5 Jun

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.

Adverse Events

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.

Special Considerations

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:

www.hiva- tis.org
www.hopkins-aids. edu
http://aidsinfo. nih.gov

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.

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