title: Therapy-Emergent Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Patients: A Subgroup Meta-Analysis of Clinical Trials.
abstract: BACKGROUND
  Integrase strand transfer inhibitors (INSTIs) are a novel class of anti-HIV agents that show high activity in inhibiting HIV-1 replication. Currently, licensed INSTIs include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG); these drugs have played a critical role in AIDS therapy, serving as additional weapons in the arsenal for treating patients infected with HIV-1. To date, long-term data regarding clinical experience with INSTI use and the emergence of resistance remain scarce. However, the literature is likely now sufficiently comprehensive to warrant a meta-analysis of resistance to INSTIs.
  
  
  METHODS
  Our team implemented a manuscript retrieval protocol using Medical Subject Headings (MeSH) via the Web of Science, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases. We screened the literature based on inclusion and exclusion criteria and then performed a quality analysis and evaluation using RevMan software, Stata software, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). We also performed a subgroup analysis. Finally, we calculated resistance rates and risk ratios (RRs) for the three types of drugs.
  
  
  RESULTS
  We identified 26 references via the database search. A meta-analysis of the RAL data revealed that the resistance rate was 3.9% (95% CI = 2.9%-4.9%) for the selected randomized controlled trials (RCTs). However, the RAL resistance rate reached 40.9% (95% CI = 8.8%-72.9%) for the selected observational studies (OBSs). The rates of resistance to RAL that were associated with HIV subtypes A, B, and C as well as with more complex subtypes were 0.1% (95% CI = -0.7%-0.9%), 2.5% (95% CI = 0.5%-4.5%), 4.6% (95% CI = 2.7%-6.6%) and 2.2% (95% CI = 0.7%-3.7%), respectively. The rates of resistance to EVG and DTG were 1.2% (95% CI = 0.2%-2.2%) and 0.1% (95% CI = -0.2%-0.5%), respectively. Furthermore, we found that the RRs for antiviral resistance were 0.414 (95% CI = 0.210-0.816) between DTG and RAL and 0.499 (95% CI = 0.255-0.977) between EVG and RAL. When RAL was separately co-administered with nuclear nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs), the rates of resistance to RAL were 0.2% (95% CI = -0.1%-0.5%) and 0.2% (95% CI = -0.2%-0.6%), respectively. The ten major integrase mutations (including N155H, Y143C/R, Q148H/R, Y143Y/H, L74L/M, E92Q, E138E/A, Y143C, Q148Q and Y143S) can reduce the sensitivity of RAL and EVG. The resistance of DTG is mainly shown in 13 integrase mutations (including T97T/A, E138E/D, V151V/I, N155H, Q148, Y143C/H/R, T66A and E92Q).
  
  
  CONCLUSIONS
  Our results reveal that the DTG resistance rate was lower than the RAL resistance rate in a head-to-head comparison. Moreover, we confirmed that the EVG resistance rate was lower than the RAL resistance rate. In addition, our results revealed that the resistance rate of RAL was lower than that of efavirenz. The rates of resistance to RAL, EVG and DTG were specifically 3.9%, 1.2% and 0.1%, respectively. Compared with other types of antiviral drugs, the rates of resistance to INSTIs are generally lower. Unfortunately, the EVG and DTG resistance rates could not be compared because of a lack of data.
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jiangzhou
authors.identifier: http://orcid.org/0000-0002-1333-1808
authors.initials: J
authors.lastname: You
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Hongren
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Baoning
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Li
mesh_terms: D002986:Clinical Trials as Topic; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir