Fusion inhibitors are included in the general group of entry inhibitors. Entry inhibitors bind to speciﬁc proteins and pre- vent HIV from entering otherwise healthy cells. A diagram of this mechanism is shown in Fig. 2.2. The currently approved fusion inhibitor, enfuvirtide, appears to interact with biological membranes, based on the molecular sequence and the eventual arrangement in an alpha helix. Enfu- virtide, however, does not form the alpha helix when binding to membranes. Instead, it remains in a random-coil confor- mation when inserted into the membranes. Enfuviritide enters the external layer of the plasmalemma and cannot translocate due to the negatively charged lipids of the inner layer. When HIV tries to enter the cell, the virus lipidic membrane cannot remove the enfuvirtide from the outer cell surface. The high cholesterol content and the concentration of
enfuvirtide effect a barrier to penetration by the HIV parti- cle (293,294).
Fusion inhibitors have an advantage over the other anti- HIV drugs in that many patients develop resistance to PIs, NRTIs, and/or NNRTIs. Because entry inhibitors are a differ- ent class of drugs, it is thought that this type of resistance will not develop in entry inhibitors. It is predicted in the future that optimal treatment of HIV infection will require various combinations of drugs that attack novel stages of HIV-1 entry and replication (295–297).
Enfuvirtide (ENF, T-20, pentafuside, Fuzeon)
Enfuvirtide blocks the ability of HIV to infect healthy CD4 cells. When used with other antiretrovirals, the amount of HIV RNA in the blood lowers and the number of CD4 cells increases (298). Enfuvirtide protects CD4 T cells from enve- lope presentation and therefore inhibits virus replication and blocks HIV-1 envelope-induced cell death. This protec- tion could lead to a better immune restoration of HIV-1- infected patients treated with enfuvirtide (299). Figure 2.22 shows the structure, brand name, and usage for enfuvirtide. Enfuvirtide is not approved for use by itself—it must be com- bined with other antiretrovirals and the choice of these anti- virals is between the patient and physician, based on each
individual patient’s circumstances. Enfuvirtide will most likely be used as “salvage” therapy, replacements for other antiretrovirals to which the HIV has become resistant. Because resistance in one class of drugs does not equate to resistance in another class of drugs, enfuvirtide has been heralded as a great breakthrough in HIV/AIDS therapy. However, relega- tion of the drug to “salvage” therapy is probably not the best approach in that it is least likely to work with seriously immunocompromised individuals. Instead, the drug should become a replacement therapy earlier in the drug regimen process, probably combined with an NNRTI, one or two PIs, and nucleoside/nucleotide analogs, based on susceptibility (300). Enfuvirtide provides signiﬁcant viral suppression and immunologic beneﬁt over a 24-week period in HIV-infected patients who had previously received multiple antiretroviral drugs (301,302). In one laboratory study, all viral isolates known to provide genetic resistance to more common antiret- rovirals were sensitive to enfuvirtide (303). For clinical tri- als, enfuvirtide was injected or delivered intravenously with the intermittent injections being superior to continuous infu- sions (304). In some patients, the beneﬁt was short-lived, suggesting the development of resistance (305). Pharmaco- kinetics studies indicate that the absorption process is com- plex and that enfuvirtide is completely absorbed when subcutaneously injected abdominally (306). In that enfur- virtide is newly approved, many side effects have not yet been documented.
Injection site reactions. Minor injection site reactions are frequent, but are rarely treatment limiting and in- clude redness, itching, hardened skin, tenderness, bruising, and swelling (307).
Serious allergic reactions. For those who may be aller- gic to any of the ingredients in enfuvirtide, serious al- lergic reactions can occur. These include difﬁculty breathing, fever with vomiting, hematuria, and swelling of feet. Patients should seek immediate medical help if any of these symptoms occur.
Patient compliance. Acceptance of enfuvirtide by pa- tients appears to be low because of the two abdominal injections/day for administration of the drug and the high cost of the drug per patient per year (~$14,000–$20,000)(308). Auto-injection devices are being ex- plored as are multidose vials to serve as near-term modiﬁcations. An oral enfuvirtide is years from becom- ing a reality (309). Patient issues with injections may be resolved through better training of nurses for better patient comprehension and an effective nurse-patient relationship (310,311).
Other side effects. Some of the other side effects of en- fuvirtide include: pain or numbness in feet or legs, loss of sleep, depression, decreased appetite, weak- ness or loss of strength, muscle pain, constipation, and pancreatitis.
Bacterial pneumonia. Although bacterial pneumonia is not common among patients taking enfuvirtide, more patients on enfuvirtide developed bacterial pneumonia than those who were not on enfuvirtide (312).
At the time of this writing, there are 23 new antiretroviral agents under current development and study. Five nucleoside ana- logues, six NNRTIs and seven PIs show promise based on early study results. New classes of antiretroviral drugs are currently under investigation, with possible alternative mechanisms for effective therapy against HIV. Zintevir (AR177) is the main compound under development as an integrase inhibitor (313). In vitro, this compound is a potent inhibitor of the HIV inte- grase enzyme, but its in vivo actions have yet to be confirmed.
Four different fusion inhibitor compounds are currently under- going evaluation.
As the population of HIV-infected individuals increases, the need for better access to antiretroviral therapy becomes more critical. In countries where HAART is available, however, the role of the physician has expanded from therapy of HIV and associated opportunistic infections to include the adverse effects of antiret- roviral therapy, drug resistance, and noncompliance. Not only will it be necessary to be aware of these limitations of HAART, it will also be necessary to be knowledgeable of drugs that are incompatible with antiretroviral agents. Since there are now more than 20 FDA-approved antiretroviral drugs, many avail- able in combination tablets and capsules, and many more anti- retroviral drugs in clinical trials, therapy of HIV disease is constantly in evolution. Therefore, it is imperative that physi- cians be aware of the following Web sites for HIV treatment information:
The collection of antiretroviral medications is in a con- stantly changing state, due to the rapid and exciting advances in HIV therapy. While ﬁve classes of antiretroviral drugs are now the mainstay of therapy, new groups of drugs are cur- rently under development and investigation in order to inhibit HIV through additional mechanisms. Combination therapy regimens using drugs from two or more separate classes have proven to be more effective in delaying both the progression of HIV infection and the development of resistant viruses.
Although antiretroviral drugs have led to decreased mor- bidity and mortality for the less than 5% of the world that can afford them, they have produced no cures. Hope for control of the epidemic lies in public health measures such as absti- nence/safer sex, condoms, testing of blood products, elimination of sharing of needles, education, and the development of vac- cines to prevent HIV infection.