High-dose pulsed therapy - the future for structured treatment breaks?

A study conducted before the availability of HAART, but only recently published in the July 1^st edition of the Journal of Acquired Immune Deficiency Syndromes, has found that using pulses of high dose d4T monotherapy can achieve a significant reduction in HIV viral load and transient increases in CD4 cell count in HIV-positive individuals who have been extensively pre-treated with AZT.

Although the investigators from the University of Minnesota do not advocate high doses of pulsed NRTI monotherapy as a viable treatment option, they do believe that their study could have important implications for the development of treatment interruption strategies using high doses of HAART for heavily treated individuals with limited treatment options.

The study involved eleven patients, who had been treated with AZT monotherapy for an average of 78 months. At baseline, mean CD4 cell count was 429 cells/mm³ and mean viral load was 31,500 copies/mL. Patients were treated with a four week cycle of d4T dosed at 280mg a day split between two equal doses. Treatment with d4T was then discontinued for four weeks, but recommenced in four weeks cycles once HIV viral load returned to above 75% of baseline. The study lasted 44 weeks, with patients returning to the clinic every four weeks for blood tests to monitor viral load and CD4 cell count and blood concentrations of d4T. Resistance tests were also performed.

The eleven patients received a total of 38 cycles of d4T, however two patients did not complete the study. By the end of the fourth and final cycle of high-dose d4T, HIV viral load had fallen to an average of approximately 8,000 copies/mL. CD4 cell counts showed a transient increase with each cycle of treatment, but had fallen by an average of 2 cells/mm³ from baseline by the end of the study.

Target plasma concentrations of d4T (336ng/mL) were achieved by eight of the eleven patients, and high dose d4T was well tolerated.

Nucleoside resistance mutations were detected in baseline plasma samples of nine patients. Only one patient acquired an additional resistance mutation by the end of the study.

In conclusion the investigators note that high-dose pulsed d4T montherapy was well tolerated and resulted in a decrease in viral load. Although the patients in the study had background resistance to NRTIs, and a detectable viral load through the 44 weeks of the study, a new resistance mutation only emerged in one patient.

”Although high-dose NRTI monotherapy is not clinically feasible, the results of our trial support further examination of high-dosed pulse therapy using combinations of antiretroviral drugs, which may be particularly appropriate for heavily treated patients whose theraputic options are limited”, suggest the investigators.

Further information on this website

Structured treatment interruptions - overview

Treatment interruptions - factsheet