New 2-Drug Regimens to Treat HIV

Key Takeaways:

• Despite occasional studies suggesting that 2-drug regimens might be adequately effective when the right drugs are offered in the right doses, interest waned until relatively recent trials, such as GEMINI-1 and GEMINI-2, provided compelling evidence that 2-drug regimens can compete with 3-drug regimens for sustained control in many patients.

• Various strategies to increase the likelihood of long-term control with 2-drug regimens, such as achieving viral suppression on triple therapy before switching to a dual therapy, were shown feasible in such trials as TANGO and SALSA.

• Some major guidelines, including those from the US Department of Health and Human Services (DHHS) and the European AIDS Clinical Society (EACS), now include a 2-drug regimen among recommended first-line therapies.

• Many of the 2- and 3-drug regimens involve one pill taken once daily, but the simplicity of 2-drug antiretroviral therapy has now been tested in the form of long-term injectable agents, which have demonstrated good control in such trials as ATLAS, with injections up to 2 months apart.

• Questions remain about the viability of 2-drug regimens in specific subgroups, such as those with high viral loads, genotypes associated with resistance, and other factors that might make HIV control more difficult, but it is generally accepted that 2-drug regimens are a reasonable option in selected patients.

This transcript has been edited for clarity.

Thinking about 2-drug therapy, it’s been sort of a tortuous course. Remember, we started historically treating people with 2 drugs. We would give people two nucleoside, for instance. AZT [zidovudine]-3TC [lamivudine], for example, was something that I prescribed early in my career, and then we found out that it wasn’t all that we had hoped. It didn’t have the potency. It didn’t have the durability. Resistance developed pretty quickly. So, 2-drug therapy fell by the wayside for quite a long time. 

It wasn’t for years that we started to appreciate that, maybe, we can get around the rubric of 3-drug therapy and use two drugs if we chose the right two drugs. One of the first inklings we got of this was a very, very large clinical trial that was done many years ago by the AIDS Clinical Trials Group here in the United States, in which lopinavir, ritonavir, and efavirenz were put together.^[1] Although not well tolerated, for those who did tolerate it and take it, we saw virologic successes that looked just as good as triple-drug therapy that was also studied in this study. 

So, it was a signal, I think, to many of us that maybe 2-drug therapy is something we could get away with if we have the right partners. Subsequent to that, we’ve seen now a renaissance of 2-drug therapy.^[2] And there has been a whole bunch of work done, mostly in Europe, looking at trying to minimize therapy, probably driven by economic considerations. We saw things like boosted PI [protease inhibitor] monotherapy, but also studies that looked at combining boosted PIs, which, at the time, were the most potent antiretroviral, with other partners, with a mix-and-match approach but only one partner. So, it could be 3TC; it could be one of the newer integrase inhibitors at the time, which was raltegravir. 

Also, we saw that we can see combinations of boosted PIs with an NNRTI [non-nucleoside reverse transcriptase inhibitor]. So, we saw this mix and match, and some successes there, indicating, again, that perhaps two drugs—if they’re the right two drugs with an anchor that has a high barrier to resistance and is potent and well tolerated—may be an option for many of our patients. 

I think the line that got crossed that made a huge difference, however, was when we saw the SWORD studies^[3]: This is SWORD-1 and [SWORD]-2, where dolutegravir and rilpivirine were combined as a switch option for patients who [were] virologically suppressed. And it worked rather well. Not only that, patient satisfaction was high in those who had switched to dolutegravir-rilpivirine off of their triple-drug therapy. And efficacy was good. It maintained virologic suppression. That’s not a regimen that really caught on. But again, the proof of concept was there: If you had a potent anchor—in this case dolutegravir—an integrase inhibitor that has a high barrier to resistance, [is] really well tolerated, really potent, even with an NNRTI like rilpivirine, which has its issues and has a lower barrier to resistance, requires food, et cetera, to get absorbed, we saw really good outcomes.

Jump forward, of course, and we saw the most minimalist therapy that has been tried so far, [with] dolutegravir and 3TC in the GEMINI studies.^[4] This is the GEMINI trial of treatment-naïve patients: a large study. And this [study] showed us that dolutegravir-3TC can hold its own against triple-drug therapy that was standard of care at the time. This has been followed now by the switch studies TANGO^[5] and SALSA,^[6] which dance around the issue of, Can you switch people to dolutegravir-3TC? And the answer is, Yes, you can, and maintain very high levels of virologic suppression. Again, with dolutegravir being in the mix, we’re not seeing much in the way of failure with resistance, although there was one case that’s been documented in TANGO in a person who had some adherence issues apparently late in the study who did develop failure with resistance. But generally, we’re seeing that these are well-tolerated, popular regimens. 

More recently, we’ve seen, of course, long-acting injectables. Long-acting injectables are based upon a combination of two different agents, much like we saw in the SWORD study, where we had an integrase inhibitor plus an NNRTI. In this case, it’s cabotegravir injected along with rilpivirine, where rilpivirine is injected rather than ingested, which gets around some of the rilpivirine absorption issues. 

And again, we’ve seen a series of really well-thought-out studies going from ATLAS^[7] to FLAIRE.^[8]FLAIRE [involved] people who were treatment-naïve, induced with oral therapy, and then switched to the injectables. ATLAS switched people to an injectable, and then ATLAS-2 looked at not monthly administration but every-2-month administration.^[9] 

This is, again, a really big deal. And importantly, it gives us an insight into the future of HIV therapy in that we’re going to see more and more long-acting agents, of course, which is what I think the community wants and people are very interested in. This is a lifelong therapy until there’s a cure. And intermittent therapy, I think, is what people want—less frequent. Even a pill a day may be too much for a lot of folks. 

So, where do guidelines stand on this? Well, guidelines have been pretty clear that 2-drug therapy is an option. We see for initial therapy, both the US Department of Health and Human Services guidelines^[10] and the European guidelines^[11] have shown us that there’s a balance here, that we can use 2-drug therapy, namely dolutegravir and 3TC, or FTC [emtricitabine], depending on the guideline. There’s a little bit of flexibility there on the European side. The US, we see it really sticking closely to the clinical trial data, but there should be no reason the FTC shouldn’t work as well.

Of course, the fixed-dose combination of dolutegravir-3TC is available, but it’s an option for people who aren’t hepatitis B infected. That’s important because almost all of our 2-drug therapies that we’re talking about would not be appropriate in people who are chronically infected with hepatitis B, because there’s no active agent that provides tenofovir, which is what we see commonly used in our triple-drug therapy and people with higher viral loads, greater than 500,000 [copies/mL], because they weren’t studied in some of the dolutegravir-3TC studies. That’s important. That’s a limitation there, too. And then, people who fail PrEP [pre-exposure prophylaxis] in the EACS guidelines, given that there may be some underlying resistance to 3TC or FTC, that should preclude use of dolutegravir-3TC or [dolutegravir]-FTC. 

Whereas in the US guidelines, it’s more about [whether there] is a genotype available at all, and whether or not there is any evidence of underlying NRTI [nucleoside reverse transcriptase inhibitor] resistance vis-a-vis, again, the 3TC or FTC. Basically, they align very closely. So, dolutegravir-3TC is an option for those people who fall into the categories, which looks a lot like the inclusion criteria for the GEMINI trials that show that dolutegravir-3TC works really well. 

What about for a switch? Well, for switch, it’s actually interesting. There are a little bit more options and wiggle room here because we have more studies that can show us, over time, that people can transition from being suppressed on triple-drug therapy to being suppressed on dual therapy. So, again, for EACS, there’s a little bit of some difference between that and the US guidelines, but not that much. 

So, for EACS, again, dolutegravir-3TC, given what we saw from SALSA and TANGO, makes a lot of sense and is supported by the data. We also see that there are some historic data looking at darunavir boosted with ritonavir, and also using that with 3TC or FTC for those who need it. Again, there are not too many people [for] whom that would probably fit, but there may be some who fit into that category. And then thinking about a dolutegravir-rilpivirine combination could also, this would be the SWORD studies, be an option for people who want to switch. And then lastly, more recently, cabotegravir-rilpivirine. And based upon the clinical trial data that we’ve seen, using cabotegravir-rilpivirine for suppressed patients makes sense. 

Now, one thing we should just keep in mind is, in the studies that we’re talking about, there has been a slight tendency towards failure with resistance in 2-drug therapies—the least happening with dolutegravir-3TC, but it isn’t impossible, as we mentioned with the TANGO case, but certainly, a little bit more so with the cabotegravir-rilpivirine. It’s not very common, but you can’t say that it can’t happen. Whereas, I think for some of the triple-drug combinations that we’ve seen in clinical trials with dolutegravir and bictegravir, we really haven’t seen failure with resistance. [With] dolutegravir in triple-drug therapy, sometimes we’ve seen failure with resistance in parts of the world where this has been studied, especially in sub-Saharan Africa^[12]—again, under circumstances with different clade that we have to investigate further. 

In the clinical trials that we’re talking about with triple-drug therapy in the United States, Europe, and Australia, we haven’t seen failure with resistance with dolutegravir in the triple-drug regimen or bictegravir in the triple-drug regimen. Again, the US guidelines [are] very similar to the EACS guidelines. And switch is an option to 2-drug therapy if needed. Based on the data, [there’s] heavy reliance upon clinical trial efficacy and tolerability: So, dolutegravir, along with 3TC is there; so is dolutegravir with rilpivirine; and again, cabotegravir-rilpivirine. We’ll just have to see how this all fits in. 

I think the story for most of us for cabotegravir and rilpivirine moving forward is, How do we operationalize this? And is monthly or every other month the best way to go? Given the failures with resistance that we’ve seen, even in people who are on time for their every-2-month administration of cabotegravir-rilpivirine IM, we’re a little concerned that maybe that 2-month period is a little bit too long. Maybe a month—every 4 weeks—is a little too short; maybe 8 weeks is a little too long; maybe there’s an in-between, but that wasn’t what was studied. 

I think we’re going to have to think a little bit harder about this: whether or not we have to have a lead-in period where people stay on monthly injection for a while and then switch over to every 2 months. That’s something that I think some of us are looking at and considering. Again, the risk is really low, but it does take advising your patients, coming up with some shared decision-making about the risks and benefits of switching to something like cabotegravir-rilpivirine vs staying on an oral regimen. 

So, we’ve come a long way from 2-drug therapy that really didn’t do as much as we wanted and ushered in an era of triple-drug therapy. Now, going back towards thinking, Can we get away with two drugs? We know that we can if it’s the right 2 drugs in the right patient. So, hopefully, that provides a little bit of insight into where we are with 2-drug therapy—an evolving story. This is not the end of it.