Salvage therapy may work better after a drug holiday

A randomised trial investigating the effects of a treatment interruption in people starting a multi-drug regimen following advanced treatment failure, suggests the break results in an improved initial viral load response to the new combination. These new data, from the French GIGHAART study (ANRS 097), are preliminary and it’s unclear how long this benefit will persist.

GIGHAART randomised 70 people with heavy treatment experience to switch their failing HIV treatment to a salvage regimen of at least eight drugs either immediately, or after an eight week treatment interruption. The rationale for this comparison is that in the absence of treatment, drug resistant HIV – which would be expected to be present in this context – would disappear from the circulation as it is outgrown by wild-type HIV, the name given to HIV which has not been exposed to treatment.

Treatment interruptions are commonly associated with a loss of CD4 cells, and so their use has raised particular concern in people whose CD4 count is low, or has previously been so. In GIGHAART, the average CD4 count was already very low – around 27 cells. Use of HIV treatments was also very advanced – over 80% of participants had high level resistance to AZT, at least three AZT/d4T resistance mutations, at least one NNRTI mutation, and at least two protease mutations.

After twelve weeks on the new ‘mega-HAART’ regimen, significantly more of those in the treatment interruption arm had sustained at least a one log drop in viral load, and had viral load below 400 copies, than the immediate treatment group. 

*non significant difference (p = 0.05)

Drug level testing at weeks eight and sixteen of therapy found no differences between arms in the proportions with either high or low levels, suggesting that differences in adherence or drug absorption were not the cause of differences in response.

Despite the high number of drugs involved, tolerance of treatment appeared surprisingly good over this short initial period. Five people reduced the number of drugs in their regimen to less than six, and sixteen stopped hydroxyurea, one of the mandated treatments used.

Because drug resistant HIV is ‘archived’ and can re-grow if drugs to which these viruses are less susceptible are re-introduced, it’s possible that the virological benefit observed in the treatment break group will be short-lived. Nevertheless, any enhancement in viral load response may be viewed positively in this setting. What GIGHAART is unable to establish is whether effective salvage therapy requires the use of so many drugs. A trial currently recruiting in the UK and abroad, OPTIMA, is looking at both this question, and the strategic use of a treatment interruption in people with a similar shortage of viable treatment options.