Enfuvirtide, also known as T-20, is the first medication in a class of anti-HIV drugs called fusion inhibitors. It is a synthetic 36-amino-acid peptide derived from the HIV-1 envelope glycoprotein gp41 and it interferes with the entry of HIV-1 into cells by inhibiting the fusion of viral and cellular membranes. The drug is indicated to treat HIV infection in antiretroviral-experienced patients with evidence of ongoing viral replication despite ongoing antiretroviral therapy (i.e., show resistance to current HIV treatments). Enfuvirtide should be used in combination with an individualized antiretroviral regimen. It remains active against HIV strains in patients who have previously received and developed resistance to other classes of antiretroviral agents. In clinical trials, patients receiving enfuvirtide in addition to an individualized antiretroviral regimen were less likely to experience virologic failure or relapse compared to those receiving an individualized antiretroviral regimen alone; patients whose virus was sensitive to a greater number of antiretroviral drugs did demonstrate a greater sensitivity to enfuvirtide. During use, at least 98% of patients will develop injection site reactions to varying degrees, with almost 85% of patients developing the reactions within the first week of use. Patients should be appropriately counseled regarding injection site reactions before therapy is initiated.
General Administration Information
For storage information, see specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Injections may be self-administered after training by a medical professional using aseptic technique. For any questions regarding drug administration, instruct patients to contact a healthcare provider by calling 1-877-438-9366 or visiting the FUZEON website.
-Patients should be made fully aware of the high incidence of injection site reactions before initiating therapy. They should be taught to recognize the signs and symptoms of injection site reactions and instructed when to contact their healthcare provider about these reactions.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Subcutaneous Administration
Reconstitution
-Reconstitute vial with 1 mL of Sterile Water for Injection for a resultant concentration of 90 mg/mL.
-DO NOT shake the vial, but gently tap the vial for 10 seconds to start dissolving the powder. Gently roll the vial between the hands to reduce the mixing time and to ensure all drug particles are in contact with the diluent with no drug remaining on the vial wall. Then, allow the vial to stand until the powder goes completely into solution; this could take up to 45 minutes.
-The reconstituted solution should be clear and colorless, without bubbles or particulate matter. If the product is foamy or jelled, allow more time for it to dissolve.
-Storage: Once reconstituted, inject the solution immediately or refrigerate in the original vial for up to 24 hours.
-Bring the refrigerated reconstituted solution to room temperature before injection, then inspect again to ensure the contents are fully dissolved and the solution is clear and colorless without bubbles or particulate matter.
Subcutaneous Injection
-Administer by subcutaneous injection in the upper arm, abdomen, or anterior thigh at a site different from the preceding injection site and only where there is no current injection site reaction.
-Avoid the following injection sites: anatomical areas near where large nerves course close to the skin (e.g., elbow, knee, groin, inferior or medial sections of the buttocks), near skin abnormalities (e.g., moles, scar tissue, bruises, tattoos, burn sites), over blood vessels, or near the navel.
-To minimize local reactions, apply ice or heat after injection or gently massage injection site to better disperse the dose.
An increased rate of bacterial pneumonia infection was observed in patients treated with enfuvirtide in the Phase III clinical trials compared to the control arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively). Approximately half of the study patients with pneumonia required hospitalization and 3 deaths in the enfuvirtide arm were attributed to pneumonia. Additional clinical trials report the incidence of pneumonia at 2.7% (3.2 events per 100 patient-years) in those subjects receiving enfuvirtide in addition to a background HIV treatment regimen. Risk factors for pneumonia included low initial CD4 lymphocyte count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease. It is unclear if the increased incidence of pneumonia was related to enfuvirtide use. However, because of this finding, patients with HIV infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Enfuvirtide has been studied in 63 pediatric patients 5 to 16 years of age with a duration of enfuvirtide exposure ranging from 1 dose to 134 weeks of treatment. Adverse experiences seen during clinical trials were similar to those observed in adult patients. However, infections at the injection site, such as cellulitis or abscess, were more frequently seen in adolescents (4 events were reported in 3 of 28 patients), compared to adults. Other infectious adverse events reported include herpes simplex (3.5%), influenza-like illness (2.4%), and sepsis.
Injection site reaction (ISR) occurred at least once during clinical trials in 98% of patients treated with enfuvirtide, with a majority reporting reactions within the first week of treatment (85% of patients). ISRs involving pain and discomfort were reported in 96% of patients, 11% experiencing severe pain, which required prescription analgesics or limited usual daily activities. Indurations were reported in 90% of patients, with 39% of indurations being greater than 25 mm but less than 50 mm and 18% being at least 50 mm average diameter. Erythema at the site of injection was reported in 91% of patients, with an average diameter greater than 50 mm but less than 85 mm in 22% and at least 85 mm in 10% of the reported reactions. Nodules and cysts were seen in 80% of patients, 23% were greater than 3 cm, and 0.2% were draining. Pruritus was seen in 65% of patients, with 3% experiencing pruritus refractory to topical treatment or requiring oral or parenteral treatment. Ecchymosis was seen in 52% of patients, greater than 3 cm but 5 cm or less in 5% and greater than 5 cm in 2% of those affected. Seven percent of patients discontinued enfuvirtide during trials, 4% because of ISRs, and 3% because of difficulties with injecting (i.e., injection fatigue and inconvenience). For most patients in clinical trials, the severity of signs and symptoms associated with ISRs did not change during 48 weeks of treatment. On average, ISRs lasted 3 to 7 days in 41% of patients and longer than 7 days in 24%. The number of ISRs present in an individual patient at one time was between 6 and 14 in 26% and more than 14 in 1.3%; infection at the injection site, including abscess and cellulitis, was reported in 1.7% of adults. Postmarketing reports have included incidences of nerve pain (neuralgia or paresthesias) lasting up to 6 months associated with the Biojector 2000 Needle-Free device used for injecting enfuvirtide. This particularly occurs when the administration is at anatomical sites where large nerves course close to the skin. Bruising and hematoma have also been reported with this device.
Hypersensitivity reactions have been reported during treatment with enfuvirtide (less than 1%) and in some cases have recurred upon rechallenge. Such reactions have included, individually and in combination: chills, difficulty breathing or dyspnea, peripheral edema (specifically seen in the feet), elevated hepatic transaminases, fever, hematuria, hypotension, feeling nauseated, vomiting, rigors, and rash. Other adverse reactions that may be immune-mediated and have been reported in subjects receiving enfuvirtide include primary immune complex reaction, acute respiratory distress syndrome (ARDS), glomerulonephritis, and Guillain-Barre syndrome. Therapy should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity have not been identified.
In clinical trials, the gastrointestinal events most frequently reported in patients receiving enfuvirtide plus background regimen include diarrhea (31.7%), nausea (22.8%), abdominal pain (3.9%), decreased appetite (3.2%), anorexia (2.3%), and xerostomia (2.1%). Other, less common events include constipation, upper abdominal pain, and taste disturbance (dysgeusia).
Eosinophilia was reported with the use of enfuvirtide. In clinical trials, 9.1% of patients had eosinophil counts 1- to 2-times the upper limit of normal (ULN) and 1.8% of patients had eosinophil counts greater than 2-times the ULN. Less commonly reported hematologic adverse events include thrombocytopenia and neutropenia.
Infrequently reported nervous system or psychiatric adverse events during enfuvirtide clinical trials include insomnia, depression, anxiety, suicide attempt or suicidal ideation, sixth nerve palsy (cranial nerve palsies), and peripheral neuropathy.
There is a theoretical risk that enfuvirtide use may lead to antibody formation, resulting in anti-enfuvirtide antibodies that cross-react with HIV gp41. This could result in a false-positive HIV test with an ELISA assay; a confirmatory western blot test would be expected to be negative. Enfuvirtide has not been studied in individuals without HIV.
Fatigue (20.2%) was one of the most commonly reported adverse events during enfuvirtide clinical trials. Weight loss was reported in 6.6% of patients, while limb pain was noted in 2.9% of patients. Other general adverse events reported less commonly during trials include asthenia, fever, and lymphadenopathy.
Respiratory adverse events reported during enfuvirtide clinical trials include sinusitis (6%) and cough (3.9%). Other, less commonly reported adverse events include pneumopathy and respiratory distress.
Pancreatitis was reported in 3% of patients during enfuvirtide clinical trials. Elevated amylase and lipase concentrations were noted less frequently.
Myalgia was reported in 2.7% of patients during enfuvirtide clinical trials. Elevated creatine phosphokinase (CPK) concentrations were also noted. In trials, 6.9% of patients had Grade 3 CPK increases, while 2.6% of patients had Grade 4 CPK increases.
Folliculitis was reported in 2.4% of patients during enfuvirtide clinical trials; pruritus was less commonly reported. During postmarketing use, cases of cutaneous amyloidosis have been noted; however, due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Conjunctivitis was reported in 2% of patients during enfuvirtide clinical trials.
Renal tubular necrosis, renal insufficiency, and renal failure (unspecified) were infrequently reported during enfuvirtide clinical trials.
Hyperglycemia and hypertriglyceridemia were infrequently reported during enfuvirtide clinical trials.
Unstable angina pectoris was reported infrequently during enfuvirtide clinical trials.
Elevated hepatic enzymes have been reported with the use of enfuvirtide and may be associated with a hypersensitivity reaction. Grade 3 increases in ALT occurred in 4.1% of patients and Grade 4 increases were noted in 1.2% of patients during clinical trials. Toxic hepatitis and hepatic steatosis were less commonly reported during clinical trials.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
To better ensure compliance, patients should be given sufficient warning and explanation of injection site reactions before beginning treatment with enfuvirtide. Ninety-eight percent of patients in clinical trials experienced at least 1 injection site reaction during treatment. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis, and reactions are often present at more than one injection site. Patients must be familiar with the enfuvirtide injection instructions in order to know how to inject enfuvirtide appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection. The risk of post-injection bleeding may be higher in patients receiving anticoagulant therapy or persons with hemophilia or other coagulopathy.
An increased rate of bacterial respiratory infection (i.e., pneumonia) was observed in subjects treated with enfuvirtide in the phase III clinical trials, compared to those in the control group. It was unclear if the increased incidence of pneumonia was related to enfuvirtide use; therefore, an observational study was conducted to evaluate the risk of developing pneumonia. During this observational study, a total of 62 of 740 enfuvirtide treated patients (3.2 events/100 patient years) and 61 of 1110 non-enfuvirtide treated patients (1.8 events/100 patient years) experienced a confirmed or probable pneumonia event (hazard ratio 1.34; 95% CI = 0.9-2). Thus, an increased risk of pneumonia cannot be excluded. The manufacturer advises health care providers to carefully monitor patients with HIV infection for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous substance abuse, tobacco smoking, and a prior history of pulmonary disease.
Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Data regarding administration of enfuvirtide during pregnancy are too limited to rule out any potential association with birth defects; therefore, enfuvirtide-containing regimens should not be initiated in pregnant patients. However, it may be appropriate to continue use of the drug in some virally suppressed pregnant patients. If the decision is made with the patient to continue use of enfuvirtide, frequent viral load monitoring (every 1 to 2 months) and patient counseling regarding a lack of safety data is recommended. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to enfuvirtide; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). There are limited data regarding enfuvirtide use during breast-feeding, and excretion into human breast milk is unknown. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy with enfuvirtide may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experienced with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Initiation of therapy for HIV infection:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV infection:
-Enfuvirtide may be used in patients with HIV-1 infections who are treatment-experienced. There are insufficient data to recommend use as initial therapy in antiretroviral-naive patients; data from in vitro studies show HIV-2 to be intrinsically resistant to enfuvirtide.
-Data are limited regarding use of enfuvirtide during pregnancy; therefore, the drug cannot be recommended for routine use in pregnant women. However, it may be appropriate to continue use of the drug in some virally suppressed pregnant women.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of advanced human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in treatment-experienced patients with evidence of HIV replication despite ongoing antiretroviral therapy:
Subcutaneous dosage:
Adults: 90 mg subcutaneously twice daily.
Infants, Children, and Adolescents weighing 11 kg or more: 2 mg/kg/dose (Max: 90 mg/dose) subcutaneously twice daily.
For human immunodeficiency virus (HIV) prophylaxis* after occupational HIV exposure:
Subcutaneous dosage:
Adults: The US Public Health Service guidelines suggest enfuvirtide 90 mg subcutaneously twice daily in combination with one of the following backbones (in order of preference) as acceptable alternative regimens for HIV post-exposure prophylaxis (PEP): tenofovir plus emtricitabine; tenofovir plus lamivudine; zidovudine plus lamivudine; zidovudine plus emtricitabine. However, prior to administering an enfuvirtide containing regimen, the US Public Health Service recommends consultation with a clinician experienced in the management of PEP. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).
Maximum Dosage Limits:
-Adults
180 mg/day subcutaneously.
-Geriatric
180 mg/day subcutaneously.
-Adolescents
4 mg/kg/day (Max: 180 mg/day) subcutaneously.
-Children
weight 11 kg or more: 4 mg/kg/day (Max: 180 mg/day) subcutaneously.
weight less than 11 kg: Safety and efficacy have not been established.
-Infants
weight 11 kg or more: 4 mg/kg/day subcutaneously.
weight less than 11 kg: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed in patients with hepatic impairment.
Patients with Renal Impairment Dosing
No dosage adjustments are needed in patients with hepatic impairment.
*non-FDA-approved indication
Tipranavir: (Moderate) Phase 3 trials showed that the coadministration of enfuvirtide increases tipranavir trough concentrations by 45%; however, the mechanism for this increase is unknown. The manufacturer of tipranavir states that tipranavir dosage adjustments are not recommended.
Enfuvirtide interferes with the entry of HIV-1 into host cells by inhibiting the fusion of the virus and cell membranes. In order for HIV-1 to enter and infect a human cell, the viral surface glycoprotein gp120 binds to the host CD4+ cell receptor, along with a chemokine co-receptor (CXCR4 or CCR5; both expressed on lymphocytes and mononuclear cells). Then, the viral transmembrane glycoprotein gp41 undergoes a conformational change facilitating the fusion of cellular and viral membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational change required for membrane fusion and subsequent viral entry into target cells. This novel mechanism results in a lack of cross-resistance to enfuvirtide for viral isolates resistant to one or more currently available antiretrovirals.
Avoid the use of enfuvirtide in patients with HIV-2, as HIV-2 is intrinsically resistant to enfuvirtide. To identify the HIV strain, The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.
Enfuvirtide is administered as a subcutaneous injection. It is approximately 92% bound to plasma proteins, predominantly to albumin and, to a lesser extent, alpha-1 acid glycoprotein. The CSF concentrations, measured from 2 to 18 hours, in 4 patients with HIV were below the quantifiable limit (0.025 mcg/mL). Enfuvirtide is a peptide and is expected to undergo catabolism to its constituent amino acids. In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3; the hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in plasma following administration, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.
-Route-Specific Pharmacokinetics
Intravenous Route
The mean steady-state volume of distribution following IV administration of a 90 mg dose is 5.5 +/- 1.1 L.
Subcutaneous Route
The time to peak serum concentrations (Tmax) is approximately 8 hours (range of 3 to 12 hours) following a single 90 mg subcutaneous injection, with an absolute bioavailability is 84.3% +/- 15.5% compared to a 90 mg intravenous (IV) dose. With twice-daily subcutaneous dosing of 90 mg enfuvirtide in combination with other antiretroviral agents, the median Tmax decreases to 4 hours (range of 4 to 8 hours). Absorption of the 90 mg dose is comparable when injected into the subcutaneous tissue of the abdomen, thigh, or arm. The mean elimination half-life following a 90 mg single subcutaneous dose is 3.8 +/- 0.6 hours with a mean apparent clearance of subcutaneous dosing, in combination with other antiretroviral agents.
-Special Populations
Hepatic Impairment
Formal pharmacokinetic studies of enfuvirtide have not been conducted in patients with hepatic impairment.
Renal Impairment
Plasma concentration data from patients in clinical trials indicate that the clearance of enfuvirtide is not affected in patients with creatinine clearance more than 35 mL/min. In patients with severe renal impairment (CrCl = 11 to 35 mL/min), the clearance of enfuvirtide was reduced by 38% compared to those with normal renal function. Patients with end-stage renal disease receiving dialysis showed a 14% to 28% reduction in enfuvirtide clearance. Hemodialysis did not significantly affect the clearance of enfuvirtide.
Pediatrics
Children and Adolescents 6 years and older
Drug exposure in children and adolescents is independent of age, body weight, surface area, and sexual maturity. Pharmacokinetic data from clinical trials in pediatric patients (6 to 16 years, n = 23), with doses of 2 mg/kg (Max: 90 mg) given twice daily, who were also receiving concomitant medications including antiretroviral agents, revealed enfuvirtide plasma concentrations similar to those obtained in adult patients receiving 90 mg twice daily. The mean apparent steady-state clearance was 40 +/- 17 mL/hour/kg in pediatric patients as compared to 30.6 +/- 10.6 mL/hour/kg in adults.
Geriatric
The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.
Gender Differences
While no dosage adjustments are recommended regarding weight or gender, enfuvirtide appears to have a 20% lower clearance in females as compared to males, after adjusting for body weight, and the clearance decreases with decreased body weight, irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.
Ethnic Differences
Enfuvirtide clearance does not appear to be affected by race.
Other
Body Weight
While no dosage adjustments are recommended regarding weight or gender, enfuvirtide appears to have a 20% lower clearance in females as compared to males, after adjusting for body weight, and the clearance decreases with decreased body weight, irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.
Pregnancy
There are limited pharmacokinetic data in human pregnancy. Based on these scant data, there appears to be minimal placental transfer to the fetus.