Prescribing for patients on antiretrovirals

The GPs are really the key linchpin between all specialties, and so effective and excellent communication with GPs and specialists is, to be honest, probably one of the most important things.

{Music] Welcome to the Australian Prescriber podcast. The Australian Prescriber, independent, peer-reviewed, and free.

I'm Dhineli Perera, your host for this episode. And it's a pleasure to be speaking to Dr Yasmin Hughes. Yasmin is an advanced trainee in sexual health medicine at the Melbourne Sexual Health Clinic. Yasmin brings us up to speed with understanding the adverse-effect profiles and common drug interactions involved with antiretrovirals. Yasmin, welcome to the program.

Thank you very much for having me. It's a real pleasure to be invited.

Yasmin, would it be safe to say that most of us who do not regularly see antiretrovirals being prescribed, would often pop it in the too-hard basket? Why do you think they are medications that GPs and other health professionals should be more aware of?

Yeah, so you make a fantastic point there. I'm sure many people would potentially feel slightly daunted by the prospect of antiretroviral therapy, but the purpose of this article is really not for people to become proficient prescribers of antiretroviral therapy, but just to be aware that they exist. And also to be aware of very important drug–drug interactions, because it's often that patients won't necessarily see their specialist for general health problems. They're far more likely to go and see their GP. And there are lots of frequently prescribed medications that can interact with patients' HIV drugs. So as that prescribing doctor, it's really important to have that awareness.

Okay. So it's really the concomitant medications that you want us to be wary of both commencing, stopping and changing doses while patients are on antiretrovirals.

Absolutely.

And so would it be fair to say that we still have a bit of work to do with changing our mindset with HIV? My understanding now is that the lifespan and quality of life is really comparable if not better than other chronic diseases. Is that right?

Yeah, absolutely. So antiretroviral therapy now is incredibly effective. And yes, once somebody's diagnosed and engaged in care and on antiretroviral therapy and has continued adherence, then yes, absolutely, we can expect that that person will have a long, healthy life, just the same as somebody living without HIV.

I guess, one of the big issues that we faced with HIV has been huge amounts of stigma around this infection and this condition. And hopefully, we are some way to reducing that. I think a real kind of catalyst for that has been the U=U campaign, so undetectable equals untransmissible. And essentially what this means is that if somebody's taking antiretroviral therapy, they're engaged in care and they have a undetectable viral load, meaning that they have a low level of the virus in the blood system, it means that they can't transmit the virus onto sexual partners through vaginal or anal sex. And that's really been a huge turnaround, if you like, in terms of HIV medicine and the way that we think about HIV.

Could you briefly explain why combination therapy is required, and how specialists decide between two- and three-drug regimens?

The concept of combination therapy has been around for some time, and it largely relates to the fact that HIV is a virus that has a very high replication rate. And in doing that, it can mutate and can result in resistance to drugs. Now, if you use multiple drugs that target the virus at different areas in the replication cycle, then you're going to reduce the risk of drug resistance. And that's essentially the concept of combined therapy. So for many decades now, we've used triple therapy, and that's kind of been the bedrock of HIV care for some time. More recently though, the paradigm, if you like, is kind of shifting towards two-drug regimes. And the background to that is that now we have really effective drugs that have what we call a very high genetic barrier to resistance. So they are excellent at controlling the virus, and therefore, there's a much lower risk of resistance developing with these drugs.

And so now, rather than kind of being absolutely obsessed with ensuring that the patient doesn't develop drug resistance, we're now thinking along the lines of toxicity. And people are living with HIV for the rest of their lives, they're going to be taking medication every day, so now we're thinking about reducing the number of drugs to reduce the potential toxic effects of these drugs. Two-drug regimes are still not commonly used. Currently, there are two ones that are available. So a drug called Dovato, which includes dolutegravir and lamivudine, and another one Juluca, which again is dolutegravir and rilpivirine. We only use them in certain settings. But who knows? In the future, there may be far more of a shift towards two-drug regimes.

On the other extreme, Yasmin, could you tell us a bit about booster drugs? What are they, and why are they important considerations for patients on antiretroviral therapy?

Boosting agents include cobicistat and ritonavir. And essentially, these drugs inhibit cytochrome P450, which is the mechanism by which antiretroviral therapies, including protease inhibitors and the integrase inhibitor elvitegravir are metabolised. And as a result of that, essentially you get higher levels of those drugs, so higher serum concentrations, and therefore, they're able to suppress the virus.

So that's fantastic, but the flip side to that is because these boosted drugs don't necessarily discriminate between boosting antiretroviral therapy and other drugs that are also metabolised through the same pathway, it means that other drugs can also be boosted. And therefore, you can get toxic levels of drugs that we commonly use in practice, which can result in quite severe drug–drug interactions and toxicity. So that's why being aware of this is incredibly important.

Right. Now, if anyone was listening extra carefully there, you might have heard Yasmin mention ritonavir. Now ritonavir might be actually a bit more on people's radars these days, given that it's one of the agents in Paxlovid, one of the oral therapies for COVID-19. So I won't digress there, but it is probably one that more and more GPs and health professionals in the community are going to be more aware of, and the complexities of prescribing other therapies alongside of it. I guess, the difference is COVID therapies are only for five days, versus antiretrovirals, which are much more longer term. But, I guess, moving on to the classes of antiretrovirals, you described the nucleoside and nucleotide reverse transcriptase inhibitors as the backbone of HIV therapy, and that we usually need two of these drugs in the combination. Is that right?

Yeah, absolutely. So this has kind of been the bedrock of HIV care for some time. So two NRTI drugs in combination with an anchor drug from a different class, either an integrase inhibitor or a protease inhibitor or an NNRTI.

Right. And then you break it down further into abacavir combinations or a tenofovir combination.

Mm-hmm.

Could you talk us through some of the considerations and adverse effects with these particular combinations?

So I guess the combinations of backbone that we frequently see would be abacavir paired with lamivudine, or a tenofovir-based regime. So either tenofovir disoproxil fumarate, or tenofovir alafenamide in combination with emtricitabine. So in terms of deciding between those backbone agents, with any person living with HIV, before prescribing any antiretroviral therapy, you would always want to check their baseline resistance assay. And that's just to check for any transmitted drug resistance. And you also would want to take a bit of a history about what treatments that they've had in the past.

With abacavir, there's an extra consideration. So abacavir is known to cause a potential hypersensitivity reaction, which is a multisystem disorder, typically occurs within the first six weeks of starting the medication, and it can be fatal. And so before prescribing abacavir, we check a particular genotype. It's called the HLA-B*5701. And if somebody is positive for that, then essentially, abacavir is contraindicated, because of the significant risk of this adverse reaction.

Another important consideration for abacavir is that for some time it's been associated with a potential increased risk in cardiovascular side effects. Now, the data is a little bit conflicting, but as a general rule of thumb, most experts and most guidelines would advise if somebody has significant cardiovascular risk factors, then you would avoid abacavir. So those are the kind of main considerations for that regime.

In terms of tenofovir-based regimes, so the major things to think about with tenofovir are renal and bone health. Tenofovir disoproxil fumarate has a rare, but very serious potential side effect, and that can result in Fanconi syndrome. It's really rare. It happens in less than 1% of people. It can also cause renal toxicity. So it's contraindicated in people with an eGFR of less than 60. Tenofovir alafenamide, which is similar to tenofovir disoproxil fumarate, may also affect renal function, but to a much less extent than tenofovir disoproxil fumarate. And that's partly because the intracellular concentrations of TAF are much higher, and that results in less of the drug in the serum. And therefore, it's less likely to cause renal toxicity. There are a few other factors at play there as well.

The other thing, as I mentioned, is bone health. So if somebody has a history of osteoporosis, or perhaps has a number of risk factors for that, then again, you may want to steer clear of tenofovir.

These are things that the specialist is obviously going to be keeping a close check on, but given the frequency of visits to the specialist, the GP and the community health providers can definitely assist with the monitoring for these sort of adverse effects.

Yeah, absolutely. The GPs are really the key linchpin between all specialties, and so effective and excellent communication with GPs and specialists is, to be honest, probably one of the most important things.

Absolutely. So your article touches on the importance of adherence for hepatitis B patients, Yasmin. I thought this was really interesting, because I think this is probably something that could slip under the radar perhaps a little bit.

Yeah.

So could you tell us a bit more about this and why it's important for this population?

A number of agents that we use for HIV therapy are also used to manage chronic hepatitis B. So those agents include things like tenofovir-based regimes, but also lamivudine, emtricitabine. So these agents, essentially, in a similar way to how they work with HIV, they stop the hepatitis B virus from replicating and they control the levels of DNA. Now, if somebody has well-controlled hepatitis B and they stop their medication, then the virus may then start producing lots more DNA. And as a result of that, you may get an immune response that is essentially trying to clear the virus.

Now, the issue with hepatitis B is not necessarily the infection itself, but rather how our immune system tackles it. So we tend to get quite a significant inflammatory response that then causes the hepatitis and the liver damage. And so for that reason, we advise people living with hepatitis B on treatment, either have hep B HIV co-infection, or just hep B mono infection, not to stop their medications abruptly without seeking advice first.

In a similar kind of fashion, people that have chronic hep B that would like to start PrEP. So PrEP is pre-exposure prophylaxis, so this is using HIV medications to reduce the risk of HIV acquisition if someone were to become in contact with the virus through a high-risk exposure. And the drug that we tend to use in Australia is Truvada. It's a combination of tenofovir disoproxil fumarate with emtricitabine. This is also a very effective hepatitis B treatment. And so we would advise these people to only take regular PrEP, rather than what we call on-demand PrEP, which is another way that you can take the medicine, which is just around a time of high-risk activity. And that's for exactly the same reason or rationale, so that's an important consideration for prescribers as well.

And so from here, the third agent is typically one of either an integrase strand inhibitor, protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor. Have I got that right? And how do specialists decide on this third agent?

That's completely correct. So as you said, we have the NRTI backbone, and then a choice of the anchor drug. So that would be an integrase protease inhibitor, or an NNRTI. So what you would look at when you're constructing any regime would be your resistance assay to begin with, and especially for prescribing abacavir, you'd think about the HLA-B*57 status of the person. Other important considerations would be if that person has any co-infections, such as hep B or hep C co-infection, if they have any comorbidities. And also, to consider their drug history, for potential drug–drug interactions.

But for a person who, let's say that there's no other competing interests or no other issues, then generally speaking, we tend to use integrase inhibitors as the preferred agent. And the reason for that is that the newer integrase inhibitors have what we call a very high genetic barrier to resistance. They're generally very well-tolerated. They don't tend to have many interactions with other agents. There are some important exceptions, but generally speaking, they're pretty good. And they're also available as fixed drug combinations. So the three drugs come in one tablet, and that's really helpful for patients to reduce the pill burden.

In terms of other medications, protease inhibitors still play a role. These, again, have a fantastic genetic barrier to resistance, probably more so than the integrase inhibitors. But that kind of benefit is offset by the fact that they need to be boosted. And the fact that that can result in a number of drug–drug interactions. Proteinase inhibitors can also increase cholesterol levels, and they have some GI side effects as well.

Right.

In terms of the NNRTI class of drugs, there's only two that we tend to use nowadays. So rilpivirine is still used quite frequently. And rilpivirine is a relatively good drug, there are some issues with it though. So it can't be used if there's a very, very high viral load, because it's not quite as effective as, say, the integrase inhibitors or the protease inhibitors, in terms of that genetic barrier to resistance and bringing the viral load down very quickly. Another really important consideration, and this is particularly an issue for patients, is that it has what we call a meal requirement. So essentially rilpivirine requires an acidic pH in order for it to be absorbed. And so patients need to eat a full meal in order to get lots of stomach acid in order for the drug to be absorbed.

So that can be a real issue and a bit of a hindrance. It also is vulnerable to a number of really important side effects. So on the same theme of needing an acidic pH for absorption, it means that any drugs that interfere with that, such as the proton pump inhibitors, can actually mean that rilpivirine doesn't get absorbed at all. And that can actually result in virological failure, which is a complete disaster.

The other issue is that they can increase the QT interval. And if it's taken with other drugs that also increase the QT interval, then there's a potential risk of an arrhythmia there, which would be quite serious. Efavirenz is another type of drug in that class. Generally speaking, we don't tend to use efavirenz that commonly any anymore. It has, again, a low genetic barrier to resistance, and also has some really terrible neuropsychiatric side effects, so you wouldn't generally use it. Essentially, that's a very long-winded way of basically saying that integrase inhibitors tend to be the most commonly prescribed. They're definitely my favourites in clinic, and the ones I often will put patients on.

You mentioned the Liverpool HIV Drug Interaction website. Could you tell me a bit more about how you use this, Yasmin, in your day-to-day practice, and how it fits in with everything we've just talked about?

The Liverpool HIV Drug Interaction website is essentially my go-to in clinic. I pretty much have this open on my desktop for the duration of my clinic visit. And whenever a patient comes in, I will always ask about any new medications, even over-the-counter medications. And it's a great tool. You basically just plug in the patient's HIV medicine, and then there's an option to put in the other medication. You just flick a button, and basically, it will just come up as either green, no interaction, yellow, possible interaction, or red, basically, don't prescribe it. And it's really fantastic.

I do believe that it's available on phone versions as well. And often, patients will use this themselves to check for interactions if, say, they get something over-the-counter on the weekend, say, when they can't call us up for advice and they'll just check for themselves to determine if there's any interactions. There's also one for the hepatitis C drugs as well, which again, have lots of drug interactions, but it really is a fantastic resource.

I guess the one thing I would love to add in at that point is that the presumption that if a drug isn't mentioned on there, that it's safe, is probably one to be wary of.

Most definitely. I think you've made an excellent point there. And part of the issue as well is that sometimes patients will source things that are, I don't know, vitamin supplements or something, and perhaps the particular ingredients aren't available as a sort of dropdown menu.

Have you had firsthand experience yourself, seeing the impact of a drug interaction with an antiretroviral, and how was it managed?

Yeah, I think the most memorable experience I had of this was as a first-year registrar.

Of course, it's always in your first year.

It is, absolutely. I was involved in the care of the patient, I'll just add that in quickly. But it was discussed at our team meeting, and this was a really profound drug interaction, and it was really serious, that this patient was on a boosted regime. And essentially, was prescribed a steroid inhaler by their GP. They developed Cushing's as a side effect of that.

From a steroid inhaler?

Absolutely. This is the power of the sort of boosting agent.

Wow.

And then I think they stopped the therapy, and they had an addisonian crisis, and they had to be rushed off to hospital. So that will always stick with me, I think.

That's amazing. So finally, Yasmin, with regards to vaccinations, how important are they for patients on HIV medications? And what are the concerns with the live attenuated vaccines as well as the hep B vaccine?

Vaccinations are a really important consideration for people living with HIV. So people living with HIV are at significant risk of many vaccine-preventable illnesses. And so that's one of the first things that we do with patients when we first meet them, is take a thorough vaccination history, and ensure that things are up to date.

In terms of the live vaccines, so there's some important considerations in people with advanced immunosuppression. So when they have a CD4 count of less than 200, live vaccines are contraindicated in this case. And that's basically because the person doesn't have a sufficient ability to provide an immune response, and therefore, they could get seriously unwell from that live vaccine.

In terms of the hepatitis B question, so people living with HIV have a less effective response to standard doses of hep B vaccination. And for that reason, we double the dose of the vaccination. So patients will get a 40 microgram dose rather than a 20 microgram dose of three doses of vaccination, then we'll typically check that they have immunity. And if not, we'll then repeat the vaccination course. So we do see quite a lot of non-responders in people living with HIV.

Fascinating. I actually feel like we could keep talking for a while on this one. It’s fascinating. But thanks so much for joining us today, Yasmin.

Oh, my absolute pleasure. Thank you so much for having me.

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Yasmin's full article is available online. The views of the hosts and guests on the podcasts are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber podcast.