September 17, 2003
Jamie Hernandez, M.D. and colleagues from GlaxoSmithKline (GSK) presented this summary analysis examining factors related to hypersensitivity reactions (HSR) among over 8,000 study subjects receiving abacavir (ABC, Ziagen) in a large number of GSK-sponsored trials (expanding on a previous analysis of 5,000 subjects receiving abacavir that was published in Clinical Therapy 2002; 23: 565-573).
All GSK-sponsored trials utilizing abacavir for at least six months were included. After 1999, GSK implemented a standardized HSR case report form (CRF) into all new abacavir-containing protocols. In this new HSR-risk factor analysis, nine studies that utilized the HSR-CRF were now included in the analysis. Key demographic, clinical, surrogate marker, details regarding time and type of antiretroviral treatment (ART) and laboratory data were entered into a single database. Univariate and multivariable regression models were constructed. For the multivariable analysis, a stepwise selection procedure was employed. Model 1 maximized the number of subjects considered for the model while Model 2 maximized the number of factors to be considered.
Overall, 503 of the 8,038 (5 percent) subjects experienced an abacavir HSR (with 7,652 subjects serving as controls) with the incidence/protocol ranging from 0-14 percent.
For the univariate model, the factors that were significantly (p<0.10) associated with a risk for abacavir HSR included, and the odds ratios, were:
|CDC class C status||0.57|
|Baseline CD4 T-cell count||1.25|
|Concurrent NNRTI use||0.76|
|Concurrent AZT (zidovudine, Retrovir) + 3TC (lamivudine, Epivir) use||0.82|
|Latin American region||1.88|
|Year of abacavir initiation||1.28|
|Use of abacavir HSR-CRF||2.20|
For the Model 1 multivariable analysis (including 389 of the HSR cases), the significant factors identified (p<0.05 with odds ratios) were:
|Use of HSR-CRF||2.21|
|CDC class C status||0.74|
For the Model 2 multivariable analysis (including 240 of the HSR cases), the significant factors identified were:
|Concurrent protease inhibitor (PI)||2.04|
|Use of HSR-CRF||1.71|
For the issue of concurrent NNRTI use, the rate of abacavir HSR was 4 percent among subjects recorded to be receiving nevirapine (NVP, Viramune) versus 5 percent for those receiving efavirenz (EFV, Sustiva).
There was an impression that concurrent use of PIs or NNRTIs (which obviously is immensely common) may increase the reporting of possible abacavir HSRs due to possible rash/reactions to those agents making a specific diagnosis of possible abacavir HSR more difficult. Patients with prior treatment or more advanced disease may report fewer signs associated with abacavir HSR. One of the most significant predictors for reporting abacavir HSR is the availability of the HSR CRF. The authors concluded that no changes in the approach to a diagnosis or the management of abacavir HSR within GSK trials are recommended. These data suggest to me that the 9 percent rate of possible abacavir HSR reported in the CNA30024 trial could be partially explained by the frequent concomitant use of efavirenz and the blinding of the study drugs.
It is my usual practice to try to not start abacavir at the same time as a PI or NNRTI so that I can isolate any effect of the abacavir and be in a better position to decide whether a set of symptoms is an abacavir HSR. I dislike losing any drug from our HIV armamentarium so I don't like dropping abacavir due to a possible HSR. I often intensify a given regimen with abacavir (often the patient is already on Combivir [AZT + 3TC]) so that after four to six weeks I can simplify to Trizivir plus another drug.
Read the poster of the abstract covered in this article.
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