Hit Hard, Hit Early Redux

RTB: A retrospective study and editorial published in the New England Journal of Medicine yesterday is once again pushing for early intervention with toxic drugs for those testing positive on flawed tests, based on questionable markers.

Most people will not read beyond the headline or the one-sentence conclusion. If they did, they would realize that this “study” is more about promoting drugs than saving lives. The abstract of this report is already showing up on blogs with no references to critical information, such as this from an editorial in the same issue (emphasis added):

The strengths of the study notwithstanding, the results of the NA-ACCORD study cannot be considered definitive evidence that everyone with HIV should start receiving antiretroviral therapy. This was not a randomized trial, and the patients who chose to begin therapy early might have differed in other important ways from those who chose to defer therapy — ways that improved survival but were not measured. Although NA-ACCORD investigators tried to account for this potential bias by controlling for known associations with an increased risk of death in patients with HIV infection (e.g., increased rates of coinfection with hepatitis C virus and of injection-drug use), some unmeasured factors inevitably remain.

For example, in many ways, patients who were offered and began potent combination antiretroviral therapy with a high CD4+ count in the late 1990s were the ideal patients: highly adherent, committed to doing whatever they could to prevent AIDS, and willing to push through the sometimes punishing side effects and drug-regimen burdens of the early therapies. This sort of “health-seeking” behavior cannot be measured in the NA-ACCORD study yet could still substantially influence outcomes; its effects can be accounted for only in a randomized, prospective study. In addition to differences in baseline factors, such as HCV infection and injection-drug use, the rates of virologic suppression after 12 months of therapy differed between the two groups among patients with a CD4+ count of more than 500 cells per cubic millimeter (81% in the early-therapy group vs. 71% in the deferred-therapy group), which suggests different levels of adherence to therapy.

Some additional limitations should be considered. A relatively high proportion (approximately 45%) of patients in each study-specified stratum of CD4+ counts either did not initiate antiretroviral therapy or did not have a decline in the CD4+ count. These patients are not included in the comparative analysis, and we have no way of knowing whether antiretroviral therapy would have been beneficial in this group.

Broader use of antiretroviral agents may increase the incidence of viral resistance. However, since data regarding resistance are unavailable at this time, we do not know how an earlier starting strategy would influence future treatment options. Data on certain toxic effects of antiretroviral therapy (most notably, metabolic and morphologic side effects) are not provided, and potential long-term toxicity cannot be addressed. The causes of death are available for only 16% of the patients who died; it will be important to obtain more complete follow-up on these patients to better understand the deleterious effects of poorly controlled HIV infection on end-organ dysfunction. It also must be determined whether some of the deaths might have been related to underlying differences (including lifestyle choices) between the two nonrandomized study groups.

As if that weren’t reason enough to wonder why the Journal even thought this study was worth publishing, the editorial continues:

As we learned regarding the use of estrogen in postmenopausal women,14 we must be cautious in interpreting observational data despite efforts to control for confounding. The NA-ACCORD data do not provide definitive proof that we should be starting antiretroviral therapy in all patients with HIV infection. Such a conclusion would require data from a randomized, prospective clinical trial, and at least three such studies are either ongoing or planned.

All those disclaimers are not enough to prevent the editorial authors, Paul E. Sax, M.D., and Lindsey R. Baden, M.D. to conclude the above paragraph with:

However, the supportive evidence for the benefits of earlier therapy continues to increase, making strategies to identify patients with HIV infection before the onset of substantial immunodeficiency all the more compelling.15

Finally, there is the fine print concerning disclosure. First, Dr. Sax, author of the editorial:

Dr. Sax reports receiving research support from GlaxoSmithKline, Merck, and Tibotec and consulting fees from Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, and Tibotec. No other potential conflict of interest relevant to this article was reported.

And those conducting the published study:

Dr. Saag reports receiving consulting fees from Ardea Biosciences, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Monogram Biosciences, Pain Therapeutics, Panacos, Pfizer, Progenics, Roche Laboratories, Tibotec, Tobira Therapeutics, and Vicro and research support from Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, GlaxoSmithKline, Merck, Panacos, Pfizer, Progenics, Theratechnologies, and Tibotec; Dr. Hogg, receiving grant support from Merck; Dr. Deeks, receiving consulting fees from GlaxoSmithKline, Roche, Gilead, and Boehringer Ingelheim and grant support from Merck, Gilead, Bristol-Myers Squibb, and Pfizer; Dr. Eron, receiving consulting fees from Tibotec, Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Pfizer, lecture fees from Roche, Bristol-Myers Squibb, Tibotec, and Merck, and grant support from GlaxoSmithKline, Merck, and Boehringer Ingelheim; Dr. Gill, receiving consulting fees from Gilead, GlaxoSmithKline, Abbott, Merck, Boehringer Ingelheim, Tibotec, and Pfizer and grant support from GlaxoSmithKline, Abbott, Tibotec, and Pfizer; Dr. Klein, receiving consulting fees from GlaxoSmithKline, Abbott, Pfizer, and Boehringer Ingelheim, lecture fees from Abbott, Gilead, Tibotec, Bristol-Myers Squibb, and GlaxoSmithKline, and research support from the Canadian HIV Trials Network, the Ontario HIV Treatment Network, and Schering-Plough Canada; Dr. Rodriguez, receiving consulting fees from Gilead and Bristol-Myers Squibb, lecture fees from Bristol-Myers Squibb, and grant support from STERIS; Dr. Rachlis, receiving consulting and lecture fees from GlaxoSmithKline, Abbott, Merck, Pfizer, Bristol-Myers Squibb, Gilead, and Tibotec and grant support from GlaxoSmithKline, Tibotec, Boehringer Ingelheim, Abbott, Merck, Pfizer, and Roche; Dr. Horberg, receiving grant support from Gilead, Abbott, and Bristol-Myers Squibb; Dr. Silverberg, receiving grant support from Pfizer, Merck, Gilead, the Universitywide AIDS Research Program, and Community Benefit/Kaiser Permanente; Dr. Gebo, receiving consulting fees from Tibotec and grant support from the Johns Hopkins University Richard Ross Award; Dr. Benson, receiving consulting fees from GlaxoSmithKline, Pfizer, Merck, and Achillion and grant support from Gilead; Dr. Collier, receiving consulting fees from Merck, Pfizer, and GlaxoSmithKline and grant support from Schering-Plough, Tibotec-Virco, Gilead, Koronis, and Merck and having an equity interest in Bristol-Myers Squibb and Abbott; and Dr. Moore, receiving consulting fees from Bristol-Myers Squibb and GlaxoSmithKline, lecture fees from Gilead, and grant support from Pfizer, Merck, and Gilead. No other potential conflict of interest relevant to this article was reported.

You gotta’ love the last line: “No other potential conflict of interest relevant to this article was reported.”

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

Mari M. Kitahata, M.D., M.P.H., Stephen J. Gange, Ph.D., Alison G. Abraham, Ph.D., Barry Merriman, M.A., Michael S. Saag, M.D., Amy C. Justice, M.D., Ph.D., Robert S. Hogg, Ph.D., Steven G. Deeks, M.D., Joseph J. Eron, M.D., John T. Brooks, M.D., Sean B. Rourke, Ph.D., M. John Gill, M.B., Ch.B., Ronald J. Bosch, Ph.D., Jeffrey N. Martin, M.D., M.P.H., Marina B. Klein, M.D., Lisa P. Jacobson, Sc.D., Benigno Rodriguez, M.D., Timothy R. Sterling, M.D., Gregory D. Kirk, M.D., Ph.D., Sonia Napravnik, Ph.D., Anita R. Rachlis, M.D., Liviana M. Calzavara, Ph.D., Michael A. Horberg, M.D., Michael J. Silverberg, Ph.D., Kelly A. Gebo, M.D., M.P.H., James J. Goedert, M.D., Constance A. Benson, M.D., Ann C. Collier, M.D., Stephen E. Van Rompaey, Ph.D., Heidi M. Crane, M.D., M.P.H., Rosemary G. McKaig, Ph.D., Bryan Lau, Ph.D., Aimee M. Freeman, M.A., Richard D. Moore, M.D., for the NA-ACCORD Investigators


Background The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.

Methods We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group).

Results In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001).

Conclusions The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
Source Information

The authors’ affiliations are listed in the Appendix.

This article (10.1056/NEJMoa0807252) was published at NEJM.org on April 1, 2009. It will appear in the April 30 issue of the Journal.

Address reprint requests to Dr. Kitahata at the University of Washington, Harborview Medical Center, 325 Ninth Ave., Box 359931, Seattle, WA 98104, or at kitahata{at}u.washington.edu.

Study published here: http://content.nejm.org/cgi/content/full/NEJMoa0807252

Editorial here: http://content.nejm.org/cgi/content/full/NEJMe0902713

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