April 8, 2019
Today, the FDA approved DOVATO, a two-drug fixed dose regimen containing 50 mg of dolutegravir and 300 mg of lamivudine. DOVATO is approved as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with no antiretroviral treatment history and with no known or suspected substitutions associated with resistance to the individual components of DOVATO. The recommended dosage regimen of DOVATO in adults is one tablet taken orally once daily with or without food.
The DOVATO label contains a Box Warning regarding use in patients coinfected with HIV-1 and hepatitis B virus (HBV). All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.
Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment.
Clinicians are also reminded to perform pregnancy testing before initiation of DOVATO in individuals of childbearing potential due to the risk of neural tube defects.
The safety and efficacy of DOVATO is supported by data from 2 randomized, double-blind, controlled trials GEMINI-1 and GEMINI-2 in HIV–1-infected adults with no antiretroviral treatment history.
GEMINI-1 and GEMINI-2 are identical Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received treatment in the trials. Subjects were enrolled with a screening plasma HIV-1 RNA of 1,000 to ≤500,000 copies/mL and without evidence of major resistance-associated mutations or evidence of HBV infection. Subjects were randomized to receive a 2-drug regimen of TIVICAY 50 mg plus EPIVIR 300 mg (DTG+3TC) administered once daily or TIVICAY 50 mg plus fixed-dose TRUVADA (DTG+FTC/TDF) administered once daily.
The pooled data from GEMINI-1 and GEMINI-1 showed that the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 was 91% for DTG+3TC and 93% for DTG+FTC/TDF. The treatment difference and 95% CI was -1.7% (-4.4, 1.1%).
At Week 48, no subjects had any detectable treatment-emergent substitutions associated with resistance to dolutegravir or NRTIs.
In both trials, lower response rates (HIV-1 RNA < 50 copies/mL) were observed in subjects with baseline CD4+≤200 cells/mm3. These findings were seen irrespective of baseline plasma HIV-1 RNA.
The response rates (HIV-1 RNA < 50 copies/mL) by baseline CD4+ is as follows:
- Baseline CD4+ < 200 cells/mm3
- GEMINI-1: 81% (25/31) for DTG+3TC vs 90% (26/29) for DTG+FTC/TDF
- GEMINI-2: 78% (25/32) for DTG+3TC vs 96% (25/26) for DTG+FTC/TDF
- Baseline CD4+ > 200 cells/mm3
- GEMINI-1: 91% (295/325) for DTG+3TC vs 93% (306/329) for DTG+FTC/TDF
- GEMINI-2: 95% (310/328) for DTG+3TC vs 94% (312/333) for DTG+FTC/TDF
The adverse reactions observed for DTG+3TC in the Week 48 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm included: headache, nausea, diarrhea, insomnia, fatigue and dizziness.
The rates of adverse events leading to discontinuation in the pooled analysis were 2% of subjects in both treatment arms. The most common adverse events leading to discontinuation were psychiatric disorders: < 1% of subjects in both treatment arms.
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