Tivicay
dolutegravir, or DTG
INSTI: Integrase strand transfer inhibitor (integrase inhibitor)
image of drug

MANUFACTURER:
ViiV Healthcare viivhealthcare.com , tivicay.com
(877) 844-8872

AWP:
$1,479.59 / month

Standard Dose:

One 50 mg tablet once daily for people on HIV therapy for the first time or treatment-experienced people with no previous INSTI use. One 50 mg tablet twice daily when also taking efavirenz (Sustiva), Lexiva/Norvir, Aptivus/Norvir, or rifampin, or in people with INSTI (Isentress or elvitegravir) drug resistance or suspected resistance. Tivicay is approved for patients 12 years and older weighing at least 88 pounds. It may be taken with or without food.

Take missed dose as soon as possible, unless it is within 4 hours of your next dose, then skip the missed dose. Do not double up on your next dose. Not recommended for people with severe liver impairment. Use with caution in people with severe kidney impairment who have INSTI drug resistance or suspected resistance because Tivicay levels may be decreased.

Potential side effects and toxicity

The most common moderate to severe side effects in clinical studies were insomnia (3%) and headache (2%). Mild insomnia was seen in 7% of participants in one study. Rarely (in less than 1%), hypersensitivity (an allergy-like reaction) may occur. Stop taking Tivicay if signs or symptoms of hypersensitivity occur (including but not limited to severe rash or rash with: a fever, feeling ill, fatigue, muscle or joint aches, blisters or skin peeling, blisters or sores in the mouth, redness or swelling of the eyes, facial swelling, liver inflammation, angioedema (swelling under the skin), and difficulty breathing. Associated with a small increase in creatinine (a marker of kidney function; this has been a laboratory increase not found to be a sign of kidney toxicity). Liver enzymes should be monitored in people with hepatitis B or C. Stop taking Tivicay if you experience signs of liver problems (yellowing of the skin or whites of the eyes, dark or tea-colored urine, pale-colored bowel movements, nausea or vomiting, loss of appetite, and pain, aching, or tenderness on the right side below the ribs).

Check for potential drug class side effects.

Potential drug interactions

Tell your provider or pharmacist about all medications, herbs, and supplements you are taking or thinking of taking, prescribed or not. Do not take with the anti-arrhythmic dofetilide (Tikosyn), due to the potential for serious or life-threatening reaction. Reyataz increases Tivicay levels while Prezista and rifabutin have been shown to decrease them, but no dosage adjustment is needed. Intelence decreases Tivicay levels by 88%. This interaction must be counteracted by the addition of Kaletra, ritonavir-boosted Prezista, or boosted Reyataz. Tivicay should be taken two hours before or six hours after taking laxatives or antacids containing aluminum, magnesium (such as Maalox), or calcium, the ulcer medication sucralfate (Carafate), oral iron or calcium supplements, or buffered medications. When taken together, these medications can reduce the absorption of Tivicay. Acid reducers (such as omeprazole) and proton pump inhibitors are okay to use as no change in Tivicay levels was seen. Avoid taking with oxcarbazepine, phenytoin, phenobarbital, carbamazepine, and St. John’s wort. Closely monitor with metformin; metformin dose may need to be adjusted. Use alternatives to rifampin, efavirenz, Aptivus/Norvir, and Lexiva/Norvir when possible in people with INSTI experience or with certain INSTI drug resistance patterns or clinically suspected resistance. Tivicay can be taken with oral contraceptives as it is expected to have minimal effect on their levels.

More information

Tivicay was approved by the FDA in August 2013. According to DHHS HIV treatment guidelines, all three INSTIs on the market have been shown to be non-inferior to preferred guideline regimens and are now themselves preferred regimens. The guidelines noted that while Tivicay has been found non-inferior to Isentress and superior to Norvir-boosted Prezista and regimens containing efavirenz (such as Atripla), “largely because of more discontinuations for adverse events or other reasons in the comparator arms,” it also has the shortest follow-up data and post-marketing (real world) experience. Tivicay is a second-generation INSTI, meaning that it can work in many individuals whose virus has developed resistance to other drugs in its class, like Isentress and elvitegravir (in Stribild), but it needs to be dosed twice daily in these people. This could have financial impact. It is about the size of an aspirin. Based on current data, Tivicay appears to be an exciting addition to current antiretrovirals. It will likely be co-formulated as one pill once daily with Epzicom for treatment-naïve patients (see 572-Trii). It has fewer drug interactions than Stribild and appears to be well tolerated. In laboratory studies, Tivicay has been shown to have a high barrier to drug resistance. In clinical studies to date, drug resistance has not been seen in treatment-naïve people (those on HIV therapy for the first time) whose therapy with Tivicay has stopped working; this potentially gives them more options for future treatment, but there is no switch data to date—time will tell.

In various studies in patients on their first regimen, Tivicay has been shown to be superior to Atripla and Prezista/Norvir, and Isentress in treatment-experienced patients naïve to INSTIs, but time will tell.

The ongoing SINGLE study in patients who are treatment-naïve, demonstrated superiority of Tivicay/Epzicom compared to the single-tablet regimen Atripla. At 48 weeks, 88% of study participants on the Tivicay regimen were virologically suppressed (undetectable) vs. 81% of participants on Atripla. Differences in the slightly better outcomes for Tivicay were mostly driven by a higher rate of discontinuation due to side effects in the Atripla group. It is being studied at a twice-daily dose with an optimized background regimen (the best regimen a medical provider can create for an individual) in people with current or a history of treatment failure with an INSTI (basically, those for whom Isentress no longer works, but also those who experienced virologic failure on elvitegravir). The SPRING-1 four-arm dose-ranging study looked at people who are treatment naïve. At week 96, 88% of patients on Tivicay 50 mg were able to achieve an undetectable viral load (less than 50 copies/mL) vs. 72% for Sustiva (taken with either Truvada or Epzicom). Responses in the Tivicay 10 mg and 25 mg arms were 79% and 78%, respectively. Based on this dose-ranging study, the dose selected for larger studies in treatment-naïve patients was 50 mg (tablet or capsule). The SPRING-2 study, again in treatment-naïve patients, compared Tivicay to Isentress, each with either Truvada or Epzicom. At week 48, once-daily Tivicay was found to be non-inferior to twice-daily Isentress with 88% vs. 85% of patients respectively with undetectable viral loads. In the VIKING-3 Phase 3 (advanced) study, Tivicay was added to a failing therapy in people with multi-class HIV drug resistance (including integrase inhibitor resistance) for seven days, and then continued on Tivicay with their background regimen optimized. Despite this resistance profile, at 24 weeks (still early results) 63% of patients who had Tivicay added to their failing regimen were able to achieve an undetectable viral load. This is a large study, with 183 individuals. Data from the SAILING study investigating once-daily Tivicay in treatment-experienced patients with no previous exposure to integrase inhibitors is due to be presented at upcoming scientific meetings.

A pediatric sprinkle formulation of Tivicay is being studied. Data on its use in children ages 6 to 12 are expected this year. See package insert for more complete information on potential side effects and interactions.

Doctor’s comments

Tivicay (dolutegravir) is the newest INSTI, and it looks like a winner. It’s taken as a single tablet once a day without the need for boosting, is well tolerated, and may be less prone to resistance than the other two INSTIs. At double the usual dose, it can be active against some INSTI-resistant virus, though if you have enough INSTI mutations—and the right ones—you can have cross-resistance to Tivicay as well. We expect approval of a single-tablet regimen combining dolutegravir with abacavir and lamivudine soon (see 572-Trii).
—JOEL GALLANT, MD, MPH

Activist’s comments

Tivicay was approved in August 2013 and is considered a second-generation integrase inhibitor because it appears to work against virus that’s resistant to Isentress. Tivicay appears to be well tolerated and does not need to be boosted. It is currently being dosed once a day for treatment-naïve patients and twice a day for treatment-experienced patients who need to construct a new, viable regimen.
—DAWN AVERITT