The Medical Letter on Drugs and Therapeutics
Dolutegravir (Tivicay) for HIV
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The FDA has approved dolutegravir (doll-you-TEG-rah-veer; Tivicay – Viiv Healthcare), an integrase strand transfer inhibitor (INSTI), for treatment of HIV-1 infection in adults and in children ≥12 years old who weigh at least 40 kg. It is the third INSTI to be approved by the FDA; raltegravir and elvitegravir were approved earlier.1,2

TREATMENT OF HIV — Preferred first-line therapy of HIV infection includes either the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva), a ritonavir-boosted protease inhibitor (atazanavir [Reyataz] or darunavir [Prezista]), or the INSTI raltegravir, plus the 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) emtricitabine (Emtriva) and tenofovir (Viread).3,4

INSTIs — INSTIs block the activity of HIV-1 integrase, preventing viral DNA from integrating with cellular DNA.

Raltegravir is generally well tolerated and is not metabolized by CYP3A, but must be taken twice daily and is not available in a fixed-dose combination with NRTIs. Elvitegravir is only available in combination (Stribild) with the NRTIs emtricitabine and tenofovir and the CYP3A inhibitor cobicistat, which permits once-daily dosing of elvitegravir, but interacts with many other drugs. Stribild must be taken with food and should not be used in patients with renal insufficiency. HIV strains that become resistant to raltegravir are often cross-resistant to elvitegravir, and vice versa.

CLINICAL STUDIES — The results of three 48-week trials comparing dolutegravir-based therapy to first-line HIV regimens in antiretroviral-naive patients, and one comparing dolutegravir-based therapy to raltegravir-based therapy in patients resistant to ≥2 classes of antiretrovirals but naive to INSTIs, are summarized in table 2.5-8 Patients receiving dolutegravir were less likely than those receiving raltegravir to develop treatment-emergent INSTI resistance.8

In an open-label single-arm trial (VIKING-3), available only as an abstract, 183 patients with virologic failure and current or historical resistance to raltegravir or elvitegravir received dolutegravir 50 mg twice daily, with optimized background therapy added after one week. By day 8, mean viral load had decreased by 1.4 log10 copies/mL. At 24 weeks, 69% of all patients, but only 25% of patients with ≥3 INSTI-resistance substitutions, had HIV RNA <50 copies/mL.9

ADVERSE EFFECTS — Dolutegravir was generally well tolerated in clinical trials. Hypersensitivity reactions have been reported in <1% of patients treated with the drug in clinical trials; it should be discontinued permanently if hypersensitivity occurs. Elevations in liver transaminases were reported in patients co-infected with hepatitis B or C. Dolutegravir is classified as category B (no evidence of risk in animals) for use during pregnancy.

DRUG INTERACTIONS — Drugs containing polyvalent cations (such as sucralfate, buffered medications, and calcium, magnesium, or iron supplements) can decrease the absorption of dolutegravir; it should be taken 2 hours before or 6 hours after any of these agents. Dolutegravir inhibits the renal organic cation transporter OCT2 and can inhibit tubular secretion of serum creatinine and drugs eliminated by OCT2, such as metformin and the antiarrhythmic drug dofetilide; concurrent use of dolutegravir and dofetilide is contraindicated. Drugs that induce UGT1A1 or CYP3A, such as rifampin, efavirenz, and etravirine, can reduce dolutegravir's serum concentrations and decrease its effectiveness.

DOSAGE AND ADMINISTRATION — The recommended dosage of dolutegravir in INSTI-naive patients is 50 mg taken once daily with or without food. INSTI-naive patients concomitantly taking efavirenz, rifampin, or ritonavir-boosted fosamprenavir (Lexiva) or tipranavir (Aptivus) should take 50 mg twice daily. INSTI-experienced patients with documented or clinically suspected INSTI-associated resistance substitutions should also take 50 mg twice daily10; in such patients, alternatives to rifampin, efavirenz, and ritonavir-boosted fosamprenavir or tipranavir should be used if possible. Dolutegravir has not been studied in INSTI-experienced children or in patients with severe hepatic impairment.

CONCLUSION — Dolutegravir (Tivicay), an integrase strand transfer inhibitor (INSTI) used in combination with other antiretroviral drugs for treatment of HIV-1 infection, is generally effective and well tolerated, and appears to be effective in some patients who have developed resistance to other INSTIs. Whether dolutegravir should be used before or after other INSTIs remains to be determined.

1. Two new drugs for HIV infection. Med Lett Drugs Ther 2008; 50:2.

2. A 4-drug combination (Stribild) for HIV. Med Lett Drugs Ther 2012; 54:95.

3. Panel of Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Updated February 12, 2013. Available at Accessed September 23, 2013.

4. Drugs for HIV infection. Treat Guidel Med Lett 2011; 9:29.

5. F Raffi et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomized, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381:735.

6. S Walmsley et al. Dolutegravir + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results - SINGLE. Presented at 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA; September 9-12, 2012. Available at Accessed September 20, 2013.

7. J Feinberg et al. Once-daily dolutegravir (DTG) is superior to darunavir/ritonavir (DRV/r) in antiretroviral naive adults: 48 week results from FLAMINGO. Presented at 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Denver, CO; September 10-13, 2013. Available at Accessed September 20, 2013.

8. P Cahn et al. Dolutegravir versus raltegravir in antiretroviralexperienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomized, double-blind, non-inferiority SAILING study. Lancet 2013; 382:700.

9. G Nichols et al. Phase 3 assessment of dolutegravir 50 mg twice daily in HIV-1-infected subjects with raltegravir and/or elvitegravir resistance in VIKING-3: week 24 results of all 183 patients enrolled. Presented at 7th IAS Conference on HIV pathogenesis, treatment, and prevention. Kuala Lumpur, Malaysia; June 30-July 3, 2013. Available at: Accessed September 23, 2013.

10. JJ Eron et al. Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study. J Infect Dis 2013; 207:740.

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