T-20 or enfuvirtide as it is now known, will be the first of a new class of drugs in the treatment of HIV. Tracy Barnes explains
Drug Name:
Enfuvirtide
Drug Class:
Fusion inhibitors (FIs)
Brand Name:
FuzeonŽ
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How enfuvirtide works
Enfuvirtide is member of a new class of antiretrovirals referred to as Fusion Inhibitors. This class combats viral replication of HIV by blocking the fusion of viral membrane with the CD4 cell membrane and preventing the entry of the virus into the CD4 cell.
History
The former code name of enfuvirtide was T-20; it was developed by a group of researchers from Duke University, USA, who subsequently formed the company Trimeris. The opportunity to develop enfuvirtide was declined by several other pharmaceutical companies before Roche agreed to manufacture and co-market the drug. The manufacturing process of enfuvirtide is 10 times more complex than that for protease inhibitors, requiring 106 steps, in three distinct operations, making it the most complex HIV drug to manufacture to date.
Enfuvirtide was licensed in the USA in March 2003 and is expected to receive its European licence very soon. The proposed indication for enfuvirtide is for the drug to be used in combination with other antiretrovirals for the treatment of HIV-1 in adults and children over the age of six years. Patients will be treatment experienced and have experienced failure on antiretroviral regimes that contain at least one drug from each antiretroviral class, e.g. protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors or they will have intolerance to previous antiretroviral regimens.
Combination therapy
Enfuvirtide must be taken as part of an antiretroviral combination regimen. In separate pharmacokinetic interaction studies, co-administration of ritonavir or saquinavir in combination with a booster dose of ritonavir did not result in clinically significant changes in the pharmacokinetics of enfuvirtide. Co-administration of rifampicin did not result in clinically significant changes in the pharmacokinetics of enfuvirtide.
Dosing
Enfuvirtide is only to be administered by subcutaneous injection. It is a white to off-white powder that requires reconstitution with 1.1ml of sterile water prior to injection.
The recommended dose for adults and children over 16 years of age is 90mg powdered enfuvirtide, reconstituted with 1.1ml of sterile water and injected twice daily subcutaneously into the upper arm, outer thigh or abdomen. Dosing for children over the age of 6 years is weight based (see paediatric use). No dose adjustment is required for patients with mild to moderate kidney mpairment. However, no data is available to establish a dose recommendation for patients with severe kidney impairment, or those receiving dialysis or for patients with liver impairment.
Dosing restrictions
Because some hypersensitivity reactions have occurred with the use of enfuvirtide that may occur if treatment is recommenced, anyone who has had a prior hypersensitivity reaction should not be treated with enfuvirtide.
Enfuvirtide's safety and efficacy has not been specifically studied in patients with significant underlying liver disorders. Patients with chronic hepatitis B and C and treated with antiretroviral therapy are at an increased risk of severe hepatotoxicity and careful consideration should be given to choice of antiretroviral regimes to be used alongside enfuvirtide.
There is no experience in patients with reduced liver function or in patients with severe kidney impairment and only limited data in patients with moderate kidney impairment. Enfuvirtide should be used with caution in these populations.
Side effects
An increased rate of some bacterial infections, most notably an increased rate of bacterial pneumonia, has been seen in patients treated with enfuvirtide. Patients should be monitored closely for signs and symptoms of bacterial pneumonia.
Some people have experienced a hypersensitivity reaction to enfuvirtide. Symptoms have included rash, fever, nausea, vomiting, chills, rigors, low blood pressure and raised liver enzymes. Patients developing signs of a systemic hypersensitivity reaction should seek medical advice immediately. Enfuvirtide should be discontinued and not restarted following a hypersensitivity reaction.
Common side effects
Injection site reactions have been the most frequently reported side effect of enfuvirtide, occurring in 98% of patients with only 3% discontinuing treatment. Most injection site reactions occurred within the first week of treatment.
other side effects
Adding enfuvirtide to a background antiretroviral regime did not generally increase the frequency or severity of any side effects.
Side effects occurring in more than 10% of patients generally included insomnia and headache.
Less common side effects (seen in 1% to 10% of patients included:
Bacterial pneumonia
Oral thrush
Herpes simplex
Skin warts and inflamed hair follicles
Peripheral neuropathy
Influenza and flu-like illnesses
Sinusitis, sore throat, cough
Increased sweating and night sweats
Decreased appetite and weight loss
Constipation
Pain in the abdomen, back, limbs, joints and muscles
Depression and anxiety
Fatigue and dizziness
Pancreatitis
Lymph node disorders
Pre-existing conditions
Enfuvirtide is contraindicated in all patients who have experienced a hypersensitivity reaction to treatment with enfuvirtide or who have known hypersensitivity to any of its active ingredients.
Paediatric use
Data based on a limited number of children over the age of six years supports the following weight-based dosing. (No data exists to support the use of enfuvirtide in children below 6 years old.)
11-15.5kg - 27mg
15.6-20kg - 36mg
20.1-24.5kg - 45mg
24.6-29kg - 54mg
29.1-33.5kg - 63mg
33.6-38kg - 72mg
38.1-42.5kg - 81mg
over 42.6kg - 90mg
Laboratory anomolies
The majority of patients had no change in liver enzymes or creatine clearance. Abnormalities that did occur were more common in those receiving enfuvirtide in combination with other antiretrovirals than in those receiving other antiretrovirals alone. The most commonly occurring abnormalities were raised liver enzymes and eosinophillia (increased number of eosinophils - white cells).
Use during pregnancy
There are no adequate and well-controlled studies of enfuvirtide in pregnant women. For this reason enfuvirtide should only be used during pregnancy if the benefits justify any potential risks.
It is not known whether enfuvirtide is secreted in breast milk. Because of the potential for HIV transmission mothers are advised not to breastfeed their infants.
Enfuvirtide-resisitant HIV
As with all antiretrovirals, incomplete viral suppression may lead to the development of drug resistance to one or more components of the regimen. Resistance to enfuvirtide has been observed both in vitro and in vivo and appears to be related to degree of resistance to other background antiretroviral drugs present at commencement of treatment.
Cross-resistance between enfuvirtide and other antiretrovirals has not been observed.
