Enfuvirtide for Enfuvirtide for Drug-Resistant HIV Drug-Resistant HIV Infection in North Infection in North and South Americaand South America

Simon R. BababeygySimon R. Bababeygy

Enfuvirtide (T-20)Enfuvirtide (T-20) Enfuvirtide is the first "fusion Enfuvirtide is the first "fusion

inhibitor" druginhibitor" drug Approved in 2003 as a Approved in 2003 as a

medication against HIV medication against HIV injected twice dailyinjected twice daily Resistance to Enfuvirtide can Resistance to Enfuvirtide can

develop quickly if it is taken develop quickly if it is taken by itself. Must take with by itself. Must take with combination therapy so that combination therapy so that HIV mutates much more HIV mutates much more slowlyslowly

Enfuvirtide StructureEnfuvirtide Structure

Mechanism of ActionMechanism of Action Attachment, coreceptor binding, Attachment, coreceptor binding,

and fusion. CD4+ T lymphocytes and fusion. CD4+ T lymphocytes express both CD4 and suitable express both CD4 and suitable coreceptors on their surfacecoreceptors on their surface

Viral envelope glycoprotein Viral envelope glycoprotein gp120 attaches to the CD4 gp120 attaches to the CD4

receptorreceptor

Conformational change Conformational change occurs in gp120, allowing occurs in gp120, allowing further association with further association with

cellular coreceptorscellular coreceptors

Further conformational Further conformational change with viral envelope change with viral envelope

glycoprotein gp41, glycoprotein gp41, inserting hydrophobic N-inserting hydrophobic N-

terminus into the host cell terminus into the host cell membranemembrane

HR2 domain folds back on HR2 domain folds back on itself and associates with itself and associates with

the second helical the second helical structure, the HR1 domainstructure, the HR1 domain

This “gp41 zipping” leads This “gp41 zipping” leads to infection of the cell by to infection of the cell by

fusion of the viral and host fusion of the viral and host cell membranescell membranes

Presence of a T-20 fusion Presence of a T-20 fusion inhibitorinhibitor

Binding of the fusion Binding of the fusion inhibitor to gp41inhibitor to gp41

Prevents the successful Prevents the successful completion of gp41 zippingcompletion of gp41 zipping

Study DesignStudy Design 6-week screening phase, followed by 48 6-week screening phase, followed by 48

week treatment, with optional 48 week treatment, with optional 48 extension treatmentextension treatment

4 week follow-up for safety4 week follow-up for safety 11stst screening for med hx, plasma HIV-1 screening for med hx, plasma HIV-1

RNA, genotype and phenotype resistance RNA, genotype and phenotype resistance testingtesting

22ndnd screening for plasma HIV-1 RNA and screening for plasma HIV-1 RNA and safety assessmentsafety assessment

Patients randomized to 2:1 ratio; allowed Patients randomized to 2:1 ratio; allowed to add Enfuvirtide if in control groupto add Enfuvirtide if in control group

Study PopulationStudy Population Older than 16 years oldOlder than 16 years old At least 1 nucleoside RT inhibitorAt least 1 nucleoside RT inhibitor At least 1 non-nucleoside RT inhibitorAt least 1 non-nucleoside RT inhibitor At least 2 protease inhibitorsAt least 2 protease inhibitors Ineligible if already received Enfuvirtide Ineligible if already received Enfuvirtide

treatment, experimental fusion inhibitor treatment, experimental fusion inhibitor T-1249, or bothT-1249, or both

Informed consent obtained from all Informed consent obtained from all patientspatients

Study MedicationStudy Medication Enfuvirtide (90mg) given twice daily Enfuvirtide (90mg) given twice daily

by subcutaneous injection into by subcutaneous injection into abdomen, anterior thigh, or upper abdomen, anterior thigh, or upper arm arm

Optimized background regimen Optimized background regimen included tenofovir (nucleoside RT included tenofovir (nucleoside RT inhibitor), lopinavir-ritonavir inhibitor), lopinavir-ritonavir (protease inhibitors), or both(protease inhibitors), or both

Study PopulationStudy Population

501 patients in 48 centers in U.S., Canada, 501 patients in 48 centers in U.S., Canada, Mexico, BrazilMexico, Brazil

491 (326 in Enfuvirtide and 165 in control 491 (326 in Enfuvirtide and 165 in control [2:1]) used study medication at least once[2:1]) used study medication at least once

Time to Virologic Failure, Time to Virologic Failure, as of Week 24as of Week 24

OutcomesOutcomes Bacterial Pneumonia and Sepsis occurred Bacterial Pneumonia and Sepsis occurred

more frequently in the combined more frequently in the combined Enfuvirtide groupsEnfuvirtide groups

Eosinophilia (increase in peripheral blood Eosinophilia (increase in peripheral blood eosinophilic leukocytes) occurred in eosinophilic leukocytes) occurred in greater proportion of Enfuvirtide patientsgreater proportion of Enfuvirtide patients

Study allowed patients to access best Study allowed patients to access best possible treatment optionspossible treatment options

Positive outcome mainly due to Positive outcome mainly due to adherence of treatmentadherence of treatment

ConclusionsConclusions Looked at TORO 1 and supported by Looked at TORO 1 and supported by

TORO 2 studies (Europe and Australia)TORO 2 studies (Europe and Australia) HIV-1 glycoprotein 41 is a viable target HIV-1 glycoprotein 41 is a viable target

for effective treatment of HIV-1 infectionfor effective treatment of HIV-1 infection Addition of Enfuvirtide to optimized Addition of Enfuvirtide to optimized

antiretroviral regimen provides antiretroviral regimen provides immunologic benefit through week 24 for immunologic benefit through week 24 for patients with multi-drug resistant HIV-1 patients with multi-drug resistant HIV-1 infectioninfection