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Information about FDA HIV product approvals, safety warnings, medical product labeling changes, notices of upcoming public meetings, and notices about proposed regulatory guidances.
On August 15, 2017, the FDA approved revisions to the GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) package insert to include 144 week safety, efficacy and resistance data from Studies GS-US-292 0104 and GS-US-292 0111 in antiretroviral treatment-naïve adults. Additionally drug-drug interaction data were updated. The major revisions include the following:
Section 6 Adverse Reactions was updated as follows with the 144 week safety data
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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Clinical Trials in Treatment-Naïve Adults: The primary safety assessment of GENVOYA was based on Week 144 pooled data from 1,733 subjects in two randomized, double-blind, active-controlled trials, Study 104 and Study 111, in antiretroviral treatment-naïve HIV-1 infected adult subjects. A total of 866 subjects received one tablet of GENVOYA once daily
Table 2 Adverse Reactionsa (All Grades) Reported in ≥ 5% of HIV-1 Infected Treatment-Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis)
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GENVOYA N=866
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STRIBILD N=867
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Nausea
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11%
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13%
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Diarrhea
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7%
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9%
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Headache
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6%
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5%
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Fatigue
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5%
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4%
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a Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator.
The majority of events presented in Table 2 occurred at severity Grade 1
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Bone Mineral Density Effects: Treatment-Naïve Adults: In a pooled analysis of Studies 104 and 111, the effects of GENVOYA compared to STRIBILD on bone mineral density (BMD) change from baseline to Week 144 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 144 was −0.92% with GENVOYA compared to −2.95% with STRIBILD at the lumbar spine and −0.75% compared to −3.36% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. The long-term clinical significance of these BMD changes is not known.
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Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving GENVOYA in Studies 104 and 111 are presented in Table 3.
Table 3 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis)
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Laboratory Parameter Abnormalitya
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GENVOYA N=866
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STRIBILD N=867
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Creatine Kinase (≥10.0 x ULN)
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11%
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10%
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LDL-cholesterol (fasted) (>190 mg/dL)
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11%
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5%
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Total cholesterol (fasted) (>300mg/dL)
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4%
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3%
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Amylase
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3%
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5%
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ALT
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3%
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3%
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AST
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3%
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4%
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Urine RBC (Hematuria) (>75 RBC/HPF)
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3%
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3%
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a Frequencies are based on treatment-emergent laboratory abnormalities.
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Serum Lipids: Subjects receiving GENVOYA experienced greater increases in serum lipids compared to those receiving STRIBILD.
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 4.
Table 4 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Studies 104 and 111a
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GENVOYA
N=866
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STRIBILD
N=867
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Baseline
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Week 144
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Baseline
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Week 144
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mg/dL
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Changeb
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mg/dL
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Changeb
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Total Cholesterol (fasted)
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162
[N=647]
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+31
[N=647]
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165
[N=627]
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+14
[N=627]
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Triglycerides (fasted)
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111
[N=647]
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+31
[N=647]
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115
[N=627]
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+17
[N=627]
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LDL-cholesterol (fasted)
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103
[N=647]
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+18
[N=643]
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107
[N=628]
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+8
[N=628]
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HDL-cholesterol (fasted)
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47
[N=647]
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+7
[N=647]
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46
[N=627]
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+3
[N=627]
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Total Cholesterol to HDL ratio
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3.7
[N=647]
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0.2
[N=647]
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3.8
[N=627]
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0.1
[N=627]
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a Excludes subjects who received lipid lowering agents during the treatment period.
b The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values.
Section 7: DRUG INTERACTIONS was updated with clinical comments for corticosteroids
Table 5 Established and Other Potentially Significanta Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
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Concomitant Drug Class: Drug Name
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Effect on Concentrationb
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Clinical Comment
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Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids:
e.g.,
betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone
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¯ elvitegravir
¯ cobicistat
corticosteroids
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Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to elvitegravir. Consider alternative corticosteroids.
Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.
Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use [see Drug Interactions (7.6)].
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Section 14: Clinical Studies was updated to include the Week 144 efficacy data as follows
14.2 Clinical Trial Results in HIV-1 Treatment-Naïve Subjects
In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either GENVOYA (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily. The mean age was 36 years (range 18–76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL. The mean baseline CD4+ cell count was 427 cells per mm3 (range 0–1360) and 13% had CD4+ cell counts less than 200 cells per mm3.
Pooled treatment outcomes of Studies 104 and 111 through Week 144 are presented in Table 13.
Table 13 Pooled Virologic Outcomes of Randomized Treatment in Studies 104 and 111 at Week 144a in Treatment-Naïve Subjects
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GENVOYA (N=866)
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STRIBILD (N=867)
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HIV-1 RNA < 50 copies/mLb
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84%
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80%
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HIV-1 RNA ≥ 50 copies/mLc
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5%
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4%
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No Virologic Data at Week 144 Window
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11%
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16%
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Discontinued Study Drug Due to AE or Deathd
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2%
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3%
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Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLe
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9%
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11%
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Missing Data During Window but on Study Drug
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1%
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1%
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a Week 144 window was between Day 966 and 1049 (inclusive).
b The primary endpoint was assessed at Week 48 and the virologic success rate was 92% in the GENVOYA group and 90% in the STRIBILD group, with a treatment difference of 2.0% (95% CI: -0.7% to 4.7%). The difference at Week 144 was primarily driven by discontinuations due to other reasons with last available HIV-1 RNA <50 copies/mL.
c Included subjects who had ≥50 copies/mL in the Week 144 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
d Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
e Includes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 144 was 326 cells per mm3 in GENVOYA-treated subjects and 305 cells per mm3 in STRIBILD-treated subjects.
The updated labels will soon be available drugs@fda or DailyMed
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
For more information about the HIV Liaison Program visit the FDA Patient Network
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