Regular changes in antiretroviral drug regimens have been considered, following theoretical modelling studies suggesting that switching drug regimens on a regular basis could be of benefit. The theory postulated that by changing drug regimens before the development of virological failure, the length of time the patients are exposed to a failing drug regimen would be reduced. This was expected to minimise the emergence of drug resistance mutations in HIV.

The SWATCH study, outlined below, suggested that this approach may be of use, but larger trials with more contemporary drug regimens are needed before this can be introduced into practice.

A small study has also shown that continuously alternating therapy in patients with multi-drug resistance can lead to drug desensitisation. The study alternated patients between double protease inhibitor and triple nucleoside reverse transcriptase inhibitor therapy, with switches occurring whenever viral loads had risen by 0.5log₁₀. Although more trials of this approach are needed, it may enable patients with few options to keep viral loads suppressed and CD4 cell counts stable (Stocker 2004).

SWATCH study

The SWATCH study compared the strategies of sticking with a single regimen over 48 weeks or alternating two regimens over the same period. This study used combinations AZT (zidovudine, Retrovir), ddI (didanosine, Videx / VidexEC) and efavirenz (Sustiva), and d4T (stavudine, Zerit), 3TC (lamivudine, Epivir) and nelfinavir (Viracept). Continuous therapy with each of these regimens was compared with a strategy of alternating the regimens every twelve weeks. 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.

The study showed that virological failure was delayed in the patients alternating their regimen compared to the patients taking therapy continuously. The investigators found significant differences in the rate of virological failure and the likelihood of the patients having viral loads below either 400 or 50 copies/ml between the two groups (Martinez-Picado 2003).

For most other endpoints, no difference was detected. CD4 cell changes, treatment adherence, side-effects and quality of life were all similar between the study arms. This is somewhat surprising, given the fact that most side-effects are seen in the induction period, the time when drug levels are still stabilising and peaks in drug levels can be especially high.

A note of caution

SWATCH has caught the attention of many observers in the HIV field since preliminary data were reported in 2001. Following a series of largely negative results from various attempts to wring benefit from interruptions in treatment, alternate regimens may be taken up as the latest cause c鬨bre by treatment advocates.

Although the strategy deserves further exploration, it is 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 and ddI is now frowned upon due to reduced tolerability, and single protease inhibitors such as nelfinavir are considered less effective than non-nucleoside reverse transcriptase inhibitors (NNRTIs) or ritonavir (Norvir)-boosted protease inhibitors.

More positively, the ill-fated Quattro study, which compared eight-week cycles of monotherapy with either dual or quadruple therapy arms found less risk of drug resistance when alternating regimens (Quattro Study Group 2002).

References

Martinez-Picado J et al. Alternation of anti-HIV drug regimens for HIV infection: A randomized, controlled trial. Ann Intern Med 139: 81-89, 2003.

Stocker H et al. Continuously alternating therapy (CAT) can lead to resensitisation to antiretroviral drugs in patients with multi-drug resistant HIV-1. Fifteenth International AIDS Conference, Bangkok, abstract TuPeB4556, 2004.

Quattro Study Group. Observations of HIV-1 genotypic drug resistance in a trial of four reverse transcriptase inhibitors (Quattro Trial). Antivir Ther 7: 11-20, 2002.