General Information

Tivicay (dolutegravir) is an integrase inhibitor. It blocks HIV replication by preventing viral DNA from integrating into the genetic material of human immune cells (T-cells).

Tivicay is specifically indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children aged 12 years and older and weighing at least 40 kg.

Tivicay (dolutegravir) tablets and Tivicay PD (dolutegravir) tablets for suspension are indicated to treat HIV-1 infection in pediatric patients at least four weeks old and weighing at least 3 kg (6.61 pounds) in combination with other antiretroviral treatments.

Tivicay is supplied as a tablet for oral administration. The recommended dose is as follows:

Adults

Treatment-naïve or treatment-experienced INSTI-naïve: 50 mg once daily

Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with the following potent UGT1A/CYP3A inducers: efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin: 50 mg twice daily

INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance: 50 mg twice daily

Pediatrics

Treatment-Naïve or Treatment-Experienced INSTI-Naïve: The recommended dose in pediatrics aged 12 years and older and weighing at least 40 kg is 50 mg administered orally once daily.

Clinical Trial Results

The FDA approval of Tivicay was based on the following: two trials, SPRING-2 (ING113086) and SINGLE (ING114467), in treatment-naïve, HIV-1-infected subjects (n = 1,641); one trial, SAILING (ING111762), in treatment-experienced, INSTI-naïve HIV-1-infected subjects (n = 715); and from VIKING-3 (ING112574) trial in INSTI-experienced HIV-1-infected subjects (n = 183). The use of Tivicay in pediatric patients aged 12 years and older was based on evaluation of safety, pharmacokinetics, and efficacy through 24 weeks in a multi-center, open-label trial in subjects (n = 23) without INSTI resistance.

SPRING-2
This study evaluated once-daily Tivicay versus twice-daily raltegravir in 822 HIV-infected, treatment-naïve patients, in each case in combination with a fixed-dose dual-NRTI treatment. At week 48, the proportion of subjects who were virologically suppressed (HIV-1 RNA <50 c/mL) was 88% for the regimen containing Tivicay and 86% for the regimen containing raltegravir, meeting the 10% non-inferiority criteria.
SINGLE
This study evaluated once-daily Tivicay plus abacavir/lamivudine versus the single tablet regimen Atripla in 833 HIV-infected, treatment-naïve patients. At 48 weeks, the proportion of subjects who were virologically suppressed (HIV-1 RNA <50 c/mL) was 88% for the Tivicay regimen and 81% for Atripla. This difference was statistically significant.
SAILING
This study evaluatied once-daily Tivicay versus twice-daily raltegravir in 719 patients with HIV who were failing on current therapy, but had not been treated with an integrase inhibitor, in each case in combination with an investigator-selected background regimen consisting of up to two agents, including at least one fully active agent. At week 24, 79% of subjects on the regimen containing Tivicay were virologically suppressed (HIV-1 RNA <50 c/mL) versus 70% of subjects on the regimen containing raltegravir. This difference was statistically significant.
VIKING 3
This study evaluated twice-daily Tivicay in 183 HIV-infected adults currently on medication whose HIV was resistant to multiple classes of HIV medicines, including integrase inhibitors (raltegravir and/or elvitegravir). In the study, mean HIV RNA levels declined by 1.4 log10 c/mL after seven days of treatment with the addition of Tivicay to their background regimen. The proportion of subjects who were subsequently virologically suppressed (HIV-1 RNA <50 c/mL) with the addition of Tivicay to their background regimen was 63% at week 24. However, poor virologic response was observed in subjects treated with Tivicay twice daily with an integrase strand transfer inhibitor (INSTI) resistance called Q148 plus two or more additional INSTI resistance substitutions.
Pediatric Study - IMPAACT P1093
This was a phase I/II 48-week, multicenter, open-label trial to evaluate the pharmacokinetic parameters, safety, tolerability, and efficacy of Tivicay in combination treatment regimens in HIV-1-infected infants, children, and adolescents. The initial dose-finding stage included intensive pharmacokinetic evaluation in 10 INSTI-naïve subjects (aged 12 to 18 years). Dose selection was based upon achieving similar dolutegravir plasma exposure and trough concentration as seen in adults. After dose selection, an additional 13 subjects were enrolled for evaluation of long-term safety, tolerability, and efficacy. At 24 weeks, 70% of subjects treated with Tivicay once daily (35 mg: n = 4, 50 mg: n = 19) plus optimized background therapy achieved a viral load <50 copies/mL. The median CD4+ cell count (percent) increase from baseline to Week 24 was 63 cells/mm3 (5%).