Enfuvirtide (T-20): predicting success and modelling survival benefits
Graeme Moyle, NATAP
Enfuvirtide (Fuzeon, formerly T-20) has been evaluated into randomised, comparative studies in which individuals who have been experienced with all three approved drug classes were given a new antiretroviral regimen optimised by the use of resistance testing with or without enfuvirtide in a 2:1 ratio.
Both studies, known as TORO 1&2, demonstrated substantial virological and immunological advantage to including enfuvirtide in the new treatment regimen. Characteristics associated with treatment response in the Toro 1 study were recently reported at the ICAAC conference. A similar analysis of the Toro 2 study was presented at the Glasgow conference. In Toro 2, 335 individuals received enfuvirtide with optimised background therapy and 169 individuals received optimised background therapy alone. The changing baseline viral load over 24 weeks was -1.43 log in the enfuvirtide recipients and -.65 in those who received optimised background alone. This advantage of 0.78 log was highly statistically significant (p<0.0001). Enfuvirtide recipients experienced a rise of 65 CD4 cells compared with just 38 in the control group. The number of individuals who reached a viral load less than 400 copies was 28% in the end for the enfurtide group and 14% in the control group, with 12% and 5% respectively achieving less than 50 copies/ml.
Subgroup analyses indicated that the benefits of the enfuvirtide were consistently observed in both male and female, white and non-white and all patients that were older and younger than 40 years of age. Of note, individuals who entered the study with an age less than 40 years experienced a more modest and not statistically significant advantage for enfuvirtide relative to background therapy alone, whereas in individuals who entered the trial with an age greater than 40 years, a greater and statistically significant advantage was observed.
When groups were stratified by baseline viral load less than or greater than 40,000 copies/ml and by baseline CD4 less than or greater than 100 cells/mm3, significant and consistent advantages to enfuvirtide over optimised background therapy alone were observed.
Using resistance information derived from baseline samples patients were given genotypic and phenotypic sensitivity scores whereby a score of one was given for every drug included in the optimised background that was likely to be active in the regimen. Individuals with a genotypic sensitivity score of two or more achieved the greatest reductions in viral load from baseline. However, individuals randomised to enfuvirtide had consistently larger reductions in viral load from baseline relative to those who only received optimised background regardless of the genotypic sensitivity score. Similar benefits were seen when evaluating the phenotypic sensitivity scores, although individuals with phenotypic sensitivity scores of three or more in the optimised background therapy group in this analysis achieved similar responses to the enfuvirtide group, whereas the enfuvirtide group had significant advantage in those individuals entering the study with a phenotypic sensitivity score of two or less.
As reported in the analysis of the Toro 1 study, individuals naïve to Kaletra at baseline achieved larger reductions in viral load than those with prior Kaletra experience. When stratifying individuals by prior Kaletra experience, individuals randomised to enfuvirtide had significantly greater reductions in viral load from baseline both in individuals naïve to Kaletra and experienced with Kaletra at entry to the study.
In a multiple regression analysis investigating factors associated with the change in viral load from baseline to week 24, inclusion of enfuvirtide in the regimen was associated with an estimated 0.8 log reduction in viral load, factors including lower baseline viral load, higher baseline CD4 count, phenotypic or genotypic sensitivity score indicating greater number of active drugs in the optimised background regimen, and better adherence were associated with 0.1 to 0.3 log reductions in viral load. Individuals with prior Kaletra experience were estimated to have a 0.86 log smaller reduction in viral load than those naïve to Kaletra at study entry.
These subgroup analyses of the TORO 1 and 2 studies provide useful practical guidance as to how we should use enfuvirtide in clinical practice. The studies indicate that the best responses to a regimen containing enfuvirtide are seen in individuals with at least two and preferably three active agents to include in the accompanying regimen, and that treatment response may also be better if commenced with a relatively lower viral load and a higher CD4 count. Support for adherence appears critical, with a 10% increase in adherence in the Toro 2 study being associated with an estimated 0.11 log greater reduction in viral load. There are also issues about the use of Kaletra raised by the studies. If being naive to Kaletra at the time of initiation of enfuvirtide is truly critical to achieving the greatest virological response to an enfuvirtide containing regimen, then physicians may need to consider “saving” Kaletra for the time in the treatment sequence that they may plan to use enfuvirtide.
Results from the Toro 1 and 2 studies were placed in a complex mathematical model to estimate the advantage of enfuvirtide relative to optimised background therapy alone in delaying the time to development of an AIDS defining event or death. The model suggested that inclusion of enfuvirtide in the regimen would delay the development of a new AIDS defining event by approximately 1.5 years (from 3.3 years in the optimised background regimen to 4.8 years in the enfuvirtide containing regimen) and increase overall survival by 1.6 years (from 4.8 years in the optimised background alone regimen to 6.2 years in the enfuvirtide containing regimen). This information suggests that enfuvirtide is likely to be a highly cost-effective therapy and that it is likely to buy not only years of good quality (due to the prevention of new AIDS defining illnesses) but also time for new treatment options to become available.
Lange J et al. Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs OB alone: week 24 response among categories of baseline (BL) demographics, treatment experience, and HIV antiretroviral (ARV) resistance. 6th International Congress on Drug Therapy in HIV Infection 17-21 November 2002, Glasgow, UK. Abstract PL14.3