Pharmacology Update: Dolutegravir Tablets (Tivicay®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
Dolutegravir, a once daily hiv-1 integrase strand transfer inhibitor (INSTI), has been approved by the FDA. The drug joins raltegravir and elvitegravir as the three INSTIs currently marketed. These drugs exert their antiviral activity by inhibiting the insertion of viral genome into the chromosome of the host cell. Both raltegravir and dolutegravir are available as single agents. Elvitegravir is only available as part of a four-drug combination (Stribild). Dolutegravir is manufactured by GlaxoSmithKline for ViiV Healthcare and marketed as Tivicay.
Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infections in adults and children 12 years of age or older weighing at least 40 kg.1
The recommended dose is 50 mg once daily taken without regard to meals.1 However, it should be taken 2 hours before or 6 hours after taking a cation (e.g., aluminum, magnesium) containing antacid or laxative, sucralfate, oral iron supplement and calcium supplement, or buffered medications. The dose is 50 mg twice daily in patients coadministered with potent UGT1A/CYP3A inducers: efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin. The dose is also 50 mg twice daily in patients who have been treated with an integrase inhibitor with selected INSTI-resistance associated mutations. The pediatric dose is 50 mg once daily or 50 mg twice daily if UGT1A/CYP3A inducer is coadministered.
Dolutegravir is available as 50 mg tablets.
Dolutegravir may have limited cross-resistance to raltegravir and has shown activity in treatment-experienced subjects with raltegravir-resistance.1,2 In vitro data suggest that it may have a higher genetic barrier to resistance compared to raltegravir and elvitegravir.3 Dolutegravir is generally dosed once daily compared to twice daily for raltegravir.
Dolutegravir has been associated with elevated (grade 2-4) ALT (8%), AST (6%), cholesterol (8%), lipase (8%), hyperglycemia (12%), and elevated serum creatinine (mean change of 0.11 mg/dL).1 Adverse events include nausea, diarrhea, nasopharyngitis, upper respiratory infections, and headache.4,5
Dolutegravir is a HIV-1 integrase inhibitor similar to raltegravir and elvitegravir. The efficacy and safety of dolutegravir were studied in five clinical trials, including two treatment-naïve, one treatment-experienced, one integrase inhibitor-experienced, and one pediatric trial.1,4,5 In treatment-naïve subjects, dolutegravir (50 mg once daily, n = 403) was compared to raltegravir (400 mg twice daily, n = 405) in combination with tenofovir/emtricitabine or abacavir/lamivudine with a non-inferiority margin of 10%.1,4 At 48 weeks, the proportion of subjects with virologic response (HIV-1 RNA < 50 copies/mL) was 88% for dolutegravir and 86% for raltegravir. No treatment-emergent resistance occurred with dolutegravir. However, one patient had integrase inhibitor resistance (6%) and four had NRTI resistance (21%).4 In the second treatment-naïve study, subjects were randomized to dolutegravir and abacavir/lamivudine (n = 414) or efavirenz/emtricitabine/tenofovir (n = 419). The proportion of subjects achieving virologic response was 88% and 81%, respectively.1 In the treatment-experienced study, subjects were randomized to dolutegravir (n = 354) or raltegravir (n = 361) with investigator-selected background therapy.1,5 At 48 weeks, virologic response was 79% and 70%, respectively, suggesting an advantage for dolutegravir. The study with integrase inhibitor-experienced subjects included those who had virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance (n = 183). In this study, subjects received dolutegravir 50 mg twice daily while continuing a failing regimen for 7 days, then dolutegravir with an optimized regimen from day 8. Mean reduction from HIV-RNA at day 8 was 1.4 log10 and response at week 24 was 63%. The response rate was 36% with integrase inhibitor resistance substitution (mutation) at Q148 at baseline. Efficacy was evaluation in a small pediatric population (n = 24) showing a 70% response rate.1 The adverse reaction profile of dolutegravir and raltegravir appears to be similar. The rate of discontinuation due to adverse events was 2% for dolutegravir and raltegravir.1,4
Dolutegravir provides another INSTI for the treatment of HIV-1 infections as an alternative to raltegravir. Currently, the combination of raltegravir/tenofovir/emtricitabine is one of the recommended regimens with strong evidence for treatment-naïve patients.6 The quad pill (elvitegravir/cobicistat, emtricitabine/tenofovir) was recommended with moderately strong evidence.7 The wholesale cost for dolutegravir (50 mg once daily) is $1175 per 30-day supply compared to $1074 for raltegravir (400 mg twice daily).
- Tivicay Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; August 2013.
- Eron JJ, et al. J Infect Dis 2013;207:740-748.
- Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552-4559.
- Raffi F, et al. Lancet 2013;381:735-743.
- Cahn P, et al. Lancet 2013;382:700-708.
- http://aidsinfo.nih.gov/contentfiles/lvguidelines/aa_ recommendations.pdf. Accessed August 30, 2013.
- http://www.hivandhepatitis.com/hiv-treatment/approved-hiv-drugs/3791-dhhs-panel-adds-stribild-quad-pill-as-alternative-regimen-for-treatment-naive-hiv-patients. Accessed August 30, 2013.