An intense course of HIV treatment lasting no more than six to ten months may be enough to set the stage for long-term maintenance with fewer drugs, and that it may be best to start this intensified treatment several days or weeks after beginning the drugs that will form the maintenance regimen, according to a mathematical modelling study published in the July edition of PLoS Computational Biology.
Although the findings of the study are conventional in their prediction of the need for an induction period lasting up to a year, the idea of intensifying treatment after starting the maintenance regime is new. Called `booster` therapy by the authors, it would employ a completely different set of drugs from the underlying `maintenance` regime, and might be started as much as 40 days after maintenance treatment.
The shorter the intensified treatment phase, the more appropriate it would be to start intensified treatment after maintenance treatment, the authors say.
“[Booster therapy] results in higher eradication rates because drug-resistant viral populations are predicted to decline transiently after the start of maintenance therapy.” Meanwhile, viruses resistant to the maintenance regimen are suppressed during this second-decay phase of treatment because viral load is suppressed even further, and so drug-resistant viruses are prevented from infecting the emergent population of cells that might support these fast-replicating viruses.
By eradicating as many viruses resistant to the maintenance regime as possible at this stage, `booster` treatment limits the population available to undermine maintenance treatment after the booster regime is discontinued.
The model is based on the potential for the development of resistance to three-drug therapy, and assumes that high-level resistance could develop to two of the three drugs, while partial resistance to the third drug could emerge. This reflects the typical patterns of resistance seen after the failure of regimens containing efavirenz, 3TC and tenofovir or AZT, the most commonly prescribed first-line regimens in many countries.
The model assumes that viral load decays in two phases: the first, faster phase lasts ten days, the second – during which viral load falls below 50 copies – last 120 days. Decay of the virus population in latently infected cells begins around day 200.
The model also assumes that drug-resistant viruses have less fitness than drug-sensitive ones, and therefore don’t replicate as well.
But the authors say that one of the major limitations of the model is predicting accurately how large the viral population is, and how quickly the moderately long-lived HIV-infected cells of the immune system die off.
They say that the proposed model of treatment may be particularly relevant for resource-limited settings where drug options are limited, since it could reduce the risk of first-line treatment failure.
“Our experience has been that clinicians and policy makers are often hesitant to consider, sometimes even hostile towards, mathematical modeling approaches. Instead, they rely on intuition or await the results of expensive, long-term clinical trials,” said John Mittler of the University of Washington, Seattle, one of the paper’s authors.
Curlin ME et al. Optimal timing and duration of induction therapy for HIV-1 infection. PLoS Computational Biology 3 (7): e133, 2007. doi:10.1371/journal.pcbi.0030133