Skin rash associated with atazanavir: report of three cases

Abstract

Atazanavir is a new azapeptide inhibitor of HIV protease suitable for patients with marked lipodystrophy. Rash is reported in 6% of patients treated with atazanavir, but no cutaneous reactions have so far been reported in detail [1]. We describe three cases of cutaneous reactions to atazanavir. Case 1 A 40-year-old man was admitted to our unit on 30 August 2004 for diffuse macular rash, jaundice and arthralgia. He had been HIV seropositive since 1991 and was infected by hepatitis B virus in September 2002. He had received various antiretroviral drugs (zidovudine, lamivudine, stavudine, nelfinavir and nevirapine) since 1997, and had been treated with ritonavir (100 mg per day), indinavir (800 mg per day), lamivudine (300 mg per day) and tenofovir (245 mg per day) since September 2002. On 20 August 2004, indinavir was replaced (because of ingrowing toe nail and skin dryness) with atazanavir (300 mg per day). On admission, physical examination showed a diffuse pruritic macular erythematous rash and afebrile subclinical jaundice. The total bilirubin level was 28 mg/l. No other biological abnormalities were found. The HIV-RNA level was undetectable and his CD4 cell count was 612 cells/μl. The atazanavir serum concentration was 324 ng/ml (expected range > 600 ng/ml after 24 h). As the symptoms were mild, the treatment was continued and the rash disappeared spontaneously. No other adverse effects occurred during more than one year of follow-up. Case 2 A 33-year-old man presented to our department on 28 August 2004 with a diffuse macular rash. Eleven days before symptom onset he had started a regimen of atazanavir (400 mg per day), didanosine (400 mg per day) and lamivudine (300 mg per day) after a 5-month treatment-free period. HIV infection had been diagnosed in 1999, and he had had chronic hepatitis of unknown origin since 2003. He received multiple antiretroviral drugs (didanosine, stavudine, efavirenz, zidovudine, lamivudine and nevirapine) between 1999 and March 2004, with no adverse effects. On admission, physical examination showed a diffuse macular rash and jaundice. The total bilirubin level was 202 mg/l, without cholestasis; the serum alanine transferase level was 63 IU/l and the aspartate aminotransferase level was 40 IU/l; the blood cell count and C-reactive protein level were normal. His HIV-RNA level was 4.97 log10 copies/ml and CD4 cell count was 246 cells/μl. The atazanavir plasma concentration was 899 ng/ml. The rash disappeared within 48 h, but the treatment was discontinued after 3 days because of the persistent hyperbilirubinemia and pre-existing chronic hepatitis. Case 3 A 40-year-old man was admitted to our department on 9 September 2004 with a diffuse maculopapular rash. He had been HIV seropositive since 1993 and had received multiple antiretroviral drugs (zidovudine, didanosine, stavudine, indinavir, lamivudine, saquinavir, ritonavir, abacavir, tenofovir and lopinavir); the only noteworthy adverse effect had been a cutaneous reaction to nevirapine 2 years before. Because of viral escape, he started to take a combination of atazanavir (300 mg per day), lopinavir (100 mg per day) and lamivudine (300 mg per day) on 31 August 2004. On admission, physical examination showed a generalized pruritic maculopapular rash. Laboratory tests were normal. His HIV-RNA level was 4.05 log10 copies/ml and his CD4 cell count was 471 cells/μl. An antihistamine was prescribed. The patient was seen 48 h later and the antiretroviral treatment was discontinued because the rash had worsened, but there was no mucous membrane involvement nor fever. Discussion Adverse cutaneous reactions are a treatment-limiting adverse effect of antiretroviral drugs, and are mainly seen with reverse transcriptase inhibitors (nevirapine, abacavir and efavirenz). Two factors point to the probable responsibility of atazanavir in the three cutaneous reactions described here. First, the mean interval between atazanavir introduction and clinical onset was 10 days in all three cases; and second, the antiretroviral drugs combined with atazanavir at the onset of rash had previously been well tolerated. These were the only three cutaneous adverse reactions observed among 323 patients treated with atazanavir in our department since March 2004, giving a prevalence rate of approximately 1%. The rash was sufficiently severe to warrant treatment withdrawal in only one case. Clinicians must be aware of adverse cutaneous reactions to atazanavir, which may require treatment discontinuation.