 count and CD4/CD8 ratio) and a large suite of T cell markers that are perturbed by HIV infection (including activation, exhaustion and immunosenescence markers). Focusing primarily on untreated HIV infection, the researchers find that the CD4/CD8 ratio is the best predictor of the combined pathological changes to the T cell immune system that occur in HIV-positive people compared to uninfected controls. The paper concludes: “these findings are of particular interest to future therapy or cure studies, in which simple measurements are required to monitor ongoing pathological events of the T cell repertoire in HIV-infected subjects.”

HIV Med. 2014 Jan;15(1):40-9. doi: 10.1111/hiv.12081. Epub 2013 Sep 6.

The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery.

Serrano-Villar S, Moreno S, Fuentes-Ferrer M, Sánchez-Marcos C, Avila M, Sainz T, de Villar NG, Fernández-Cruz A, Estrada V. 

Abstract

OBJECTIVES: Inversion of the CD4:CD8 ratio (< 1) has been identified as a hallmark of inmmunosenescence and an independent predictor of mortality in the general population. We aimed to assess the association between the CD4:CD8 ratio and markers of age-associated disease in treated HIV-infected patients with good immunovirological response.

METHODS: A cross-sectional analysis was conducted in 132 HIV-infected adults on antiretroviral therapy (ART), with plasma HIV RNA < 50 HIV-1 RNA copies/mL for at least 1 year, CD4 count > 350 cells/μL and age < 65 years. We analysed the associations between the CD4:CD8 ratio and subclinical atherosclerosis [assessed using carotid intima-media thickness (IMT)], arterial stiffness [assessed using the augmentation index (AIx)], the estimated glomerular filtration rate (eGFR), muscle wasting and sarcopenia [assessed using appendicular lean mass/height(2) (ALM) measured by dual-energy X-ray absorptiometry (DEXA)].

RESULTS: CD4:CD8 ratio inversion was associated with higher IMT, lower eGFR and lower ALM (all values P < 0.05), but not with AIx. In multivariate analyses adjusted for age, sex, hypertriglyceridaemia, tobacco use and cumulative ART exposure, inversion of the CD4:CD8 ratio was independently associated with higher IMT [odds ratio (OR) 2.9; 95% confidence interval (CI) 1.2-7.1], arterial stiffness (OR 4.8; 95% CI 1.0-23.5) and lower eGFR (OR 5.2; 95% CI 1.0-64.4), but not sarcopenia (OR 0.7; 95% CI 0.2-2.7). These associations persisted when models were applied to subjects with nadir CD4 counts > 200 cells/μL and those with CD4 counts > 500 cells/μL.

CONCLUSIONS: The CD4:CD8 ratio in treated HIV-infected subjects with good immunovirological response is independently associated with markers of age-associated disease. Hence, it might be a clinically useful predictor of non-AIDS-defining conditions.

PLoS ONE 9(1): e85798. doi:10.1371/journal.pone.0085798 

Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio

Sergio Serrano-Villar, María Jesús Pérez-Elías, Fernando Dronda, José Luis Casado, Ana Moreno, Ana Royuela, José Antonio Pérez-Molina, Talia Sainz, Enrique Navas, José Manuel Hermida, Carmen Quereda, Santiago Moreno

Published: January 30, 2014DOI: 10.1371/journal.pone.0085798 

Abstract

Background

A low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events.

Methods

Case-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts.

Results

We analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3–6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5–5.3).

Conclusions

The CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.

The Journal of Immunology

Published online before print February 3, 2014, doi: 10.4049/​jimmunol.1302596

Multiparametric Bioinformatics Distinguish the CD4/CD8 Ratio as a Suitable Laboratory Predictor of Combined T Cell Pathogenesis in HIV Infection

Marcus Buggert, Juliet Frederiksen, Kajsa Noyan, Jenny Svärd, Babilonia Barqasho, Anders Sönnerborg, Ole Lund, Piotr Nowak, and Annika C. Karlsson

Abstract

HIV disease progression is characterized by numerous pathological changes of the cellular immune system. Still, the CD4 cell count and viral load represent the laboratory parameters that are most commonly used in the clinic to determine the disease progression. In this study, we conducted an interdisciplinary investigation to determine which laboratory parameters (viral load, CD4 count, CD8 count, CD4 %, CD8 %, CD4/CD8) are most strongly associated with pathological changes of the immune system. Multiparametric flow cytometry was used to assess markers of CD4+ and CD8+ T cell activation (CD38, HLA-DR), exhaustion (PD-1, Tim-3), senescence (CD28, CD57), and memory differentiation (CD45RO, CD27) in a cohort of 47 untreated HIV-infected individuals. Using bioinformatical methods, we identified 139 unique populations, representing the “combined T cell pathogenesis,” which significantly differed between the HIV-infected individuals and healthy control subjects. CD38, HLA-DR, and PD-1 were particularly expressed within these unique T cell populations. The CD4/CD8 ratio was correlated with more pathological T cell populations (n = 10) and had a significantly higher average correlation coefficient than any other laboratory parameters. We also reduced the dimensionalities of the 139-unique populations by Z-transformations and principal component analysis, which still identified the CD4/CD8 ratio as the preeminent surrogate of combined T cell pathogenesis. Importantly, the CD4/CD8 ratio at baseline was shown to be significantly associated with CD4 recovery 2 y after therapy initiation. These results indicate that the CD4/CD8 ratio would be a suitable laboratory predictor in future clinical and therapeutic settings to monitor pathological T cell events in HIV infection.