Dovato

WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV-1): EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment [see Warnings and Precautions ( 5.1 )] . WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV-1): EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV See full prescribing information for complete boxed warning. • All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. • Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment. ( 5.1 )

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported with dolutegravir. Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. ( 5.2 ) • Hepatotoxicity has been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with DOVATO. Monitoring for hepatotoxicity is recommended. ( 5.3 ) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.4 ) • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.6 ) 5.1 Patients Co-infected with HIV-1 and HBV: Emergence of Lamivudine-Resistant HBV and the Risk of Posttreatment Exacerbations of HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV‑1–infected subjects who have received lamivudine‑containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer DOVATO to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. Severe Acute Exacerbations of HBV in Patients Co-infected with HIV-1 and HBV Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of DOVATO. Patients who are co-infected with HIV-1 and HBV who discontinue DOVATO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DOVATO. If appropriate, initiation of anti-HBV 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 Hypersensitivity Reactions Hypersensitivity reactions have been reported with the use of dolutegravir, a component of DOVATO, and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in <1% of subjects receiving dolutegravir in Phase 3 clinical trials. Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with DOVATO or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction [see Contraindications ( 4 )] . 5.3 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen [see Adverse Reactions ( 6.1 )] . Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of DOVATO [see Adverse Reactions ( 6.1 )] . In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or HBV reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended. 5.4 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine (a component of DOVATO). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Monitor closely when administering DOVATO to any patient with known risk factors for liver disease. Treatment with DOVATO 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. 5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The coadministration of DOVATO and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications ( 4 ), Drug Interactions ( 7.4 )] : • Loss of therapeutic effect of DOVATO and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of coadministered drugs. See Table 5 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 therapy with DOVATO, review coadministered drugs during therapy with DOVATO, and monitor for the adverse reactions associated with the coadministered drugs. 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including DOVATO. 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, and Guillain-Barré syndrome) 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 treatment.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Patients co-infected with HIV-1 and HBV [see Warnings and Precautions ( 5.1 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] • Hepatotoxicity [see Warnings and Precautions ( 5.3 )] • Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.4 )] • Immune reconstitution syndrome [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in ≥2% (in those receiving DOVATO) were headache, nausea, diarrhea, insomnia, fatigue, and anxiety. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials in Adults with No Antiretroviral Treatment History The safety assessment of DOVATO in HIV-1–infected adults with no antiretroviral treatment history and with a plasma viral load ≤500,000 HIV-1 RNA copies/mL at the screening visit, is based on the pooled Week 144 analyses of data from 2 identical, multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received either dolutegravir (TIVICAY) 50 mg plus lamivudine (EPIVIR) 300 mg, as a complete regimen once daily, or TIVICAY 50 mg plus fixed-dose combination tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (TRUVADA), administered once daily. The rates of adverse events leading to discontinuation in the pooled analysis were 4% of subjects who received TIVICAY plus EPIVIR and 5% in subjects who received TIVICAY plus TRUVADA. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects who received TIVICAY plus EPIVIR and 1% in subjects who received TIVICAY plus TRUVADA. Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 144 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2 . The adverse reactions observed for TIVICAY plus EPIVIR in the Week 144 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. Table 2. Adverse Reactions (All Grades) Reported in ≥2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 144 Pooled Analysis) a Fatigue: includes fatigue, asthenia, and malaise. Adverse Reaction TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Headache 3% 4% Nausea 2% 6% Diarrhea 2% 3% Insomnia 2% 3% Fatigue a 2% 2% Anxiety 2% 1% Dizziness 1% 2% Adverse reactions of at least Grade 2 occurring in ≥1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, suicidal ideation, and insomnia (all at 1%). Less Common Adverse Reactions: The following adverse reactions (all grades) occurred in <2% of subjects receiving dolutegravir plus lamivudine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events have been included because of their seriousness and assessment of potential causal relationship. Blood and Lymphatic Systems Disorders: Anemia, neutropenia, thrombocytopenia. Gastrointestinal Disorders: Abdominal discomfort, abdominal pain, flatulence, upper abdominal pain, vomiting. General: Fever. Hepatobiliary Disorders: Hepatitis. Immune System Disorders: Hypersensitivity, immune reconstitution syndrome. Musculoskeletal Disorders: Myositis. Nervous System Disorders: Somnolence. Psychiatric Disorders: Abnormal dreams, depression. Suicidal ideation, attempt, behavior, or completion; these events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus, rash. Clinical Trials in Virologically Suppressed Adults The safety of DOVATO in virologically suppressed adults was based on Week 144 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 148 weeks; at Week 148, the subjects randomized to continue with their TBR were switched to DOVATO once daily. All subjects are followed up to Week 200. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies ( 14.3 )]. Adverse reactions observed in at least 2% of subjects in the TANGO trial who were treated with DOVATO were weight increased (3%) and insomnia (2%). Laboratory Abnormalities Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 3 . The mean change from baseline observed for selected lipid values is presented in Table 4 . Table 3. Selected Laboratory Abnormalities (Grades 2 to 4; Week 144 Pooled Analyses) in GEMINI-1 and GEMINI-2 Trials ULN = Upper limit of normal. Laboratory Parameter Abnormality TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Alanine aminotransferase (ALT) Grade 2 (2.5 to <5.0 x ULN) 4% 4% Grade 3 to 4 (≥5.0 x ULN) 4% 3% Aspartate aminotransferase (AST) Grade 2 (2.5 to <5.0 x ULN) 5% 5% Grade 3 to 4 (≥5.0 x ULN) 3% 4% Total bilirubin Grade 2 (1.6 to <2.6 x ULN) 3% 4% Grade 3 to 4 (≥2.6 x ULN) 1% 1% Creatine kinase Grade 2 (6.0 to <10 x ULN) 5% 5% Grade 3 to 4 (≥10.0 x ULN) 8% 9% Hyperglycemia (glucose) Grade 2 (126 to 250 mg/dL) 11% 8% Grade 3 to 4 (>250 mg/dL) 1% 1% Hypophosphatemia (phosphate) Grade 2 (1.4 to <2.0 mg/dL) 11% 12% Grade 3 to 4 (<1.4 mg/dL) 1% 2% Lipase Grade 2 (1.5 to <3.0 x ULN) 7% 8% Grade 3 to 4 (≥3.0 x ULN) 3% 5% Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 144 Pooled Analyses a ) in GEMINI 1 and GEMINI 2 Trials HDL = High density lipoprotein; LDL = Low density lipoprotein. a Subjects on lipid-lowering agents at baseline are excluded (TIVICAY plus EPIVIR, n = 30; TIVICAY plus TRUVADA, n = 23). The last available fasted, on-treatment lipid value prior to initiation of a lipid-lowering agent was carried forward in place of observed values after initiation of a lipid-lowering agent. A total of 51 and 28 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post-baseline. Laboratory Parameter Preferred Term TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Cholesterol (mg/dL) 15 -2 HDL cholesterol (mg/dL) 7 4 LDL cholesterol (mg/dL) 7 -4 Triglycerides (mg/dL) 10 -9 Total cholesterol/HDL cholesterol ratio -0.2 -0.4 Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology ( 12.2 )] . Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through 144 weeks. A mean change from baseline of 0.144 mg/dL and 0.176 mg/dL was observed after 144 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant. Clinical Trial Experience in Adolescents The safety of DOVATO was evaluated in HIV‑1–infected treatment-naïve subjects between 12 to less than 18 years of age and weighing at least 25 kg (N = 32) through Week 48, in an open label clinical trial, DANCE (Trial 205861). Overall, the observed safety profile in adolescent subjects was similar to those seen in adults [see Use in Specific Populations ( 8.4 ), and Clinical Studies ( 14.4 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or lamivudine-containing regimen. Because postmarketing 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. Body as a Whole Redistribution/accumulation of body fat. Endocrine and Metabolic Hyperglycemia. General Weakness. Hemic and Lymphatic Anemia (including pure red cell aplasia, sideroblastic anemia, and severe anemias progressing on therapy). Hepatic and Pancreatic Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of HBV [see Warnings and Precautions ( 5.1 , 5.4 )] . Hepatobiliary Disorders Acute liver failure, hepatotoxicity. Hypersensitivity Anaphylaxis, urticaria. Investigations Weight increased. Musculoskeletal Arthralgia, creatinine phosphokinase (CPK) elevation, muscle weakness, myalgia, rhabdomyolysis. Nervous System Paresthesia, peripheral neuropathy. Skin Alopecia.

<table ID="_Ref163822332" width="100%"><caption>Table 2. Adverse Reactions (All Grades) Reported in &#x2265;2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 144 Pooled Analysis)</caption><col width="39%"/><col width="31%"/><col width="29%"/><tfoot><tr><td align="left" colspan="3" valign="top">^a Fatigue: includes fatigue, asthenia, and malaise.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY plus EPIVIR</content></paragraph><paragraph><content styleCode="bold">(n = 716)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY plus TRUVADA</content></paragraph><paragraph><content styleCode="bold">(n = 717)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue^a</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anxiety</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>

<table ID="_Ref163822366" width="100%"><caption>Table 3. Selected Laboratory Abnormalities (Grades 2 to 4; Week 144 Pooled Analyses) in GEMINI-1 and GEMINI-2 Trials</caption><col width="36%"/><col width="32%"/><col width="32%"/><tfoot><tr><td align="left" colspan="3" valign="top">ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Laboratory Parameter</content></paragraph><paragraph><content styleCode="bold">Abnormality</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY plus EPIVIR</content></paragraph><paragraph><content styleCode="bold">(n = 716)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY plus TRUVADA</content></paragraph><paragraph><content styleCode="bold">(n = 717)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Alanine aminotransferase (ALT)</paragraph></td><td valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (2.5 to &lt;5.0 x ULN)</paragraph></td><td align="center" valign="bottom"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&#x2265;5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Aspartate aminotransferase (AST)</paragraph></td><td styleCode="Rrule Lrule " valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (2.5 to &lt;5.0 x ULN)</paragraph></td><td align="center" valign="bottom"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&#x2265;5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Total bilirubin</paragraph></td><td styleCode="Rrule Lrule " valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (1.6 to &lt;2.6 x ULN)</paragraph></td><td align="center" valign="bottom"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&#x2265;2.6 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Creatine kinase</paragraph></td><td styleCode="Rrule Lrule " valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (6.0 to &lt;10 x ULN)</paragraph></td><td align="center" valign="bottom"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&#x2265;10.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Hyperglycemia (glucose)</paragraph></td><td styleCode="Rrule Lrule " valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (126 to 250 mg/dL)</paragraph></td><td align="center" valign="bottom"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&gt;250 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Hypophosphatemia (phosphate)</paragraph></td><td styleCode="Rrule Lrule " valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (1.4 to &lt;2.0 mg/dL)</paragraph></td><td align="center" valign="bottom"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&lt;1.4 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Lipase</paragraph></td><td styleCode="Rrule Lrule " valign="bottom"/><td styleCode="Rrule Lrule " valign="bottom"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (1.5 to &lt;3.0 x ULN)</paragraph></td><td align="center" valign="bottom"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Grade 3 to 4 (&#x2265;3.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bottom"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bottom"><paragraph>5%</paragraph></td></tr></tbody></table>

<table ID="_Ref163822392" width="100%"><caption>Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 144 Pooled Analyses^a) in GEMINI 1 and GEMINI 2 Trials</caption><col width="44%"/><col width="28%"/><col width="28%"/><tfoot><tr><td align="left" colspan="3" valign="top">HDL = High density lipoprotein; LDL = Low density lipoprotein.</td></tr><tr><td align="left" colspan="3" valign="top">^a Subjects on lipid-lowering agents at baseline are excluded (TIVICAY plus EPIVIR, n = 30; TIVICAY plus TRUVADA, n = 23). The last available fasted, on-treatment lipid value prior to initiation of a lipid-lowering agent was carried forward in place of observed values after initiation of a lipid-lowering agent. A total of 51 and 28 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post-baseline.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Laboratory Parameter</content></paragraph><paragraph><content styleCode="bold">Preferred Term</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY plus EPIVIR</content></paragraph><paragraph><content styleCode="bold">(n = 716)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY plus TRUVADA</content></paragraph><paragraph><content styleCode="bold">(n = 717)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cholesterol (mg/dL)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>HDL cholesterol (mg/dL)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>LDL cholesterol (mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Triglycerides (mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>-9</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Total cholesterol/HDL cholesterol ratio</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>-0.2</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>-0.4</paragraph></td></tr></tbody></table>