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

Enfuvirtide for Drug-Resistant HIV Infection in North and South America. Simon R. Bababeygy. Enfuvirtide (T-20). Enfuvirtide is the first "fusion inhibitor" drug Approved in 2003 as a medication against HIV injected twice daily

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

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  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

  17. Time to Virologic Failure, as of Week 24

  18. 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

  19. 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

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