Listen as Dr Josep M. Llibre reviews the essentials on ART selection for treatment-experienced people with HIV and comorbidities, including key principles for designing ART regimens for persons with multidrug-resistant HIV and considerations for comorbidities and drug–drug interactions.
In this episode, Dr Josep M. Llibrereviews the essentials on ART selection for treatment-experienced people with HIV and comorbidities.
Topics covered include:
Presenters:
Josep M. Llibre, MD, PhD
Senior Consultant
Infectious Diseases Division
Fight Infections Foundation
University Hospital Germans Trias
Badalona, Barcelona, Spain
Link to full program:
https://bit.ly/4oiYxEx
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Introduction
Dr. Josep Llibre (University Hospital Germans Trias): My name is Josep Maria Llibra, and I am Senior Consultant in the Infectious Disease Division of the University Hospital Germans Trias in Barcelona, Spain.
Remember that this is part three of a four-part program, HIV Care for Treatment-Experienced People: Optimizing Antiretroviral Treatment and Improving Outcomes. I invite you to be with 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 Healthcare.
Let us start with the antiretroviral treatment choice in treatment-experienced people with HIV and comorbidities.
How can anyone get multidrug-resistant HIV when there are so many excellent, amazing antiretroviral treatment options available nowadays? It is not an easy process. It is a long sequence of failures.
First of all, failure of sequential, partially suppressive, older antiretroviral treatment regimens. They started with mono or dual nucleoside reverse transcriptase inhibitors treatment, then first-generation NNRTIs, efavirenz and nevirapine, or unboosted first-generation PIs with a low resistance barrier. Sequential functional monotherapy with newly developed antiretroviral treatments and regimens with low barriers of resistance, typically, as we said, first-generation NNRTIs plus two nucleosides or first-generation PIs plus two nucleosides.
Typically people who you see with multi-drug resistance started treatment in the old days before 2006. This has to be combined with some background factors, typically a bad or an irregular treatment of events. This is based on the complexity or bad tolerability of early regimens in the old days, and very important, severe social problems, including psychiatric diseases or any addiction, typically drugs or alcohol.
It is very important that you treat these situations because otherwise, in your new salvage treatment, they are going to persist and you are going to face again another treatment failure.
These are complex cases, two typical scenarios. The one is long brokers, people who started treatment in the 90s or in 2000 who have very long-lasting HIV infection. The second one is people who acquired HIV infection through mother to child transmission, and they have been facing many virological failures during the childhood and adolescence.
Very importantly, do not forget transmitted drug resistance that can jeopardize all the situation.
People with multidrug-resistance typically have many comorbidities. Actually, you can say that all people with HIV, all our cohorts and all the people you see in your offices, they are aging, they are having more comorbidities, but people with multi-drug resistance typically they are older and they have more comorbidities.
The ARTISTRY 1 study is a phase II/III clinical trial proving the efficacy of a combination of two-drug regimen composed of bictegravir and lenacapavir, a capsid inhibitor. As you know, it proved to have high grades of virological suppression in people with complex regimens, typically because of multi-drug resistance.
In this clinical trial with 128 participants, the median age was 60 years. Remember that in the overall HIV cohort in developed countries, the median age is between 50 and 52 years. People with multidrug-resistance are older. They have a long median duration of HIV infection and treatment, and median duration of HIV treatment of 27 years. They had typically multi-drug resistance with resistance against NRTIs 64%, NNRTIs, 52%, PIs 36%, and as an entry criteria, they could not have integrase resistance.
The reasons for this contact regimen were mainly based on history of resistance or multi-drug resistance. You can see that the comorbidities were common:
The Netherlands HIV cohort have been studying the people with comorbidities. They analyzed people with more than 45 years, and they had the median duration of HIV infection of six years.
Most of them were receiving antiretroviral treatment, and most of them were having virological suppression below 40 copies per ml.
As we said before, the number of comorbidities is significantly higher in people with HIV than in people without HIV. You can see that they had been treated typically with thymidine analogs in the past. Not surprisingly, they had higher levels of c-reactive protein, D-dimer, interleukin-6 and soluble CD14 and CD163, and fatty acid binding protein. These differences between people with and without HIV infection were statistically significant.
They had higher rates of hypertriglyceridemia, and they had also higher rates of hypertension.
Regarding inflammation and the immune activation associated with age-related conditions, typically, HIV and antiretroviral treatment is the most important. Having an HIV infection and having a non-suppressed virological plasma in association with the HIV infection, but also all the co-infections. Typically, hepatitis B and C, chronic hepatitis, tuberculosis, sexually transmitted infections.
It is also related with the gut-associated lymphoid tissue, so with the immune dysfunction or the lymphoid tissue dysfunction. This relates, as you know, very well with the epithelial integrity of the gut and translocation of bacteria through the blood and the HIV persistence.
Many, many lifestyle conditions are associated with persistent inflammation. Typically, the most important ones are smoking, alcohol consumption, and a bad diet and a weight increase. Typically, people with HIV smoke more than the overall population. They have more alcohol consumption, and they have more frequently consumption of drugs or other abuse conditions.
This is associated with many comorbidities, many diseases, and actually this is associated in both senses. So persistent inflammation increases the probability of suffering these comorbidities and all these comorbidities in turn increase persistent inflammation, so cardiovascular disease, all cancers, but typically also non AIDS cancers, diabetes, neurocognitive dysfunction, osteoporosis, frailty associated with aging, chronic kidney or liver diseases, and chronic obstructive pulmonary disease and many others.
All these conditions increase inflammation and chronic inflammation increases the risk of all these conditions in both senses.
What can we do to improve chronic persistent inflammation? It is not easy. We have been trying in the past, many anti-inflammatory treatments. Many immune suppressive treatments, broadly neutralizing antibodies. None of them have found a persistent association with an improvement in the inflammation.
If I had to say that the best is statins. With the REPRIEVE clinical trial, it has been proven that in people with low to moderate cardiovascular risk, the administration of a statin that was pitavastatin reduced the rates of major atherosclerotic cardiovascular events. The reduction was modus, 36%, but it was statistically significant. It has changed all the treatment guidelines of people with HIV.
The outdoor, Steven Grinspoon believed that these statins have an associated anti-inflammatory effect in addition to the lipid lowering effect. If I had to say, which could be the best treatment we can give to people with HIV with persistent inflammation in addition to antiretroviral treatment, probably is statin.
Well, let us go to treating people with multidrug-resistant HIV and comorbidities. What do we pretend with the new regimen?
Obviously, the goal of the new regimen is reestablishing virological suppression. This is the most important thing we can do in this situation, so reestablishing and maintaining virological suppression. Obviously, this is going to prevent HIV transmission, and this is going to be associated with the best normalization possible of the CD4 cell count and the CD4, CD8 ratio.
In people with comorbidities, which are frequent, as we said before, is the best tool we have to reduce inflammation. All the guidelines but particularly the US Department of Health and Human Services guidelines say that virological suppression with antiretroviral treatment is the only and most important recommended strategy to reduce persistent inflammation in this situation.
Two main messages regarding the reduction of inflammation with antiretroviral treatment. The first one comes with the START clinical trial. In this trial, we proved that every person with HIV infection had to be treated with independence of the CD4 cell count or the HIV viral load. All people will have a benefit with antiretroviral treatment.
No longer we have to face a decision who to treat or not to treat. Every people with HIV infection has to be treated. This was associated with an improvement, in this case, of levels of interleukin-6 and D-dimer over five years.
The second one, the earlier initiation of antiretroviral treatment is associated with the reduction of inflammation. This is because the early initiation of treatment is associated with a smaller HIV reservoir. The earlier you start antiretroviral treatment and you achieve virological suppression, the smaller the HIV reservoir. This is associated with lower rates of lower level viremia, blips, virological failure, and also persistent inflammation. Very important. That is why all guidelines recommend to treat everyone, and the sooner the better.
Regarding the general principles to design antiretroviral treatment regimen for people with multidrug-resistant HIV, sometimes with limited treatment options, the recommendation is to construct a salvage regimen or a new regimen with three active drugs.
If you can combine three active drugs, it is better that at least two. The only situation where the guidelines accept only two drugs is if you can combine dolutegravir and darunavir, so the best integrase inhibitor and the best protease inhibitor. But if you have to construct to build a regimen with different drugs, sometimes with intermediate or residual activity, if you can, you must include three active drugs or sum up the equivalent in activity with partially active drugs, which is not easy to estimate.
You have get a precise estimation of the residual activity, as it has been set in other modules having an expert advice is important in this situation.
Obviously, you have to choose the best optimized background regimen with a high barrier of resistance. This is going to be based on a boosted PI, an integrase inhibitor, nucleoside reverse transcriptase inhibitors with a high resistance barrier, which include tenofovir and sometimes an NNRTI, which could be etravirine.
These are the drugs with the highest resistance barrier. The drugs are more likely to retain activity in people with multi-drug resistant HIV, twice daily ritonavir boosted darunavir, twice daily dolutegravir. If you failed an integrase inhibitor in the past, tenofovir usually TAF to avoid bone and kidney toxicity associated with TDF and sometimes non-nucleoside.
The only situation where we are not going to use any of these drugs, if you have full resistance, this means more than 60 points in the Stanford HIV database, or if you have a severe treatment limiting toxicity, then you can choose one or more than one, but usually one new drug with a new mechanism of action and no cross resistance.
These drugs are only approved in people with multidrug-resistance and usually limited treatment options that cannot build or maintain a suppressive regimen. This include fostemsavir, which is given orally twice a day, 600 milligrams; ibalizumab, which is a neutralizing antibody, which is given intravenous every 14 days, 800 milligrams. It can be given by a slow infusion or a quick shot intravenous.
Then you have lenacapavir that is going to be started orally, but which is administered subcutaneously with two subcutaneous injections at the same time with 927 milligrams every six months.
Then we have the investigational drugs, including the nucleoside nucleotide reverse transcriptase inhibitor and translocation inhibitor, which is islatravir, and the broadly neutralizing antibodies with limited data so far and no data specifically in salvage.
Do not forget the CCR5 blockers, the CCR5 antagonist, maraviroc. But if you have a low CD4 cell count in this situation, it is quite unlikely that you are going to maintain a R5 tropic virus.
Where are you going to think in administering one of these drugs? It is quite easy. If you do not have a complete activity of darunavir and dolutegravir. If you do not have a complete activity of both or either darunavir and dolutegravir, you probably need a new drug with a new mechanism of action in your salvage regimen.
The tolerability of all these drugs is good. They do not have specific adverse events, patterns. Obviously adverse events are not typically analyzed in salvage studies because these people receive complex optimized background regimens. They receive not only ibalizumab or lenacapavir, but they also receive a complex regimen with boosted PIs, integrase inhibitor, nucleoside analogs. It is not easy to identify the toxicity specifically associated with these drugs, but we can say that overall the tolerability is good and it is not a limitation in the use of all these drugs.
A key point, particularly in people with multidrug-resistance and comorbidities and old age, is the association of the comorbidities and the problem of drug-drug interactions. This is very specifically related to boosted PIs, because the booster, either ritonavir or cobicstat may drive many drug-drug interactions that they can be treatment-limiting because these people usually receive drugs to treat hyperlipidemia, statins, or other drugs, antiaggregants, antiarrhythmics, some anti-hypertensives. So you can face important drug-drug interactions that can be treatment limited.
In some people, you are going to try to substitute the boosted PI with a different drug to avoid these interactions. This is very important, and you have to monitor this always in people with multidrug-resistance.
The booster is the perpetrator of the drug-drug interactions, and a different situation is lenacapavir, which is metabolized by the CYP3A4. Every inducer or blocker of this CYP3A4 can have a significant traction with lenacapavir, which is not common, but you have to have this in mind in people with lenacapavir.
What happens with the inflammation in people with multidrug-resistance when you start the salvage regimen?
Well, you can see the evolution of the CD4 cell count. You see that persistent CD4 cell increase, which has not plateaued yet at the four years. This is very important, a median increase of 300 cells. Remember that when you overcome the 200 CD4 cell threshold, we consider that like a life-saving threshold. It is very important, this recovery of CD4 cells.
You can see that this is associated with an improvement in CD14. This is the most important improvement we see. Also an improvement in soluble CD163, and it is maintained flat in the D-dimer.
What happens with the immune activation?
You can see the improvement in the CD4/CD8 ratio in relation with the virological suppression. The greatest improvement is seen in people who reach and maintain virological suppression below 40 copies. But also people who have declines in viral load below 400 copies or 1,000 copies also have important improvements in CD4/CD8 ratio. That is because even if you do not reach undetectability, if you have a significant improvement in your vital load, you are going to see an increase not only in CD4 cells, but also in the CD4/CD8 ratio.
The only ones that do not show this are people who maintain more than 1000 copies.
Last but not least, remember that a multidrug-resistance in people with comorbidities and low CD4 cell counts is a life-threatening situation. Do not wait too long to start the salvage treatment because this condition is associated with mortality. This has been analyzed, again, in the BRIGHTE study.
Remember that the non-randomized cohort in the BRIGHTE study were people with no active drugs remaining. In people with no active drugs remaining in the non-randomized cohort, the mortality at one year was 14%. This is extremely high.
In the randomized cohort with one or two maximum active drugs, the mortality was 4%. But this was very well related with the CD4 recovery. People who maintain a CD4 below 20 cells had a mortality of 15%. People who had an increase between 20 and 200 CD4 cells, the mortality was 6%.
People who had a recovery above 200 CD4 cells, the mortality was only 2%.
The mortality in this scenario of people with multidrug-resistance and comorbidities and limited treatment options is high. We do not delay the initiation of the salvage treatments.
Well, this is all. These are my take-home messages. People with HIV and long treatment history and multidrug-resistant, HIV are usually older, have many comorbidities that have an interaction with the virological failure and the antiretroviral treatment salvage.
Recent studies have investigated the role of many ongoing treatments against the inflammation and the development of chronic morbidities in this scenario, and probably as we said before, the control of the cardiovascular disease, the lifestyle conditions, and the administration of statin together with virological suppression with the new treatment is the best we can do to reduce this ongoing inflammation.
When forming a new regimen for multidrug-resistant HIV after a virological failure, the new agents with novel mechanisms of action can be incorporated into the regimen. Not only can, but must be incorporated if you do not have a full activity of either dolutegravir or darunavir.
Obviously, the primary goal of this new regimen is reestablishment of biological repression. As we said, many studies have looked at the reduction of inflammation coupling together with the virological suppression.
Finally, a message of caution. In the interpretation of the evolution of this soluble markers of inflammation in plasma, if they do not show a consistent profile in all the markers, and until further research provides more clarity in this scenario.
Thank you very much for your attention.