Integrase inhibitors

Along with reverse transcriptase and protease, a third HIV enzyme – integrase – is essential for viral replication. Integrase is responsible for inserting viral genomic DNA into the host chromosome. The integrase enzyme binds to host cell DNA, prepares an area on the viral DNA for integration, and then transfers this processed strand into the host cell’s genome.

There are various types of integrase inhibitors, including diketo acids, napthyridines, pyranodipyrimidines, and dihydroxythiophenes. The first drug from this class to be approved was:

  • raltegravir (Isentress)

Merck’s raltegravir (formerly known as MK-0518) gained accelerated marketing approval in the US in 2007 and in Europe in early 2008 for use in treatment-experienced patients. Raltegravir’s approval was based upon the results from the BENCHMRK 1 and 2 studies that demonstrated a durable anti-HIV effect in patients with triple-class resistant HIV.1

In treatment-naive patients, the Protocol 004 phase III study compared raltegravir to efavirenz, each given with tenofovir and 3TC. At week 96, raltegravir had a sustained antiretroviral effect, similar in effect to the efavirenz treatment arm. Raltegravir had a faster initial viral load decline; whether this is of consequence long-term is not known.2

Based on the results from the STARTMRK trial, a larger phase III study that also compared raltegravir versus efavirenz, this time given with tenofovir and emtricitabine (Truvada), in treatment-naive patients, raltegravir was approved in the US and the UK in 2009 for use in first-line regimens.3

Other studies are looking at whether individuals who are virologically suppressed on a boosted protease inhibitor-based regimen can be safely switched to a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen of raltegravir and atazanavir and at the safety and efficacy of raltegravir dosed once daily at 800mg.4

Elvitegravir (formerly GS 9137 and JTK-303) is a promising integrase inhibitor in late clinical development by Gilead Science. When studied in treatment-experienced patients with extensive drug resistance, viral load was more likely to fall below 50 copies/ml in the two higher-dose elvitegravir groups than in the protease inhibitor arm. Elvitegravir was well tolerated and few participants stopped taking the drug due to side-effects.5 6   

Unfortunately, there will probably be cross-resistance of this drug to raltegravir.7 8

In 2008, two phase III multicentre clinical trials began enrolling treatment-experienced individuals into non-inferiority studies comparing elvitegravir to raltegravir, each combined with an optimised treatment regimen. More ambitiously, another study is looking at elvitegravir, emtricitabine/tenofovir (Truvada), and the PK-enhancer GS-9350 combined in a once-daily 'quad' pill regimen versus Atripla (fixed-dose combination of emtricitabine, tenofovir, and efavirenz) as a first-line regimen.

ViiV Healthcare, the recently launched HIV specialist company formed by GlaxoSmithKline and Pfizer, is looking at an 'heir and a spare' in investigational integrase inhibitors 1349572 and S/GSK 1265744.

The second-generation drug 1349572 (also referred to as GSK 1349572 or GSK-572) performed well in a ten-day monotherapy, dose-ranging study in integrase inhibitor-naive patients. A phase III clinical study is moving ahead, looking at GSK-572 in combination with abacavir and 3TC. The product is dubbed '572-Tri'.9 10

S/GSK 1265744, ViiV's second integrase inhibitor, performed well in a dose-ranging monotherapy phase I/II study and further studies are planned. The half-life of this drug is 30 hours, nearly twice that of 1349572.11

For more information on raltegravir and elvitegravir, see A to Z of antiretroviral drugs.

References

  1. Steigbigel RT et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med359(4): 339-54, 2008
  2. Markowitz M et al. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr 52(3): 350-356, 2009
  3. Lennox JL et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374(9692): 796-806, 2009
  4. Mena A et al. A pilot study assessing Raltegravir (Isentress) QD versus BID in HIV patients inclluded in a simplification trial. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Franciso, abstract H-920, 2009
  5. Zolopa AR et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 143LB, 2007
  6. DeJesus E et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 43(1): 1-5, 2006
  7. Goethals O et al. Resistance mutations in HIV-1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 82(21):10366-10374, 2008
  8. Serrao E et al. Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 5(6): 25, 2009
  9. Lalezari J et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor, in integrase inhibitor naïve HIV-1-infected patients. Fifth IAS Conference on HIV Treatment, Pathogenesis and Prevention, abstract TuAb105, 2009
  10. Lou Y et al. Meta-analysis of safety for short-term dosing of an HIV integrase inhibitor, S/GSK1349572, from seven clinical studies. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-931/414, 2009
  11. Min S et al. Pharmacokinetics (PK) and safety in healthy and HIV-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-1228, 2009