Correspondence AIDS 2014, 28:931–936

Acquired haemophilia A associated with HIV infection: a rare disease Acquired haemophilia A is a rare bleeding disorder, caused by acquired autoantibodies directed against coagulation factor VIII [1]. In the European ACquired Haemophilia Registry (EACH 2) [2], 50% of cases are linked to an underlying disease including malignancies (11.8%), autoimmune disorders (11.6%) and pregnancy (8.4%). Infections have been less frequently involved (3.8%): tuberculosis [3], replicative hepatitis B (HBV) [4], hepatitis C treated with interferon [5] and herpes human virus-8 [6]. Until now, only one case has been reported in an HIV infected patient [7]. Here, we described two new cases of acquired haemophilia during HIV infection. A 51-year-old Caucasian man was hospitalised for spontaneous bruising and macroscopic haematuria. Computed tomography (CT)-scan revealed no profound haematoma neither tumor. Laboratory exams showed no thrombocytopenia, normal prothrombin time but a prolonged activated partial thromboplastin time (APTT) (2.52  control time). Factor VIII level was less than 1% and a FVIII inhibitor [titer: 11 Bethesda Units (BU)] was discovered. HIV-1 screening test was positive: HIV-1 viral load was 11 032 copies/ml and lymphocytes TCD4þ cell count was 334 per ml (25%). Antinuclear antibodies, rheumatoid factor, anti-beta2GP1, IgM anti cardiolipine antibodies were negative. IgG anti cardiolipine antibodies were positive (62 UGPL). No active hepatitis infection was found. Lymphocyte phenotype revealed no monoclonal population. To treat FVIII inhibitor, patient received four weekly infusions of rituximab (375 mg/m2) while antiretroviral therapy (ART) was initiated (efavirenz, tenofovir and emtricitabine). FVIII inhibitor titer decreased, to become negative 6 months later. Undetectable viral load was obtained at month 3, and was sustained since then. The patient was still in complete remission 4 years after ART initiation. No serious adverse effect of rituximab was observed. A 53-year-old African woman was hospitalized for multiple spontaneous bruising and uterine bleedings. She was treated for HIV-1 infection for 18 years with an irregular adherence to ART and a spontaneous ART interruption 2 months prior to hospitalization. At admission, haemoglobinemia was 6.6 g/dl, platelets count was normal. APTT was increased (3.4  control) with a factor VIII level less than 1% with an anti-FVIII antibody (160 BU). HIV-1 viral load was 45 000 copies/ml and lymphocytes TCD4þ cell count was 197 per ml (20%). CT scan showed a left psoas haematoma and a large

uterine fibroma. Biopsy of fibroma showed no sign of malignancy. Antinuclear and antiphospholipid antibodies, rheumatoid factor and hepatitis C virus serology were negative, lymphocytes phenotype revealed no monoclonal population. Isolated HBc antibodies were present with a negative HBV viral load. Bleedings were treated with recombinant activated factor VII. Steroids associated with five monthly infusions of cyclophosphamide (750 mg/m2) were used to eradicate anti-FVIII antibody. Rituximab was not prescribed because of her HIV history. ART regimen was resumed with tenofovir, raltegravir and darunavir/ritonavir. The patient outcome was good: factor VIII inhibitor activity decreased with a normalization of factor VIII level at week 8. Corticosteroids were progressively tapered. At her last visit, 11 months later, the patient was still in complete remission with a normal level of FVIII (134%) and a good response to ART [TCD4þ cell count: 231 per ml (20%) and HIV-RNA load less than 160 copies/ml]. No serious adverse effect occured. Autoimmune disorders are not rare in the evolution of HIV infection whether at the time of diagnosis or during immune reconstitution syndrome after ART initiation [8]. At the time of HIV-diagnosis, autoimmune disorders could be explained by the activation of B resting lymphocytes by intestinal translocated bacterial lipopolysaccharides (promoted by the loss of mucosal CD4þ T cells) and the loss of immune control (depletion of circulating Treg cell) [9]. During immune reconstitution inflammatory syndrome, autoimmunity may be induced by an efficient reconstitution of a TH1 response and proinflammatory cytokines secretion [10]. In the two cases reported here and in the one reported in the literature, infection contexts are different. The previously reported patient was slightly immunocompromized (CD4þ >500 per ml and viral load < 40 copies/ml), and has been cured with an immunosuppressive therapy containing prednisolone and rituximab (4 infusions of 375 mg/m2) [7]. In our two cases, FVIII inhibitor appeared during HIV replication. Our first patient was diagnosed with a moderate immunodeficiency. On the contrary, our second patient presented an advanced disease (nadir of lymphocytes TCD4þ: 27 per ml) and autoimmune manifestations appeared during an antiretroviral treatment interruption. Immunosuppressive treatment combined with ART led to regression of autoimmunity with a prompt delay as it has been previously described in non-HIV infected patients.

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Acknowledgements Conflicts of interest There are no conflicts of interest. Claire Rivoisya, Roselyne D’Oironc, Melanie Cherinb, Olivier Se´ge´ral a , Jean-Luc Meynard b , Thierry Lambertc and Ce´cile Goujarda, aInternal Medicine department, Bicetre Hospital, Le Kremlin Biceˆtre, b Infectious Disease department, Saint Antoine Hospital, Paris, and cHemophilic Care Center, Biceˆtre Hospital, Le Kremlin Biceˆtre, France. Correspondence to Claire Rivoisy, Internal Medicine department, Bicetre Hospital, Le Kremlin Biceˆtre. Tel: +33 145212733; fax: +33 145212949; e-mail: [email protected] Received: 15 November 2013; revised: 29 November 2013; accepted: 29 November 2013.

References 1. Huth-Ku¨hne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Le´vesque H, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009; 94:566–575.

2. Knoebl P, Marco P, Baudo F, Collins P, Huth-Ku¨hne A, Nemes L, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost JTH 2012; 10:622–631. 3. Aurousseau MH, Eclache V, Fain O, Thomas M. Acquired factor VIII inhibitor in a patient with tuberculosis. Haemostasis 1996; 26:319–320. 4. ThE´venot T, Lambert M, Canva-Delcambre V, Sugishita K, Goudemand J. Acquired haemophilia and viral hepatitis B infection. Httpwwwem-Premiumcomdatarevues0399832000300005800 [Internet]. 26 mars 2008 [cite´ 20 aouˆt 2013]; Disponible sur: http://www.em-premium.com/article/129924/ 5. Goyal J, Tyagi P, Kumar N. Acquired haemophilia in a patient treated with interferon-a for hepatitis C infection. Haemoph Off J World Fed Hemoph 2012; 18:e73–e74. 6. Cashin P, Lundberg LG, Hagberg H, Ejerblad E, Karlbom U. Acquired haemophilia A and Kaposi’s sarcoma in an HIVnegative, HHV-8-positive patient: a discussion of mechanism and aetiology. Acta Haematol 2010; 124:40–43. 7. Migliore E, Allione A, Dutto L, Bernardi E, Vettorazzi LA, Ricca M, et al. Acquired factor VIII inhibitor in patient infected with HIV: a casual association or a prone immunological setting? Haemoph Off J World Fed Hemoph 2009; 15:1334–1335. 8. Dhasmana DJ, Dheda K, Ravn P, Wilkinson RJ, Meintjes G. Immune reconstitution inflammatory syndrome in HIVinfected patients receiving antiretroviral therapy: pathogenesis, clinical manifestations and management. Drugs 2008; 68:191–208. 9. Stratton R, Slapak G, Mahungu T, Kinloch-de Loes S. Autoimmunity and HIV. Curr Opin Infect Dis 2009; 22:49–56. 10. Breton G. Immune reconstitution inflammatory syndrome or IRIS. Me´decine Sci 2010; 26:281–289.

DOI:10.1097/QAD.0000000000000172

Long-term control of HIV replication with dolutegravir and pegylated interferon alpha-2a in an HIV-infected patient with sixtuple-class resistance With contemporary antiretroviral therapy (ART), the risk of virological failures leading to multiclass resistance has dramatically diminished. However, there are still patients from the pre highly active ART era with multiple-class resistance for whom designing salvage regimens can be very challenging. We report the use of a novel combination – dolutegravir (DTG) and peginterferon alfa-2a – in a patient with sixtuple-class resistance. The patient is a 56-year-old man, diagnosed with HIV infection in 1992. After diagnosis, he started treatment with azydothimidine monotherapy and subsequently received dual [nucleoside reverse transcriptase inhibitor NRTI] and triple (NRTI þ non-NRTI/protease inhibitor)-drug antiretroviral regimens, as part of routine care and through clinical trials such as TORO (enfuvirtide) [1], DUET (darunavir/ritonavir) [2] (randomized to control arm), and raltegravir expanded access. He had been treated with all of the following: dideoxycytidine dideoxyinosine saquinavir, nelfinavir, nevirapine, abacavir, efavirenz, hydroxyurea, lopinavir/ritonavir, amprenavir, enfuvirtide, tipranavir, tenofovir, emtricitabine (FTC), darunavir/ritonavir, etravirine, maraviroc and raltegravir. Unfortunately, he received many of these

antiretovirals as functional monotherapy, without other active drugs. He had never achieved sustained virological suppression. In 2010, while receiving tenofovir difumarate (TDF)/ FTC and darunavir/ritonavir and maraviroc, he developed oral candidiasis and wasting. At that time, his CD4þ cell count was 28 cells/ml and the HIV-RNA viral load 1 100 000 copies/ml. Drug resistance genotype testing showed the following as described below. (1) Reverse transcriptase (bold: mutations present in historical genotypes, but not in the last available genotype): M41L, K101E, V108I, V118I, Y181C, M184 V, G190A L210W, T215Y, V179F. According to the Stanford University HIV Drug Resistance Database interpretation algorithm these mutations confer highlevel resistance to all nucleos(t)ides and non-nucleoside reverse transcriptase inhibitors. (2) Protease: L10F, V32I, I54L, Q58E, G73S, V82L, I84V, L90M, V11I, M36L, L89V. These mutations confer high-level resistance to all protease inhibitors. (3) Fusion inhibitor resistance: V38M V38A. These mutations reduce enfuvirtide susceptibility by more than 10-fold in site-directed mutants and most clinical isolates.

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Correspondence Table 1. HIV-RNA and CD4R evolution. Date 03/03/2011 13/04/2011 25/04/2011 03/05/2011 17/05/2011 23/05/2011 03/06/2011 08/06/2011 17/06/2011 17/06/2011 01/07/2011 24/08/2011 25/10/2011 14/12/2011

HIV-RNA (copies/ml)

CD4þ (cells/ml)

1 100 000 2 900 000 3900 100 118 77 210 74 130

A case of lung involvement due to anaplastic lymphoma kinase negative anaplastic large cell lymphoma in an HIV-infected patient.

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