View source for Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate

{{DrugProjectFormSinglePage
|authorTag={{Alonso}}
|genericName=Elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate
|aOrAn=a
|drugClass=atiretroviral
|indicationType=treatment
|indication=[[HIV]]-1 infection in adults who are antiretroviral treatment-naïve
|hasBlackBoxWarning=Yes
|adverseReactions=[[diarrhea]], [[nausea]], [[proteinuria]]
|blackBoxWarningTitle=WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
|blackBoxWarningBody=<i><span style="color:#FF0000;">LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B:</span></i> Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate, in combination with other antiretrovirals.

Elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarateis not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued emtricitabineor tenofovir disoproxil fumarate, which are components of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate. If appropriate, initiation of anti-hepatitis B therapy may be warranted
|fdaLIADAdult======Dosage Information=====
The recommended dosage of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate is one tablet taken orally once daily with food.

=====Dosage Adjustment in Patients with Renal Impairment=====
Initiation of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is a fixed-dose combination tablet, [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate as dose interval adjustment required for [[emtricitabine]] and [[tenofovir]] disoproxil fumarate (DF) cannot be achieved.

=====Dosage in Patients with Hepatic Impairment=====
No dosage adjustment of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is not recommended for use in patients with severe hepatic impairment.

=====Testing Prior to Initiation of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate =====
Prior to initiation of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, patients should be tested for hepatitis B infection and estimated creatinine clearance, urine glucose and urine protein should be documented in all patients.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate in pediatric patients.
|contraindications=Coadministration of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate and possible resistance) are listed in Table 1

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 1.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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|warnings======Lactic Acidosis/Severe Hepatomegaly with Steatosis=====
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including [[tenofovir]] DF, a component of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate , in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate 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).

=====Patients Coinfected with HIV-1 and HBV=====
It is recommended that all patients with [[HIV]]-1 be tested for the presence of chronic [[hepatitis B virus]] ([[HBV]]) before initiating antiretroviral therapy. [[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is not approved for the treatment of chronic [[HBV]] infection and the safety and efficacy of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate have not been established in patients coinfected with [[HBV]] and [[HIV]]-1. Severe acute exacerbations of [[hepatitis B]] have been reported in patients who are coinfected with [[HBV]] and [[HIV]]-1 and have discontinued [[emtricitabine]] or [[tenofovir]] DF, two of the components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. In some patients infected with HBV and treated with [[emtricitabine]], the exacerbations of [[hepatitis B]] were associated with liver decompensation and liver failure. Patients who are coinfected with [[HIV]]-1 and [[HBV]] should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

=====New Onset or Worsening Renal Impairment=====
Renal impairment, including cases of [[acute renal failure]] and [[Fanconi syndrome]] (renal tubular injury with severe [[hypophosphatemia]]), has been reported with the use of [[tenofovir]] DF, a component of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, and with the use of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate.

In the clinical trials of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate over 96 weeks, 10 (1.4%) subjects in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate group (N=701) and 2 (0.3%) subjects in the combined comparator groups (N = 707) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate group and 1 in the combined comparator groups occurred during the first 48 week. Four (0.6%) of the subjects who received [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate compared to none in the comparator groups. Two of these four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these 4 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. Renal replacement therapy was not required for these subjects.

Estimated creatinine clearance, urine glucose and urine protein should be documented in all patients prior to initiating therapy. Initiation of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in patients with estimated creatinine clearance below 70 mL per minute is not recommended.

[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple [[non-steroidal anti-inflammatory drugs]] ([[NSAID]]s)). Cases of acute renal failure after initiation of high dose or multiple [[NSAID]]s have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on [[tenofovir]] DF. Some patients required hospitalization and renal replacement therapy. Alternatives to [[NSAID]]s should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, [[fractures]] and/or [[muscular pain]] or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein should be performed during [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate therapy in all patients. Additionally, serum phosphorus should be measured in patients at risk for renal impairment. Although [[cobicistat]] (a component of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.

The [[emtricitabine]] and [[tenofovir]] DF components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate are primarily excreted by the kidney. [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for [[emtricitabine]] and [[tenofovir]] DF cannot be achieved with the fixed-dose combination tablet.

=====Avoid Use with Other Antiretroviral Products=====
[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is indicated for use as a complete regimen for the treatment of [[HIV]]-1 infection and coadministration with other antiretroviral products is not recommended.

[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is not recommended for coadministration with the following:
[[emtricitabine]] or [[tenofovir]] DF ([[ATRIPLA]], COMPLERA, EMTRIVA, [[TRUVADA]], [[VIREAD]]); products containing [[lamivudine]] (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR) or adefovir dipivoxil (HEPSERA);
[[ritonavir]] (NORVIR, KALETRA).

=====Bone Effects of Tenofovir DF=====
======Bone Mineral Density======
In clinical trials in [[HIV]]-1 infected adults, [[tenofovir]] DF (a component of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) was associated with slightly greater decreases in [[bone mineral density]] ([[BMD]]) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects receiving [[tenofovir]] DF. For additional information, see Adverse Reactions (6.1) and consult the [[VIREAD]] prescribing information.

The effects of [[tenofovir]] DF-associated changes in [[BMD]] and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for [[HIV]]-1 infected patients who have a history of pathologic bone fracture or other risk factors for [[osteoporosis]] or bone loss. Although the effect of supplementation with calcium and [[vitamin D]] was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

======Mineralization Defects======
Cases of [[osteomalacia]] associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of [[tenofovir]] DF. [[Arthralgias]] and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. [[Hypophosphatemia]] and [[osteomalacia]] secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing [[tenofovir]] DF.

=====Fat Redistribution=====
Redistribution/accumulation of body fat including [[central obesity]], dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "[[cushingoid appearance]]" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

=====Immune Reconstitution Syndrome=====
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. During the initial phase of combination antiretroviral treatment, patients whose immune system responds 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.
|clinicalTrials=The following adverse drug reactions are discussed in other sections of the labeling:
* [[Lactic Acidosis]]/Severe [[Hepatomegaly]] with [[Steatosis]].
* Severe Acute Exacerbations of [[Hepatitis B]].
* New Onset or Worsening Renal Impairment.
* Bone Effects of [[Tenofovir]] DF.
* Immune Reconstitution Syndrome.

=====Adverse Reactions from 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.

The safety assessment of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is based on the Week 96 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve [[HIV]]-1 infected adult subjects. A total of 701 subjects received [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate once daily for at least 96 weeks.

The proportion of subjects who discontinued treatment with [[elvitegravir]] 150 mg/[[cobicistat]] 150 mg/[[emtricitabine]] 200 mg/[[tenofovir]] DF 300 mg; [[efavirenz]] 600 mg/[[emtricitabine]] 200 mg/[[tenofovir]] DF 300 mg); or [[atazanavir]] (ATV) + [[ritonavir]] (RTV) + [[emtricitabine]] 200 mg/[[tenofovir]] DF 300 mg due to adverse events, regardless of severity, was 4.6%, 6.8% and 5.9%, respectively. Table 2 displays the frequency of adverse drug reactions greater than or equal to 5% of subjects in any treatment arm.

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 2.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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See Warnings and Precautions (5.3), for a discussion of renal adverse reactions from clinical trials experience with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate.

======Adverse Reactions from Clinical Trials of the Components of STRIBILD======
[[Emtricitabine]] and [[Tenofovir]] Disoproxil Fumarate: In addition to the adverse reactions observed with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate combination, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving [[emtricitabine]] or [[tenofovir]] DF with other antiretroviral agents in other clinical trials: [[depression]], [[abdominal pain]], [[dyspepsia]], [[vomiting]], [[fever]], [[pain]], [[nasopharyngitis]], [[pneumonia]], [[sinusitis]], upper respiratory tract infection, [[arthralgia]], [[back pain]], [[myalgia]], [[paresthesia]], peripheral [[neuropathy]] (including peripheral [[neuritis]] and neuropathy), [[anxiety]], increased [[cough]], and [[rhinitis]].

Skin discoloration has been reported with higher frequency among [[emtricitabine]]-treated subjects; it was manifested by [[hyperpigmentation]] on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

======Laboratory Abnormalities======
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in Studies 102 and 103 are presented in Table 3.

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 3.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects. Mean percentage decreases in BMD from baseline to Week 96 in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate group (N = 47) were comparable to the [[ATV]] + [[RTV]] + [[TRUVADA]] group (N = 53) at the lumbar spine (-2.0% versus -3.5%, respectively) and at the hip (-3.2% versus -4.2%, respectively). In Studies 102 and 103, bone fractures occurred in 14 subjects (2.0%) in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate group, 8 subjects (2.3%) in the [[ATRIPLA]] group, and 14 subjects (3.9%) in the [[ATV]] + [[RTV]] + [[TRUVADA]] group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving [[tenofovir]] DF + [[lamivudine]] + [[efavirenz]].

Proteinuria (all grades) occurred in 46% of subjects receiving [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, 38% of subjects receiving [[ATRIPLA]], and 37% of subjects receiving [[ATV]] + [[RTV]] + [[TRUVADA]].

The cobicistat component of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, after which they stabilized. Table 4 displays the mean changes in serum creatinine and eGFR levels at Week 96 and the percentage of subjects with elevations in serum creatinine (All Grades).

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 4.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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[[Emtricitabine]] or [[Tenofovir]] DF: In addition to the laboratory abnormalities observed with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate , the following laboratory abnormalities have been previously reported in subjects treated with [[emtricitabine]] or [[tenofovir]] DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of [[ALT]] (M: greater than 215 U per L; F: greater than 170 U per L), [[alkaline phosphatase]] (greater than 550 U per L), [[bilirubin]] (greater than 2.5 × ULN), serum glucose (less than 40 or greater than 250 mg per dL), [[glycosuria]] (greater than or equal to 3+), [[neutrophils]] (less than 750 per mm3), fasting [[cholesterol]] (greater than 240 mg per dL), and fasting [[triglycerides]] (greater than 750 mg per dL).

Serum Lipids: In the clinical trials of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, a similar percentage of subjects receiving [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, [[ATRIPLA]], and [[ATV]] + [[RTV]] + [[TRUVADA]] were on lipid lowering agents at baseline (11%, 11%, and 12%, respectively). While receiving study drug through Week 96, an additional 8% of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate subjects were started on lipid lowering agents, compared to 9% of [[ATRIPLA]] and 8% of ATV + RTV + TRUVADA subjects.

Changes from baseline in total cholesterol, [[HDL]]-cholesterol, [[LDL]]-cholesterol, and [[triglycerides]] are presented in Table 5.

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 5.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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|postmarketing=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. The following adverse reactions have been identified during post approval use of [[tenofovir]] DF. No additional postmarketing adverse reactions specific for [[emtricitabine]] have been identified.
* '''Immune System Disorders:''' [[allergic reaction]], including [[angioedema]]
* '''Metabolism and Nutrition Disorders:''' [[lactic acidosis]], [[hypokalemia]], [[hypophosphatemia]]
* '''Respiratory, Thoracic, and Mediastinal Disorders:''' [[dyspnea]]
* '''Gastrointestinal Disorders:''' [[pancreatitis]], increased [[amylase]], [[abdominal pain]]
* '''Hepatobiliary Disorders:''' [[hepatic steatosis]], [[hepatitis]], increased [[liver enzymes]] (most commonly [[AST]], [[ALT]], [[GGT]])
* '''Skin and Subcutaneous Tissue Disorders:''' [[rash]]
* '''Musculoskeletal and Connective Tissue Disorders:''' [[rhabdomyolysis]], [[osteomalacia]] (manifested as bone pain and which may contribute to [[fractures]]), muscular weakness, [[myopathy]]
* '''Renal and Urinary Disorders:''' [[acute renal failure]], [[renal failure]], [[acute tubular necrosis]], [[Fanconi syndrome]], proximal renal tubulopathy, [[interstitial nephritis]] (including acute cases), [[nephrogenic diabetes insipidus]], [[renal insufficiency]], increased creatinine, [[proteinuria]], [[polyuria]]
* '''General Disorders and Administration Site Conditions:''' [[asthenia]]

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: [[rhabdomyolysis]], [[osteomalacia]], [[hypokalemia]], muscular weakness, [[myopathy]], [[hypophosphatemia]].
|drugInteractions======Other Antiretroviral Medications=====
[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is a complete regimen for the treatment of [[HIV]]-1 infection; therefore, [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

=====Potential for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate to Affect Other Drugs=====
[[Cobicistat]], is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Thus, coadministration of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs. [[Elvitegravir]] is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.

=====Potential for Other Drugs to Affect One or More Components of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate=====
[[Elvitegravir]] and [[cobicistat]], components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate , are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6.

Drugs that induce CYP3A activity are expected to increase the clearance of [[elvitegravir]] and [[cobicistat]], resulting in decreased plasma concentration of [[cobicistat]] and [[elvitegravir]], which may lead to loss of therapeutic effect of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate and development of resistance (see Table 6).

Coadministration of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 6).

=====Drugs Affecting Renal Function=====
Because [[emtricitabine]] and [[tenofovir]], components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of [[emtricitabine]], [[tenofovir]], and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to [[acyclovir]], [[cidofovir]], [[ganciclovir]], [[valacyclovir]], [[valganciclovir]], [[aminoglycosides]] (e.g. [[gentamicin]]), and high-dose or multiple [[NSAIDs]].

=====Established and Other Potentially Significant Interactions=====
Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, the components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate as individual agents and/or in combination, or are predicted drug interactions that may occur with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. The table includes potentially significant interactions but is not all inclusive.

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 6.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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=====Drugs without Clinically Significant Interactions with Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate=====
Based on drug interaction studies conducted with the components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, no clinically significant drug interactions have been either observed or are expected when [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is combined with the following drugs: [[entecavir]], [[famciclovir]], [[H2 receptor antagonists]], [[methadone]], [[proton pump inhibitors]] and [[ribavirin]].
|FDAPregCat=B
|useInPregnancyFDA=There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

=====Animal Data=====
'''Elvitegravir:''' Studies in animals have shown no evidence of [[teratogenicity]] or an effect on reproductive function. In offspring from rat and rabbit dams treated with [[elvitegravir]] during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.

'''Cobicistat:''' Studies in animals have shown no evidence of [[teratogenicity]] or an effect on reproductive function. In offspring from rat and rabbit dams treated with [[cobicistat]] during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal NOAELs in rats and rabbits were respectively 1.8 and 4.3 times higher than the exposure in humans at the recommended daily dose of 150 mg.
'''Emtricitabine:''' The incidence of fetal variations and malformations was not increased in embryo-fetal toxicity studies performed with [[emtricitabine]] in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose.
'''Tenofovir DF:''' Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to [[tenofovir]].
|useInNursing=The Centers for Disease Control and Prevention recommend that [[HIV]]-infected mothers not breastfeed their infants to avoid risking postnatal transmission of [[HIV]]. Studies in rats have demonstrated that [[elvitegravir]], [[cobicistat]], and [[tenofovir]] are secreted in milk. It is not known whether [[elvitegravir]] or [[cobicistat]] is excreted in human milk.

In humans, samples of breast milk obtained from five HIV-1 infected mothers show that [[emtricitabine]] is secreted in human milk. Breastfeeding infants whose mothers are being treated with [[emtricitabine]] may be at risk for developing viral resistance to [[emtricitabine]]. Other [[emtricitabine]]-associated risks in infants breastfed by mothers being treated with [[emtricitabine]] are unknown.

Samples of breast milk obtained from five [[HIV]]-1 infected mothers show that [[tenofovir]] is secreted in human milk. [[Tenofovir]]-associated risks, including the risk of viral resistance to [[tenofovir]], in infants breastfed by mothers being treated with [[tenofovir]] disoproxil fumarate are unknown.
Because of both the potential for [[HIV]] transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate.
|useInPed=Safety and effectiveness of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in pediatric patients less than 18 years of age have not been established
|useInGeri=Clinical studies of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|useInRenalImpair=Initiation of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in patients with estimated creatinine clearance below 70 mL per min is not recommended. Because [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is a fixed-dose combination tablet, [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate as dose interval adjustment required for [[emtricitabine]] and [[tenofovir]] DF cannot be achieved
|useInHepaticImpair=No dose adjustment of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is required in patients with mild ([[Child-Pugh Class]] A) or moderate ([[Child-Pugh Class]] B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in patients with severe hepatic impairment ([[Child-Pugh Class]] C). Therefore, [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is not recommended for use in patients with severe hepatic impairment
|administration=Oral
|monitoring=[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is not approved for the treatment of chronic [[hepatitis B virus]] ([[HBV]]) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with [[HIV]]-1 and [[HBV]] who have discontinued [[emtricitabine]] or [[tenofovir]] disoproxil fumarate, two of the components of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
|overdose=No data are available on overdose of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate in patients. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

'''Elvitegravir:''' Limited clinical experience is available at doses higher than the therapeutic dose of [[elvitegravir]]. In one study, boosted [[elvitegravir]] equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As [[elvitegravir]] is highly bound to plasma proteins, it is unlikely that it will be significantly removed by [[hemodialysis]] or peritoneal [[dialysis]].

'''Cobicistat:''' Limited clinical experience is available at doses higher than the therapeutic dose of [[cobicistat]]. In two studies, a single dose of [[cobicistat]] 400 mg (2.7 times the dose in [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As [[cobicistat]] is highly bound to plasma proteins, it is unlikely that it will be significantly removed by [[hemodialysis]] or [[peritoneal dialysis]].

'''Emtricitabine:''' Limited clinical experience is available at doses higher than the therapeutic dose of [[emtricitabine]]. In one clinical pharmacology study, single doses of [[emtricitabine]] 1200 mg (6 times the dose in [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.

[[Hemodialysis]] treatment removes approximately 30% of the [[emtricitabine]] dose over a 3 hour dialysis period starting within 1.5 hours of [[emtricitabine]] dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether [[emtricitabine]] can be removed by [[peritoneal dialysis]].

'''Tenofovir DF:''' Limited clinical experience at doses higher than the therapeutic dose of [[tenofovir]] disoproxil fumarate 300 mg is available. In one study, 600 mg [[tenofovir]] DF (2 times the dosage in [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. [[Tenofovir]] is efficiently removed by [[hemodialysis]] with an extraction coefficient of approximately 54%. Following a single 300 mg dose of [[tenofovir]] disoproxil fumarate, a 4-hour [[hemodialysis]] session removed approximately 10% of the administered [[tenofovir]] dose.
|drugBox=| type              = combo
| component1        = Elvitegravir
| class1            = [[Integrase inhibitor]]
| component2        = Cobicistat
| class2            = [[Cytochrome P450]] [[enzyme inhibitor|inhibitor]]
| component3        = Emtricitabine
| class3            = [[Reverse-transcriptase inhibitor]]
| component4        = Tenofovir disoproxil fumarate
| class4            = [[Reverse-transcriptase inhibitor]]

<!-- Clinical data -->
| tradename         = Stribild
| Drugs.com         = {{Drugs.com|parent|stribild}}
| MedlinePlus       = 
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US      = B
| pregnancy_category= 
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| legal_US = Rx-only
| legal_status      = 
| routes_of_administration = Oral

<!-- Identifiers -->
| CAS_number        = 
| ATCvet            = 
| ATC_prefix        = J05
| ATC_suffix        = AR09
| PubChem           = 
| DrugBank          = http://www.drugbank.ca/drugs/DB00300
}}
|mechAction='''Elvitegravir:''' [[Elvitegravir]] inhibits the strand transfer activity of [[HIV]]-1 integrase (integrase strand transfer inhibitor; INSTI), an [[HIV]]-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of [[HIV]]-1 DNA into host genomic DNA, blocking the formation of the [[HIV]]-1 provirus and propagation of the viral infection. [[Elvitegravir]] does not inhibit human topoisomerases I or II.
'''Cobicistat:''' [[Cobicistat]] is a selective, mechanism-based inhibitor of [[cytochromes P450]] of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by [[cobicistat]] enhances the systemic exposure of CYP3A substrates, such as [[elvitegravir]], where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.
'''Emtricitabine:''' [[Emtricitabine]], a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the [[HIV]]-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.
'''Tenofovir DF:''' [[Tenofovir]] DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. [[Tenofovir]] DF requires initial diester hydrolysis for conversion to [[tenofovir]] and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of [[HIV]]-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

=====Antiviral Activity in Cell Culture=====
'''Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF:''' The triple combination of [[elvitegravir]], [[emtricitabine]], and [[tenofovir]] was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of [[cobicistat]].
'''Elvitegravir:''' The antiviral activity of [[elvitegravir]] against laboratory and clinical isolates of [[HIV]]-1 was assessed in T lymphoblastoid cell lines, [[monocyte]]/[[macrophage]] cells, and primary peripheral blood [[lymphocytes]]. The 50% effective concentrations (EC50) ranged from 0.02 to 1.7 nM. [[Elvitegravir]] displayed antiviral activity in cell culture against [[HIV]]-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 value of 0.53 nM). [[Elvitegravir]] did not show inhibition of replication of [[HBV]] or [[HCV]] in cell culture.
'''Cobicistat:''' [[Cobicistat]] has no detectable antiviral activity in cell culture against [[HIV]]-1, [[HBV]], or [[HCV]] and does not antagonize the antiviral activity of [[elvitegravir]], [[emtricitabine]], or [[tenofovir]].
'''Emtricitabine:''' The antiviral activity of [[emtricitabine]] against laboratory and clinical isolates of [[HIV]]-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for [[emtricitabine]] were in the range of 0.0013–0.64 micromolar. [[Emtricitabine]] displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 micromolar).
'''Tenofovir DF:''' The antiviral activity of [[tenofovir]] against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary [[monocyte]]/]]macrophage]] cells and peripheral blood lymphocytes. The EC50 values for [[tenofovir]] were in the range of 0.04–8.5 micromolar. [[Tenofovir]] displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6–5.5 micromolar).

=====Resistance=====
======In Cell Culture======
* '''Elvitegravir:''' [[HIV]]-1 isolates with reduced susceptibility to [[elvitegravir]] have been selected in cell culture. Reduced susceptibility to [[elvitegravir]] was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M.
* '''Emtricitabine and Tenofovir DF:''' [[HIV]]-1 isolates with reduced susceptibility to [[emtricitabine]] or [[tenofovir]] have been selected in cell culture. Reduced susceptibility to [[emtricitabine]] was associated with M184V/I substitutions in [[HIV]]-1 RT. [[HIV]]-1 isolates selected by [[tenofovir]] expressed a K65R substitution in [[HIV]]-1 RT and showed a 2–4 fold reduction in susceptibility to tenofovir.
 
======In Clinical Studies======
In Treatment-Naïve HIV-1-Infected Adult Subjects: In Studies 102 and 103 [see Clinical Studies (14)], the development of one or more primary substitutions associated with resistance to elvitegravir (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), emtricitabine, and/or tenofovir was observed in 53% (16/30) of the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate-treatment failure subjects with evaluable genotypic resistance data who received at least 8 weeks of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate and had HIV-1 RNA greater than 400 copies per mL at Week 96 or at the time of early study drug discontinuation. The most common substitutions that emerged were M184V/I (N=15) in HIV-1 RT and the primary [[elvitegravir]] resistance-associated substitutions, E92Q (N=9), N155H (N=5), Q148R (N=3), and T66I (N=2) in integrase; K65R in RT was also detected (N=5). In virus isolates harboring the observed primary [[elvitegravir]] resistance substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, G70R, I73V, G140C, S153A and E157Q. All subjects with evaluable data for RT and IN and who developed integrase substitutions associated with elvitegravir resistance (N=13) also developed the M184I/V RT substitutions, conferring reduced susceptibility to both [[elvitegravir]] and [[emtricitabine]]. In phenotypic analyses, HIV-1 isolates expressing M184V/I RT substitutions showed reduced susceptibility to [[emtricitabine]] (42- to greater than 152-fold); those expressing the primary elvitegravir resistance-associated integrase substitutions showed reduced susceptibility to [[elvitegravir]] (6- to greater than 198-fold); and those expressing the K65R RT substitution showed reduced susceptibility to [[tenofovir]] (0.8- to 1.6-fold), compared to wild-type reference [[HIV]]-1.

======Cross Resistance======
[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate-treatment failure subject isolates exhibited varying degrees of cross resistance within the INSTI and NRTI drug classes depending on the specific substitutions observed. These isolates remained susceptible to all NNRTIs and protease inhibitors.
* '''Elvitegravir:''' Cross-resistance has been observed among INSTIs. [[Elvitegravir]]-resistant viruses showed varying degrees of cross-resistance in cell culture to [[raltegravir]] depending on the type and number of substitutions in HIV-1 integrase. Of the primary [[elvitegravir]] resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to [[raltegravir]] (above the biological cutoff for [[raltegravir]]) when introduced individually into a wild-type virus by site-directed mutagenesis. Of the primary [[raltegravir]] resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to [[elvitegravir]] (above the biological cutoff for [[elvitegravir]]).
*  '''Emtricitabine:''' Cross-resistance has been observed among NRTIs. [[Emtricitabine]]-resistant isolates harboring an M184V/I substitution in [[HIV]]-1 RT were cross-resistant to [[lamivudine]]. [[HIV]]-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by [[emtricitabine]].
* '''Tenofovir DF:''' Cross-resistance has been observed among NRTIs. The K65R substitution in [[HIV]]-1 RT selected by [[tenofovir]] is also selected in some [[HIV]]-1-infected patients treated with [[abacavir]] or [[didanosine]]. [[HIV]]-1 isolates with the K65R substitution also showed reduced susceptibility to [[emtricitabine]] and [[lamivudine]]. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. [[HIV]]-1 isolates from patients (N=20) whose [[HIV]]-1 expressed a mean of 3 [[zidovudine]]-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to [[tenofovir]]. Subjects whose virus expressed an L74V RT substitution without [[zidovudine]] resistance-associated substitutions (N=8) had reduced response to [[tenofovir]]. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in HIV-1 RT, all of whom had a reduced response in clinical trials.
|structure=[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is a fixed-dose combination tablet containing [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate for oral administration.
[[Elvitegravir]] is an [[HIV]]-1 [[integrase]] strand transfer inhibitor.

[[Cobicistat]] is a mechanism-based inhibitor of [[cytochrome P450]] (CYP) enzymes of the CYP3A family.
[[Emtricitabine]] is a synthetic nucleoside analog of cytidine. [[EMTRIVA]] is the brand name for [[emtricitabine]].
[[Tenofovir]] DF is converted in vivo to [[tenofovir]], an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. [[VIREAD]] is the brand name for [[tenofovir]] DF.

Each tablet contains 150 mg of [[elvitegravir]], 150 mg of [[cobicistat]], 200 mg of [[emtricitabine]], and 300 mg of [[tenofovir]] DF (equivalent to 245 mg of [[tenofovir]] disoproxil). The tablets include the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate. The tablets are film-coated with a coating material containing indigo carmine (FD&C Blue #2) aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

'''Elvitegravir:''' The chemical name of [[elvitegravir]] is 6-(3-Chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:

[[File:Elvitegravir Structure.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
{{clr}}

[[Elvitegravir]] is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.

'''Cobicistat:''' The chemical name for [[cobicistat]] is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate.
It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:

[[File:Cobicistat Structure.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
{{clr}}

Cobicistat is adsorbed onto silicon dioxide. [[Cobicistat]] on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg per mL in water at 20 °C.

'''Emtricitabine:''' The chemical name of [[emtricitabine]] is 5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. [[Emtricitabine]] is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.25. It has the following structural formula:

[[File:EmtricitabineStructure.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
{{clr}}

[[Emtricitabine]] is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25 °C.

'''Tenofovir Disoproxil Fumarate:''' [[Tenofovir]] DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of [[tenofovir]]. The chemical name of [[tenofovir]] DF is 9-[(R)-2-([bis([(isopropoxycarbonyl)oxy]-methoxy)phosphinyl]methoxy)propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P ∙ C4H4O4 and a molecular weight of 635.51. It has the following structural formula:

[[File:Tenofovir disoproxil fumarate Structure.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
{{clr}}

[[Tenofovir]] DF is a white to off-white crystalline powder with a solubility of 13.4 mg per mL in water at 25 °C. All dosages are expressed in terms of tenofovir DF except where otherwise noted.
|PD======Effects on Electrocardiogram=====
Thorough QT studies have been conducted for [[elvitegravir]] and [[cobicistat]]. The effect of the other two components, [[tenofovir]] and [[emtricitabine]], or the combination regimen [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate on the [[QT interval]] is not known.

The effect of multiple doses of [[elvitegravir]] 125 and 250 mg (0.83 and 1.67 times the dose in [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) (coadministered with 100 mg [[RTV]] to boost the blood levels of [[elvitegravir]]) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 msec. In this study, there was no clinically relevant prolongation of the QTc interval.

The effect of a single dose of [[cobicistat]] 250 mg and 400 mg (1.67 and 2.67 times the dose in [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate) on QTc interval was evaluated in a randomized, placebo- and active-controlled ([[moxifloxacin]] 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was below 10 msec, the threshold for regulatory concern. Prolongation of the [[PR interval]] was noted in subjects receiving [[cobicistat]] in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg dose and 20.2 (22.8) for 400 mg dose [[cobicistat]]. Because the 150 mg [[cobicistat]] dose used in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate will result in clinically relevant [[PR prolongation]].
|PK======Absorption and Bioavailability=====
[[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate: Following oral administration of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate with food in [[HIV]]-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for [[elvitegravir]], 3 hours post-dose for [[cobicistat]], 3 hours post-dose for [[emtricitabine]], and 2 hours for [[tenofovir]] following the conversion of [[tenofovir]] DF (see Table 7 for additional pharmacokinetic parameters).

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 7.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
{{clr}}

=====Effect of Food on Oral Absorption=====
Relative to fasting conditions, the administration of single dose [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate with a light meal (~373 kcal, 20% fat) increased the mean systemic exposure of [[elvitegravir]] and [[tenofovir]] by 34% and 24%, respectively. The alterations in mean systemic exposures of [[cobicistat]] and [[emtricitabine]] were not clinically significant.

Relative to fasting conditions, the administration of single dose [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate with a high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of [[elvitegravir]] and [[tenofovir]] by 87% and 23%, respectively. The alterations in mean systemic exposures of [[cobicistat]] and [[emtricitabine]] were not clinically significant.

[[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate tablets should be taken with food.

=====Distribution=====
* '''Elvitegravir:''' [[Elvitegravir]] is 98–99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73.
* '''Cobicistat:''' [[Cobicistat]] is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.
* '''Emtricitabine:''' In vitro binding of [[emtricitabine]] to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02–200 micrograms per mL.
* '''Tenofovir Disoproxil Fumarate:''' In vitro binding of [[tenofovir]] to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01–25 micrograms per mL.
 
=====Metabolism=====
* '''Elvitegravir:''' The majority of [[elvitegravir]] metabolism is mediated by CYP3A enzymes. [[Elvitegravir]] also undergoes glucuronidation via UGT1A1/3 enzymes.  
* '''Cobicistat:''' [[Cobicistat]] is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation. 
* '''Emtricitabine and tenofovir''' are not significantly metabolized. 

=====Elimination=====
'''Elvitegravir:''' The median terminal plasma half-life of [[elvitegravir]] following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] [[elvitegravir]] (coadministered with 100 mg [[RTV]]), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively.
'''Cobicistat:''' The median terminal plasma half-life of [[cobicistat]] following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] [[cobicistat]] after multiple dosing of [[cobicistat]] for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively.
'''Emtricitabine and tenofovir''' are primarily excreted in the urine by a combination of glomerular filtration and active tubular secretion.

=====Special Populations=====
======Patients with Renal Impairment======
'''Elvitegravir and cobicistat:''' A study of the pharmacokinetics of [[cobicistat]]-boosted [[elvitegravir]] was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in [[elvitegravir]] or [[cobicistat]] pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.
'''Emtricitabine and Tenofovir Disoproxil Fumarate:''' The pharmacokinetics of [[emtricitabine]] and [[tenofovir]] are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring [[dialysis]].

 
======Patients with Hepatic Impairment======
* '''Elvitegravir and cobicistat:''' A study of the pharmacokinetics of [[cobicistat]]-boosted [[elvitegravir]] was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in [[elvitegravir]] or [[cobicistat]] pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of [[elvitegravir]] or [[cobicistat]] is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of [[elvitegravir]] or [[cobicistat]] has not been studied.
* '''Emtricitabine:''' The pharmacokinetics of [[emtricitabine]] has not been studied in subjects with hepatic impairment; however, [[emtricitabine]] is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
* '''Tenofovir Disoproxil Fumarate:''' The pharmacokinetics of [[tenofovir]] following a 300 mg dose of [[VIREAD]] has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in [[tenofovir]] pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.

======Hepatitis B and/or Hepatitis C Virus Co-infection======
* '''Elvitegravir:''' Limited data from population pharmacokinetic analysis (N=24) indicated that [[hepatitis B]] and/or [[hepatitis C|C]] virus infection had no clinically relevant effect on the exposure of [[cobicistat]]-boosted [[elvitegravir]].
* '''Cobicistat:''' There were insufficient pharmacokinetic data in the clinical trials to determine the effect of [[hepatitis B]] and/or [[hepatitis C|C]] virus infection on the pharmacokinetics of [[cobicistat]].
* '''Emtricitabine and Tenofovir:''' Pharmacokinetics of [[emtricitabine]] and [[tenofovir]] DF have not been fully evaluated in subjects coinfected with [[hepatitis B]] and/or [[hepatitis C|C]] virus.

======Race======
* '''Elvitegravir:''' Population pharmacokinetic analysis of [[elvitegravir]] in [[HIV]]-1 infected subjects indicated that race had no clinically relevant effect on the exposure of [[cobicistat]]-boosted [[elvitegravir]].
* '''Cobicistat:''' Population pharmacokinetics analysis of [[cobicistat]] in [[HIV]]-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI.
* '''Emtricitabine:''' No pharmacokinetic differences due to race have been identified following the administration of [[emtricitabine]].
* '''Tenofovir Disoproxil Fumarate:''' There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of [[tenofovir]].

======Gender======
No clinically relevant pharmacokinetic differences have been observed between men and women for [[cobicistat]]-boosted [[elvitegravir]], [[emtricitabine]] and [[tenofovir]] DF.

======Pediatric Patients======
[[Emtricitabine]] has been studied in pediatric subjects from 3 months to 17 years of age. [[Tenofovir]] DF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of [[elvitegravir]] or [[cobicistat]] in pediatric subjects have not been established.

======Geriatric Patients======
Pharmacokinetics of [[elvitegravir]], [[cobicistat]], [[emtricitabine]] and [[tenofovir]] have not been fully evaluated in elderly (65 years of age and older) patients.

=====Assessment of Drug Interactions=====
The drug-drug interaction studies described in Tables 8 and 9 were conducted with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, [[elvitegravir]] (coadministered with [[cobicistat]] or [[RTV]]), or [[cobicistat]] administered alone.

As [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is indicated for use as a complete regimen for the treatment of [[HIV]]-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided.

The effects of coadministered drugs on the exposure of [[elvitegravir]] are shown in Table 8. The effects of [[elvitegravir]] or [[cobicistat]] on the exposure of coadministered drugs are shown in Table 9. For information regarding clinical recommendations, see Drug Interactions (7).

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 8.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 9.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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|nonClinToxic='''Elvitegravir:''' Long-term carcinogenicity studies of [[elvitegravir]] were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day [[RTV]] at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, respectively in male and female, the human systemic exposure.
* [[Elvitegravir]] was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, [[elvitegravir]] was negative with metabolic activation; however, an equivocal response was observed without activation.
* [[Elvitegravir]] did not affect fertility in male and female rats at approximately 16- and 30-fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.
* Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.

'''Cobicistat:''' In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). [[Cobicistat]] exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of [[cobicistat]] in rats, an increased incidence of follicular cell [[adenomas]] and/or [[carcinomas]] in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and [[thyroid hormone]] imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.
* [[Cobicistat]] was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
* [[Cobicistat]] did not affect fertility in male or female rats at daily exposures (AUC) approximately 4-fold higher than human exposures at the recommended 150 mg daily dose.
*Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.

'''Emtricitabine:''' In long-term carcinogenicity studies of [[emtricitabine]], no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the therapeutic dose).
* Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
* Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

'''Tenofovir Disoproxil Fumarate:''' Long-term oral carcinogenicity studies of [[tenofovir]] DF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for [[HIV]]-1 infection. At the high dose in female mice, liver [[adenomas]] were increased at exposures 10 times of that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 4 times that observed in humans at the therapeutic dose.
* [[Tenofovir]] DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, [[tenofovir]] DF was negative when administered to male mice.
* There were no effects on fertility, mating performance or early embryonic development when [[tenofovir]] DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
|clinicalStudies=The efficacy of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is based on the analyses of 96-week data from two randomized, double-blind, active-controlled trials, Study 102 and Study 103, in treatment-naïve, [[HIV]]-1 infected subjects (N=1408, randomized and dosed) with baseline estimated creatinine clearance above 70 mL per min.

In Study 102, subjects were randomized in a 1:1 ratio to receive either [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate (N=348) once daily or [[ATRIPLA]] ([[efavirenz]] 600 mg/[[emtricitabine]] 200 mg/[[tenofovir]] DF 300 mg; N=352) once daily. The mean age was 38 years (range 18–67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino. The mean baseline plasma [[HIV]]-1 RNA was 4.8 log10 copies per mL (range 2.6–6.5). The mean baseline CD4+ cell count was 386 cells per mm3 (range 3–1348) and 13% had CD4+ cell counts less than 200 cells per mm3. Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In Study 103, subjects were randomized in a 1:1 ratio to receive either [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate (N=353) once daily or ATV 300 mg + RTV 100 mg + [[TRUVADA]] ([[emtricitabine]] 200 mg/[[tenofovir]] DF 300 mg) (N=355) once daily. The mean age was 38 years (range 19–72), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 1.7–6.6). The mean baseline CD4+ cell count was 370 cells per mm3 (range 5–1132) and 13% had CD4+ cell count less than 200 cells per mm3. Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In both studies, subjects were stratified by baseline [[HIV]]-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).

Treatment outcomes of Study 102 and Study 103 through 96 weeks are presented in Table 10.

[[File:Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Table 10.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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In Study 102, the mean increase from baseline in CD4+ cell count at Week 96 was 278 cells per mm3 in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate-treated subjects and 247 cells per mm3 in the ATRIPLA -treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 96 was 242 cells per mm3 in the [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate-treated subjects and 240 cells per mm3 in the [[ATV]] + [[RTV]] + [[tenofovir]] disoproxil fumarate-treated subjects.
|howSupplied=STRIBILD tablets are green, capsule-shaped, film-coated, debossed with "GSI" on one side and the number "1" surrounded by a square box (figure) on the other side. Each bottle contains 30 tablets (NDC 61958-1201-1), a silica gel desiccant and closed with a child-resistant closure.
|storage=Store at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).
* Keep container tightly closed.
* Dispense only in original container.
* Do not use if seal over bottle opening is broken or missing.
|fdaPatientInfo=A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate.
Patients should be advised that:
* [[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort.
* Patients should remain under the care of a healthcare provider when using [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate.
* Patients should be informed that [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate is not a cure for [[HIV]]-1 infection. Patients should stay on continuous [[HIV]] therapy to control [[HIV]]-1 infection and decrease [[HIV]]-related illnesses. Patients should be told that sustained decreases in plasma [[HIV]] RNA have been associated with a reduced risk of progression to [[AIDS]] and death.
* Patients should avoid doing things that can spread [[HIV]]-1 infection to others.
* Do not share needles or other injection equipment.
* Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
* Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
* Do not breastfeed. At least two of the drugs contained in [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate can be passed to the baby in breast milk. It is not known whether this could harm the baby. Also, mothers with [[HIV]]-1 should not breastfeed because [[HIV]]-1 can be passed to the baby in breast milk.
* It is important to take [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate on a regular dosing schedule with food and to avoid missing doses.
* Do not miss a dose of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. If a patient misses a dose of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate, the patient should not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate at any one time.
* Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Advise patients that treatment with [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be suspended if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness).
* Instruct the patient that hepatitis B testing is recommended prior to initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with [[HBV]] and [[HIV]]-1 and have discontinued [[emtricitabine]], or [[tenofovir]] disoproxil fumarate. [[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should not be discontinued without first informing their healthcare provider.
* Renal impairment, including cases of acute renal failure and [[Fanconi syndrome]], has been reported in association with the use of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. [[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high dose or multiple [[NSAID]]s).
* [[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should not be coadministered with other antiretroviral products because it provides a complete treatment regimen and because of potential drug interactions .
* [[Elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate should not be administered in combination with [[ATRIPLA]], COMPLERA, [[EMTRIVA]], [[TRUVADA]], or [[VIREAD]]; with drugs containing [[lamivudine]], including COMBIVIR, EPIVIR or EPIVIR-HBV, EPZICOM, or TRIZIVIR; with drugs containing [[RTV]] or regimens containing [[RTV]]; or with HEPSERA.
* Decreases in bone mineral density have been observed with the use of [[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
* Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known.
* In some patients with advanced [[HIV infection]] ([[AIDS]]), signs and symptoms of inflammation from previous infections may occur soon after anti-[[HIV]] treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Patients should be advised to inform their healthcare provider immediately of any symptoms of infection.
|alcohol=Alcohol-[[elvitegravir]], [[cobicistat]], [[emtricitabine]], and [[tenofovir]] disoproxil fumarate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Stribild
}}
{{LabelImage
|fileName=Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate Package.png
}}

[[Category:Antiretroviral]]
[[Category:Wikinfect]]