February 23, 2005
The recent availability in the United States and Europe of new fixed-dose combinations of the previously approved nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) and tenofovir/emtricitabine (TDF/FTC, Truvada) has refocused commercial and community interest in the characteristics of nucleoside backbones for combination antiretroviral therapy.
Each combination drug, when administered with a third drug, offers the possibility of a low-pill burden, once-daily option for the treatment of HIV.
For the abacavir/lamivudine combination, long-term tolerability has been demonstrated in a number of clinical studies -- the principal limitation for the use and management of this medication comes from some patients' allergic or hypersensitivity reaction to abacavir ("abacavir HSR"). This reaction, which has been well characterized over the years, includes a constellation of symptoms that may include rash, fever, respiratory symptoms or gastrointestinal symptoms. The recognition and clinical management of patients with HSR is essential to the use of abacavir-containing HIV treatments.
With the recently approved change in the dosing of abacavir from twice daily to once daily, due attention has been directed to the question of whether the characteristics of HSR have been altered with once-daily administration.
Lastly, because of recent concerns about the safety of U.S. Food and Drug Administration (FDA)-approved drugs, such as rofecoxib (Vioxx) and paroxetine (Paxil), increased (and welcomed) scrutiny exists over the possibility of unexpected side effects of other drugs.
Two poster presentations at the 2005 Conference on Retroviruses and Opportunistic Infections refine our understanding of HSR.
The first, presented by Andrea James from the FDA, reviewed 9 recent clinical trials and found that the overall rate of HSR had increased from previous studies from ~5% to 8% (ranging from 2% to 9%). This review prompted the FDA to force a modification in the abacavir package insert to note the increase in the observed rate of HSR from 5% to 8%.
The FDA also evaluated the CNA30021 clinical trial -- a study that compared once-daily to twice-daily dosed abacavir and found that, while the overall frequency of HSR was similar in both groups, the observed frequency of moderate to severe HSR had increased slightly.
A second study on this subject was presented by Jamie Hernandez from GlaxoSmithKline (GSK), the maker of abacavir. Through an analysis of all of GSK's clinical trials (both earlier ones and the 9 more recent studies reviewed by the FDA), the group concluded that the rate had increased from the previous labeled rate of 5% to 5.4%.
In the more recent abacavir-containing studies, a study tool called the HSR case report form (CRF) was used to more consistently collect data on the symptoms of suspected cases.
Using multivariate analysis to tease out factors associated with an increased or decreased risk of developing HSR, the group confirmed previous GSK observations1 that persons of African ethnicity and male gender who have an AIDS diagnosis (U.S. Centers for Disease Control and Prevention class C) had a lower risk of having HSR. The use of the HSR CRF was also associated with a significantly greater likelihood of the diagnosis of HSR. Hernandez speculated that the use of the CRF in the studies prompted a more comprehensive search for potential HSR cases.
GSK's present analysis suggests that the presence of rash alone was found not to indicate the presence of HSR. And, in contrast to the CNA30021 study of once-daily abacavir, cumulative data from 3 additional large studies (with 940 subjects) showed no apparent increase in the observed rate of HSR. A limitation of this analysis is that these other studies did not compare once-daily to twice-daily dosing, but rather, all patients in these studies received once-daily abacavir.
Taken together, these 2 analyses agree that there may be an increase in the reported rate of HSR in comparison with previous studies. So, how does one reconcile the different details of the FDA and GSK reports?
First, the consistent use of a research tool to collect potential HSR cases should increase the surveillance among abacavir-receiving study subjects. Because of this shift in HSR case acquisition, it might be expected that the CRF could increase the sensitivity to detect cases, but also decrease the specificity of HSR diagnoses.
Consistent with this concept are observations from the CNA30024 study,2 which was a double-blinded, placebo-controlled study that used the abacavir HSR CRF and that compared abacavir to zidovudine (AZT, Retrovir).
The researchers found that 3% of zidovudine-receiving patients were diagnosed by their physicians as having HSR -- which suggests that abacavir HSR may be incorrectly diagnosed in a small percentage of patients in other studies.
In summary, while the FDA and GSK will debate whether the abacavir HSR rate is 5.4% or 8%, there is agreement that abacavir HSR happens to a small, but important minority of patients.
Because of the significance of HSR for the clinical management of patients, clarity about the diagnosis of HSR is important to healthcare providers. As such, information about the pre-treatment risk of HSR and the observation that the presence of rash alone was insufficient for the diagnosis of HSR will be clinically useful immediately.
Abstract: Once-daily administration of abacavir is not a clinical risk factor for suspected hypersensitivity reactions in clinical trials, and rash alone is not sufficient to diagnose the reaction (Poster 836)
Authored by: C Brothers, A Cutrell, H Zhao, M Edwards, J Fleming, T Scott, J Hernandez
Affiliations:GlaxoSmithKline, Research Triangle Park, NC, USA
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|