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Dolutegravir

Drug Watch |
September 10, 2013

Dolutegravir

  1. Helmut Albrecht, MD

The FDA has approved the integrase inhibitor dolutegravir for treatment of HIV infection, in combination with other antiretrovirals.

  1. Helmut Albrecht, MD

On August 12, 2013, the FDA approved dolutegravir (Tivicay) for treatment of HIV infection, in combination with other antiretrovirals. Like elvitegravir and raltegravir, dolutegravir is an integrase strand transfer inhibitor (INSTI); it interferes with HIV replication by binding to the integrase active site and blocking the strand-transfer step of HIV DNA integration.

Dosage and Administration

The recommended dose for treatment-naive and for treatment-experienced but INSTI-naive patients (including children/adolescents aged ≥12 years and weighing ≥40 kg) is one 50-mg tablet once daily. Individuals who are taking potent UGT1A or CYP3A inducers such as rifampin, efavirenz, ritonavir-boosted fosamprenavir or tipranavir, and adults who have certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance, should receive 50 mg twice daily. In adults with INSTI-resistance mutations in the Q148 position plus two or more additional INSTI-resistance substitutions, dolutegravir has poor efficacy and should probably be avoided.

There are no food requirements, but dolutegravir should be taken 2 hours before or 6 hours after taking cation-containing products (e.g., certain antacids and laxatives, sucralfate, buffered medications, or certain multivitamins and supplements).

Pharmacology

Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. It is eliminated in the urine (metabolites) and feces (parent drug). No dosage adjustment is necessary for patients with mild-to-moderate hepatic impairment (Child-Pugh Score A or B). Dolutegravir plasma concentrations were unaffected by mild-to-moderate renal impairment but significantly decreased in subjects with end-stage renal disease. The drug should be used only with caution in patients with severe renal impairment, especially those with documented or suspected INSTI-resistance mutations.

Drug Interactions

Dolutegravir is contraindicated in patients on dofetilide. Unlike cobicistat-boosted elvitegravir, dolutegravir can be used in patients taking darunavir. In individuals receiving etravirine, dolutegravir should not be prescribed except together with a boosted protease inhibitor (PI). Drugs that should not be used in combination with dolutegravir include phenytoin or carbamazepine. For many other agents, data are not yet available.

Like trimethoprim, cimetidine, and cobicistat, dolutegravir inhibits the renal tubular resorption of creatinine. Such inhibition results in a slight increase in serum creatinine (in my experience, by approximately 0.2–0.3 mg/dL), without a change in glomerular filtration rate. It also results in potentially important increases in the plasma concentrations of drugs eliminated via the renal organic cation transporter 2 (e.g., dofetilide, metformin)

Adverse Effects

The most common moderate-to-severe adverse effects were insomnia and headache. Serious side effects included abnormal liver function, particularly in patients with hepatitis B or C virus coinfection, and potentially serious hypersensitivity reactions.

Clinical Studies

Approval was based on several studies, including three large, multinational, double-blind trials (SPRING-2, SINGLE, and SAILING).

In SPRING-2, 822 treatment-naive adults were randomized to either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each in combination with a fixed-dose nucleoside reverse transcriptase inhibitor combination (either abacavir/3TC or FTC/tenofovir). Dolutegravir was found to be noninferior to raltegravir (NEJM JW AIDS Clin Care Feb 11 2013). In SINGLE, 833 treatment-naive adults were randomized either to dolutegravir 50 mg with fixed-dose abacavir/3TC or to fixed-dose efavirenz/FTC/tenofovir, both given once daily. Although dolutegravir was associated with a superior treatment response, most of the difference was attributable to a higher rate of treatment-limiting side effects in the comparator arm. In SAILING, 719 treatment-experienced but INSTI-naive adults were randomized to either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each with an investigator-selected background regimen consisting of up to two agents, at least one of which was fully active. Dolutegravir use was associated with a statistically superior virologic response rate and a lower rate of resistance development (NEJM JW AIDS Clin Care Jul 22 2013).

In the subsequent open-label FLAMINGO study, treatment-naive adults were randomized to once-daily dolutegravir or once-daily darunavir/r (along with either tenofovir/FTC or abacavir/3TC). Dolutegravir was superior to darunavir/r, with no resistance emerging in either treatment arm (Feinberg J et al. ICAAC 2013; Denver, CO. Abstract H-1464a).

Preliminary data from IMPAACT P1093 — a 48-week, multicenter, open-label trial involving INSTI-naive pediatric patients — suggest good safety, tolerability, and efficacy for dolutegravir at 50 mg daily among those aged 12 to 17 years and weighing ≥40 kg.

Cost and Availability

Dolutegravir is now available in pharmacies. The annual wholesale acquisition cost is US$14,105.

Comment

With a half-life of approximately 14 hours, dolutegravir is the only integrase strand transfer inhibitor recommended for once-daily use without boosting. In the pivotal trials, it was at least as effective as current first-line regimens and, like raltegravir and elvitegravir, had a favorable side-effect profile. Despite significant cross-resistance with these INSTIs, dolutegravir has a slightly higher barrier to resistance, thus allowing (in the absence of certain resistance mutations) potential salvage of patients with treatment failure on raltegravir or elvitegravir.

  • Disclosures for Helmut Albrecht, MD at time of publication Grant / research support Department of Defense; Health Resources and Services Administration; Housing Opportunities for Persons with AIDS / U.S. Department of Housing and Urban Development Leadership positions in professional societies Palmetto Health Richland Hospital (Chief of Staff); South Carolina Infectious Diseases Society (President)

Citation(s):

Reader Comments (1)

Joep Lange Physician, Infectious Disease, Academic Medical Center, University of Amsterdam

Very nice and useful summary.

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