CD4-guided Treatment Interruptions vs Continuous Antiretroviral Therapy in Staccato Trial

By Liz Highleyman

Structured treatment interruption has been proposed as a strategy for reducing the side effects and costs of antiretroviral therapy, but carries the risk of HIV disease progression.

Results from the SMART trial, presented at the recent XVI International AIDS Conference in Toronto, indicated that patients who underwent structured treatment interruptions guided by CD4 cell counts were more than twice as likely to experience disease progression or death compared with those who received continuous antiretroviral therapy.

But new data from the Staccato trial, published in the August 5, 2006 HIV/AIDS special issue of The Lancet, showed that individuals who interrupted therapy with high CD4 counts and low viral loads did not experience more AIDS-defining events, suggesting that treatment interruption may still be an appropriate strategy for selected patients.

Staccato, conducted by the HIV Netherlands Australia Thailand Research Collaboration, included 430 participants, 80% from Thailand, 18% from Europe, and 2% from Australia. All Thai patients took ritonavir-boosted saquinavir (Invirase) plus two nucleoside reverse transcriptase inhibitors (NRTIs).

Participants who had CD4 counts greater than 350 cells/mm3 and viral loads below 50 copies/mL for at least 3 months were randomly assigned to continue therapy (n = 146) or to undergo treatment interruptions (n = 284). Treatment was restarted if a patient's CD4 count fell below 350 cells/mm3, and again discontinued once the CD4 count rose above this level. At the end of the randomized phase of the study, all patients were followed for an additional 12 weeks on continuous therapy.

Results

The median follow-up time on randomized treatment was 21.9 months (range 16.4-25.3 months).

Patients in the treatment interruption arm used antiretroviral drugs for 37.5% of their total days in the study, compared with 99% of days for those on continuous therapy.

In the treatment interruption group, the total "drug savings" was 61.5%.

257 of 284 patients (90.5%) achieved viral loads less than 50 copies/mL in the treatment interruption arm, compared with 134 of 146 (91.8%) in the continued therapy group (P = 0.90, not a statistically significant difference).

Patients in the treatment interruption arm reached significantly lower CD4 cell counts than those on continuous therapy (402 vs 619 cells/mm3; P = 0.001).

About half the patients in the treatment interruption arm had to restart therapy within 18 weeks; this was more common among patients who had lower CD4 counts and higher viral loads before starting treatment.

No AIDS-defining events or deaths considered to be related to HIV or antiretroviral drug toxicity occurred in either arm (the study was too small to detect a significant difference in rates of AIDS or death).

Diarrhea (23 vs 16%; P = 0.04) and peripheral neuropathy (5 vs 2%; P = 0.03) occurred more frequently in the continuous treatment arm.

Patients in the continuous therapy arm had higher serum cholesterol levels and were more likely to report lipodystrophy.

Oral and genital candidiasis (thrush) was more common in the treatment interruption arm.

A total of 10 patients (2.3%) developed drug resistance mutations, but there was no significant difference between the two arms.

Conclusion

The authors concluded that, "Drug savings with scheduled treatment interruption were substantial, and no evidence of increased treatment resistance emerged. Treatment-related adverse events were more frequent with continuous treatment, but low CD4 counts and minor manifestations of HIV infection were more frequent with scheduled treatment interruption."

"Staccato indicates that ritonavir-boosted protease-inhibitor-based HAART can be interrupted without undue harm, provided that CD4 counts are monitored," they added.

The SMART study, which was discontinued in January 2006 after data showed that the treatment interruption strategy was detrimental, included patients with more advanced disease than those in Staccato, had a longer follow-up period (up to 6 years), and allowed patients' CD4 counts to fall to 250 cells/mm3 before restarting therapy (compared with 350 cells/mm3 in Staccato).

Unexpectedly, in addition to increased risk of progression to AIDS or death, SMART also showed that patients who interrupted therapy had higher rates of cardiovascular, liver, and kidney complications, which researchers initially had hoped would be reduced by taking treatment breaks.

"It would be wrong to conclude that SMART means the end of all HIV treatment interruption," the Staccato authors wrote, but acknowledged that, "such a striking discrepancy is unlikely due to chance and requires explanation."

Until further data from large clinical trials is available, with wisdom of structured treatment interruptions remains a subject of controversy.

09/01/06

Reference
J Ananworanich, A Gayet-Ageron, M Le Braz, and others. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. The Lancet 368(9534):459-65. August 5, 2006.