Enfuvirtide

Fuzeon, T-20, DP-178, pentafuside

Antimicrobial & antiviral

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Enfuvirtide is an approved prescription antiretroviral, the first HIV fusion inhibitor. It was never a research-only or community compound, and it is now being withdrawn from most markets because better-tolerated drugs have replaced it. This page explains the published science and the current status.

1What it is

Enfuvirtide is a 36-residue peptide whose sequence is lifted directly from HIV-1's own fusion machinery. When HIV docks on a CD4 cell, its gp41 protein unfolds like a harpoon; two helical regions (HR1 and HR2) then snap together into a six-helix bundle, dragging the viral and cell membranes together. Enfuvirtide is a copy of HR2. It binds the exposed HR1 groove during that brief intermediate state and prevents the bundle from forming, so the virus is stuck on the outside of the cell.

It was discovered at Duke University in the early 1990s, developed by Trimeris with Roche, and approved by the FDA in March 2003 as the first drug in a new class, for treatment-experienced patients whose virus had become resistant to other drugs. Because it is a large peptide, it has to be injected twice a day, and nearly everyone gets injection-site reactions. Once integrase inhibitors and other once-daily options arrived, use collapsed. Genentech (Roche) announced in August 2024 that US distribution would end on 28 February 2025, citing "much lower medical need" rather than any safety or quality issue; France's ANSM announced the end of supply on 30 September 2025 for the same reason.

2How it's thought to work

It is a competitive mimic of gp41 HR2. Binding to the HR1 trimer blocks six-helix-bundle formation, the step that pulls the membranes together.

It acts outside the cell, before entry, so it works against virus resistant to reverse-transcriptase, protease and integrase inhibitors, and has no cross-resistance with them.

Resistance develops readily if the virus is not fully suppressed, through mutations in gp41 residues 36–45 of HR1; this is why it was always combined with an "optimised background" of other drugs.

It has no activity against HIV-2 and little against some HIV-1 subtypes with HR1 variation.

A 36-amino-acid copy of part of HIV gp41, binding the other half of the same protein so it cannot fold back on itself. Without that fold the viral and cell membranes are never pulled together, and entry fails before the virus is inside.Schematic — not to scale

3What the research shows

Treatment-experienced HIV-1 infection

Two Phase 3 trials, TORO 1 (North and South America, n=501) and TORO 2 (Europe and Australia, n=512), randomised heavily treatment-experienced patients to optimised background therapy with or without enfuvirtide. At 24 weeks viral load fell by about 1.7 log10 copies/mL with enfuvirtide versus about 0.8 log10 with background alone, and more patients reached undetectable virus; CD4 counts rose more (Lalezari 2003, NEJM; Lazzarin 2003, NEJM). Benefits held at 48 weeks (Nelson 2005, HIV Clin Trials). These are the pivotal data and they are solid; the problem was never efficacy but tolerability and the arrival of easier drugs. [3][4][5]

Graded A/B

Use with newer agents in deep salvage

Trials of raltegravir, darunavir and maraviroc in treatment-experienced patients (e.g. BENCHMRK, POWER, MOTIVATE) showed that adding enfuvirtide as a new active drug alongside the study agent improved suppression rates, which is how it was used in the late 2000s. It also served as a short bridge in people who later switched off it once suppressed (Morales-Ramirez and others, small studies).

Graded B (negative)

Treatment intensification in early or primary infection

Adding enfuvirtide to a standard first-line regimen in severely immunosuppressed patients did not improve CD4 recovery (ANRS 130 APOLLO, n=195; Joly 2013, Antimicrob Agents Chemother), and small intensification studies in suppressed patients found no effect on residual virus. [6]

Community / self-directed use

None documented, and none plausible.

4Reported side effects and interactions

Literature-reported

Injection-site reactions in about 98% of patients in TORO — pain, redness, hardened nodules and cysts, lasting days to weeks and sometimes causing discontinuation (around 4%). Higher rate of bacterial pneumonia than comparators (about 7 vs 0.6 per 100 patient-years in TORO), mechanism unclear; the label advises watching for it. Hypersensitivity reactions (rash, fever, nausea, low blood pressure, raised transaminases) in under 1%; do not rechallenge. Peripheral neuropathy, insomnia, depression, eosinophilia and weight loss were reported but often attributable to background therapy or disease. Rare: amyloid deposition at injection sites in long-term users.

Community-reported

none; no community use.

Theoretical. immune-complex formation or antibody development to the peptide was looked for and found to be of no clinical consequence.

Interactions. none of significance; it is not metabolised by cytochrome P450 and had no effect on ritonavir, saquinavir or rifampicin levels in studies.

Markers researchers commonly monitor

These follow HIV clinical practice; enfuvirtide adds few specific markers.

Marker	Why it's watched
HIV-1 RNA (viral load)	the direct measure of effect; a rebound while on the drug usually means gp41 resistance.
CD4 count	the clinical goal of therapy.
Genotypic resistance testing of gp41 (HR1 codons 36–45)	the specific test if virological failure occurs on enfuvirtide.
Injection-site inspection	the main tolerability issue; nodules, cellulitis and amyloid deposits are tracked by examination rather than labs.
Symptoms of bacterial pneumonia (fever, cough)	because of the pneumonia signal in TORO.
Eosinophils, liver enzymes	part of hypersensitivity work-up if rash or fever develop.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

This is the one approved peptide whose patients did at home: each 108 mg vial is dissolved in 1.1 mL sterile water to give 90 mg per mL; the powder can take up to 45 minutes to dissolve fully and must not be shaken (gently roll or tap). Draw up 1 mL and inject subcutaneously into the upper arm, thigh or abdomen, rotating sites and avoiding scars, moles or current reaction sites. Reconstituted vials can be refrigerated for up to 24 h. A needle-free gas-powered injector (Biojector 2000) was once used to reduce reactions but was associated with nerve pain and bruising. Supplies are now being withdrawn; this section is retained for reference only. The site calculator is not applicable.

6Commonly studied alongside

Optimised background antiretroviral therapy in every trial: protease inhibitors (darunavir, tipranavir, lopinavir/ritonavir), integrase inhibitors (raltegravir), CCR5 antagonists (maraviroc), nucleoside analogues. No peptide-community pairings exist. Newer long-acting HIV peptides and capsid inhibitors (lenacapavir) are the successor strategy, not combinations.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved (Fuzeon, March 2003). Genentech ended all US marketing and distribution on 28 February 2025; no generic exists, so the drug is effectively unavailable
European Union	EMA marketing authorisation held by Roche Registration GmbH (granted 27 May 2003) and still listed as authorised as of the last EMA page update; supply ended in France on 30 September 2025 and withdrawal of the EU authorisation is expected †
United Kingdom	MHRA-licensed; supply status following the Roche withdrawal †
Australia	TGA-registered historically (Fuzeon, Roche); current supply †
South Africa	Registered historically; not in national treatment guidelines; current status †
Sport	Not prohibited by WADA

8Open questions

Why bacterial pneumonia was more common in TORO has never been explained.
Whether the fusion-inhibitor mechanism will return in long-acting or orally bioavailable forms (several HR2-derived peptides and albumin-conjugated variants have been studied in China; albuvirtide is approved there).
Practical: how patients still on enfuvirtide in 2025–2026 are being transitioned as supply ends.

9References

1Wild CT et al. (1994). Peptides corresponding to a predictive α-helical domain of HIV-1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci USA. PubMed · DOI
2Kilby JM et al. (1998). Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med. PubMed · DOI
3Lalezari JP et al. (2003). Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America (TORO 1). NEJM. PubMed · DOI
4Lazzarin A et al. (2003). Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia (TORO 2). NEJM. PubMed · DOI
5Nelson M et al. (2005). Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr. PubMed · DOI
6Joly V et al. (2013). Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo). Antimicrob Agents Chemother. PubMed · DOI
7Genentech (19 August 2024). Statement: update on Fuzeon (enfuvirtide) in the United States. PubMed
8EMA. Fuzeon EPAR — product information (current). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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11Page history

30 Oct 2026Profile published — awaiting medical review

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