Results from the first proof-of-principle for injection only HIV treatment (ART) was presented as an oral late breaker by David Margolis from ViiV Healthcare.
This phase two study required an induction period using oral drugs and compared monthly and two-monthly intramuscular injections to a control group that remained on oral drugs throughout.
The was an open-label phase 2b study in 301 treatment-naive participants, randomised 2:2:1 to 4-weekly (4W) or 8-weekly (8W) injections or to oral ART (cabotegravir plus abacavir/3TC).
The 20-week induction phase used cabotegravir (30 mg once-daily) plus abacavir/3TC once-daily, adding in oral rilpivirine (25 mg once-daily) for the last four weeks. After induction, 91% (n=286) of participants continued into the randomised phase because their viral load was <50 copies/mL. The primary analysis at week 32 of the main study (ie starting after the induction period) was presented at CROI 2016 earlier this year -- and these data were used to select the 4-weekly dose for phase 3 studies.2
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 pre-specified 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).
By week 48, the percentage with <50 copies/mL dropped slightly to 91%, 92% and 89% of the 4W, 8W and oral arms respectively. Virologic non-response was greater in the 8W vs 4W arms (7% vs <1%) but this lead to few discontinuations (<1% vs 0). Discontinuations due to side effects or death was lower in the 8W group (0 vs 5%).
Tolerability at 48 weeks -- mainly linked to injection site reactions (ISRs) -- was similar to the 32 week results. Slightly higher rates of ISRs in the 8W group levels out to approximately 30% of participants by week 48. Of these, 82% were mild and 17% were moderate: 90% resolved within 7 days. The most common symptoms were pain (67%, nodules (7%) and swelling (6%). Only 2/230 participants (<1%) discontinued due to ISRs.
Other side effects generally occurred at low levels and were similar between injection groups: fever 5% vs 3% vs 0; fatigue 4% vs 2% vs 1%; flu-like symptoms 2% vs 3% vs 0; in the 4W, 8W and oral arms respectively, with headache reported by 2% in all arms.
Virological failure only occurred in two people in the 8W arm and 1 person in the oral group. Mutations associated with drug resistance to integrase inhibitors (Q148R) were only reported in one person in the 8W group.
In a patient survey, participants reported higher rates of satisfaction with injections compared to oral drugs and higher preference for continuing with current combination.
Even with the potential obstacles and disadvantages of intramuscular injections with very long half-lives, the option to not take daily pills has always been seen as exciting by many people -- even now once-daily single pill formulations are available.
Injectable long-acting ART is steadily getting closer, with phase 3 studies now planned using 4-weekly injections.
Long-acting cabotegravir injections are also being studied at PrEP in a phase2b/3 study in HIV negative men and transgender women, compared to a control arm of daily oral tenofovir/FTC.3
A poster at AIDS 2016 from a phase 2 study of cabotegravir LA PrEP reported preference over daily oral PrEP.4
- Margolis D et al. Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE-2 week 48 results. AIDS 2016, 18-22 July 2016, Durban. Oral late breaker abstract THAB0206LB.
www.natap.org/2016/IAC/IAC_48.htm (Slides online thanks to natap.org)
- 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.
- Clinicaltrials.gov. Safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis in HIV-uninfected cisgender men and transgender women who have sex with men.
- Kerrigan D et al. Experiences with long acting injectable (LAI) cabotegravir (CAB) as PrEP: a qualitative study among men participating in a phase II study (ECLAIR) in New York and San Francisco. AIDS 2016, 18-22 July 2016, Durban. Poster abstract WEPED393.
http://programme.aids2016.org/PAGMaterial/eposters/0_5405.pdf (Poster PDF)