Darunavir and Trimethoprim-Sulfamethoxazole Cross-Reactivity
Darunavir and Trimethoprim-Sulfamethoxazole Cross-Reactivity
Objective Both darunavir (DRV) and trimethoprim-sulfamethoxazole (TMP-SMX) carry a sulfonamide moiety and a warning for this cross-reactivity is given in the label of DRV. The aim of this study was to investigate the potential cross-reactivity between both drugs.
Design Retrospective cohort study with a nested case–control study.
Methods HIV-infected patients that received DRV-containing antiretroviral therapy at any time during the period of their HIV infection were included. Patients with no history of TMP-SMX use were excluded. The incidence of a DRV allergy, according to the Naranjo probability scale, was investigated in patients with an allergy to TMP-SMX compared with those without such an allergy. In order to identify possible risk factors associated with a DRV allergy among patients allergic to TMP-SMX, a nested case–control study was subsequently performed.
Results A total of 405 patients were included, of whom 79 (17.5%) had a history of allergy to TMP-SMX. A DRV allergy was seen in four patients (5.1%) with a TMP-SMX allergy compared with four (1.2%) without a TMP-SMX allergy (P = 0.05). Patients with a TMP-SMX allergy were at higher risk for a DRV allergy (odds ratio 4.29; 95% confidence interval, 1.05–17.56). No additional risk factors for a DRV allergy among patients allergic to TMP-SMX were identified in the nested case–control study.
Conclusion Although DRV allergy is uncommon, making cross-reactivity with TMP-SMX a rare clinical problem, it appears to exist more often in the background of a TMP-SMX allergy.
Darunavir (DRV), a frequently prescribed anti-HIV protease inhibitor in combination with the pharmacokinetic booster ritonavir (DRV/r), contains a sulfonamide moiety (SO2NH2) and is therefore classified as a sulfonamide nonantibacterial drug. Trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly prescribed sulfonamide antibacterial drug, especially as prophylaxis against Pneumocystis jirovecii pneumonia (PJP) in HIV-infected patients with low CD4 cell counts. It is thought that patients, who have had a previous allergic reaction to TMP-SMX, are at greater risk for an allergic reaction to sulfonamide-containing drugs like DRV.
Allergic reactions associated with sulfonamide drugs include type I through IV of the Gell and Coombs classification of hypersensitivity reactions. Sulfonamide-related cutaneous drug reactions include urticaria, exanthemas, fixed drug eruptions, erythema multiforme and life-threatening conditions such as Stevens–Johnson syndrome and toxic epidermal necrolysis. The incidence of allergic cutaneous reactions to TMP-SMX in HIV-infected patients lies between 21.5 and 39%. The DRV registration trials reported hypersensitivity reactions up to 16%, irrespective of known TMP-SMX allergy as this was not documented. Therefore, since the introduction of DRV in 2007, multiple TMP-SMX-allergic patients must have been exposed to DRV/r-containing combination antiretroviral therapy (cART).
Two recent studies, in relatively small groups of Asian HIV-infected patients, found no association between the occurrence of DRV/r rash and TMP-SMX allergy. Furthermore, DRV/r does not contain an arylamine group, which is believed to be a necessity for this drug hypersensitivity. Although no clinical evidence of cross-reactivity exists, a warning for this potential cross-reactivity is included in the labeling of DRV based on the sulfonamide structure. Therefore, the aim of this study is to investigate the potential cross-reactivity between DRV and TMP-SMX in a large number of HIV-infected patients.
Abstract and Introduction
Abstract
Objective Both darunavir (DRV) and trimethoprim-sulfamethoxazole (TMP-SMX) carry a sulfonamide moiety and a warning for this cross-reactivity is given in the label of DRV. The aim of this study was to investigate the potential cross-reactivity between both drugs.
Design Retrospective cohort study with a nested case–control study.
Methods HIV-infected patients that received DRV-containing antiretroviral therapy at any time during the period of their HIV infection were included. Patients with no history of TMP-SMX use were excluded. The incidence of a DRV allergy, according to the Naranjo probability scale, was investigated in patients with an allergy to TMP-SMX compared with those without such an allergy. In order to identify possible risk factors associated with a DRV allergy among patients allergic to TMP-SMX, a nested case–control study was subsequently performed.
Results A total of 405 patients were included, of whom 79 (17.5%) had a history of allergy to TMP-SMX. A DRV allergy was seen in four patients (5.1%) with a TMP-SMX allergy compared with four (1.2%) without a TMP-SMX allergy (P = 0.05). Patients with a TMP-SMX allergy were at higher risk for a DRV allergy (odds ratio 4.29; 95% confidence interval, 1.05–17.56). No additional risk factors for a DRV allergy among patients allergic to TMP-SMX were identified in the nested case–control study.
Conclusion Although DRV allergy is uncommon, making cross-reactivity with TMP-SMX a rare clinical problem, it appears to exist more often in the background of a TMP-SMX allergy.
Introduction
Darunavir (DRV), a frequently prescribed anti-HIV protease inhibitor in combination with the pharmacokinetic booster ritonavir (DRV/r), contains a sulfonamide moiety (SO2NH2) and is therefore classified as a sulfonamide nonantibacterial drug. Trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly prescribed sulfonamide antibacterial drug, especially as prophylaxis against Pneumocystis jirovecii pneumonia (PJP) in HIV-infected patients with low CD4 cell counts. It is thought that patients, who have had a previous allergic reaction to TMP-SMX, are at greater risk for an allergic reaction to sulfonamide-containing drugs like DRV.
Allergic reactions associated with sulfonamide drugs include type I through IV of the Gell and Coombs classification of hypersensitivity reactions. Sulfonamide-related cutaneous drug reactions include urticaria, exanthemas, fixed drug eruptions, erythema multiforme and life-threatening conditions such as Stevens–Johnson syndrome and toxic epidermal necrolysis. The incidence of allergic cutaneous reactions to TMP-SMX in HIV-infected patients lies between 21.5 and 39%. The DRV registration trials reported hypersensitivity reactions up to 16%, irrespective of known TMP-SMX allergy as this was not documented. Therefore, since the introduction of DRV in 2007, multiple TMP-SMX-allergic patients must have been exposed to DRV/r-containing combination antiretroviral therapy (cART).
Two recent studies, in relatively small groups of Asian HIV-infected patients, found no association between the occurrence of DRV/r rash and TMP-SMX allergy. Furthermore, DRV/r does not contain an arylamine group, which is believed to be a necessity for this drug hypersensitivity. Although no clinical evidence of cross-reactivity exists, a warning for this potential cross-reactivity is included in the labeling of DRV based on the sulfonamide structure. Therefore, the aim of this study is to investigate the potential cross-reactivity between DRV and TMP-SMX in a large number of HIV-infected patients.