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Re: Renal Outcomes in SMART
Submit responseWe concur with Dr. Gupta that the renal outcomes before and after the protocol modification in SMART are interesting and require further study. The interaction p-value corresponding to the treatment hazard ratio comparison before and after the protocol change was significant (p=0.014);however, the number of participants with renal events, defined in SMART as death from renal disease or end stage renal disease (ESRD), was too small (a total of 18 across both treatment groups) to reliably study predictors (1). A careful study of risk factors for renal disease in the SMART study requires more events. Thus, we are exploring the possibility of using stored plasma samples to measure creatinine on SMART participants over the entire follow-up period. With these data, an expanded renal outcome (e.g., death due to renal failure, end stage renal disease or large decline in estimated glomular filtration rate) would result in more events and would allow reliable assessment of risk factors for renal disease as Dr. Gupta suggests.
Our finding that treatment interruption increases risk of renal progression is supported by another recent investigation in SMART (2,3). Stored samples were used to measure cystatin C, a marker of renal function, during the first year of the study, but before the protocol change. Cystatin C levels increased significantly in the treatment interruption group compared to those randomly assigned to receive continuous antiretroviral therapy (3).
Ultimately, we think that the risk and benefits of antiretroviral treatment are best assessed in a randomized trial of early therapy instead of a treatment interruption study like SMART. A trial called the Strategic Timing of AntiRetroviral Therapy (START) study is scheduled to begin next year and is designed to investigate the risk/benefit of early antiretroviral treatment on clinical outcomes, including renal disease, as well as other serious non-AIDS conditions such as cardiovascular disease, liver disease and malignancies.
1. The SMART Study Group. Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy. Ann Intern Med 2008; 149:289-299.
2. The SMART Study Group. CD4+ count-guided interruption of antiretroviral therapy. NEJM 2006; 255:2283-2296.
3. Mocroft A, Wyatt C, Szczech L, Neuhaus J, El-Sadr W, et al. Interruption of antiretroviral therapy is associated with increased plasma cystatin C: results from the SMART study. AIDS (in press).
James D. Neaton for the INSIGHT SMART Study Group
Conflict of Interest:
None declared
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Renal Outcomes in SMART
Submit responseTO THE EDITOR: In the recent analysis by the SMART Study Group (1), resumption of continuous antiretroviral therapy after a structured treatment interruption did not fully abrogate the increased risk of serious adverse events and mortality associated with initial assignment to the drug conservation arm of the trial. This suggests that even short periods of untreated HIV infection may confer a greater overall risk of major complications than that posed by the antiretroviral treatments themselves. However, there was a significant interaction between the study period (pre-modification vs. post-modification) and the treatment group assignment (continuous virologic suppression vs. drug conservation) for renal disease events. Although the renal event rates were quite low, this result implies that longer-term, continuous antiretroviral therapy may eventually lead to a higher rate of nephropathy.
It would be of interest to describe more fully the medical and antiretroviral treatment histories, including that of the potentially nephrotoxic antiretroviral drug tenofovir disoproxil fumarate, received by those study participants who developed renal disease and compare them to matched control groups, from both study periods, of those who did not develop such complications. Such an analysis from this well-characterized cohort would be of great value in identifying potential risk factors for renal disease in HIV-infected patients.
References
1. The SMART Study Group. Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy. Ann Intern Med. 2008;149:289-299.
Conflict of Interest:
Dr. Gupta reports having received advisory and speaking fees from Gilead Sciences, Inc. (the manufacturer of tenofovir disoproxil fumarate) and is the Principal Investigator of a phase IV study, sponsored by Gilead Sciences, Inc., studying renal toxicities associated with antiretroviral therapies.