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Maculo-papular rash induced by lopinavir/ritonavir

European Journal of Dermatology. Volume 15, Number 2, 97-8, March-April 2005, Clinical report

Summary

Author(s) : Donato Calista , Dermatology Unit, M. Bufalini Hospital, 47023 Cesena, Italy.

Summary : Two patients with HIV disease developed a pruritic, maculo-papular rash shortly after introducing an association of 2 protease inhibitors (PI) lopinavir/ritonavir (Kaletra ^®). The dermatitis started respectively 7 and 10 days after taking Kaletra ^®, improved on withdrawal, and relapsed following its reintroduction. Although itchy, the dermatitis was not life-threatening, and the patients were treated “through the rash” without suspending the drug. Histopathologic examination of lesional skin showed a non-specific inflammatory infiltration consisting of neutrophils and lymphocytes, but there were no eosinophils, nor dilatation of capillaries in the papillary dermis. HIV positive patients are more prone to drug-related rashes than the general population. Awareness of the side-effects of PI plays an important role in keeping compliance with the treatment and helps patients reach their goal in controlling the development of HIV. The safety profile of Kaletra ^® and its cutaneous side effects have yet to be completely elucidated.

Keywords : cutaneous side effect, protease inhibitors, lopinavir, ritonavir, maculo-papular rash

ARTICLE

Auteur(s) :, Donato Calista^*

Dermatology Unit, M. Bufalini Hospital, 47023 Cesena, Italy

accepté le 3 Août 2004

Kaletra^® (Abbott Laboratories, North Chicago, IL, USA), is a combination of two protease inhibitors: ritonavir (r) and lopinavir (LPV). Ritonavir acts as a pharmacokinetic enhancer, by inhibiting cytochrome P450 (CYP3A), slowing the metabolism of LPV and consequently increasing its plasmatic concentration [1, 2]. Kaletra^® is generally well-tolerated. The most common side-effects are diarrhoea, asthenia, nausea, and headaches [3]. Kaletra^® also increases triglycerides, cholesterol, hepatic enzyme and glucose levels. In addition, pancreatitis and bradyarrhythmia have also been observed occasionally [1, 3]. We report 2 patients who developed a severe, pruritic, maculo-papular drug reaction on the trunk, buttocks, arms and thighs shortly after LPV/r was started.

Case 1

A 41-year-old man, diagnosed with AIDS, and chronic active hepatitis C, presented with a pruritic erythema that started on the back and spread to the inner part of the upper and lower extremities. The rash appeared 7 days after antiretroviral combination therapy, including nevirapine, didanosine (ddI), and stavudine (d4T), was changed to LPV/r, lamivudine (3CT) and d4T because the viral RNA load, initially undetectable, increased to 20,120 copies/mL. The patient denied any sense of prostration, any history of drug reactions and had received no other treatment during the previous 2 months. Laboratory evaluation revealed the patient’s chemistry profile and urinalysis within normal values: haemoglobin (Hb) 12.8 g/dL (n.v.12-14); white blood cell count (WBC) 5.200 mm³ (n.v. 4.600-9.800); platelet 48.100 mm³ (n.v. 142.000-424.000); albumin 3.9 g/dL (n.v.3.8-5.1); gamma glutamyltransferase 32 U/L (n.v. < 28); alanine amino transferase 35 U/L (n.v. < 37); aspartate amino transferase 38 U/L (n.v. < 40), IgE 66 (n.v. < 90).

Clinical examination revealed several erythematous macules and papules on the trunk, buttocks and arms. Under a normal epithelium, histopathologic examination of the lesional skin showed a mild lymphocytic inflammation and dilatation of capillaries in the papillary dermis. LPV/r was suspected of being the culprit drug since the patient had previously been treated with zidovudine (ZDV), ddI, d4T, 3TC, ritonavir and indinavir without cutaneous problems. Kaletra^® was discontinued and the erythema regressed over the next 5 days, with no need for symptomatic medication such as antihistamines or corticosteroids. Four weeks later, patch-tests with LPV/r diluted at 20 p. 100 in petrolatum were performed, giving negative results on Day 2 and Day 3. Ten days later, the drug was started again at full dose and without any premedication. The rash reappeared within 48 hours, in a minor clinical form. Treatment was continued as the symptoms were well-tolerated. HIV-RNA is undetectable at 33 weeks of treatment.

Case 2

A 46-year-old man with AIDS and chronic active hepatitis C developed a bright-red, pruritic, macular eruption on the trunk 10 days after he started antiretroviral therapy with LPV/r, 3TC and d4T. The patient had previously been treated with HAART including various combinations of saquinavir, ritonavir, indinavir, nelfinavir, ZDV, ddI, d4T, and 3TC. The latest switch in the regimen was due to the onset of HIV resistant strains during therapy with nelfinavir, d4T and 3TC and to the increase of the viral RNA load to 41.647 copies/ml. Physical examination revealed numerous erythematous macules and papules on his trunk and arms.

Laboratory tests resulted as follows: haemoglobin (Hb) 13.1 g/dL (n.v.12-14); white blood cell count (WBC) 4,200 mm³ (n.v. 4.600-9.800); platelet 88,800 mm³ (n.v. 142.000-424.000); albumin 4.3 g/dL (n.v. 3.8-5.1); gamma glutamyltransferase 30 U/L (n.v. < 28); alanine amino transferase 30 U/L (n.v. < 37); aspartate amino trasferase 41 U/L (n.v. < 40), IgE 66 (n.v. < 90). A biopsy specimen of affected skin showed a mild, non-specific inflammatory infiltration composed of neutrophils and lymphocytes, but no eosinophils, nor dilatation of the capillaries in the papillary dermis. Erythema regressed once Kaletra^® was discontinued. Four weeks later, patch-tests with LPV/r diluted at 20 p. 100 in petrolatum gave negative results on Day 2 and Day 3. After another 20-day washout period, the LPV/r association was restarted at full dose and without any premedication. The patient reported mild pruritus on the trunk, which persisted for some weeks and then regressed within 2 months. It was not necessary to suspend treatment. HIV-RNA is undetectable at 32 weeks of treatment.

Comment

This is the first report of a cutaneous maculo-papular rash induced by the association LPV/r. The fact that the dermatitis started shortly after treatment with Kaletra^® began, regressed after its discontinuation, and relapsed following its reintroduction, confirms the causal relationship. Histopathologic examination of lesional skin failed to detect lymphocytic infiltration in the dermis or an immune reaction against keratinocytes or membrane basement, excluding implication of an immune process. Non-immunologic mechanisms such as overdoses, interaction between drugs, metabolic alterations, activation of specific cytokine pathways, inherited enzyme or protein deficiencies, are more likely to be involved [4]. Hepatic diseases may also be connected with an increased risk of cutaneous drug reactions [5, 6]. In our patients, previous personal or familial episodes of drug allergy or intolerance were excluded, and the mechanism of the cutaneous eruptions is unclear. No mucosal nor vesicles, blister or urticarial lesions were detected in our patients. Although itchy, the dermatitis was not life-threatening, and we chose to rechallenge Kaletra^® and treat the patients “through the rash”. No symptomatic medication such as antihistamines and topical corticosteroids were needed to control the pruritus. After re-challenging was carried out, the dermatitis reappeared in both patients but in a minor clinical form, then regressed within 2 months. HIV-RNA is still undetectable after 33 and 32 weeks of treatment respectively.

Awareness of the side-effects of PI plays an important role in keeping compliance with the treatment and helps patients reach their goal in controlling the development of HIV. The safety profile of Kaletra^® and its cutaneous side effects have yet to be completely elucidated.

References

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2 Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction. Drug Metab Dispos 1999; 27: 902-8.

3 Kikuchi Y, Genka I, Ishizaki A, Sunagawa K, Yasuoka A, Oka S. Serious bradyarrhythmia that was possibly induced by lopinavir-ritonavir in 2 patients with acquired immunodeficiency syndrome. Clin Infect Dis 2002; 35: 488-90.

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5 Gulick R. When to switch and what to switch to: strategic use of antiretroviral therapy. AIDS Read 2000; 10: 156-61.

6 Lascaux AS, Lesprit P, Bertocchi M, Levy Y. Inflammatory oedema of the legs: a new side-effect of lopinavir. AIDS 2001; 15: 819.