Dr Jesper D Gunst, PhD, Dr Thomas A. Rasmussen, PhD, Associate Professor, and Dr Ole S. Søgaard, PhD
Broadly neutralizing antibodies (bNABs) as a component of an HIV cure: results from the TITAN study
Drs Jesper D. Gunst PhD, Thomas A. Rasmussen PhD and Ole S. Søgaard PhD of Aarhus University Hospital, Denmark share the results of the TITAN study exploring bNABs towards an HIV cure with NAPWHA, ahead of publication in Nature Magazine on the 11th of September. The TITAN study is the first HIV cure study of its kind undertaken in Australia.
The current standard treatment for HIV is combination antiretroviral therapy, usually called treatment. Life-long treatment is needed to avoid disease progression, maintain undetectable viral load (VL), and to prevent forward transmission of HIV. Cure-related interventional studies investigate therapies that could potentially control HIV without the need to take treatment.
The TITAN study followed 46 people with HIV on treatment with undetectable viral loads. They were randomized into one of four treatment groups. The study was placebo-controlled and double-blinded meaning that some groups received placebo instead of active study drug, and neither the participants nor study personnel knew who received placebo or active study drug.
The study drugs were:
- Lefitolimod, a Latency Reversing Agent (LRI), that was given weekly for eight weeks.
- A combination of two broadly neutralizing antibodies (bNABs), teropavimab and zinlirvimab, that were given at weeks 3 and 6.
The four study groups were:
| Group 1 | placebo (instead of lefitolimod) | + | placebo (instead of bNABs) |
| Group 2 | lefitolimod (active drug) | + | placebo (instead of bNABs) |
| Group 3 | placebo (instead of lefitolimod) | + | bNABs (active antibodies) |
| Group 4 | lefitolimod (active drug) | + | bNABs (active antibodies) |
A closely monitored 25-week treatment interruption period was started the day after the third dose of letifolimod (or placebo for lefitolimod) and the day after the first dose of bNABs (or placebo for bNABs) were given. In HIV cure research, a treatment interruption period is called an Analytical Treatment Interruption (ATI).
The study wanted to know if giving lefitolimod and two bNABs together would work better if given when treatment was interrupted, and how long the immune system could continue to control HIV without treatment.
In Group 1 (placebo + placebo) participants became detectable on average at 4.5 weeks after stopping treatment.
In Group 2 (lefitolimod + placebo) participants became detectable on average at 5 weeks. One individual in this group had partial treatment free virologic control with a VL ranging from less than 20 copies to 5,500 copies continuously through the 25-week ATI.
In Group 3 (placebo + bNABs) participants became detectable on average at 17 weeks. However, four of 11 participants (36%) remained undetectable continuously throughout the 25-week ATI, with two of these individuals having partial treatment-free virologic control with VL (from <20 – 70,000 copies), and the other two of these four individuals maintained an undetectable VL.
In Group 4 (lefitolimod + bNABs) participants became detectable on average at 14 weeks. One individual had partial treatment-free virologic control with VL (from <20 to 65,100 copies) throughout the ATI. One participant was reported to have taken treatment during the ATI, however all six individuals in this group tested negative for any HIV treatment in blood tests at week 25 of the ATI.
What were the results?
While there was no difference in time to viral rebound between the lefitolimod/placebo group and the placebo/placebo group, viral rebound occurred significantly later in both bNABs groups. This is consistent with other studies using the same bNABs. There was no difference in time to viral rebound between the two bNABs groups. In all groups both lefitolimod and the bNABs were well tolerated with mild injection site reactions (redness) being the main side effect reported.
These findings demonstrate that compared to placebo, combining two bNABs significantly delayed viral rebound, and was associated with partial or complete treatment-free virologic control in some but not all participants. Lefitolimod did not impact the time to loss of virologic control during ATIs in any group.
Size of the HIV-1 reservoir in CD4 T cells
The size of the HIV-1 reservoir can be estimated using several laboratory tests. The study used tests that measure the level of HIV in CD4 cells. Six weeks after starting the ATI, the level of HIV in CD4 cells increased in the placebo/placebo and lefitolimod/placebo groups. In contrast the level of HIV in CD4 cells among the two antibody groups did not increase during this period, suggesting that the bNABs were holding the HIV reservoir in check during the ATIs.
Virus-specific CD8 T cell response
The study also measured ‘virus specific CD8 T cells’ * as a marker of the immune response against viral rebound. The virus-specific (VS) CD8 T cell response increased during the first 6 weeks of ATI in all four treatment groups. The VS CD8 T cell responses were elevated with increasing VL during ATI. We hoped that the bNABs would have helped the participants immune systems to control HIV, but we did not observe an increase in their VS CD8 T cell responses among participants that were given bNABs. Such a response is known as a vaccinal effect of the bNABs.
The bottom line – bNABs as an HIV cure?
While there was no added benefit of combining lefitolimod with bNABs compared to bNABs alone, this was the first placebo-controlled, double-blinded trial to show prolonged ART-free virologic control during ATI in individuals receiving just two doses of bNABs. These findings provide further support for investigating bNABs as a component of HIV cure-related interventions.
There are many other studies investigating many bNABs, in efforts toward finding a cure for HIV. Watch this space for more updates.
Ends.
Definitions
Broadly neutralising antibodies (bNAbs) are a type of antibody that can recognise and block the entry of a broad range of different strains of HIV into healthy cells. Research indicates that bNAbs may also activate other immune cells to help destroy HIV-infected cells. There are many different bNABs that are being studied, alone and in combination with other bNABs and/or cure strategies.
HIV antibodies are disease-fighting proteins that your immune system makes when you have an HIV infection. In most people the immune system cannot generate an effective consistent antibody response to HIV. Research indicate that bNABs may be able to help the immune system to maintain a continuous and effective response to HIV, further research is underway.
Cure-related interventional studies investigate a range of interventions including monoclonal antibodies, vaccines, and personalised therapies to search for a cure for HIV.
A virus-specific CD8 T cell response is the ability of CD8 T-cells to recognize and destroy other cells containing HIV.
Analytical treatment interruption (ATI) – an HIV cure study strategy involving taking a planned treatment break under pre‐specified conditions, in a supervised and closely monitored clinical setting.
The authors
Dr Jesper D Gunst, PhD, Dr Thomas A. Rasmussen, PhD, Associate Professor, and Dr Ole S. Søgaard, PhD, professor have all worked on several HIV-1 cure-related interventional clinical trials. All work at the Department of Clinical Medicine, Aarhus University and Department of Infectious Diseases, Aarhus University Hospital, Denmark. Thomas A. Rasmussen is also affiliated to Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infections and Immunity, Melbourne, Australia.
