EFFICACY AND RESISTANCE

SAILING: DOLUTEGRAVIR-BASED REGIMENS PUT TO THE TEST IN PATIENTS WITH PRIOR ART RESISTANCE1

A randomized, double-blind, active-control, noninferiority trial in 719 treatment-experienced, INSTI-naïve adult (≥18 years) patients with HIV-1. Eligible participants had to have 2 consecutive plasma HIV-1 RNA assessments of ≥400 copies/mL (unless >1000 copies/mL at screening).

Baseline characteristics
Median age was 43 years; 68% of patients were male, 42% were of African American/African heritage, 49% were white, 20% had HIV-1 RNA >100,000 copies/mL, 72% had CD4+ T-cell counts <350 cells/mm3, 16% had hepatitis B and/or C virus coinfection, and 46% were CDC Class C (AIDS)

Primary endpoint
Proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 (FDA snapshot analysis with 12% noninferiority margin with prespecified tests for superiority)

BASELINE RESISTANCE PRIOR TO ART
100% of patients had at least 2-class resistance (not including INSTIs) and 49% were resistant to ≥3 classes

Virologic Response

When put to the test in patients with prior ART resistance, DTG-based regimens showed a statistically superior difference in virologic response at Week 48 (ITT–E; primary endpoint)1,2†

STATISTICALLY SUPERIOR DIFFERENCE

Treatment difference (7.4% [95% CI; 0.7%, 14.2%]) was primarily driven by the rates of virologic nonresponse (20% for the regimens with TIVICAY vs 28% for the raltegravir regimens)1

VIROLOGIC RESPONSE IN PATIENTS WITH HIGH BASELINE VIRAL LOAD1

SUBGROUP ANALYSIS‡

Virologic response (HIV-1 RNA <50 copies/mL) stratified by baseline viral load

Treatment difference (15.2% [95% CI; 1.9 to 28.4])

VIROLOGIC RESPONSE IN PATIENTS WITH LOW BASELINE VIRAL LOAD1

SUBGROUP ANALYSIS‡

Virologic response (HIV-1 RNA <50 copies/mL) stratified by baseline viral load

Treatment difference (3.8% [95% CI; –3.9 to 11.6])

Resistance Results

High barrier to resistance with dolutegravir is supported by 48-week results in SAILING1

No patients receiving dolutegravir had decreases in susceptibility (>2-fold) to dolutegravir in the resistance analysis data set (n=28 with confirmed PDVF^§ at last visit through Week 48 and having resistance data)

Number of patients with treatment-emergent INSTI substitutions based on the resistance analysis data set through 48 weeks2

*BR was investigator-selected and consisted of up to 2 agents, including at least 1 fully active agent. Most common BRs: darunavir/r + TDF, lopinavir/r + TDF, darunavir/r + etravirine, lopinavir/r, atazanavir/r + TDF, darunavir/r + maraviroc.
†Four patients were excluded from the efficacy and safety analyses: 3 from the arm receiving TIVICAY and 1 from the raltegravir arm due to good clinical practices noncompliance at one site.
‡Prespecified secondary endpoint; ITT-E population.
§PDVF was defined as either virologic nonresponse (a decrease in plasma HIV-1 RNA <1 log₁₀ copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA was <400 copies/mL; or confirmed plasma HIV-1 RNA ≥400 copies/mL on or after Week 24) or virologic rebound (confirmed rebound in plasma HIV-1 RNA to ≥400 copies/mL after prior confirmed suppression to <400 copies/mL, or confirmed plasma HIV-1 RNA >1 log₁₀ copies/mL above the nadir value, where nadir is the lowest HIV-1 RNA value ≥400 copies/mL).
||One subject isolate had pre-existing raltegravir resistance substitutions E138A, G140S, and Q148H at baseline and had additional emergent INSTI-resistance substitutions T97A and E138A/T with a corresponding 148-fold reduction in dolutegravir susceptibility at failure.

ART=antiretroviral therapy; BR=background regimen; CDC=Centers for Disease Control and Prevention; CI=confidence interval; DTG=dolutegravir; FDA=Food and Drug Administration; INSTI=integrase strand transfer inhibitor; ITT-E=intention-to-treat–exposed; PDVF=protocol defined virologic failure; r=ritonavir; TDF=tenofovir disoproxil fumarate.

References: 1. Cahn P, Pozniak AL, Mingrone H, et al; on behalf of the extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700-708. 2. Data on file, ViiV Healthcare.

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IMPORTANT SAFETY INFORMATION

Contraindications

Do not use TIVICAY or TIVICAY PD in patients with previous hypersensitivity reaction to dolutegravir
Do not use TIVICAY or TIVICAY PD in patients receiving dofetilide

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IMPORTANT SAFETY INFORMATION

Contraindications

Do not use TIVICAY or TIVICAY PD in patients with previous hypersensitivity reaction to dolutegravir
Do not use TIVICAY or TIVICAY PD in patients receiving dofetilide

Warnings and precautions

Hypersensitivity Reactions:

Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury
Discontinue dolutegravir immediately if signs or symptoms of hypersensitivity reaction develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated

Hepatotoxicity:

Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure) in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors
Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of dolutegravir. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn
Monitoring for hepatotoxicity is recommended

Embryo-Fetal Toxicity:

Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects
Pregnancy testing is recommended before use of TIVICAY or TIVICAY PD. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of dolutegravir and other drugs may occur (see Contraindications and Drug Interactions)

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of dolutegravir

Different Formulations Are Not Interchangeable:
TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis. If a patient switches from one formulation to the other, the dose must be adjusted

Adverse reactions

The most common adverse reactions (incidence ≥2%, Grades 2-4) in treatment-naïve adults receiving TIVICAY in a combination regimen were insomnia (3%), headache (2%), and fatigue (2%)

Drug interactions

Consult the full Prescribing Information for more information on potentially significant drug interactions
Drugs that induce or inhibit UGT1A1 and/or CYP3A may affect plasma concentrations of dolutegravir
Administer TIVICAY or TIVICAY PD 2 hours before or 6 hours after taking antacids, polyvalent cation-containing products or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, TIVICAY and supplements containing calcium or iron can be taken with food

Use in specific populations

Pregnancy: There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Advise adolescents and adults of childbearing potential of the potential risk of neural tube defects. Assess the risks and benefits of continuing TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester
Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant
Females and Males of Reproductive Potential: Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD. Counsel adolescents and adults of childbearing potential taking TIVICAY or TIVICAY PD on the consistent use of effective contraception

indication-target

INDICATION

TIVICAY and TIVICAY PD are human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitors (INSTIs) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults (treatment-naïve or -experienced) and in pediatric patients (treatment-naïve or -experienced, but INSTI-naïve) aged ≥4 weeks and weighing ≥3 kg

TIVICAY is indicated in combination with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for ≥6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent

Please see full Prescribing Information for TIVICAY and TIVICAY PD.

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To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at
1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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