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  12th Conference on Retroviruses and Opportunistic Infections (CROI)
Feb 22-25, 2005
Boston, MA
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Enfuvirtide (ENF, T-20) Resistance, fast and pretty complete, studies from 12th CROI
  Written for NATAP by Nancy Shulman, MD, Stanford University
Enfuvirtide (ENF) is the first and only fusion inhibitor licensed for the treatment of HIV infection. Unfortunately, administration requires twice daily injection and frequently is accompanied by local injection site reactions, and costs about $20,000 per year for treatment due to the difficulties in manufacturing the drug. Although we know that mutations in the HR1 (heptad repeat - 1) region of HIV gp41 (amino acids 36-45) are associated with ENF resistance. Until now, little was reported on how fast these mutations develop in patients on treatment, how many mutations are required for resistance, and whether ENF is providing any benefit in patients with detectable virus and documented ENF resistance. In the 12th CROI there were several studies presented addressing ENF resistance.
Dynamics of ENF resistance:
Beatty, et al, presented a study of 30 multidrug-resistant, ENF-naive patients who were randomized to receive ENF + optimized background regimen right away or following a 4 month treatment interruption. There were no differences between the immediate treatment vs. interruption/treatment group in the primary outcome of week 24 virologic suppression from baseline: 53% vs. 36%, p non significant. In other words, interrupting therapy did not improve response to Fuzeon containing therapy. Only the number of susceptible drugs in the background regimen, determined by a phenotypic susceptibility score was predictive of a response. As has been shown in most other ENF studies to date, baseline ENF susceptibility is quite variable and is not predictive of a response to ENF based therapy.
A more important finding in this study was the rapid development of resistance to Fuzeon. They observed the viral dynamics of patients failing ENF on the study and found that most patients experienced rapid viral rebound towards baseline within 4-8 weeks of therapy (similar to what we see with NNRTIs and 3TC). When they sequenced the patients at the earliest timepoints (2 - 4 weeks), most had HR1 mutations. There was a sustained increase in CD4 counts in these patients despite rapid virologic rebounds, at least through the relatively short 24 weeks of observation.
Cabrera, et al, reported resistance evolution of 15 patients on non-suppressive regimens that contained ENF. All patients had an initial viral load reduction with the new ENF based regimen at 4 weeks that rapidly rebounded toward baseline in almost all patients, similar to the Beatty study. All patients had HR1 mutations detectable by 2-4 weeks of ENF treatment.
What happens if you stop the ENF in these partially suppressed, ENF-resistant patients? Leave it to Deeks, et al, at UCSF, the originators of "partial treatment interruption" strategy to address this question. This is particularly important question with the high cost of ENF. They had previously found in small uncontrolled studies of treatment interruption that NRTIs retain activity, but PIs and NNRTIs tend to have little activity once a substantial amount of resistance is present. What about ENF?
They enrolled only 22 patients who were failing treatment that included ENF and had HIV RNA levels of >400 copies for 4 weeks and were judged to be adherent. Patients had received a median of 29 weeks of ENF, and had high baseline viral loads, with a median of 5 logs (100,000 copies/ml). Median CD4 at baseline was 89. Patients discontinued ENF and remained on the other drugs in the regimen. The median observation period was 24 weeks (IQR 18-36 weeks). At 2 weeks and 4 weeks, the median viral loads had increased by a mere 0.11 log (SD 0.27) and 0.27 log (SD 0.56) copies compared with the baseline values, p=0.3 and 0.05, respectively.
They sequenced multiple clones at each time in all patients and found HR1 mutations in all but 1 patient at baseline, which decreased in proportion over time and were no longer detectable by week 16, confirming a relative fitness disadvantage for ENF resistant vs. wild-type GP41 in the absence of ENF.
Although there was an antiretroviral and fitness benefit of ENF in these ENF resistant patients, the affect was pretty small compared with the 0.5 logs that have been seen in most of the nucleoside withdrawal studies, and argues in favor of stopping ENF in these resistant patients. The obvious shortcomings of the study as with all of the partial treatment interruption studies to date are the lack of controls and the small size of the study.
So in summary, use ENF with other active drugs where you can (like boosted tipranavir), consider saving it if you can't construct a regimen with a reasonable chance of suppression, and consider discontinuing it if the patients have detectable virus on ENF. This also brings into question the utility of adding gp41 sequencing to standard RT and protease sequencing for patient management. It appears that like 3TC and the NNRTIs, if you are on the drug and have detectable virus, you can assume resistance without sequencing. By the way, Fuzeon phenotypic susceptibility re-emerged by 16 weeks after Fuzeon was interrupted in most subjects & this correlated with a median increase in fitness. As well, Fuzeon discontinuation was associated with loss of Fuzeon mutations.
Ed note from Jules Levin: so, why did significant viral rebound occur in one study above after stopping Fuzeon but not in the Deeks study? The answer does not appear obvious, but perhaps this is due to which Fuzeon mutations are present, and the other drugs in the regimen and the resistance to those drugs. References:
1. Beatty, et al. Randomized pilot study of immediate enfuvirtide-based therapy vs. a treatment interruption followed by enfuvirtide-based therapy in highly treatment-experienced patients. Abstract 581. 12th CROI
2. Cabrera, et al. Genotypic evolution of T-20 resistance-associated mutations in heavily treated HIV-infected patients on long-term treatment with T-20. Abstract 718. 12th CROI.
3. Deeks, et al. Interruption of enfuvirtide in patients with enfuvirtide resistance. Abstract 680. 12th CROI.