Also called enfuvirtide or Fuzeon, T-20 is something of an enigma among HIV treatments. It’s one of the most effective and technologically advanced drugs we have – something that is attested to by the numerous stories of positive people whose lives have literally been turned around after taking it. But it is administered by twice-daily injections, making it inconvenient and not appropriate for all patients. Because of this, its use is restricted almost exclusively to salvage therapy settings – often as a ‘last resort’ drug for people who have otherwise exhausted their treatment options.
The manufacturer of T-20, Roche, is understandably concerned that, after investing millions of dollars bringing the drug to market, only a handful of positive people are using it. The company is worried that concerns about patients’ abilities to manage the twice-daily injection routine are discouraging doctors from prescribing T-20 to people who might gain a benefit from the treatment, and perhaps risking treatment failure by holding T-20 back for too long.
But the question of when is the best time to start T-20 is a thorny one. We know that, whatever stage of HIV therapy you’re at, the best results come from starting on or switching to a treatment regimen made up of drugs you’ve never taken before, and to which there’s no pre-existing resistance or cross-resistance. Ideally, each new regimen should include drugs from a treatment class that has not been used before. But with just two HAART).”>drug classes – protease inhibitors and non-nucleosides – forming the basis of the vast majority of treatment regimens, this gives each patient just two bites of the treatment cherry – called ‘first-line’ and ‘second-line’ treatment – before treatment choices start to become more complex.
Eventually, some people end up needing ‘salvage’ treatment which, as the name suggests, involves using whatever tools are at hand to preserve health, and sometimes paying less attention to the rules that guide first and second-line regimens.
Somewhere into this spectrum – from first-line treatment to salvage – fits T-20. While the major clinical trials of T-20 were carried out in heavily pre-treated people using optimised background regimens often composed of ‘recycled’ treatments (which the participants had previously taken and/or were resistant to), the arrival of newer drugs presents the opportunity to use T-20 in a less of a ‘last-ditch’ fashion.
In recent clinical trials, patients taking experimental treatments such as tipranavir, darunavir (TMC-114) and CCR5 inhibitors had significantly better results if they also took T-20 during the trials – the so-called ‘Fuzeon effect’ (see graphic). With tipranavir and darunavir now available through special assistance schemes and other new drugs on-track to become available in the next few years, there is the prospect of inserting another step into the treatment spectrum, a ‘third line’ of intensified treatment with new agents and T-20, and delaying, perhaps inevitably, the need for a salvage approach.
As with any anti-HIV treatment, resistance to T-20 can develop if the drug is taken in a ‘sub-optimal’ way. If the viral load is not brought down to undetectable levels, the unsuppressed virus will evolve to become resistant to the treatments the individual is taken, and the viral load will start to rise. With T-20 being held in reserve as a last resort, there’s a risk that it will be added to an already-failing regimen, with limited effect and possibly the creation of T-20 resistance.
Making the decision about when to introduce T-20 is complex, Professor Christine Katlama, the head of the AIDS Clinical Research Unit at the Pitié-Salpêtrière Hospital in Paris, told the meeting, and simple recommendations are difficult to make due to different patient characteristics, CD4 count and individual treatment experience. Katlama argued that, as well as the objective of preventing disease progression, HIV treatment needs to help preserve the patient’s quality of life, and it needs to be acknowledged that any HIV treatment, with or without T-20, needs to be taken over many years to be effective.
For people living with HIV, the decision to start on T-20 can be a hard one. As well as the nuisance and pain of the daily injections, many positive people say that the prospect of taking such a ‘hard-core’ treatment provides a sudden indication that their medical condition has worsened.
In order to understand the barriers to starting treatment on T-20, in early 2005 Roche funded a study, called “Open Mind”, in which physicians and HIV-positive people in five European countries and the United States were interviewed about their experience with T-20 and attitudes towards it. The results were presented as posters at the 10th European AIDS Clinical Society (EACS) conference in November 2005.
While there are significant questions about this study – it generated a heated debate at the Sydney meeting – some of the statistics are striking. Among HIV-positive people who had taken eight or more previous antiretrovirals (the definition of ‘highly treatment experienced’ used for this study) only 10 percent were currently taking T-20, and less than 30 percent had ever discussed it with their doctor. But 76 percent of people not taking T-20 said they’d be likely to do so if their doctor recommended it, and most felt they could handle the complex routine of self-injecting.
Anecdotal and clinical evidence from people taking T-20 also shows that, despite the time-consuming and often painful process of daily injections, most people quickly adapt to the routine and are able to manage the self-administration process, and are surprisingly sanguine about the bruising, swelling and painful injection site reactions they have to endure, as long as the drug is having a clear clinical benefit.
Christine Katlama told the meeting that she works with patients to relieve their concerns about T-20, encouraging them to try the drug and agreeing at the outset that, if a clear clinical benefit isn’t seen within a reasonable period of time, the T-20 therapy can be stopped. Using this cooperative approach enables patients to start T-20 with the clear understanding that their decision can be reviewed if the process is too hard for them and that they aren’t necessarily signing up to use injectable therapies for the rest of their life.
“Putting the virus down at any point is clearly the best approach,” she said, “but we need to remember that treatment needs to be continued for decades.”
There is only limited clinical evidence available to date on stopping T-20 after the viral load has been reduced to undetectable levels, sparing the patient the injection process and downshifting to a less onerous maintenance regimen, then re-introducing the T-20 if the virus creeps up again. But anecdotally, this clearly is happening, and Katlama presented several case studies to support this approach.
Other developments also hold out the promise of reducing the barriers to T-20 treatment. Roche have successfully trialled a needle-free injection device (Bioject) with T-20. The Bioject device, not currently available in Australia, uses compressed air to deliver drugs through the skin, and is said to result in fewer painful injection site reactions. Roche have also trialled the use of narrower-gauge needles with T-20, and are currently comparing the Bioject with the two different needle gauges to see which approach works best.
Finally, the company which originally developed T-20, Trimeris, is working on several new compounds (notably TRI-999 and TRI-1144) with a view to reducing the number of injections required from twice a day to once or twice a week. Clinical trials on these compounds haven’t started yet, but the idea of more widespread use of fusion inhibitors in the future certainly isn’t far-fetched.
