The future of long-acting formulations for HIV – an interview with Jose Arribas

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Currently we have 11 combinations of antiretrovirals that can be given as single, once-daily pills for the treatment of HIV; so why is this tolerable, simple regimen not enough?

In this interview we talk to Jose Arribas (La Paz Hospital, Madrid, Spain) about the challenges facing antiretroviral treatments and the future of long-acting formulations for HIV. What new drugs might we have for this disease in the coming years? Read our interview to find out more.

First, could you introduce yourself and give a brief summary your career to date?

My name is Jose Arribas, I’m a Head of the Infectious Diseases Unit and Research Director of HIV and Infectious Diseases at La Paz Hospital, and an Associate Professor of Medicine at Autonoma University School of Medicine (Madrid, Spain). I’ve been working on HIV for many, many years and my interests include in antiretroviral therapy, development of new antiretrovirals and aging with HIV.

What are the issues with current antiretroviral treatments for HIV?

With current antiretroviral therapy I think we’ve reached the limit of what we can do with oral formulations – we have great drug regimens that are extremely efficacious, very simple to give and we have seen that these are very resilient to resistance. In terms of oral formulation, I think there is little room for improvement, but with long-term treatment there are questions around whether we can simplify this regimen even more, and that’s the attraction for long-acting formulations for HIV.

Long-acting formulations would not only require less frequent administration, but also with regards to simplification many researchers are looking at whether we can use less than three drugs for the treatment of HIV. Lots of the long-acting formulations currently being developed are two drugs regimens, thus feeding into this aim for simplified treatment.

In addition, we shouldn’t underestimate the challenges around health privacy and stigma with current antiretroviral therapy – many individuals feel a stigma around taking a pill to treat HIV every day – and long-acting formulations could combat this. There are also issues with adherence to a daily pill, particularly in certain populations, and long-acting formulations could also give us new options for pre-exposure prophylaxis (PrEP). Finally, long-acting options for other drugs, such as implant options for contraception, have suggested long-acting therapeutics are successful and acceptable.

Are there currently any long-acting formulations for HIV in the clinical pipeline you feel particularly optimistic about?

First, we have the US FDA approval for ibalizumab – a monoclonal antibody that needs to be administered every 2 weeks in combination with other HIV drugs. For me this is a niche drug for patients with drug resistance and it is also expensive, so I don’t see ibalizumab in general clinical use but it’s a very important drug for patients who need it – it’s very efficacious and it has not cross- resistance with current drugs.

What is coming, and what I think we need, is cabotegravir and rilpivirine, which can be dosed every 4 weeks. We’ve seen data from the Phase III trials for this combination, and I think that data it is quite convincing. The ATLAS study and the FLAIR study have demonstrated the non-inferiority of cabotegravir and rilpivirine compared with the standard-of-care, and have also demonstrated high efficacy rates for this long-acting formulation in virologically suppressed HIV-1 infected individuals. These drugs are not perfect but I think this is the combination that we’ll need to use in clinic and make decisions about how to use them when they are approved. I think the Phase III data will prove meaningful for approval and we should see this very soon.

Overall, I feel that we are just at the beginning off the long-acting antiviral era and there will be much more to come.

What are the main challenges currently facing bringing long-acting formulations for HIV to the market?

For long-acting agents there are questions around long-term tolerability and the fact that they can’t be self-administered – thus there will be the need for increased clinic visits every month, which will put more pressure on healthcare services. Finally, their long terminal half-life is an issue as the long ‘tail’ of drug remaining in the body increases the risk of resistance arising, so we need to find some way to manage that.

You mentioned long-acting formulations for PrEP, could you expand on that?

Well for PrEP we have a very efficacious regimen, and we’ve seen positive data on its implementation – there is interest in many parts of the world who are thinking of taking this up. However, there are places where even taking drugs to prevent HIV is associated with stigma, so I think that if we have drugs that can be administered very infrequently this like cabotegravir, which can be taken every few weeks – it might not be perfect because of issues with long-term tolerability and increased clinic needs – but this could help.

There are two huge trials going on and I think we will have to wait for those results, again the issue is the long tail of drugs in the body that could give rise to resistance. I am coming from a country that is yet to have PrEP so I don’t have a lot of experience with it, but I think there’s a lot of interest worldwide.

Do you feel with the advent of pre-exposure prophylaxis this is still a large area of need? Is prevention better than cure?

Well I look with envy on London and on other cities that are really making progress in the reduction of HIV infection. In Spain, we have plateaued and stopped decreasing the number of infections per year. I don’t think that PrEP is a magic bullet, but if we treat everybody, if we treat people very soon after diagnosis and if we use treatment as a prevention, it could work. However, I think that in lots of countries PrEP is a long way off.

Do you have any other comments you’d like to add?

Just to stress that this is the first-generation of long-acting formulations for HIV, we are at the beginning of an era and there will be very interesting drugs coming down the pipeline!

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