Entry and Fusion Inhibitors

Entry and fusion inhibitors prevent HIV from entering CD4 cells. They are reserved for multidrug-resistant HIV in treatment-experienced patients and are prescribed by HIV specialists. Maraviroc blocks the CCR5 co-receptor, enfuvirtide binds gp41 to stop membrane fusion, fostemsavir binds gp120 and stops attachment, and ibalizumab binds the CD4 receptor.

Related agent. Lenacapavir is a capsid inhibitor, not an entry inhibitor, with a long-acting subcutaneous formulation used in heavily treated patients and in prevention where licensed.

• Maraviroc: 300 mg twice daily. Acts only on CCR5-tropic virus, so a tropism assay is required. Dose 150 mg twice daily with strong CYP3A inhibitors (boosted protease inhibitors) and 600 mg twice daily with inducers such as efavirenz or etravirine.
• Enfuvirtide: 90 mg subcutaneously twice daily. Injection site reactions are common, so it is little used.
• Fostemsavir: 600 mg (extended-release) twice daily. For multidrug-resistant virus. QT prolongation.
• Ibalizumab: intravenous loading dose 2000 mg, then 800 mg every 2 weeks. Always with an optimised background regimen.
• Lenacapavir: oral lead-in followed by subcutaneous injection every 6 months for treatment; doses and licensing differ by country.

Indication. Failure of other classes with limited remaining active drugs. Use at least two, preferably three, fully active drugs; never add an entry inhibitor alone to a failing regimen.

Selection.

• Maraviroc if tropism testing shows CCR5-only virus and liver function is acceptable.
• Fostemsavir or ibalizumab for broad multidrug resistance with no other active options.
• Enfuvirtide when no alternative exists.

Dose adjustment.

• Kidney: maraviroc with strong CYP3A inhibitors is avoided in severe impairment because of postural hypotension; fostemsavir needs no adjustment in mild to moderate impairment.
• Liver: maraviroc needs caution and monitoring; avoid in severe disease.
• Children: maraviroc from 2 years by weight with the same interaction rules; others are limited.

Region. In East Africa, these agents are rarely available through public programmes; refer for specialist access.

Contraindications. Fostemsavir with strong CYP3A inducers (rifampicin, carbamazepine, phenytoin, St John's wort). Maraviroc needs caution in severe cardiovascular disease and liver disease.

Serious adverse effects. Maraviroc: hepatotoxicity (sometimes preceded by allergic features), postural hypotension, infection. Enfuvirtide: injection site reactions, hypersensitivity, bacterial pneumonia. Fostemsavir: QT prolongation, hepatitis B reactivation. Ibalizumab: immune reconstitution syndrome, rash.

Monitoring. Tropism testing before maraviroc; liver enzymes at baseline and during therapy; ECG with fostemsavir when other QT drugs are used; viral load at 4 and 8 weeks to confirm response.

Interactions. Maraviroc: protease inhibitors (reduce dose), efavirenz and rifampicin (increase dose). Fostemsavir: avoid with inducers; keep ethinylestradiol to 30 micrograms or less.

Special groups.

• Pregnancy: data are limited; use only when no alternative exists.
• Breastfeeding: insufficient data; specialist decision.

Referral and escalation. All patients require HIV specialist input.