Learning from a case of breakthrough infection with long-acting cabotegravir for prevention

Long-acting cabotegravir (LA cab, sold as Apretude) has been approved in the U.S. and European Union. LA cab is used as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV infection.

In large clinical trials, HIV infections were relatively rare among people who used LA cab, who received injections on schedule and whose levels of cabotegravir in blood samples were in the expected range. In these trials, about 0.3% of these people became infected. The reason(s) that they became infected is not clear.

Diagnosing HIV

Researchers found that levels of HIV were initially very low in people who used LA cab and became infected. As a result, production of HIV antibodies by the immune system was greatly delayed—by several months after infection had occurred. These effects of a delayed antibody response to HIV infection can lead to a delayed diagnosis of HIV when using routine screening tests that rely on antibodies or HIV proteins. Prolonged and undetected HIV infection in people on LA cab could allow HIV to develop the ability to resist cabotegravir and other drugs that have a similar structure to it. These drugs are called integrase inhibitors.

Commonly used integrase inhibitors for the treatment of people with HIV include the following:

• bictegravir (in Biktarvy)
• dolutegravir (in Dovato, Juluca, Tivicay and Triumeq)
• raltegravir

Both bictegravir- and dolutegravir-containing regimens are highly effective, generally well tolerated and have relatively few interactions with other medicines. So, the development of HIV that is resistant to these drugs has consequences. Such resistance not only reduces future treatment options but may cause future combinations of treatment to be complex.

A team of researchers in the U.S. has noted that rare breakthrough infections that occur in people who use oral PrEP (tenofovir + FTC) can also result in delayed production of antibodies. However, such delays happen less often than they do with LA cab. The researchers noted that “the overwhelming majority of [tenofovir + FTC] breakthrough infections are a consequence of non- or poor adherence.” As a result of having low or no tenofovir + FTC in their blood, the chance of HIV developing resistance to these drugs is very small.

In 2021, the U.S. Centers for Disease Control and Prevention (CDC) recommended a combination of antibody and antigen testing and, in some circumstances, the addition of a viral load test to help clinicians uncover recent HIV infection in PrEP users. The CDC’s guidance is available here:

HIV Guidelines - Preventing New HIV Infections

Case details

A team of U.S. researchers recently published a report of the first documented case of HIV infection in a person who was taking LA cab outside of a clinical trial.

The patient was a young adult described by the researchers as a “sex diverse” person assigned male at birth. They had been taking tenofovir alafenamide (TAF) + FTC for PrEP once daily. The combination of TAF + FTC is sold as Descovy. The patient disclosed to their healthcare provider that they missed a dose of PrEP once a week. Therefore, they were interested in LA cab, as it could make adherence easier.

The researchers noted that the patient had hypothyroidism (low levels of thyroid hormone) that was poorly controlled with prescribed therapy. The patient also engaged in what the researchers described as “unsupervised” injections of testosterone. These injections, the researchers stated, led to “frequent injection site [bacterial infections of skin and soft issue].”

The person had oral and condomless anal sex with between 20 and 30 cisgender male partners a month. They had also begun to engage in receptive anal fisting. In the past six months they had been diagnosed with syphilis and anogenital mpox infection (formerly called monkeypox).

The person’s primary partner had HIV that was kept suppressed for the past two years on a combination of darunavir, cobicistat and dolutegravir.

The patient’s doctors stopped prescribing TAF + FTC and switched them directly to LA cab 600 mg injected into their left buttock on day zero and again 27 days later. At those times, HIV testing for antibodies and antigens was negative. HIV viral load testing (with a lower limit of 20 copies/mL) was also negative.

On day 76, the patient reported a flu-like illness. They tested positive for SARS-CoV-2 (the cause of COVID-19) and were prescribed a five-day course of Paxlovid (nirmatrelvir + ritonavir). This helped to clear their symptoms quickly.

On day 91, the patient received their third injection of LA cab. At this time, antibody and antigen tests for HIV were negative. However, a viral load test revealed that the person was likely infected with HIV, as their viral load was 30 copies/mL.

On day 100, the patient returned for repeat testing and the antibody and antigen tests were positive. Viral load was then 20 copies/mL. Subsequently that day, doctors prescribed TAF + FTC (Descovy) in addition to the LA cab that they were already taking.

On day 112, further blood tests revealed that the person’s antibody and antigen tests were negative and viral load was not detected. However, this does not mean that they were cured of HIV. Rather, their infection was caught relatively early, and their regimen was keeping the virus suppressed. As their viral load was too low to analyse for HIV that could be resistant to different drugs, and in order to ensure that the patient’s viral load stayed suppressed, doctors changed the regimen to darunavir, cobicistat and dolutegravir. This was the same combination that the patient’s partner was taking.

On day 128, the level of cabotegravir in the person’s blood was still relatively high.

On day 191, the person’s blood samples continued to test negative for HIV antibodies and antigens and their viral load was undetectable.

Long-acting early viral inhibition syndrome (LEVI)

According to the researchers, this person’s lab tests, minimal symptoms of early HIV infection, and delayed or “flickering” HIV antibody/antigen reactivity were consistent with long-acting early viral inhibition syndrome (LEVI). This has been recently described in people in clinical trials of LA cab who became infected with HIV. In contrast, in people who are not on long-acting PrEP, recent HIV infection is associated with a flu-like syndrome of varying severity and people test positive for HIV much sooner.

The U.S. researchers stated that their findings “underscore the significance of screening patients on long-acting PrEP agents with HIV-1 RNA assays rather than standard fourth generation antigen/antibody tests alone.” They added: “Had the standard HIV screening algorithm been utilized, this case would have gone undiagnosed potentially for several more weeks, increasing their risk of [resistance to integrase inhibitors]. Clinical trial data suggest that when fully suppressive ART [antiretroviral therapy] is initiated early after LEVI detection, [resistance to integrase inhibitors] may be avoided.”

Why did HIV infection occur?

The researchers are not sure why HIV infection occurred in this case. One possibility is a drug interaction—perhaps the use of Paxlovid reduced cabotegravir levels in the blood. However, this has not been previously reported and there is no background data to support it.

The researchers advanced the idea that perhaps the patient was exposed to a very high viral load that could have overwhelmed the protective effect of cabotegravir. Given the patient’s sexual history, the researchers suggested that injury to the anal mucosa could have occurred via fisting or from sexually transmitted infections. Syphilis and mpox can cause ulcers on the delicate anal mucosa, augmenting the amount of HIV that could get into the body.

The researchers noted the “transition from TAF + FTC to long-acting cabotegravir without overlap may represent a period of vulnerability [to HIV].” Infection during the period between the first and second injections of LA cab could also have occurred. The researchers underscore that some people can have low levels of cabotegravir in their blood after their first injection.

The researchers stated that an overlap of one month between tenofovir + FTC and the first injection of LA cab “may warrant further discussion.”

Note that in clinical trials that have enrolled thousands of people, participants first take oral cabotegravir (30 mg) in one pill per day for several weeks to raise and maintain the concentration of cabotegravir in the blood. After this, they then begin injections of LA cab. In the case of the person reported here, there was no initial phase of taking oral cabotegravir.

Cabotegravir concentrations

Research by scientists outside of this case report suggests that blood levels of cabotegravir when there is no oral lead in period (no pills are used and the patient goes directly to injection of LA cab) reach high protective levels in 90% of patients about three days after the first injection. A week after the first injection 95% of patients have high protective levels of cabotegravir in their blood.

The amount of cabotegravir in the blood that is considered protective is based on experiments with monkeys exposed to high concentrations of SHIV (simian human immunodeficiency virus). This virus is used in experiments with monkeys as it is infectious and can cause disease relatively quickly.

The dose of LA cab used in studies with people was chosen based on the data from monkeys so that maximal protection from HIV would occur in people. This is why researchers stated that rates of infection were “rare” among people who received injections on time in such trials. To put such infections in context, the researchers stated that in clinical trials, “we have now identified six cabotegravir infections to date that occurred despite on-time injections.” Furthermore, the researchers stated that these six cases occurred “among 2,282 participants assigned to long-acting PrEP (LA cab).” Note that six out of 2,282 is 0.26%.

The present case report likely represents a very rare event. Note that very rare cases of breakthrough infection have also occurred in people who used tenofovir DF + FTC as PrEP. However, the data to date suggest that when used as directed for PrEP, either LA cab or tenofovir + FTC reduces the risk of HIV infection by more than 99%.

For the future

The researchers noted that the present case “highlights the diagnostic and management challenges that may occur with such PrEP failures. Prescribers of long-acting PrEP agents need to be able to identify LEVI syndrome and act urgently to prevent possible [resistance to integrase inhibitors].” Furthermore, they added that “this potential benefit of including HIV-1 RNA testing in diagnostic algorithms must be carefully balanced against the possibility of false positive results that can lead to delays in PrEP administration and significant emotional distress for the patient and confusion/frustration for the medical team.”

The researchers call for “robust” partnerships between academic medical centres and healthcare providers working in the community “to ensure access to provider education and resources.”

As mentioned earlier, the patient’s intermittent positive HIV antibody/antigen tests and very low viral load in the context of long-acting PrEP use, combined with early detection of HIV, may have implications for cure research. For instance, it is possible that the pool of infected cells in their body is relatively low compared to what would typically be found in a person not taking PrEP who became infected. If this is the case, then the researchers suggest that perhaps attempts at effecting a cure for HIV may have a greater chance of success in someone who was on LA cab and whose infection was caught early than in someone not on LA cab. This idea needs to be tested in clinical trials.

—Sean R. Hosein

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