Providing that a patient’s virus is fully susceptible to one drug in a new combination, introducing a new salvage regimen after a five month treatment interruption is likely to result in sustained virologic suppression, according to a study reported in the latest edition of AIDS.
Dr Steven Deeks of San Francisco General Hospital followed 24 patients in a prospective study designed to test the response to a new regimen after a treatment interruption of at least 12 weeks. All patients had viral load above 2,500 copies/ml at baseline and 12 months of prior protease inhibitor experience. Patients were encouraged to resume therapy if they experienced viral load rebounds of more than 1 log, or CD4 cell count declines of more than 50%.
Drug sensitivity was tested during the treatment interruption to evaluate how many patients regained susceptibility to particular agents and so aid selection of the new salvage regimen.
At the time of treatment interruption, participants had a median CD4 cell count of 218 cells/mm3, and a median viral load of 4.6 log copies/ml.
Nineteen participants resumed therapy with a regimen containing a ritonavir-boosted protease inhibitor and a non-nucleoside reverse transcriptase inhibitor (NNRTI). Nine were NNRTI-naïve.
After 48 weeks on the new regimen, the average viral reduction was –2 log10 copies/ml, and 63% sustained viral load below 200 copies/ml (undetectable) for a median of 98 weeks.
Participants had substantial resistance to all drugs in all classes at baseline, but after a median treatment interruption of twenty weeks, 20 patients experienced improvements in drug susceptibility, to such an extent that the median drug susceptibility for all drugs could once more be classified as `sensitive`.
Drug susceptibility was strongly correlated with response to the new regimen. Response was analysed in relation to phenotype in the 20 patients who experienced improvements in drug susceptibility. All nine patients who were fully susceptible to at least one drug in the new regimen had a sustained response to treatment; five of these patients were receiving an NNRTI for the first time. Four of five patients who were fully susceptible to two or more agents had a sustained response.
In the remaining seven patients who had experienced improvements in drug susceptibility, failure was associated with the re-emergence of resistance mutations that had been archived prior to the treatment interruption.
“Patients who initiated a subsequent salvage regimen generally did well, particularly if they were able to construct a salvage regimen containing a therapeutic class to which they were treatment naïve”, the authors say. “Patients who have only one remaining therapeutic option may be the most likely to benefit.”
The findings provide an interesting counterpoint to the recent secondary analyses of TORO 1 and 2, the international studies that looked at the addition of enfuvirtide (T-20) to a background regimen optimised by phenotypic resistance testing. Both analyses found that virologic response was strongly correlated with the number of active agents in the background regimen, with a relatively modest response seen in patients who had less than two active agents. Full data on baseline susceptibility to individual agents in the TORO 1 and 2 studies that might assist comparison with the San Francisco study are still to be presented, but Dr Deeks is interested in exploring the use of structured treatment interruptions to improve the response to a T-20 containing regimen in highly treatment-experienced patients.
Dr Deeks told aidsmap: "We are currently conducting a randomized study of patients with highly
resistant HIV who need to initiated T-20. Given the limited activity of T-20
in patients with high level resistance to the other three therapuetic
classes, and our pilot STI data, we believe that those patients who have no
remaining options except T-20 will benefit from a treatment interruption. We
are therefore enrolling individuals into a study in which they are
randomized to an optimal treatment regimen plus T-20 versus a 16 week STI
followed by an optimal regimen plus T-20."
Deeks SG et al. Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response. AIDS 17: 361-370, 2003.