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HIVR4P 2016: The Long Tail Problem -- Injectable PrEP Trial To Be Extended Due to Drug Persistence

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

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In the ECLAIR study, cabotegravir levels 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, for treatment, lowers HIV replication by 90%.

Obviously, if people stop receiving PrEP injections they become vulnerable to HIV infection unless they start oral PrEP or another methods of HIV prevention. In addition, though, the "long tail" of cabotegravir seen in some people means that there is a lengthy period during which, if they catch HIV, they could develop drug resistance. Resistance only arises in situations like this where 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 800 mg injections every 12 weeks or 600 mg injections every 8 weeks, so it may be possible to find out if smaller and more frequent injections can shorten the "tail."

This may slightly delay the start of a planned Phase 3 efficacy study, HPTN 083, which intends to measure the efficacy of cabotegravir for preventing HIV. ECLAIR and HPTN 077, as Phase 2 studies, are designed to measure safety and drug absorption, not efficacy. People enrolled in HPTN 083 are being informed of the ECLAIR findings and being re-consented to allow for any variations needed in the trial protocol. "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."

The ECLAIR Study

The principal results of the ECLAIR study were announced at the Conference on Retroviruses and Opportunistic Infections 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 3 intramuscular injections of cabotegravir spaced 12 weeks apart, at 5, 17, and 29 weeks after the start of the study; 21 other volunteers were given placebo pills and injections.

The main findings of the study were as follows. There were no significant safety concerns and no serious drug-related adverse events. 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. For the majority of participants, cabotegravir reached higher peak levels and was actually eliminated faster from the body than expected -- but this was not the case for 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 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 drug resistance.

In measurements taken at 24, 36, and 48 weeks after the last injection, and another 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 6 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 4 times that value (644 ng/mL), which was pre-defined as the minimum desirable trough level in injection recipients, while 5% had levels between 4 times IC90 and the average level seen in the LATTE trial of injectable cabotegravir for HIV treatment, which was 1350 ng/mL.  However, 41% of participants 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 the acute stage of 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 8 months after their last injection -- 9% of participants still had drug levels between the IC90 level and the 4 times IC90 level, and nearly a quarter (22%) had drug levels 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 between the LLOQ and the IC90 and the same individuals (14 people) still had measurable drug a month later, 1 year after their last injection.

Body Weight Influences Drug Absorption

Given that the average study participant actually eliminated cabotegravir from their body faster than anticipated, what was different about 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" had a median BMI of about 25 and a range of 18-37. 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. There was also a group of 10 intermediate absorbers/eliminators whose average BMI was 27.5 and the range was 23-41.5.

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 HIV 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.

11/14/16

Source

S Ford, B Stancil, M Markowitz, et al. ECLAIR Study of Cabotegravir LA Injections: Characterization of Safety and PK During the "PK Tail" Phase. HIV Research for Prevention (HIVR4P 2016). Chicago, October 17-21, 2016. AbstractOA12.06LB.