HIV treatment guideline recommends two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third antiretroviral agent (ART) for the treatment of naïve patients.1 Integrase strand transfer inhibitors (INSTIs) represent a novel class of ART agents. It blocks the action of HIV integrase, thus preventing insertion of the viral genome into the DNA of the host cell.2 The Food and Drug Administration (FDA) approved a third INSTI, dolutegravir (DTG), brand name Tivicay, in August 12, 2013 for the treatment of HIV-1 infection in adults and children aged 12 years and older and weighing at least 40 kg.2
The first generation INSTIs, raltegravir (RAL) and elvitegravir (EVG) are effective and well tolerated in combination therapy in both treatment-naïve and treatment-experienced patients. However, RAL has to be given twice daily,3 while EVG is given once daily with food. EVG requires cobicistat or ritonavir (RTV) to boost its plasma concentrations.1 Both RAL and EVG share common resistance pathways4,5 and do not appear to have activity against opposing-resistant isolates.5
DTG is given once daily without regards to food and has a long plasma half-life (about 14 hours) without a pharmacokinetic booster. In-vitro studies suggest that DTG also exhibits lower propensities for resistance development and limited cross-resistance compared to RAL and EVG.2,3 Twice daily dosing is recommended in INSTI-resistance substitutions and with concomitant administration of potent UGT1A/CYP3A inducers. Coadministration with dofetilide is contraindicated.2
In clinical trials, DTG has been shown to be non-inferior compared to efavirenz (EFV) and RAL as part of an ART regimen with a primary endpoint of undetectable viral load. In dose-ranging SPRING-1 trial, treatment naïve patients in all DTG groups showed higher response rates (defined as proportion of subjects who met the primary endpoint) vs. EFV group (66% vs. 18%) in week 4.4 At week 96, response rates in the DTG group was 88% vs. 72% in EFV group.6 Median CD4 counts increased from baseline to week 96 and the DTG group has achieved higher counts than the EFV group, however this was not statistically significant.6
In the SPRING-2 trial, response rates in DTG and RAL group were 88% vs. 85% and 81% vs. 76% at weeks 48 and 96, respectively. However, the adjusted differences were not statistically significant.1,7 CD4 counts increased to 276 and 264 cells per µL in the DTG and RAL groups, respectively.1 The SAILING trial compared DTG with RAL in INSTI naïve patients with at least two drug class resistances and found response rates of 71% in DTG compared to 64 in RAL group (p=0.03).3 In the SINGLE trial, DTG plus abacavir (ABC) and lamivudine (3TC) had higher response rates of 88% vs. 81% in Atripla at week 48 in treatment-naïve adults. It was also statistically superior in CD4 change from baseline. 8
The VIKING trial studied the activity of DTG in HIV-1 patients with ...