Immunologic benefits of enfuvirtide in patients enrolled in a drug assistance program
ABSTRACT Randomized clinical trials have demonstrated that enfuvirtide plus an optimized background regimen can cause a significant increase in CD4+ cell counts and a reduction in HIV RNA levels.
To describe and analyze CD4+ cell count and HIV RNA changes in HIV-infected patients receiving enfuvirtide and a prescribed background regimen (PBR) in a primarily clinical setting.
A retrospective review from September 1998 through August 2005 of CD4+ cell counts and HIV RNA changes from baseline was conducted in patients receiving enfuvirtide. Data were stratified and analyzed according to baseline CD4+ cell count and HIV RNA.
A mean CD4+ cell count increase of approximately 102 cells/mm(3)was observed, regardless of baseline CD4+ cell count, in 187 patients receiving enfuvirtide during a mean of 19.4 months of follow-up. During 3 years of follow-up, patients initiating enfuvirtide at CD4+ cell counts less than 100 cells/mm(3)never achieved absolute CD4+ cell counts comparable to the counts in patients starting enfuvirtide at CD4+ cell counts of 100 cells/mm(3)or more. In 38.3% of patients achieving an undetectable HIV RNA level, a mean CD4+ cell count increase of 185 cells/mm(3)was observed. An unexpected finding was that a mean CD4+ cell count increase of 76 cells/mm(3)occurred in 61.7% of patients not achieving complete viral suppression.
Immunologic benefits were observed in subjects continuing enfuvirtide plus a PBR irrespective of baseline CD4+ cell count, complete viral suppression, or antiretroviral susceptibility data. Data suggest that initiation of enfuvirtide at CD4+ cell counts greater than 100 cells/mm(3)may be immunologically advantageous and independent of complete virologic response.
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ABSTRACT: In previous studies on mechanisms of HIV-1-mediated pathogenesis we showed that bystander apoptosis mediated by cell surface-expressed HIV-1 Env correlated with the fusogenic properties of the gp41 subunit of Env. A crucial step in HIV gp41-mediated fusion is the refolding of the protein into a six-helix bundle along the N- and C-terminal coiled-coil domains. These domains have been targeted by peptide inhibitors that inhibit gp41-mediated fusion. One of these inhibitors, enfuvirtide, is the first such drug approved for therapy. More recently, clinical data suggest that the beneficial effects of enfuvirtide extend beyond virus suppression and are associated with certain resistance mutations in gp41. In this study we characterized the bystander apoptosis-inducing potential of mutants associated with increased CD4 counts that arise during enfuvirtide therapy. Whereas all mutant clones were reduced in both cell-to-cell fusion activity and apoptosis induction there was limited effect on virus infection or replication. The viruses were found to have apoptosis-inducing activity in the order WT > V38M > V38A > G36D > V38E, which correlated with cell-to-cell fusion but not infection. Interestingly, the level of resistance as determined by the IC(50) of enfuvirtide also correlated inversely with both cell fusion and apoptosis in that the most resistant Envs were the least fusogenic and pathogenic. This suggests the beneficial effects of enfuvirtide therapy beyond virus suppression may be mediated by selecting less pathogenic HIV isolates over time.AIDS research and human retroviruses 08/2009; 25(8):811-7. DOI:10.1089/aid.2009.0010 · 2.46 Impact Factor
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ABSTRACT: Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. Objective: To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). Multicenter, retrospective cohort study. The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm( 3) (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm(3) (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression.Journal of the International Association of Physicians in AIDS Care (JIAPAC) 12/2010; 9(6):382-9. DOI:10.1177/1545109710382041