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Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review.

ABSTRACT: Since the discovery of the first inhibitors of HIV replication, drug resistance has been a major problem in HIV therapy due in part to the high mutation rate of HIV. Therefore, the development of a predictive animal model is important to identify impending resistance mutations and to possibly inform treatment decisions. Significant advances have been made possible through use of nonhuman primates infected by SIV, SHIV, and simian-tropic HIV-1 (stHIV-1), and use of humanized mouse models of HIV-1 infections. In this review, we describe some of the findings from animal models used for the preclinical testing of integrase strand transfer inhibitors. These models have led to important findings about the potential role of integrase strand transfer inhibitors in both the prevention and treatment of HIV-1 infection.

SUBMITTER: Hassounah SA

PROVIDER: S-EPMC6423640 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review.

Hassounah Said A SA Mesplède Thibault T Wainberg Mark A MA

Pathogens & immunity 20160531 1

Since the discovery of the first inhibitors of HIV replication, drug resistance has been a major problem in HIV therapy due in part to the high mutation rate of HIV. Therefore, the development of a predictive animal model is important to identify impending resistance mutations and to possibly inform treatment decisions. Significant advances have been made possible through use of nonhuman primates infected by SIV, SHIV, and simian-tropic HIV-1 (stHIV-1), and use of humanized mouse models of HIV-1 ...[more]

PMID: 30993244

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Project description: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.

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Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review.

Publications

Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review.

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