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Dapsone for thrombocytopenic purpura related to human immunodeficiency virus infection
CLINICAL STUDIES
Dapsone for Thrombocytopenic Purpura Related to Human Immunodeficiency Virus Infection JEAN MARCDURAND, M.D., PATRICELEF~'VRE,M.D., PHILIPPEHOVEI-rE, M.D., SOUMANAISSIFI, M.D., MAURICEMONGIN, M.D., Marseille, France
PURPOSE: The purpose of this study was to determlne the effect of dapsone on platelet count in patients with h , mAn immunodeficiency virus (HIV)-related autoimmune thrombocytopeniRPATIENTS AND METHODS: Eleven patients with HIV-related thrombocytopenia received dapsone (50 to 125 mg/day) for 2 to 43 months. Patients with the acquired immunodeficiency syndrome were not enrolled. RESULTS: Of the 11 patients, six developed platelet counts above 50 X 109/L and did not require any other specific therapy. No significant side effects were observed. CONCLUSION: We conclude that dalJsone may be effective in some patients with HIV-related thrombocytopenia.
From the Clinique M(~dicale B, Pr M. Mongin, CHU Timone, Marseille, France. f Requests for reprints should be addressed to Dr. J.M. Durand, Clinique M(~dicale B, Pr M. Mongin, CHU Timone, Bd J. Moulin, 13385, Marseille, France. Manuscript submitted August 8, 1990, and accepted in revised form March 13, 1991.
A
utoimmune thrombocytopenic purpura (AITP) can occur at any stage of the natural history of human immunodeficiency virus (HIV) infection. Different therapeutic approaches have been used, but the most effective, least toxic regimen remains to be defined [1]. We decided to use dapsone to treat patients with HIV-related thrombocytopenia on the basis that the drug might modulate the macrophage behavior responsible for the platelet lysis.
PATIENTS AND METHODS Patients Eleven patients with HIV-associated AITP decided to enter our trial of dapsone therapy (Table I). In eight patients, thrombocytopenia was the only symptom of HIV infection, whereas three patients had persistent generalized lymphadenopathy with moderate splenomegaly in one case and oral candidiasis in two cases. No patient who enrolled had acquired immunodeficiency syndrome. Six patients presented with moderate clinical bleeding at the initial evaluation, i.e., increased bruising, petechiae, gingival bleeding, or epistaxis. The median platelet count before therapy was 27 X 109/L (range: 10 to 58 X 109/L) and the mean duration of thrombocytopenia was 4 months (range: 2 to 18 months). Patients had received previous therapy, including colchicine, danazol, high-dose polyvalent IgG, or anti-Rhesus IgG, with no or only transient efficacy. None had undergone splenectomy or received steroid or antiviral drugs. All patients gave informed consent. Laboratory Studies All serum samples were positive for antibodies to HIV by Western blot analysis. HIV p24 antigen measured by enzyme-linked immunosorbent assay (Abbott Laboratories, Abbott Park, Illinois) was negative. Bone marrow aspiration showed a normal or increased megakaryocyte count. Platelet-bound IgG were positive in eight of 11 patients. CD4+ and CD8+ cells were counted with the use of monoclonal antibodies and flow eytometry. The mean T4 cell number was 0.400 x 109/L (range: 0.296 to 0.632 X 109/L). Hemoglobin values ranged from 126 g/L to 153 g/L (mean: 137 g/L). June 1991 The American Journal of Medicine Volume 90
675
DAPSONE FOR HIV-RELATED THROMBOCYTOPENIA / DURAND ET AL TABLE I Clinical Data and Platelet Count Evolution During Therapy with Dapsone
Patient
Age and Sex
AIDS Risk Group
1 2 3 4 5 6 7 8 9 10 11
31 M 25 M 30M 26M 25M 26 F 18M 38 M 27 M 63 M 49 M
Drug abuser Drug abuser Drug abuser Drug abuser Drug abuser Drug abuser Drug abuser Homosexual Unknown Transfused Transfused
CD4 T Cells (109/L) 0.312 0.296 0.410 0.381 0.378 0.423 0.358 0.632 0.398 0.426 0.394
p24 Antigen
Pretreatment Platelet Count (109/L)
Maximal Platelet Count (109/L)
20 15 58 21 24 23 34 20 42 10 30
20 42 232 110 161 120 147 40 151 10 72
-
Last Platelet Duration Count of Response (109/L) (months) 20 25 100 50 70 50 42 37 100 10 20
NR >12 >43 >12 >33 >22 >11 >04 >10 NR 2
Hemoglobin(g/L) Before/After Dapsone 132/126 126/118 153/147 130/124 134/129 128/111 130/124 147/138 136/125 138/128 145/138
NR= no response.
Drug Regimen
Patients were given dapsone orally (50 to 125 rag/ day, mean dosage 75 rag/day) for 2 to 43 months. Platelet counts had been obtained three times before enrollment. Laboratory studies, including complete blood cell count, measurement of lactate dehydrogenase and methemoglobin, and renal and liver function tests, were performed weekly for the first 2 months and monthly thereafter. CD4+ and CD8+ cell counts and platelet-bound IgG and HIV p24 antigen were measured every month.
'
dL, and a slight increase in the lactate dehydrogenase level from 226 IU/L to 260 IU/L. The effect of dapsone on the platelet count was not dose-related and did not correlate with the degree of induced hemolysis. COMMENTS
This uncontrolled study confirms the beneficial effects of dapsone that were observed in a patient with systemic lupus and thrombocytopenia whose skin problems and thrombocytopenic purpura have been controlled for 6 years with no side effects [2]. RESULTS Six of our 11 patients with HIV-related thrombocyRelevant data are shown in Table I. Of the 11 toper/ia had persistent increases in their platelet patients, nine have responded to the therapy. Six counts to above 50 × 109/L and did not require any had a persistent riseof their plateletcount above 50 other specific therapy. This response is similar to or × 109/L. In three other patients, only a mild in- better than that obtained with other therapeutic crease was noted (20 to 40 × 109/I,).The peak value approaches [1]. The drug's beneficial effect on was 119 × 109/L (range: 42 to 232 × 109/I,)versus platelet counts could be maintained over long peri32.5 X 109/L before therapy (p <0.01). T w o patients ods of time, but the platelet count decreased when failedto respond. Time to maximal response ranged the drug was stopped. Clinical and biologic tolerfrom Day 9 to Day 366 (mean: Day 117), but a two- ance to the drug was good. The administration of fold increase was present on Day 24. The response dapsone was not associated with an improvement in persisted for 18.4 months (range: 4 to 43 months) in certain markers of HIV disease activity, but the eight patients and was transient (2 months) in one drug did not increase the susceptibility of patients patient. Thrombocytopenia recurred when dapsone to infection and may be useful as prophylaxis for was discontinued, but the platelet count increased Pneumocystis carinii pneumonia [3]. when therapy was restarted. None of the patients The mechanism by which dapsone induces remisdeveloped opportunistic infections or Kaposi's sar- sion is unknown. Excessive red blood cell destruccoma while undergoing treatment. No significant tion leads to erythrophagocytosis and may interfere changes in platelet-bound IgG, CD4+ lymphocyte, with platelet sequestration by the reticuloendotheor neutrophil counts were noted during the study. lial system [4]. In this study, the increase in platelet Serum p24 antigen became positive in one patient counts, without pronounced hemolysis, does not after 24 months. There were no other side effects corroborate this hypothesis. Dapsone affects except for mild hemolysis. The mean hemoglobin phagocyte-mediated cytotoxicity [5], which provalue declined from 137 g/L to 128 g/L. The level of vides a possible explanation for its beneficial effects methemoglobin remained below 4%. Hemolysis was in thrombocytopenia. We are currently investigatdocumented by an increase of the reticulocyte ing the effect of dapsone on phagocytic function. count from 48 to 92 × 109/L, a reduction of the In conclusion, no treatment should be recomserum haptoglobin value from 114 mg/dL to 95 rag/ mended in patients with no hemorrhagic symptoms 676
June 1991 The American Journal of Medicine Volume 90
DAPSONE FOR HIV-RELATEDTHROMBOCYTOPENIA / DURAND ET AL
and moderate HIV-related thrombocytopenia. Intravenous immunoglob, llin and Rhesus antibodies may be considered as first-line treatment for clinical bleeding [6,7]. Splenectomy appears useful in patients with persistent and symptomatic thrombocytopenia [8]. Zidovudine has been proposed in patients with severe or mild thrombocytopenia, but the expense and potential toxicity of zidovudine warrant evaluation of alternative therapies [9]. Dapsone is an inexpensive therapy that may be useful in some cases of HIV-associated AITP. REFERENCES 1. Ratner L. Human immunodeficiency virus-associated autoimmune thrombocytopenic purpura: a review. Am J Med 1989; 86: 194-8. 2. Moss C, Hamilton PJ. Thrombocytopenia in systemic lupus erythernatosus
responsive to dapsone (letter). Br Med J 1988; 297: 266. 3. Leoung GS, Mills J, Hopewell PC, Hugues W, WofsyC. Dapsone-trimethoprim for Pneumocystiscarin#pneumonia in acquired immunodeficiency syndrome. Ann Intern Med 1986; 105: 45-8. 4. Shulman NR, Weinrach RS, Libre EP, Andrews HL. The role of the reticuloendothelial system in the pathogenesis of idiopathic thrombocytopenic purpura. Trans Assoc Am Physicians 1965; 78: 374-90. 5. Stendahl O, Molin L, Dahlgren C. The inhibition of polymorphonuclear leucocyte cytotoxicity by dapsone. J Clin Invest 1978; 62: 214-20. 6. Delfraissy JF, Tertian G, Dreyfus M, Tchernia G. Intravenous gammaglobulin, thrombocytopenia, and the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103: 478-9. 7. Durand JM, Harle JR, Verdot JJ, Weiller PJ, Mongin M Anti-Rh(D) immunoglobulin for immune thrombocytopenic purpura. Lancet 1986; 2: 49-50. 8. Schneider PA, Abrams DI, Rayner AA, Hohn DC. Immunodeficiency-associated thrombocytopenic purpura: response to splenectomy. Arch Surg 1987; 12: 1175-8.
9.Gottiieb MS, Wolfe PR, Chafey S. Case report: response of AIDS-related thrombocytopenia to intravenous and oral azidothymidine. AIDS Res Hum Retroviruses 1987; 3: 109-14.
June 1991 The American Journal of Medicine Volume 90
677
Dapsone for Thrombocytopenic Purpura Related to Human Immunodeficiency Virus Infection JEAN MARCDURAND, M.D., PATRICELEF~'VRE,M.D., PHILIPPEHOVEI-rE, M.D., SOUMANAISSIFI, M.D., MAURICEMONGIN, M.D., Marseille, France
PURPOSE: The purpose of this study was to determlne the effect of dapsone on platelet count in patients with h , mAn immunodeficiency virus (HIV)-related autoimmune thrombocytopeniRPATIENTS AND METHODS: Eleven patients with HIV-related thrombocytopenia received dapsone (50 to 125 mg/day) for 2 to 43 months. Patients with the acquired immunodeficiency syndrome were not enrolled. RESULTS: Of the 11 patients, six developed platelet counts above 50 X 109/L and did not require any other specific therapy. No significant side effects were observed. CONCLUSION: We conclude that dalJsone may be effective in some patients with HIV-related thrombocytopenia.
From the Clinique M(~dicale B, Pr M. Mongin, CHU Timone, Marseille, France. f Requests for reprints should be addressed to Dr. J.M. Durand, Clinique M(~dicale B, Pr M. Mongin, CHU Timone, Bd J. Moulin, 13385, Marseille, France. Manuscript submitted August 8, 1990, and accepted in revised form March 13, 1991.
A
utoimmune thrombocytopenic purpura (AITP) can occur at any stage of the natural history of human immunodeficiency virus (HIV) infection. Different therapeutic approaches have been used, but the most effective, least toxic regimen remains to be defined [1]. We decided to use dapsone to treat patients with HIV-related thrombocytopenia on the basis that the drug might modulate the macrophage behavior responsible for the platelet lysis.
PATIENTS AND METHODS Patients Eleven patients with HIV-associated AITP decided to enter our trial of dapsone therapy (Table I). In eight patients, thrombocytopenia was the only symptom of HIV infection, whereas three patients had persistent generalized lymphadenopathy with moderate splenomegaly in one case and oral candidiasis in two cases. No patient who enrolled had acquired immunodeficiency syndrome. Six patients presented with moderate clinical bleeding at the initial evaluation, i.e., increased bruising, petechiae, gingival bleeding, or epistaxis. The median platelet count before therapy was 27 X 109/L (range: 10 to 58 X 109/L) and the mean duration of thrombocytopenia was 4 months (range: 2 to 18 months). Patients had received previous therapy, including colchicine, danazol, high-dose polyvalent IgG, or anti-Rhesus IgG, with no or only transient efficacy. None had undergone splenectomy or received steroid or antiviral drugs. All patients gave informed consent. Laboratory Studies All serum samples were positive for antibodies to HIV by Western blot analysis. HIV p24 antigen measured by enzyme-linked immunosorbent assay (Abbott Laboratories, Abbott Park, Illinois) was negative. Bone marrow aspiration showed a normal or increased megakaryocyte count. Platelet-bound IgG were positive in eight of 11 patients. CD4+ and CD8+ cells were counted with the use of monoclonal antibodies and flow eytometry. The mean T4 cell number was 0.400 x 109/L (range: 0.296 to 0.632 X 109/L). Hemoglobin values ranged from 126 g/L to 153 g/L (mean: 137 g/L). June 1991 The American Journal of Medicine Volume 90
675
DAPSONE FOR HIV-RELATED THROMBOCYTOPENIA / DURAND ET AL TABLE I Clinical Data and Platelet Count Evolution During Therapy with Dapsone
Patient
Age and Sex
AIDS Risk Group
1 2 3 4 5 6 7 8 9 10 11
31 M 25 M 30M 26M 25M 26 F 18M 38 M 27 M 63 M 49 M
Drug abuser Drug abuser Drug abuser Drug abuser Drug abuser Drug abuser Drug abuser Homosexual Unknown Transfused Transfused
CD4 T Cells (109/L) 0.312 0.296 0.410 0.381 0.378 0.423 0.358 0.632 0.398 0.426 0.394
p24 Antigen
Pretreatment Platelet Count (109/L)
Maximal Platelet Count (109/L)
20 15 58 21 24 23 34 20 42 10 30
20 42 232 110 161 120 147 40 151 10 72
-
Last Platelet Duration Count of Response (109/L) (months) 20 25 100 50 70 50 42 37 100 10 20
NR >12 >43 >12 >33 >22 >11 >04 >10 NR 2
Hemoglobin(g/L) Before/After Dapsone 132/126 126/118 153/147 130/124 134/129 128/111 130/124 147/138 136/125 138/128 145/138
NR= no response.
Drug Regimen
Patients were given dapsone orally (50 to 125 rag/ day, mean dosage 75 rag/day) for 2 to 43 months. Platelet counts had been obtained three times before enrollment. Laboratory studies, including complete blood cell count, measurement of lactate dehydrogenase and methemoglobin, and renal and liver function tests, were performed weekly for the first 2 months and monthly thereafter. CD4+ and CD8+ cell counts and platelet-bound IgG and HIV p24 antigen were measured every month.
'
dL, and a slight increase in the lactate dehydrogenase level from 226 IU/L to 260 IU/L. The effect of dapsone on the platelet count was not dose-related and did not correlate with the degree of induced hemolysis. COMMENTS
This uncontrolled study confirms the beneficial effects of dapsone that were observed in a patient with systemic lupus and thrombocytopenia whose skin problems and thrombocytopenic purpura have been controlled for 6 years with no side effects [2]. RESULTS Six of our 11 patients with HIV-related thrombocyRelevant data are shown in Table I. Of the 11 toper/ia had persistent increases in their platelet patients, nine have responded to the therapy. Six counts to above 50 × 109/L and did not require any had a persistent riseof their plateletcount above 50 other specific therapy. This response is similar to or × 109/L. In three other patients, only a mild in- better than that obtained with other therapeutic crease was noted (20 to 40 × 109/I,).The peak value approaches [1]. The drug's beneficial effect on was 119 × 109/L (range: 42 to 232 × 109/I,)versus platelet counts could be maintained over long peri32.5 X 109/L before therapy (p <0.01). T w o patients ods of time, but the platelet count decreased when failedto respond. Time to maximal response ranged the drug was stopped. Clinical and biologic tolerfrom Day 9 to Day 366 (mean: Day 117), but a two- ance to the drug was good. The administration of fold increase was present on Day 24. The response dapsone was not associated with an improvement in persisted for 18.4 months (range: 4 to 43 months) in certain markers of HIV disease activity, but the eight patients and was transient (2 months) in one drug did not increase the susceptibility of patients patient. Thrombocytopenia recurred when dapsone to infection and may be useful as prophylaxis for was discontinued, but the platelet count increased Pneumocystis carinii pneumonia [3]. when therapy was restarted. None of the patients The mechanism by which dapsone induces remisdeveloped opportunistic infections or Kaposi's sar- sion is unknown. Excessive red blood cell destruccoma while undergoing treatment. No significant tion leads to erythrophagocytosis and may interfere changes in platelet-bound IgG, CD4+ lymphocyte, with platelet sequestration by the reticuloendotheor neutrophil counts were noted during the study. lial system [4]. In this study, the increase in platelet Serum p24 antigen became positive in one patient counts, without pronounced hemolysis, does not after 24 months. There were no other side effects corroborate this hypothesis. Dapsone affects except for mild hemolysis. The mean hemoglobin phagocyte-mediated cytotoxicity [5], which provalue declined from 137 g/L to 128 g/L. The level of vides a possible explanation for its beneficial effects methemoglobin remained below 4%. Hemolysis was in thrombocytopenia. We are currently investigatdocumented by an increase of the reticulocyte ing the effect of dapsone on phagocytic function. count from 48 to 92 × 109/L, a reduction of the In conclusion, no treatment should be recomserum haptoglobin value from 114 mg/dL to 95 rag/ mended in patients with no hemorrhagic symptoms 676
June 1991 The American Journal of Medicine Volume 90
DAPSONE FOR HIV-RELATEDTHROMBOCYTOPENIA / DURAND ET AL
and moderate HIV-related thrombocytopenia. Intravenous immunoglob, llin and Rhesus antibodies may be considered as first-line treatment for clinical bleeding [6,7]. Splenectomy appears useful in patients with persistent and symptomatic thrombocytopenia [8]. Zidovudine has been proposed in patients with severe or mild thrombocytopenia, but the expense and potential toxicity of zidovudine warrant evaluation of alternative therapies [9]. Dapsone is an inexpensive therapy that may be useful in some cases of HIV-associated AITP. REFERENCES 1. Ratner L. Human immunodeficiency virus-associated autoimmune thrombocytopenic purpura: a review. Am J Med 1989; 86: 194-8. 2. Moss C, Hamilton PJ. Thrombocytopenia in systemic lupus erythernatosus
responsive to dapsone (letter). Br Med J 1988; 297: 266. 3. Leoung GS, Mills J, Hopewell PC, Hugues W, WofsyC. Dapsone-trimethoprim for Pneumocystiscarin#pneumonia in acquired immunodeficiency syndrome. Ann Intern Med 1986; 105: 45-8. 4. Shulman NR, Weinrach RS, Libre EP, Andrews HL. The role of the reticuloendothelial system in the pathogenesis of idiopathic thrombocytopenic purpura. Trans Assoc Am Physicians 1965; 78: 374-90. 5. Stendahl O, Molin L, Dahlgren C. The inhibition of polymorphonuclear leucocyte cytotoxicity by dapsone. J Clin Invest 1978; 62: 214-20. 6. Delfraissy JF, Tertian G, Dreyfus M, Tchernia G. Intravenous gammaglobulin, thrombocytopenia, and the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103: 478-9. 7. Durand JM, Harle JR, Verdot JJ, Weiller PJ, Mongin M Anti-Rh(D) immunoglobulin for immune thrombocytopenic purpura. Lancet 1986; 2: 49-50. 8. Schneider PA, Abrams DI, Rayner AA, Hohn DC. Immunodeficiency-associated thrombocytopenic purpura: response to splenectomy. Arch Surg 1987; 12: 1175-8.
9.Gottiieb MS, Wolfe PR, Chafey S. Case report: response of AIDS-related thrombocytopenia to intravenous and oral azidothymidine. AIDS Res Hum Retroviruses 1987; 3: 109-14.
June 1991 The American Journal of Medicine Volume 90
677