HIV integrase inhibitors

Integrase strand transfer inhibitors (INSTIs) prevent the integration of HIV DNA into the nucleus of the host cell. Elvitegravir is only available as part of an FDC tablet with tenofovir or emtricitabine and cobicistat, unlike raltegravir and dolutegravir which are available as individual medications. Dolutegravir is also available co-formulated with abacavir and lamivudine or rilpivirine in a FDC tablet. Bictegravir is only available coformulated with tenofovir AF and emtricitabine. All four INSTIs are metabolised by glucuronidation via the enzyme UDP-glucuronosyltransferases (UGT1A1) to varying degrees, influencing their potential for drug-drug interactions with medications metabolised by cytochrome p450 enzymes. Raltegravir is exclusively metabolised by UGT1A1 whereas dolutegravir also has some elimination by CYP3A4 and elvitegravir is primarily metabolised by cytochrome p450 with a minor contribution from UGT1A1. Bictegravir is metabolised by both UGT1A1 and CYP3A. Dolutegravir inhibits OCT-2 in renal tubule cells, which is important for the excretion of creatinine and metformin. This inhibition results in an increase of the serum creatinine level by about 10 umol/L that does not indicate a true renal impairment. Bictegravir also does this to a lesser degree. No dose adjustment is needed for metformin when co-administrated. The potential for drug-drug interactions is greater when metabolised by cytochrome p450 enzymes, except for some circumstances when coadministered with potent UGT1A1 inducers, such as rifampicin. A long acting injectable version of a dolutegravir analogue (cabotegravir) is currently in development as a 2 monthly injectable therapy (Phase III).

Guidelines for INSTI dosing can be found in Table 6 and adverse effects are listed in Table 7.

Table 6. Guidelines on INSTI dosing

Table 7. Adverse effects of INSTIs