By Liz Highleyman

In an effort to reduce the long-term toxicities, inconvenience, and cost of antiretroviral therapy, researchers have explored structured treatment interruption (STI), a strategy in which patients stop therapy periodically either according to a fixed schedule or based on changing CD4 cell counts.

Fixed-duration Interruption in African DART Trial

Several studies, including the large SMART trial, have shown that CD4 cell-guided treatment interruption is a risky approach, but data have been less consistent regarding fixed-duration interruptions.

In the January 11, 2008 issue of AIDS, investigators reported data from the African DART (Development of Anti-Retroviral Therapy in Africa) trial; results were previously presented at the XVI International AIDS Conference in Toronto in August 2006.

DART was designed to compare strategies for monitoring antiretroviral treatment in Uganda and Zimbabwe; a nested sub-study looked at fixed duration structured treatment interruption. The main trial included 3316 treatment-naive, symptomatic adult participants with a CD4 cell count < 200 cells/mm³ at the time of antiretroviral therapy initiation. Patients were randomly assigned to receive a 3-drug regimen containing AZT (Retrovir) plus 3TC (Epivir) plus either tenofovir (Viread), abacavir (Ziagen), or nevirapine (Viramune),

Of these, 813 patients who attained ≥ 300 cells/mm³ after 48 or 72 weeks on treatment were randomly assigned to either receive continuous therapy or undergo periodic treatment interruption in fixed-duration cycles of 12 weeks on/12 weeks off. At the time of this second randomization, the median patient age was 37 years (range 19-67) and the median CD4 cell count was 358 cells/mm³ (range 300-1054).

Results

• Sub-study randomization was terminated in March 2006 and all participants were put on continuous therapy due to inferior outcomes in the STI arm.

• At the time of termination, the median follow-up period was 51 weeks (range 0-85); patients in the continuous therapy arm spent 99% of the total time on therapy, compared with 50% in the STI arm.

• First new World Health Organization (WHO) stage 4 events or death occurred more frequently in the STI arm (24 events/deaths; 6.4 per 100 person-years [PY]) than in the continuous therapy arm (9 events/deaths; 2.4 per 100 PY) (hazard ratio 2.73; P = 0.007).

• The most frequent event was esophageal candidiasis, with 13 occurrences in the STI arm vs 3 in the continuous therapy group.

• A total of 9 patients (1%) died, 5 in the STI arm and 4 in the continuous therapy group.

• There was no difference between the 2 arms in time to first serious adverse event (P = 0.78), although treatment changes due to toxicity occurred more often in the continuous therapy arm than in the STI arm (2.6 vs 0.5 per 100 PY; P = 0.02).

Based on these findings, the researchers concluded, “Although absolute rates of WHO stage 4 events/death were low, 12 week STIs initiated at a CD4 cell count ≥= 300 cells/mm³ resulted in a greater than 2-fold increased relative rate of disease progression compared with continuous therapy in adult Africans initiating antiretroviral therapy with advanced disease, and cannot be recommended.”

Risk of HIV Rebound in UK CHIC Study

In the second study, reported in the January 30 issue of AIDS, researchers with the UK Collaborative HIV Cohort (UK CHIC) Study investigated whether previous treatment interruptions were associated with an elevated risk of HIV viral rebound in individuals who attained virological suppression.

All cohort participants who achieved an undetectable viral load (< 50 copies/mL) while on antiretroviral therapy were followed until viral rebound occurred or until the last viral load measurement. Poisson regression was used to describe the independent impact of treatment interruption on rebound rates.

Results

• 12,977 patients achieved HIV RNA < 50 copies/mL, contributing a total of 37,314 person-years of follow-up.

• The overall virological rebound rate was 8.07 per 100 PY.

• In adjusted analyses, rates of viral rebound were up to 64% higher in patients who had previously interrupted therapy compared with those who had not (rate ratio 1.64).

• Patients who had interrupted treatment with a detectable viral load had up to a 74% higher chance of experiencing viral rebound compared with those who had not done so (rate ratio 1.74).

• However, there was no evidence that interrupting treatment with an undetectable viral load was associated with virological rebound.

In conclusion, the authors wrote, “Among patients with an undetectable viral load, having previously interrupted therapy while the viral load was detectable is associated with a raised risk of rebound.”

Together, these studies add to the accumulating evidence that treatment interruption is a potentially risky strategy.

At the upcoming 48^th Conference on Retroviruses and Opportunistic Infections in Boston (February 3-6, 2008), investigators with the SMART study will present new data on outcomes in patients who re-introduce antiretroviral therapy after treatment interruption.