Laura Waters, MD, FRCP: Can Two Drugs Tango?

In a symposium presentation at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019), Laura Waters, MD, FRCP, discussed the developments of 2-drug regimens for HIV treatments, as well as the questions that remain unanswered.

Contagion^® sat down with Dr. Waters for an exclusive interview about her presentation and to discuss new data from several studies presented at the meeting.

Interview transcript (modified slightly for readability):

Contagion®: What are some of the promising results we have seen recently about 2 drug-regimens?

Dr. Waters: So, 2-drug regimens for HIV treatment have been a real focus over the last year or so and including at this conference. And, there are 2 main types as that oral therapy and injectables — it's the injectables that really hit the headlines because we saw the results of 2 phase 3 injectable studies looking at long-acting cabotegravir/rilpivirine, FLAIR and ATLAS, both of them showed incredible results: people prefer the injections, high rates of viral suppression.

[There are a] couple of concerns in that the people who failed treatment with resistance were all subtype A, which is a subtype that's often been underrepresented in historical trials and I think there's some more exploratory work needed to find out whether or not some of the integrase polymorphisms in people with that subtype are actually going to predict for virological failure going forward. But, by and large, well-tolerated, high efficacious and really quite fantastic and exciting results.

The other really exciting data for me was some more analysis from the GEMINI trial. So, GEMINI, of course, compared a 2-drug regimen of dolutegravir lamivudine with TDF/FTC dolutegravir as a 3-drug option, and we saw last year at week 48, non-inferior efficacy and no resistance emergence in the virological failures.

There's been some concern about whether 2 drugs really are as potent and effective as 3, and what we saw was a ‘target not detected’ analysis, so really sensitive virological suppression analysis, and actually both arms perform just as well. At higher baseline viral loads, the 2-drug regimen actually outperformed 3 drugs. Although we don't really understand the clinical significance of ’target not detected’ for me, as a basic clinician, it feels like a real step in the right direction for drug therapy.

Contagion®: What are some gaps in knowledge about 2-drug regimens? What should future studies focus on?

Dr. Waters: So [with] the gaps with regards to drug regimens, I think if we focus on the injectables, for me, those gaps are really about the implementation in real life and their efficacy in the context of poor adherence. These are drugs with long pharmacokinetic tails in the setting of missed appointments and missed injections in real life, I think that's something we just don't understand yet; how busy services will deliver those injections every 1 to 2 months in real life is also something that we need to see.

And for me, as a bit of a pessimist, I'm interested to see in real life people who haven't selected themselves to go forwards for injectable trials how acceptable those injections are long term in the more general population. For oral therapy, I think for me the real crux is around the importance of baseline resistant, there says some probe viral DNA data suggesting that based on resistance may be more common than we realize. I think as we see trials looking at proviral DNA, but also looking at the use of dual therapy in people with a risk of, or no history of resistance mutations we're going to learn a lot more. On a global level, I think the big question is around hepatitis B and ensuring that people are on dolutegravir, lamivudine, or rilpivirine for that matter, who are not hep B immune or vaccinated because they're not going to have the protective effect of tenofovir in terms of hep B acquisition.

Contagion®: Can you speak to your point in the abstract summary about embracing progress and employing caution?

Dr. Waters: I think it's a real difficult balance to make progress in an era when the standard-of-care is so efficacious and so acceptable. If we think back to the earlier days of HIV treatment — very toxic drugs, poorly tolerated, not as good virological outcomes – and I think it was easier then to challenge the status quo and to perform some of the trials.

When standard-of-care is so good, it's a much more difficult balance. I think the key thing is, and I said in my talk, is about the ethics. It's about ensuring that we continually review the ethics of trial design and of our practice and making sure that if you are taking a risk on an untested strategy, those risks are fully discussed with a patient, [there is] fully informed consent, and that we respond to new data in a timely way for ongoing trials. So, it's a difficult balance but by discussing it with patients with the right information and shared decision-making, I think we can still make progress in a way that's safe.