Clinical Use of HIV Integrase Inhibitors: A Systematic Review and Meta-Analysis

Abstract

BackgroundOptimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings.MethodsMEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted.Results48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59–0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11–0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89–2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir.ConclusionIn first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment.

Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors

“…Our results show that viruses that were resistant to DTG were impaired in their ability to develop resistance against each of 3TC and NVP. These results help to explain why DTG resistance mutations that have the potential to lead to virological failure were only observed during the SAILING study [9] and not in clinical trials [10] that employed DTG in first-line therapy. …”

“…In clinical trials performed to date (reviewed in [10]), only four treatment-experienced INI-naive participants receiving DTG failed therapy with resistance mutations in integrase. All these individuals were enrolled in the SAILING trial and, in two cases, the R263K mutation was detected [8,9].…”

“…Individuals participating in the SAILING study were highly antiretroviral therapy-experienced and had been treated with suboptimal regimens due to the presence of multiple resistance mutations in each of the reverse transcriptase and protease regions of the viral genome. In contrast, no virological failure with resistance mutations has been reported for DTG in studies performed to date on treatment-naive individuals [10]. Yet, patients who have failed RAL-containing or EVG-containing regimens and who have developed mutations in integrase associated with these two drugs may not always respond well to DTG and may, in fact, develop further RAL-associated mutations in the event that treatment with DTG is not successful [8].…”

Multifunctional facets of retrovirus integrase

“…RAL and EVG were FDA approved for clinical use in 2007 and 2012, respectively, while DTG was approved in 2013. IN STIs are superior to other regimens in first-line therapies [80,81] . All three IN STIs have a high safety record and display strong efficacy [81] .…”

Quantitative structure–activity relationships study of potent pyridinone scaffold derivatives as HIV-1 integrase inhibitors with therapeutic applications

“…2,3 Hence, integrase is a signi¯cant target for chemotherapy and development of therapeutic anti-HIV-1 agents. 4 There are a number of diverse classes of compounds that inhibit integrase activity in vitro. Nevertheless, introducing novel anti-HIV-1 active integrase inhibitors is one of the main signi¯cant challenges, since toxicity, resistance and drug-drug interactions are important issues with anti-HIV drugs.…”