HIV and ID Observations

Something interesting happens when you poll people who treat HIV — and people who have HIV — about whether they’d prefer a treatment option that consists of a periodic injection or infusion in place of the pill or pills that they take every day.

Lots of them say yes. Even people who are taking just one pill a day, and are having no side effects.

As a famous comedian (repeatedly) says, What’s the deal with that?

Given the success of currently available oral therapies — in which essentially 100% of people who take it are virologically suppressed — why do so many people say they want shots instead?

Part of it, of course, is the way the question is framed, and human nature. There’s a tendency to favor the shiney new toy. Here’s a typical headline on this topic:

And the simple question — “Would you prefer a shot over pills?” — implies an optimal available strategy. Let’s imagine a single shot administered quarterly, with a small required volume, low rates of injection site reactions, few side effects, and plenty of forgiveness around missed doses. Now we’re talking!

The reason I bring this up is because a couple of recent studies show that non-pill treatments for HIV are at the very least feasible.

Most promisingly, there’s the LATTE-2 study of the long-acting antivirals cabotegravir and rilpivirine — given as injections either every 4 or every 8 weeks — which maintained virologic suppression as well as a standard 3 drug regimen. (More details expected soon.)

And there’s this study of the broadly neutralizing antibody VRC01, which when infused to patients with viremia, dropped HIV RNA 1.1-1.8 log (10-100 fold) in 6 of 8 with a single infusion. It follows an earlier study showing an even more potent antiviral response using a different antibody, 3BNC117. Both treatments dropped HIV RNA long after the single dose.

So we’re on our way, right? Soon we’ll be offering injections or infusions as an alternative to pills, and we’ll all live happily ever after!

But it’s not so simple. Here are a few compelling reasons why we’re not going to see these injectables as viable treatment options in the near future:

• Current treatment is really, really good. Let’s start with the obvious one. Out of 100 newly diagnosed patients, how many can’t get by with one of the Recommended or Alternative DHHS regimens? So the motivation to develop long-acting injectable treatments isn’t quite a life or death matter. “But not everyone can take pills every day,” you say. Indeed that’s true, but …
• Many poorly adherent patients would be lousy candidates for long-acting therapies. This is counterintuitive, as they are the first group one would consider for injectable treatments — people who don’t take their meds now. But to be eligible for cabotegravir plus rilpivirine maintenance therapy, first virologic suppression needs to be achieved — which requires adherence to pills. An oral lead-in is also prudent to screen for acute toxicities that would be very tricky to reverse given the 40-day half-life of injectable cabotegravir. “You’re not getting it back once you inject it,” is what one PharmD memorably said. Finally, what if this non-adherent person decides to be non-adherent to the injections? Misses a few scheduled shots? Takes off for Honduras, as one of my intermittently compliant patient unpredictably does, sometimes with and sometimes without his prescribed ART. Then you have the l – o – n – g tail of low drug levels, which could allow for virologic rebound and selection of resistance.
• So far, it’s not even close to a “simple injection.” It’s not like an insulin shot, or a flu vaccine. The cabotegravir/rilpivirine treatment will almost certainly be at least two intramuscular injections, volume and time between doses to be determined. And monoclonal antibody treatments will likely require an infusion of some sort — time consuming!
• Use of broadly neutralizing antibodies for treatment has many significant hurdles. These “bNAbs” (as they’re cleverly nicknamed) are fascinating scientifically, but will be a bear to get into a practical treatment regimen. Here are a few issues to consider:  1) Some patients have pre-treatment resistance (2 of 8 in the VRC01 study, for example) — will this require a pre-therapy test, akin to viral tropism testing? 2) Treatment selects for escape mutants — in other words, resistance. Combination therapy will be required, perhaps with complimentary bNAbs — will each require a separate pre-therapy test to determine susceptibility? 3) Monoclonal antibody treatments can be antigenic, triggering allergic reactions. 4) If penetration into the CNS is important for at least some component of ART, these monoclonal antibodies aren’t getting there. 5) See above regarding infusion time. All in all, I confess to not quite getting the fascination with bNAbs for treatment, but maybe that’s just me.
• The entire regimen has to be long acting, and preferably also not require pills. If there’s a parenteral therapy that can be given every 2 months, but patients still need to take pills every day to complement the treatment, what’s the point? This is why the cabotegravir/rilpivirine regimen is so far ahead of anything else.

Granted, even as the cabotegravir/rilpivirine treatment is currently configured — a few shots every 8 weeks — there will be a subset of patients for whom this is their preferred way of receiving therapy. Could be cost-effective, too, especially if it’s priced reasonably.

But I’m thinking it’s going to be small group who actually prefer this treatment to a single pill a day. And we’re not going to see it anytime soon.

Pop Tarts, Jerry?

[youtube http://www.youtube.com/watch?v=itWxXyCfW5s]