Dual long-acting injections of cabotegravir plus rilpivirine: 32-week results from LATTE-2 study

22 March 2016. Related: Conference reports, Antiretrovirals, CROI 23 (Retrovirus) 2016.

Simon Collins, HIV i-Base

The idea of injections every few months as an alternative to daily oral drugs has always been popular. Although current ART is safe, effective and tolerable, some people hope for alternatives to pills.

The preference appears to persist – at least based on results from a late-breaking phase 2b study presented at CROI – even when the injections involve relatively large volumes into gluteal muscle.

David Margolis from ViiV Healthcare presented 32-week results from the LATTE-2 study, using a dual long-acting (LA) formulation of the integrase inhibitor cabotegravir (CAB) and the NNRTI rilpivirine (RPV). [1] Safety and efficacy of oral versions of these two drugs were previously established over 96 weeks in the LATTE-1 study.

LATTE-2 enrolled 309 treatment naive participants into a 20-week oral drug induction phase (CAB 30 mg + abacavir/3TC). Oral rilpivirine was added for the final four weeks and people with undetectable viral load from week 16 to 20 (91%, n=286) were randomised 2:2:1 to one of three open label arms: 4-weekly (4W) injections (n=115), 8-weekly (8W) injections (n=115) or a control arm continuing with oral CAB plus abacavir/3TC (n=56).

Baseline CD4 and viral load were 489 cells/mm³ and 4.3 log copies/mL (with 18% >5 logs). Only 8% of participants were women and 15% were African American.

At week 32, viral suppression to <50 copies/mL was achieved in 94%, 95% and 91% of the 4W, 8W and oral arms respectively, which met prespecificed criteria for showing each intramuscular injection (IM) arm was not worse than the oral treatment group. Virologic non-response rates were slightly lower in the 4W arm (<1% v 4% in the other arms) with lower non-virologic reasons for discontinuation in the 8W arm (vs 5% in each of the other two arms).

There were two protocol defined virologic failures (confirmed viral load >200 copies/mL), one in each of the 8W and oral arms, none with evidence of drug resistance.

Excluding injection site reactions (ISRs), tolerability was good, but with higher rates of fever (3%), fatigue (3%) and flu-like illness (2%) in the combined injection arm compared to a single report of fatigue in the oral arm. None of the grade 3/4 side effects were judged related to study drug, including the single death related to epilepsy.

ISRs were very commonly reported but reduced from 86% of participants at day 1 to 33% at week 32. Most were grade 1 (80%) or grade 2 (19%). Median duration of ISR was 3 days with 90% lasting less than 7 days. Most common reactions were pain (67%), swelling (7%) and nodules (6%). Only two participants stopped due to ISRs.

In a patient satisfaction survey >95% of participants reported injections were preferable to daily oral induction phase and that they would be willing to continue injection in the future.

In the PK analysis, cabotegravir stayed between the 10 to 30 mg target concentrations established in LATTE-1, with troughs well above the protein adjusted IC90. Although rilpvirine levels also remained well above the PA IC90, levels were lower over the first 16 weeks than achieved with 25 mg oral dose, and this was highlighted as an area that will need further study.

Comment

The translation of long-acting injectables from research studies to the real world may bring additional concerns, for example, how to withdraw drug when adverse events and drug reactions occur?

With the move to annual CD4 and viral load monitoring, undetected viral rebounds risk accumulating resistance over months of replication in the face of ongoing drug pressure? A related question is the impact of not being able to remove drug pressure on resistant virus once it is detected? Both these issues might be especially important for rilpivirine, which as an NNRTI is more vulnerable to drug resistance.

It is unclear whether cabotegravir will have the same resilience to drug resistance as dolutegravir in naive patients, or have the same vulnerability in people with previous integrase experience.

References:

Margolis DA et al. Cabotegravir+rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results
. 23rd CROI, 22-25 February 2016, Boston. Oral late breaker abstract 31LB.
http://www.croiconference.org/sessions/cabotegravirrilpivirine-long-acting-maintenance-therapy-latte-2-week-32-results (Abstract)
http://www.croiwebcasts.org/console/player/29459 (Webcast)