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Antiretroviral Therapy in Early HIV Infection To the Editor: In the INSIGHT Strategic Timing of Antiretroviral Treatment (START) study, Lundgren et al. (Aug. 27 issue)1 conclude that antiretroviral therapy should be recommended for every patient with human immunodeficiency virus (HIV) infection regardless of the CD4+ count. However, we believe that the study design and the shortage of both data and efficacy analyses make it difficult to support their conclusions. Regarding the design, the grouping of several types of events that may not always be related to HIV infection into a single primary end point complicates the interpretation. Moreover, by limiting the evaluation to just an intention-to-treat analysis, the investigators do not provide important information that would allow the reader to properly evaluate the results and conclusions. Furthermore, 118 of the 2359 patients (5%) in the deferred-initiation group started treatment when their CD4+ count was less than 180 cells per cubic millimeter. This is the same number of patients who had conditions that were associated with the acquired immunodeficiency syndrome (AIDS) or that were otherwise indicative of HIV progression. Are they the same patients? If so, it would suggest an erratic follow-up that could invalidate the conclusions. Luis F. Lopez‑Cortes, M.D., Ph.D. Alicia Gutiérrez‑Valencia, Ph.D. Omar J. Ben‑Marzouk‑Hidalgo, Ph.D.

To the Editor: Lundgren et al. describe the risks and benefits of the immediate initiation of antiretroviral therapy in asymptomatic HIV-positive patients regardless of CD4+ count. The authors found a significant benefit in the immediateinitiation approach and conclude that health systems should expand the use of antiretroviral therapy to all HIV-positive patients. However, we are concerned about four issues. First, the investigators found no between-group differences when hard and true end points — death from any cause and potentially life-threatening symptomatic events — were considered. Second, only 23% of the patients were followed for more than 4 years, and larger between-group differences were reported after 4 years of follow-up. Thus, the findings could be biased. Third, no data were provided about the continuation of therapy and daily adherence. Fourth, at least 3 years of therapy could be saved in almost 50% of the patients, given the median time until the initiation of antiretroviral therapy in the deferred-initiation group. Our evidence-based remarks raise questions about whether health care systems should be charging patients for therapy without substantial clinical benefits. Salvatore Corrao, M.D. University of Palermo Palermo, Italy s​.­corrao@​­tiscali​.­it

this week’s letters

Hospital Universitario Virgen del Rocio Seville, Spain lflopez@​­us​.­es

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Antiretroviral Therapy in Early HIV Infection

No potential conflict of interest relevant to this letter was reported.

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Randomized Trial of Reduced-Nicotine Standards for Cigarettes

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10-Year Survival of Patients with AIDS Receiving Antiretroviral Therapy in Haiti

1. The INSIGHT START Study Group. Initiation of antiretrovi-

ral therapy in early asymptomatic HIV infection. N Engl J Med 2015;​373:​795-807. DOI: 10.1056/NEJMc1513311

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Tullio Prestileo, M.D. Francesco Di Lorenzo, M.D. Arnas Civico di Cristina e Benfratelli Palermo, Italy No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1513311

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pendix, available with the full text of our article at NEJM.org). More important, in the deferredinitiation group, only 5 patients had a primary event when their latest CD4+ count was less than 350 cells per cubic millimeter. In 59% of the patients with a primary event, the event occurred when the latest CD4+ count was more than 500 cells per cubic millimeter (Fig. S4 in the Supplementary Appendix of our article). Thus, our study provides strong evidence of a clinically relevant benefit for the initiation of antiretroviral therapy when the CD4+ count is more than 500 cells per cubic millimeter and hence supports the recommendation that such therapy should be offered to all HIV-positive patients regardless of the CD4+ count. Corrao et al. comment on the use of anti­ retroviral therapy and the length of follow-up in our study. Data on the use of therapy are provided in Figure 1A of the article, which also shows a high level of adherence to therapy. We do not see how the length of follow-up could lead to biased findings, particularly since the hazard ratio did not vary significantly during follow-up. Jens Lundgren, M.D.

The authors reply: Lopez-Cortes and colleagues question our conclusions on the basis of the results of the START study. Regarding the choice of end points (a question that was also raised by Corrao and colleagues), we included serious AIDS and non-AIDS conditions as part of the primary end point in part because the presence of HIV infection and the use of antiretroviral therapy may affect these life-threatening outcomes, for which the expected incidence was greater than that for AIDS outcomes, as has been shown in previous studies, including the Strategies for Management of Antiretroviral Therapy (SMART) study.1 The fact that we observed a consistent benefit for immediate initiation of antiretroviral therapy for both serious AIDS and serious nonAIDS events shows the clinical benefit of such an approach for a wide range of conditions. Regarding the analytic approach, we opted for an inten- University of Copenhagen tion-to-treat method, since it could not induce Copenhagen, Denmark bias against deferred treatment. However, we can jens​.­lundgren@​­regionh​.­dk confirm that we have also carried out analyses Abdel G. Babiker, Ph.D. that included only follow-up time during which University College London patients strictly adhered to their assigned strat- London, United Kingdom egy. As would be expected from such an analysis, James D. Neaton, Ph.D. the benefits of early antiretroviral therapy were University of Minnesota even more pronounced than in the intention-to- Minneapolis, MN treat analysis. Since publication of their article, the authors report no furOnly 21 of the 2359 patients in the deferred- ther potential conflict of interest. initiation group (not 118) started therapy with 1. The Strategies for Management of Antiretroviral Therapy a latest CD4+ cell count of 178 cells per cubic (SMART) Study Group. CD4+ count–guided interruption of antimillimeter or less (5th percentile of the study retroviral treatment. N Engl J Med 2006;​355:​2283-96. population) (Table S1 in the Supplementary Ap- DOI: 10.1056/NEJMc1513311

Randomized Trial of Reduced-Nicotine Standards for Cigarettes To the Editor: Donny and colleagues (Oct. 1 issue)1 found that, as compared with the use of standard-nicotine cigarettes, the use of reducednicotine cigarettes was associated with reductions in nicotine exposure and dependence and the number of cigarettes smoked. However, when they smoke reduced-nicotine cigarettes, smokers 394

who are already addicted to nicotine may compensate by blocking the ventilation holes and inhaling longer, harder, and more frequently to get enough nicotine. In doing so, they inhale more tar than they would inhale with regular cigarettes.2 In the study by Donny et al., the total puff volume was calculated with the use of a device

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