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Dolutegravir for treatment of HIV: SPRING forwards? Commentary
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The Lancet, Early Online Publication, 8 January 2013
Laura J Waters, *Tristan J Barber
Genitourinary and HIV Medicine, Mortimer Market Centre,
Central and North West London NHS Foundation Trust,
London WC1E 6JB, UK

Dolutegravir is an integrase strand transfer inhibitor that has shown high and similar rates of efficacy to efavirenz in phase 2 trials,1 and superiority to efavirenz in the SINGLE study.2 In The Lancet, Francois Raffi and colleagues3 present 48-week results from the phase 3 randomised, double-blind SPRING-2 non-inferiority study, comparing two integrase inhibitors-raltegravir (400 mg twice daily) and dolutegravir (50 mg once daily)-in combination with two coformulated nucleoside reverse transcriptase inhibitors, tenofovir/emtricitabine or abacavir/lamivudine. Dolutegravir was non-inferior to raltegravir for the primary endpoint of the proportion of participants with viral loads of less than 50 copies per mL at 48 weeks, by US Food and Drug Administration (FDA) snapshot analysis. 361 (88%) patients in the dolutegravir group achieved the primary endpoint versus 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1; non-inferiority margin 10%), with similar low rates of adverse events in both groups.

Patients and clinicians will welcome any new, effective, and well tolerated addition to the repertoire of antiretroviral drugs, but several issues remain unaddressed by Raffi and colleagues' study. As is common in many phase 3 trials, the study population is arguably not representative of people living with HIV globally. Most study participants were white males and additional studies are needed to examine this promising drug combination in a broader demographic. Furthermore, the participants had fairly non-advanced disease with a median baseline HIV-1 RNA viral load of 4·52 (IQR 4·08-5·06) log10 copies per mL and a median baseline CD4 count of 359 (276-470) cells per μL; data are needed for more advanced disease. These limitations mean that commenting on the efficacy of the study regimens is difficult in individuals with advanced disease. Because dolutegravir will be available as a fixed-dose coformulation with abacavir and lamivudine, its performance at high viral loads has been of interest, but findings from the SPRING-2 or SINGLE studies do not suggest that choice of nucleoside reverse transcriptase inhibitors has any effect on virological effectiveness.

Findings from in-vitro and phase 3 studies1, 2, 4 have shown that dolutegravir has a high genetic barrier to resistance development. In SPRING-2, one patient in the raltegravir group with high baseline viral load developed resistance to both integrase and nucleoside reverse transcriptase inhibitors; the fold change in susceptibility at virological failure was 2·02 for dolutegravir and 34 for raltegravir.

Rates of primary resistance to integrase inhibitors are presently low,5 but how the prevalence of background resistance evolves with increased use of this class, and the effect that change will have on treatment response rates in the future, will be of great interest. The high genetic barrier of dolutegravir is particularly appealing, and whether this characteristic will enable us to use this drug as we use protease inhibitors-eg, combined with another drug, or even as monotherapy-is clearly something that should be explored.

The issue of cardiovascular risk is pertinent to the planned dolutegravir coformulation. Abacavir has been inconsistently associated with an increased risk of myocardial infarction in cohort studies,6-9 and most consensus guidelines10, 11 recommend that this drug is avoided in individuals with a high risk of cardiovascular disease. In SPRING-2, selection of the nucleoside reverse transcriptase inhibitor backbone was at the investigators' discretion and 41% of study participants received coformulated abacavir/lamivudine. Reassuringly, the updated FDA analysis12 of clinical trials showed no effect of abacavir on rates of myocardial infarction. The effect of dolutegravir on surrogate markers of cardiovascular risk should be assessed in prospective, randomised, longitudinal studies. Similar to raltegravir, dolutegravir has a favourable effect on lipids.

Dolutegravir has an advantage as a once-daily drug compared with raltegravir; however, because of the double-blind, controlled design of SPRING-2, the effect of this advantage could not be assessed. Like raltegravir, dolutegravir has a favourable pharmacokinetic interaction profile.13 Dolutegravir provides an effective, well tolerated addition to an effective, well tolerated drug class. In the USA, two integrase inhibitors-raltegravir and elvitegravir-are licensed. Elvitegravir requires pharmacokinetic boosting and is only available as a fixed-dose combination (with tenofovir, emtricitabine, and cobicistat). By the end of 2013, a choice of four single-tablet regimens is expected: tenofovir disoproxil fumarate/emtricitabine/efavirenz, tenofovir disoproxil fumarate/emtricitabine/rilpivirine, tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat, and abacavir/lamivudine/dolutegravir. Single-tablet regimens have definite advantages and, not surprisingly, are preferred to regimens with several pills, as shown in patient surveys; however, data are scarce to support an advantage in effectiveness of single-pill regimens compared with use of separate drug components. These data are important because cost is a crucial consideration in all countries, and with key antiretrovirals scheduled to come off patent (eg, efavirenz in 2013), the evolution of new drugs and fixed-dose combinations will probably be defined by cost as much, if not more, than any other single factor. At a time when high levels of effectiveness are assumed and safety expected, alternative differentiators such as cost-effectiveness, convenience, patients' preferences, and quality of life, will need to be considered.
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