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
1 Hurst M, Faulds D. Lopinavir. Drugs 2000; 60: 1371-9.
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.
4 Swensson CK, Cowen EW, Gaspari AA. Cutaneous
drug reactions. Pharmacol Rev 2001; 53: 357-79.
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.
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