Today we will discuss HIV seroconversion while on PrEP, a daunting scenario that we hope does not arise very often in care.

This scenario is illustrated by the case study of a 27-year-old cisgender man who has been on emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) PrEP for 2 years and has been doing well.

At one of his routine follow-up visits, his fourth-generation HIV antigen (Ag)/antibody (Ab) test came back indeterminate. Understandably, he is very concerned that he may have HIV, and so we must try to walk him through this situation.

His key lab parameters are shown in the table on the right. He is hepatitis B immune and hepatitis C negative, his body mass index is normal, and his key biochemistry parameters are essentially normal.

The question is, what would you do?

This graph illustrates some of the key information that I think we need in order to interpret the results. It shows how key lab parameters evolve in the period immediately after someone acquires HIV.¹

The first lab parameter that could potentially be detectable in someone who has recently acquired HIV is the HIV RNA, the viral genetic material, which is represented by the blue line. However, as we know, that is not used as a diagnostic test for HIV in most circumstances.

The very first thing that can be picked up by a standard fourth-generation HIV Ag/Ab test is the p24 Ag, which is represented by the green line. The p24 Ag peaks within the second to third week after infection. Later, p24 Ag levels drop, paradoxically, because some of the Ag is bound by the person’s emerging Ab response. That Ab response, represented by the purple line, is the key parameter that we rely on to diagnose HIV infection from that point forward in a person's HIV diagnosis. Typically, the Ab becomes detectable at about three weeks after infection, although that period can vary a lot from person to person.

We can also try to detect any clinical symptoms the person may be experiencing. People may have the classic symptoms of a flu-like illness, but may also have what I call “falsely localizing” symptoms, like pharyngitis, diarrhea, bad headache, or even aseptic meningitis. We must be astute at screening for HIV symptoms because they could be a clue that someone has seroconverted, and that is represented by the purple rectangle at the top of the slide.

Our case study patient, with a fourth-generation test that is indeterminate, is potentially starting to mount a response to HIV, but it is not definitively detectable by the assay. This leaves us with a conundrum of whether or not this person actually just acquired HIV. Depending on whether they have HIV, we are going to manage them very differently in the context of their PrEP care.

The decision also has implications beyond the patient. In the case of someone who is taking PrEP and continues to have sexual partners, diagnosing whether they have acquired HIV becomes very important from a public health perspective.

HIV infection in the context of a long-acting drug like CAB can lead to long-acting early viral inhibition syndrome, which is named this way because the early phase of viral replication is significantly inhibited by the antiretroviral drug, and that makes the detection of the infection even more challenging. The viral replication is now smoldering, rather than explosive, and the corresponding symptoms may be much milder.

In this setting, HIV infection can be detected with some of the assays that we looked at previously. But in this case, the Ab tests are going to be much poorer at early detection because there simply has not been enough viral replication to trigger a robust Ab response.

Therefore, to diagnose HIV early we would need an ultrasensitive RNA assay. As shown in the “duration” row of this table, it can take months before the Ab levels are definitively detectable. Fortunately, it would be less likely for onward transmission to occur.

Later, we will discuss the potential for drug resistance to emerge, which has important clinical and public health implications.

Given that HIV infection can occur on PrEP, how should we monitor people for potential HIV infection when they are taking PrEP?

In 2021, the CDC published guidelines that for the first time recommended HIV-1 RNA assays for monitoring people when they are taking PrEP.³ This recommendation is not only for the LA injectable PrEP but also for oral PrEP: every 3 months with oral PrEP and every 2 months with injectable LA CAB.

This is a shift from previous recommendations where we relied on standard Ag/Ab tests. The shift was based on data from the HPTN 083 trial of LA CAB as PrEP in gay, bisexual, and other men who have sex with men as well as transgender women.⁴

The table shows that in the HPTN 083 trial, when using a standard Ag/Ab test, the delay in detecting HIV infection, compared to when the diagnosis would have been made using an RNA test, was 98 days in people who acquired HIV while receiving LA CAB (and were tested with Ag/Ab tests) vs 31 days in people who acquired HIV while receiving oral FTC/TDF.^5,6 Therefore, we could pick up infections about 3 months earlier if we used HIV RNA testing in the context of LA CAB PrEP instead of a standard Ag/Ab test.

So, what are our options? On this slide, 3 key medical management options are shown with respect to a person who has an indeterminate HIV diagnostic test while receiving PrEP.

Option 1: Intensify
On the left-hand side, one option, perhaps the most conservative, would be to intensify their antiretroviral regimen: add additional drug or drugs to their PrEP in order to create a complete antiretroviral treatment regimen. Doing so is effectively assuming that a real infection has occurred. The challenge with this approach is that moving forward we want to confirm the diagnosis by repeating the test.

However, if we and the patient decide to add more drugs, we are going to suppress the viremia that might exist and potentially make it more difficult for that Ab response to emerge.

The impact on the person is also important. If they are not actually seroconverting—if this is some kind of false positive—it could take a powerful psychological toll on the person who thinks they have acquired HIV. After starting HIV treatment, it can be difficult to undo the message and explain that they have not acquired HIV.

Option 2: Continue PrEP
In the middle of the slide is a less-conservative option, which would be to simply continue PrEP, enhance adherence counseling, and repeat the testing in order to hopefully confirm what the true diagnosis is with the passage of a bit more time.

In discussing this option with the person, we would have to be clear about the disadvantage of this approach: if the person is indeed seroconverting, we could drive the emergence of new resistance by exposing the virus to an incomplete regimen of antiretrovirals. Therefore, repeating the test at a fairly short interval would be important. Keeping the person in close follow-up so that we can also screen them for symptoms would also be important to help to clarify the diagnosis.

Option 3: Stop PrEP
On the right-hand side there is another approach, which applies to oral PrEP only: to stop their PrEP altogether.

We and the person affected might do this to clarify the diagnosis without the picture being confused by the presence of PrEP drugs. This would allow any virus that is actually starting to replicate to more definitively move into that explosive phase of replication. That should definitively drive a clear Ag/Ab response that we would be able to pick up with a subsequent test.

The disadvantage of this is, of course, that we leave the person vulnerable to acquisition of HIV if they haven't actually seroconverted in the first place. With this management option, it would be important to counsel the person very carefully about the need to use alternative prevention strategies (such as traditional barrier precautions like condoms) or to take a break from their usual sexual activities.

If someone acquires HIV while they are taking PrEP (which is technically an incomplete HIV treatment regimen), what is the risk that we could drive the emergence of resistance?

There are 2 potential scenarios underlying the emergence of this resistance. One is that a person can seroconvert without realizing it and, if they continue to take their PrEP (particularly if they take it inconsistently), this can drive the emergence of resistance. That is the main scenario that we worry about.

By contrast, it is also possible that a person takes their PrEP consistently but is exposed to a virus that is resistant. We would call this transmitted resistance that leads to the PrEP failing.

We have good data from PrEP studies describing the frequency with which PrEP drug–associated resistance mutations are seen in the few people who do seroconvert. The table shows the frequency and proportion of cases in which mutations associated with resistance to FTC and/or TDF were observed in different types of studies. In many of the early studies, the percentage was in the single digits but in the larger population studies, the percentage is around 22%.⁷

Data are also emerging from the HPTN 083 and HPTN 084 trials with injectable LA CAB regarding the frequency of resistance to integrase strand transfer inhibitors (INSTIs). In those trials, there have been a modest number of breakthrough HIV infections that have harbored major INSTI mutations.^5,6,8 This is important because these mutations could potentially compromise our ability to use many first-line treatment options, which usually rely on integrase inhibitors plus 2 NRTIs as the core regimen.

What are we going to decide with our case patient? As mentioned earlier, perhaps one of the more conservative options would be to rapidly initiate an ART regimen by intensifying what he is already receiving.

Why would we and the person choose to do this? There is a lot of good evidence accumulated across multiple studies—in any HIV diagnosis, not just after PrEP—demonstrating that rapidly initiating ART is beneficial to the patient. It is associated with several positive outcomes summarized in the forest plot, including better retention in care, better viral suppression at 12 months, and even improved mortality.^9-13

Although these studies were done in largely resource-limited settings, on the next slide you will see that the spirit underlying these data has been adopted by major guidelines around the world.

The Department of Health and Human Services, International AIDS Society USA, European AIDS Clinical Society, and World Health Organization guidelines all recommend this concept of rapid initiation of ART.^14-17

This is not only because of the benefits to the individual, but because there is a broader public health benefit of reducing the risk of onward transmission to potential sexual partners. This is particularly relevant in the setting of someone who seroconverts while on PrEP.

If we are going to intensify, if we are going to recommend that this person use ART, what are we actually going to recommend?

If we look at these common guidelines, the first-line recommended treatment options are 3-drug regimens that typically consist of a later-generation INSTI such as bictegravir (BIC) or dolutegravir (DTG) combined with a tenofovir-based nucleoside reverse transcriptase inhibitor (NRTI) backbone, either TDF or tenofovir alafenamide (TAF), with either lamivudine (3TC) or FTC.^14-16

Some guidelines also recommend boosted darunavir with a NRTI backbone. This may be a particularly helpful regimen to use if you have someone who has seroconverted in the context of LA CAB use because of the concern about INSTI resistance that we have just alluded to from the HPTN 083 and 084 trials.

We discussed earlier how, if someone seroconverts in the context of PrEP, there is the risk of resistance. In the case of oral FTC/TDF or FTC/TAF PrEP, one might be concerned about that small but nontrivial risk of NRTI resistance.

So how do we square that risk with the first-line recommended treatment regimens that we reviewed on the previous slide?

Fortunately, data from the NADIA trial demonstrate that even in the setting of NRTI resistance, some key first-line treatment options that rely on a later-generation integrase inhibitor are still associated with virologic success.¹⁸

The NADIA trial was a multicentered two-by-two factorial randomized controlled trial where participants were randomized to an anchor drug that was either DTG (blue box) or ritonavir-boosted darunavir (DRV) (orange box).

To the right-hand side of the anchor drug, the different NRTI backbones used are shown: 3TC/TDF or 3TC/zidovudine.

Of most importance, this was a trial of second-line therapy—hence 50% of participants had a K65 mutation that would have conferred resistance to tenofovir, and 86% of participants had an M184 mutation that would have conferred resistance to 3TC or FTC.

On the next slide, we can see what the results were with these regimens.

Among the participants who received DTG with a nucleoside backbone, 90% had an undetectable viral load at Week 48. Those high success rates were maintained at Week 96.^18,19 This was not significantly different from the outcomes with ritonavir-boosted DRV.

These results tell us is that in individuals with a resistant virus where the NRTIs are only partially effective, these regimens are still able to overcome that resistance and produce virologic success.

Observational data with BIC from the prospective, observational cohort BICSTaR study also support this notion. On this regimen, 97.8% of the treatment experienced patients with M184V/I achieved the primary endpoint.²⁰

The 48-week data from Study 380-4030 further demonstrated that switching from a DTG-based regimen to a BIC-based regimen was safe and effective, even in the presence of some baseline NRTI mutations.²¹

The early data leading to regulatory approval of INSTI-based regimens as first-line regimens showed that resistance to any agents within the regimen is rare. These are regimens with a high genetic barrier to resistance such that a rapid start—even without knowing for certain whether NRTI-resistance mutations are present—can be associated with virologic success.

If we and the person affected decide to start treatment, what are the treatment options?

As shown on the left of the slide, if the person was taking tenofovir-based PrEP, it is reasonable and appropriate to initiate a BIC-based or DTG-based 3-drug regimen (including a tenofovir-based backbone), and to adjust the regimen once the results of HIV genotyping are obtained.

The regimens listed on the right of the slide are appropriate when someone acquires HIV while taking CAB-based PrEP or has recently been exposed to that agent as PrEP. In this instance, the risk of INSTI mutation is a little higher and is not something that we would expect to be overcome by BIC or DTG. In this situation, it is recommended to start with a boosted protease inhibitor (PI), specifically ritonavir or cobicistat-boosted DRV, with TDF or TAF, and 3TC or FTC.^14,15

To help with regimen choice, a useful tool is the computer-assisted decision support program called HIV-ASSIST.

When we plug our case details into the HIV-ASSIST tool, it generates a ranked list of treatment options that mirror the regimens that we just discussed.

As shown here, BIC with TAF and FTC, and DTG with TAF and FTC are recommended as potentially first-line options, as is a boosted DRV-based regimen.

For an individual like our patient who seroconverted while taking oral FTC/TDF PrEP, I think one of the best treatment strategies would be to rapidly start an INSTI-based regimen (BIC or DTG). This is supported by the rapid start literature that we have reviewed and by the various guidelines around the world, all of which support this as an excellent first-line treatment regimen.

We have also discussed that even though there is a small risk that this person could have either acquired or transmitted NRTI resistance related to their PrEP use, this regimen would still be expected to overcome that resistance and be associated with very high levels of treatment success in the long term.

I think that a rapid start with a DRV-based regimen would also be reasonable.

By contrast, in someone who seroconverts while taking LA CAB as PrEP, we have spoken about how the early data suggested that there is a nontrivial risk of major INSTI mutations that would compromise the success of the BIC- or DTG-based regimen. In that scenario, the rapid start option with a PI would be the clearly preferred option, and this is recommended in a number of guideline documents around the world. This PI regimen could potentially be tweaked once we get the baseline genotyping results back.