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Dermatologic complications associated with administration of 2′,3′-dideoxycytidine in patients with human immunodeficiency virus infection
Dermatologic complications associated with administration of 2',3'-dideoxycytidine in patients with human immunodeficiency virus infection M. Carol McNeely, MD, PhD,a Robert Yarchoan, MD,b Samuel Broder, MD,b and Thomas J. Lawley, MDa Bethesda, Maryland We describe a distinctive mucocutaneous eruption that occurred in 14 of 20 (70%) patients with human immunodeficiency virus infection while they were being treated with a new therapeutic agent, 2' 3'-dideoxycytidine. A maculopapular eruption developed in these patients on day 10 or 11 of treatment. Seven of 14 patients, especially those receiving higher-dose therapy, also had systemic symptoms. In addition, oral ulcers developed in 9 of 14 patients on days 4 to 6 of therapy. The occurrence of the cutaneous and oral lesions correlated with dose, route, and schedule of administration of 2'3' -dideoxycytidine. In most instances the mucocutaneous lesions resolved even with continuation of therapy. (J AM ACAD DERMATOL 1989:21:1213-7.) Identification of the acquired immunodeficiency syndrome (AIDS)1-3 and its etiologic agent, human immunodeficiency virus (HIV),4, 5 has led to an intense search for therapeutic agents that might prevent infection or inhibit progression of the disease. The use of a 2! ,3'-dideoxynucleoside, 3'-azido-2'3'deoxythymidine (zidovudine [AZT]; previouslyused name azidothymidine), confers improved clinical and immunologic status in infected patients but also results in significant bone marrow toxicity.6-8 In efforts to identify another agent with similar or possibly greater clinical activity but with a different profile of toxicity, a cytidine analogue, 2' ,3'-dideoxycytidine (ddC), recently has been administered to patients with AIDS or AIDS-related complex. 9 During the course of this clinical trial, a distinctive transient complex of mucocutaneous lesions developed, which is described in this report.
Institutes of Health in Bethesda, Maryland. 9 Informed consent was obtained from all patients. The patients with AIDS had either a documented history of Pneumocystis carinii pneumonia or Kaposi's sarcoma; those with AIDSrelated complex had weight loss or oral candidiasis. All patients were either homosexuals or previous users of intravenous drugs with circulating antibodies to HIV and fewer than 350 helper (CD4) T lymphocytes/rom3 . Patients were assigned to one offive intravenous dose schedules for an initial2-week period, followed by oral administration at the same dose for 4 or more additional weeks. Other oral or systemic medications were given only when medically indicated. During the course of intravenous therapy with ddC, a distinctive spectrum of mucosal and cutaneous lesions with occasionally associated systemic symptoms developed in 14 of 20 patients (Table I). The following two case reports exemplify the clinical variability of the cutaneous, mucosal, and systemic involvement.
PATIENTS AND METHODS
Patient III (8)*
Twenty men with AIDS or AIDS-related complex were entered into a phase I (dose seeking) trial of ddC at the Warren G. Magnuson Clinical Center of the National
P. carinii began a course of intravenous ddC at a dosage
From the Dermatology Branch" and Clinical Oncology Program, b National Cancer Institute, National Institutes of Health, Accepted for publication Dec, 28, 1988. Reprint requests: M. Carol McNeely, MD, PhD, Dermatology Branch, Bldg. 10, Rm 12N254, N.I.H. Bethesda, MD 20892.
16/1/10306
A 42-year-old white man with AIDS and a history of of 0.03 mg/kg every 4 hours. An asymptomatic maculopapular eruption with numerous pinkish-red macules and papules, (2 to 4 rom in diameter) developed on his chest and back on day 9 oftherapy. The lesions had no scale and blanched with pressure. No mucosal, palmar, or plantar *Case numbers are cross-referenced with arabic numerals to correlate with notations concerning these same patients in the article by Yarchoan etal. 9
1213
1214 McNeely et ai.
Journal of the American Academy of Dermatology
Fig. 1. Patient XI (17). A 56-year-old man with AIDS and Kaposi's sarcoma, with superficial oral ulcerations on lower lip mucosae (right lower lip) that occurred on day 6 of intravenous ddC therapy. Fig. 2. A, Patient XI (17). Erythematous, edematous papules distributed on trunk and extremities, which occurred on day 10 of intravenous ddC therapy. B, Closer examination revealing edematous, raised character of individual lesions.
lesions were noted. The patient was afebrile and completely asymptomatic from the eruption. He continued the ddC and began oral therapy on day 14 despite the persistence of the eruption. The eruption resolved on days 17 and 18 with continued oral ddC administration.
Patient XI (17) A 56-year-old white man with AIDS and Kaposi's sarcoma began intravenous ddC therapy at a dosage of 0.09 mg/kg every 4 hours. The patient first noted slightly tender ulcers on his buccal mucosae on day 6 of intravenous therapy (Fig. 1). Five erythematous shallow erosions,3 to 5 mm in diameter, with gray borderswere noted
on the lower lip and buccal mucosae. Multiple cultures were negative for herpe~ simplex, varicella, and cytomegalovirus. On day 10 of intravenous therapy a diffuse eruption of erythematous macules and papules developed on the patient's arms, legs, and trunk. The lesions were brightly erythematous and edematous without scaling or target lesions (Fig. 2, A and B). The palmoplantar surfaces were not involved. In addition to the oral and cutaneous lesions, symptoms included fevers, malaise, myalgias, and generalized pruritus. In spite of these mucocutaneous lesions and systemic symptoms, the intravenous course of ddC was completed, and therapy was changed to an oral dosage of 0.09 mg/kg every 4 hours.
Volume 21 Number 6 December 1989
Dermat%gic complications with use of Y,3' -dideoxycytidine 1215
Table I. Dermatologic findings Dosage Patient
I II III IV V VI VII VIII IX X XI XII XIII XIV
Cutaneous lesions
Oral lesions
Morbilliform, trunk Morbilliform, trunk Maculopapular, trunk Erythroderma, scaling macules Erythroderma Generalized papulovesicular Morbilliform Morbilliform Maculopapular, trunk Papules, generalized Papules, generalized Generalized papules, plaques Morbilliform Morbilliform
Aphthae Aphthae None None Aphthae Aphthae None Aphthae, lip edema None Aphthae Aphthae Aphthae None Aphthae
(mgjkg)
(3) (4) (8) (10) . (11) (12) (13) (14) (15) (16) (17) (18) (19) (20)
0.03 0.03 0.03 0.06 0.06 0.06 0.06 0.06 0.09 0.09 0.09 0.09 0.09 0.25
q.8h. q.8h. qAh. qAh. qAh. q.4h. qAh. q.4h. q.4h. q.4h. q.4h. qAh. qAh. q.8h.
10 10 9 30 10 10 11-12 10 12 10 10 11 10 10
Systemic reaction
+ + + + + + +
*Casc numbers are cross-referenced with arabic numerals to correlate with notations concerning these patients in the article by Yarchoan et aU
Table II. Histologic findings Patient
I No.*
II IV V
(4) (10) (11)
VI VII IX X XI XII
(12) (13) (15) (16) (17) (18)
XIV
(20)
1--------------H-j-st-OIO-g-ic-fi-nd-j-ng-s--------------
No epidermal change; mild perivascular lymphocytic infiltrate Mild spongiosis with minimal exocytosis; diffuse perivascular lymphocytic infiltrate No epidermal change; minimal exocytosis; extravasated red blood cells in papillary dermis; deep and superficial perivascular lymphocytic infiltrate with occasional eosinophils Mild exocytosis; moderate papillary edema; superficial perivascular lymphocytic infiltrate Mild perivascular lymphocytic infiltrate Minimal perivascular lymphocytic infiltrate Moderate papillary edema with focal perivascular lymphocytic infiltrate Moderate papillary edema with focal perivascular lymphocytic infiltrate Marked papillary edema with dermoepidermal separation; marked lymphocytic infiltrate in papillary dermis and dermal vessels Focal epidermal spongiosis; perivascular lymphocytic infiltrate
*Case numbers are cross-referenced with arabic numerals to correlate with notations concerning these patients in the article by Yarchoan et al.9
The systemic symptoms abated within 48 to 72 hours and the mucocutaneous lesions within a 3- to 7-day period with continuation of oral ddC therapy.
Light microscopy After informed consent was obtained, skin biopsy specimens, 3 or 4 mm in diameter, were taken from involved sites in 10 patients, fixed in 10% neutral formalin, and processed for routine hematoxylin-eosin staining. RESULTS
Clinical presentation An overview of the results from administration of ddC to 20 patients with HIV infection recently has
been reported by Yarchoan et a1. 9 In this study the use of ddC in various dosage schedules resulted in an early increase in absolute numbers of patients' helper T cells and a decrease in serum levels of HIV p24 antigen, suggesting in vivo suppression of HIY. Nondermatologic side effects and complications of ddC included neutropenia and thrombocytopenia (at high doses) and a painful peripheral neuropathy that developed after 8 or more weeks of continuous high-dose therapy. The latter complication was the dose-limiting toxicity of this drug. All side effects were reversible with discontinuation of the drug, although at high doses the peripheral neuropathy took weeks or months to resolve. All toxicities occurred
1216
Journal of the American Academy of Dermatology
McNeely et at.
during a 4- to 10-day period. Two patients in whom ddC therapy had been stopped, patients V( 11) and VI(l2), were rechallenged after a period of abstention, and a recurrence of their mucocutaneous lesions with systemic symptoms developed within 2A hours of receiving a single oral dose. In addition to cutaneous lesions associated with the administration of ddC, either the onset or the exacerbation of oral ulcers on the buccal, mucosae, soft palate, tongue, and pharynx occurred in 9 of 14 patients. Cultured tissue biopsy specimens or smears of the lesions were consistently negative for herpes simplex virus, candidal species, and cytomegalovirus. These oral lesions resolved with either discontinuation of ddC or within the third week of oral ddC therapy (patients U(4), V( 11), VI(L2), VIII(l4), and XIV(20). Histologic findings
Fig. 3. Histologic section of cutaneous lesion from patient receiving ddC shows a superficial perivascular infiltrate of lymphocytes. (Hematoxylin-eosin stain; X40).
more commonly in the patients receiving higher doses of ddC. Table I presents a correlation of the dermatologic findings in 14 patients with the dosage schedule of ddC, time ofonset of mucocutaneous lesions, and the presence or absence of systemic symptoms. The patients received dosages of ddC ranging from 0.03 mg/kg to 0.25 mg/kg every 4 to 8 hours intravenously for 2 weeks, followed by oral administration of the same dosage schedule for an additional 4 or more weeks. Cutaneous lesions varied from small erythematous macules and papules on the trunk to a generalized distribution of red edematous papules associated with signs and symptoms of fever, arthralgias, and myalgias. Fifty percent (7/14) of the patients also had systemic symptoms. The onset of cutaneous lesions with or without systemic symptoms usually occurred on day 10 or 11 of the intravenous drug schedule. In all patients, including those who continued receiving the drug, the systemic side effects of fevers, arthralgias, or myalgias resolved within 48 to 72 hours after onset, and cutaneous lesions resolved
Skin biopsy specimens were obtained from 10 patients with various cutaneous lesions. The histologic findings are summarized in Table II with a representative histologic section shown in Fig. 3. DISCUSSION
2',3'-Dideoxycytidine is a nucleoside analogue lO with potent in vitro inhibitory effects on the replication of HIV-infected helper T cells. I1-13 Recently ddC was administered in a phase I trial in persons infected with HIV. 9 Most patients given ddC were observed to have a decrease in viral load and/or an increase in immunologic function. Cutaneous complications, however, developed in 70% of patients. It is interesting that in the nine patients who continued therapy after these complications developed, the systemic symptoms resolved within 48 to 72 hours and the oral and/or cutaneous lesions resolved within 4 to 7 days. The relationship between resolution of systemic and mucocutaneous side effects and the continued administration of ddC therapy is somewhat complex. In the patients who discontinued therapy, symptoms and lesions resolved without recurrence. Two patients were later rechallenged with a single oral dose of ddC after a 2- to 4-week drug-free period; this administration resulted in a recurrence (within hours) of mucocutaneous lesions and fever. Yet, as noted, in nine patients all cutaneous lesions resolved while they received therapy. The resolution of symptoms possibly could be associated with a change in route of administration of the drug, in part
Volume 21 Number 6 December 1989
Dermatologic complications with use of 2',3' -dideoxycytidine 1217
because only 70% to 80% of this drug is absorbed by the oral route. Development of symptoms, however, is not likely to be restricted to the intravenous route of administration inasmuch as cutaneous eruptions have not been noted in patients given ddC by the oral route only (R. Yarchoan and S. Broder, unpublished observations). 14 In either case the cutaneous side effects were transient and resolved with continued therapy in more than 60% of affected patients. It is also worth stressing that these side effects do not develop, or they develop in a very mild form, in patients given lower doses of ddC (e.g., 0.05 or 0.01 mg/kg every 8 hours).9, 14 REFERENCES 1. Gottlieb MS, Schroff R, Schanker HM, et aL Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981 ;305: 1425-31. 2. Masur H, Michelis MA, Greene JB, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305:1431-8. 3. Siegal FP, Lopez, Hammer GS, et aL Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981;305:1439-44. 4. Barre-Sinoussi F, Chermann JC, Rey F, et aL Isolation of a T -lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868-71. 5. Gallo RC, Salahuddin SZ, Popovic M, et aL Frequent detection and isolation of cytopathic retroviruses from patiaents with AIDS and at risk for AIDS. Science 1984; 224:500-3.
6. Yarchoan R, Klecker RW, Weinhold KJ, et al. Administration of 3'-azido-3' deoxythymidine, an inhibitor of HTLV-I1I/LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1986;1:575-80. 7. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo controlled triaL N Engl J Med 1986;317:185-91. 8. Richman 0, Fischl MA, Greico MH, et aL The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo controlled triaL N Engl J Med 1986;317:192-97. 9. Yarchoan R, Perno CF, Thomas R, et al. Phase I studies of2' ,3-didcoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988;1:76-81. 10. Horowitz JP, Chua J, Da Rooge MA, et al. Nuc1eosides. IX. The formation of2'3' -unsaturated pyrimidine nucleosides via a novel elimination reaction. J Org Chern 1964;31:205-8. 11. Mitsuya H, Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV) by 2',3'dideoxynucleosides. Proc Nat! Acad Sci USA 1986;83:1911-5. 12. Mitsuya H, Weinhold KJ, Furman PA, et al. 3' Azido-3'deoxythymidine (BWA509U): an anti-viral agent that inhibits the infectivity and cytopathic effect of human Tlymphotropic virus type III/lymphadenopathy associated virus in vitro. Proc N atl Acad Sci USA 1985;82:7096-100. 13. Mitsuya H, Jarrett RF, Matsukura M, et al. Long-term inhibition of human T-Iymphotropic virus type III/lymphadel1opathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2' ,3 I -dideoxynuclcosides in vitro. ProcN atlAcad Sci USA 1987;84:2033-7. 14. Skowron G, Merigan TC, Bozzette S, et al. 2',3' -Dideoxycytidine (ddC) in the treatment of patients with ARC and advanced AIDS. Abstracts of the Fourth International Conference on AIDS, Stockholm, Sweden. June 12-16, 1988.
Institutes of Health in Bethesda, Maryland. 9 Informed consent was obtained from all patients. The patients with AIDS had either a documented history of Pneumocystis carinii pneumonia or Kaposi's sarcoma; those with AIDSrelated complex had weight loss or oral candidiasis. All patients were either homosexuals or previous users of intravenous drugs with circulating antibodies to HIV and fewer than 350 helper (CD4) T lymphocytes/rom3 . Patients were assigned to one offive intravenous dose schedules for an initial2-week period, followed by oral administration at the same dose for 4 or more additional weeks. Other oral or systemic medications were given only when medically indicated. During the course of intravenous therapy with ddC, a distinctive spectrum of mucosal and cutaneous lesions with occasionally associated systemic symptoms developed in 14 of 20 patients (Table I). The following two case reports exemplify the clinical variability of the cutaneous, mucosal, and systemic involvement.
PATIENTS AND METHODS
Patient III (8)*
Twenty men with AIDS or AIDS-related complex were entered into a phase I (dose seeking) trial of ddC at the Warren G. Magnuson Clinical Center of the National
P. carinii began a course of intravenous ddC at a dosage
From the Dermatology Branch" and Clinical Oncology Program, b National Cancer Institute, National Institutes of Health, Accepted for publication Dec, 28, 1988. Reprint requests: M. Carol McNeely, MD, PhD, Dermatology Branch, Bldg. 10, Rm 12N254, N.I.H. Bethesda, MD 20892.
16/1/10306
A 42-year-old white man with AIDS and a history of of 0.03 mg/kg every 4 hours. An asymptomatic maculopapular eruption with numerous pinkish-red macules and papules, (2 to 4 rom in diameter) developed on his chest and back on day 9 oftherapy. The lesions had no scale and blanched with pressure. No mucosal, palmar, or plantar *Case numbers are cross-referenced with arabic numerals to correlate with notations concerning these same patients in the article by Yarchoan etal. 9
1213
1214 McNeely et ai.
Journal of the American Academy of Dermatology
Fig. 1. Patient XI (17). A 56-year-old man with AIDS and Kaposi's sarcoma, with superficial oral ulcerations on lower lip mucosae (right lower lip) that occurred on day 6 of intravenous ddC therapy. Fig. 2. A, Patient XI (17). Erythematous, edematous papules distributed on trunk and extremities, which occurred on day 10 of intravenous ddC therapy. B, Closer examination revealing edematous, raised character of individual lesions.
lesions were noted. The patient was afebrile and completely asymptomatic from the eruption. He continued the ddC and began oral therapy on day 14 despite the persistence of the eruption. The eruption resolved on days 17 and 18 with continued oral ddC administration.
Patient XI (17) A 56-year-old white man with AIDS and Kaposi's sarcoma began intravenous ddC therapy at a dosage of 0.09 mg/kg every 4 hours. The patient first noted slightly tender ulcers on his buccal mucosae on day 6 of intravenous therapy (Fig. 1). Five erythematous shallow erosions,3 to 5 mm in diameter, with gray borderswere noted
on the lower lip and buccal mucosae. Multiple cultures were negative for herpe~ simplex, varicella, and cytomegalovirus. On day 10 of intravenous therapy a diffuse eruption of erythematous macules and papules developed on the patient's arms, legs, and trunk. The lesions were brightly erythematous and edematous without scaling or target lesions (Fig. 2, A and B). The palmoplantar surfaces were not involved. In addition to the oral and cutaneous lesions, symptoms included fevers, malaise, myalgias, and generalized pruritus. In spite of these mucocutaneous lesions and systemic symptoms, the intravenous course of ddC was completed, and therapy was changed to an oral dosage of 0.09 mg/kg every 4 hours.
Volume 21 Number 6 December 1989
Dermat%gic complications with use of Y,3' -dideoxycytidine 1215
Table I. Dermatologic findings Dosage Patient
I II III IV V VI VII VIII IX X XI XII XIII XIV
Cutaneous lesions
Oral lesions
Morbilliform, trunk Morbilliform, trunk Maculopapular, trunk Erythroderma, scaling macules Erythroderma Generalized papulovesicular Morbilliform Morbilliform Maculopapular, trunk Papules, generalized Papules, generalized Generalized papules, plaques Morbilliform Morbilliform
Aphthae Aphthae None None Aphthae Aphthae None Aphthae, lip edema None Aphthae Aphthae Aphthae None Aphthae
(mgjkg)
(3) (4) (8) (10) . (11) (12) (13) (14) (15) (16) (17) (18) (19) (20)
0.03 0.03 0.03 0.06 0.06 0.06 0.06 0.06 0.09 0.09 0.09 0.09 0.09 0.25
q.8h. q.8h. qAh. qAh. qAh. q.4h. qAh. q.4h. q.4h. q.4h. q.4h. qAh. qAh. q.8h.
10 10 9 30 10 10 11-12 10 12 10 10 11 10 10
Systemic reaction
+ + + + + + +
*Casc numbers are cross-referenced with arabic numerals to correlate with notations concerning these patients in the article by Yarchoan et aU
Table II. Histologic findings Patient
I No.*
II IV V
(4) (10) (11)
VI VII IX X XI XII
(12) (13) (15) (16) (17) (18)
XIV
(20)
1--------------H-j-st-OIO-g-ic-fi-nd-j-ng-s--------------
No epidermal change; mild perivascular lymphocytic infiltrate Mild spongiosis with minimal exocytosis; diffuse perivascular lymphocytic infiltrate No epidermal change; minimal exocytosis; extravasated red blood cells in papillary dermis; deep and superficial perivascular lymphocytic infiltrate with occasional eosinophils Mild exocytosis; moderate papillary edema; superficial perivascular lymphocytic infiltrate Mild perivascular lymphocytic infiltrate Minimal perivascular lymphocytic infiltrate Moderate papillary edema with focal perivascular lymphocytic infiltrate Moderate papillary edema with focal perivascular lymphocytic infiltrate Marked papillary edema with dermoepidermal separation; marked lymphocytic infiltrate in papillary dermis and dermal vessels Focal epidermal spongiosis; perivascular lymphocytic infiltrate
*Case numbers are cross-referenced with arabic numerals to correlate with notations concerning these patients in the article by Yarchoan et al.9
The systemic symptoms abated within 48 to 72 hours and the mucocutaneous lesions within a 3- to 7-day period with continuation of oral ddC therapy.
Light microscopy After informed consent was obtained, skin biopsy specimens, 3 or 4 mm in diameter, were taken from involved sites in 10 patients, fixed in 10% neutral formalin, and processed for routine hematoxylin-eosin staining. RESULTS
Clinical presentation An overview of the results from administration of ddC to 20 patients with HIV infection recently has
been reported by Yarchoan et a1. 9 In this study the use of ddC in various dosage schedules resulted in an early increase in absolute numbers of patients' helper T cells and a decrease in serum levels of HIV p24 antigen, suggesting in vivo suppression of HIY. Nondermatologic side effects and complications of ddC included neutropenia and thrombocytopenia (at high doses) and a painful peripheral neuropathy that developed after 8 or more weeks of continuous high-dose therapy. The latter complication was the dose-limiting toxicity of this drug. All side effects were reversible with discontinuation of the drug, although at high doses the peripheral neuropathy took weeks or months to resolve. All toxicities occurred
1216
Journal of the American Academy of Dermatology
McNeely et at.
during a 4- to 10-day period. Two patients in whom ddC therapy had been stopped, patients V( 11) and VI(l2), were rechallenged after a period of abstention, and a recurrence of their mucocutaneous lesions with systemic symptoms developed within 2A hours of receiving a single oral dose. In addition to cutaneous lesions associated with the administration of ddC, either the onset or the exacerbation of oral ulcers on the buccal, mucosae, soft palate, tongue, and pharynx occurred in 9 of 14 patients. Cultured tissue biopsy specimens or smears of the lesions were consistently negative for herpes simplex virus, candidal species, and cytomegalovirus. These oral lesions resolved with either discontinuation of ddC or within the third week of oral ddC therapy (patients U(4), V( 11), VI(L2), VIII(l4), and XIV(20). Histologic findings
Fig. 3. Histologic section of cutaneous lesion from patient receiving ddC shows a superficial perivascular infiltrate of lymphocytes. (Hematoxylin-eosin stain; X40).
more commonly in the patients receiving higher doses of ddC. Table I presents a correlation of the dermatologic findings in 14 patients with the dosage schedule of ddC, time ofonset of mucocutaneous lesions, and the presence or absence of systemic symptoms. The patients received dosages of ddC ranging from 0.03 mg/kg to 0.25 mg/kg every 4 to 8 hours intravenously for 2 weeks, followed by oral administration of the same dosage schedule for an additional 4 or more weeks. Cutaneous lesions varied from small erythematous macules and papules on the trunk to a generalized distribution of red edematous papules associated with signs and symptoms of fever, arthralgias, and myalgias. Fifty percent (7/14) of the patients also had systemic symptoms. The onset of cutaneous lesions with or without systemic symptoms usually occurred on day 10 or 11 of the intravenous drug schedule. In all patients, including those who continued receiving the drug, the systemic side effects of fevers, arthralgias, or myalgias resolved within 48 to 72 hours after onset, and cutaneous lesions resolved
Skin biopsy specimens were obtained from 10 patients with various cutaneous lesions. The histologic findings are summarized in Table II with a representative histologic section shown in Fig. 3. DISCUSSION
2',3'-Dideoxycytidine is a nucleoside analogue lO with potent in vitro inhibitory effects on the replication of HIV-infected helper T cells. I1-13 Recently ddC was administered in a phase I trial in persons infected with HIV. 9 Most patients given ddC were observed to have a decrease in viral load and/or an increase in immunologic function. Cutaneous complications, however, developed in 70% of patients. It is interesting that in the nine patients who continued therapy after these complications developed, the systemic symptoms resolved within 48 to 72 hours and the oral and/or cutaneous lesions resolved within 4 to 7 days. The relationship between resolution of systemic and mucocutaneous side effects and the continued administration of ddC therapy is somewhat complex. In the patients who discontinued therapy, symptoms and lesions resolved without recurrence. Two patients were later rechallenged with a single oral dose of ddC after a 2- to 4-week drug-free period; this administration resulted in a recurrence (within hours) of mucocutaneous lesions and fever. Yet, as noted, in nine patients all cutaneous lesions resolved while they received therapy. The resolution of symptoms possibly could be associated with a change in route of administration of the drug, in part
Volume 21 Number 6 December 1989
Dermatologic complications with use of 2',3' -dideoxycytidine 1217
because only 70% to 80% of this drug is absorbed by the oral route. Development of symptoms, however, is not likely to be restricted to the intravenous route of administration inasmuch as cutaneous eruptions have not been noted in patients given ddC by the oral route only (R. Yarchoan and S. Broder, unpublished observations). 14 In either case the cutaneous side effects were transient and resolved with continued therapy in more than 60% of affected patients. It is also worth stressing that these side effects do not develop, or they develop in a very mild form, in patients given lower doses of ddC (e.g., 0.05 or 0.01 mg/kg every 8 hours).9, 14 REFERENCES 1. Gottlieb MS, Schroff R, Schanker HM, et aL Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981 ;305: 1425-31. 2. Masur H, Michelis MA, Greene JB, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305:1431-8. 3. Siegal FP, Lopez, Hammer GS, et aL Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981;305:1439-44. 4. Barre-Sinoussi F, Chermann JC, Rey F, et aL Isolation of a T -lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868-71. 5. Gallo RC, Salahuddin SZ, Popovic M, et aL Frequent detection and isolation of cytopathic retroviruses from patiaents with AIDS and at risk for AIDS. Science 1984; 224:500-3.
6. Yarchoan R, Klecker RW, Weinhold KJ, et al. Administration of 3'-azido-3' deoxythymidine, an inhibitor of HTLV-I1I/LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1986;1:575-80. 7. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo controlled triaL N Engl J Med 1986;317:185-91. 8. Richman 0, Fischl MA, Greico MH, et aL The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo controlled triaL N Engl J Med 1986;317:192-97. 9. Yarchoan R, Perno CF, Thomas R, et al. Phase I studies of2' ,3-didcoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988;1:76-81. 10. Horowitz JP, Chua J, Da Rooge MA, et al. Nuc1eosides. IX. The formation of2'3' -unsaturated pyrimidine nucleosides via a novel elimination reaction. J Org Chern 1964;31:205-8. 11. Mitsuya H, Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV) by 2',3'dideoxynucleosides. Proc Nat! Acad Sci USA 1986;83:1911-5. 12. Mitsuya H, Weinhold KJ, Furman PA, et al. 3' Azido-3'deoxythymidine (BWA509U): an anti-viral agent that inhibits the infectivity and cytopathic effect of human Tlymphotropic virus type III/lymphadenopathy associated virus in vitro. Proc N atl Acad Sci USA 1985;82:7096-100. 13. Mitsuya H, Jarrett RF, Matsukura M, et al. Long-term inhibition of human T-Iymphotropic virus type III/lymphadel1opathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2' ,3 I -dideoxynuclcosides in vitro. ProcN atlAcad Sci USA 1987;84:2033-7. 14. Skowron G, Merigan TC, Bozzette S, et al. 2',3' -Dideoxycytidine (ddC) in the treatment of patients with ARC and advanced AIDS. Abstracts of the Fourth International Conference on AIDS, Stockholm, Sweden. June 12-16, 1988.