Symtuza

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] . WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA. Hepatic function should be monitored closely in these patients. If appropriate, anti-hepatitis B therapy may be warranted. ( 5.1 )

5. WARNINGS AND PRECAUTIONS Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) including some fatalities can occur with SYMTUZA. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. ( 5.2 ) Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis may occur with SYMTUZA. Discontinue treatment if severe skin reaction develops. ( 5.3 ) Patients receiving SYMTUZA may develop new onset or exacerbations of immune reconstitution syndrome. ( 5.5 ) Monitor in patients with a known sulfonamide allergy. ( 5.7 ) Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.8 ) Patients receiving SYMTUZA may develop new onset or exacerbation of diabetes mellitus/hyperglycemia and redistribution/accumulation of body fat. ( 5.9 , 5.10 ) Patients with hemophilia may develop increase bleeding events. ( 5.11 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy [see Dosage and Administration (2.1) ] . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.2 Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions. Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA. 5.3 Severe Skin Reactions In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia. Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial [see Adverse Reactions (6.1) ] . Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%. 5.4 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions which may lead to [see Contraindications (4) and Drug Interactions (7.5) ] : Clinically significant adverse reactions from greater exposures of concomitant drugs. Clinically significant adverse reactions from greater exposures of SYMTUZA. Loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s). Loss of therapeutic effect of SYMTUZA and possible development of resistance from lower exposures of SYMTUZA. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7) ] . When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . 5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment. 5.6 New Onset or Worsening Renal Impairment Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1 , 6.2) ] . SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, 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 SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety. 5.7 Sulfa Allergy Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy. 5.8 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 emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA 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). 5.9 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established. 5.10 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.11 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.

6. ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe acute exacerbations of hepatitis B [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Severe skin reactions [see Warnings and Precautions (5.3) ] Immune reconstitution syndrome [see Warnings and Precautions (5.5) ] New onset or worsening renal impairment [see Warnings and Precautions (5.6) ] Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions (5.8) ] The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) 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 Adults Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX ® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively. An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3. Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 adverse reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA (N=362) PREZCOBIX+FTC/TDF (N=363) All Grades At least Grade 2 All Grades At least Grade 2 Diarrhea 9% 2% 11% 2% Rash Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% - 4% <1% Flatulence 2% <1% 1% - Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor (bPI) [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC/TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a bPI with FTC/TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%. Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir). Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive System and Breast Disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis Laboratory Abnormalities Table 2: Laboratory Abnormalities (Grade 2–4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) Laboratory Parameter Grade Limit SYMTUZA N=362 PREZCOBIX+FTC/TDF N=363 Creatinine Grade 2 >1.3 to 1.8 × ULN 4% 14% Grade 4 ≥3.5× ULN <1% 0 Triglycerides Grade 2 301–500 mg/dL 7% 4% Grade 3 501–1,000 mg/dL 1% 1% Grade 4 >1,000 mg/dL <1% <1% Total Cholesterol Grade 2 240–<300 mg/dL 17% 4% Grade 3 ≥ 300 mg/dL 2% 1% Low-Density Lipoprotein Cholesterol Grade 2 160–189 mg/dL 9% 4% Grade 3 ≥190 mg/dL 5% 1% Elevated Glucose Levels Grade 2 126–250 mg/dL 6% 6% Grade 3 251–500 mg/dL <1% 0 ALT and/or AST elevations (Grade 2–4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF. Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA N=362 PREZCOBIX+FTC/TDF N=363 Baseline Week 48 Baseline Week 48 Mean The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. mg/dL Change mg/dL Change N N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). N=304 One subject did not have a Week 48 result for LDL cholesterol (n=303). N=290 Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 100 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to HDL ratio 4.1 0.2 4.0 0.1 The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively. Renal Laboratory Tests In the AMBER trial, which enrolled 725 adults with no prior antiretroviral treatment history, subjects had a median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF). From baseline to Week 48, mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-creatinine ratio (UPCR) was 47 mg/g (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg/g (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48. In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg/g (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg/g (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48. Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with PREZCOBIX + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. EMERALD In EMERALD, bPI and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with bPI + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of bPI + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of bPI + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. Clinical Trials in Pediatric Patients Adverse Reactions in Pediatric Patients Weighing At Least 40 kg No clinical trials with SYMTUZA were performed in pediatric patients. However, the safety of the components of SYMTUZA was evaluated in pediatric subjects of 12 to less than 18 years of age through clinical trials GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) for darunavir co-administered with cobicistat and other antiretroviral agents, and GS-US-292-0106 (treatment-naïve, N=50 with weight ≥35 kg) for a fixed-dose combination regimen containing cobicistat, emtricitabine, and tenofovir alafenamide together with elvitegravir. Safety analyses of the trials in these pediatric subjects did not identify new safety concerns compared to the known safety profile of SYMTUZA in adult subjects [see Clinical Studies (14.3) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of darunavir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and Nutrition Disorders: Redistribution of body fat Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.3) ] Renal and Urinary Disorders: Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, Fanconi syndrome [see Warnings and Precautions (5.6) ] , crystal nephropathy, and crystalluria

<table width="90%"><caption>Table 1: Adverse Reactions Reported in &#x2265;2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)</caption><col width="34%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th/><th colspan="2">SYMTUZA (N=362) </th><th colspan="2">PREZCOBIX+FTC/TDF (N=363) </th></tr><tr><th styleCode="Lrule Rrule"/><th>All Grades</th><th styleCode="Rrule">At least Grade 2</th><th>All Grades</th><th styleCode="Rrule">At least Grade 2</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash<footnote ID="K1629">Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria</footnote></td><td styleCode="Rrule">8%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal discomfort</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">-</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">&lt;1%</td></tr><tr><td styleCode="Lrule Rrule">Flatulence</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">-</td></tr></tbody></table>

<table width="90%"><caption>Table 2: Laboratory Abnormalities (Grade 2&#x2013;4) Reported in &#x2265;2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)</caption><col width="30%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Laboratory Parameter Grade </th><th styleCode="Rrule" valign="bottom">Limit</th><th styleCode="Rrule" valign="bottom">SYMTUZA N=362 </th><th styleCode="Rrule" valign="bottom">PREZCOBIX+FTC/TDF N=363 </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Creatinine</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 2</td><td styleCode="Rrule">&gt;1.3 to 1.8 &#xD7; ULN</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">14%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 4</td><td styleCode="Rrule">&#x2265;3.5&#xD7; ULN</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Triglycerides</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 2</td><td styleCode="Rrule">301&#x2013;500 mg/dL</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 3</td><td styleCode="Rrule">501&#x2013;1,000 mg/dL</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 4</td><td styleCode="Rrule">&gt;1,000 mg/dL</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">&lt;1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Total Cholesterol</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 2</td><td styleCode="Rrule">240&#x2013;&lt;300 mg/dL</td><td styleCode="Rrule">17%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 3</td><td styleCode="Rrule">&#x2265; 300 mg/dL</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Low-Density Lipoprotein Cholesterol</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 2</td><td styleCode="Rrule">160&#x2013;189 mg/dL</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 3</td><td styleCode="Rrule">&#x2265;190 mg/dL</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Elevated Glucose Levels</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Grade 2</td><td styleCode="Rrule">126&#x2013;250 mg/dL</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Lrule Rrule"> Grade 3</td><td styleCode="Rrule">251&#x2013;500 mg/dL</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="90%"><caption>Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)</caption><col width="34%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th colspan="2" styleCode="Rrule">SYMTUZA N=362 </th><th colspan="2" styleCode="Rrule">PREZCOBIX+FTC/TDF N=363 </th></tr><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Baseline</th><th styleCode="Rrule">Week 48</th><th styleCode="Rrule">Baseline</th><th styleCode="Rrule">Week 48</th></tr><tr styleCode="Botrule"><th styleCode="Lrule Rrule">Mean<footnote ID="K2119">The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline.</footnote></th><th styleCode="Rrule">mg/dL</th><th styleCode="Rrule">Change</th><th styleCode="Rrule">mg/dL</th><th styleCode="Rrule">Change</th></tr><tr><th styleCode="Lrule Rrule">N<footnote ID="K2137">N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF).</footnote></th><th colspan="2" styleCode="Rrule">N=304<footnote ID="K2143">One subject did not have a Week 48 result for LDL cholesterol (n=303).</footnote></th><th colspan="2" styleCode="Rrule">N=290</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Total cholesterol</td><td styleCode="Rrule">168</td><td styleCode="Rrule">+30</td><td styleCode="Rrule">164</td><td styleCode="Rrule">+11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">HDL cholesterol</td><td styleCode="Rrule">45</td><td styleCode="Rrule">+6</td><td styleCode="Rrule">44</td><td styleCode="Rrule">+2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">LDL cholesterol</td><td styleCode="Rrule">100</td><td styleCode="Rrule">+19</td><td styleCode="Rrule">98</td><td styleCode="Rrule">+5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Triglycerides</td><td styleCode="Rrule">117</td><td styleCode="Rrule">+34</td><td styleCode="Rrule">112</td><td styleCode="Rrule">+21</td></tr><tr><td styleCode="Lrule Rrule">Total cholesterol to HDL ratio</td><td styleCode="Rrule">4.1</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">4.0</td><td styleCode="Rrule">0.1</td></tr></tbody></table>