Top Ten Research Reports of 2003
1. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2003 Nov 10.
BackgroundAlthough not a research paper per se, the U.S. Department of Health and Human Services (DHHS) guidelines and their now-frequent updates are extremely influential and informative. However, as is the case for presidential biographies and tell-all memoirs, most people who like to talk about the guidelines have not actually read them. But they are worth a close reading. The guidelines were developed by the Panel on Clinical Practices for Treatment of HIV Infection convened by the DHHS, and the concise and carefully worded text describes the data supporting the panel's recommendations. The 2003 updates were most notable for their recommendations regarding when to initiate therapy and detailed lists of which therapies to use.
What Is New Here?While many clinicians and persons living with HIV infection are understandably fixated on the new drug pipeline and when the hottest new antiretrovirals will become available, it still remains less than perfectly clear at what point in the course of HIV infection it is optimal to initiate HIV treatment. The complexity of this issue has been reflected in the varying recommendations throughout the many versions of the DHHS guidelines (as well as the International AIDS Society guidelines) and, most critically, in the clinical practices of physicians across the United States.
It was not long ago when the DHHS recommended that all HIV-positive patients with a CD4 cell count below 500 cells/uL should be prescribed antiretroviral therapy. Paradoxically, in the interim, HIV therapies have become more potent, yet their limitations (toxicity, cross resistance, cost) have prompted greater caution regarding their use. While most clinicians are delaying the start of therapy until after a patient's CD4 cell count has dropped well below 500 cells/uL, a stalemate has emerged between the "hit early" versus "hit late" camps. This has led to the creation of a gray area between 200 and 350 cells/uL in which the merits of therapy remain debated.
In the 2003 edition of the treatment guidelines, the focus is still on the importance of using a patient's CD4 cell count to decide when therapy should begin. As in earlier versions, the new guidelines state that serious consideration to initiate treatment should begin when a patient's CD4 cell count falls below 350 cells/uL or, of course, if symptoms of HIV develop.
The striking difference in the July update to the guidelines was the addition of the new designations of "preferred" and alternative" to certain antiretroviral regimens and the bold positions that were taken regarding the superiority of certain agents and regimens over others.
The guidelines designated as "preferred" regimens for initial therapy those combinations containing two NRTIs plus either efavirenz (EFV, Sustiva, Stocrin) or lopinavir/ritonavir (LPV/r, Kaletra). The guidelines did not mince words; efavirenz or lopinavir/ritonavir were determined to be superior to all other agents in their respective classes based on available evidence. "Alternative" regimens included commonly used combinations.
Based on recent clinical trial results, including results from AIDS Clinical Trials Group (ACTG) 5095 (see next report), it was recommended that triple-NRTI regimens should be considered only if an NNRTI- or protease inhibitor (PI)-anchored regimen is not possible. The important caveat was the specification that only ZDV (zidovudine, Retrovir) + 3TC (lamivudine, Epivir) + abacavir (ABC, Ziagen) be used and not other triple NRTI regimens, such as tenofovir (TDF, Viread) + 3TC + abacavir or tenofovir + 3TC + ddI (didanosine, Videx) -- regimens that have shown extremely high rates of failure in recent studies.
The Bottom LineThe DHHS guidelines are an evolving document that reflects, as much as it dictates, how clinicians approach the management of HIV. The new recommendations certainly reflect what clinicians across the United States already have been doing, but they also add nuanced arguments that challenge some of our assumptions -- e.g., though many clinicians believe that efavirenz and nevirapine (NVP, Viramune) are as similar as Coke and Pepsi, the guidelines state a clear preference for efavirenz. The ascendance of lopinavir/ritonavir to the same throne as efavirenz also surprised some clinicians and signals a shift back to PI-based therapy as initial HIV treatment.
It is for Vegas odds-makers and panel watchers to predict future changes to the guidelines. In the short term, the rise of ritonavir-boosted atazanavir as an initial treatment -- which seems to be the newest practice among clinicians -- may lead this drug to a coveted berth, particularly if more data supporting this approach emerge. In the long run, how the guidelines evolve will be interesting to see. In the 2003 changes the panel responsible for the guidelines seemed to have become more willing to make recommendations that may be seen as controversial. An example of this is the current version's rationale for the preference of efavirenz over nevirapine as a first-line agent.
I think that the latest changes increase the relevance of the recommendations, particularly for seasoned HIV treaters. For clinicians with few HIV-infected patients, the guidelines have always been an indispensable resource. However, the guidelines tended to be less useful to veteran HIV providers whose practice the guidelines mirror. In my practice, I find that the guidelines validate my choice of medications, reassure my patients that my recommendations are not the ravings of a mad, scruffy clinical scientist and, I admit it, they actually influence my clinical decisions. Whether you agree with the recommendations or not, and increasingly many do, it is a compelling read.
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