FDA label 7e55b122-534a-4fcc-9b47-f7263d25b363

5 WARNINGS AND PRECAUTIONS Monitor for Immune Reconstitution Syndrome ( 5.1 ). 5.1 Immune Reconstitution Syndrome During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.

6 ADVERSE REACTIONS The most common adverse reactions of moderate to severe intensity (≥2%) which occurred at a higher rate than the comparator are insomnia, headache, nausea, asthenia and fatigue ( 6.1 ). Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 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. Treatment-Naïve Studies The following safety assessment of ISENTRESS in treatment-naïve subjects is based on the randomized double-blind active controlled study of treatment-naïve subjects, STARTMRK (Protocol 021) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 300 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir was 247 patient-years and 241 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir. In Protocol 021, the rate of discontinuation of therapy due to adverse reactions was 3% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir and 6% in subjects receiving efavirenz + emtricitabine (+) tenofovir. The clinical adverse drug reactions (ADRs) listed below were considered by investigators to be causally related to ISENTRESS + emtricitabine (+) tenofovir or efavirenz + emtricitabine (+) tenofovir. Clinical ADRs of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS and occurring at a higher rate than efavirenz are presented in Table 1. Table 1: Adverse Reactions Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug of Moderate to Severe Intensity Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Efavirenz (48 Week Analysis) System Organ Class, Preferred Term Randomized Study Protocol 021 ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir (n = 281) n = total number of subjects per treatment group % Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (n = 282) % Psychiatric Disorders Insomnia 4 3 Less Common Adverse Reactions The following ADRs occurred in <2% of subjects receiving ISENTRESS + emtricitabine (+) tenofovir. These events have been included because of their seriousness, increased frequency on ISENTRESS compared with efavirenz or investigator's assessment of potential causal relationship. General Disorders and Administration Site Conditions: fatigue Psychiatric Disorders: abnormal dreams Laboratory Abnormalities The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or efavirenz in Protocol 021 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening from baseline are presented in Table 2. Table 2: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects (48 Week Analysis) Randomized Study Protocol 021 Laboratory Parameter Preferred Term (Unit) Limit ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir (N = 281) Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (N = 282) ULN = Upper limit of normal range Hematology Absolute neutrophil count (10 3 /μL) Grade 2 0.75 - 0.999 3% 3% Grade 3 0.50 - 0.749 1% <1% Grade 4 <0.50 <1% 0% Hemoglobin (gm/dL) Grade 2 7.5 - 8.4 <1% <1% Grade 3 6.5 - 7.4 <1% <1% Grade 4 <6.5 0% 0% Platelet count (10 3 /μL) Grade 2 50 - 99.999 2% 0% Grade 3 25 - 49.999 0% <1% Grade 4 <25 0% .0% Blood chemistry Fasting (non-random) serum glucose test (mg/dL) Grade 2 126 - 250 2% 3% Grade 3 251 - 500 <1% 0% Grade 4 >500 0% 0% Total serum bilirubin Grade 2 1.6 - 2.5 x ULN 4% 0% Grade 3 2.6 - 5.0 x ULN <1% 0% Grade 4 >5.0 x ULN 0% 0% Serum aspartate aminotransferase Grade 2 2.6 - 5.0 x ULN 3% 4% Grade 3 5.1 - 10.0 x ULN 1% 1% Grade 4 >10.0 x ULN <1% <1% Serum alanine aminotransferase Grade 2 2.6 - 5.0 x ULN 4% 6% Grade 3 5.1 - 10.0 x ULN <1% 2% Grade 4 >10.0 x ULN <1% <1% Serum alkaline phosphatase Grade 2 2.6 - 5.0 x ULN <1% 2% Grade 3 5.1 - 10.0 x ULN 0% <1% Grade 4 >10.0 x ULN 0% 0% Lipids, Change from Baseline Changes from baseline in fasting lipids are shown in Table 3. Table 3: Lipid Values, Mean Change from Baseline, Protocol 021 Laboratory Parameter Preferred Term ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir N = 281 Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir N = 282 Change from Baseline at Week 48 Change from Baseline at Week 48 Baseline Mean (mg/dL) Week 48 Mean (mg/dL) Mean Change (mg/dL) Baseline Mean (mg/dL) Week 48 Mean (mg/dL) Mean Change (mg/dL) Notes: N = Number of subjects in the treatment group. The analysis is based on all available data. If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving ISENTRESS and 3% in the efavirenz group. Through Week 48, serum lipid-reducing agents were used in 6% of subjects in the group receiving ISENTRESS and 6% in the efavirenz group. LDL-Cholesterol Fasting (non-random) laboratory tests. 97 103 6 92 108 16 HDL-Cholesterol 38 42 4 38 48 10 Total Cholesterol 159 169 10 156 188 33 Triglyceride 125 122 -3 136 174 37 Treatment-Experienced Studies The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 48 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 387 patient-years versus 156 patient-years on placebo. The rates of discontinuation due to adverse events were 2% in subjects receiving ISENTRESS and 3% in subjects receiving placebo. Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS and occurring at a higher exposure adjusted rate compared to placebo are presented in Table 4. Table 4: Adverse Drug Reactions Includes adverse reactions at least possibly, probably, or definitely related to the drug. of Moderate to Severe Intensity Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Exposure Adjusted Rate Compared to Placebo (48 Week Analysis, Exposure Adjusted Incidence Rates) System Organ Class, Adverse Reactions Randomized Studies Protocol 018 and 019 ISENTRESS 400 mg Twice Daily + OBT (n = 462) n=total number of subjects per treatment group. Placebo + OBT (n = 237) Rate per 100 Patient-Years Rate per 100 Patient-Years Nervous System Disorders Headache 3 1 Gastrointestinal Disorders Nausea 2 1 General Disorders and Administration Site Conditions Asthenia 2 1 Fatigue 2 1 Less Common Adverse Reactions The following ADRs occurred in <2% of subjects receiving ISENTRESS + OBT. These events have been included because of either their seriousness, increased frequency on ISENTRESS compared with placebo or investigator's assessment of potential causal relationship. Gastrointestinal Disorders : abdominal pain, gastritis Hepatobiliary Disorders : hepatitis Immune System Disorders : hypersensitivity Infections and Infestations: genital herpes, herpes zoster Nervous System Disorders : dizziness Renal and Urinary Disorders : renal failure Laboratory Abnormalities The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Protocols 018 and 019 with selected Grade 2 to 4 laboratory abnormalities representing a worsening from baseline are presented in Table 5. Table 5: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (48 Week Analysis) Randomized Studies Protocol 018 and 019 Laboratory Parameter Preferred Term (Unit) Limit ISENTRESS 400 mg Twice Daily + OBT (N = 462) Placebo + OBT (N = 237) ULN = Upper limit of normal range Hematology Absolute neutrophil count (10 3 /μL) Grade 2 0.75 - 0.999 3% 5% Grade 3 0.50 - 0.749 3% 3% Grade 4 <0.50 1% <1% Hemoglobin (gm/dL) Grade 2 7.5 - 8.4 1% 3% Grade 3 6.5 - 7.4 1% <1% Grade 4 <6.5 <1% 0% Platelet count (10 3 /μL) Grade 2 50 - 99.999 3% 5% Grade 3 25 - 49.999 1% <1% Grade 4 <25 1% <1% Blood chemistry Fasting (non-random) serum glucose test (mg/dL) Grade 2 126 – 250 8% 5% Grade 3 251 – 500 2% 1% Grade 4 >500 0% 0% Total serum bilirubin Grade 2 1.6 - 2.5 x ULN 5% 3% Grade 3 2.6 - 5.0 x ULN 2% 2% Grade 4 >5.0 x ULN 1% 0% Serum aspartate aminotransferase Grade 2 2.6 - 5.0 x ULN 8% 6% Grade 3 5.1 - 10.0 x ULN 3% 3% Grade 4 >10.0 x ULN <1% 1% Serum alanine aminotransferase Grade 2 2.6 - 5.0 x ULN 7% 8% Grade 3 5.1 - 10.0 x ULN 3% 2% Grade 4 >10.0 x ULN 1% 2% Serum alkaline phosphatase Grade 2 2.6 - 5.0 x ULN 2% <1% Grade 3 5.1 - 10.0 x ULN <1% 1% Grade 4 >10.0 x ULN 1% <1% Serum pancreatic amylase test Grade 2 1.6 - 2.0 x ULN 2% 1% Grade 3 2.1 - 5.0 x ULN 3% 3% Grade 4 >5.0 x ULN <1% 0% Serum lipase test Grade 2 1.6 - 3.0 x ULN 4% 3% Grade 3 3.1 - 5.0 x ULN 1% <1% Grade 4 >5.0 x ULN 0% 0% Serum creatine kinase Grade 2 6.0 - 9.9 x ULN 2% 2% Grade 3 10.0 - 19.9 x ULN 3% 3% Grade 4 ≥20.0 x ULN 2% 1% Selected Adverse Events Regardless of Drug Relationship Cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm 3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator. Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 5). Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions. Patients with Co-existing Conditions Patients Co-infected with Hepatitis B and/or Hepatitis C Virus In the randomized, double-blind, placebo-controlled trials, treatment-experienced subjects (N = 114/699 or 16%) and treatment-naïve subjects (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. In treatment-experienced subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 25%, 31% and 12%, respectively, of co-infected subjects treated with ISENTRESS as compared to 8%, 7% and 8% of all other subjects treated with ISENTRESS. In treatment-naïve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17%, 22% and 11%, respectively, of co-infected subjects treated with ISENTRESS as compared to 4%, 4% and 3% of all other subjects treated with ISENTRESS. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ISENTRESS. 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. Psychiatric Disorders: anxiety, depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors, paranoia Skin and Subcutaneous Tissue Disorders : rash, Stevens-Johnson syndrome

<table width="682.000" ID="id_6a40b476-77d1-414e-8e87-fb929d22f9b7"> <caption ID="id_3936dd30-258b-4353-9a83-b7eed717e63e">Table 1: Adverse Reactions<footnote ID="id-379c4450-7615-49e1-9820-7b5af30ad3e0">Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug </footnote> of Moderate to Severe Intensity<footnote ID="id-166c4bc7-c58f-443a-a2a1-7d35992e64ca">Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).</footnote> Occurring in &#x2265;2% of Treatment-Na&#xEF;ve Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Efavirenz (48 Week Analysis)</caption> <col width="26.5%"/> <col width="36.4%"/> <col width="37.1%"/> <thead> <tr ID="id_f3a4643e-c705-4415-baa3-937a16bf1343"> <td align="center" valign="top" rowspan="2" styleCode="Toprule"> <content styleCode="bold">System Organ Class, Preferred Term</content> </td> <td align="center" valign="top" colspan="2" styleCode="Botrule"> <content styleCode="bold">Randomized Study Protocol 021</content> </td> </tr> <tr ID="id_d44f49f8-7514-4767-a6d4-01969c5daf68"> <td align="center" valign="top"> <paragraph> <content styleCode="bold">ISENTRESS 400 mg </content> <content styleCode="bold">Twice Daily +</content> <content styleCode="bold">Emtricitabine (+) Tenofovir</content> <content styleCode="bold">(n = 281)<footnote ID="id-b7508106-17fe-4044-aaba-60db0e28d04d">n = total number of subjects per treatment group </footnote> </content> <content styleCode="bold">%</content> </paragraph> </td> <td align="center" valign="top"> <paragraph> <content styleCode="bold">Efavirenz 600 mg </content> <content styleCode="bold">At Bedtime +</content> <content styleCode="bold">Emtricitabine (+) Tenofovir</content> <content styleCode="bold">(n = 282)<footnoteRef IDREF="id-b7508106-17fe-4044-aaba-60db0e28d04d"/> </content> <content styleCode="bold">%</content> </paragraph> </td> </tr> </thead> <tbody> <tr ID="id_a5ecb7f3-89e5-4626-8594-823652b66e36" styleCode="BotRule"> <td align="left" valign="top" colspan="3"> <content styleCode="bold">Psychiatric Disorders</content> </td> </tr> <tr ID="id_2bc18958-eadb-4688-8031-293c005cb33e"> <td align="left" valign="top">Insomnia</td> <td align="center" valign="top">4</td> <td align="center" valign="top">3</td> </tr> </tbody> </table>

<table width="632.000" ID="id_b91911c9-9e9b-45f4-a6e3-58090986d09a"> <caption ID="id_4e9dba23-991c-48f6-ad24-3fc873e4a9cd">Table 2: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Na&#xEF;ve Subjects (48 Week Analysis)</caption> <col width="26.9%"/> <col width="21.8%"/> <col width="25.2%"/> <col width="26.1%"/> <thead> <tr ID="id_3a4c1481-ad37-4173-bcdb-93ae34db47cf"> <td align="left" valign="top" styleCode="Toprule"/> <td align="justify" valign="top" styleCode="Toprule"/> <td align="center" valign="top" colspan="2" styleCode="Botrule"> <content styleCode="bold">Randomized Study Protocol 021</content> </td> </tr> <tr ID="id_88732854-db44-4a74-adf9-64d000c4c805"> <td align="left" valign="top"> <content styleCode="bold">Laboratory Parameter Preferred Term (Unit)</content> </td> <td align="center" valign="top"> <content styleCode="bold">Limit</content> </td> <td align="center" valign="top"> <paragraph> <content styleCode="bold">ISENTRESS 400 mg</content> <content styleCode="bold">Twice Daily +</content> <content styleCode="bold">Emtricitabine (+) Tenofovir</content> <content styleCode="bold">(N = 281)</content> </paragraph> </td> <td align="center" valign="top"> <paragraph> <content styleCode="bold">Efavirenz </content> <content styleCode="bold">600 mg</content> <content styleCode="bold">At Bedtime +</content> <content styleCode="bold">Emtricitabine (+) Tenofovir (N = 282)</content> </paragraph> </td> </tr> </thead> <tfoot ID="id_d10dd002-c16f-48e8-a861-ff48c963ecff"> <tr> <td align="left" valign="top" colspan="4">ULN = Upper limit of normal range </td> </tr> </tfoot> <tbody> <tr ID="id_cc01be05-7528-422f-b20b-f6a2b10dacf5" styleCode="BotRule"> <td align="left" valign="top" colspan="4"> <content styleCode="bold">Hematology </content> </td> </tr> <tr ID="id_40f5ed87-26b5-49ca-9a36-bcb8e506365f"> <td align="left" valign="middle" colspan="4">Absolute neutrophil count (10³/&#x3BC;L)</td> </tr> <tr ID="id_29a65ee7-3ec8-4a84-bbed-5cb4028a20b0"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">0.75 - 0.999</td> <td align="center" valign="top">3%</td> <td align="center" valign="top">3%</td> </tr> <tr ID="id_6a5414f2-6c47-48d9-9c21-d28ed7595432"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">0.50 - 0.749</td> <td align="center" valign="top">1%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_6c5a2601-e613-4a51-90ba-c1a1bb11cc91" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&lt;0.50</td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_3b9e54c7-1e8c-4e25-b9f7-34149b5a79af"> <td align="left" valign="middle" colspan="4">Hemoglobin (gm/dL) </td> </tr> <tr ID="id_be1a6f06-6ea5-426c-ab11-4e0628e34c3e"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">7.5 - 8.4</td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_59a63083-c509-466d-bd98-6ad95887fcdb"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">6.5 - 7.4</td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_ff1547e5-7614-4fb0-ae68-15ba08f8fb1f" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&lt;6.5</td> <td align="center" valign="top">0%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_ff68da84-dd4e-4813-831b-daf3c1dd58f3"> <td align="left" valign="middle" colspan="4">Platelet count (10³/&#x3BC;L)</td> </tr> <tr ID="id_72043cc0-fb48-4be0-8df2-6f851824841f"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">50 - 99.999</td> <td align="center" valign="top">2%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_703a2897-aad9-4267-8ad4-a6167f0ffd2b"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">25 - 49.999</td> <td align="center" valign="top">0%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_9151536e-dfe4-4797-9a8f-d14762a596d3" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&lt;25</td> <td align="center" valign="top">0%</td> <td align="center" valign="top">.0%</td> </tr> <tr ID="id_8c59d74e-71bc-4b46-80d6-cfae3469281b" styleCode="BotRule"> <td align="left" valign="top" colspan="4"> <content styleCode="bold">Blood chemistry</content> </td> </tr> <tr ID="id_ae65d726-1e49-47e3-8a96-fd0145185717"> <td align="left" valign="middle" colspan="4">Fasting (non-random) serum glucose test (mg/dL)</td> </tr> <tr ID="id_49307146-89e8-476d-93f7-c0e201396abe"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">126 - 250 </td> <td align="center" valign="top">2%</td> <td align="center" valign="top">3%</td> </tr> <tr ID="id_5bcdc48e-001d-402e-a054-168acec416a7"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">251 - 500 </td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_4669903a-c4a2-4970-8bef-52c4d590f767" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&gt;500 </td> <td align="center" valign="top">0%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_a34e8bdb-2b1f-485d-944a-56adb7a560f2"> <td align="left" valign="middle" colspan="4">Total serum bilirubin </td> </tr> <tr ID="id_1cbe4e09-7789-4898-bf08-068d1c17ec1a"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">1.6 - 2.5 x ULN</td> <td align="center" valign="top">4%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_fd2a5b08-b002-4729-bbc7-9c5e5fe3b85f"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">2.6 - 5.0 x ULN </td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_d9eaa058-ee6f-4225-a226-c82424c8c95b" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&gt;5.0 x ULN </td> <td align="center" valign="top">0%</td> <td align="center" valign="top">0%</td> </tr> <tr ID="id_d29b9661-7d04-4610-924b-d494d9883ec7"> <td align="left" valign="middle" colspan="4">Serum aspartate aminotransferase </td> </tr> <tr ID="id_a07b3244-cc5a-4552-85bf-9766d266e410"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">2.6 - 5.0 x ULN </td> <td align="center" valign="top">3%</td> <td align="center" valign="top">4%</td> </tr> <tr ID="id_c827abb2-039c-4a4a-8961-4c8941d1f873"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">5.1 - 10.0 x ULN </td> <td align="center" valign="top">1%</td> <td align="center" valign="top">1%</td> </tr> <tr ID="id_9180facd-fb26-40bc-9227-35272a074311" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&gt;10.0 x ULN</td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_72368b1a-2e33-443a-80a1-be6d703ceedb"> <td align="left" valign="middle" colspan="4">Serum alanine aminotransferase </td> </tr> <tr ID="id_a840cd7d-0e3f-4df4-99fa-02ac8b580271"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">2.6 - 5.0 x ULN </td> <td align="center" valign="top">4%</td> <td align="center" valign="top">6%</td> </tr> <tr ID="id_625d79ec-7295-4bf4-892c-aefd9081a5a2"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">5.1 - 10.0 x ULN</td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">2%</td> </tr> <tr ID="id_fd44b90f-9ad4-4b8d-b877-5a19a3b14f38" styleCode="BotRule"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&gt;10.0 x ULN</td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_bb5ee1b1-04c2-412a-ac5b-a15a274bde5f"> <td align="left" valign="middle" colspan="4">Serum alkaline phosphatase </td> </tr> <tr ID="id_bb99d43c-f741-4827-8cff-4b381d5dc6fe"> <td align="center" valign="middle">Grade 2</td> <td align="center" valign="top">2.6 - 5.0 x ULN </td> <td align="center" valign="top">&lt;1%</td> <td align="center" valign="top">2%</td> </tr> <tr ID="id_be9e31b2-f350-46b9-8245-2b6b4d8dd487"> <td align="center" valign="middle">Grade 3</td> <td align="center" valign="top">5.1 - 10.0 x ULN</td> <td align="center" valign="top">0%</td> <td align="center" valign="top">&lt;1%</td> </tr> <tr ID="id_8b6fb48d-2a78-4628-9ab5-dab244816131"> <td align="center" valign="middle">Grade 4</td> <td align="center" valign="top">&gt;10.0 x ULN</td> <td align="center" valign="top">0%</td> <td align="center" valign="top">0%</td> </tr> </tbody> </table>

<table width="707.000" ID="id_abb658f7-bcf4-46ef-ae01-1a406a86729a"> <caption ID="id_6dd4f043-f03c-4263-8e0c-f6d1b7b875c2">Table 3: Lipid Values, Mean Change from Baseline, Protocol 021 </caption> <col width="22.5%"/> <col width="11.6%"/> <col width="11.6%"/> <col width="15.6%"/> <col width="11.6%"/> <col width="11.6%"/> <col width="15.6%"/> <thead> <tr ID="id_524a2938-ec7d-4e73-84d0-c85bc8f2cde8" styleCode="BotRule"> <td align="center" valign="top" styleCode="RRule"> <paragraph> <content styleCode="bold">Laboratory Parameter </content> <content styleCode="bold">Preferred Term </content> </paragraph> </td> <td align="center" valign="top" colspan="3" styleCode="RRule"> <paragraph> <content styleCode="bold">ISENTRESS 400 mg </content> </paragraph> <paragraph> <content styleCode="bold">Twice Daily + Emtricitabine (+) Tenofovir </content> </paragraph> <content styleCode="bold">N = 281</content> </td> <td align="center" valign="top" colspan="3"> <paragraph> <content styleCode="bold">Efavirenz 600 mg </content> </paragraph> <paragraph> <content styleCode="bold">At Bedtime + Emtricitabine (+) Tenofovir </content> </paragraph> <content styleCode="bold">N = 282 </content> </td> </tr> <tr ID="id_7e2ecbb7-9571-49e7-9a7a-df01380220ed" styleCode="BotRule"> <td align="center" valign="top" styleCode="RRule"/> <td align="center" valign="top" colspan="2" styleCode="RRule"/> <td align="center" valign="top" styleCode="RRule"> <paragraph> <content styleCode="bold">Change from Baseline at Week 48</content> </paragraph> </td> <td align="center" valign="top" colspan="2" styleCode="RRule"/> <td align="center" valign="top"> <paragraph> <content styleCode="bold">Change from Baseline at Week 48</content> </paragraph> </td> </tr> <tr ID="id_8a3f642c-815b-4756-880f-b6e33cb3ad79"> <td align="center" valign="top" styleCode="RRule"/> <td align="center" valign="top" styleCode="RRule"> <content styleCode="bold">Baseline Mean</content>(mg/dL)</td> <td align="center" valign="top" styleCode="RRule"> <content styleCode="bold">Week 48 Mean</content>(mg/dL)</td> <td align="center" valign="top" styleCode="RRule"> <content styleCode="bold">Mean Change </content> (mg/dL)</td> <td align="center" valign="top" styleCode="RRule"> <content styleCode="bold">Baseline Mean</content>(mg/dL)</td> <td align="center" valign="top" styleCode="RRule"> <content styleCode="bold">Week 48 Mean</content>(mg/dL)</td> <td align="center" valign="top"> <content styleCode="bold">Mean Change </content> (mg/dL)</td> </tr> </thead> <tfoot ID="id_3ba47ec1-d51b-418f-8d52-16a2f13191b2"> <tr> <td align="left" valign="top" colspan="7">Notes: </td> </tr> <tr> <td align="left" valign="top" colspan="7">N = Number of subjects in the treatment group. The analysis is based on all available data.</td> </tr> <tr> <td align="justify" valign="top" colspan="7"> <paragraph>If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. </paragraph> At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving ISENTRESS and 3% in the efavirenz group. Through Week 48, serum lipid-reducing agents were used in 6% of subjects in the group receiving ISENTRESS and 6% in the efavirenz group.</td> </tr> </tfoot> <tbody> <tr ID="id_cf47246e-7d6e-4a7a-96da-903dbf1f7a51"> <td align="left" valign="top" styleCode="RRule"> LDL-Cholesterol<footnote ID="id-c7cfd854-6441-4e1c-813d-b6c425b79551">Fasting (non-random) laboratory tests.</footnote> </td> <td align="center" valign="top" styleCode="RRule">97</td> <td align="center" valign="top" styleCode="RRule">103</td> <td align="center" valign="top" styleCode="RRule">6 </td> <td align="center" valign="top" styleCode="RRule">92</td> <td align="center" valign="top" styleCode="RRule">108</td> <td align="center" valign="top">16</td> </tr> <tr ID="id_275df783-7ce3-4e40-9a73-9058366aafee"> <td align="left" valign="top" styleCode="RRule">HDL-Cholesterol<footnoteRef IDREF="id-c7cfd854-6441-4e1c-813d-b6c425b79551"/> </td> <td align="center" valign="top" styleCode="RRule">38</td> <td align="center" valign="top" styleCode="RRule">42</td> <td align="center" valign="top" styleCode="RRule">4 </td> <td align="center" valign="top" styleCode="RRule">38</td> <td align="center" valign="top" styleCode="RRule">48</td> <td align="center" valign="top">10 </td> </tr> <tr ID="id_d2abca24-2134-437d-ae70-a7d23d40631b"> <td align="left" valign="top" styleCode="RRule"> <paragraph>Total Cholesterol<footnoteRef IDREF="id-c7cfd854-6441-4e1c-813d-b6c425b79551"/> </paragraph> </td> <td align="center" valign="top" styleCode="RRule">159</td> <td align="center" valign="top" styleCode="RRule">169</td> <td align="center" valign="top" styleCode="RRule">10 </td> <td align="center" valign="top" styleCode="RRule">156</td> <td align="center" valign="top" styleCode="RRule">188</td> <td align="center" valign="top">33 </td> </tr> <tr ID="id_794195dc-a7d8-45a5-acc2-8cc23fe548d4"> <td align="left" valign="top" styleCode="RRule">Triglyceride<footnoteRef IDREF="id-c7cfd854-6441-4e1c-813d-b6c425b79551"/> </td> <td align="center" valign="top" styleCode="RRule">125</td> <td align="center" valign="top" styleCode="RRule">122</td> <td align="center" valign="top" styleCode="RRule">-3 </td> <td align="center" valign="top" styleCode="RRule">136</td> <td align="center" valign="top" styleCode="RRule">174</td> <td align="center" valign="top">37 </td> </tr> </tbody> </table>