1. Enfuvirtide for Drug-Resistant HIV Infection in North and South America
Simon R. Bababeygy

2. Enfuvirtide (T-20) 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

3. Enfuvirtide Structure

4. Mechanism of Action
Attachment, coreceptor binding, and fusion. CD4+ T lymphocytes express both CD4 and suitable coreceptors on their surface

5. Viral envelope glycoprotein gp120 attaches to the CD4 receptor

6. Conformational change occurs in gp120, allowing further association with cellular coreceptors

7. Further conformational change with viral envelope glycoprotein gp41, inserting hydrophobic N-terminus into the host cell membrane

8. HR2 domain folds back on itself and associates with the second helical structure, the HR1 domain

9. This “gp41 zipping” leads to infection of the cell by fusion of the viral and host cell membranes

10. Presence of a T-20 fusion inhibitor

11. Binding of the fusion inhibitor to gp41

12. Prevents the successful completion of gp41 zipping

13. Study Design
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

14. Study Population 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

15. Study Medication
Enfuvirtide (90mg) given twice daily by subcutaneous injection into abdomen, anterior thigh, or upper arm
Optimized background regimen included tenofovir (nucleoside RT inhibitor), lopinavir-ritonavir (protease inhibitors), or both

16. Study Population
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

19. Time to Virologic Failure, as of Week 24

21. Outcomes
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

22. Conclusions
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 multi-drug resistant HIV-1 infection