New breakthrough in HIV treatment
By Tonya Blackwood, PharmD Candidate McWhorter School of Pharmacy Samford University, Birmingham, AL
Fuzeon (enfuvirtide), also known as T-20, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in March 2003. It is the first drug in a unique class of antiretrovirals, known as fusion inhibitors. Enfuvirtide is the newest development in drugs used to treat the human immunodeficiency virus (HIV-1).
Other medications available to treat HIV-1 exert their effects mainly by inhibiting one of two enzymes: protease or reverse transcriptase. These older medications are capable of decreasing the morbidity and mortality associated with HIV-1; however, these medications are usually unable to achieve or maintain suppression of the HIV viral replication below clinically detectable levels. Another problem with the older medications is that many patients are becoming resistant to at least one medication in each class currently available for treatment.
Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes through binding to a region of the envelope glycoprotein 41 of HIV-1. As a result of binding to this particular protein, the conformational changes required for the fusion of viral and cellular membranes is prevented. Enfuvirtide’s mechanism of action is unique in that it inhibits HIV-1 cellular entry; whereas, the previous medications available to treat HIV inhibit replication after it enters into human cells. However, enfuvirtide is not a cure for HIV and must be used in combination with other antiretroviral agents.
Enfuvirtide’s pharmacokinetic properties have been studied in both children (> 6 years old) and adults who have been treated with other classes of antiretrovial agents available. The maximum plasma concentration of enfuvirtide ranges from 2.48 to 8.05 mcg/mL for 30-90 mg doses given subcutaneously. The half-life ranges from 3.46 to 4.35 hours. Enfuvirtide is provided as a powder that must be reconstituted before injection and can be injected into the abdomen, thigh, or arm to provide steady state concentrations that are fairly similar to one another. The site should be rotated each time an injection is given to decrease the pain and discomfort. Effects of decreased hepatic and renal function have not been established; however, clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. Enfuvirtide is 92% bound to plasma proteins, mainly albumin and to a lesser extent alpha-1 acid glycoprotein.
There have been two major Phase III trials conducted with enfuvirtide: TORO 1 and TORO 2 (T-20 vs. Optimized Regimen Only Study 1 and 2). The TORO 1 study was conducted in North and South America; the TORO 2 study was conducted in Europe and Australia. The study design, patient inclusion/exclusion criteria, and monitoring were identical in both TORO 1 and 2, except for two minor differences in criteria for inclusion. In TORO 1, a requirement of at least six months of previous treatment and treatment with at least two protease inhibitors was in the criteria. In TORO 2, a requirement of at least three months of previous treatment with at least one antiretroviral drug from each of the three approved classes, and demonstrated resistance to each class or both was set forth in the criteria.
Both studies were published in the New England Journal of Medicine. In the studies, enfuvirtide was combined with a regimen that was optimized by the investigator for each individual based on each patient’s previous medications. The primary endpoints evaluated were the same in each study: the change in baseline to 24 weeks in the plasma HIV-1 RNA level (measured on a logarithmic [base 10] scale). A secondary endpoint measured in both studies was the change from baseline to week 24 in the CD4+ cell count. In TORO 1, the plasma HIV-1 RNA levels mean change from baseline was greater in the enfuvirtide group, 1.696 log10/mL, and only 0.764 log10/mL mean change from baseline in the control group. The enfuvirtide group in TORO 1 also produced a greater increase in CD4+ cell count from baseline, 76.2 cells/mm3; whereas, the control-group only increased by 32.1 cells/mm3 from baseline. In TORO 2, the plasma HIV-1 RNA levels mean change from baseline was a decrease of 1.429 log10/mL in the enfuvirtide group and only a decrease of 0.648 log10/mL in the control group. The CD4+ cell count increased in both groups in the TORO 2 study. The enfuvirtide group increased by 65.5 cells/mm3 as opposed to an increase of 38.0 cells/mm3 in the control group. In both studies, the differences in measured outcomes between the enfuvirtide and the control groups were statistically significant.
Even though enfuvirtide appears to be efficacious, it does have some disadvantages. One of the most common adverse drug events is injection site reactions. In TORO 1 and 2, 98% of the patients developed some type of injection site reaction; however, only a small percentage required discontinuation of the therapy due to the reactions. The high rate of compliance during the TORO 1 and 2 trials implies that the injection site reaction was not treatment-limiting. Other adverse drug reactions included nausea, diarrhea, and fatigue. The patient must be taught aseptic technique to avoid injection site infections, and how to reconstitute enfuvirtide. Each patient must also give himself/herself two subcutaneous injections a day.
Additionally, the cost is extremely high, and the supplies are limited due to the complexity of manufacturing the drug. Enfuvirtide is the most complex drug molecule manufactured on a large scale. Demand will likely exceed the initial supply; therefore, there has been a Progressive Distribution Program (PDP) that will act as a single distributor of the drug. Since the supplies are limited, the PDP will allow as many patients as possible to receive the drug and still be ensured of an uninterrupted supply of the drug. The PDP will receive prescriptions via telephone, fax, or e-mail; the drug will be allotted on a first-come, first-served basis. Initially, a supply sufficient for 8,000-10,000 patients will be manufactured; however, by mid-2005, a safety supply sufficient for 28,000-30,000 patients should be established.
As with all antiretroviral medications, patient education is required to increase compliance, and to maintain drug efficacy to prevent development of resistance. The patient must be taught to take medications exactly as prescribed by his/her physician, and the importance of not missing or skipping any doses. The patient also should consult with his/her physician regarding any new medication started, although there are no known specific drug interactions with enfuvirtide at this time. Patients should be counseled that the drug is not a cure for HIV-1, and safe practices to prevent the spread of HIV-1 still must be followed. Patients should be advised to seek medical attention if he/she suspects an infection because enfuvirtide does not reduce the risk of opportunistic infections that can occur in patients who have HIV-1. In the safety data from the TORO 1 and 2 trials, enfuvirtide was associated with a higher incidence of bacterial pneumonia and eosinophilia.
Enfuvirtide may have an extremely important and evolving role in the treatment of HIV-1. The drug’s recommended dose is 90 mg twice a day subcutaneously. Its unique mechanism of action that inhibits the viral and cellular membranes from fusing, and thus inhibiting replication before actually entering the cells, has proven to decrease the viral load below clinically detectable levels. The previous drug classes available were not able to achieve or maintain these levels, a significant new breakthrough in treating HIV-1.
Resources
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Fuzeon (enfuvirtide), also known as T-20, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in March 2003. It is the first drug in a unique class of antiretrovirals, known as fusion inhibitors. Enfuvirtide is the newest development in drugs used to treat the human immunodeficiency virus (HIV-1).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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