HIV entry inhibitors

Two antiretroviral drugs have been developed that act as entry inhibitors, forming two separate classes; the fusion inhibitor enfuvirtide and the CCR5-receptor antagonist maraviroc.

Fusion inhibitors

Enfuvirtide (also known as T-20) is a synthetic 36-amino acid peptide analogue. It binds to HIV-1 gp41, interrupting the fusion reaction and preventing the virus from infecting the host cell. Enfuvirtide, is an injectable agent licensed for use in patients with multidrug resistant HIV based on two key trials.[33][34]The main disadvantage of enfuvirtide is the universal development of injection site reactions, which are unpleasant for the patient, and appear to be associated with skin sclerosis with long-term use. Enfuvirtide is administered at a dose of 90mg bd by subcutaneous injection. Dose adjustments are not required for food or renal or hepatic impairment.  Reported adverse effects include injection site reactions (pain, erythema, induration, nodules and cysts, pruritus, ecchymosis) in almost 100% of patients and an increased rate of bacterial pneumonia. A potentially life-threatening hypersensitivity reaction occurs uncommonly (< 1% of patients) and may include rash, fever, nausea, vomiting, chills, rigors, hypotension, or elevated serum transaminases. Rechallenge is not recommended.

CCR5 inhibitors

The development of CCR5 inhibitors arose from the recognition that CCR5 is a key cell-surface receptor for HIV,[35] at least early in the disease, and that absence of CCR5 expression resulting from a homozygous 32 base pair deletion in the CCR5 gene (delta 32 homozygosity) was associated with protection against HIV infection.[36] Moreover, people with reduced levels of CCR5 expression (delta 32 heterozygotes) have an attenuated disease course with lower HIV viral loads.[36]

CCR5 inhibitors lock CCR5 into a conformation that render it incapable of binding HIV envelope proteins. Maraviroc is the only CCR5 inhibitor available in Australia. It is effective in patients whose virus utilises CCR5 for cell entry (R5 tropic) and testing of the patient’s HIV for tropism for CCR5 is essential before the use of this drug.[37][38]There is no virological efficacy in patients with CXCR4 (X4) or dual tropic HIV. A guide to dosing of maraviroc can be found in Table 7. Reported adverse effects of maraviroc are abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, skin rash, upper respiratory tract infections, hepatotoxicity and orthostatic hypotension, especially in patients with severe renal insufficiency.

 Table 7. Guidelines on dosing of CCR5 inhibitors

Drug (dose per tablet)


Food requirement

Dose adjustment for renal impairment

Dose adjustment for hepatic impairment

Maraviroc  (150mg and 300mg)

·        150 mg bd when given with all PI/r except tipranavir/r

·        300 mg bd when given with NRTIs, enfuvirtide, NVP, tipranavir/r, raltegravir and other non-potent CYP3A inhibitors or inducers

·        600 mg bd when given with CYP3A inducers including efavirenz and etravirine


Complex. If CrCL < 30mL/min:

·        Without potent CYP3A inhibitors or inducers, > 300 mg bd; reduce to 150 mg bd if postural hypotension occurs

·        With potent CYP3A inducers or inhibitors - not recommended

Concentration likely to be increased in hepatic impairment

bd: twice daily; CrCL: creatinine clearance; CYP3A: hepatic cytochrome p450 enzyme 3A; PI/r: protease inhibitor boosted with ritonavir; NRTI: nucleoside reverse transcriptase inhibitor