In phase III clinical studies HIV recombinants containing the env genes from HIV RNA samples taken up to week 24 from 187 patients showed > 4 fold reduced susceptibility to enfuvirtide compared with the corresponding pre-treatment samples. Of these, 185 (98.9%) env genes carried specific substitutions in region of aa 36 - 45 of gp41. The substitutions observed in decreasing frequency were at aa positions 38, 43, 36, 40, 42 and 45. Specific single substitutions at these residues in gp41 each resulted in a range of decreases from baseline in recombinant viral susceptibility to enfuvirtide. The geometric mean changes ranged from 15.2 fold for V38M to 41.6 fold for V38A. There were insufficient examples of multiple substitutions to determine any consistent patterns of substitutions or their effect on viral susceptibility to enfuvirtide. The relationship of these substitutions to in vivo effectiveness of enfuvirtide has not been established. Decrease in viral sensitivity was correlated to the degree of pre-treatment resistance to background therapy (see Table 6).
Cross-resistance: Due to its novel viral target enfuvirtide is equally active in vitro against both wild-type laboratory and clinical isolates and those with resistance to 1, 2 or 3 other classes of antiretrovirals (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors). Conversely, mutations in aa 36-45 of gp41 which give resistance to enfuvirtide would not be expected to give cross resistance to other classes of antiretrovirals.
Clinical Pharmacodynamic data
Studies in Antiretroviral Experienced Patients: The clinical activity of Fuzeon (in combination with other antiretroviral agents) on plasma HIV RNA levels and CD4 counts have been investigated in two randomised, multicentre, controlled studies (TORO 1 and TORO 2) of Fuzeon of 48 weeks duration. 995 patients comprised the intent-to-treat population. Patient demographics include a median baseline HIV-1 RNA of 5.2 log10 copies/ml and 5.1 log10 copies/ml and median baseline CD4 cell count of 88 cells/mm3 and 97 cells/mm3 for Fuzeon + OB and OB, respectively. Patients had prior exposure to a median of 12 antiretrovirals for a median of 7 years. All patients received an optimised background (OB) regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance measurements.
The proportion of patients achieving viral load of <400 copies/ml at week 48 was 30.4% among patients on the Fuzeon + OB regimen compared to 12% among patients receiving OB regimen only. The mean CD4 cell count increase was greater in patients on the Fuzeon + OB regimen than in patients on OB regimen only (see Table 5).
Table 5 Outcomes of Randomised Treatment at Week 48 (Pooled Studies TORO 1 and TORO 2, ITT)
Outcomes
Fuzeon + OB
90 mg bid
(N=661)
OB
(N=334)
Treatment Difference
95% Confidence Interval
p-value
HIV-1 RNA
Log Change from baseline (log10 copies/ml)*
-1.48
-0.63
LSM
-0.85
-1.073, -0.628
<.0001
CD4+ cell count
Change from baseline (cells/mm3)#
+91
+45
LSM
46.4
25.1, 67.8
<.0001
HIV RNA ≥1 log below Baseline**
2
