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.