Structured Treatment Interruptions: A Risky Business

Three clinician/researchers from the British Columbia Center for Excellence in HIV/AIDS wrote a commentary on the use of structured treatment interruptions that appears in the current issue of Clinical Infectious Diseases (February 15, 2005.) Following are selected highlights from their commentary. A reading of the entire text is recommended:

“Various forms of structured treatment interruptions scheduled at specific time points with specific thresholds for reinitiation of therapy have been explored in both early infection and in chronically infected patients. In chronically infected patients, the aim was initially to boost HIV-specific immune responses and, more recently, to try to decrease overall drug exposure and thus reduce drug-related morbidity and drug costs.

“Comparison between these studies has been complicated by the heterogeneity in the thresholds for stopping and reinitiating therapy. Results of several studies exploring reinstitution of treatment at fixed time intervals, from months to weekly periods receiving and not receiving treatment (so-called "pulse" therapy), have now been reported.

“The overall effectiveness of this approach remains controversial. Among the important concerns in this context is the potential role of structured treatment interruptions or pulse therapy in promoting the emergence of drug-resistant strains of HIV.

“Indeed, substantial rates of emergence of drug-resistant HIV were observed among therapy-adherent patients treated with fixed intermittent regimens in the PART study. Similarly, other groups have observed the emergence of new and archived resistance mutations during structured treatment interruptions.

“Furthermore, the use of structured treatment interruptions or pulse therapy in patients with chronic HIV infection who have controlled viremia assumes that less drug treatment will be associated with less toxicity, lower cost, and improved adherence while preserving overall outcomes.

“Sobering news has emerged in this regard from the HIV Netherlands Australia Thailand Research Collaborative (HIVNAT) Stacatto trial, as reported in the current issue of Clinical Infectious Diseases. An unacceptably high rate of viral breakthrough was observed in patients with previously controlled viremia who were randomized to receive antiviral therapy in cycles of 1 week on, 1 week off, leading to the early discontinuation of this arm of the study.

“On the basis of these observations, structured treatment interruptions, intermittent therapy, and pulse therapy during chronic HIV infection cannot be recommended at this time.

“Considerable effort has focused on trying to characterize the potential role of treatment interruptions in patients who have acute or chronic HIV infection or who have experienced treatment failure. Although this issue arises frequently in the clinical setting, it is not adequately addressed by current therapeutic guidelines.

“Treatment interruptions can be expected to reduce pill burden, cost, and toxicity related to antiretroviral therapy. However, treatment interruptions can also be associated with a decrease in CD4 cell counts, an increase HIV-related morbidity, and a potential increase in HIV transmission resulting from uncontrolled viremia.

“Also, there is a very real concern that treatment interruptions can promote the emergence of drug-resistant HIV strains and, thus, have a negative impact on future therapeutic outcomes.

“Therefore, with the exception of single treatment interruptions dictated by emerging toxicities, by comorbidities, or in patients who started therapy prematurely on the basis of prior guidelines, treatment interruptions are not recommended.

“Structured treatment interruption should be regarded strictly as an experimental procedure to be undertaken in the context of carefully designed, prospective, comparative clinical trials under the supervision of experienced investigators.

“In this context, the results of several large, prospective, randomized trials currently underway that are evaluating various CD4 cell countdriven, intermittent therapy approaches, including the Stacatto, PART, CTN 164 (S. Walmsley, personal communication), Trivacan, Window, and SMART studies, are eagerly awaited.”

British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.

02/02/05

Reference
J Montaner, M Harris and R Hogg. Structured Treatment Interruptions: A Risky Business. Clinical Infectious Diseases 40(4): 601-603. February 15, 2005.