SWATCH – alternating antiretroviral regimens
Paul Blanchard, HIV i-Base
Combination antiretroviral therapy is almost universally prescribed as a set combination which is administered until either therapeutic failure occurs or lack of tolerability forces a switch.
D’Amato and colleagues in a paper from 1998 used mathematical modelling to compare different strategies to decide when to change antiretroviral combinations. Proactive switching produced the best outcome in this model because it may reduce the duration of viral replication under pressure of a failing regimen before detection of viral rebound. D’Amato suggested that such a strategy should be evaluated in clinical trials leading to the initiation of the SWATCH study (SWiching Antiretroviral Therapy Combinations against HIV).
Data at 48 weeks from this ongoing study were presented at the meeting by Javier Martinez-Picado. SWATCH is a multicentre randomised open label trial enrolling HIV-1 infected patients who are antiretroviral naive. Patients are randomised to receive either of two standard combinations (d4T/ddI/efavirenz or ZDV/3TC/nelfinavir) or the same combinations alternating every 3 months. Baseline characteristics were similar across all three groups with median plasma viral load 4.5 – 4.8 log copies/mL and median CD4 count 310 – 362 cells/mm3 for the 116 of 161 patients who had reached week 48.
It was anticipated that tolerability and adherence may be more problematic in the switching arm. Therefore, adherence and quality of life questionnaires were completed in addition to measurement of viral load and CD4 cell counts.
Disappointingly the results presented for viral load and CD4 response were not subjected to statistical significance testing, and those for viral load were limited to a less than 400 copies/mL analysis. The study was not intended or powered to detect difference between the two “stable” treatment arms and indeed did not appear to do so.
Comparing the plasma HIV RNA response in terms of proportion of subjects achieving <400 copies/mL, 70% of those in the switching arm vs. 60.5% of those in the stable group achieved this goal at week 48 (intent to treat; missing = failure analysis). Median CD4 increase was similar across all 3 groups. Results were also presented for the number of subjects experiencing viral load rebound (virologic failure) in each group. Subjects in the switch group were significantly less likely to experience virologic failure with no subjects who were alternating having a viral load rebound versus 8 in the efavirenz group and 7 in the nelfinavir group (p<0.05). Virologic failure in the efavirenz group was associated with phenotypic resistance to efavirenz whereas failure in the nelfinavir group was predominantly associated with resistance to only lamivudine.
Tolerability and adherence data showed equal adherence to therapy across all 3 groups (approximately 93% reporting adherence better than 95% throughout all 48 weeks). A similar number of patients were lost to follow-up or changed drugs due to adverse effects in each arm.
The researchers concluded that after 48 weeks of follow up:
- No plasma viral load rebound has been seen in the switching HAART group, whereas 15 patients experienced failure of HAART in the standard therapy arms.
- Proactive switching of HAART had a similar impact on CD4 count recovery to standard of care regimens.
- Patients switching HAART regimens proactively every 3 months did not experience lower adherence or a higher number of side-effects than those on non-switching regimens.
Pre-empting resistance, or not allowing resistance the chance to develop may explain the lower number of failures in the switching group.
An alternative explanation is that due to the prolonged half-life of efavirenz, subjects in the switching group were, in effect, receiving quadruple, triple-class therapy during the periods of switch from EFV to NFV containing regimens.
D’Amato RM, D’Aquila RT, Wein LM. Management of antiretroviral therapy for HIV infection: Modelling when to change therapy. Antiviral Therapy, 1998 Vol 3:147-158.
Martinez-Picado J, Negredo E, Ruiz L et al. SWATCH study: A multicentre trial of proactive treatment switching. Results at 48 weeks of follow-up. Antiviral Therapy 2001; 6 (supplement 1):63. (Abstract 81)