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Study Finds Genetic Abacavir Allergy Screening Useful
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May 15, 2007
By Martha Kerr
(Reuters Health) - Hypersensitivity to abacavir can be detected by screening for HLA-B*5701 and is recommended for HIV-infected individuals who are candidates for the antiviral agent, French researchers report.
"Because the symptoms of hypersensitivity reaction are very unspecific, the true diagnosis of abacavir hypersensitivity can be made by HLA typing, looking for HLA B*5701 positivity," principal investigator Dr. David Zucman of Hopital Necker in Paris said in an interview with Reuters Health.
In a study published in the May 1st issue of the Journal of Acquired Immune Deficiency Syndromes, Dr. Zucman and colleagues retrospectively assessed 49 HIV-positive patients exposed to abacavir. Of these, 16 patients (32.6%) had definite or possible hypersensitivity.
Of the 16, six were HLA B*5701 and abacavir was discontinued in these. Five other patients also discontinued abacavir because of ongoing fever. None of the 38 abacavir-tolerant patients were B*57-positive.
Dr. Zucman's team then prospectively screened 137 abacavir-naive patients from an ethnically mixed population, consisting of 106 whites, 30 African or Caribbean blacks and one Asian. Whites were both European and North African.
Of the group, 128 tested negative for B*57. One of these patients discontinued abacavir therapy probably as a result of hypersensitivity, while 127 tolerated abacavir.
Among the nine who were B*57-positive, six patients were found to be HLA B*5701-positive and abacavir therapy was not started in this group. The other three patients were positive for B*5703 and they tolerated abacavir.
The incidence of hypersensitivity to abacavir dropped from 12% to 0% with prescreening, the investigators calculate, and unwarranted interruption of treatment dropped from 10.2% to 0.73%.
" HLA-B*5701 screening in prevention of abacavir hypersensitivity reaction is useful in all populations except the black population, in which HLA B*5701 is very rare (below 0.5%)," Dr. Zucman said.
"If a patient has already been exposed to abacavir and has developed some symptoms possibly related to abacavir hypersensitivity reaction, the drug has to be stopped immediately," he stressed.
"Second-line treatments for HIV infection are now multiple and their efficacy is comparable to abacavir, especially tenofovir, which is very frequently used," Dr. Zucman observed.
J Acquir Immune Defic Syndr 2007;45:1-3.
Genetic Screening for Abacavir Hypersensitivity
Prospective Screening for Human Leukocyte Antigen-B*5701 Avoids Abacavir Hypersensitivity Reaction in the Ethnically Mixed French HIV Population
JAIDS Journal of Acquired Immune Deficiency Syndromes:Volume 45(1)1 May 2007pp 1-3
Zucman, David MD*; Truchis, Pierre de MD; Majerholc, Catherine MD*; Stegman, Sophia MD; Caillat-Zucman, Sophie MD
Summary:
The association of human leukocyte antigen-B*5701 (genetic variation) with abacavir hypersensitivity varies depending on ethnic origin. We confirmed the high specificity of B*5701 in the ethnically mixed French population and used a rapid and inexpensive polymerase chain reaction strategy to evaluate the predictiveness of B*5701 screening. The incidence of hypersensitivity decreased from 12% before screening to 0% after screening, and the rate of unwarranted interruptions of abacavir therapy decreased from 10.2% to 0.73%. We therefore recommend the implementation of this cost-effective screen before treatment with abacavir
Abacavir hypersensitivity is a treatment-limiting and potentially life-threatening adverse event occurring in 5% to 8% of white patients initiating the antiretroviral drug abacavir. This reaction varies in its severity and the pattern of clinical manifestations, which include fever, rash, gastrointestinal or respiratory symptoms, myalgia, arthralgia, lethargy, or malaise. This wide spectrum of symptoms leads to frequent overestimation of a hypersensitivity reaction (HSR) and excessive discontinuation of the drug.
The presence of a specific human leukocyte antigen (HLA) allele, HLA-B*5701, has been shown to represent a dominant risk factor of abacavir hypersensitivity.1,2 In the Western Australian HIV patients cohort, exclusion of HLA-B*5701-positive individuals from receiving abacavir has decreased the incidence of hypersensitivity from approximately 9% to 0%.3 The association of HLA-B57 with abacavir hypersensitivity has been more controversial in other populations, however. In 2 other studies conducted by investigators of GlaxoSmithKline (Research Triangle Park, NC), the manufacturer of abacavir,4,5 the predictiveness of HLA-B*5701 testing accounted for only half of white patients with hypersensitivity. Furthermore, the sensitivity of HLA-B*5701 was reduced to 20% in Hispanic patients and was not demonstrated in African-American patients, presumably because of most of them express the B*5703 subtype. This illustrates the potential need to perform genetic testing in various cohorts that have specific hypersensitivity but differ on the basis of ethnicity.6,7
The French Paris urban and suburban population is characterized by its mixed ethnicity, with approximately 80% white (80% European and 20% North African origin) and 20% black (African or Caribbean origin) HIV-infected patients. We thus aimed to address whether the HLA-B*5701 association holds true in this mixed French population and to re-evaluate the predictive value of B*5701 screening.
We retrospectively studied 49 patients (40 whites and 9 blacks) previously exposed to abacavir. Among them, 16 (32.6%, 13 whites and 3 blacks) had developed possible hypersensitivity on the basis of wide clinical criteria, leading to interruption of abacavir therapy (Table 1, top). Low-resolution HLA-B genotyping was done by polymerase chain reaction sequence-specific oligonucleotide typing (PCR-SSO; InnoLipa, Ghent, Belgium), and high-resolution subtyping was performed in B*57-positive individuals using sequence-specific primers (PCR-SSP B*57; Olerup SSP; Bionobis, Montfort l'Amaury, France). Of the 16 patients with suspected abacavir hypersensitivity, 6 were B*5701-positive (all whites) and abacavir was definitely denied. Among the 10 B*57-negative patients with a possible HSR, 5 (3 whites and 2 blacks) had a history of mild symptoms, which occurred during the first week of abacavir treatment, and abacavir was subsequently resumed without any adverse reaction. Five other patients (all whites) had presented with a fever episode occurring within 2 months of treatment, but an abacavir HSR could not be excluded and these patients were not rechallenged with the drug. Altogether, in this retrospective analysis, the proportion of patients having abacavir discontinued was 32.6% (16 of 49 patients) and the incidence of suspected hypersensitivity was 22.5% (11 of 49 patients). None of the 38 abacavir-tolerant subjects was B*57-positive (P < 10-4, odds ratio = 91, 95% confidence interval [CI]: 4.5 to 1851.2). The low sensitivity of B*57 in this study (46%) was likely underestimated because of the wide clinical criteria chosen for a possible hypersensitivity diagnosis. By contrast, the high specificity and positive predictive value of B*5701 (100% for each) suggested that genetic screening for HLA-B*5701 might be useful to avoid abacavir hypersensitivity in our French population.
We thus decided to perform HLA-B*5701 prospective testing in all abacavir-naive individuals starting treatment during a study period from January 2004 through January 2006 (see Table 1, bottom). Because high-resolution HLA class I genotyping is labor- and cost-intensive, we used a 2-step PCR-SSP amplification technique, which first identifies B*57-positive individuals using 2 group-specific primer pairs (Dynal, Invitrogen, Cergy Pontoise, France) and then defines B*57-subtypes in a second step only if needed (Olerup SSP-B*57). This approach is slightly different from the multiplex PCR-SSP assay described by Martin et al.8 Among 137 consecutive patients screened to initiate abacavir therapy (106 whites [84 European and 22 North African], 30 African or Caribbean blacks, and 1 Asian), 128 (93.4%) were found to be negative for HLA-B*57 and were given abacavir. Only 1 of them had abacavir discontinued within 6 weeks because of fever that was not consistent with a drug HSR (probably related to Mycobacterium infection). All others (n = 127) were tolerant to abacavir. Nine (6.6%) of 137 patients were found to be positive for HLA-B*57. After B*57 subtyping, 3 of them (all blacks) were B*5703-positive and were given abacavir. The 6 remaining patients were B*5701-positive (3 European and 3 North African whites) and were denied abacavir. Thus, the prevalence of B*5701 in this prospectively screened population was 4.4% (6 of 137 patients), with all cases occurring in European or North African whites, which is consistent with expected results. Using this strategy, it seems that the incidence of suspected hypersensitivity has decreased from 22.5% to <1% after implementation of our genetic screening (P < 10-4) and the incidence of true hypersensitivity has decreased from 12% to 0%. Moreover, the proportion of patients stopping abacavir therapy because of symptoms that did not meet criteria for drug hypersensitivity also dropped from 10.2% before genetic screening to 0.73% after introduction of screening (P < 10-4). This means that genetic screening lowers the rate of false-positive diagnosis of hypersensitivity.
In conclusion, we propose that genotyping for HLA-B*5701 should be performed in white subjects before prescription of abacavir. To facilitate routine screening, we have developed a convenient strategy for HLA-B*57 genotyping using commercially available B*57-specific primers. This method is simple, rapid (4 hours), and inexpensive (27 Euros per test), and it thus provides a cost-effective screen before treatment with abacavir. B*57 subtyping may then be performed in a second step in B*57-positive patients. In our ethnically mixed population, this prospective testing resulted in an absence of the occurrence of hypersensitivity and reduced the rate of unwarranted interruptions of abacavir therapy. Given the prevalence of HLA-B*5701 (5%-8% in Europe and North Africa), the low cost of the test, and the strong disease association, we recommend the widespread implementation of this pharmacogenetic test before prescribing abacavir.
REFERENCES
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