Enfuvirtide

HIV entry requires gp41 to fold into a six-helix bundle in which three HR1 helices form a central coiled coil packed against three HR2 helices, pulling the viral and cell membranes together. Enfuvirtide is a synthetic peptide copy of part of the HR2 region; it binds the exposed HR1 groove in the transient pre-hairpin intermediate and occupies the site that the real HR2 helix would fill, so the bundle never forms and fusion aborts. Because it acts outside the cell, it needs no intracellular activation and works against virus already resistant to reverse transcriptase, protease and integrase inhibitors. Its practical limits are severe: it must be injected twice daily, it costs a great deal, injection-site reactions are near-universal, and resistance emerges quickly via mutations in the gp41 HR1 residues 36-45 if the background regimen is not fully suppressive.

Targets: HIV-1 gp41 HR1 domain, Viral membrane fusion

• · 90 mg (1 mL of the reconstituted 90 mg/mL solution) twice daily. Rotate sites every single injection and never inject into an existing nodule, a mole, scar tissue or the navel area. It must always be used with an optimised background antiretroviral regimen, never alone.
• · Dose figure is per kilogram: 2 mg/kg twice daily, capped at 90 mg per dose.

Work out your exact syringe units →

• very commonInjection-site reactions— Affects roughly 98% of patients — painful erythematous nodules, induration and cysts at the site. This, more than anything else, is why people stop the drug. Rotating sites and injecting at room temperature helps but does not eliminate it.
• very commonDiarrhoea and nausea
• commonIncreased rate of bacterial pneumonia— Documented in the pivotal trials at a higher rate than the control arm. New respiratory symptoms need evaluating rather than dismissing.
• commonPeripheral neuropathy
• commonEosinophilia
• rareHypersensitivity reaction— Rash, fever, chills, hypotension and elevated transaminases. It can recur on rechallenge, so the drug should not be restarted after a systemic hypersensitivity reaction.

• Known hypersensitivity to enfuvirtide — rechallenge after a systemic reaction has caused more severe recurrence.
• Never as monotherapy or added as a single active agent to a failing regimen; resistance develops within weeks.
• Practical contraindication in anyone unable or unwilling to self-inject twice daily indefinitely.

• synergyother antiretrovirals — Enfuvirtide is designed to be used with an optimised background regimen; no significant pharmacokinetic interactions have been found with protease or reverse transcriptase inhibitors, because it is catabolised as a peptide rather than by CYP enzymes.
• synergymaraviroc — Both block entry at different steps (CCR5 binding versus fusion) and have been combined in salvage regimens.

• · HIV-1 RNA viral load and CD4 count on the usual antiretroviral schedule.
• · Injection sites at every visit, looking for cellulitis versus expected nodule formation.
• · Chest symptoms, given the pneumonia signal.
• · Liver enzymes and eosinophils if hypersensitivity is suspected.

Prescription-only injectable, approved in the US and EU for HIV-1 infection in treatment-experienced patients with ongoing viral replication.

• Lalezari et al. 2003, TORO 1 trial of enfuvirtide in treatment-experienced HIV-1 infection (trial)
• Lazzarin et al. 2003, TORO 2 trial of enfuvirtide (trial)
• Fuzeon (enfuvirtide) US prescribing information (label)

A 36-residue synthetic peptide copying the HR2 region of HIV-1 gp41. It binds the HR1 groove during fusion and prevents the six-helix bundle from forming, so the viral and cell membranes never merge. It is the only approved fusion inhibitor and works entirely outside the cell, which is why it retains activity against virus resistant to every intracellular drug class.

Injection site reactions occur in almost everyone - nodules, erythema and induration at essentially every site - and are the main reason people stop. Twice-daily subcutaneous injection indefinitely is a heavy burden, and adherence failure produces resistance rather than simply lost benefit. There is also a recognised increase in bacterial pneumonia risk.

• HIV-1 gp41 HR1 region — High, sequence-specific

  Blocks six-helix bundle formation and membrane fusion

• TORO 1 and TORO 2 Phase 3 · n=995 · 24 weeks · 2003

  Greater HIV-1 RNA reduction when added to an optimised background regimen in treatment-experienced patients.

Viral load falls within the first weeks alongside the rest of the regimen.

• ?Its place in modern therapy is small and shrinking as newer agents with oral or long-acting injectable options cover multidrug-resistant HIV.