Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis

Abstract

Background: Optimal 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.

Methods: MEDLINE 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.

Results: 48 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.

Conclusion: In 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.

Figure 1. Prisma 2009 Flow diagram literature search and study selection.

PRISMA diagram showing the different steps of systematic review, starting from literature search to study selection and exclusion. At each step, the reasons for exclusion are indicated.

Figure 2. Quality assessment of the selected studies in systematic review.

Summary of the proportion of studies that fulfilled each quality assessment criterion. When no clear answer could be obtained for a specific criterion, it was classified as “unclear”. ART = Antiretroviral Treatment.

Figure 3. Forest Plot of mITT meta-analyses.

Panel A: Forest plot showing the meta-analysis of mITT data extracted from studies with therapy-naïve patients. Besides an overall analysis, three sub-analyses for three different comparisons are depicted. The black line indicates OR = 1, signifying no benefit of the INI arm compared to the non-INI arm. The dotted line shows the odds ratio of all included studies. The individual odds ratios as well as the proportionate weight in the overall analysis are shown in the right column. Panel B: Forest plot showing the meta-analysis of mITT data extracted from studies with ART-experienced patients in case of virological failure. Panel C: Forest plot showing the meta-analysis of mITT data extracted from studies with ART-experienced patients switching with suppressed viral load. mITT = modified intention-to-treat; ART = antiretroviral treatment; INI = integrase inhibitor; (N)NRTI = (non-)nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; T20 = enfuvirtide: OR = odds ratio.