Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/microl.

We appreciate the authors' careful review of our manuscript and prepared the following response to their comments.The first comment is that the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) trial was underpowered to detect the additional response to atrioventricular (AV) optimization. Importantly, the authors performed a post hoc power calculation, basing their calculations on the observed fixed-group response. These calculations do not have the same validity as prospective power calculations and must be interpreted with great caution. 1 Second, the noninferiority margin of 15 mL for a left ventricular end-systolic volume difference from baseline to 6 months post-cardiac resynchronization therapy was chosen by the SMART-AV Steering Committee as reflecting a clinically meaningful difference. Moreover, the primary and secondary end points and the statistical analysis plan were reviewed with the Food and Drug Administration before the initiation of the SMART-AV trial and have been previously published in detail. 2 Third, a larger trial would always provide more power to detect smaller differences. Based on the trial design, we cannot exclude the possibility that AV optimization with either echo or the SmartDelay can lead to smaller changes in these end points. The 95% confidence limits for the median differences observed in the trial suggest that the true difference in improvement in left ventricular end-systolic volume between the echo and fixed arms is between 12 mL and Ϫ3 mL. The 95% confidence limits for the median differences observed in the trial suggest that the true difference in improvement in left ventricular end-systolic volume between the SmartDelay and fixed arms is between 11 mL and Ϫ3 mL.Finally, this trial should not be interpreted as providing evidence "that AV optimization does not work for anyone." In fact, we explicitly conclude that "these data do not exclude possible utility in selected patients who do not respond to CRT," and we provide the results of a subgroup analysis suggesting a possible benefit to AV optimization in women, as well. 3 Disclosures

Background-One variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. Methods and Results-A total of 1014 patients (68% men; mean age, 66Ϯ11 years; mean left ventricular ejection fraction, 25Ϯ7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were Ϫ21 mL (Ϫ45 and 6 mL), Ϫ19 mL (Ϫ45 and 6 mL), and Ϫ15 mL (Ϫ41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (Pϭ0.52) or the SmartDelay and fixed arms (Pϭ0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. Conclusions-Neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy. Clinical Perspective on p 2668Achieving the optimal outcome from CRT may be dependent on proper programming of the optimal atrioventricular (AV) delay. 13,14 Suboptimal AV delay programming can result in as much as a 10% to 15% decline in cardiac output. 15,16 However, the large-scale randomized clinical trials establishing the overall efficacy of CRT have differed widely in their approach to AV optimization. In the CONTAK CD trial, there was no AV optimization. 6 In contrast, the Cardiac Resynchronization-Heart Failure (CARE-HF) and Multicenter InSync Randomized Clinical Evaluation (MIRACLE) investigators used Doppler echocardiography of transmitral flow to select the optimal AV delay, 2,3,13,14,17 an approach endorsed by the American Society of Echocardiography. 18 In further contrast, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) investigators used an algorithm based on the i...

Background Low CD4+ increases risk for both AIDS- and non–AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate duration of immune depletion. Methods We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up. Results Mean pretreatment CD4+ was 221 cells/μL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/μL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (≥50 cells/μL; rate = 2.7/100 personyears) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01). Conclusions Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.