Activity Transcript

David Back, PhD: Hello. I'm David Back, Emeritus Professor of Pharmacology at Liverpool University in the UK, and I'm delighted to welcome you to this educational program. It's entitled, "Demystifying Drug-Drug Interactions in Today's People Living with HIV." This is part of a series of Curbside Consults on a range of topics. And the goal of this specific program is to improve knowledge of drug-drug interactions in people who will often have comorbidities and a high prevalence of polypharmacy or will be at risk of specific drug interactions. And I'm delighted today to be joined by my friend and colleague, Esteban Martinez, who is Associate Professor of Medicine at the University of Barcelona. Esteban, you're very welcome.

Esteban Martinez, MD, PhD: Thank you, David. My pleasure.

Professor Back: Now, the goal of our discussion and the direction of our discussion is going to be to look at drug interactions in people living with HIV, particularly, initially, the aging population with comorbidities and polypharmacy. Then we'll look at the clinical implications of drug interactions, with a focus on management of the antiretrovirals and the co-medications. We'll do this in relation to a couple of clinical cases, which I think will illustrate this point extremely well. It will bring out the risk of drug interactions and the challenges. Then, we'll look briefly at available tools and long-acting antivirals in the future.

I think we're aware that, as we look at today's issue of antiretroviral therapy, there is the prevalence of comorbidities and polypharmacy in an aging population of HIV. Here are just 4 studies from the US NA-ACCORD, Dat'Aids from France, GEPPO from Italy, and EuroSIDA, in which there's been this documentation of comorbidities. I wonder, Esteban, if you could just give us a broad brushstroke of the demographics of your current population and how things have been changing maybe, over the last few years?

Dr Martinez: Yes, absolutely Dave. As a result of the success of antiretroviral therapy, people living with HIV is living longer fortunately, and the age of the cohorts have been increasing steadily. In the ACCORD cohort, the median age is about 50 years, and for those over 50 years, more than half of them have comorbidities. This is the picture.

Professor Back: Thank you. I think when we think about that, and we recognize that we do have these comorbidities, then we have to think of polypharmacy. This was a really interesting study, I think, which highlighted that in different age groups you see polypharmacy. We define polypharmacy, normally, as greater than 5 co-meds, and many patients are taking more than 5 co-meds. On this particular slide, if you look at the younger age group, for example, 18 to 29, you can see that the prevalence of comorbidities, it's certainly greater in the HIV positive, which is the brown bar, vs HIV negative from cross-sectional data from Madrid.

But as you get older, you can see this increase in both groups of polypharmacy. But as you get older and older, then there's a convergence, also. So by the time patients are over 75, then there's no statistical difference. I think it illustrates very well this issue of polypharmacy. But it's not just the number of drugs. It's also specific drugs that are clearly important. Esteban, you've got a couple of really important cases for us to just delve into.

Dr Martinez: I would like to present the case of a woman who had these problems of interactions between antiretroviral therapy and commonly prescribed drugs. She was a woman, 55 years. She was diagnosed in 2015, because her husband had been diagnosed with Pneumocystis jirovecii pneumonia and later found HIV positive. Although the woman was performing well on HIV diagnosis, she was a late diagnosis with a CD4 cell count lower than 200 per milliliter and also with a viral load of 200,000 copies per milliliter.

Genotypic resistance test showed a 103N mutation, and, therefore, she was resistant to non-nucleosides. For that reason, she was prescribed darunavir/ritonavir plus TDF/FTC. She had no other concomitant drugs or illnesses. She was doing well. She was holding a healthy lifestyle, and she was also normal concerning weight.

And when she was diagnosed with HIV, she was performed, by protocol, densitometry, and she was found to have osteoporosis with no indication for pharmacological therapy. With antiretroviral therapy, she initially went well. Good tolerability led to good biological and immunological responses. However, after time, with a non-scheduled visit, she had an urgent consultation. She presented with acute back pain and, along with this, other symptoms, such as proximal muscle weakness, facial edema, truncal enlargement, mood change, and oropharyngeal candidiasis. The patient was looking ill. Also, blood tests showed raised glucose in plasma and also lymphocytosis with relative lymphopenia, decreased CD4 and CD8 counts, although her viral load was quite suppressed. She was at that time performed a magnetic resonance image. She was diagnosed with vertebral fracture in the lumbar spine, as you can see here.

Professor Back: Yeah, thanks, Esteban. And I think this is one of the most critical areas that we come across and some of the most risky drug interactions. You've got a lady who's 55, she's on a boosted regimen, and she has been receiving, from another doctor, or the osteopath in this case, triamcinolone.

You can look at the interactions between a range of different corticosteroids and boosted protease inhibitors. And the red means contraindicated or not recommended, whereas the orange means a potential interaction. So these are, in a sense, risky drugs in the context of a booster, particularly triamcinolone. And this is intra-articular or periarticular or intramuscular or subdermal routes of administration of this drug. But notice, it's inhaled fluticasone and inhaled budesonide, for example, which are also problems. So steroids generally are difficult with boosters. There's only really beclomethasone as an inhaled steroid where we have this nice green color, no interaction expected, which is what we want.

Things are different if you have an integrase inhibitor, because with the later drugs bictegravir, dolutegravir, raltegravir, it's virtually all green, no interaction expected. So it really is in the context of a booster, that we're worried about this. And there was a really interesting study from France just a few months ago, which showed the cost implications of someone having a boosted regimen with a corticosteroid and having Cushing's syndrome or osteoporosis. The cost implication was around 3000 euros for hospitalization. So this isn't just a theoretical interaction. This is actually a practical interaction with cost implications for the hospital as well.

Dr Martinez: Yeah, you're right. You're completely right. And I think because of the profusion of a prescription of corticosteroids in so many ways of delivery by doctors other than HIV physicians... We have to be very aware of these potential drug-drug interaction.

So the second case is about a younger patient. She was a transgender woman, and the transgender HIV population is an increasingly seen population at the HIV clinics, despite transgender issues are complex and not well reflected in guidelines. She was diagnosed in Colombia, and we do not know many things about her past medical history. But she was receiving therapy with TDF/FTC plus nevirapine. She had not tolerated efavirenz due to neuropsychological problems. She was a sex worker and had started sporadic hormonal therapy in previous years without any medical control. However, early this year, she had a sex change intervention and had been put on continuous hormonal therapy with estrogens.

She came to our clinic for the first time in February 2020. And at that time she was doing well with an undetectable viral load with CD4 cell count that was reasonably preserved. However, in the next visit, there was a pathological failure with a viral load of 5,000 copies per mL. When we studied about the possibility of genotypic resistance, we found several mutations involving nucleosides and non-nucleosides. And she admitted at this time that she'd had a suboptimal adherence to antiretroviral therapy due to concerns of interference with hormonal effects.

This situation is well collated in some publications, such as this one, in which transgender women treated with hormonal therapy sometimes find it very conflictive to continue antiretroviral therapy, due to real or subjective concerns of toxicity or lack of efficacy with this drugs.

Professor Back: So this is a really important topic because there are, as you say, so many different estrogen preparations and so many androgen blocking preparations. Many of the transgender women will be taking both estrogen and an androgen blocker, and the transgender men will be taking other hormones. So it really is important that we get an understanding, and there are a number of drug interactions, which it's really too much to go into in detail, but the table, which is on the Liverpool website and also in the IAS Guidelines, for example, highlights some of those cases. I mean, she was on a nevirapine base; nevirapine is an enzyme inducer and is likely to have an impact on the estradiol if she was on estradiol, so the estrogen exposure is going to be less, and her concern, clearly, is that the hormone is affected. So she was probably not taking it, as you say, because of adherence issues, her antiretroviral therapy regularly.

And this becomes a real problem in the paper in the previous discussion, highlighted that really, really well, that probably half of those patients in that study, were not taking either their antiretroviral therapy or that hormone replacement therapy or both. And so this does become critical. So just to be aware of the interactions that can take place, but not only the interactions, the implications for adherence therapy as well. But it's not just PK, is it, Esteban? Maybe you could just briefly tell us about the cardiovascular issues?

Dr Martinez: Yes, absolutely. As you know, Dave, HIV-infected patients already have a higher risk for cardiovascular disease, despite biological control. So, both in transgender woman and also in transgender men, hormonal therapies may increase cardiovascular toxicity by giving abnormal lipids, also having a propensity for hypercoagulation and also other cardiovascular issues. So yes, that's very important, not only the interaction itself, but the potential toxicity of these drugs, if taken without any control.

Coming to this point, I would like to ask you Dave, "When are you interactions of concern? Because sometimes they may be theoretical, some others they may be important. When are they of concern?"

Professor Back: Yeah. So, I think it's really when the co-administration of the antiretroviral and a co-medication leads to safety, efficacy, tolerability issues greater than when the drugs are given alone. And you're right. We do relatively few drug interaction studies, and given the number of co-medications that our patients can be on, then, we're making often some inference about whether an interaction is going to be clinically relevant. One of the things that we do... we have a Liverpool resource, an interaction checker, is that we do try to get the evidence for a drug-drug interaction.

And I think what's interesting is, when you look across the board for all the different antiretrovirals that we have now, and clearly we have a lot of potential choice of antiretrovirals. And if we classify them according to whether they're more risky... the way that we classify in the Liverpool website, if it's green, there's no interaction. And just a snapshot of these pie charts show that the boosted antiretrovirals only have about 50% of co-meds being green, similarly with efavirenz and etravirine and nevirapine. But dolutegravir, bictegravir and raltegravir, the integrase inhibitors, have far less risk of drug interaction; there's far more greens. And this is because of the way the body handles these drugs.

Now that's not to say that bictegravir, dolutegravir, the newer integrase inhibitors, are without interactions. They're not. And just to highlight 2 different types of interactions... so, for example, dolutegravir and bictegravir can increase the anti-diabetic drug metformin exposure, through an interaction in the kidney. And the integrase inhibitor here is the perpetrator; it causes the interaction. But they're not the same; dolutegravir is greater than bictegravir. Elvitegravir is expected to be the same, but raltegravir has no effect.

On the other hand, a drug like rifampicin in TB therapy is really important. Rifampicin has an interaction by increasing the metabolism. And in this case, it increases the metabolism of bictegravir, much greater than dolutegravir for example, or raltegravir.

And we can overcome the interaction with dolutegravir by doubling the dose to 50 milligrams twice daily, whereas you can't do that with bictegravir. So you have these different magnitudes of interaction, even with integrase inhibitors.

And as we move towards 2 drug regimens, just really to highlight the point here, and it doesn't matter in a sense of what the drugs are, in the co-meds. But if you compare the 2-drug regimen of dolutegravir-3TC with dolutegravir-rilpivirine, then rilpivirine is far more risky, and you have these contraindications, whereas you don't have that for dolutegravir-3TC. So there are differences in 2-drug regimens.

So a key message, I think, for clinicians, and we've seen as we've gone through this presentation, that there's a risk of the booster to cause interactions. The integrase inhibitors non-boosted have massively changed the landscape of DDIs, and there are relatively few clinically relevant interactions. But I think it's always necessary to use a drug interaction checker to avoid inappropriate use, and constantly we have new drugs. So for example, fostemsavir has recently been approved in the US, so that's going to be another drug that we have to get our heads around. And it's necessary, particularly in elderly patients, to look at periodic reviews of the medications.

But as we go forward, Esteban, we're going to be having other kinds of drugs as well, so long-acting. Can you just give us a brief idea of where this field is moving?

Dr Martinez: Long-acting antiretroviral therapy will be a major step in treating HIV. It will change, in a huge manner, the way of receiving antiretroviral therapy, because it has to be indefinitely taken. Some patients may experience fatigue, or some others may experience stigma with oral therapies, and long-acting therapy may ease therapy for these patients. Cabotegravir and rilpivirine have been approved in some countries and are in the process of approval.

However, despite the advantages, there will be also some unknowns. And one of these unknowns may be the pharmacokinetics because of the long half-life and the long interval of dose. The residual plasma concentration may put the patient at risk, of either toxicity or lack of efficacy if there are interactions or interruption of the medication. And I would like to ask David what we know about the profile of oral cabotegravir, oral rilpivirine, and also long-acting formulation of these drugs.

Professor Back: Thanks, Esteban. I think this is an important issue and one that we're learning as we go along. We actually have very little study data on the long-acting cabotegravir/rilpivirine. So we're inferring a lot of what we think will happen with drug interactions from the oral cabotegravir and oral rilpivirine data. But contrary to what I think some people may think, there will be some drug interactions that we'll have to consider, particularly with enzyme inducers, which will lower the exposure of the drugs.

And you're right. The pharmacokinetic tale is one specifically for drug interactions. So I think we have a lot of challenges ahead of us. And, in summary, when we look at what we have now in terms of antiretroviral therapy where we're going, we have to recognize multimorbidity; we have to recognize polypharmacy, also polydoctory or different prescribers, and the potential, then, for drug interactions to lead to reduced efficacy of either the HIV agent or the co-medication or potential adverse effects. And we've discussed a little bit about the cost implications of getting things wrong. So this is an important topic. It's not going to go away and it's been really good to be able to discuss with you Esteban.

Professor Back: Thanks very much. And I'd like to thank people for listening and participating in this activity. Thank you.

This is a verbatim transcript and has not been copyedited.