Cure Research and The CTN

The CTN first became involved in HIV cure research in 1998 with CTN 033. This study aimed to show if injection of a vaccine (VaxSyn) would slow disease progression and strengthen participants’ immune systems as part of a functional cure but found no clinical benefit. Similarly, a set of three studies (CTN 229, 239, and 256) tested the safety and immunogenicity of a treatment made from participants’ own white blood cells (AGS-004) to increase immune function. Immunogenicity refers to the ability of a treatment to stimulate different immune system responses needed to fight a virus but does not necessarily mean clinical beneficial. More needs to be learned to understand which specific responses will be effective to control HIV. Although CTN 229 and 239 found that AGS-004 was safe and showed promise by stimulating the immune system, CTN 256 found that there was no antiviral effect compared to placebo.

The pilot trial CTNPT 020 is examining the safety and immunogenicity of a different vaccine (PENNVAX) delivered directly using a pulse of electricity. Another pilot trial, CTNPT 027, is testing the ability of metformin, a natural treatment for diabetes, to boost the immune system and reduce the size of the viral reservoir.

CTN 140, an early proof-of-concept study, tested if intensification of ART in combination with a therapeutic vaccine (Remune) would allow participants to control HIV without ART. A later pilot study, CTN 173, found that vaccination with Remune plus ALVAC – which was used in order to boost CD8 T cell responses – showed a slight trend in the delay of viral rebound during structured treatment interruption within the study populations but it was not significant. The size of the reservoir was not decreased in trial participants. The safety and tolerability of a different combination vaccine (Remune plus Amplivax) was confirmed by CTN 203.

Valproic acid, a treatment for epilepsy, was tested in CTN 205 as a candidate to determine if it could reduce the size of the viral reservoir when combined with ART. Valproic acid is thought to stimulate hiding HIV, preventing it from staying dormant in immune cells. Although the trial was able to be done using a unique study design, valproic acid was not shown to reduce reservoir size in this study.

Research in early HIV infection has pointed investigators towards the gut as a site of initial damage, inflammation, and microbial translocation. Microbial translocation is when bacteria in the gut pass into the general blood stream, contributing to harmful immune activation and inflammation. This makes the gut a potential target for interventional strategies. CTN 257 assessed the impact of HIV infection and ART on mucosal (gut) and circulating immune cells in the early stages of HIV infection.

CTNPT 022b is determining whether a probiotic supplement in combination with ART can help reduce inflammation and harmful immune activation, a potential component of a funct. Reducing inflammation may reduce the number of immune cells targeted by HIV for infection and return the gut to a condition of relative health, therefore preserving immune function.

In a recent pilot trial (CTNPT 031), CTN Postdoctoral Fellow Dr. Michaeline McGuinty tested whether vedolizumab, an anti-α4β7 integrin monoclonal antibody currently used to treat inflammatory bowel disease, is effective for ART-free virologic control of HIV. It is believed to work by targeting and preventing CD4 cells from localizing in the lining of the bowel. The project was initiated after a 2016 publication showed that a similar treatment in monkeys induced viral load suppression and maintained CD4 count after stopping antiretrovirals. Presented at CROI 2019, initial results did not show this treatment to be as effective as in the monkey studies. However, vedolizumab did appear to slow down the viral load rebound time and lower the peak viral load rebound after stopping ART. These results suggest that future studies with vedolizumab should investigate a larger dose and longer treatment duration with a greater number of participants. In response to these findings, the CTNPT 031 team added a high-dose arm to the study, which is currently underway.

Dr. Routy and CTN Postdoctoral Fellow Dr. Stéphane Isnard are leading two pilot studies about HIV and gut health. CTNPT 032 is studying the effect of Camu Camu, an Amazonian fruit with antioxidant and anti-inflammatory properties, on the health, microbiota, inflammation and viral reservoir in the gut tissue. In CTNPT 038, they are investigating whether a fecal microbiota transplantation can reduce inflammation and improve gut health in people living with HIV who have a low CD4 count.

Individual differences in immune responses to ART and to HIV infection itself are important to researchers as the basis upon which treatments can be developed. The CANOC collaboration (CTN 242), a national retrospective observational cohort study of over 13,000 participants pulled from databases in Quebec, Ontario and BC, allows researchers to decipher which factors are most important for treatment and cure strategies. The CTN’s contribution to the CANOC collaboration is through the Clinical Care and Management (CCM) Core.

CTN 247 is following a cohort of slow progressors — people who show some natural control of HIV progression — to understand the factors that contribute to improved immune function and disease outcomes. EPIC4 (CTN 281), another ongoing cohort, is comprised of a group of children and infants who acquired HIV via vertical transmission – during childbirth, in utero, or during breastfeeding. After being started on ART shortly after birth, children in the EPIC4 cohort have achieved viral suppression. This cohort gives researchers a chance to study the effects of early ART as a functional cure but is also a long-term source of information about the immune system, treatments, and HIV characteristics. The EPIC4 cohort study is conducted through the CTN’s Prevention Core. So far, none of these children have been taken off ART but four are being closely followed to determine if the virus would rebound if treatment was stopped.

Before research gets to the clinical phase, studies are needed to understand the fundamental characteristics of the immune system and HIV, often using animal models. The Canadian HIV Cure Enterprise (CanCURE) national team is a CTN research partner and is a collaboration between CIHR, CANFAR, and IAS. CanCURE is committed to finding a cure for HIV from basic research through to clinical trials. Several CTN researchers are CanCURE investigators: Drs. Jean-Pierre Routy, Jonathan Angel, Mario Ostrowski, and Eric Cohen are principal investigators, and Drs. Rupert Kaul and Mark Wainberg are co-investigators.

CanCURE focuses its research plan on HIV in myeloid lineage cells, including macrophages. Myeloid cells are a group of immune cells in the blood that are different from lymphoid cells (the cell type that CD4 T cells belong to). The team will study these cells, often lodged in deep tissue reservoirs such as the brain, to understand the relevant mechanisms of viral persistence and relationship to persistence in CD4 cells, and to develop treatments that might deplete or control HIV in these cells.

Studies that are not directly focused on curing HIV or shrinking the viral reservoir as a principal objective can indirectly contribute significantly to the field of HIV cure research. For example, a finding from CTN 247 — the slow progressors cohort, led by Dr. Cécile Tremblay — has identified a biomarker in the blood (interleukin-32, or IL-32) that may help predict when people who could previously naturally control their HIV levels begin to lose control. Not only does this finding represent a potential monitoring tool for HIV control, it could also be used as a target for drug therapy to reduce harmful inflammation and immune dysfunction. Dr. Tremblay and her team have secured federal funding to research Il-32 in this context.

Aside from CanCURE, CTN Researchers are involved in a number of studies across Canada that aren’t directly supported by the CTN. For example, CTN Investigators Drs. Colin Kovacs and Mario Ostrowski recently completed a clinical trial looking at the impact of early, intensive cART (including raltegravir and maraviroc) on reducing the size of the viral reservoir. CTN Investigators Drs. Nicole Bernard and Cécile Tremblay recently received a 5-year project grant from CIHR to investigate how antibody dependent functions may affect HIV control and lead to design and delivery of new effective therapeutic antibodies. This research hopes to contribute to the design of therapeutic antibodies to control HIV infection. Previously Dr. Routy and others investigated the effect of IL-7 on HIV persistence. Unfortunately, that trial showed that IL-7 was of no benefit.

The CTN supports a wide range of HIV cure-related studies and our researchers are involved in many projects that contribute knowledge to this area. Beyond the CTN there are many important cure studies and clinical trials going on in Canada. CANFAR has funded research by Dr. Sadhna Joshi (University of Toronto) to further develop strategies to prevent HIV from entering the immune cells. Drs. Lisa Barrett, Sharon Oldford, Nate Stepner, and Marina Turner at Dalhousie University are part of the EpiStem collaborative project. This group seeks to guide and investigate the potential for HIV cure in HIV-infected patients who need stem cells transplantations. Dr. Zabrina Brumme (Simon Fraser University) is the principal investigator of a CIHR-funded international collaboration to synthesize knowledge about HIV, genetics, and viral behaviour with the ultimate goal of developing an HIV vaccine. These are just a few of examples showing the breadth of HIV cure-related research happening in Canada. As the dedicated group of scientists, community members, and policy makers progress towards tackling the unsolved areas of HIV, the CTN strives to continue its significant contribution and collaborative effort in clinical research, both in Canada and around the world.

HIV cure research is continuously seeing momentum with new research, discussion and debate happening. Check out this document from AVAC that shares the most up-to-date community-preferred terminology related to cure research to help those presenting new research or sharing information with lay audiences. Terminology was reviewed by global community stakeholders.