Antiretroviral therapy (ART) intramuscularly administered may have the same effectiveness as current oral treatments. This is the main conclusion of the Phase II clinical trial carried out by 50 centres around the world – 9 in Spain – to which the team of Dr Daniel Podzamczer, principal investigator of the Bellvitge Biomedical Research Institute (IDIBELL) and chief of the HIV and STD Unit of the Infectious Diseases Service of Bellvitge University Hospital (HUB) has contributed. The results of the trial pave the way to the implantation of all-injectable antiretroviral therapies with a lower frequency of administration, which would imply a significant improvement of the quality of life of HIV patients.
In the study, which involved 286 patients with previously suppressed viral loads, the effectiveness of the combination of carbotegravir – a new inegrase inhibitor – and rilpivirine – a no nucleoside – a injected intramuscularly every 4 or 8 weeks was tested in comparison to standard maintenance therapy, which includes three orally-administered drugs: carbotegravir and abacavir – lamivudine.
"This is the first time that all-injectable ART has been used in a trial; In addition, it consists of only 2 drugs, something that is not new but that supports the paradigm shift of 3 to 2 drugs in some virologically suppressed patients," says Podzamczer. The injected drugs are nanoparticles, which allows them to have a longer half-life of several weeks.
After 96 weeks, researchers found that 87% of patients in the group treated every 4 weeks and 94% in the one treated every 8 weeks maintained viral load suppression, a better figure than the one achieved in the standard oral treatment group, a 84%.
"With HIV, we are at a point of chronification of the disease; in a few years we have moved from giving 14 pills a day to one or two, but it is still a daily treatment that requires strict compliance. Therefore, spacing drug administration to once every month or every two months will potentially translate into improved adherence rates and improved quality of life for patients," explains Podzamczer.
At the same time, the levels of satisfaction of the participating patients were also evaluated; at the end of the trial, about 90% of patients in the groups treated intramuscularly were very satisfied with the idea of continuing with this type of treatment.
At the moment, participating centers and research teams are already working on the development of a new Phase III clinical trial that corroborates the results in terms of efficacy, safety and tolerability for both injectable treatments, every 4 and every 8 weeks.
Background: Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks.
Methods: In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir–lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir–lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352.
Findings: Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI −5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [−4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related.
Interpretation: The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated.
David A Margolis, Juan Gonzalez-Garcia, Hans-Jürgen Stellbrink, Joseph J Eron, Yazdan Yazdanpanah, Daniel Podzamczer, Thomas Lutz, Jonathan B Angel, Gary J Richmond, Bonaventura Clotet, Felix Gutierrez, Louis Sloan, Marty St Clair, Miranda Murray, Susan L Ford, Joseph Mrus, Parul Patel, Herta Crauwels, Sandy K Griffith, Kenneth C Sutton, David Dorey, Kimberly Y Smith, Peter E Williams, William R Spreen
[link url="https://www.sciencedaily.com/releases/2017/08/170803091942.htm"]IDIBELL-Bellvitge Biomedical Research Institute material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31917-7/fulltext"]The Lancet article summary[/link]