Induction/maintenance approach revived – but will patients stick with it?

In the early years of the protease inhibitor era, there was much interest in an approach called induction/maintenance – starting with three or four drugs and stepping down to one or two after viral load had been controlled. Results were disappointing and the approach fell into disuse. At this week’s Ninth European AIDS Conference, results of a trial called TIME showed that drug companies at least have not given up on the idea of induction/maintenance. Whether it will suit patients is another question.

24 week results from the induction phase of the TIME study (it stands for Trizivir Induction Maintenance in Europe) were presented on Monday by Dr Margaret Johnson of the Royal Free Hospital in London. During the induction phase all 377 patients received Trizivir (a combination tablet containing abacavir, 3TC and AZT) twice daily and efavirenz once daily. After the 24 week induction phase, participants are randomised to drop efavirenz immediately, continue with Trizivir/efavirenz for a further 24 weeks before dropping efavirenz or to maintain Trizivir/efavirenz for the full 48 week follow-up period.

The population recruited to this study had relatively advanced HIV disease, with an average viral load of around 85,000 copies/ml (4.95 log₁₀ copies/ml) and an average CD4 cell count of 230 cells/mm3. 49% had viral load above 100,000 copies/ml.

After 24 weeks of treatment, 64% had viral load below 50 copies by intent to treat, switch equals failure analysis. This means that any switch from the initially assigned drugs was counted as a treatment failure (although the protocol was subsequently amended to allow a switch from efavirenz to nevirapine). 19% discontinued treatment due to adverse events, of which nearly half (9%) were hypersensitivity reactions.

Although this discontinuation rate may overestimate the true incidence of hypersensitivity reaction because of the strict requirement to discontinue therapy in any patient with signs that might indicate hypersensitivity, the rate of discontinuations due to central nervous system toxicities was not driven by any strict protocol definition. Twenty six of the 73 patients who discontinued therapy cited central nervous system toxicity as the reason for stopping efavirenz, even though only 2% of trial participants (7 patients) had grade 3 or 4 sleep disturbance. The extent to which the protocol change midway through the study might have minimised the rate of discontinuation amongst later study entrants able to switch from efavirenz to nevirapine was not addressed in the presentation.

These findings suggest that combining abacavir with efavirenz does not make for a easy ride. As this year’s BHIVA guidelines have made clear, there are now enough drugs available with well understood toxicities. It really shouldn’t be necessary to combine two with well known problematic side effects, particularly in a study seeking to test the acceptability of a more intense initial regimen in patients with advanced HIV disease.

In response to a question on why much higher discontinuation rates should have been seen in this study compared with ACTG 5095, Dr Margaret Johnson pointed out that the TIME study had recruited a more advanced population. Patients with higher viral loads at baseline had tended to withdraw more frequently due to adverse events, she said, adding, “When patients are less well, they tend to tolerate therapy less well.”

Virologic failure was not a major problem in this study; 15 patients (4%) experienced virologic failure (viral load above 50 copies at week 24), and genotyping was possible in six of these cases. It revealed two wild type viruses, two K103N mutations associated with efavirenz resistance, one M184V associated with 3TC/abacavir, and one virus isolate with dual resistance (K103N and M184V).