DEVELOPMENT OF AUTOANTIBODIES AND FACTOR VIII INHIBITOR IN AN HIV‐INFECTED HAEMOPHILIAC FOLLOWING TREATMENT WITH COMBINATION ANTI‐RETROVIRAL THERAPY

Abstract

The benefit of protease inhibitor therapy in HIV-infected haemophiliacs has been summarized recently ( 4). We have observed a variety of immunological complications following immune reconstitution in a patient treated successfully with protease inhibitors. A 14-year-old boy, diagnosed at birth in 1983 with severe haemophilia A (factor VIII level < 0.0 iu/dl), was treated on demand with factor VIII replacement until 1989 and prophylactic replacement thereafter (25 units/kg three times weekly). Between 1985 and 1991 he received intermediate purity factor VIII (NHS 8Y, BPL, U.K.) and, from 1991, high-purity factor VIII (8SM/Replenate, BPL, U.K.). He was found to be antibody positive for human immunodeficiency virus in 1985 and for hepatitis C in 1991. In 1988 he developed immune thrombocytopenia which was refractory to steroids but splenectomy produced a complete sustained remission. In 1991, when his CD4 count was 0.4 × 109/l, he developed HIV encephalopathy and commenced zidovudine with improvement in cognitive function. In 1997 he was admitted for investigation of pyrexia of unknown origin. No infective or neoplastic cause could be found. However, with a CD4 count below the limit of detection and a HIV viral load of 160 000/ml, he was converted to combination antiretroviral therapy with the addition of lamivudine and the protease inhibitor indinavir. Six months later his CD4 count had risen to 1.76 × 109/l and HIV RNA was undetectable in peripheral blood by nucleic acid sequence based amplification. At this time the frequency of spontaneous joint bleeds increased and a poor clinical response to factor VIII infusion was observed. A factor VIII inhibitor was quantified at 4 Bethesda units (BU). His prophylactic factor VIII replacement was increased to 50 units/kg three times weekly as low-dose immunotolerance and acute bleeding episodes were treated with FEIBA (Immuno, U.K.). 6 weeks later he developed bleeding from venepuncture sites and spontaneous muscle bleeds. The factor VIII inhibitor had risen to 57 BU. A full blood count revealed Hb 7.6 g/dl, WBC 8.3 × 109/l. neutrophils 0.2 × 109/l and platelet count 6 × 109/l. The direct antiglobulin test (DAGT) was positive. A bone marrow examination was not performed, but 3 d after administration of intravenous immunoglobulin 1 g/kg/d for 2 d and prednisolone 1 mg/kg/d his platelet count rose to 197 × 109/l, indicating a probable diagnosis of immune thrombocytopenia (ITP). Concurrently his neutrophil count rose to 1.49 × 109/l after 5 d and his DAGT became negative. In view of his severe haemorrhagic tendency and rapidly rising inhibitor titre the patient was commenced on a high-dose immune tolerance programme with 100 units/kg twice daily factor VIII (NHS 8Y) ( 2). After only 10 d of this regimen the inhibitor became undetectable in the Bethesda assay. Over the subsequent weeks his factor VIII recovery normalized, and 8 weeks after starting the tolerance programme a factor VIII half-life study was normal (t1/2 = 17 h). His factor VIII replacement has now been reduced to 25 units/kg three times weekly. Factor VIII inhibitors occur in approximately a quarter to a third of patients with severe congenital factor VIII deficiency after a median of 10 treatment days ( 3). Our patient is unusual as he developed an inhibitor to factor VIII after > 300 treatments and without a recent change in factor concentrate. He also developed other immune phenomena: ITP, autoimmune haemolysis, and possibly autoimmune neutropenia. All responded extremely rapidly to therapy and have not subsequently relapsed. These observations raise the possibility that immune reconstitution due to successful combination anti-retroviral therapy resulted in de novo autoimmune phenomena and an inhibitor to factor VIII. As 20% of HIV-positive individuals develop immune thrombocytopenia it is impossible to know if our patient's previous thrombocytopenia was indicative of an underlying predisposition to autoimmunity. However, in patients with haemophilia who receive factor concentrate the likelihood of alloantibody formation following immune reconstitution may be similar to that following initial exposure to factor VIII. There has been concern that the use of protease inhibitors leads to an increased bleeding tendency in haemophiliacs. However, this has not usually been associated with the development of a factor VIII inhibitor. To our knowledge there has been only one case of a new inhibitor developing in a heamophiliac receiving the same combination of anti-retrovirals as the patient described here ( 1). Patients with haemophilia treated in this way may be susceptible to inhibitor development, but our observation suggests this may be transient or easily eliminated with a desensitization regime.