The ‘long tail’ problem: injected-PrEP trial will be extended due to persistence of drug in companion study

A study presented at last month’s HIV Research for Prevention (HIVR4P) conference in Chicago shows that in a minority of subjects who were given an experimental injectable drug as HIV pre-exposure prophylaxis (PrEP), the drug was still measurable in their body a full year after their last injection.

In the ECLAIR study, levels of the drug cabotegravir were above the lower limit of quantification in 14 out of 86 participants (16%) a year after their last injection, but below the IC₉₀ – the level that, in treatment, slows HIV replication by 90%.

Obviously if people stop having PrEP injections they become vulnerable to HIV unless they start oral PrEP or start/continue another method of HIV prevention. In addition, though, the ‘long tail’ in some people means that there is a lengthy period during which, if they catch HIV, they could develop drug resistance. Drug resistance only arises in situations like this when there is some drug in the body but not enough to fully suppress an infection. 

Because of this unexpected persistence of cabotegravir, the study’s principal investigator, Raphael Landovitz, in answer to a question, told delegates that a companion study to ECLAIR, HPTN 077, would be extended by 24 weeks to find out how long measurable drug levels persist. In HPTN 077, cabotegravir is being given either as 800mg injections every twelve weeks, or 600mg every eight weeks, so it may be possible to find out if smaller and more frequent injections may shorten the 'tail'.

This may slightly delay the start of the planned phase III efficacy study, HPTN 083, which is planned to measure the efficacy of cabotegravir in preventing HIV (ECLAIR and HPTN 077, as phase II studies, are designed to measure safety and drug absorption, not efficacy). “We hope HPTN 083 will only be delayed slightly,” Landovitz told delegates, "and we still hope to have it up and running by the end of the year. People enrolled in HPTN 083 are being informed of the ECLAIR findings and being re-consented to allow for any variations being needed in the trial protocol.

The ECLAIR study

The principal results of the ECLAIR study were announced at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last February. In brief, after a month taking oral cabotegravir to rule out short-term side-effects, 105 volunteers, all gay men aged 18 to 65 defined as being at low risk of HIV, were given three intramuscular injections of cabotegravir spaced 12 weeks apart, at 5, 17 and 29 weeks after the start of the study. Twenty-one other volunteers were given placebo pills/injections.

The main findings of the study were as follows. There were no significant safety concerns and no serious drug-related adverse events. Also, although people complained that the injections (in the buttocks) were painful, they nonetheless said they would prefer injectable PrEP to having to take daily pills.In the majority of participants, cabotegravir reached higher peaks and was actually eliminated faster from the body than expected - but this was not the case in a minority.

The follow-up phase of ECLAIR looked at how drug levels decayed in the body after the last injection. At week 41 of the study, 12 weeks after the last injection, 3% of cabotegravir recipients had no detectable drug in their blood, while in 12% levels were between the lowest detectable quantity (25 nanograms/ml (ng/ml)) and the IC₉₀ (166 ng/ml). This is of concern as it means that 15% people would not be protected from HIV unless they start/continue some other form of HIV prevention, and 12% could be at risk of developing resistance.

In measurements taken at 24, 36, and 48 weeks after the last injection (and another one taken at week 52 to get levels a full year after the last injection), the interest shifted to people who did still have detectable drug in their body.

At week 53 of the study, 24 weeks or just under six months after their last injection, nearly a quarter of people still had cabotegravir levels that would probably be effective as PrEP: 19% had levels between the IC₉₀ and four times that value (644 ng/ml), which was pre-defined as the minimum desirable trough level in injection recipients, while 5% had levels between 4x IC₉₀ and the average level seen in the LATTE trial of injectable cabotegravir as treatment, which was 1350 ng/ml. However, 41% had levels between the lower limit of quantification (LLOQ – the level of detectability) and the IC₉₀.

This left 35% with no detectable drug in their body. One of these people caught HIV and at their visit must have been in acute HIV infection as they had no detectable HIV antibodies but a very high viral load. Their HIV had no drug resistance. (The only other person who caught HIV during the study was a person receiving placebo during the injection phase).

At week 65 of the study, 36 weeks or over eight months after their last injection, 9% still had drug levels between the IC₉₀ levels and the 4x IC9₉₀ level and nearly a quarter, 22%, had drug levels between the LLOQ and the IC_90. By week 77, 48 weeks or 11 months after their last injection, no one had potentially effective levels of PrEP in their body but 16% had measurable drug between the LLOQ and the IC₉₀ and the same individuals (14 people) still had measurable drug a month later, one year after their last injection.

Body weight affects drug absorption and elimination

Given that the average study participant actually eliminated the cabotegravir from their body faster than anticipated, what was different with the minority who eliminated it slower? The answer appears to be that heavier people both absorbed and eliminated drug much more slowly.

The average Body Mass Index (BMI) of people in the study was 26 kg/m². The 60 people classed as ‘fast absorbers/eliminators’ in the study had a median BMI of about 25 and a range of 18-37 kg/m² . None of the 14 slow absorbers/eliminators had a BMI below the trial median of 26; their median BMI was 32.5 and the range was 26-48 kg/m². There was also a group of 10 intermediate absorbers/eliminators whose average BMI was 27.5 and the range 23-41.5 kg/m².

This could imply some weight-related dose adjusting might be necessary. But it may also imply that people may need to take oral PrEP - or other prevention precautions - in order to cover the ‘long tail’ for more than a year. The extended follow-up period in HPTN 077 will hopefully see exactly how long drug levels continue to be detectable in some people.