Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial

Summary

Background

Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses.

Methods

In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per μL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015.

Findings

205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group—we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir.

Interpretation

Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials.

Funding

Shionogi-GlaxoSmithKline Pharmaceuticals, LLC, now Shionogi-ViiV Healthcare, LLC.

Introduction

Integrase inhibitors are a new class of antiretroviral drugs that block the action of HIV integrase, which catalyses several key steps in the life cycle of the virus and is essential for insertion of the viral genome into the DNA of the host cell. Because integration is a vital step in retroviral replication, integrase is a natural target for the treatment.¹ The first integrase inhibitor to receive market approval, raltegravir, is effective with good tolerability in combination therapy for HIV in both treatment-naive patients and those who have previously received antiretroviral treatment.2, 3 However, raltegravir must be given twice daily.4, 5 Elvitegravir, another integrase inhibitor in development, is given once daily but needs to be given with a pharmacokinetic booster such as ritonavir or cobicistat.⁶ Dolutegravir (S/GSK1349572) is a new drug in this class; in cell-culture assays at low nanomolar concentrations it is an effective inhibitor of HIV integrase and HIV replication.⁷ Pharmacokinetic studies in people have shown a long plasma half-life (about 14 h) without the need for a booster; in short-term monotherapy studies in adults with HIV, change from baseline in HIV RNA viral load ranged from 1·5 log₁₀ copies per mL to 2·5 log₁₀ copies per mL with 2 mg, 10 mg, and 50 mg of dolutegravir once daily.8, 9 Data from in-vitro passage experiments showed the potential for a higher barrier to resistance compared with raltegravir and elvitegravir.⁷ Finally, in-vitro experiments and data from the ongoing VIKING study (registered with ClinicalTrials.gov, number NCT00950859) suggest that dolutegravir retains activity against viral strains harbouring major integrase-inhibitor resistance mutations selected for by both raltegravir and elvitegravir, including Glu92Gln, Gln148His/Lys/Arg, Asn155His, and Gly140Ser/Gln148His.7, 10, 11, 12, 13 Therefore, dolutegravir has low cross-resistance with the potential for a higher barrier to resistance than other integrase inhibitors.

The objective of our phase 2b study was to assess the efficacy, safety, and pharmacokinetics of three doses of dolutegravir and a standard-care efavirenz-based regimen in adults not previously treated with antiretroviral drugs to select a dose for phase 3 development. Long-term follow-up of these participants will further characterise the risk to benefit ratio of the compound, including assessment of the emergence of drug-resistance isolates in the clinic.