HIV Update
Guide:
News Flash: At the British HIV Association Spring Meeting, there is exciting news that England has begun to roll out bi-monthly injectable antiretroviral therapy (ART), bringing new treatment options to people living with HIV!
Treatment Options: This innovative treatment regimen uses long-acting formulations of cabotegravir (Vocabria) and rilpivirine (Rekambys). In countries such as the United States, the two drugs are marketed jointly under the brand name Cabenuva.
Treatment Efficacy: Currently, hundreds of patients have received this injection, and the overall treatment is effective and favored by patients. However, there have also been a few cases of treatment failure due to drug resistance, which has attracted the attention of the medical community.
Treatment challenges: Although a failure rate of 1% is already a good result for oral therapy, the failure of injectable ART is worrying. Researchers are trying to find out why treatment failures persist despite perfect adherence, and how to avoid patients becoming resistant to medications.
⚕️ Patient selection: Physicians found that the main reason patients chose injectable treatment was the daily inconvenience of oral pills (74%), followed by social stigma (25%) and fear of disclosure (21%) of HIV treatment.
Statistics: Of the 12 UK clinics involved in the study, 518 people have been approved to receive injectable ART, of which 433 have received at least one injection. The average age of participants was 46 years, with 30% of participants being women.
Treatment failure cases: In the SHARE LAI-net cohort, three cases of viral failure were recorded. These cases are not entirely unexpected, and all occur after the viral load exceeds 50.
Future outlook: Despite the challenges, injectable ART offers new possibilities for HIV treatment. The medical community will continue to monitor and research to improve treatment outcomes and reduce the risk of failure.
England has started rolling out bi-monthly injectable antiretroviral therapy (ART), bringing new treatment options to people living with HIV!
In the UK, a new type of injectable HIV antiretroviral therapy (ART) has begun to be made available to patients, and hundreds of patients are currently receiving this bi-monthly injection. At the recent spring meeting of the British HIV Association in Birmingham, attendees heard for the first time some preliminary data on the roll-out of the injectable therapy in England. Overall, this injectable therapy is not only effective but also popular with patients, although a small number of patients have opted out of treatment. However, a total of two cases of virological failure due to drug resistance have been reported. This is echoed by the performance of ART injections in scientific trials, where 24 of the 2,313 patients who participated in the study experienced virologic failure.
However, two cases of virological failure and drug resistance have been reported to date. This echoes the pattern observed in the scientific trials of ART injections, with 24 cases of virologic failure among 2313 study participants.
A failure rate of 1% would be seen as an excellent outcome in oral treatment drugs, but is now a cause for concern, as researchers do not yet understand how this can happen with apparently perfect adherence, and three-quarters of participants who experienced drug failure developed resistance to one or both of the types of drugs used, which may limit future treatment options.
Injectable ART uses long-acting formulations of the drugs cabogravir (Vocabria) and rilpivirine (Rekambys). (In some countries, including the United States, the two drugs are sold together under the brand name Cabenuva.) They are given in the form of two injections, and patients are given two injections, one at each rate, one month apart between the first two injections, and every two months thereafter. Prior to this, patients could choose to take a one-month pill as a "bootstrap period", both to rule out rare intolerance to cabogravir or rilpivirine, and because for some patients, it takes time for the drug levels of the injectable therapy to reach saturation levels in the tissues.
Dr. Mary of Queen Mary University of London Kyle Ring presented data from 12 UK clinics – seven in London and one each in Liverpool, Cardiff, Walsal, Blackpool and Newcastle. The clinics launched a patient cohort called SHARE LAI-net as part of the SHARE Coalition to improve health inequities, which supports HIV and related research.
So far, 518 people in SHARE LAI-net have been approved to receive injectable ART, of which 433 have received at least one injection – the rest are waiting for the start or are in the oral guidance period. To date, people who have started the injections have been using it for an average of 7.5 months – in other words, they have had their fourth or fifth injection.
The average age at initiation of the injection was 46 years. 30% of them are women, including 3 transgender women; The rest are cisgender males. Nearly half are white and 37% are black.
Prior to initiating injection, 52% of patients used an integrase inhibitor-based regimen, 36% used an NNRTI-based regimen (including 14% with oral rilpivirine), and 13% used a protease inhibitor-based regimen. 84% of patients used a triple therapy regimen, which also included NRTI drugs; The rest (85 people) used almost exclusively two-drug combination pills containing the second-generation integrase inhibitor dolutegravir, mainly Dovato or Juluca.
Doctors were asked about the main reasons why patients choose injections. The most common was the "inconvenience" of daily pills, which was mentioned by 74 per cent, but 25 per cent mentioned "shame" and 21 per cent mentioned "fear of disclosure". 15% gave frequent travel as a reason.
Ninety-seven percent of patients who received more than one injection had repeat injections on time within the allowed seven-day window.
Twenty-five patients (6%) stopped the injection. 4 of them were due to detectable viral loads, as described below. 14 were due to side effects, including injection site reactions; 2 people found the injection inconvenient; 2 were lost to follow-up; 1 person did not start because the oral regimen was not suppressed; One was pregnant and one died (not related to HIV).
Transient elevation of the virus and viral breakthrough
A viral load test is performed at each injection. Results over 50 copies/ml were classified as:
- "Briefly elevated": This is a single viral load of 50-200 with no other before or after. This was not a criterion for stopping injections, in fact there were 24 transient elevations in 21 people (5% of the cohort). In oral therapy, a single transient elevation is usually not associated with subsequent failure.
- "Low-level viremia": this is more than a continuous transient elevation, but not more than 200. It does not count as drug failure, but 1 patient in the cohort chose to return to oral therapy due to a persistent viral load in the 50-200 range.
- "Viral failure": This means more than one consecutive viral load of more than 200. Patients are advised to switch back to oral therapy.
In the SHARE LAI-net queue, there were three cases of virus failure. None of them were entirely unexpected; The first two cases were preceded by a viral load of more than 50, and the third case was in a person who had two prior viral loads over 50, including the first injection at the end of the oral guidance phase.
The first two did not acquire drug resistance. The first, a 45-year-old black woman, tested with a viral load of 75 at the fourth injection. When she repeated the test, the viral load was 278, exceeding the stop criterion, followed by a test of 479. She resumed oral treatment Biktarvy (bictegravir, tenofovir alafenamide, emtricitabine) and resuppressed her viral load.
The second was a 63-year-old white male. He has a potential risk factor, which is that he is severely overweight, with a BMI of 40, which is close to the brink of severe obesity. Obesity can lead to problems with drug distribution in the body and may also require the use of longer needles. He had a viral load of 437 at the time of his third injection. Despite being reduced to 271 in subsequent tests, he still exceeded the criteria for viral failure, so the oral treatment Delstrigo (doravirine, tenofovir disoproxil, lamivudine) was resumed, and he also resuppressed the viral load.
The third case is even more worrying. It was a 40-year-old white male who had a staggeringly high viral load of 109,000 at his seventh shot, 11 months after starting treatment. The repeat viral load test was 10,300. He had a viral load of less than 50 on his sixth injection. Resistance tests revealed that he had HIV, with a mutation called K101E, which would normally be about twice as resistant to rilpivirine — in other words, double the usual amount of medication needed to suppress the virus.
Although his previous viral load was undetectable, his viral failure was not entirely unexpected. He ended his oral guidance before the first injection with a viral load of 64. Since there was no repeat after this, it was calculated as a brief elevation and he was cleared 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 a forced return to oral treatment. Does this indicate that he already developed some degree of resistance to one of the drugs at the time of his fifth injection? Or is this the first sign that his drug levels are at least intermittently too low? We don't know. We also don't know why his viral load has risen so quickly in a month, or why – given this high viral load on drugs that fail to inhibit it – he also didn't acquire resistance to cabogravir.
In fact, resistance tests are often difficult to perform, so in cases where he may have hidden undetected cabogravir resistance, he was given an oral regimen of Symtuza (enhanced darunavir, tenofovir alafenamide, and emtricitabine), a combination based on protease inhibitors that avoids integrase inhibitors and NNRTIs. This successfully suppressed his viral load below 50.
Another case of breakthrough in Leeds
This is not the only case of unexpected viral load breakthrough and drug resistance reported at the meeting. Dr. Leeds Teaching Hospitals NHS Trust Katie Drury, an agency not in the SHARE LAI-net, outlined their experience with the first 25 patients who used Vocabria and Rekambys.
The hospital actually evaluated 40 patients who were eligible to receive ART injections. Of these, the primary reason for physicians' assessment of eligibility was described as "psychological" in 26 (65%) – in other words, these individuals described depression, anxiety or shame associated with taking oral ART. The main reason for the other 7 cases was difficulty in compliance.
Of the 40, 12 actually rejected the offer of injections and one moved out of the area. One person has not yet started, while one person has already received injections in the FLAIR study. This means that so far, 13 men and 13 women have started to receive the injections, ranging in age from under 24 to over 65 years old. So far, the average duration of the injections is 13 months.
Two people experienced transient elevation in virology, but no change in treatment was required. One of them had a viral load of 70 at the third injection and 176 at the sixth. They have since remained suppressed in four injections. The other had a viral load of 359 on the second injection, but decided to continue. This became undetectable again over the next four injections (nine months), but at the time of the demonstration a fifth injection had just been given with a viral load of 200, so it was not known if they would be re-suppressed.
So far, only two people have had to stop. A woman is pregnant. The other is a virological failure and is resistant to both drugs. He had a viral load of just over 50 at the time of his first injection, but this was seen as a brief elevation. He had a viral load of 953 on the day of his fifth injection, retested to 1050 two weeks later, and then 1800 a week later. At this time, he was given Symtuza, the same oral regimen as one of the breakthrough patients mentioned above.
The man was found to have HIV and a resistance mutation E138K to rilpivirine, which is typical of the mutations encountered in cases of oral rilpivirine resistance, but he also had three resistance mutations to integrase inhibitors, located at positions 140, 148 and 155. He has HIV, a mixture of wild-type and resistant viruses that are often a sign of recent development. Since he has maintained virological suppression since 2009, he has not been tested for resistance for many years, but in 2009 he did not have resistance to rilpivirine. Although he was not tested for resistance to integrase inhibitors at the time, it is unlikely that he had acquired transmissible resistance to the class because of the recent introduction of the drug. Dr. Drury describes the devastating effects of failed injection therapy on patients. "He's the kind of person who thinks it's a burden to have to take ART every day and looks forward to getting rid of that burden," she said. She also mentioned that the patient had a friend who was also considering an ART injection, but decided not to do so after seeing the patient's treatment fail.
A deeper understanding of the reasons for the failure of injectable therapies is needed
It is important to emphasize that breakthrough infections with injectable therapy are still rare, with only one in every 80 to 100 people starting treatment, despite perfect adherence to treatment. However, there is still a lot we don't understand why injectable therapies occasionally fail despite perfect adherence. Neither of the two patients in this report had the A6 subtype HIV, which appears to increase the risk of treatment failure, nor did they have a propensity for treatment failure as mentioned in the report, although we did not have detailed data on their drug levels. It appears that even transient elevations at fairly low levels of the virus are associated with subsequent treatment failures – especially those found during the critical period of the first injection. However, if all people who experienced transient elevations were excluded from injection therapy, 5% of people who used this therapy would be affected.
There's a lot we don't know about integrase inhibitor resistance, including cabogravir. At last year's CROI conference, a study found that some mutations in HIV's env protein, rather than in its integrase enzyme, may contribute to integrase resistance, as these mutations help HIV "escape" from the drug's action.
A poster presentation at BHIVA 2024 found that in patients initiating ART, usually oral therapy, there is a specific env mutation called A539V that is associated with a higher rate of treatment failure. This condition is uncommon (35 occurrences in 814 people), but it is more common in people of African ancestry or in people with a subtype of HIV called CRF02_AG. At 12 months after starting ART, the proportion of people with A539V who were not suppressed was 29% compared to 12% among those who did not carry it. While not all of these people are using integrase inhibitors, carrying any mutation in the integrase enzyme with A539V greatly increases the likelihood of viral treatment failure. It appears that doctors may need to monitor more broadly to look for warning signs that may signal the failure of these otherwise popular and well-tolerated treatment options.
Resources
Ring K et al. Management of viral blips and viraemia on injectable cabotegravir + rilpivirine in the UK. British HIV Association spring conference, Birmingham, abstract O07, 2024.
Drury K et al. Real life experience of injectable anti-HIV therapy at Leeds Teaching Hospitals Trust. British HIV Association spring conference, Birmingham, abstract P008, 2024.
Kelly C et al. Env mutation A539 is prevalent in newly diagnosed with HIV in the UK and is associated with suboptimal virological outcomes. British HIV Association spring conference, Birmingham, abstract P003, 2024.
HIV Update