Long-acting HIV injection therapy is largely effective, but some breakthrough cases have raised eyebrows

Injectable HIV antiretroviral therapy (ART) was introduced in England and hundreds of patients are now injected every two months. Last week's British HIV Society spring meeting in Birmingham heard some of the first data to be rolled out in the UK. In general, injections are effective and loved by patients, although there are some withdrawals.

However, so far, two cases of virological failure due to drug resistance have been reported. This echoes the pattern in the clinical trials of ART injections, where 24 of the 2,313 study participants had virologic failures.

This 1% failure rate would be seen as an excellent outcome for oral treatments, but is a cause for concern, as researchers do not yet understand how it occurs despite apparent full compliance, and because three-quarters of participants experience drug failure that have developed resistance to one or both of the drug types used, which could limit future treatment options.

Injectable antiretroviral therapy uses long-acting formulations of the drugs cabotegravir (Vocabria) and rilpivirine (Rekambys). (In some other countries, including the United States, the same drug is packaged with the brand name of Cabenuva.) They are administered in the form of two injections, one for each drug. The first two doses are given one month apart and then every two months. There is an optional "import" of tablets for a month beforehand. This is to rule out rare cases of intolerance to cabotegravir or rilpivirine, but also because in some people, it takes time for the level of the injection therapy to reach saturation levels in the tissues.

The successes and failures of UK patients receiving injections in 12 clinics

Dr Kyle Ring from Queen Mary University of London presented data from 12 UK clinics, seven of which are located in London, with one each from Liverpool, Cardiff, Walsall, Blackpool and Newcastle. The clinics launched a patient cohort called SHARE LAI-net as part of the SHARE Alliance, which supports HIV and related research aimed at improving health inequalities.

So far, 518 people have been approved for injectable antiretroviral therapy and 433 have received at least one injection at SHARE LAI-net – others are waiting for the start or are in the process of oral introduction for a month. To date, those who have already started the injections have had an average injection time of 7.5 months – in other words, they are having their fourth or fifth injection.

The average age of people who started the injections was 46 years old. 30% are women, including 3 transgender women; The rest are cisgender men. Nearly half are white and 37% are black.

Prior to starting the injections, 52% used an integrase inhibitor-based regimen, 36% used an NNRTI-based regimen (including 14% oral rilpivirine), and 13% used a protease inhibitor-based regimen. 84% received triple therapy, which also included NRTI drugs; The rest (85 people) were almost exclusively given a combination pill of two drugs, mainly Dovato or Juluca, which contained another second-generation integrase inhibitor, dolutegravir.

Doctors were asked about the main reasons why their patients wanted injections. The most common was the "inconvenience" of taking pills daily, with 74 percent saying it was "stigmatizing" and 21 percent saying it was "afraid of disclosure." 15% cite frequent travel as a reason.

Of the patients who received more than one injection, 97% repeated the injections on time within the allowed seven-day window.

Twenty-five patients (6%) have stopped the injection. Four of these cases were due to detectable viral loads, as discussed below. Fourteen cases were due to side effects such as injection site reactions, 2 cases were found to be inconvenient injections, 2 cases were lost to follow-up, 1 case was not started because the oral regimen was not suppressed, 1 case was due to pregnancy, and 1 case died (not related to HIV).

Virus outbreaks and virus breakthroughs

A viral load test is done at each injection. Results over 50 copies/ml are classified as:

• "Flashpoints": These are individual viral loads of 50-200 with no one before or after another. These are not the criteria for stopping injections, in fact, 21 out of 24 (5% of the cohort). Spotting is not uncommon in oral treatment, where a single spot is often not associated with subsequent failure.
• "Low-level viremia": this is more than one continuous flash point of no more than 200. This does not count as a drug failure, but one patient in the cohort with a persistent viral load in the range of 50-200 opts to be re-treated with oral therapy.
• "Virus failure": This means more than 200 consecutive viral loads of more than one. Patients are advised to switch back to oral therapy.

In the SHARE LAI-net queue, there were 3 cases of virus failure. None of them were completely unexpected; Two of these had viral loads above 50 and the third was for those with viral loads above 50 on the previous two occasions, including at the time of the first injection at the end of the oral lead-in phase.

The first two did not acquire resistance. One of them was a 45-year-old black woman who tested for a viral load of 75 on her fourth shot. When she performed a repeat test, she had a viral load of 278, which was above the stop criterion, and 479 on subsequent tests. She resumed oral treatment with Biktarvy (biutegravir, tenofovir alafenamide, emtricitabine) and re-suppressed her viral load.

The second was a 63-year-old white man. He has a potential risk factor because he is very overweight, with a BMI of 40, on the verge of severe obesity. Obesity can lead to problems with the distribution of drugs in the body and may also require the use of longer needles. On the third injection, he had a viral load of 437. Although in subsequent tests, the 271 of this test was lower, it was still above the criteria for viral failure, so oral treatment with Delstrigo (doravirine, tenofovir disoproxil, lamivudine) was resumed, and he also re-suppressed the viral load.

The third case is even more worrying. This is a 40-year-old white man who had a staggering 109,000 viral load at his seventh shot, 11 months after receiving the vaccine. The repeat viral load test is 10300. On the sixth injection, he had a viral load of less than 50. A drug resistance test showed that he was carrying a mutated HIV virus called K101E, which under normal conditions developed about twice the resistance to rilpivirine — in other words, twice the amount of drug needed to suppress the virus.

Although the viral load was previously undetectable, his viral failure was not entirely unexpected. Prior to his first injection, he had a viral load of 64 at the end of his oral lead-in. Since there was no repetition later, this was counted as a flash in the pan and he was allowed to receive the injection.

However, he had a viral load of 194 at the time of his fifth injection, very close to the limit of his request for a resumption of oral therapy. Does this indicate that he had developed some level of resistance to one of his medications at the time of his fifth injection? Or is this the first sign that for some reason, his drug levels are at least intermittently too low? I don't know. We also don't know why his viral load rose so quickly in a month, or why – given the very high viral load of the drugs that failed to suppress it – he also didn't acquire resistance to cabotegravir.

In fact, resistance testing is often difficult to perform, so if he harbored undetected cabotegravir resistance, he was given an oral Symtuza (enhanced darunavir, tenofovir alafenamide, and emtricitabine) regimen as a protease-based inhibitor-based combination, avoiding integrase inhibitors and NNRTIs. This succeeded in suppressing his viral load below 50.

Another breakthrough case in Leeds

This is not the only case of an unexpected viral load breakthrough resistance reported at the meeting. Dr Katie Drury of Leeds Teaching Hospitals NHS Trust (not in SHARE LAI-net) outlines their experiences with the first 25 patients on Vocabria and Rekambys.

In fact, the hospital has assessed 40 patients as eligible for injectable antiretroviral therapy. Of these, physicians' assessment of the main reasons for eligibility was described as "psychological" in 26 (65%) – in other words, these individuals described depression, anxiety or stigma associated with oral antiretroviral therapy. In the other seven studies, the main reason was difficulty in adherence.

In fact, 12 out of 40 people rejected the offer of injections and one moved out of the area. One has not yet started, while one has already received injections because they are enrolled in the FLAIR study. This means that so far, 13 men and 13 women have started to be injected, ranging in age from under 24 to over 65. So far, the average duration of the injections is 13 months.

The two experienced a brief change in virology, but did not need to change the treatment. A person has a viral load of 70 at the third injection and 176 at the sixth injection. After that, they were suppressed for four more injections. The other had a viral load of 359 on the second injection but decided to continue with the injection. Over the next four injections (nine months), this became undetectable again, but at the time of presentation, their fifth injection had just appeared, with a viral load of 200, so it was not clear if they would be re-suppressed.

So far, only two people have had to stop. One is a pregnant woman. However, another virological failure was the case with resistance to both drugs. At the time of the first injection, he had a viral load of just over 50, but this was seen as a flash in the pan. The test was done on the day of his fifth injection, and it turned out that he had a viral load of 953 at the time, 1050 when retested two weeks later, and 1800 a week later. At this point, he was put on Symtuza, the same oral regimen as one of the breakthrough patients mentioned above.

The person was originally HIV and had a resistance mutation to rilpivirine called E138K, which is a typical mutation of resistance to oral rilpivirine, but there were also three resistance mutations to integrase inhibitors at positions 140, 148, and 155. He was infected with HIV, which is a mixture of wild-type and drug-resistant viruses, which usually indicates that it has only recently developed. Since he had been viralically suppressed since 2009, he had not been able to carry out resistance tests for several years, but in 2009 he had absolutely no rilpivirine resistance. Although he had not been tested for integrase resistance at the time, the drug was only new to the market, so it was unlikely that he would acquire transmissible resistance.

Dr. Drury describes the impact of failed injection therapy on patients as devastating. "He's someone who has experienced having to see everyday antiretroviral treatment as frustrating and looks forward to getting rid of that burden," she said. She added that a friend of his, who had also been considering an antiretroviral injection, decided not to take it when his treatment failed.

A deeper understanding of injection failure is needed

It is important to emphasize that breakthrough infections treated with injections are still rare, starting with only one case per 80-100 people. However, there is still a lot to understand about why injectable therapies occasionally fail under conditions of full compliance. Neither of the two patients in this report was infected with the A6 subtype HIV, which appears to increase the risk of failure, nor any of the other failure tendencies cited in this report, although we do not have detailed data on their drug levels. It seems to be true that the virus spots, even at fairly low levels, are associated with subsequent failures – especially those that were spotted at critical moments in the first injection. However, to remove all the "blippers" from the injections, 5% of people will be excluded from taking them.

There's a lot we don't know about resistance to integrase inhibitors, including cabotegravir. At last year's CROI, a study unexpectedly found that some mutations in HIV's env protein, rather than some in its integrase, may contribute to integrase resistance because they promote a form of "evasion" of the drug's effects.

A poster for BHIVA 2024 found that there was a higher failure rate in patients who started ART, which is usually an oral therapy, and that these patients had a specific env mutation called A539V. This condition is uncommon (35 out of 814 people) but is more common in people of African descent or people with a subtype of HIV called CRF02_AG. After 12 months of initiation of antiretroviral therapy, the rate of viral non-suppression was 29% on ART compared with 12% in those without A539V. While not all of these people are taking integrase inhibitors, any mutation in A539V plus integrase greatly increases the likelihood of viral failure.

It appears that doctors may have to expand their reach to detect warning signs that these otherwise popular and well-tolerated protocols may be failing.

Source: Liu Dahua, director of the Leather Department