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Enfuvirtide (Fuzeon, ENF, T-20), The First HIV Fusion Inhibitor
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Johns Hopkins HIV Report
http://www.hopkins-aids.edu
On March 13, 2003 the FDA-approved enfuvirtide as the first fusion inhibitor
for use in antiretroviral therapy.
Enfuvirtide Access, Administration, and Patient Education
By Shivaun A. Celano, Pharm.D., M.B.A.
Enfuvirtide is the first FDA approved antiretroviral agent that will be administered by injection for the treatment of HIV. This product will need to be prepared by the patient or caregiver and then be injected twice daily. Injection site reactions occur in the majority of patients. Extensive patient education and training will be necessary to promote proper preparation,
administration, minimization of side effects, and adherence. It is also critical that aseptic self-injection techniques and procedures be periodically re-evaluated.
Access-Fuzeon Distribution Program
Enfuvirtide is difficult to manufacture, and it is expected that initial demand will exceed supply. During this period of limited availability, the manufacturer will use a staggered launch of the product. During the first year of production, the Progressive Distribution Program (PDP) has been put into place to make the product available to as many patients as possible while ensuring uninterrupted access to drug. The PDP includes a single-source of distribution, the Fuzeon
Patient Assistance Program, and the Reimbursement Assistance Program. The program will work on a first-come first-served basis. As the supply of enfuvirtide increases and production reaches the 100% level, the drug will be
distributed through more conventional means, such as local pharmacies. Prescription enrollment forms are available through Fuzeon sales specialists, at http://www.Fuzeon.com, or by calling 1-866-694-6670. Once these forms have been completed and faxed into the PDP, they will be date and time stamped. The patient will be placed onto the pending (waiting) list, intake information and insurance eligibility will be verified, and available drug supply will be checked to determine that there is adequate supply available. Once these steps have been completed and it has been determined that drug supply is adequate, the patient will be moved to the active list, at which time the prescription will be processed and a 30-day supply of drug and injection supplies will be shipped to the patientÕs home, physicianÕs office, or a local
StatScript pharmacy.
Insurance or Reimbursement Support
The PDP Reimbursement Assistance Program is available to facilitate reimbursement issues. The staff of this program act to resolve any prescription authorization problems by working with the payor, the Fuzeon Patient Assistance Program (which is available for patients who qualify), the healthcare provider, and the patient. While insurance eligibility is being verified and potential problems are being handled, the patient name is maintained under the number that was assigned when the patient enrollment form was received by the PDP. Roche and Trimeris are currently working with private and public payors, such as medical assistance programs and ADAPs, to obtain formulary status and to determine reimbursement. Some programs may require prior authorization for this product. Some insurance plans may have a cap on the amount of money paid out per year for medications per member. These issues will need to be addressed with the patient in order to ensure uninterrupted use of the drug.
Patient Education
Patient education will be critical with this product. The drug will need to be reconstituted once to twice daily (depending on patient preference) and must be administered twice daily by subcutaneous injection. Enfuvirtide may sometimes take up to 45 minutes to go into solution and needs to be prepared aseptically. Patients or their caregivers will need to be trained on several key issues: how to mix the product and prepare their dose, the proper way to inject the dose in order to minimize injection site reactions, and the proper disposal of syringes and preparation supplies. To assist healthcare providers and patients a Nursing Hotline is staffed 24 hours per day, 7 days per week at 1-877-438-9366. Instructions and patient education materials are included in the Patient Starter Kit/Travel Pak that all patients starting on enfuvirtide will
receive. Some insurance plans may provide direct patient education on drug preparation and administration through their home health care benefit. Clinics and physician offices may develop their own internal prescribing and patient education protocols, as well. Effective use of enfuvirtide will require comprehensive patient training, adherence monitoring, side effect prevention/management, clinical monitoring and routine follow-up.
The Optimal Use ot Enfuvirtide
By Joel E. Gallant, M.D., M.P.H.
Enfuvirtide (Fuzeon, ENF, T-20) is the first fusion inhibitor, and the first inhibitor of viral entry, to be approved by the FDA. We have not seen the approval of a drug with a novel mechanism of action since 1996, when nevirapine, the first non-nucleoside reverse transcriptase inhibitor (NNRTI), was introduced. ENF inhibits one of the final steps of viral entry: gp41-mediated fusion with the CD4 cell membrane and its efficacy has been demonstrated in clinical trials [see Drug Profile: Enfuvirtide, below] It is expected that more fusion inhibitors will follow, as well as other drugs that block earlier steps in the entry process, such as attachment to the CD4 cell receptor and binding to the co-receptors, CCR5 and CXCR4.
Because of the large size of the molecule and the complexity of the manufacturing process, ENF is expensive even by antiretroviral standards. It is also a difficult drug from a patient perspective, given that it requires a time-consuming reconstitution process, twice-daily subcutaneous injection, and causes injection site reactions, reactions in most of the patients who take
it; some-times these site reactions are painful. Finally, it is difficult from the clinician’s perspective, in that it requires a great deal more patient education than the average antiretroviral agent, and, at least in the beginning, a great deal more paperwork. The hope is that in its current form, ENF will one day be looked back upon as the Model "T" of entry inhibitors. Until that time comes, what we have is a difficult and expensive drug that has a great deal to offer to treatment experienced patients. The challenge is to know how and when to best use this drug, to which access will be limited not only by cost but also by supply.
Unfortunately, ENF is already being labeled as a "Salvage Drug". Before we consign it to a position likely to minimize its utility, we should remember the words of Joep Lange, who said, "Salvage therapy only works when its not really salvage therapy". No effective agent should be relegated to a position where its least likely to work. Cost, inconvenience, and toxicity may tempt many clinicians and patients to defer the use of ENF until there are no remaining options, but such a strategy will ensure that the response to this valuable drug will be blunted and brief. The results of the TORO trials clearly indicated that ENF worked best, and longest, when it was combined with other effective drugs. This means that the optimal positioning for ENF will be somewhat earlier: not in an initial regimen and probably not in second-line therapy; but not for “deep salvage” either. Ideally, ENF would be combined either with an NNRTI in a previously NNRTI-na•ve patient, or with a boosted protease inhibitor (PI) or a double-boosted PI (e.g., LPV/r plus another PI) in a
patient with some PI experience but without extensive resistance. Nucleoside/nucleotide analogs would also be included, based on susceptibility.
Of course, our clinics are full of patients who are already beyond that point: patients who already have extensive 3-class resistance, making it difficult or impossible to come up with an effective background regimen with which to use ENF. For such patients, the decision to use this drug needs to be made with great caution. A patient with a high viral load and a CD4 count of
10 cells/mm3 despite antiretroviral therapy may derive substantial clinical benefit from an ENF-containing regimen, even if the likelihood of durable virologic suppression is slim. However, a patient with extensive drug resistance and a CD4 count of 200 cells/mm3 might be able to remain relatively stable on a regimen consisting of reverse transcriptase inhibitors and/or protease
inhibitors, allowing ENF to be reserved until it can be combined with other agents currently in development. Some promising pipeline drugs that may be beneficial in such patients include the second generation NNRTIs, capravirine and TMC-125, or the second generation PIs, tipranavir or TMC-114.
Many of our patients with high-level multi-class resistance developed that resistance through the sequential addition to failing regimens of new drugs as they became available. Though now discredited, such a practice was understandable in the early years of the HAART era, when most patients had been exposed to nucleoside analogs, and we had little understanding of
antiretroviral drug resistance. It is critical, now that the first fusion inhibitor is available, that we not repeat the mistakes of the late 1990s. For those who have at least some options for suppressive therapy, the mistake might be to use ENF too late waiting to play the ENF card until after the suppressive options had been used up. For those with no suppressive options at all, we might err in some cases by using ENF too early, using it in a non-suppressive regimen and thereby guaranteeing ENF resistance, so that it won't be effective in combination with second generation antiretrovirals when they become available.
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