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The ‘long tail’ problem: forthcoming injected-PrEP efficacy trial delayed due to persistence of drug in some volunteers

November 11, 2016

Cabotegravir levels still measurable a year after last injection in one in six participants

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. In addiiton, 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 ECLAIR was being extended by a few months to find out how long measurable drug levels persisted.

This would have the effect of delaying HPTN 083, the phase III study planned to measure the efficacy of cabotegravir in preventing HIV (ECLAIR, a phase II study, was designed to measure safety and drug absorption, not efficacy). “We hope it will only be delayed slightly,” he told delegates.

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. In the majority of participants, cabotegravir reached higher peaks and was eliminated faster from the body than expected. Because of this, the HPTN083 study will give its volunteers injections every eight weeks, not every 12. 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.

The follow-up phase 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 and 12% would be at risk of developing resistance. This is why HPTN 083 will give the drug more frequently.

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 interests 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 in the “resistance zone” 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 in the ‘resistance zone’ between the LLOQ and the IC90. 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 in the ‘resistance zone’ and the same individuals (14 people) still had measurable drug a month later, one year after their last injection.

Body weight influences drug absorption: ECLAIR extended to find out more

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 also implies that the plan to continue giving participants in HPTN 083 oral tenofovir/emtricitabine (TDF/FTC, Truvada) in order to cover the ‘long tail’ might need to be extended further than the current planned 48 weeks after the last injection. The fact that the cabotegravir injections will also be 600mg each time instead of 800mg as in ECLAIR may mean that drug levels may not persist quite so long.

The current follow-up period at ECLAIR is being extended to see exactly how long drug levels continue to be detectable in some people, and to use that as the basis for modelling to find out how the lower but more frequent dose in HPTN 083 might change that.

By Gus Cairns

Reference

Ford S. ECLAIR Study of Cabotegravir LA Injections: Characterization of Safety and PK During the “PK Tail” Phase. HIV Research for Prevention (HIVR4P) conference, Chicago, Abstract OA12.06LB, 2016.

For a webcast of this presentation, see here.

Original Article