El Dr. Anton Pozniak, del Westminster Hospital de Londres, será el segundo ponente de la sesión inaugura del XV Congreso Nacional de GeSIDA. En esta entrevista nos avanza algunos aspectos de su ponencia (Long acting therapy in the horizon) y nos habla también sobre otras cuestiones relacionadas con estas opciones terapéuticas.
What have been the main developments in long-acting treatments in recent years and months?
We have a 2-monthly combination of an integrase inhibitor cabotegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine given intramuscularly.
This regimen has been licensed in Europe in 2020 and is used principally as switch from undetectable treatment.
In August 2022 Lenacapavir was the first capsid inhibitor to be approved as an HIV treatment for multidrug resistant cases as part of a combination that includes other active HIV drugs. It is an extremely long-acting formulation and is given as a subcutaneous injection, every six months.
We are now seeing early data on new compounds, islatravir that had CD4 count issues, pro drugs of lenacapavir, and novel NNRTI and Integrases which are long acting.
What are the main challenges in the development and access to these treatments?
Risk factors for virologic failure when using CAB/RPV are prior RPV resistance mutations, high BMI and Clade A1/6 but not everyone can have these checked before starting the therapy. Measuring viral load every 2 months can be challenging. One study from Africa showed efficacy of this treatment with 6 monthly viral loads, even in those with risk factors.
In general challenges include managing adverse drug reactions without the ability to easily stop therapy, concerns regarding the potential for injection site reactions, and the potential for emergence of viral resistance during protracted periods of sub-therapeutic exposure after therapy discontinuation or missed doses.
Both of these current treatments need health care professional administration which has an impact on resources and organisation in the clinic. Training in managing injection technique and injection site reactions is needed. RPV needs a cold chain.
These drugs remain unavailable or cost-prohibitive across much of the In LIMCs, generic companies will need to provide these therapies at low cost and this requires production by generic companies, three of which have signed voluntary agreements with ViiV.
More data are needed to substantiate efficacy and cost-effectiveness among patients at risk of non-adherence and across age groups, pregnancy, and post partum.
So far no current Long acting therapy would have activity against active Hepatitis B, in comparison to standard oral three drug treatment containing a form of tenofovir.
How are patients receiving these new treatments? Do long-acting treatments really promote good adherence?
Data from people using these medicines suggest high acceptance. Clinicians have begun prescribing the agents successfully in populations who are not able to adhere to oral therapy. A recent study from the USA recruited patients with poor adherence were given financial incentives and social support and had higher rates of remaining undetectable on CAB/RPV compared with those who continued their oral therapy. However we need to see what will happen in the very long term and also such intensive support may not be available in all clinics. We have limited data on those patients who go on CAB/RPV with viraemia although small studies of lenacapavir with oral active drugs have been useful in patients who are highly treatment experienced.
Are they a good option as PrEP or other prevention strategies?
Recent studies have shown that Cabotegravir 2 monthly and lenacapavir 6 monthly are highly effective when taken as PrEP compared with oral PrEP strategies particularly in women. They have the potential to transform the way prevention is delivered.
There are some issues for long acting agents such as detecting those who are seroconverting at the time of considering starting PrEP and diagnosing breakthrough infections which may be difficult and resistance could be a consequence. Managing side effects mainly injection site reactions which occasionally be severe. A new cabotegravir formulation given intramuscularly every 4 months is being developed for PrEP.
A major issue will be access especially in LMICs and Eastern/central Europe and other regions where the epidemic is still uncontrolled.
And finally, as a preview of your presentation, what prospects do we have with long-acting treatments against HIV?
Advances in LA therapies are with new medications, new formulations of existing drugs, new drugs with a longer duration between dosing (weekly, once every month and 2 months and 6 months, and perhaps even annually), and various ways of administration (including intramuscular, subcutaneous, implantable, vaginal, and transdermal patches).
Monoclonal antibodies given 6 monthly by infusion are being explored in combination with Lenacapavir. Trial subjects need to have Clade B virus and have a sensitivity assay performed before starting the MAbs. These limitations may make current approaches with these compounds impracticable.
The future appears to be with a single oral weekly pill containing 2 ARVs which interestingly in surveys of patients was a preferred long acting option if available. There will be at least 3 such regimens moving forward, Islatravir /Lenacapavir is in the most advanced development, Islatravir plus a LA NNRTI and Lenacapavir pro drug with a long acting integrase.