Listen to learn the fundamentals on specialized agents for treatment-experienced people living with HIV and to learn how you can leverage these agents’ unique attributes to devise effective antiretroviral treatment strategies.
Tune in as Dr George Behrenspresents the fundamentals on specialized agents for treatment-experienced people living with HIV.
Topics covered include:
Presenters:
Georg Behrens, MD
Professor of Immunology
Senior Consultant
Department of Rheumatology and Immunology
Hannover Medical School, Germany
Hannover, Germany
Link to full program:
https://bit.ly/4oiYxEx
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Introduction
Dr. George Behrens (Hannover Medical School): My name is George Behrens, and I am Professor of Immunology and the Senior Consultant in the Department of Rheumatology and Immunology at Hannover Medical School in Hannover, Germany.
This is part two of a four-part program, HIV Care for Treatment Experienced People: Optimizing ART and Improving Outcomes. And of course, I invite you to view the other medical minutes and the accompanying slide sets for this program on the Clinical Care Options website.
This program is supported by an educational grant from ViiV.
Treatment Goals for Treatment-Experienced Patients With Multidrug Resistance
So if we look and treat patients which have multiple pretreatments or in a heavily treatment experience, there is two major conditions that we need to separate and to deal with. Either we've got a situation of a virological failure, or if patients are virological suppressed but have multiple pretreatments, we need to consider any change of treatment.
So in a virological failure condition, clearly the primary goal is to re-establish virological suppression and control. And the second goal, of course, is to allow and enable immune recovery and to get people out of a risky area of low CD4 cell counts.
If we switch for whatever reason, for instance, to mitigate adverse event drug-drug interactions or other issues, we always need to consider that we need to maintain viral suppression without limiting any further future options. We need to consider the pre-treatment history in these patients.
DHHS: Selection of ARVs in Virologic Failure
So how do we do this? Key point that we need to avoid is to just add a single drug to a failing regimen. We should always avoid doing this. Whenever we react and respond to a failing regimen, we should aim for adding two fully active antiretrovirals and at least one, but both of them should have a high resistance barrier.
And if at all possible, we should always aim for including three fully active antiretrovirals, if none of them has a high resistance barrier.
And another key point to consider is whenever possible, particularly in heavily treatment experienced patients to use and consider drugs with novel mechanisms of actions because that enables us to have a fully antiviral activity established.
DHHS: Selection of Switch ARVs if Virologically Suppressed
I said before, there is guidelines and also DHHS guidelines highlight it's the key treatment goal, maintain virological suppression. And before we change anything in a treatment regimen that's still active and efficient, we need in people with lots of pre-treatment to look for the past treatment associated toxicity and intolerances. And very important to have an overview about all resistant test results, because everything that has happened in the past in terms of resistance mutation development can be relevant for the future.
It's not just the last resistance test, but it's every resistance test. Every mutation that ever occurred has the potential to cause damage to future treatments.
Key Targets of Specialized HIV Drugs: HIV Entry and HIV Capsid
In terms of selecting novel drugs or drugs with novel actions. An attachment inhibitor can interfere with gp120 on HIV on the virus and prevent the interaction to CD4. It can also be a post attachment inhibitor, which prevents the binding to the co-receptor on the host cell.
And the capsid inhibitor is yet another function and mode of action. It interferes on various levels and prevents the virus from entering the nucleus, and prevents new viral productions by interfering with viral re-assemble.
Fostemsavir
So fostemsavir is a prodrug of temsavir and one of the key drugs for people with heavy or various pretreatments.
Key Targets of Specialized HIV Drugs: Fostemsavir Mechanism of Action
And this falls into the group of the attachment inhibitors. It's a prodrug, and it inhibits gp120 from binding to CD4.
BRIGHTE: Fostemsavir in Heavily Treatment–Experienced Adults
So what are the data supporting the use of these drug? In a large study, the BRIGHTE study, fostemsavir was implemented in regimens and patients recruited for this trial which had various pretreatments and multiple resistance mutations. There were only one to two remaining antiretroviral classes available, and it was otherwise not possible to construct a viable regimen with the remaining agents.
Patients were randomized to either receive fostemsavir twice daily remaining on the failing regimens for a short time just eight days, or receiving placebo. This phase is kept very short in order to show what is the single drug fostemsavir able to achieve in terms of viral reduction. We see already that the viral - viral load was reduced by about 0.8 logs in - during this early treatment phase.
And then there was a follow-up of an open-label treatment with an optimized backbone where more active drugs were added. There was also a non-randomized cohort, which even had more advanced and more complex resistance mutations in the patients that were included here.
BRIGHTE: Baseline ARV Exposure and Resistance
So how was the pre-treatment and the treatment experience in these cohorts?
Many of the other treatment classes and drug classes had been used before and had only limited options. BRIGHTE : Virologic Response Through Wk 240 in ITT-E Randomized Cohort
But despite all these limitations, that fostemsavir together with the optimized backbone enabled in about 50% and even for a long time, a continuous full virus suppression, as shown here as the proportion of patients with a viral load of less than 40 copies. So that was really remarkable and - and very important.
BRIGHTE: Change in CD4+ Cell Count Through Wk 240
But of course, in these patients we not only look for viral load but also for CD4 cell counts. And interestingly, there was a very good increase in CD4 cell counts, and that was more or less independent of the number of fully active antiretrovirals in the baseline optimized backbone, which means fostemsavir was a major contributor to the overall auto immune response.
Overall, so you see very good CD4 cell recovery and immune reconstitution, even people with very advanced immune deficiency at the beginning of this switch to a new treatment.
BRIGHTE: Safety Through Wk 240
In terms of side effects and adverse events, most drug-related adverse events are related to either nausea, diarrhea, and some other gastrointestinal side effects. Of course, these patients have a slightly higher rate of also treatment-related adverse events and also serious adverse events, which are not necessarily driven by the treatment but by their immunodeficiency and the risk to develop opportunistic diseases and complications.
So overall, fostemsavir was very well tolerated even in this population that heavily pretreatment – with heavy pretreatment and virological failures in the history.
Fostemsavir Drug–Drug Interactions
It's important to consider that fostemsavir has some drug-drug interactions. Hepatitis C, virus antiviral drugs, oral contraceptives, and also the interaction with statins can be relevant where we need to be a bit more careful with the dosing of some of these statins as for medications.
And probably most important to consider is also that there is no drug-drug interaction with any of the anti - other antivirals - retrovirus that we use, which is important and gives us a good chance to consider all other medication that we want to use in the optimized backbone.
Potential Benefits of Anti–HIV-1 gp120 Effects
There is some evidence from studies that have shown that circulating proteins from the virus like gp120 enthuses some unfavorable effects in the immune system and leads to activation of the immune system and disturbed cell function. And it may be that the use of drugs like fostemsavir that neutralizes also free proteins circulating in the blood is a beneficial effect and could also be a contributor to the good CD4 immune reconstitution.
There is even recent data that have shown that people that even are under different treatments achieve no circulating gp120 in their plasma, but they have better CD4 cell counts, less inflammatory markers increased and a bit more favorable and stable immune system. And this might be a reason to consider fostemsavir also in people with advanced disease and virological failure.
Ibalizumab
What about ibalizumab, which is a monoclonal antibody and also an attachment inhibitor.
Key Targets of Specialized HIV Drugs: Ibalizumab Mechanism of Action
Ibalizumab is a post attachment inhibitor, and it does not inhibit gp120 from binding to CD4. But it interferes with this complex, which then inhibits the binding to the host coreceptor, namely here CCR5. And as I said, this is a monoclonal antibody. And it's of course then administered differently to fostemsavir, which was an oral medication.
TMB-301/-311: Ibalizumab in Heavily Treatment–Experienced Adults Living With Multidrug-Resistant HIV
Ibalizumab was also tested and explored in heavily treatment experienced adults with limited treatment options and multidrug resistance. They received a stable ART before but had a detectable viral load of above 1000 copies, which means virological failure.
And these patients received an infusion with ibalizumab on day seven and day zero. And in this early phase, it looked for decline of viral load that was achieved by this monoclonal antibody only after 14 days, then ibalizumab treatment was intensified by adding the optimized backbone regimen and that was then continued.
So these early phase again is just a phase where we look for what can the new drug achieve in terms of viral suppression. And we want to keep this time as short as possible to prevent any resistance mutation, because this is a functional monotherapy.
There was a good decrease in the HIV RNA. With a decrease of more than half of the log. And that was maintained up to week 25. Probably more interesting is the rate of people that achieved the viral suppression of less than 50 copies. Up to 50 to 60% in the long term with this regimen achieved a full virological suppression as a response to the virological failure we've seen before.
Immunologic Outcomes, Effect of OBR Genotypic Susceptibility Score, and Safety
The CD4 cell increase with this combination was slightly less as compared to what we've seen before, on average 42 cells, that could be because of the selection of patients. And again, what we could see is that the genotypic susceptibility score of the optimized backbone regimen was not strongly related and correlated to the immune reconstitution, again arguing that ibalizumab as the new compound also dropping the viral load is an important contributor to the immune reconstitution.
Again, adverse events related to ibalizumab, relatively low percentages with 18%. Sometimes patients developed a mild rash in regard or in response to these infusion of the monoclonal antibody, which in the long-term has to be given every two week. Rarely, these side effects led to withdrawal and interruption of the treatment. And again, of course, all the patient advanced are either to AIDs or AIDS related diseases and other complications just reflecting how sick they also were when they were included into the trial and required to respond to the virological treatment failure.
Lenacapavir
So a last very important compound for heavily treatment experienced patients is Lenacapavir.
Key Targets of Specialized HIV Drugs: Lenacapavir Mechanism of Action
Lenacapavir is a capsid inhibitor, not an entry inhibitor. It does not inhibit entry, but it does inhibit capsid entry into the nucleus, the uncoating of the assembly, so it interferes at different stages of the replication cycle and probably has some synergistic activities through these different mode of action.
CAPELLA: Lenacapavir in People Living With Multidrug-Resistant HIV
Also, lenacapavir was studied in people with multi-drug resistant HIV. The CAPELLA study for the phase II/III trial and consisted also of different cohorts. Patients had detectable viral load of above 400 copies, resistance to at least two agents from three to four main antiretroviral classes, and limited treatment options to construct an effective treatment. And they were randomized into two different arms. And also here we saw smaller non-randomized cohort.
The randomized again received lenacapavir as an oral monotherapy to start with. But the aim of the study was to use lenacapavir as we know it also from prevention trials now, given as subcu injection every six months combined with the optimized backbone regimen.
So again, this oral lead-in phase of about 14 days was for tolerability because of this long half-life time. And to see what is the drug in an isolated administration, together with a failing regimen in the backbone able to achieve in terms of viral suppression.
CAPELLA: Primary Endpoint at Day 15
And lenacapavir did very well. Only two out of 12 in the placebo had a response, and there was a good response in 21 of the 24 that were in this early phase.
It is not only more than half a log, as we've seen before with the other medications also. It was after 15 days about two log decline. So very good antiviral activity of this drug. And then in the follow up, the optimized regimen of course was added in this treatment.
CAPELLA: Efficacy at Wk 156
And that is the reason why the drug and the response here was maintained over time. At week 156 we're still 61.4% at a fully suppressed viral replication.
Very few discontinuation, but there are few lost to follow up. And most patients receive their injections also for the long term within a 14-day schedule.
CAPELLA: Changes in CD4+ Cell Count to Wk 156
And also in terms of immune reconstitution, which is an important surrogate and readout and outcome in this study, did you see that patients that were randomized to receive a lenacapavir, a good immune reconstitution also, it seems like continuous increase over time over this long follow up of over 156 weeks.
And the proportion of people achieving CD4 cell counts above 200, which is an important region where we clearly reduce the risk for opportunistic infection was constantly increasing, just illustrating how important such a combination, if used in the right context, can get these people out of a risky low CD4 region[?].
CAPELLA: Safety at Wk 156
In terms of side effects and adverse events, treatment emerging adverse events are very often diarrhea and nausea. There were a few reports on nodules at the site of the injection, but no specific pattern that was described here. Again, the rate of serious adverse events are always slightly higher as compared to people that have not so advanced disease, have better immune - immune cells and CD4 cell counts to start with.
And we see here that serious adverse events occur slightly more often as we use this to see this in other trials.
Lenacapavir Drug–Drug Interactions
Relevant for lenacapavir is also to consider again some drug-drug interactions. Lenacapavir interferes with the cytochrome 3A system. It also interferes with the GTA system, UGT1A and with the transport system P - the P glycoprotein, where it's mainly a substrate.
Optimal Use of These New Agents
So I think looking back at these three different options of new drugs in different classes, it's very important to consider using these drugs at a timely fashion. We should never wait until all treatment options are used up. You've seen that also these new drugs, which have strong antiviral activity only perform in the concept of good activity coming from the optimized backbone treatment.
For highly treatment experienced persons with HIV, formation of a new regimen of the virological failure may be very challenging. Very much driven by the limited treatment options. And as we've seen also for those that just want to switch, we need to consider various arguments.
The opportunity to use the new drugs in novel classes increases the ability to form these regimens with two fully active compounds, and the availability of multiple new agents allows us to tailor the use of each agent to the patient, taking into account the patient's preferences and characteristics.