Failure of alternating week-on and week-off therapy

Two recently published studies, each based on different interruption protocols, have both shown disappointing results, with higher rates of treatment failure and development of resistance.

The rationale for these studies was that HAART-induced viral suppression could maintain viral benefit to allow short periods off treatment, with potential benefits of reduced toxicity and cost.

The first study, from NIAID, published in 1 August issue of Journal of Infectious Diseases, looked at the effect of long-cycle structured intermittent therapy (SIT). Treatment interrupted for four weeks followed by eight weeks with HAART was compared to continuous HAART. The study was prematurely terminated to new enrolment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in five patients. After 48 weeks, there was no significant difference between groups in reduced toxicity. There was also no clear autoimmunisation effect by immunologic or virologic parameters.

Results from the Staccato Study, published as a fast track article in the 17 October issue of AIDS, led to the early termination of one arm of this large international study in which 600 patients (from Thailand, Switzerland, Australia, Argentina and Australia) who were on stable HAART (viral load <50 copies/mL, CD4 >350 cells/mm3) were randomised 1:1:1 to either alternating one week on treatment with one week off, interrupting treatment and restarting by CD4 count or remaining on continuous treatment.

An interim analysis was performed after 150 patients had enroled which included 36 patients in the week-on week-off arm with 8-week data. Overall, 19/36 (53%) patients failed using this regimen. Early failures (within 12 weeks) included three out of four patients on triple nucleotides in Switzerland, and in 11 out of 17 patients on ddI/d4T/saquinavir/ritonavir in Thailand. ‘Late’ failures (after 12 weeks) included two patients on nelfinavir/3TC/AZT, one on saquinavir/ritonavir/d4T and one on nevirapine/3TC/AZT. Of eight patients on efavirenz/3TC/AZT, one has failed.

In the continuous treatment arm of the study, only two failures have occurred so far in 37 patients (P < 0.001, compared to the one-week-one-1-week-off). In the CD4-guided arm, no failures occurred in 39 patients. The week-on week-off arm of this study has now been terminated.

Comment

On these results, short course interruptions – guided more by cost than benefit regarding toxicity – are clearly ineffective, even allowing for some differences seen between regimens. Long-term interruptions, guided by CD4 count offer a longer benefit from toxicity, but it is unclear whether the cumulative risk from each interruption will prove similar to the week-on week-off arm but extended over many years. Will 50% of people fail after six interruptions irrespective of the time off therapy in between?

Additionally, there may still be utility in alternating, or cycling, regimens without interruption. The SMART study (Ann Intern Med 2003; 139:81-89) showed lower rates of viral load failure in the alternating arm compared to the continuous arms (NNRTI based and PI based). This strategy deserves to be investigated further using more contemporary regimens than those in the original study to see if the advantage of alternating holds in a more modern treatment context.

With UK guidelines suggesting that people who started treatment early by 2003, who have benefited from good CD4 recovery but are also experiencing side effects, may safely discontinue treatment and monitor, then the advice in the guidelines to switch to a combination that includes three drugs with similar half lives for the last two weeks of treatment, should also be noted.