People of African ethnicity have a lower reported rate of suspected hypersensivity reaction (HSR) to the nucleoside analogue, abacavir (Ziagen), according to an analysis of five clinical trials that included the drug. However, the analysis, presented on Thursday to the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, also notes that abacavir HSR may present differently in people of African ethnicity, suggesting that actual cases may be being missed.
Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is often taken as part of potent antiretroviral therapy. It is available alone, or co-formulated with lamivudine (3TC, Epivir) and marketed as Kivexa in Europe and Epzicom in North America; and with zidovudine (AZT, Retrovir) and 3TC, when it is marketed as Trizivir. Several generic manufacturers also produce abacavir in tablet and paediatric liquid form.
Abacavir can cause a serious hypersensitivity reaction (HSR) which can be fatal in very rare cases. The HSR is characterised by symptoms including fever, rash, respiratory and stomach problems, lethargy and malaise. This immune-mediated reaction has caused around 30 fatalities globally and results in hospitalisation in 9-20% of cases.
Studies have generally shown that this reaction occurs in around 8% of people who begin taking abacavir, almost always within the first six months. People who experience abacavir HSR must stop taking abacavir and never restart it.
In this analysis, investigators working for GlaxoSmithKline, who produce and market Ziagen, Kivexa/Epzicom and Trizivir, compared the frequency of suspected abacavir HSRs between people of different ethnicities, by combining the results of five separate randomised clinical trials done in Europe and the Americas examining first-line regimens in treatment-naïve individuals. By combining results these studies - CNA30024, ZODIAC, ALOHA, KLEAN and ACTION - HSR rates could be analysed across the combined total of 2,800 participants. A total of 99% of participants were previously unexposed to antiretrovirals; 30% were of African ethnicity; they started treatment with a median plasma HIV RNA level (viral load) of 4.89 log10 copies and a median CD4 count of 232 cells/mm3.
Suspected HSR was consistently seen less frequently in people of African ethnicity than in people of Caucasian, Hispanic or Asian ethnicities. The overall occurrence rate was 6.7% (range, 5.5%-8.3%), but this was lower in participants of African ethnicity at 3.6% (2.3%-5.7%) than in those of other ethnicities, which combined was 8% (6.3%-9.5%).
Data from these five studies were added to the cumulative risk factor analysis (RFA), which uses multivariate analysis to determine who is at higher or lower risk of a suspected abacavir HSR. This now comprises 39 studies with 10,888 participants. Unlike the five recent trials analysed, this RFA includes 25% of individuals of African ethnicity and notably just over a third are treatment-naïve.
The updated RFA still shows that individuals of African ethnicity are about half as likely to be diagnosed with a suspected HSR than people of other ethnicities (Odds Ratio 0.46; 95% CI, 0.37-0.58). Men of all ethnicities are also less likely to be diagnosed with suspected HSR than women (OR 0.64; 95% CI, 0.52-0.79).
However, there may be some differences between African and other ethnicities in the signs and symptoms reported, although the investigators say these were of borderline statistical significance (exact p value and specific 95% CI data not accurately provided). Notably, however, these involved the two most commonly reported symptoms - rash and fever. They were experienced by just over 60% of people of African ethnicity and just under 80% of those other ethnicities. Conversely stomach problems (gastrointestinal symptoms) were reported more often in people of African ethnicity.
Previous studies have suggested that the likelihood of abacavir hypersensitivity has a significant genetic basis. People, especially Caucasians, seem to be at greater risk of developing HSR if they carry a specific gene known as HLA-B*5701. Although this gene is thought to be less common in those of African ethnicity, a recent report from Brighton found unexpectedly high levels of the genetic variant in patients of both European and African ethnicity. Nevertheless, even when present, the gene may not be as significant an HSR risk factor for people of African ethnicity as for other ethnicities.
The investigators point out that a limitation of their analysis is the diagnostic precision of clinically suspected HSR, and note that this may be less accurate in people of African ethnicity who are thought to have a low prevalence of HLA-B*5701. Consequently, they stress that their findings “do not (their emphasis) suggest that clinical vigilance should be decreased in any patient initiating therapy with abacavir.”
Two large prospective studies are currently underway that may provide important new data. One, in Europe, will further assess the clinical utility of HLA-B*5701 gene testing. Another, in African American patients, will help better characterise abacavir HSR signs, symptoms and prevalence in people of African ethnicity.
Reference:
Brothers C et al. Lower reported rate of suspected hypersensitivity reaction (HSR) to abacavir (ABC) among black patients. 46th ICAAC, San Francisco, abstract H-1065, 2006.