Integrase inhibitors

crop_square Key points

  • check_circle High rates of sustained viral suppression with integrase inhibitor-based HIV treatment regimens
  • check_circle Block HIV integrase activity preventing the integration of retroviral DNA into the host cell’s genome
  • check_circle Active against HIV-1 and likely against HIV-2 (scarce data)
  • check_circle Undergo hepatic metabolization and are generally well-tolerated

crop_square Background and biochemistry

Integrase inhibitors (Integrase strand transfer inhibitors - INSTIs), are a relatively new class of antiretrovirals. Raltegravir was the first INSTI on the market after its approval in 2007. Other INSTIs have been approved as recently as 2021 (Carbotegravir). The discovery and subsequent market launch of INSTIs was another milestone in HIV therapy. INSTI-based HIV treatment regimens may achieve sustained viral suppression even in patients infected with multi-drug resistant HIV strains. The WHO currently recommend Dolutegravir-based regimens as first-line therapy for adults living with HIV. INSTIs are also used for HIV post-exposure prophylaxis (PEP).

crop_square Mechanism of action

Integrase inhibitors target HIV integrase, a key enzyme of the HIV life cycle. In its uninhibited state, integrase binds to the transcribed retroviral DNA and forms covalent bonds with cellular host DNA, facilitating the integration of retroviral DNA into the host cell’s genome. Integrase inhibitors bind to divalent cations of the enzyme which blocks the formation of covalent bonds with the cellular DNA, and prevents the integration of retroviral DNA. Numerous mutations to the integrase gene have been described which substantially reduce the enzyme’s susceptibility to one or more integrase inhibitors. However, mutations are rarely seen in treatment-naive patients with good medication adherence who were started on combination regimens. Newer integrase inhibitors like Dolutegravir have a higher genetic barrier to mutations.

crop_square Drugs and spectrum of activity

  • Bicte­gravir
  • Carbo­tegravir
  • Dolu­tegravir
  • Elvi­tegravir
  • Ral­tegravir

crop_square Pharmacokinetics

All available integrase inhibitors in clinical use are moderately to highly protein bound. Raltegravir, dolutegravir and bictegravir are (partly) metabolised by the liver enzyme uridine diphosphate glucuronyl transferase 1A1. Elvitegravir undergoes cytochrome P450 CYP3A4 metabolism and is combined with the pharmacokinetics booster Corbicistat, which inhibits CYP3A4. Integrase inhibitors are eliminated through the faeces to the largest part, while renal elimination plays a minor role in most agents.

crop_square Adverse drug effects

INSTIs are generally well-tolerated drugs. All agents may cause weight gain and a rise in serum creatinine levels. Moreover, neuropsychiatric adverse effects, rhabdomyolysis, and Steven-Johnson syndrome have been reported.