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TRIAL WATCH study, 414 patients with HIV received the -based regimen (50 mg dolutegravir plus the NRTIs and HIV inhibitor-based ) and 419 received Atripla (a single-tablet regimen composed of the regimen beats market leader NRTIs tenofovir and , and the NNRTI ) once daily. After 48 weeks, 88% of dolutegravir-treated patients were Shionogi-ViiV Healthcare has announced can develop more potent drug cocktails or virologically suppressed (<50 copies/mL) positive results from the Phase III SINGLE better second line regimens to treat those versus 81% of patients receiving Atripla. trial of their investigational HIV integrase with viral resistance. Because adherence can Only 2% of patients treated with dolutegravir inhibitor, dolutegravir, in treatment-naive be a challenge for some people, we also need discontinued the study due to adverse events, adults with HIV‑1. The dolutegravir-based to develop very long-acting formulations that compared to 10% of Atripla-treated patients. regimen demonstrated superiority over the are safe and fully suppressive.” Andrew Carr, “It will be important to see the results most widely prescribed HIV combination HIV, Immunology and Infectious Diseases of the SINGLE trial in the peer-reviewed therapy, Atripla (Gilead/BMS). Unit, St Vincent’s Hospital, Sydney, Australia, literature to fully understand its niche. Although there is no cure for HIV adds: “New drugs need to be at least equally But from the data we have seen, combination infection, progression to symptomatic potent, but also have additional advantages of dolutegravir, abacavir and lamivudine is disease can be halted or delayed in most over existing drugs — lower cost, less toxicity, a once-a-day regimen that is highly effective patients by using a combination of agents fewer drug interactions, once daily dosing, and well tolerated,” says Erbelding. targeting different stages of the viral life and a sufficiently low dose that permits ready Dolutegravir may offer advantages cycle. The current standard of care is highly co-formulation into single tablet regimens.” over other integrase inhibitors. Indeed, active antiretroviral therapy (HAART), HIV integrase inhibitors — which prevent 48‑week data from the SPRING-II Phase III which is a triple therapy that consists of viral DNA from integrating into the genetic trial indicate that once-daily dolutegravir a non-nucleoside reverse transcriptase material of the host cell, thereby blocking (50 mg) is non-inferior to twice-daily inhibitor (NNRTI), a protease HIV replication — have the potential to (400 mg) in treatment-naive inhibitor or an address some of the limitations of existing adults with HIV‑1. “Potential advantages integrase inhibitor in treatments. “Integrase inhibitors are an over raltegravir are dolutegravir’s once-daily combination with attractive fourth drug class. They have less dosing and lower dose, so increasing the two nucleoside CNS toxicity than the NNRTI efavirenz, potential for co-formulation”, notes Carr. reverse transcriptase and generally less gastrointestinal toxicity “In contrast, has several relative inhibitors (NRTIs). than protease inhibitors,” says Carr. disadvantages: it must be taken with food HAART, however, The first drug in this class, raltegravir and to enable once-daily dosing elvitegravir

NPG is associated with (Isentress; Merck), received US Food and is taken with the cytochrome P450 inhibitor several limitations, and Drug Administration approval . However, elvitegravir has the there is continued interest in in 2007, and elvitegravir advantage at present of co-formulation with the development of novel treatments. (Gilead) is next in line, tenofovir, emtricitabine and cobicistat into Emily Erbelding, National Institute closely pursued by a single-tablet regimen; co-formulation of of Allergy and Infectious Diseases, dolutegravir. dolutegravir, abacavir and lamivudine is Maryland, USA, explains: “Until we Results of the Phase anticipated”, he adds. can cure HIV, we will always be trying III SINGLE trial are Sarah Crunkhorn to identify new drug targets so that we encouraging. In the

664 | SEPTEMBER 2012 | VOLUME 11 www.nature.com/reviews/drugdisc

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