Oral PrEP, ‘resistant strains’ and rethinking HIV prevention

FEATURE (2,400 words)

Originally drafted in 2018 for the SFAF Beta Blog, I enjoyed writing this long form piece digging into a scientific puzzle with important cultural implications.

Over the past decade PrEP has gone mainstream. In the language of marketers, we’re close to saturation among innovators and early adopters and now we’re seeing uptake by the early majority (at least among those who have access). 

But for many veterans of the ‘PrEP wars’ – the intense moral panic that greeted early PrEP advocacy – this has meant answering questions that we thought we’d dealt with long ago. Chief among them: ‘But what about resistance?’ 

We know for a fact that PrEP failure is extremely uncommon in people who are fully adherent — and so is being exposed to virus that is resistant to the two drugs used in PrEP. On the PrEP groups on Facebook, however, this ‘zombie question’ just keeps coming back. Here are my thoughts on why that question is evergreen — and what to know if you’re worried about resistance. 

There’s a difference between knowing and understanding

I’ve worked as an educator and researcher in HIV prevention for twenty years. When I tell people what I do, there’s always one perennial question: ‘can you get HIV from oral sex?’ Its predictability used to grind my gears, but it’s not a dumb question. People know the answer, as a matter of fact—but  they’re asking as a way to check their understanding

And the answer to this question has, in fact, changed over time. Studies of male circumcision, advocated as a prevention strategy before PrEP existed, shifted our understanding of HIV infection. Before, we used to say HIV ‘gets into the bloodstream via micro-abrasions in your skin.’ (I was trained to recommend not performing oral sex too soon after eating potato chips.) Now, we know that HIV gets into immune cells in the mucous membranes, and membranes in the mouth have evolved to be really hostile to pathogens. 

Sometimes people say ‘ahh, but you can’t prove a negative!’ Some colleagues claim ‘we’d be legally liable if we said it was safe and then it happened.’ But forty-plus years and 70+ million infections into the epidemic, there have only been a handful of case reports of oral transmission. In scientific terms the risk is too low to estimate, so in practical terms it’s not worth worrying about. 

With the advent of PrEP and U=U, we are seeing the emergence of new perennial questions. In PrEP groups on Facebook we often see questions like: ‘I started PrEP a month ago and I’ve never missed a dose and a guy just came inside me—am I at risk?’ Questions like this highlight the gap between knowing the facts and understanding them.1

Another question we see a lot is: ‘Aren’t there resistant strains of HIV that can lead to PrEP failure?’ Sometimes, this claim is part of an argument for people to continue using condoms. However, I recently saw it asked by a guy who was using PrEP and condoms and avoiding having sex with positive guys. In his country of origin, homosexuality is punishable by death, so it’s understandable to fear HIV infection – but on PrEP he doesn’t need to.

Recent presentations at CROI showing transmitted drug resistance (TDR) is very infrequent for the two drugs used for PrEP — and only a handful of cases of PrEP ‘failure’ have ever occurred in fully-adherent users.2 These are the facts, and this piece aims to help educators and PrEP advocates understand why this is the case. The answer involves the law of the jungle, turf wars among rival gangs, and an impatient four-year old.

Resistance and replication

The philosopher John Dewey explained why it’s so hard to change our minds. We don’t learn by accumulating discrete new facts like so many grains of sand; rather, we weave what we learn into our own pre-existing web of knowledge. This explains why we readily accept facts that fit with what we already know. 

If we apply what we know about antibiotic-resistant bacteria to HIV and PrEP, the notion of ‘PrEP-resistant strains’ sounds plausible. Bacteria replicate by cloning themselves, and when a single bacterium develops resistance, all its descendants will have the same ability. A personal strain of bacteria can become an interpersonal strain that circulates from person-to-person in the community.3

Resistance in HIV is different. Viruses don’t clone themselves. Instead, they hack our DNA to trick our own cells into doing the heavy lifting — making the proteins needed to assemble a new viral particle. This is a much quicker process: studies estimate untreated HIV replicates one billion new viral particles per day. 

The virus has a famously ‘sloppy’ mechanism for copying genetic code, creating lots of opportunities for changes to creep in — changes we call mutations. Many mutations result in deformed viral particles that go nowhere, but every now and again, a mutation occurs that gives the resulting viral particle greater ‘fitness’ for the challenges in its environment. This is the law of the jungle — survival of the fittest — and it applies in your cells and in your blood.

For HIV, fitness means being able to make new copies faster. Our mutant copy infects a new cell, which begins churning out many similar copies, and they infect new cells and so on… 

If the mutation confers a significant advantage, all the copies with that mutation might become a majority quasispecies within the personal mix of strains circulating in your body. (Quasispecies is the technical name for what I’m describing as a personal strain.4)

Different quasispecies, each carrying different mutations conferring different advantages, compete like criminal gangs fighting for turf. Replication is the name of the game: whichever strain replicates fastest in your body, dominates. 

Antibodies can’t cure HIV, because it changes so rapidly — but killing infected cells can certainly slow it down. This exerts selection pressure on the mix of viruses circulating in your system. If a mutation allows a viral particle to hide the cells it has infected from your antibodies, for example, it can replicate faster, out-competing other quasispecies. In this scenario, the immune system is creating selection pressure for the mutant strain, which gets ahead because the immune response slows down all the other viral gangs. The same thing happens when a quasispecies becomes resistant to the anti-HIV drugs you are taking.

Enter the clumsy four-year old

Antiretroviral therapy (ART) also works by slowing viral replication. Different drugs work in different ways, and I’m going to focus on the drugs used in PrEP, which are known as TDF (tenofovir) and FTC (emtricitabine).

When HIV infects a cell, a protein called reverse transcriptase is responsible for taking genetic code from the virus and copying it into our own cell’s DNA. Let’s imagine that protein is a clumsy four year-old named Artie. Artie grabs the building blocks for DNA — A, C, G & T — and clicks them together in a chain, ready for insertion.

Drugs like TDF and FTC work by providing our cells with a huge supply of counterfeit building blocks. Imagine a Lego™ block, but one end has nubs missing. So Artie grabs the nearest block – one of the fakes. When he can’t attach the next block in the chain, he does what any four-year old would do — he throws a tantrum and gives up completely. 

This is why adherence is important with HIV treatment and PrEP — it ensures there’s sufficient and continuous supply of those counterfeit building blocks. The handy thing about TDF and FTC is they don’t disrupt our own cells, unlike earlier drugs. That’s one reason why we use TDF/FTC for PrEP — for most people, they cause few side effects.

Clever drug design

Apart from being pretty easy to tolerate, TDF/FTC has another handy feature. Resistance mutations can involve trade-offs. Some forms of resistance cause slower replication compared to non-resistant or ‘wild type’ virus. As long as the drug is present, the resistant strain can replicate faster than wild-type; when the drug is withdrawn, the non-resistant virus returns to dominance. 

The designers of the TDF/FTC combination did something a bit cunning: they combined two drugs whose resistance mutations cause trade-offs that amplify each other. Virus that is resistant to FTC is more susceptible to TDF, while the mutation responsible for TDF resistance absolutely tanks replication. 

Studies estimate a strain resistant to TDF replicates 57% as fast as wild type, and strains resistant to both drugs replicate only 29% as fast (Moyle, 2004).

In other words, even when the virus is resistant to both drugs, it replicates much slower than wild-type. Studies show HIV is rarely transmitted with TDF resistance, and it’s not hard to work out why. Replication rate drives the likelihood of transmission — that’s the whole point of the science behind U=U. 

Even if resistant virus is passed on, in the absence of selection pressure from TDF/FTC the majority strain quickly mutates back to wild type in the new host. 

But you might be wondering: ‘what if the new host is taking PrEP?’ 

Great question. 

A new infection is basically a race — viral particles need to infect enough cells to establish infection before they break down or the immune system wipes them out. HIV is already quite hard to transmit: research that pre-dates HIV treatment found that even anal sex, with a known-positive partner who ejaculates inside the body, estimates a 1-in-33 chance of infection. In the other 32 encounters, exposure fails to cause infection. The slower replication rate of virus resistant to TDF and FTC makes it more likely that exposure will fail to cause infection.

This may explain why we’ve seen fewer than a handful of cases of HIV infection in people who were fully-adherent to PrEP. It also explains why a person who gets HIV under those conditions is unlikely to pass it on. When they stop taking TDF/FTC, the resistant strain more or less disappears from their personal mix, although it may remain ‘archived’ in the DNA of infected cells. 

So here’s my takehome message on ‘PrEP-resistant strains’:

It is possible to develop a personal strain with resistance to the drugs used in PrEP, but this strain will have a very low rate of replication. That is what stops it from becoming a circulating strain that can pass from person-to-person in the community.

The real resistance to PrEP

If thoughts of PrEP ‘failure’ are troubling you, take a moment to imagine what would happen if you did get HIV. Anxiety about HIV might mean you miss out on hearing first-hand about the modern-day reality of life with HIV — at least as it exists for people who can afford to access PrEP and HIV treatment.5

Most people in HIV treatment are taking one pill a day and seeing their doctor once every 3, 6 or even 12 months. Getting HIV means doing some heavy identity work and negotiating disclosure and exposure to stigma, but it is no longer something to feel terrified about.

Research by Cathy Dodds at Sigma Research in the UK shows that fear of infection does not motivate people to protect themselves; in fact, it is a barrier to learning about HIV prevention skills. We should respond to fear as fear— by supporting people to grapple with their HIV-related anxiety — instead of expecting a barrage of PrEP facts to solve the problem.

Meanwhile, the ‘resistant strains’ that concern me most are only viral in the sense of circulating rapidly via social and mainstream media. 

They are initiated and passed-on by people who have learned to translate moralistic concerns about condomless sex into pseudo-scientific ‘concerns’ about the possibility of drug resistance. They are shared by people who either want to seem knowledgeable or just to stir up a bit of controversy. This can provoke a strong response from PrEP advocates who remember the Great PrEP War of 2012. Indeed, PrEP newbies sometimes get caught in the crossfire, getting slapped down for asking questions we’ve become sensitive about. 

PrEP education isn’t solely about delivering facts based on evidence established by studies. Of course, we do that when such evidence exists, but many of the practical and social aspects of PrEP use have never been studied — so we are learning as we go, partly through observational studies, partly through conversations among our peers, and partly through personal experience. 

We also need to figure out how the reality of biomedical prevention affects the myriad assumptions that underpinned prevention discourse in the Latex Era. These assumptions are implicit, unconscious and often embedded in routine practices. For example, thirty-odd years of ‘use a condom every time’ seems to have translated seamlessly into ‘take the pill every day.’ As if we can’t think about gay men having sex without a framework of regulatory norms — unregulated by the threat of misadventure.

The subtitle of the world’s largest Facebook community for PrEP users is ‘Rethinking HIV prevention.’ However, the emphasis on delivering facts could be getting in the way of having a broader conversation that could help us discover all the different aspects of prevention discourse that need updating. 

We need scientific evidence and the wisdom of experience in practice to inform the advocacy of PrEP nerds and guide us in developing new social practices that will protect the people who just want to take the pill and fuck. 

notes and references

  1. In addition, research has repeatedly shown facts doesn’t change emotions like fear or stigmatising beliefs. A person asking this question is seeking emotional containment and reassurance. Talking through the facts will provide this, but it’s time-consuming and repetitive. We may need to develop a form of CBT — ahem, that’s cognitive behavioural therapy I’m thinking of — for people whose anxiety about the possibility of infection overwhelms their knowledge and confidence about PrEP. ↩︎
  2. These findings add to the evidence on HIV resistance to TDF/FTC, the two drugs currently used for PrEP. See Chan 2012 and Buskin (CROI 2018). A study of people living with HIV found TDR against the two drugs used in PrEP did not predict subsequent treatment failure ↩︎
  3. That’s why we test the bacteria found in STI tests for antibiotic resistance — as a resistant strain begins to circulate in the community, we may need to modify our treatment guidelines.  ↩︎
  4.  ‘Strain’ is not a technical term; people also use it to refer to clades and sub-groups. In this article I’m using it to refer to a collection of genetically-related viral particles that share key mutations. ↩︎
  5. A million people died from HIV-related illnesses in 2016, and the treatment cascade for the United States shows only 49% of people with HIV are diagnosed, in treatment, and undetectable. As this article by Kenyon Farrow demonstrates, communities with the greatest need for PrEP have the lowest access to PrEP. The experience of HIV is not the same for everyone. ↩︎