Correspondence AIDS 2015, 29:1117–1121
Anti-tumor necrosis factor monoclonal antibody for steroid-dependent TB-IRIS in AIDS The immune reconstitution inflammatory syndrome (IRIS) is a well recognized inflammatory complication in HIV-infected patients receiving antituberculosis therapy [tuberculosis-related immune reconstitution inflammatory syndrome (TB-IRIS)], which includes worsening of initial clinical signs or occurrence of new symptoms. Paradoxical TB-IRIS most often presents with lack of viable bacilli [1], and is ascribed to prior CD4þ T-cell activation [2]. Severe cases may benefit from a short course of corticosteroid therapy [3]. Relapses are rare, but may require the maintenance of steroids, questioning the role for alternative effective therapies, such as thalidomide [4]. We describe here a chronic debilitating steroid-dependent TB-IRIS case successfully treated with infliximab. A 30-year-old HIV-infected patient, native of Senegal, was admitted to the Centre d’Infectiologie NeckerPasteur in November 2012 for refractory TB-IRIS. HIV1 infection was diagnosed 26 years earlier and was complicated by relapsing zoster and esophageal candidiasis. He was on combined antiretroviral treatment since the first opportunistic infection (i.e. in 1998) with a good immunovirological response. In 2003, he was successfully treated during 9 months for pleuro-pulmonary tuberculosis. Nine months after antituberculosis therapy discontinuation, he presented abdominal adenopathies, the biopsy of which revealed acid-fast bacilli, while culture grew susceptible Mycobacterium tuberculosis. Antituberculosis treatment was restarted for 9 months. At that time, plasma HIVRNA was 30 200 copies/ml and CD4þ T-cell count was 137/ml. Six weeks after antituberculosis treatment initiation, TB-IRIS was suspected and steroid therapy was started. Despite prolonged antituberculosis therapy (duration 51 months, including moxifloxacin for 8 months) and antiretroviral therapy monitoring, TB-IRIS again occurred when steroid therapy was tapered. In May 2010, he was diagnosed with the seventh TB-IRIS relapse and lenalinomide (10 mg/day, 3 weeks a month) therapy was started. During each episode, bacterial culture was negative, but M. tuberculosis DNA was locally detected. In November 2012, TB-IRIS relapse (abdominal nodes, vertebral spondylitis without diskitis involving thoracic
and lumbosacral vertebrae, epidural and prevertebral abscesses) was diagnosed (Fig. 1a). Vertebral biopsy was performed revealing nonspecific histology and M. tuberculosis DNA, but negative culture. Therapeutic adherence to lenalidomide and to combined antiretroviral therapy (maraviroc and ritonavir-boosted lopinavir) was good. HIV-RNA was undetectable and CD4þ T-cell count was 340/ml. Because of this steroiddependent TB-IRIS, relapsing despite lenalidomide and maraviroc therapy [5], peripheral neuropathy and children wish, we decided to stop lenalidomide and to start infliximab therapy (5 mg/kg monthly). Six courses were administered without any complication, and 6 months after the last infusion, no clinical IRIS activity was detected; radiologic assessment showed partial improvement (Fig. 1b). The present case illustrates the beneficial effect and safety of tumor necrosis factor-alpha (TNF-a) inhibitors on TB-IRIS in a HIV-infected patient, despite the counterintuitive feeling to use drugs, increasing the risk of severe tuberculosis in other settings [6]. Such paradoxical inflammatory syndrome may be caused by an excess of a type 1 helper T-cell (Th1) immune response as suggested by increased levels of interferon gamma (INF-g) and TNF-a in TB-IRIS [7]. We recently evidenced that the soluble interleukin (IL)-2 receptor sCD25, which is released upon CD4þ T-cell activation, was significantly increased at the time of antiretroviral initiation in patients with TB-IRIS, whereas both sCD25 and IL-7 baseline levels were independently associated with a shorter time to TB-IRIS occurrence [2]. TNF-a plays a key role in antimycobacterial immunity as proinflammatory cytokine, and through its role in granuloma formation and maintenance [8,9]. Of note, the occurrence of TB-IRIS has been reported in TNF-a inhibitortreated patients in the context of their withdrawal [10]. Similarly, Wallis et al. [11] also reported a case of lifethreatening TB-IRIS following adalimumab withdrawal and a subsequent clinical improvement after this drug was resumed. Finally, infliximab was used to control steroidresistant TB-IRIS involving the brain in a non-HIVinfected woman [12], while it was also effective in our hands in the context of severe cerebral cryptococcal IRIS in a kidney-transplant woman [13]. In conclusion, we suggest that TNFa inhibitors can be used as salvage therapy in HIV-infected patients with steroid-dependent TB-IRIS.
ISSN 0269-9370 Copyright Q 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1117
1118
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2015, Vol 29 No 9
(a)
(b)
Fig. 1. Spine remnography, sagittal section, T1 corrected fat-signal and gadolinium enhancement before (a) and after (b) infliximab therapy. Initial remnography shows thoracic (T11) and lumbo-sacral involvement with epidural and presacral abscesses improving after infliximab therapy.
Acknowledgements Funding and support: none.
Jade Ghosn and Karima Amazzough contributed equally to the writing of this article. Received: 18 February 2015; revised: 18 February 2015; accepted: 19 February 2015.
Conflicts of interest There are no conflicts of interest. Cle´mence Richauda, Jade Ghosnb,c,M, Karima Amazzougha,M, Sylvain Poireed and Olivier Lortholarya,e, a Universite´ Paris Descartes, Sorbonne Paris Cite´, Service des Maladies Infectieuses et Tropicales et Centre d’Infectiologie Necker Pasteur, IHU Imagine, b APHP, Unite´ Fonctionnelle de The´rapeutique en Immuno-Infectiologie, CHU Hoˆtel Dieu, cUniversite´ Paris Descartes, EA 7327 Faculte´ de Me´decine Site Necker, Sorbonne Paris Cite´, Paris, dUniversite´ Paris Descartes, Sorbonne Paris Cite´, Service de Radiologie adulte, CHU Necker-Enfants Malades, and eInstitut Pasteur, Unite´ de Mycologie Mole´culaire, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, Centre National de la Recherche Scientifique, Unite´ Recherche Associe´e, Paris, France. Correspondence to Cle´mence Richaud, MD, MS, Universite´ Paris Descartes, Sorbonne Paris Cite´, Service des Maladies Infectieuses et Tropicales et Centre d’Infectiologie Necker, IHU Imagine, Paris, France. E-mail: [email protected]
References 1. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8:516– 523. 2. Chakrabarti LA, Boucherie C, Bugault F, Cumont MC, Roussillon C, Breton G, et al. Biomarkers of CD4R T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2014; 28:1593– 1602. 3. Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010; 24:2381– 2390. 4. Brunel AS, Reynes J, Tuaillon E, Rubbo PA, Lortholary O, Montes B, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26:2110–2112. 5. Sierra-Madero JG, Ellenberg SS, Rassool MS, Tierney A, Belaunzaran-Zamudio PF, Lopez-Martinez A, Cadiris ST. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV 2014; 1:7:e60–e67.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Correspondence 6. Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Breban M, et al. Risk of tuberculosis is higher with antitumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009; 60:1884–1894. 7. Elliott JH, Vohith K, Saramony S, Savuth C, Dara C, Sarim C, et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J Infect Dis 2009; 200:1736–1745. 8. Plessner HL, Lin PL, Kohno T, Louie JS, Kirschner D, Chan J, Flynn JL. Neutralization of tumor necrosis factor (TNF) by antibody but not TNF receptor fusion molecule exacerbates chronic murine tuberculosis. J Infect Dis 2007; 195:1643–1650. 9. Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford) 2005; 44: 714–720.
10. Rivoisy C, Amrouche L, Carcelain G, Sereni D, Bourgarit A. Paradoxical exacerbation of tuberculosis after TNFalpha antagonist discontinuation: beware of immune reconstitution inflammatory syndrome. Joint Bone Spine 2011; 78:312–315. 11. Wallis RS, van Vuuren C, Potgieter S. Adalimumab treatment of life-threatening tuberculosis. Clin Infect Dis 2009; 48:1429– 1432. 12. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clin Infect Dis 2008; 47:e83–e85. 13. Scemla A, Gerber S, Duquesne A, Parize P, Martinez F, Anglicheau D, et al. Dramatic improvement of severe Cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient. Am J Transplant 2015; 15:560–564.
DOI:10.1097/QAD.0000000000000634
Acute myocardial infarction following thalidomide treatment for AIDS-related ulcers Thalidomide has been successfully used for two decades in HIV-positive patients to treat oral and oesophageal ulcers [1]. Mechanisms of action likely involve immunomodulatory effects, probably relating to inflammatory cytokines such as tumour necrosis factor a [2]. Typical complications include dizziness, peripheral neuropathy and neutropenia [2]. In addition, an increased risk of thromboembolic events, mainly deep vein thrombosis, has been described in individuals treated with thalidomide for multiple myeloma, highlighting the need for early antithrombotic prophylaxis in such patients [3]. We present the case of a 33-year-old HIV-positive patient who received, after informed consent, thalidomide (Thalidomide; Celgene, Paris, France) 100 mg daily for recurrent, debilitating and painful oesophageal and oral ulcers, associated with a wasting syndrome. No malignant or infectious causes were identified after serial endoscopic oesophageal biopsies and empirical antiviral therapy with aciclovir and valganciclovir showed no improvement leading to the diagnosis of HIV-related ulcers. Patient viral load and CD4þ cell count were 64 copies/ml and 4 cells/ml, respectively. Twenty-two days after initiation of thalidomide, the patient presented a cardiac arrest due to ventricular fibrillation. After successful resuscitation and restoration of sinus rhythm, an electrocardiogram demonstrated signs of myocardial infarction with ST elevation. Coronary angiography revealed a unique subocclusive thrombotic mass in the proximal right coronary artery (Fig. 1) despite the absence of atherosclerosis. This was successfully managed with mechanical thromboaspiration and an implanted, absorbable, prosthetic stent. Patient’s medical history showed a smoking history of 5–10 pack-years with no additional cardiovascular risk factors. Other medications at the time of the event were darunavir/ritonavir, amoxicillin-acid clavulanate (initiated 3 days before), fluconazole, pantoprazole, morphine sulphate, filgrastim and azithromycin.
Trials on the effect of thalidomide on oral and oesophageal ulcers in HIV-positive individuals have historically been performed on relatively small numbers of patients. Data about safety of use in this population are scarce and date from several years ago [1], although there have been increasing off-label uses in the treatment of immune reconstitution inflammatory syndrome [4]. Moreover, chronic HIV infection itself is associated with a heightened risk of coronary heart disease [5]. The present case highlights that indications of thalidomide should be carefully considered in this population and that antiaggregation therapy should be considered when starting thalidomide treatment in HIV-positive patients, as usually recommended in patients with multiple myeloma [3].
Fig. 1. Coronarography of the right coronary artery. Presence of a sub-occlusive thrombotic mass in the proximal portion of the artery.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Acknowledgements
References
Conflicts of interest There are no conflicts of interest.
1. Jacobson JM, Spritzler J, Fox L, Fahey JL, Jackson JB, Chernoff M, et al. Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. J Infect Dis 1999; 180:61–67.
Nicolas Daubya, Julien Coussementa, Eleni Karakikea, Claudiu Ungureanub, Ste´phane De Wit a and MarieChristine Payena, aDepartment of Infectious Diseases, and bDepartment of Cardiology, CHU Saint-Pierre, Brussels, Belgium. Correspondence to Nicolas Dauby, Department Of Infectious Diseases, CHU Saint-Pierre, Rue Haute 322, 1000 Brussels, Belgium. Tel: +32 2 535 4130; fax: +32 2 535 3614; e-mail: [email protected] Received: 18 February 2015; revised: 27 February 2015; accepted: 12 March 2015.
2. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet 2004; 363:1802–1811. 3. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2007; 22:414–423. 4. Brunel A-S, Reynes J, Tuaillon E, Rubbo P-A, Lortholary O, Montes B, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26:2110–2112. 5. Zanni MV, Schouten J, Grinspoon SK, Reiss P. Risk of coronary heart disease in patients with HIV infection. Nat Rev Cardiol 2014; 11:728–741.
DOI:10.1097/QAD.0000000000000656
Cobicistat–vinblastine interaction and severe peripheral neuropathy Elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/ COBI/FTC/TDF, Stribild) is a drug recently commercialized in France (February 2014) for the treatment of HIV-1 infection. This coformulation includes a new molecule, cobicistat, a cytochrome P450 inhibitor devoid of antiretroviral activity. It is used as a pharmacokinetic booster to increase the elvitegravir concentration (a second-generation integrase inhibitor). Cobicistat increases the plasma concentration of several drugs metabolized through the CYP3A pathway, including vinca-alkaloids [1]. Hodgkin lymphoma is a common nonAIDS malignancy among ageing HIV patients [2]. We report a case of severe peripheral neuropathies in a patient treated with EVG/COBI/FTC/TDF and the ABVD protocol (doxorubicin/bleomycin/vinblastine/dacarbazine) for Hodgkin lymphoma. A 46-year-old woman who had been HIV-positive since 2012 was treated immediately with antiretrovirals because of severe immunosuppression (CD4þ cell count 27 cells/ ml). She had not presented any opportunistic infection. Hodgkin’s lymphoma stage 4 (International Prognostic Index 5) was discovered during July 2014. ABVD chemotherapy protocol was started (doxorubicin 46 mg, bleomycin 18.6 mg, vinblastine 11 mg, dacarbazine 700 mg every 2 weeks). Her usual antiretroviral treatment (emtricitabine 200 mg/day, rilpivirine 25 mg/day and tenofovir 245 mg/day) was switched to EVG/COBI/ FTC/TDF because of the potential pharmacokinetic interaction between rilpivirine, doxorubicin and vinblastine. Renal clearance, estimated by the Modified Diet in Renal Disease equation, was 88 ml/min. After the first cycle, the patient described slight paresthesia of the legs, which led to difficulties with
ambulation. At the third cycle, she presented with serious sensory-motor lower and upper limbs peripheral neuropathies. A lumbar puncture was obtained and excluded a neuro-meningeal lymphoma. An electromyogram confirmed the diagnosis of evolutive axonal four limbs sensory-motor peripheral polyneuropathies. ABVD protocol was stopped. Despite the different antiretroviral treatments, the patient’s viral load remained undetectable. Drug–drug interaction between cobicistat and vinblastine was suspected. Vinblastine was stopped and replaced by etoposide 150 mg in the ABVD protocol. EVG/ COBI/FTC/TDF was also stopped and a new antiretroviral treatment (ritonavir 100 mg, abacavir 600 mg, lamivudine 300 mg and darunavir 800 mg) was started. After 2 weeks, neuropathies were decreased, although they persisted for 6 months. Peripheral neuropathy is a frequent side effect of vinblastine, a vinca-alkaloid cytotoxic mainly metabolized by the cytochrome P450 3A4 (CYP3A4). The coadministration of cobicistat can reduce the vinblastine metabolism and consequently potentiate its side effects. We speculate that the interaction between cobicistat and vinblastine was responsible for the peripheral neuropathy. To our knowledge, only one case of drug interaction with cobicistat is reported in the medical literature: cobicistat– fluticasone induced iatrogenic adrenal suppression [3], which is also described with ritonavir booster [4]. Stribild is an attractive drug as a one-pill, once-a-day treatment [1,5]. The drug includes a new booster cobicistat that is better tolerated than ritonavir’s adverse effects [5]. Cobicistat is a selective CYP3A inhibitor unlike ritonavir, which is a nonselective CYP enzyme [5].
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Correspondence
Cobicistat may address some of the limitations of ritonavir. Both drugs have potentially the same risk of interactions with CYP3A drugs [1]. Severe neurotoxicity during concomitant treatment of ritonavir and vinblastine is already known [6–8]. The interaction with cobicistat could have been forecasted. The 2013 French guidelines for antiretroviral therapy recommend close monitoring when using cobicistat or ritonavir in association with vinca-alkaloid [9]. Clinicians have to assess the risk of interaction of both, even if it has not yet been described in literature and especially for cobicistat. For HIV patients with non-AIDS malignancies, including Hodgkin’s lymphoma, it is better to implement the well documented antiretroviral combinations using raltegravir for example. Therefore, we advise, if possible, to avoid treatments that use the combination of cobicistat and substrates of CYP 3A4 drugs.
Acknowledgements Conflicts of interest None declared. Doriane Bidona, Ste´phanie Baulera, Marie-Dominique Venonb and Caroline Dupontc, aPharmacy Department, bHaematology Department, and cInfectiology Department, Ambroise Pare´ Hospital, APHP, Boulogne Billancourt, France. Correspondence to Ste´phanie Bauler, Pharmacy Department, Ambroise Pare´ Hospital, APHP, 9 avenue
Charles de Gaulle 92100, Boulogne Billancourt, France. E-mail: [email protected] Received: 11 March 2015; revised: 19 March 2015; accepted: 20 March 2015.
References 1. Manzardo C, Gatell J. Stribild (elvitegravir/cobicistat/emtricitabine/tenofivir disoproxil fumarate): a new paradigm for HIV-1 treatment. AIDS 2014; 16:35–42. 2. Beral V, Peterman T, Berkelman R, Jaffe H. AIDS-associated nonHodgkin lymphoma. Lancet 1991; 337:805–809. 3. Lewis J, Turtle L, Khoo S. A case of iatrogenic adrenal suppression after co-administration of cobicistat and fluticasone nasal drops. AIDS 2014; 28:2636–2637. 4. Pessanha T, Campos J, Barros A, Pone M, Garrido J, Pone S. Iatrogenic Cushing’s syndrome in an adolescent with AIDSs on ritonavir and inhaled fluticasone. Case report and literature review. AIDS 2007; 21:529–532. 5. Shah BM, Schafer JJ, Priano J, Squires KE. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy 2013; 33:1107–1116. 6. Cheung MC, Hicks LK, Leitch HA. Excessive neurotoxicity with ABVD when combined with protease inhibitor-based antiretroviral therapy in the treatment of AIDS-related Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2010; 10:E2. 7. Corona G, Vaccher E, Spina M, Toffoli G. Potential hazard drugdrug interaction between boosted protease inhibitors and vinblastine in HIV patients with Hodgkin’s lymphoma. AIDS 2013; 27:1033–1039. 8. Cingolani A, Torti L, Pinnetti C, de Gaetano Donati K, Murri R, Tacconelli E, et al. Detrimental clinical interaction between ritonavir-boosted protease inhibitors and vinblastine in HIVinfected patients with Hodgkin’s lymphoma. AIDS 2010; 24: 2408–2412. 9. Prise en charge me´dicale des personnes vivant avec le VIH. Recommandations du groupe d’experts. Rapport 2013; Paris: La Documentation Franc¸aise; 2013. p. 476 http://www. sante.gouv.fr/IMG/pdf/Rapport_Morlat_2013_Mise_en_ligne.pdf [Accessed 15 January 2015]
DOI:10.1097/QAD.0000000000000688
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1121
Anti-tumor necrosis factor monoclonal antibody for steroid-dependent TB-IRIS in AIDS The immune reconstitution inflammatory syndrome (IRIS) is a well recognized inflammatory complication in HIV-infected patients receiving antituberculosis therapy [tuberculosis-related immune reconstitution inflammatory syndrome (TB-IRIS)], which includes worsening of initial clinical signs or occurrence of new symptoms. Paradoxical TB-IRIS most often presents with lack of viable bacilli [1], and is ascribed to prior CD4þ T-cell activation [2]. Severe cases may benefit from a short course of corticosteroid therapy [3]. Relapses are rare, but may require the maintenance of steroids, questioning the role for alternative effective therapies, such as thalidomide [4]. We describe here a chronic debilitating steroid-dependent TB-IRIS case successfully treated with infliximab. A 30-year-old HIV-infected patient, native of Senegal, was admitted to the Centre d’Infectiologie NeckerPasteur in November 2012 for refractory TB-IRIS. HIV1 infection was diagnosed 26 years earlier and was complicated by relapsing zoster and esophageal candidiasis. He was on combined antiretroviral treatment since the first opportunistic infection (i.e. in 1998) with a good immunovirological response. In 2003, he was successfully treated during 9 months for pleuro-pulmonary tuberculosis. Nine months after antituberculosis therapy discontinuation, he presented abdominal adenopathies, the biopsy of which revealed acid-fast bacilli, while culture grew susceptible Mycobacterium tuberculosis. Antituberculosis treatment was restarted for 9 months. At that time, plasma HIVRNA was 30 200 copies/ml and CD4þ T-cell count was 137/ml. Six weeks after antituberculosis treatment initiation, TB-IRIS was suspected and steroid therapy was started. Despite prolonged antituberculosis therapy (duration 51 months, including moxifloxacin for 8 months) and antiretroviral therapy monitoring, TB-IRIS again occurred when steroid therapy was tapered. In May 2010, he was diagnosed with the seventh TB-IRIS relapse and lenalinomide (10 mg/day, 3 weeks a month) therapy was started. During each episode, bacterial culture was negative, but M. tuberculosis DNA was locally detected. In November 2012, TB-IRIS relapse (abdominal nodes, vertebral spondylitis without diskitis involving thoracic
and lumbosacral vertebrae, epidural and prevertebral abscesses) was diagnosed (Fig. 1a). Vertebral biopsy was performed revealing nonspecific histology and M. tuberculosis DNA, but negative culture. Therapeutic adherence to lenalidomide and to combined antiretroviral therapy (maraviroc and ritonavir-boosted lopinavir) was good. HIV-RNA was undetectable and CD4þ T-cell count was 340/ml. Because of this steroiddependent TB-IRIS, relapsing despite lenalidomide and maraviroc therapy [5], peripheral neuropathy and children wish, we decided to stop lenalidomide and to start infliximab therapy (5 mg/kg monthly). Six courses were administered without any complication, and 6 months after the last infusion, no clinical IRIS activity was detected; radiologic assessment showed partial improvement (Fig. 1b). The present case illustrates the beneficial effect and safety of tumor necrosis factor-alpha (TNF-a) inhibitors on TB-IRIS in a HIV-infected patient, despite the counterintuitive feeling to use drugs, increasing the risk of severe tuberculosis in other settings [6]. Such paradoxical inflammatory syndrome may be caused by an excess of a type 1 helper T-cell (Th1) immune response as suggested by increased levels of interferon gamma (INF-g) and TNF-a in TB-IRIS [7]. We recently evidenced that the soluble interleukin (IL)-2 receptor sCD25, which is released upon CD4þ T-cell activation, was significantly increased at the time of antiretroviral initiation in patients with TB-IRIS, whereas both sCD25 and IL-7 baseline levels were independently associated with a shorter time to TB-IRIS occurrence [2]. TNF-a plays a key role in antimycobacterial immunity as proinflammatory cytokine, and through its role in granuloma formation and maintenance [8,9]. Of note, the occurrence of TB-IRIS has been reported in TNF-a inhibitortreated patients in the context of their withdrawal [10]. Similarly, Wallis et al. [11] also reported a case of lifethreatening TB-IRIS following adalimumab withdrawal and a subsequent clinical improvement after this drug was resumed. Finally, infliximab was used to control steroidresistant TB-IRIS involving the brain in a non-HIVinfected woman [12], while it was also effective in our hands in the context of severe cerebral cryptococcal IRIS in a kidney-transplant woman [13]. In conclusion, we suggest that TNFa inhibitors can be used as salvage therapy in HIV-infected patients with steroid-dependent TB-IRIS.
ISSN 0269-9370 Copyright Q 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1117
1118
AIDS
2015, Vol 29 No 9
(a)
(b)
Fig. 1. Spine remnography, sagittal section, T1 corrected fat-signal and gadolinium enhancement before (a) and after (b) infliximab therapy. Initial remnography shows thoracic (T11) and lumbo-sacral involvement with epidural and presacral abscesses improving after infliximab therapy.
Acknowledgements Funding and support: none.
Jade Ghosn and Karima Amazzough contributed equally to the writing of this article. Received: 18 February 2015; revised: 18 February 2015; accepted: 19 February 2015.
Conflicts of interest There are no conflicts of interest. Cle´mence Richauda, Jade Ghosnb,c,M, Karima Amazzougha,M, Sylvain Poireed and Olivier Lortholarya,e, a Universite´ Paris Descartes, Sorbonne Paris Cite´, Service des Maladies Infectieuses et Tropicales et Centre d’Infectiologie Necker Pasteur, IHU Imagine, b APHP, Unite´ Fonctionnelle de The´rapeutique en Immuno-Infectiologie, CHU Hoˆtel Dieu, cUniversite´ Paris Descartes, EA 7327 Faculte´ de Me´decine Site Necker, Sorbonne Paris Cite´, Paris, dUniversite´ Paris Descartes, Sorbonne Paris Cite´, Service de Radiologie adulte, CHU Necker-Enfants Malades, and eInstitut Pasteur, Unite´ de Mycologie Mole´culaire, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, Centre National de la Recherche Scientifique, Unite´ Recherche Associe´e, Paris, France. Correspondence to Cle´mence Richaud, MD, MS, Universite´ Paris Descartes, Sorbonne Paris Cite´, Service des Maladies Infectieuses et Tropicales et Centre d’Infectiologie Necker, IHU Imagine, Paris, France. E-mail: [email protected]
References 1. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8:516– 523. 2. Chakrabarti LA, Boucherie C, Bugault F, Cumont MC, Roussillon C, Breton G, et al. Biomarkers of CD4R T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2014; 28:1593– 1602. 3. Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010; 24:2381– 2390. 4. Brunel AS, Reynes J, Tuaillon E, Rubbo PA, Lortholary O, Montes B, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26:2110–2112. 5. Sierra-Madero JG, Ellenberg SS, Rassool MS, Tierney A, Belaunzaran-Zamudio PF, Lopez-Martinez A, Cadiris ST. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV 2014; 1:7:e60–e67.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Correspondence 6. Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Breban M, et al. Risk of tuberculosis is higher with antitumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009; 60:1884–1894. 7. Elliott JH, Vohith K, Saramony S, Savuth C, Dara C, Sarim C, et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J Infect Dis 2009; 200:1736–1745. 8. Plessner HL, Lin PL, Kohno T, Louie JS, Kirschner D, Chan J, Flynn JL. Neutralization of tumor necrosis factor (TNF) by antibody but not TNF receptor fusion molecule exacerbates chronic murine tuberculosis. J Infect Dis 2007; 195:1643–1650. 9. Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford) 2005; 44: 714–720.
10. Rivoisy C, Amrouche L, Carcelain G, Sereni D, Bourgarit A. Paradoxical exacerbation of tuberculosis after TNFalpha antagonist discontinuation: beware of immune reconstitution inflammatory syndrome. Joint Bone Spine 2011; 78:312–315. 11. Wallis RS, van Vuuren C, Potgieter S. Adalimumab treatment of life-threatening tuberculosis. Clin Infect Dis 2009; 48:1429– 1432. 12. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clin Infect Dis 2008; 47:e83–e85. 13. Scemla A, Gerber S, Duquesne A, Parize P, Martinez F, Anglicheau D, et al. Dramatic improvement of severe Cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient. Am J Transplant 2015; 15:560–564.
DOI:10.1097/QAD.0000000000000634
Acute myocardial infarction following thalidomide treatment for AIDS-related ulcers Thalidomide has been successfully used for two decades in HIV-positive patients to treat oral and oesophageal ulcers [1]. Mechanisms of action likely involve immunomodulatory effects, probably relating to inflammatory cytokines such as tumour necrosis factor a [2]. Typical complications include dizziness, peripheral neuropathy and neutropenia [2]. In addition, an increased risk of thromboembolic events, mainly deep vein thrombosis, has been described in individuals treated with thalidomide for multiple myeloma, highlighting the need for early antithrombotic prophylaxis in such patients [3]. We present the case of a 33-year-old HIV-positive patient who received, after informed consent, thalidomide (Thalidomide; Celgene, Paris, France) 100 mg daily for recurrent, debilitating and painful oesophageal and oral ulcers, associated with a wasting syndrome. No malignant or infectious causes were identified after serial endoscopic oesophageal biopsies and empirical antiviral therapy with aciclovir and valganciclovir showed no improvement leading to the diagnosis of HIV-related ulcers. Patient viral load and CD4þ cell count were 64 copies/ml and 4 cells/ml, respectively. Twenty-two days after initiation of thalidomide, the patient presented a cardiac arrest due to ventricular fibrillation. After successful resuscitation and restoration of sinus rhythm, an electrocardiogram demonstrated signs of myocardial infarction with ST elevation. Coronary angiography revealed a unique subocclusive thrombotic mass in the proximal right coronary artery (Fig. 1) despite the absence of atherosclerosis. This was successfully managed with mechanical thromboaspiration and an implanted, absorbable, prosthetic stent. Patient’s medical history showed a smoking history of 5–10 pack-years with no additional cardiovascular risk factors. Other medications at the time of the event were darunavir/ritonavir, amoxicillin-acid clavulanate (initiated 3 days before), fluconazole, pantoprazole, morphine sulphate, filgrastim and azithromycin.
Trials on the effect of thalidomide on oral and oesophageal ulcers in HIV-positive individuals have historically been performed on relatively small numbers of patients. Data about safety of use in this population are scarce and date from several years ago [1], although there have been increasing off-label uses in the treatment of immune reconstitution inflammatory syndrome [4]. Moreover, chronic HIV infection itself is associated with a heightened risk of coronary heart disease [5]. The present case highlights that indications of thalidomide should be carefully considered in this population and that antiaggregation therapy should be considered when starting thalidomide treatment in HIV-positive patients, as usually recommended in patients with multiple myeloma [3].
Fig. 1. Coronarography of the right coronary artery. Presence of a sub-occlusive thrombotic mass in the proximal portion of the artery.
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Acknowledgements
References
Conflicts of interest There are no conflicts of interest.
1. Jacobson JM, Spritzler J, Fox L, Fahey JL, Jackson JB, Chernoff M, et al. Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. J Infect Dis 1999; 180:61–67.
Nicolas Daubya, Julien Coussementa, Eleni Karakikea, Claudiu Ungureanub, Ste´phane De Wit a and MarieChristine Payena, aDepartment of Infectious Diseases, and bDepartment of Cardiology, CHU Saint-Pierre, Brussels, Belgium. Correspondence to Nicolas Dauby, Department Of Infectious Diseases, CHU Saint-Pierre, Rue Haute 322, 1000 Brussels, Belgium. Tel: +32 2 535 4130; fax: +32 2 535 3614; e-mail: [email protected] Received: 18 February 2015; revised: 27 February 2015; accepted: 12 March 2015.
2. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet 2004; 363:1802–1811. 3. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2007; 22:414–423. 4. Brunel A-S, Reynes J, Tuaillon E, Rubbo P-A, Lortholary O, Montes B, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26:2110–2112. 5. Zanni MV, Schouten J, Grinspoon SK, Reiss P. Risk of coronary heart disease in patients with HIV infection. Nat Rev Cardiol 2014; 11:728–741.
DOI:10.1097/QAD.0000000000000656
Cobicistat–vinblastine interaction and severe peripheral neuropathy Elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/ COBI/FTC/TDF, Stribild) is a drug recently commercialized in France (February 2014) for the treatment of HIV-1 infection. This coformulation includes a new molecule, cobicistat, a cytochrome P450 inhibitor devoid of antiretroviral activity. It is used as a pharmacokinetic booster to increase the elvitegravir concentration (a second-generation integrase inhibitor). Cobicistat increases the plasma concentration of several drugs metabolized through the CYP3A pathway, including vinca-alkaloids [1]. Hodgkin lymphoma is a common nonAIDS malignancy among ageing HIV patients [2]. We report a case of severe peripheral neuropathies in a patient treated with EVG/COBI/FTC/TDF and the ABVD protocol (doxorubicin/bleomycin/vinblastine/dacarbazine) for Hodgkin lymphoma. A 46-year-old woman who had been HIV-positive since 2012 was treated immediately with antiretrovirals because of severe immunosuppression (CD4þ cell count 27 cells/ ml). She had not presented any opportunistic infection. Hodgkin’s lymphoma stage 4 (International Prognostic Index 5) was discovered during July 2014. ABVD chemotherapy protocol was started (doxorubicin 46 mg, bleomycin 18.6 mg, vinblastine 11 mg, dacarbazine 700 mg every 2 weeks). Her usual antiretroviral treatment (emtricitabine 200 mg/day, rilpivirine 25 mg/day and tenofovir 245 mg/day) was switched to EVG/COBI/ FTC/TDF because of the potential pharmacokinetic interaction between rilpivirine, doxorubicin and vinblastine. Renal clearance, estimated by the Modified Diet in Renal Disease equation, was 88 ml/min. After the first cycle, the patient described slight paresthesia of the legs, which led to difficulties with
ambulation. At the third cycle, she presented with serious sensory-motor lower and upper limbs peripheral neuropathies. A lumbar puncture was obtained and excluded a neuro-meningeal lymphoma. An electromyogram confirmed the diagnosis of evolutive axonal four limbs sensory-motor peripheral polyneuropathies. ABVD protocol was stopped. Despite the different antiretroviral treatments, the patient’s viral load remained undetectable. Drug–drug interaction between cobicistat and vinblastine was suspected. Vinblastine was stopped and replaced by etoposide 150 mg in the ABVD protocol. EVG/ COBI/FTC/TDF was also stopped and a new antiretroviral treatment (ritonavir 100 mg, abacavir 600 mg, lamivudine 300 mg and darunavir 800 mg) was started. After 2 weeks, neuropathies were decreased, although they persisted for 6 months. Peripheral neuropathy is a frequent side effect of vinblastine, a vinca-alkaloid cytotoxic mainly metabolized by the cytochrome P450 3A4 (CYP3A4). The coadministration of cobicistat can reduce the vinblastine metabolism and consequently potentiate its side effects. We speculate that the interaction between cobicistat and vinblastine was responsible for the peripheral neuropathy. To our knowledge, only one case of drug interaction with cobicistat is reported in the medical literature: cobicistat– fluticasone induced iatrogenic adrenal suppression [3], which is also described with ritonavir booster [4]. Stribild is an attractive drug as a one-pill, once-a-day treatment [1,5]. The drug includes a new booster cobicistat that is better tolerated than ritonavir’s adverse effects [5]. Cobicistat is a selective CYP3A inhibitor unlike ritonavir, which is a nonselective CYP enzyme [5].
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Correspondence
Cobicistat may address some of the limitations of ritonavir. Both drugs have potentially the same risk of interactions with CYP3A drugs [1]. Severe neurotoxicity during concomitant treatment of ritonavir and vinblastine is already known [6–8]. The interaction with cobicistat could have been forecasted. The 2013 French guidelines for antiretroviral therapy recommend close monitoring when using cobicistat or ritonavir in association with vinca-alkaloid [9]. Clinicians have to assess the risk of interaction of both, even if it has not yet been described in literature and especially for cobicistat. For HIV patients with non-AIDS malignancies, including Hodgkin’s lymphoma, it is better to implement the well documented antiretroviral combinations using raltegravir for example. Therefore, we advise, if possible, to avoid treatments that use the combination of cobicistat and substrates of CYP 3A4 drugs.
Acknowledgements Conflicts of interest None declared. Doriane Bidona, Ste´phanie Baulera, Marie-Dominique Venonb and Caroline Dupontc, aPharmacy Department, bHaematology Department, and cInfectiology Department, Ambroise Pare´ Hospital, APHP, Boulogne Billancourt, France. Correspondence to Ste´phanie Bauler, Pharmacy Department, Ambroise Pare´ Hospital, APHP, 9 avenue
Charles de Gaulle 92100, Boulogne Billancourt, France. E-mail: [email protected] Received: 11 March 2015; revised: 19 March 2015; accepted: 20 March 2015.
References 1. Manzardo C, Gatell J. Stribild (elvitegravir/cobicistat/emtricitabine/tenofivir disoproxil fumarate): a new paradigm for HIV-1 treatment. AIDS 2014; 16:35–42. 2. Beral V, Peterman T, Berkelman R, Jaffe H. AIDS-associated nonHodgkin lymphoma. Lancet 1991; 337:805–809. 3. Lewis J, Turtle L, Khoo S. A case of iatrogenic adrenal suppression after co-administration of cobicistat and fluticasone nasal drops. AIDS 2014; 28:2636–2637. 4. Pessanha T, Campos J, Barros A, Pone M, Garrido J, Pone S. Iatrogenic Cushing’s syndrome in an adolescent with AIDSs on ritonavir and inhaled fluticasone. Case report and literature review. AIDS 2007; 21:529–532. 5. Shah BM, Schafer JJ, Priano J, Squires KE. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy 2013; 33:1107–1116. 6. Cheung MC, Hicks LK, Leitch HA. Excessive neurotoxicity with ABVD when combined with protease inhibitor-based antiretroviral therapy in the treatment of AIDS-related Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2010; 10:E2. 7. Corona G, Vaccher E, Spina M, Toffoli G. Potential hazard drugdrug interaction between boosted protease inhibitors and vinblastine in HIV patients with Hodgkin’s lymphoma. AIDS 2013; 27:1033–1039. 8. Cingolani A, Torti L, Pinnetti C, de Gaetano Donati K, Murri R, Tacconelli E, et al. Detrimental clinical interaction between ritonavir-boosted protease inhibitors and vinblastine in HIVinfected patients with Hodgkin’s lymphoma. AIDS 2010; 24: 2408–2412. 9. Prise en charge me´dicale des personnes vivant avec le VIH. Recommandations du groupe d’experts. Rapport 2013; Paris: La Documentation Franc¸aise; 2013. p. 476 http://www. sante.gouv.fr/IMG/pdf/Rapport_Morlat_2013_Mise_en_ligne.pdf [Accessed 15 January 2015]
DOI:10.1097/QAD.0000000000000688
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