Genetic testing for prevention of severe drug‐induced skin rash

Ana Alfirevic; Munir Pirmohamed; Branka Marinovic; Linda Harcourt‐Smith; Andrea L Jorgensen; Tess E Cooper

doi:10.1002/14651858.CD010891.pub2

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Figure 1

Flowchart of interventions (genetic testing) and outcomes (skin rash) in a patient population prescribed drug X

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Figure 2

Study flow diagram.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 5

Forest plot of comparison: 1 Genetic testing vs no testing, outcome: 1.1 Hypersensitivity (HSS).

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Figure 6

Forest plot of comparison: 1 Genetic testing with skin patch testing versus no genetic testing with skin patch testing, outcome: 1.1 Hypersensitivity (HSS) immunologically confirmed.

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Figure 7

Drug‐induced skin rash: top panel = maculopapular exanthema, bottom panel = Steven Johnson Syndrome (blistering skin rash with skin detachment)

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Analysis 1.1

Comparison 1 Genetic testing with skin patch testing versus no genetic testing with skin patch testing, Outcome 1 Hypersensitivity (HSS), immunologically confirmed.

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Analysis 2.1

Comparison 2 Genetic testing versus no testing, Outcome 1 Hypersensitivity (HSS).

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*Prospective genetic HLA‐B57:01 screening compared with standard care for drug‐induced skin rash**
Patient or population: patients with HIV‐1 infection and a pre‐established clinical need for treatment with an antiretroviral drug regimen containing abacavir but with an unknown HLA‐B57:01 status. Settings:* secondary care clinics Intervention: prospective genetic screening for the HLA‐B57:01 allele Comparison:* no prospective genotyping, standard‐of‐care treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Standard Care^a	*Prospective genetic HLA‐B57:01 screening**
Severe skin drug‐induced rash	No data		‐	‐	‐	Not assessed
Long‐term sequelae	No data		‐	‐	‐	Not assessed
Hospitalisation for drug‐induced skin reaction	No data		‐	‐	‐	Not assessed
SJS/TEN (Stevens‐Johnson syndrome/toxic epidermal necrolysis)	See hypersensitivity		‐	‐	‐	Not assessable
AGEP (acute generalised exanthematous pustulosis)	No data		‐	‐	‐	Not assessed
HSS (hypersensitivity) reaction including SJS/TEN (clinically diagnosed) (6 weeks clinical assessment)	78 per 1000	34 per 1000 (22 to 52)	RR 0.43 (0.28 to 0.67)	1650 participants (1 study)	⊕⊕⊕⊝ moderate^b	‐
HSS reaction including SJS/TEN (immunologically confirmed) (6 weeks clinical assessment)	27 per 1000	0 per 1000	RR 0.02 (0.00 to 0.37)	1644 participants (1 study)	⊕⊕⊕⊝ moderate^b	‐
Death	No data		‐	‐	‐	Not assessed
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^a The assumed risk is estimated from the event rate (confirmed clinically diagnosed occurrences of HSS including SJS/TEN or immunologically confirmed) in the control arm of the included study. ^b We downgraded the evidence to moderate quality, due to study limitations (high risk of detection and attrition bias).

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Table 1. Glossary of terms

Term	Explanation
Allele	One of two or more alternative forms of a gene at corresponding sites (loci) on homologous chromosomes
Antiretroviral	A class of drugs that inhibit the activity of retroviruses that cause HIV infection
Hardy‐Weinberg equilibrium	This states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences
HLA	Human leukocyte antigen: a group of protein molecules located on bone marrow and other cells that can provoke an immune response
Hypersensitivity	A state of altered reactivity in which the body reacts with an exaggerated immune response to a foreign substance, such as a drug
Immunologically confirmed	Patch testing is done to see whether a particular drug is causing allergic skin reaction. Patch test can detect delayed allergic or immunological reaction and confirm the diagnosis of hypersensitivity.
Phenotypes	The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment
Polymorphic	A variation in the DNA that is too common to be due merely to new mutation. A polymorphism must have a frequency of at least 1% in a population
Maculopapular rash	A rash with both macules (flat and coloured like a freckle) and papules (a small raised spot)
Sequelae	A condition that is a consequence of a previous disease or injury
T‐cells	Another term for T‐lymphocyte, a type of cell that participates in immune response

Table 1. Glossary of terms

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Table 2. Associations between drug‐induced skin injury and genetic variants in the HLA genes

Drugs associated with skin injury	Class of drug	HLA allele	Population	Reference
Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
Allopurinol	Antiuric acid	B*5801	Han Chinese	Hung 2005
‐	‐	‐	Thai	Tassaneeyakul 2009
‐	‐	‐	Japanese	Kaniwa 2008
‐	‐	‐	Malay	Ding 2010
Carbamazepine	Antiepileptic	B*1502	Han Chinese	Cheung 2013; Chung 2004; Chong 2013; Hung 2006; Man 2007
‐	‐	‐	Thai	Kulkantrakorn 2012; Locharernkul 2008; Tassaneeyakul 2010; Tangamornsuksan 2013
‐	‐	‐	Malay	Ding 2010
‐	‐	‐	Indian	Mehta 2009
‐	‐	A*3101	White	Amstutz 2013; McCormack 2011;
‐	‐	A*3101	Japanese	Ozeki 2011
Phenytoin	Antiepileptic	B*1502	Han Chinese	Hung 2010; Man 2007
‐	‐	‐	Thai	Locharernkul 2008;
Oxicam	Non‐steroidal anti‐inflammatory drug (NSAID)	A2, B12	White	Roujeau 1987
Sulphamethoxazole	Antibiotic	A29, B12, DR7	White	Roujeau 1986
Hypersensitivity syndrome (drug‐induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS))
Abacavir	Antiretroviral	B*57:01	White	Hetherington 2002; Hughes 2004a; Mallal 2002; Mallal 2008; Martin 2004
‐	‐	‐	African American	Hughes 2004b; Saag 2008
Aminopenicillins	Antibiotic	A2, Drw52	White	Romano 1998
Nevirapine	Antiretroviral	DRB1*01	White ‐ Australian	Martin 2005
‐	‐	DRB1*01	White ‐ French	Vitezica 2008
‐	‐	Cw8, B14	White ‐ Italian	Littera 2006
‐	‐	Cw8	Japanese	Gatanaga 2007
‐	‐	B*3505	Thai	Chantarangsu 2009
‐	‐	Cw4	Thai	Likanonsakul 2009
‐	‐	C*0404	Black African	Carr 2013
‐	‐	Cw*04	Chinese	Gao 2012
Aspirin	NSAIDs	DRB11302, DQB10609	‐	Kim 2005; Palikhe 2008
‐	NSAIDs	DR11	‐	Quiralte 1999
Iodine contrast media	‐	DR	White ‐ Spanish	Torres 2008
Paraphenylenediamine	Hair dye	DP	White ‐ German	Sieben 2002
Gold sodium thiomalate	Treatment of rheumatoid arthritis	DR5	White ‐ Spanish	Rodriguez‐Pérez 1994
Lamotrigine	Antiepileptic	B5801, A6801	White	Kazeem 2009
Trichloroethylene	Industrial solvent, dry cleaning	B*1301	Japanese	Li 2007; Watanabe 2010
Fixed drug eruptions
Co‐trimoxazole	Antibiotic	A30, B13, Cw6	White ‐ Turkish	Ozkaya‐Bayazit 2001
Feprazone	Analgesic	B22	‐	Pellicano 1997

Table 2. Associations between drug‐induced skin injury and genetic variants in the HLA genes

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Comparison 1. Genetic testing with skin patch testing versus no genetic testing with skin patch testing

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hypersensitivity (HSS), immunologically confirmed Show forest plot	1	1644	Risk Ratio (M‐H, Fixed, 95% CI)	0.02 [0.00, 0.37]

Comparison 1. Genetic testing with skin patch testing versus no genetic testing with skin patch testing

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Comparison 2. Genetic testing versus no testing

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hypersensitivity (HSS) Show forest plot	1	1650	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.28, 0.67]

Comparison 2. Genetic testing versus no testing

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