Cutaneous side effects induced by indinavir

ARTICLE

Highly active anti-retroviral therapy (HAART) is the association of a protease inhibitor (PI) with one or two nucleoside reverse transcriptase inhibitors (NRTI's) for the treatment of patients with HIV infection [1]. The double or triple-combination of such drugs provides strong activity against HIV replication, reducing the viral load to under the PCR test cut-off and partially restoring the immune system in nearly 80% of the patients after 24 weeks [2-4].

Protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and more recently amprenavir) demonstrated such high efficacy in the first short-term studies that the FDA has accepted them for use, even though their long-term efficacy and possible toxicity remain to be verified [4].

We report our experience of adverse cutaneous effects observed in a group of 101 patients, followed for 12 months and treated with indinavir in association with two NRTI's chosen from zidovudine (ZDV), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC) or stavudine (d4T).

Patients and methods

This study was performed at the San Patrignano Medical Centre, Rimini, Italy. San Patrignano is the largest therapeutic recovery community centre for drug addicts in Europe. It accommodates about 1,450 people from all over Italy, 377 (26%) of them affected by HIV disease.

Between January 1997 and August 1998, 101 patients were followed up to monitor the side effects of combined anti-HIV therapy.

Seventy-three were male, 28 female; their ages ranged from 25 to 60 years, with an average of 34. At the time they started indinavir therapy, 23 patients were classified as B2, 24 as B3, and 37 as C3 using the Centers for Disease Control and Prevention staging classification.

The treatment was offered to subjects who had not responded to previous therapies with two RTI, or to naive patients (i.e. never treated before) with CD4⁺ cell count less than 300 mm³, and/or HIV-RNA viral load of over 50,000 copies/ml. Seventy-one (70%) had previously received multiple anti-retroviral therapy, monotherapy (ZDV since 1989) or dual therapy (ZDV, ddI, ddC, 3TC or d4T since 1995), thirty were naive.

Sixty-one patients were given triple combination therapy with indinavir (800 mg t.i.d.), 3TC (150 mg b.i.d.) and d4T (30-40 mg b.i.d.); 29 took indinavir, ZDV (300 mg b.i.d.) and 3TC; 11 were given indinavir, ddI (400 mg once a day) and d4T.

In addition, most of the patients were on prophylactic drugs for opportunistic infections: 45 were taking cotrimoxazole, 42 azithromycin or clarythromycin, 10 pentamidine aerosol and 5 dapsone.

The baseline examinations included blood cell laboratory tests and serum chemistry, specifically cholesterol, tryglicerid, glycaemia, LDH, hepatic and renal function, CD4⁺ and CD8⁺ lymphocyte counts, ß-2 microglobulin, immunoglobulins and serum HIV-1 RNA levels.

Results

Seven patients were lost to follow-up because of a relapse into addiction. Ten discontinued HAART therapy within 4 months for reasons not related to dermatological problems. In this group, 4 had renal colic, 3 abdominal pain and 3 were non-compliant and were therefore excluded from the study. Eighty-four patients, followed for at least 12 months, were eligible for evaluation (range 12-20 months, average 16 months). After 12 months of treatment, the patient's CD4⁺ cell count had increased significantly from an average base line value of 106 mm³ to 434 mm³. The HIV-RNA levels had dropped from a baseline of 75,000 copies/mm³ to below 200 copies/ml in 82% of the subjects within the same time. All the patients experienced a rapid general improvement while on the medication and in some cases the prophylactic treatment could be reduced or even suspended.

Cutaneous side effects

Forty-eight of the 84 patients (57.1%) developed cheilitis within the 3rd month of therapy (Fig. 1). Symptoms varied in intensity from simple reddening with dryness, to rough cracked aspects. Cheilitis was treated with greasy ointments.

Thirty-four (40.5%) experienced generalised xerosis and pruritus without signs of dermatitis after about 2 months. Only 16 subjects required a treatment with bath oils or emollients.

Ten patients (11.9%) developed asteatotic dermatitis: round plaques were distributed symmetrically on the back, buttocks, arms and thighs and/or erythematous, slightly scaly lesions appeared on the trunk in an irregular netlike pattern (Figs. 2 and 3). The dermatitis occurred within
2 months after indinavir was started. Pruritus and a moderate tendency to dryness were the main symptoms. In one patient a lichenoid papular eruption was observed on the flexor aspect of the wrists. Histological examinations showed psoriasiform acanthosis, hypergranulosis with focal parakeratosis and scale-crusts, vasodilatation and mild to moderate perivascular lymphocytic infiltration in the superficial and mid dermis. Bath oil and urea-based emollients relieved the symptoms. Two patients were treated with topical corticosteroids, while another two, initially diagnosed as having psoriasiform dermatitis, were treated with psoralen plus UVA (PUVA).

At first we missed the connection between the onset of the dermatitis and the administration of indinavir, but subsequently the link became evident. When this drug was occasionally discontinued in two patients, pruritus faded and the dermatitis disappeared in 10 days. Symptoms reappeared when indinavir was restarted. Furthermore, when indinavir was replaced with nelfinavir in six patients, the dermatitis persistently regressed in 10 days.

After an average of 5 months of treatment, ten patients (11.9%), 8 men and 2 women, complained that their body hair had become fairer, finer and thinner because of significant shedding. In some cases the lighter eyebrows changed the patient's appearance considerably (Fig. 4).

Severe alopecia was observed in 1 subject, moderate defluvium in 8, thinning of eyebrows, eyelashes, armpits and arms in 8. Hair loss then stabilised in 7 patients who were still taking indinavir and regressed in another 3 after they had stopped the drug. Multiple pyogenic granulomas on the toes were observed in 5 patients (5.9%), without any precedent trauma. Softening of the nail plate was noted in 5.

Lipodystrophy syndrome, a reduction of adipose tissue deposits of the face, limbs and upper trunk or, conversely, an accumulation of fat in abdomen, breast and neck, was noted in 12 patients (14.3%) after a median of 8 months from the beginning of therapy. The lower amount of fat in the cheeks and nose-labial folds gave the patient's face an emaciated appearance (Fig. 5), while on the arms, buttocks and legs the superficial veins became more noticeable (Fig. 6). One patient developed a "buffalo hump" and another had diffuse lipomatosis. Due to the onset of lipodystrophy all the patients stopped taking indinavir but the symptoms did not regress.

Discussion

The leading aim of antiretroviral therapy for HIV is the suppression of viral replication. Since its introduction in 1987 and for several years ZDV monotherapy was the only treatment available for patients with HIV infection [5]. In 1993, combination therapy, in which ddI or ddC were added to ZDV, demonstrated higher efficacy in reducing the progression of the disease and its mortality [6].

Since 1996, PIs have changed physicians' opinion about the futility of treating HIV disease [7, 8].

PIs selectively block HIV protease, by inhibiting the post-translational processing of gag and gag-pol polyprotein precursors, thus resulting in the production of non-infectious virions [4, 8].

Evidence indicates that, to avoid the onset of HIV viruses resistant to PI, the best way of suppressing HIV replication is by starting the combination therapy using PI in double or triple-combination with NRTI or other analogue nucleoside drugs [4, 7, 8]. The selection of the combination therapy must take into consideration the patient's prior administration of antiretroviral drugs, the potential interactions that occur among these agents and with other drugs as well, and their side effects [4, 7, 8].

The assessment of cutaneous reactions in patients with AIDS is sometimes difficult, as they are often treated with multiple drugs, and are particularly prone to developing hypersensitivity [2].

We did not observe hypersensitivity or allergic reactions to indinavir, probably because our sample was too small, the time of observation too short and not least because indinavir is a relatively safe drug. We did observe unexpected cutaneous toxic effects to indinavir.

Most of the adverse cutaneous events associated with indinavir: dryness, pruritus, cheilitis, dermatitis, scalp or body defluvium, alopecia, and pyogenic granulomas in the toenails [10-14], are similar to those caused by retinoids and in fact these could be the consequence of an altered retinoic acid metabolism [9, 15, 16]. Even histologically patients treated with retinoids may present aspects of epithelial differentiation, such as hyperplasia and hypergranulosis of the epidermis, which also occurred in our patients.

Homologies between the amino acid sequences of retinoic-acid binding protein and the catalytic site of HIV-1 protease have been noted [15]. The structural identity between indinavir and retinoids could explain why some specific retinoic acid receptors, which regulate the activity of vitamin A and/or its synthetic analogues, may be occupied and activated by indinavir [15].

Asteatotic dermatitis induced by indinavir has not been previously reported. We hypothesise that the altered retinoic acid metabolism induced by indinavir may have reduced the secretion of the sebaceous glands and consequently impaired the horny layer water-binding capacity.

A similar rash that appeared within two weeks from the beginning of indinavir therapy has recently been described in 67% of 110 patients by Mann et al. [17].

The international literature reports several observations of PI related lipodystrophy [15-21]. Indinavir-induced lipodystrophy is characterised by a fat loss from the face and limbs and an abnormal abdominal or neck fat accumulation often accompanied by hypertriglyceridaemia, hypercholesterolemia or insulin resistance. It has been observed in 24 to 64% of patients taking HAART and appears at an average of 10 months after treatment began [21].

In our experience, peripheral lipodystrophy occurred in 14.2% of patients. We have no explanation for this lower prevalence: selection bias could play a role, as could different methods of assessing the thickness or quantity of adipose tissue. The pathophysiological mechanism for these events remains unclear and a casual link to a specific drug or drug class is uncertain. However, the abnormal body fat distribution clearly develops with the administration of PIs, while it does very rarely with other antiretroviral therapies [17]. Indinavir-related alopecia [11, 13], paronychia [12, 14] pyogenic granuloma [12] and Stevens-Johnson syndrome [21] have occasionally been reported. We did not observe any connection between the number of CD4⁺ lymphocytes, the viral load, the clinical stage of HIV disease and the side effects that occurred in our patients. These cutaneous side effects led to the interruption of therapy in 8 out of 84 patients (9.5%) soon after the start of treatment. Interestingly, hair loss was the most annoying and alarming of all. Some patients, who simultaneously experienced renal colic, nausea, vomiting, diffuse and itchy dermatitis, troublesome cheilitis and abnormal distribution of their subcutaneous fat, demanded to stop the treatment only after realising their hair was falling out.

We believe that the patients staying at San Patrignano, like those in similar community centres are unique, in that they have been regularly subjected to medical examinations and can receive the consultation of a specialist within their clinic. Two or more members of the staff at all times of the day follow each patient and consequently compliance to the therapeutic regimens is almost total [22]. San Patrignano is a privileged observatory where we can easily watch for the cutaneous findings associated with HIV-1, monitor their progression and possibly study new secondary effects of the administered drugs. A multidisciplinary team is desirable to approach HAART therapy adequately and further effort has to be made to achieve better knowledge of its side effects.

Article accepted on 17/1/00

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