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Integrase Inhibitors, Once-Daily Dosing Boost
First-ART Response in 77,999-Person Analysis
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HIV Drug Therapy, Glasgow 2018, October 28-31, 2018, Glasgow
Mark Mascolini
Starting antiretroviral therapy (ART) with an integrase inhibitor, with a once-daily regimen, or with a higher CD4 count raised virologic response rates in a 181-study, 77,999-person meta-analysis [1]. Response rates at weeks 48, 96, and 144 improved substantially after 2010.
Researchers at St. Vincent's Hospital and the University of New South Wales in Sydney noted that antiretroviral treatment guidelines rest on "serial assessment" of randomized controlled trial. Systematic reviews, they proposed, can offer more data and greater power to pinpoint predictors of treatment success.
The analysis built on an earlier 1994-2012 review of adult antiretroviral efficacy through week 144. Searching electronic databases, major HIV conferences, and HIV Web sites including NATAP, the researchers added studies up to July 2017. They excluded substandard regimens and observational studies. The researchers defined antiretroviral efficacy by the standard intention-to-treat approach. Predictive analyses used mixed-effect, meta-regression, and forward, stepwise variable selection.
All told, the Sydney team analyzed 181 studies involving 77,999 people, 37,875 of them added after 2012. Overall efficacy at 48 weeks improved from 57.2% for the earliest studies to 83.8% for the latest studies. Respective efficacy rates after 96 weeks were 51.6% and 79.9% and after 144 weeks 45.1% and 77.1% (P < 0.001 for all early-to-late comparisons). The researchers cautioned that only 41% of study groups had follow-up through week 96 and only 13% through week 144, so the potential for bias creeps in with analyses after week 48.
Multivariate analysis identified several independent predictors of greater efficacy:
> Taking a regimen based on an integrase inhibitor rather than a nonnucleoside or protease inhibitor improved response rates 9.3% or more at week 48, 9.0% or more at week 96, and 5.6% or more at week 144.
> Once-daily dosing (versus twice-daily) improved virologic response 3.4% at week 48.
> Every 100-cell higher pre-ART CD4 count improved week-48 virologic response by 2.2% and week-144 response by 0.8%.
> Every younger year of age improved week-144 responses by 1.0%.
Other factors independently associated with better response rates were (1) pretreatment genotyping, (2) no CD4 count restriction, (3) a placebo-controlled design, (4) a randomized design, and (5) a phase 3 versus 4 trial. Using a TDF (or TAF)/FTC backbone improved response rates in multivariate analysis, but that backbone was not superior to abacavir/lamivudine after exclusion of studies that did not incorporate HLA-B*5701 screening for abacavir hypersensitivity.
Despite the greater virologic efficacy of integrase inhibitor regimens, the researchers noted that those combinations failed in more than 20% of post-2010 trial participants through 144 weeks. Another cautionary note: The rate at which people stopped ART for virologic failure in these studies has not changed for more than 20 years. The researchers added that phase 3 trial results "progressively overestimate real-world efficacy."
Reference
1. Carr A, Richardson R, Liu Z. Success and failure of initial ART in adults: an updated systematic review including 77,999 subjects from 1994 to 2017. HIV Drug Therapy, Glasgow 2018, October 28-31, 2018, Glasgow. Abstract P051.
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