The Future of Antiretroviral Therapy (ART) in HIV

As the final symposium of the Conference on Retroviruses and Opportunistic Infections (CROI) begins, and after hearing about all of the new research predominantly in HIV over the last 4 days, it’s hard not to wonder where it’s all pointing. Fortunately, one of the final symposia sought to provide an answer - ART: The Next 25 Years.

The general themes discussed at the conference would be to say that in general, we are doing quite well with controlling incidence of HIV in MSM in the developed world, the caveat being hot-spots of predominantly Black and Latinx men, or White guys who inject drugs. We’re not doing so well with women in general, particularly in the African setting, and the pregnancy/post-partum complex is perhaps more ominous that we’d initially thought. All of this is constructive, however, and allows us to check the temperature, so to speak, and re-evaluate our approaches to HIV management. 

View the Presentations: Chloe Orkin | Daniel R Kuritzkes | Helena Rabie | Tendani Gaolathe

Dr Chloe Orkin of the NHS wants us to ask ourselves what roles we can play in the next 25 years of implementing antiretrovirals. A good question, given that everyone has a potential role to play, whether it’s developing new drugs, monitoring adherence in South African trial participants, performing better screening of sexual and mental health, developing better clinical recall systems or implementing more effective social supports.

Dr Orkin says we should really look at the efficacy of our first line treatment with antiretrovirals and really pin-down the basics: to ensure treatment is safe and well tolerated by patients, to reduce the exposure to ART, and know when to start treatment.

One of the ways we could ensure treatment is safe and well tolerated is to perhaps shift the way we monitor for adverse outcomes in studies. Some studies have even experienced significant attrition from participants as a result of toxicity and poor tolerability. An example of one is the ACTG 5257 study which drove efficacy for raltegravir simply because more people could tolerate it and remained in that leg of the trial. Whilst most studies wait for toxicity to manifest or for participants to discontinue due to poor tolerability, the GS-104/111 study actively looked into the issue, which is more of what we need, says Dr Orkin. Aware of issues with NRTI backbone regimes, the investigators of GS-104/111 combined the backbone with Tenofovir Alafenamide (TAF) and proved that the combination eliminated both renal and bone-density related adverse outcomes. It’s about making the regimes more sophisticated with the ultimate endpoint of increased adherence. Locally, we have seen moves like this when overnight hundreds if not thousands of patients were switched from their regimes to Genvoya, which switched the aged Tenofovir disoproxil fumarate (TDF) for it’s newer verision TAF because of it’s improved safety and tolerability profile.

Another way we could improve the delivery of ART was highlighted in the LATTE-2 trial, where participants indicated they would like the option to receive ART administered through different modalities, such as long acting injectibles or orals. This makes sense, given the success of using long-acting reversible contraceptives (LARCs). Adherence could be improved if it were possible to self-administer these medications, similarly to how we see patients using Bydureon once a week through subcutaneous injection for diabetes mellitus. Dr Orkin says implantable long-acting antiretrovirals could also be considered.

All of these modalities could be considered for trials, and this presents a key opportunity to address some of the major limitations with clinical trials in HIV - they are mostly looking at a very homogenous population - young to middle aged MSM. Dr Orkin says we need to start including some diversity in trial cohorts, and this makes sense because ART is used to treat women, older people, trans and non-binary individuals, as well as people from different ethnic backgrounds and those co-infected with hepatitis B and C.

Dr Daniel Kuritzkes echoed Dr Orkin in saying that this diverse community of people need more options, and several clinical trials are planned to examine new ways of treating HIV. The latest frontier in ART appears to be similar to those in many other areas of medicine currently - the biologics, or in ART terms - broadly-neutralising antibodies (bNAbs). These are human monoclonal antibodies that target the viral envelope and enhance complement-mediated lysis, amongst other immunological actions. They can be genetically engineered to broaden their application with different HIV isolates and to have a longer half-time.

Potentially, these agents could have significant benefit for users, such as less frequent dosing than current oral regimes, no cross-resistance with existing oral agents, and overcoming adherence issues. These agents - in different forms - are already broadly in use in other areas of medicine, and this is only increasing.

Simian models have shown that dual-antibody therapy is indistinguishable in efficacy from oral ART in treating Simian Immunodeficiency Virus (SIV), the cousin virus to HIV. 2 large phase II efficacy trials are currently running for the use of bNAbs as PrEP, one of which is being performed in 1,500 African women.

What are the challenges of studying and implementing these agents? The trials themselves present a hurdle - given the vast number of combinations that are possible it is quite difficult to choose which to study in combination. There’s also the issue of dosing - as the majority of research exists within the simian model can we really apply the same dosing rules to human trials? There is also the potential for adverse effects, especially with the synthetic bNAbs, as these have a tendency to be immunogenic in general. 

Whatever the challenges, it seems well worth our resources studying the efficacy of this new category of ART in the hopes that we can use it to challenge issues of access and adherence and pull down the walls separating us from widespread and successful HIV management in the future.