HLA typing, demographic and immunological risk factors for nevirapine and efavirenz reactions were studied in a French cohort of HIV patients. Cases with isolated rash were significantly associated with HLA-DRB1*01 allele. No liver toxicity was observed and no association was detected with the percentage of CD4 T-cells. This study suggests that HLA-DRB1*01 allele plays an important role in susceptibility to cutaneous reactions associated with nevirapine and efavirenz in HIV patients.
aINSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
bUniversité Toulouse III Paul-Sabatier, UMRs563, Toulouse, France
cCHU Bordeaux, Service de Dermatologie, Hôpital Saint André, Bordeaux France
dLIPM, CNRS INRA UMR 2594, Castanet Tolosan, France
eCHU Nantes, Service de Dermatologie, Nantes France.
Received 20 September, 2007
Accepted 18 October, 2007
Nevirapine (NVP) and efavirenz (EFV) are non-nucleoside reverse transcriptase inhibitors commonly used in the treatment of HIV-1-infected patients. Although 20–35% of patients receiving NVP treatment develop cutaneous adverse reactions [1,2], 32% of patients develop a rash when treated with EFV . In both cases, the development of hypersensitive reactions occurs within 6 weeks of treatment initiation .
Increasing evidence shows that drug hypersensitive reactions are genetically determined. Genetic screenings of human leukocyte antigen (HLA) markers (located within the class I and class II regions of the major histocompatibility complex) have demonstrated the involvement of genetic factors in the susceptibility to hypersensitive reactions to abacavir  and NVP . Recently, hepatotoxic/multisystem NVP reactions (defined by serum alanine aminotranferase levels five-fold greater or more than the upper normal limit) were associated with two risk factors: HLA-DRB1*0101 and CD4 status. Higher pretreatment CD4 T-cell counts (≥ 25%) and HLA-DRB1*0101 were associated with an increased risk of developing these reactions . By contrast, neither HLA-DRB1*0101, nor the percentage of CD4 T cells alone were associated with NVP-induced rash . However, evidence that the mechanism of NVP-induced rash is immune-mediated was provided in an animal model .
We explored the association between HLA-DRB1 alleles and EFV/NVP hypersensitivity in an HIV French Caucasian cohort with skin rash. At the same time, patient immunological characteristics were also evaluated for any possible role in EFV/NVP hypersensitive reactions.
From 2002 to 2004, 21 HIV-infected Caucasian patients (aged > 18 years) were prospectively enrolled in the study. Patients were recruited from nine hospitals in France, according to French laws governing participation in biomedical research and with the approval of the local Ethics Committee. In accordance with the principles of the Helsinki Declaration, each participant received information about the study and provided their informed consent. Patient data protection and confidentiality were ensured.
Among the 21 patients, seven and 14 subjects were treated with EFV and NVP, respectively. Six of the 21 individuals had developed cutaneous adverse drug reactions (hypersensitive group). The control group (15 individuals) had received antiretroviral treatment for at least 6 months without any evidence of cutaneous adverse reactions (tolerant group).
All patients and controls were typed for the HLA-DRB1 locus. Low resolution HLA-DRB1 genotyping was performed by the polymerase chain reaction (PCR) with sequence-specific primers (OLERUP SSP HLA-DRB1 kit; GenoVision, Vienna, Austria). After migration of PCR products on 2% agarose gels, HLA-DRB1 allele types were determined with HELMBERG-SCORE software (GenoVision).
The two groups of NVP/EFV hypersensitive and tolerant patients were compared for age, sex, CD4 T-cell count and HIV viral load. Demographic (sex, age), and immunological data (CD4 T-cell count and HIV viral load) were tested using Fisher's exact tests for categorical data and t-tests for continuous data. The HLA typing was analysed using a logistic regression model. P < 0.05 was considered statistically significant. The corrected P-values (Pc) were adjusted using Bonferroni's correction for comparison of multiple alleles (11 observed alleles for the HLA-DRB1 locus). All statistical analysis were performed using R statistical software (http://www.r-project.org/).
None of the considered variables was significantly associated with hypersensitive reactions (Table 1). All the patients with NVP/EFV hypersensitivity developed isolated skin rash and none showed liver toxicity. Eighty-three percent (five of six) of the NVP/EFV hypersensitive subjects had the HLA-DRB1*01 allele compared to 7% (one of 15) in the tolerant group (P = 0.004, Pc = 0.04). The HLA-DRB1*01 allele, present in 14% of the study cohort, was associated with isolated rash.
No significant differences in the risk of isolated rash were found between the NVP/EFV-hypersensitive and tolerant groups stratified by the percentage of CD4 T cells (≥ 25% and < 25%). These results are in agreement with the data presented for isolated rash by Martin et al.  in which no association was detected with the percentage of CD4 T cells.
The results of our study suggest that the mechanism of NVP/EFV-related isolated rash is different from the mechanism in cases with hepatic/systemic reactions. The isolated rash risk appears to depend on the presence of the predisposing allele HLA-DRB1*01 alone, whereas the risk of hepatic/systemic reactions is associated with an interaction between genetic and immunological factors. Further studies characterizing the NVP/EFV-associated reactions (e.g. hepatotoxicity, fever and/or rash) with larger cohorts are needed. New studies should allow the identification of the underlying risk factors. This would lead to the development of a diagnostic test, and help decrease or eliminate the incidence of NVP/EFV hypersensitive reactions.
Financial support was provided by ANRS and SIDACTION.
1. Barreiro P, Soriano V, Casas E, Estrada V, Tellez MJ, Hoetelmans R, et al
. Prevention of nevirapine-associated exanthema using slow dose escalation and/or corticosteroids. AIDS 2000; 14:2153–2157.
2. Barner A, Myers M. Nevirapine and rashes. Lancet 1998; 351:1133.
3. Havlir DV, Lange JMA. New antiretroviral and new combinations. AIDS 1998; 12(Suppl. A):S165–S174.
4. Cattelan AM, Trevenzoli M, Sasset L, Sgarabptto D, Lanzafame M, Meneghetti F. Toxic epidermal necrolysis induced by nevirapine therapy: description of two cases and review of the literature. J Infect 2001; 43:246–249.
5. Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, et al
. Predisposition to abacavir hypersensitivity conferred by HLA-B*
5701 and a haplotypic Hsp70-Hom variant. PNAS 2004; 101:4180–4185.
6. Martin AM, Nolan D, James I, Cameron P, Keller J, Moore C, et al
. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*
0101 and abrogated by low C T-cell counts. AIDS 2005; 19:97–99.
7. Shenton JM, Popovic M, Chen J, Masson MJ, Uetrecht JP. Evidence of an immune-mediated mechanism for an idiosyncratic nevirapine-induced reaction in the female brown norway rat. Chem Res Toxicol 2005; 18:1799–1813.