Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate for HIV

INDICATIONS AND USAGE STRIBILD ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD [see Clinical Studies (14) ] . STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir disoproxil fumarate (TDF), both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD. ( 1 , 14 )

DOSAGE AND ADMINISTRATION Testing: Prior to initiation of STRIBILD, test patients for hepatitis B virus infection. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, serum phosphorous, estimated serum creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) Recommended dosage: One tablet taken once daily with food. ( 2.2 ) Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute. ( 2.3 ) 2.1 Testing Prior to Initiation and During Treatment with STRIBILD Prior to initiation of STRIBILD, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage STRIBILD is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF. The recommended dosage of STRIBILD is one tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with a body weight at least 35 kg and creatinine clearance greater than or equal to 70 mL per minute [see Clinical Pharmacology (12.3) ] . 2.3 Dosage Adjustment in Patients with Renal Impairment Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute during treatment with STRIBILD, as the dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.2) , Adverse Reactions (6.1) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . No data are available to make dose recommendations for pediatric patients with renal impairment. 2.4 Not Recommended in Patients with Severe Hepatic Impairment STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.5 Not Recommended During Pregnancy STRIBILD is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters [see Use in Specific Populations (8.1) ] . STRIBILD should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with STRIBILD [see Use in Specific Populations (8.1) ] .

WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. ( 5.2 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.3 ) Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of STRIBILD and possible development of resistance; clinically significant adverse reactions from greater exposures of concomitant drugs; or loss of therapeutic effect of concomitant drugs. ( 5.4 ) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.5 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.6 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage and Administration (2.1) ] . Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued emtricitabine or TDF, two of the components of STRIBILD. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.2 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of STRIBILD, and with the use of STRIBILD [see Adverse Reactions (6.2) ] . In the clinical trials of STRIBILD over 144 weeks, 13 (1.9%) subjects in the STRIBILD group (N=701), 8 (2.3%) subjects in the atazanavir (ATV) + ritonavir (RTV) + TRUVADA ® (emtricitabine 200 mg/TDF 300 mg) group (N=355), and no subjects in the ATRIPLA ® (efavirenz 600 mg/emtricitabine 200 mg/TDF 300 mg) group (N=352) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the STRIBILD group and 1 in the ATV+RTV+TRUVADA group occurred during the first 48 weeks. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction, leading to discontinuation of STRIBILD during the first 48 weeks of treatment. Two of the four subjects had renal impairment (i.e., estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects. One (0.3%) subject who received ATV+RTV+TRUVADA developed laboratory findings consistent with proximal renal tubular dysfunction, leading to discontinuation of ATV+RTV+TRUVADA after Week 96. STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.4) ] . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue STRIBILD in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended [see Dosage and Administration (2.1) ] . Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function [see Adverse Reactions (6.1) ] , patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety. The emtricitabine and TDF components of STRIBILD are primarily excreted by the kidney. STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for emtricitabine and TDF cannot be achieved with the fixed-dose combination tablet [see Use in Specific Populations (8.6) ] . 5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and emtricitabine, components of STRIBILD, alone or in combination with other antiretrovirals. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7) ]: Loss of therapeutic effect of STRIBILD and possible development of resistance. Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, from greater exposures of concomitant drugs metabolized by CYP3A. Loss of therapeutic effect of concomitant drugs that utilize CYP3A to form active metabolites. See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during STRIBILD therapy; review concomitant medications during STRIBILD therapy; and monitor for the adverse reactions associated with the concomitant drugs. 5.5 Bone Loss and Mineralization Defects Bone Mineral Density In clinical trials in HIV-1 infected adults, TDF (a component of STRIBILD) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. For additional information, [see Adverse Reactions (6.1) ] and consult the TDF prescribing information. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest

DRUG INTERACTIONS STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. ( 7.1 ) STRIBILD can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of STRIBILD. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. ( 4 , 7.2 , 7.3 , 12.3 ) 7.1 Not Recommended with Other Antiretroviral Medications STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications (4) , Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] . 7.2 Potential for STRIBILD to Affect Other Drugs Cobicistat, a component of STRIBILD, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: P-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3, may result in increased plasma concentrations of such drugs. Coadministration of STRIBILD with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentration of these active metabolite(s) (Table 5). Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates. 7.3 Potential for Other Drugs to Affect One or More Components of STRIBILD Elvitegravir and cobicistat, components of STRIBILD, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (Table 5). Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (Table 5). 7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir, components of STRIBILD, are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.2) ] . 7.5 Established and Other Potentially Significant Interactions Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD or the components of STRIBILD (elvitegravir, cobicistat, emtricitabine, and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction see Clinical Pharmacology (12.3) ]. The table includes potentially significant interactions but is not all inclusive [see Contraindications (4) and Clinical Pharmacology (12.3) ]. Table 5 Established and Other Potentially Significant This table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect on Concentration ↑=Increase, ↓=Decrease Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antiarrhythmics: e.g., amiodarone bepridil digoxin Indicates that a drug-drug interaction trial was conducted. disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine ↑ antiarrhythmics ↑ digoxin Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. Antibacterials: clarithromycin ↑ clarithromycin ↑ cobicistat Patients with CLcr greater than or equal to 60 mL/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/minute and 60 mL/minute: The dose of clarithromycin should be reduced by 50%. Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban betrixaban dabigatran edoxaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for coadministration with STRIBILD depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. ↑ rivaroxaban Coadministration of rivaroxaban with STRIBILD is not recommended because it may lead to an increased bleeding risk. ↑ betrixaban ↑ dabigatran ↑ edoxaban Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as STRIBILD depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information. warfarin Effect on warfarin unknown Monitor international normalized ratio (INR) upon coadministration of warfarin with STRIBILD. Anticonvulsants: carbamazepine phenobarbital phenytoin ↓ elvitegravir ↓ cobicistat Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance. oxcarbazepine Alternative anticonvulsants should be considered when STRIBILD is coadministered with oxcarbazepine. clonazepam ethosuximide ↑ clonazepam ↑ ethosuximide Clinical monitoring is recommended upon coadministration of clonazepam or ethosuximide with STRIBILD. Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine ↑ SSRIs (except sertraline) ↑ TCAs ↑ trazodone Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with STRIBILD. Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion trazodone Antifungals: itraconazole ketoconazole voriconazole ↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole When coadministered with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD. Anti-gout: colchicine ↑ colchicine STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterial: rifampin ↓ elvitegravir ↓ cobicistat Coadmin

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.3) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.6) ] . Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Clinical Trials in HIV-1 Infected Adult Subjects with No Antiretroviral Treatment History The safety assessment of STRIBILD is based on the Week-144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve HIV-1 infected adult subjects [see Clinical Studies (14) ]. A total of 701 subjects received STRIBILD once daily in these two studies. The proportion of subjects who discontinued treatment with STRIBILD, ATRIPLA, or ATV+RTV+TRUVADA due to adverse events, regardless of severity, was 6.0%, 7.4%, and 8.5%, respectively. Table 1 displays the frequency of adverse reactions greater than or equal to 5% of subjects in any treatment arm. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drugs. (All Grades) Reported in ≥5% of Adult Subjects in Any Treatment Arm in Studies 102 and 103 (Week-144 Analysis) STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 EYE DISORDERS Ocular icterus <1% 0% 13% GASTROINTESTINAL DISORDERS Diarrhea 12% 11% 17% Flatulence 2% <1% 8% Nausea 16% 9% 14% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 4% 8% 6% HEPATOBILIARY DISORDERS Jaundice 0% <1% 9% NERVOUS SYSTEM DISORDERS Somnolence 1% 7% 1% Headache 7% 4% 6% Dizziness 3% 21% 5% PSYCHIATRIC DISORDERS Insomnia 3% 9% 1% Abnormal dreams 9% 27% 4% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria. 4% 15% 6% See Warnings and Precautions (5.2) for a discussion of renal adverse reactions from clinical trials experience with STRIBILD. Additional adverse reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a preexisting history of depression or psychiatric illness. Clinical Trials in Virologically Suppressed HIV-1 Infected Adult Subjects No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed adult subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). In a combined analysis of studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI+TRUVADA or NNRTI+TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events was 2%, 3%, and 1%, respectively. Clinical Trials of the Components of STRIBILD in Adult Subjects Emtricitabine and TDF: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or TDF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving STRIBILD in studies 102 and 103 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Adult Subjects Receiving STRIBILD in Studies 102 and 103 (Week-144 Analysis) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. , For subjects with serum amylase >1.5 × upper limit of normal (ULN), lipase test was also performed. The frequency of increased lipase (Grades 3–4) occurring in STRIBILD (N=69), ATRIPLA (N=40), and ATV+RTV+TRUVADA (N=38) was 17%, 15%, and 24%, respectively. STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 AST (>5.0 × ULN) 3% 6% 6% ALT (>3.0 × ULN) 2% 5% 4% Amylase (>2.0 × ULN) 3% 3% 5% Creatine Kinase (≥10.0 × ULN) 8% 15% 11% Urine RBC (Hematuria) (>75 RBC/HPF) 4% 2% 4% In Study 103, BMD was assessed by DEXA in a nonrandom subset of 120 subjects (STRIBILD group, N=54; ATV+RTV+TRUVADA group, N=66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to that in the ATV+RTV+TRUVADA group at the lumbar spine (−1.43% versus −3.68%, respectively) and at the hip (−2.83% versus −3.77%, respectively). In studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV+RTV+TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving TDF + lamivudine + efavirenz. Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV+RTV+TRUVADA. The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which levels stabilized. Table 3 displays the mean changes in serum creatinine and eGFR levels at Week 144 and the percentage of subjects with elevations in serum creatinine (all grades). Table 3 Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and 103 at Week 144 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Serum Creatinine (mg/dL) Mean change ± standard deviation 0.14 (±0.14) 0.01 (±0.12) 0.09 (±0.15) eGFR by Cockcroft-Gault (mL/minute) −14.0 (±16.6) −1.9 (±17.9) −9.8 (±19.4) Subjects with Elevations in Serum Creatinine (All Grades) (%) 12 2 6 Emtricitabine or TDF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or TDF with other antiretroviral agents in other clinical trials: Grade 3 o