FDA approves new once-daily treatment option for HIV

FDA approved dolutegravir (Tivicay, GlaxoSmithKline) in August 2013, for treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as part of combination antiretroviral therapy. Dolutegravir is an integrase strand transfer inhibitor (INSTI), which prohibits HIV-1 virus multiplication by interfering with HIV integrase, an enzyme required for viral replication. Dolutegravir is indicated for treatment of both INSTI-naïve and INSTI-experienced adults, but is indicated for pediatric patients only if they are INSTI-naive. A new, once-daily option, dolutegravir may allow improved personalization of a patient’s medication regimen.

Efficacy

FDA based its approval of dolutegravir for adults on four Phase III trials. In the studies, patients received dolutegravir or raltegravir plus additional appropriate antiretroviral therapy.

Two trials, SPRING-2 (n=822) and SINGLE (n=833) evaluated once-daily dolutegravir in INSTI treatment-naïve patients. By 48 weeks, dolutegravir demonstrated statistically equal or superior virological suppression, achieving <50 copies/mL of HIV-1 RNA in participants, vs. raltegravir comparison regimens.

Use of dolutegravir in treatment-experienced patients was investigated in two studies, SAILING (n=719) and VIKING-3 (n=183). In both studies, the addition of dolutegravir to patients’ background therapy improved virologic suppression at 24 weeks. VIKING-3 investigated the use of twice-daily dolutegravir in patients with multidrug-resistant infection, including resistance to other approved integrase inhibitors (raltegravir, elvitegravir). Subjects with INSTI resistance Q148 and two or more additional INSTI resistance substitutions demonstrated poor virologic response with the addition of twice-daily dolutegravir treatment to their background regimen.

FDA approved use of dolutegravir as part of combination antiretroviral therapy in pediatric patients ≥12 years of age and weighing a minimum of 40 kg based on a 24-week open-label trial of INSTI-naïve participants. Findings were similar to those for adults: At week 24, 70% of participants taking dolutegravir demonstrated viral suppression by achieving a viral load of <50 copies/mL, with improved CD4+ cell count compared to baseline levels. Dolutegravir therapy has not been studied in INSTI treatment-experienced pediatric patients and is not indicated for this patient population.

Safety 

In trials, dolutegravir was well tolerated. The most common adverse reactions occurring with moderate-to-severe intensity and a frequency of at least 2% were headache and insomnia. Rare but serious adverse effects demonstrated with this therapy include redistribution or accumulation of body fat, immune reconstitution syndrome, and hypersensitivity reactions. Patients who have experienced a serious hypersensitivity reaction should discontinue the medication and avoid rechallenge with the drug to prevent progression to a life-threatening reaction. Patients with hepatitis B and/or C co-infection may be at increased risk for worsening liver enzyme elevations. Baseline laboratory tests should be performed before therapy is initiated and should be monitored periodically throughout treatment. Dolutegravir should be used with caution in geriatric patients, as this group was not represented in trials sufficiently to permit identification of differences in response to the medication. Patients taking dofetilide should not take dolutegravir. This combination is contraindicated due to the increase in dofetilide levels and the potential for serious adverse effects. Dolutegravir is classified pregnancy category B.  

Dosage

In adult patients without INSTI resistance, the daily dose of dolutegravir is 50 mg orally. Dolutegravir 50 mg twice daily is recommended for patients with INSTI resistance. The recommended dosage for pediatric patients is 50 mg daily. There are no dosing adjustments necessary for patients with renal or hepatic impairment. There are several clinically significant drug interactions requiring dosing adjustments or avoidance of co-administration. Strong inducers of CYP3A4 and UGT1A1 may reduce plasma concentrations of dolutegravir and necessitate a dose adjustment. The full prescribing information provides a chart of interactions with clinical comments and recommendations. Dolutegravir may be taken with or without food but should be administered two hours before or six hours after administration of polyvalent medications. Dolutegravir is highly plasma protein-bound (98.9%). 

Kathryn Wheeler, PharmD, is assistant clinical professor of pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.