“Because we’ve always suspected that this potentially could happen, and now we’ve shown that it can happen, people need this information to make decisions about their sexual health that feel right for them,” Dr. David Knox told me by phone yesterday. “The more information, the better. And that’s the bottom line.”
Dr. Knox was the lead author on a case last week reported at Conference on Retroviruses and Opportunistic Infections (CROI) regarding the first recorded apparently PrEP-adherent MSM (man who has sex with men) who contracted a strain of HIV that showed drug resistance. Dr. Knox, who practices at the Maple Leaf Medical Clinic in Toronto, is also the subject’s doctor. He told me that about 20 of his patients are on PrEP and there’s around 100 in total at Maple Leaf.
Dr. Knox further discussed with me his findings (you can listen to his presentation here), what they mean in the bigger picture of PrEP use and HIV prevention, and where those who study HIV are looking next in light of these results. A slightly edited and condensed transcript of our conversation, which Dr. Knox jumped right into as soon as we started talking, is below.
Dr. David Knox: We thought that people who were really, really pro-PrEP essentially wouldn’t be able to handle the results that we were presenting, and would call into question the patient’s adherence to the medication, which is fair. The one thing, though, that’s a bit subtle is that in a number of the PrEP studies, there were actually cases of suspected breakthrough infection, but they couldn’t prove that the patient had long-term adherence to the medication. In one of the studies, they just went back in time and looked at random blood samples to see whether or not they could find the drugs in the blood, and if they were there, they thought, “OK, this person was probably adherent.” If they weren’t there, then they said, “Well, this person probably wasn’t.”
I think the reason why this case made it to CROI, which is by far the largest HIV conference in the world, and the reason why it got airtime is because this was the first case where we rigorously documented several lines of evidence pointing to the fact that this patient was adherent to the medication. While we think it’s possible that this has happened in the past, that’s the reason why this case got so much traction in the medical community.
It’s newer technology, for sure. Sometimes the other PrEP studies happened in resource-limited settings. They definitely did not use dried blood-spot tests. It’s pretty interesting to see that [previous potential breakthrough cases] were discussed and then [researchers] said, “You know what? We can’t prove this.” And it was just kind of dropped, mostly because they didn’t have evidence of long-term adherence. And then obviously in some PrEP studies if you can’t rule out that the patient was actually HIV infected at enrollment into the study, then you can’t report that as being a breakthrough infection either.
I know that the blood-spot testing has some limitations and it seems like there’s slight hedging in some of the language in this reporting. In your presentation you mentioned that efficacy is difficult to prove and [iPrEx principal researcher] Dr. Robert Grant said, “I believe him,” regarding the subject in question. It does seem that your findings are based on at least a slight degree of self-reporting.
Does that even matter given the drug-resistant mutations you found in his strain of HIV?
Even in the context of the most rigorous, randomized placebo-controlled clinical trial, you can always call into question the patient’s adherence. Even in cases of directly observed therapy, where you’re watching the patient swallow the pill, you don’t know what happens when that patient leaves the room. Adherence is a very, very tricky issue in clinical trials. There will always kind of be that question, which is why we had to go one step further in this case and collect the patient’s pharmacy records and do the dried blood spots and make sure there was medication in his blood prior to his knowledge of his HIV status. We had to line all those things up to really solidify this case and adherence.
But you’re right about the mutations: This is a resistance pattern that I’ve never seen before. The number of mutations there and the way the medication would have been rendered ineffective or considerably less effective is not one that is particularly common.
You made the point in your presentation that you believe this was transmitted resistance, versus acquired resistance. Does that answer to fears regarding PrEP causing the mutation, as opposed to the apparent reality that the mutation already existed and PrEP failed to block it?
Yes. This is also a bit subtle, unless you know HIV medicine. There were mutations in the patient’s resistance profile to medications that he himself had never taken. So in the NNRTI class there was resistance to a medication called Nevirapine, and in the INSTI class, there was a mutation to a medication called Elvitegravir. Our patient had never ingested those medications himself. In order to get those mutations they would have had to have been transmitted to him from somebody else. So if he’s already having those mutations transmitted to him, it makes sense that he would have had these other mutations as well, rather then selectively taking PrEP and causing those mutations to develop or be acquired in his own body.
Can you shed any light on how you came to treat this patient?
I took over his care about two years ago, after I took over someone else’s practice in Toronto. He was already on PrEP. I believe he became interested in PrEP when he read a news article about it. He was one of the true early adopters in the community outside of a clinical trial. When he essentially confirmed his adherence, that’s when we thought we would have to investigate this fully.
How much does this patient’s sexual behavior—his number of partners, his risk-reduction beyond PrEP, as two examples—matter in understanding this transmission? Or is all of that a moot point?
I think the latter is more true. There are going to be guys out there that use PrEP as an anti-anxiety pill. They can’t have sex that’s enjoyable even with condoms unless they know they have this extra added layer of protection. At the opposite end of the spectrum are people who decide that condom use for them is not something they want to do, and they will take PrEP and accept the risks. There could be STIs, and there could potentially be a breakthrough, but they decide what’s right for them. When you look at the stories people share on these PrEP forums, I don’t think he was doing anything unusual.
[Note: In his CROI presentation last week, Dr. Knox said that, “Between two and six weeks prior to the active HIV screen (in May 2015), the patient reported multiple acts of anal receptive sex with casual partners without the use of condoms.”]
How much do you stress condom use to patients?
I do recommend it. Something that I hear a lot of people talking about is using condoms “whenever possible.” That’s basically it. That’s your best protection—PrEP and condoms.
Do you expect to see more cases like this? Anti-PrEP people have all along bandied about the idea of drug resistance being PrEP’s undoing.
I wouldn’t let this single case of PrEP failure discourage anybody who’s on PrEP or who’s considering PrEP. Clearly, it works. There is robust data out there that suggests PrEP works the majority of the time. This is just a single case. The next steps really are to monitor the rate at which these mutations do occur. But PrEP’s evolving, too. In a couple of years from now, we could be using injectable medication. I don’t feel like this one case should discourage anybody to use PrEP if it’s right for them.
The silver lining of this case is this guy’s very invested in his sexual health and testing for STIs, so we did discover this infection very, very early—probably within six weeks of being infected. Therefore, he’s on medication, he’s undetectable. It makes him a good candidate in the future for cure research, as he might have limited virus in his peripheral reservoir.