Apretude

WARNING: RISK OF DRUG RESISTANCE WITH USE OF APRETUDE FOR HIV-1 PRE‑EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED HIV-1 INFECTION Individuals must be tested for HIV-1 infection prior to initiating APRETUDE or oral cabotegravir, and with each subsequent injection of APRETUDE, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of APRETUDE by individuals with undiagnosed HIV-1 infection. Do not initiate APRETUDE for HIV-1 PrEP unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving APRETUDE for PrEP must transition to a complete HIV-1 treatment regimen [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF DRUG RESISTANCE WITH USE OF APRETUDE FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED HIV-1 INFECTION See full prescribing information for complete boxed warning. Individuals must be tested for HIV-1 infection prior to initiating APRETUDE or oral cabotegravir, and with each subsequent injection of APRETUDE, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of APRETUDE for HIV-1 PrEP by individuals with undiagnosed HIV-1 infection. Do not initiate APRETUDE for HIV-1 PrEP unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving APRETUDE for PrEP must transition to a complete HIV-1 treatment regimen. ( 2.2 , 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS • Comprehensive management to reduce the risk of HIV-1 acquisition. ( 5.1 ) • Potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE. Reassess risk of HIV-1 acquisition and test before each injection to confirm HIV-1 negative status. ( 5.2 ) • Residual concentrations of cabotegravir may remain in the systemic circulation of individuals up to 12 months or longer. ( 5.3 ) • Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. ( 5.4 ) • Hepatotoxicity has been reported in individuals receiving cabotegravir. Clinical and laboratory monitoring should be considered. Discontinue APRETUDE if hepatotoxicity is suspected. ( 5.5 ) • Depressive disorders have been reported with APRETUDE. Prompt evaluation is recommended for depressive symptoms. ( 5.6 ) 5.1 Comprehensive Management to Reduce the Risk of HIV-1 Infection Use APRETUDE for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). APRETUDE is not always effective in preventing HIV-1 acquisition [see Clinical Studies ( 14.1 )] . The time from initiation of APRETUDE for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals about and support their efforts in reducing sexual risk behavior. Use APRETUDE to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV‑1 negative [see Contraindications ( 4 )] . HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV‑1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology ( 12.4 )] ; therefore, care should be taken to minimize the risk of initiating or continuing APRETUDE before confirming the individual is HIV-1 negative. • Prior to initiating APRETUDE for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash). • If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. When using APRETUDE for HIV-1 PrEP, HIV-1 testing should be repeated prior to each injection and upon diagnosis of any other STIs [see Dosage and Administration ( 2.2 , 2.5 )] . • If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following an exposure event, additional HIV testing to determine HIV status is needed. If an individual has confirmed HIV-1 infection, then the individual must be transitioned to a complete HIV-1 treatment regimen. Counsel individuals without HIV-1 to strictly adhere to the recommended dosing and testing schedule for APRETUDE in order to reduce the risk of HIV-1 acquisition and the potential development of resistance [see Dosage and Administration ( 2.3 , 2.5 ), Microbiology ( 12.4 )] . Some individuals, such as adolescents, may benefit from frequent visits and counseling to support adherence to the dosing and testing schedule [see Use in Specific Populations ( 8.4 ), Microbiology ( 12.4 ), Clinical Studies ( 14 )] . 5.2 Potential Risk of Resistance with APRETUDE There is a potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE [see Warnings and Precautions ( 5.1 , 5.3 )] . To minimize this risk, it is essential to clinically reassess individuals for risk of HIV-1 acquisition and to test before each injection to confirm HIV-1 negative status. Individuals who are confirmed to have HIV-1 infection must transition to a complete HIV-1 treatment regimen. Alternative forms of PrEP should be considered following discontinuation of APRETUDE for those individuals at continuing risk of HIV-1 acquisition and initiated within 2 months of the final injection of APRETUDE. 5.3 Long-Acting Properties and Potential Associated Risks with APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). It is important to carefully select individuals who agree to the required every-2-month injection dosing schedule because non-adherence to every‑2-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance. Healthcare providers should take the prolonged-release characteristics of cabotegravir into consideration when APRETUDE is prescribed [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.2 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.1 , 8.2 ), Overdosage ( 10 )] . 5.4 Hypersensitivity Reactions Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Adverse Reactions ( 6.2 )] . Administration of cabotegravir oral lead-in dosing was used in clinical studies to help identify participants who may be at risk of a hypersensitivity reaction. Remain vigilant and discontinue APRETUDE if a hypersensitivity reaction is suspected [see Dosage and Administration ( 2.4 ), Contraindications ( 4 ), Adverse Reactions ( 6 )] . Discontinue APRETUDE 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, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of APRETUDE [see Warnings and Precautions ( 5.3 )] . 5.5 Hepatotoxicity Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors [see Adverse Reactions ( 6.1 )] . Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated. For information regarding the long-acting properties of APRETUDE [see Warnings and Precautions ( 5.3 )] . 5.6 Depressive Disorders Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE [see Adverse Reactions ( 6.1 )] . Promptly evaluate individuals with depressive symptoms to assess whether the symptoms are related to APRETUDE and to determine whether the risks of continued therapy outweigh the benefits. 5.7 Risk of Reduced Drug Concentration of APRETUDE Due to Drug Interactions The concomitant use of APRETUDE and other drugs may result in reduced drug concentration of APRETUDE [see Contraindications ( 4 ), Drug Interactions ( 7.2 , 7.3 )] . See Table 8 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 use of, and after discontinuation of APRETUDE; review concomitant medications during use of APRETUDE [see Drug Interactions ( 7.3 , 7.4 )] .

6 ADVERSE REACTIONS The following adverse reactions are described below and in other sections of the labeling: • Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] • Hepatotoxicity [see Warnings and Precautions ( 5.5 )] • Depressive disorders [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in at least 1% of participants receiving APRETUDE were injection site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, decreased appetite, somnolence, back pain, and upper respiratory tract infection. ( 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 rates observed in practice. Clinical Trials Experience in Adults The safety assessment of APRETUDE is based on the analysis of data from 2 international, multicenter, double-blind trials, HPTN 083 and HPTN 084 [see Clinical Studies ( 14.1 )] . Adverse reactions were reported while on blinded study product following exposure to APRETUDE extended-release injectable suspension and oral cabotegravir tablets as oral lead-in. The median time on blinded study product in HPTN 083 was 65 weeks and 2 days (range: 1 day to 156 weeks and 1 day), with a total exposure on cabotegravir of 3,231 person‑years. The median time on blinded study product in HPTN 084 was 64 weeks and 1 day (range: 1 day to 153 weeks and 1 day), with a total exposure on cabotegravir of 2,009 person‑years. The most common adverse reactions regardless of severity reported in at least 1% of participants in HPTN 083 or HPTN 084 are presented in Table 4 . In HPTN 083, 6% of participants in the group receiving APRETUDE intramuscular injection every 2 months and 4% of participants receiving oral TRUVADA [emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] once daily discontinued due to adverse events (all causality). Non-injection-site–associated adverse events leading to discontinuation and occurring in ≥1% of participants were increased alanine aminotransferase with APRETUDE and TRUVADA. In HPTN 084, 1% of participants receiving APRETUDE and 1% of participants receiving TRUVADA discontinued due to adverse events. The most commonly reported adverse event (all causality) leading to discontinuation was increased alanine aminotransferase (<1%) with APRETUDE and TRUVADA. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials. Table 4. Adverse Drug Reactions a (All Grades) Reported in at Least 1% of Participants Receiving APRETUDE in Either HPTN 083 or HPTN 084 a Adverse reactions defined as “treatment-related” as assessed by the investigator, with exception of injection site reactions, where all injection site reactions were reported regardless of causality. b Participants who received injection: HPTN 083, APRETUDE (n = 2,117) and TRUVADA (n = 2,081); HPTN 084, APRETUDE (n = 1,519) and TRUVADA (n = 1,516). c Pyrexia includes pyrexia, feeling hot, chills, influenza-like illness. d Fatigue includes fatigue, malaise. e Sleep disorders includes insomnia, abnormal dreams. f Abdominal pain includes abdominal pain, upper abdominal pain. g Rash includes rash, erythema, pruritis, macular, papular, maculopapular. Adverse Reactions HPTN 083 HPTN 084 APRETUDE Every 2 Months (n = 2,281) TRUVADA Once Daily (n = 2,285) APRETUDE Every 2 Months (n = 1,614) TRUVADA Once Daily (n = 1,610) Injection site reactions b 82% 35% 38% 11% Diarrhea 4% 5% 4% 4% Headache 4% 3% 12% 13% Pyrexia c 4% <1% <1% <1% Fatigue d 4% 2% 3% 3% Sleep disorders e 3% 3% 1% 1% Nausea 3% 5% 4% 8% Dizziness 2% 3% 4% 6% Flatulence 1% 1% <1% <1% Abdominal pain f 1% 1% 2% 2% Vomiting <1% 1% 2% 5% Myalgia <1% <1% 2% 1% Rash g <1% <1% 2% 1% Decreased appetite <1% <1% 2% 4% Somnolence <1% <1% 2% 2% Back pain <1% <1% 1% <1% Upper respiratory tract infection 0 <1% 4% 4% Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs) with APRETUDE: The most frequent adverse reactions associated with the intramuscular administration of APRETUDE in HPTN 083 were ISRs. After 20,286 injections, 8,900 ISRs were reported. Of the 2,117 participants who received at least one injection of APRETUDE, 1,740 (82%) participants experienced at least one ISR, of which a total of 3% of participants discontinued APRETUDE because of ISRs. Among the participants who received APRETUDE and experienced at least one ISR, the maximum severity of reactions was mild (Grade 1) in 41% of participants, moderate (Grade 2) in 56% of participants, and severe (Grade 3) in 3% of participants. The median duration of overall ISR events was 4 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs decreased over time. The most commonly reported ISRs (all causality and grades) in at least 1% of participants who received APRETUDE and experienced at least one ISR from HPTN 083 are presented in Table 5 . The most frequent adverse reactions associated with the intramuscular administration of APRETUDE in HPTN 084 were ISRs. After 13,068 injections, 1,171 ISRs were reported. Of the 1,519 participants who received at least one injection of APRETUDE, 578 (38%) participants experienced at least one ISR. No participants discontinued APRETUDE because of ISRs. Among the participants who received APRETUDE and experienced at least one ISR, the maximum severity of reactions was mild (Grade 1) in 66% of participants, moderate (Grade 2) in 34% of participants, and severe (Grade 3) in less than 1% of participants. The median duration of overall ISR events was 8 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs generally decreased over time. The most commonly reported ISRs (all causality and grades) in at least 1% of participants who received APRETUDE and experienced at least one ISR from HPTN 084 are presented in Table 5 . Table 5. Injection Site Reactions (All Grades) Reported in at Least 1% of Participants Who Experienced at Least One Injection Site Reaction (All Causality) with APRETUDE in Either HPTN 083 or HPTN 084 a Placebo injectable suspension: intralipid 20% fat emulsion. Injection Site Reactions HPTN 083 HPTN 084 APRETUDE (n = 1,740) TRUVADA a (n = 724) APRETUDE (n = 578) TRUVADA a (n = 166) Pain/tenderness 98% 95% 90% 87% Nodules 15% 2% 14% 2% Induration 15% <1% 12% 2% Swelling 12% 1% 18% 3% Bruising 4% 4% 1% 0 Erythema 4% 2% 5% 2% Pruritus 3% 3% 6% 11% Warmth 3% 1% <1% 0 Anesthesia 1% 2% 1% 2% Abscess <1% 0 2% 3% Discoloration <1% 0 1% 0 Other Injection-Associated Adverse Reactions: In the HPTN 083 clinical trial, an increased incidence of pyrexia (including pyrexia, feeling hot, chills, influenza-like illness) (4%) was reported by participants receiving APRETUDE compared with participants receiving TRUVADA (<1%). There were no differences reported in the incidence of pyrexia between groups in HPTN 084. Vasovagal or pre-syncopal reactions considered treatment related were reported in <1% of participants after injection with APRETUDE in HPTN 083. None were reported as treatment related by the investigators in HPTN 084. Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in <1% of participants receiving APRETUDE in HPTN 083 or HPTN 084. Hepatobiliary Disorders: Hepatotoxicity. Investigations: Weight increase (see below). Psychiatric Disorders: Depression; suicidal ideation, and suicide attempt (these events were observed primarily in participants with a pre‑existing history of depression or other psychiatric illness). Weight Increase: At the Week 41 and Week 97 timepoints in HPTN 083, participants who received APRETUDE gained a median of 1.2 kg (Interquartile Range [IQR]; -1.0, 3.5; n = 1,623) and 2.1 kg (IQR; -0.9, 5.9; n = 601) in weight from baseline. Those who received TRUVADA gained a median of 0 kg (IQR; -2.1, 2.4; n = 1,611) and 1 kg (IQR; -1.9, 4.0; n = 598) in weight from baseline, respectively. At the Week 41 and 97 timepoints in HPTN 084, participants who received APRETUDE gained a median of 2 kg (IQR; 0.0, 5.0; n = 1,151) and 4 kg (IQR; 0.0, 8.0; n = 216) in weight from baseline, respectively. Those who received TRUVADA gained a median of 1 kg (IQR; -1.0, 4.0; n = 1,131) and 3 kg (IQR; -1.0, 6.0; n = 218) in weight from baseline, respectively. Laboratory Abnormalities: Grade 3 or 4 post-baseline maximum toxicity laboratory abnormalities for HPTN 083 or HPTN 084 are summarized in Table 6 . Table 6. Laboratory Abnormalities (Grades 3 to 4) in ≥1% of Participants in Either HPTN 083 or HPTN 084 ALT = Alanine transaminase, ULN = upper limit of normal, AST = Aspartate aminotransferase. Laboratory Parameter HPTN 083 HPTN 084 APRETUDE Every 2 Months (n = 2,281) TRUVADA Once Daily (n = 2,285) APRETUDE Every 2 Months (n = 1,614) TRUVADA Once Daily (n = 1,610) ALT (≥5.0 x ULN) 2% 2% <1% 1% AST (≥5.0 x ULN) 3% 3% <1% <1% Creatine phosphokinase (≥10.0 x ULN) 15% 14% 2% 2% Lipase (≥3.0 x ULN) 3% 3% <1% <1% Creatinine (>1.8 x ULN) or increase to ≥1.5 x baseline) 3% 3% 5% 4% Serum Lipids: Changes from baseline to Month 15 in total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio in HPTN 083 and HPTN 084 are presented in Table 7 . Table 7. Fasting Lipid Values, Median Change from Baseline a at Week 57, Reported in HPTN 083 and HPTN 084 a Nearly 60% of participants with baseline data available had Week 57 data available in both arms of both trials. Within each trial, baseline values were comparable among participants receiving APRETUDE and TRUVADA. HPTN 083 HPTN 084 APRETUDE TRUVADA APRETUDE TRUVADA Total cholesterol (mg/dL) +1.0 -10.0 +0.2 -3.9 LDL cholesterol (mg/dL) +1.0 -6.0 -1.1 -5.0 HDL cholesterol (mg/dL) -0.2 -3.0 -0.8 -2.6 Triglycerides (mg/dL) +2.7 0.0 +3.1 +0.7 Total cholesterol: HDL cholesterol ratio +0.1 +0.0 +0.1 +0.1 Clinical Trials Experience in Adolescents In adolescents receiving APRETUDE for HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving APRETUDE for HIV-1 PrEP [see Use in Specific Populations ( 8.4 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of APRETUDE or cabotegravir-containing regimens. 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. Immune System Disorders Hypersensitivity reactions (including angioedema and urticaria) [see Warnings and Precautions ( 5.4 )] . Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Warnings and Precautions ( 5.4 )] .

<table ID="_RefTable_4" width="100%"><caption>Table 4. Adverse Drug Reactions^a (All Grades) Reported in at Least 1% of Participants Receiving APRETUDE in Either HPTN 083 or HPTN 084</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tfoot><tr><td align="left" colspan="5" valign="top">^a Adverse reactions defined as &#x201C;treatment-related&#x201D; as assessed by the investigator, with exception of injection site reactions, where all injection site reactions were reported regardless of causality.</td></tr><tr><td align="left" colspan="5" valign="top">^b Participants who received injection: HPTN 083, APRETUDE (n = 2,117) and TRUVADA (n = 2,081); HPTN 084, APRETUDE (n = 1,519) and TRUVADA (n = 1,516).</td></tr><tr><td align="left" colspan="5" valign="top">^c Pyrexia includes pyrexia, feeling hot, chills, influenza-like illness.</td></tr><tr><td align="left" colspan="5" valign="top">^d Fatigue includes fatigue, malaise.</td></tr><tr><td align="left" colspan="5" valign="top">^e Sleep disorders includes insomnia, abnormal dreams.</td></tr><tr><td align="left" colspan="5" valign="top">^f Abdominal pain includes abdominal pain, upper abdominal pain.</td></tr><tr><td align="left" colspan="5" valign="top">^g Rash includes rash, erythema, pruritis, macular, papular, maculopapular.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">HPTN 083</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">HPTN 084</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">APRETUDE</content></paragraph><paragraph><content styleCode="bold">Every 2 Months</content></paragraph><paragraph><content styleCode="bold">(n = 2,281)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TRUVADA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 2,285)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">APRETUDE</content></paragraph><paragraph><content styleCode="bold">Every 2 Months</content></paragraph><paragraph><content styleCode="bold">(n = 1,614)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TRUVADA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 1,610)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reactions^b</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>82%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</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>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</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>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</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>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pyrexia^c</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue^d</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</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><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sleep disorders^e</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>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</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>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</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><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</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>Flatulence</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal pain^f</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</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="bottom"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1%</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>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Myalgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>&lt;1%</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 Lrule Botrule " valign="bottom"><paragraph>Rash^g</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>&lt;1%</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 Lrule Botrule " valign="bottom"><paragraph>Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>&lt;1%</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>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Somnolence</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>&lt;1%</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="bottom"><paragraph>Back pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="bottom"><paragraph>Upper respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>

<table ID="_RefTable_5" width="100%"><caption>Table 5. Injection Site Reactions (All Grades) Reported in at Least 1% of Participants Who Experienced at Least One Injection Site Reaction (All Causality) with APRETUDE in Either HPTN 083 or HPTN 084</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tfoot><tr><td align="left" colspan="5" valign="top">^a Placebo injectable suspension: intralipid 20% fat emulsion.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Injection Site Reactions</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">HPTN 083</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">HPTN 084</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">APRETUDE</content></paragraph><paragraph><content styleCode="bold">(n = 1,740)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TRUVADA^a</content></paragraph><paragraph><content styleCode="bold">(n = 724)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">APRETUDE</content></paragraph><paragraph><content styleCode="bold">(n = 578)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TRUVADA^a</content></paragraph><paragraph><content styleCode="bold">(n = 166)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pain/tenderness</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>98%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>95%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>90%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>87%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nodules</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</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>14%</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>Induration</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</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>Swelling</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</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>Bruising </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Erythema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</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>5%</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>Pruritus</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>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Warmth</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>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anesthesia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</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><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abscess</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>0</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 Botrule Lrule " valign="top"><paragraph>Discoloration</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bottom"><paragraph>0</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>0</paragraph></td></tr></tbody></table>

<table ID="_RefTable_6" width="100%"><caption>Table 6. Laboratory Abnormalities (Grades 3 to 4) in &#x2265;1% of Participants in Either HPTN 083 or HPTN 084</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tfoot><tr><td align="left" colspan="5" valign="top">ALT = Alanine transaminase, ULN = upper limit of normal, AST = Aspartate aminotransferase.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Laboratory Parameter</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">HPTN 083</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">HPTN 084</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">APRETUDE</content></paragraph><paragraph><content styleCode="bold">Every 2 Months</content></paragraph><paragraph><content styleCode="bold">(n = 2,281)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">TRUVADA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 2,285)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">APRETUDE</content></paragraph><paragraph><content styleCode="bold">Every 2 Months</content></paragraph><paragraph><content styleCode="bold">(n = 1,614)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">TRUVADA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 1,610)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>ALT (&#x2265;5.0 x ULN)</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><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>AST (&#x2265;5.0 x ULN)</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>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Creatine phosphokinase (&#x2265;10.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</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>Lipase (&#x2265;3.0 x ULN)</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>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Creatinine (&gt;1.8 x ULN) or increase to &#x2265;1.5 x baseline)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>