Alternating drug regimens may delay HIV treatment failure

A Spanish-led study set up to test the effects of alternating between two different HAART regimens, compared to standard three drug therapy, has reported improved virological response rates in those who cycled their treatment. Results from the SWATCH trial were presented at last week’s International AIDS Society Conference in Paris, and are published in the current issue of Annals of Internal Medicine.

SWATCH was an open-label study which randomised participants to receive either d4T/ddI/efavirenz (Arm A) or AZT/3TC/nelfinavir (Arm B), or to alternate between the two regimens, switching one for the other every three months without a break (Arm C). The researchers hypothesised that switching regimens would shorten any period where failing treatments were continued, and thereby reduce the potential for drug resistance, and consequent treatment failure to emerge.

Participants were enrolled from clinics in Spain and Argentina. All had viral load above 400 copies, and there was no restriction to entry based on CD4 count. The trial would investigate the rate at which the different arms failed virologically, along with CD4 count changes, side-effects, the development of resistance, adherence to the allocated regimen, and participants’ quality of life. One hundred and sixty-one people were randomised, all of whom were starting HIV therapy for the first time. At entry, median viral load was around 50,000 copies (4.7 logs), and median CD4 was 335 cells. Seventy-eight per cent of the group were men.

Results at 48 weeks

After 48 weeks on treatment, there were no differences between Arms A and B regarding the time which elapsed before treatment failed, or in the proportion of participants whose viral load was below 400 copies. This was true whether results from those who stopped their allocated treatment early were included or excluded. Consequently, the researchers pooled data from Arms A and B and compared responses in the alternating arm to the collective data from the standard of care arms.

The headline result from this comparison was that viral load failure was delayed in the group who alternated regimens compared to those who received standard therapy. During the 48 week follow-up period, the rate of viral load failure was 1.2 per 1,000 person-weeks of treatment in Arm C, and 4.8 per 1,000 person-weeks in Arms A and B combined. These differences were significant, as were those noted in the likelihood of participants sustaining a viral load below either 400 or 50 copies, measures on which the alternating arm also outstripped the standard therapy arms.

For most other endpoints, no difference was detected; CD4 changes, treatment adherence, side-effects and quality of life were all similar between arms. As there were relatively few treatment failures in the study, resistance data from those whose viral load was not suppressed successfully are a little difficult to interpret. The trend in those from the standard of care arms appears to fit the usual pattern however, with resistance to efavirenz detected most frequently in Arm A, and 3TC mutants the more common in Arm B.

A note of caution

SWATCH has caught the attention of many observers in the HIV field since preliminary data were reported at the 8th Retroviruses Conference two years ago. Following a series of largely negative results from various attempts to wring benefit from interruptions in treatment, it may be that the strategy employed by SWATCH, that of alternating drug regimens, will be taken up as the latest cause celebre by treatment advocates.

Though the strategy deserves further exploration, it’s worth reviewing the limitations of this particular study, which was always intended to be a pilot. The regimens adopted by SWATCH may have reflected the standard of care when the study was planned, but neither would fit that description today. The combined use of d4T/ddI is now frowned upon due to reduced tolerability, and single protease inhibitors (PI) such as nelfinavir are considered less effective than NNRTIs or boosted PIs. In fact the HAART regimens evaluated in SWATCH also made an appearance in last year’s headline-grabbing study ACTG 384, where they were roundly beaten by a combination of efavirenz/AZT/3TC, the regimen of choice within various treatment guidelines at present.

More positively, and proving there is nothing new under the sun in HIV, seasoned observers will recall the ill-fated Quattro study, which compared eight week cycles of monotherapy with either dual or quadruple therapy arms. Though the alternating treatment arm produced less viral load suppression, it also appeared less likely to generate drug resistance to three of the four drugs used than the combination therapy arms.