The best responses to the experimental integrase inhibitor elvitegravir are seen when it is taken with T-20 (enfuvirtide, Fuzeon) and other active drugs, such as boosted protease inhibitors, according to results of an analysis presented on Tuesday at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.
Elvitegravir is an investigational integrase inhibitor (technically, a dihydroquinoline carboxylic acid strand transfer inhibitor). Its efficacy and safety is being evaluated in an ongoing randomised Phase II study, partially blinded (as to dose).
Data from this study, presented to the Conference on Retroviruses and Opportunistic Infections (CROI) earlier this year, showed that patients taking once-daily elvitegravir boosted by ritonavir had superior time-weighted reductions in viral load after 24 weeks compared to individuals randomised to receive a comparator ritonavir-boosted protease inhibitor.
The 278 original study participants all had significant prior exposure to antiretroviral therapy, with viral loads of at least 1000 copies/ml and at least one major protease inhibitor resistance mutation.
Participants were randomised to receive elvitegravir (at either 20mg, 50mg or 125mg daily) boosted with 100mg ritonavir, or a comparator ritonavir-boosted protease inhibitor chosen for maximal effect. All participants also received a background regimen of NRTIs, with or without the fusion inhibitor, T-20. After eight weeks, patients were permitted to add a boosted protease inhibitor to their regimen.
At baseline, the 73 patients who received elvitegravir had a median viral load of 80,000 copies/ml, with a median of eleven pre-existing protease inhibitor resistance mutations and three thymidine analogue resistance mutations (TAMs).
The CROI report describes the responses seen in the various treatment arms. New analyses presented at ICAAC by Andrew Zolopa now provide additional detail on how outcomes were affected by background therapy options and pre-existing resistance patterns.
Unsurprisingly, greater responses were seen in the patients with more active agents in their optimised background therapy (OBT). Considering only data from before the point at which protease inhibitors were added to the treatment protocol, 26 elvitegravir-treated patients began OBT that actually contained no drugs with phenotypic anti-HIV activity. Another 28 had at least one active drug in their OBT.
At week 24, viral load in the first group had fallen by 0.7 log10 copies/ml, compared to a 1.7 log10 copies/ml drop in the active-drug group. The largest drop, 2.9 log10 copies/ml, occurred in the 19 individuals who initiated treatment with T-20 for the first time when they started the trial. These differences were statistically significant (p = .027).
Considering only patients who began T-20 for the first time, the viral load drop at week 24 was 2.6 log10 copies/ml for those receiving elvitegravir versus 1.6 log10 copies/ml for those taking a comparator PI (p=.03). In this same (new to T-20) group, 74% (14/19) of patients taking elvitegravir reached a viral load level below 50 copies/ml by week 16, compared to only a quarter (3/12) of the comparator PI patients (p = 0.012).
Elvitegravir/ritonavir-treated patients who added a protease inhibitor to their therapy (23 individuals) had a further viral load decrease of 1.1 log10 copies/ml by week 16.
The investigators suggest that “regimens with elvitegravir/ritonavir 125mg and optimised background therapy including boosted protease inhibitors from the onset could have even greater antiviral activity and are planned for study.”