Transcript Enfuvirtide for Drug-Resistant HIV Infection in North and

Enfuvirtide for DrugResistant HIV Infection
in North and South
America
Simon R. Bababeygy
Enfuvirtide (T-20)
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Enfuvirtide is the first "fusion
inhibitor" drug
Approved in 2003 as a medication
against HIV
injected twice daily
Resistance to Enfuvirtide can develop
quickly if it is taken by itself. Must
take with combination therapy so that
HIV mutates much more slowly
Enfuvirtide Structure
Mechanism of Action
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Attachment, coreceptor binding, and fusion.
CD4+ T lymphocytes express both CD4 and
suitable coreceptors on their surface
Viral envelope glycoprotein gp120
attaches to the CD4 receptor
Conformational change occurs in
gp120, allowing further association
with cellular coreceptors
Further conformational change with
viral envelope glycoprotein gp41,
inserting hydrophobic N-terminus
into the host cell membrane
HR2 domain folds back on itself and
associates with the second helical
structure, the HR1 domain
This “gp41 zipping” leads to
infection of the cell by fusion of the
viral and host cell membranes
Presence of a T-20 fusion inhibitor
Binding of the fusion inhibitor to
gp41
Prevents the successful completion
of gp41 zipping
Study Design
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6-week screening phase, followed by 48 week
treatment, with optional 48 extension treatment
4 week follow-up for safety
1st screening for med hx, plasma HIV-1 RNA,
genotype and phenotype resistance testing
2nd screening for plasma HIV-1 RNA and safety
assessment
Patients randomized to 2:1 ratio; allowed to add
Enfuvirtide if in control group
Study Population
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Older than 16 years old
At least 1 nucleoside RT inhibitor
At least 1 non-nucleoside RT inhibitor
At least 2 protease inhibitors
Ineligible if already received Enfuvirtide
treatment, experimental fusion inhibitor T-1249,
or both
Informed consent obtained from all patients
Study Medication
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Enfuvirtide (90mg) given twice daily by
subcutaneous injection into abdomen, anterior
thigh, or upper arm
Optimized background regimen included
tenofovir (nucleoside RT inhibitor), lopinavirritonavir (protease inhibitors), or both
Study Population
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501 patients in 48 centers in U.S., Canada, Mexico,
Brazil
491 (326 in Enfuvirtide and 165 in control [2:1])
used study medication at least once
Time to Virologic Failure, as of
Week 24
Outcomes
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Bacterial Pneumonia and Sepsis occurred more
frequently in the combined Enfuvirtide groups
Eosinophilia (increase in peripheral blood
eosinophilic leukocytes) occurred in greater
proportion of Enfuvirtide patients
Study allowed patients to access best possible
treatment options
Positive outcome mainly due to adherence of
treatment
Conclusions
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Looked at TORO 1 and supported by TORO 2
studies (Europe and Australia)
HIV-1 glycoprotein 41 is a viable target for
effective treatment of HIV-1 infection
Addition of Enfuvirtide to optimized
antiretroviral regimen provides immunologic
benefit through week 24 for patients with multidrug resistant HIV-1 infection