What is the role of integrase strand-transfer inhibitors in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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The crystal structure of HIV integrase was first described in 1994 and led to the identification of novel inhibitors. [55] No homolog for HIV integrase exists in humans; therefore, identification of selective inhibitors is expected to result in a low frequency of adverse effects. [56, 57] The FDA approved raltegravir (Isentress) in 2007 as the first integrase strand-transfer inhibitor (INSTI) available for use. [58]

In 2017, a once daily dosage form of raltegravir (Isentress HD) was approved for adults and adolescents who weigh at least 40 kg. It is administered as a 1200 mg once-daily dose that is given as two 600-mg tablets in combination with other antiretroviral agents in patients who are either treatment-naïve or virologically suppressed on an initial regimen of raltegravir 400 mg BID. The ONCEMRK clinical trial found raltegravir 1200 mg once daily to be noninferior to 400 mg BID. [59]

Elvitegravir was initially approved in August 2012 as a component of the FDA-approved ‘quad’ pill, elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild). The 4-component tablet contains a complete once-daily regimen for treatment-naïve adults and includes the pharmacokinetic booster, cobicistat (a CYP3A4 inhibitor without antiviral activity), to augment the serum concentrations of elvitegravir. [60]

Approval of the ART fixed dose combination product was based on analyses of 48-week data from 2 randomized, double-blind, active-controlled trials in treatment-naïve, HIV-1 infected individuals (n=1408). Results showed a single tablet regimen of Stribild met its primary objective of noninferiority compared to (efavirenz/emtricitabine/tenofovir DF) fixed-dose combination (Atripla) and to a regimen containing ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF (Truvada). [61, 62]  

A newer fixed dose formulation as elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya) was approved by the FDA in November 2015 to improve the renal and bone safety profile of tenofovir.  Noninferiority was demonstrated in two phase III studies when compared with the elivitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild) formulation. [63]

Dolutegravir (Tivicay) was approved by the FDA in August 2013 for treatment of HIV-1 infection in combination with other antiretroviral agents in adults and children aged 12 years or older who weigh at least 40 kg.

A wide-ranging phase III trial program included 2 trials in treatment-naïve patients. The first trial included 822 HIV-infected, treatment-naïve patients randomized to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily) in combination with a fixed-dose dual-NRTI treatment. At week 48, virologic suppression was similar between the 2 groups; 88% for dolutegravir and 86% for raltegravir. [64]

The second trial also included treatment-naïve patients (n=833) and compared a once-daily dolutegravir regimen plus abacavir/lamivudine to once-daily efavirenz/emtricitabine/tenofovir DF (Atripla). A statistically significant improvement in virologic suppression was observed with dolutegravir (88%) compared with Atripla (81%). [65]

A third phase III trial studied 719 treatment-experienced patients who were failing on current therapy but had not previously been treated with an integrase inhibitor. Participants were randomized to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg. At week 24, 79% of patients on the regimen containing dolutegravir were virologically suppressed compared with 70% of patients on the regimen containing raltegravir. [66]

The VIKING-3 trial studied 183 treatment-experienced patients with resistance to multiple antiretroviral classes, including resistance to integrase inhibitors. Researchers evaluated the effectiveness of twice-daily dolutegravir on reducing viral loads in these patients and found the regimen improved virologic suppression at 24 weeks (63%). However, poor response was observed with INSTI-resistance involving Q148 plus 2 or more INSTI resistance substitutions. [67]

Approval of dolutegravir for the indication in children aged 12 years or older was based on data in integrase-naïve patients.

Bictegravir is an INSTI that was FDA approved as a once-daily, fixed dose combination tablet with emtricitabine/tenofovir AF in February 2018 (Biktarvy).  This combination is indicated for the treatment of antiretroviral-naïve patients or as a replacement for existing antiretroviral therapy in patients with viral suppression below 50 copies/mL for at least three months and no history of prior treatment failure or underlying resistance. 

FDA approval of bictegravir is based in part on two phase III, randomized, double-blind, non-inferiority studies comparing the fixed dose combination of bictegravir/emtricitabine/tenofovir AF with dolutegravir and lamivudine/abacavir either administered as separate components or as a coformulation in antiretroviral-naïve patients.  At 48 weeks, 89-92% and 93% of patients achieved viral suppression below 50 copies/mL in the bictegravir and dolutegravir treatment arms, respectively. [68, 69]

Two additional phase III, randomized studies examined switching patients with stable viral suppression below 50 copies/mL for at least three months from dolutegravir- or boosted protease inhibitor (atazanavir, darunavir)-based regimens to bictegravir/emtricitabine/tenofovir AF.  After 48 weeks, 92-94% in the bictegravir treatment arms maintained viral suppression compared with 95% and 89% in the dolutegravir and boosted protease inhibitor treatment arms, respectively, meeting the study definition for noninferiority. [70, 71]

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