Correspondence AIDS 2014, 28:447–451
Azathioprine can be safely used in HIV-infected individuals Azathioprine is an immunosuppressive agent used following solid organ transplant and in the treatment of autoimmune diseases [1]; however, adverse events may be severe and, although often nonspecific, may include life-threatening myelosuppression [2–4]. As HIV infection is associated with a decline in CD4þ lymphocyte subset count, the benefits of administration of immunosuppressive agents in HIV-infected individuals need to be assessed carefully [5]. The efficacy and associated toxicity of azathioprine in HIVinfected individuals has not been well described with a single case report of an HIV-infected patient on highly active antiretroviral therapy (HAART) safely administered azathioprine for the treatment of myasthenia gravis [6]. A database of all HIV-infected patients is held within the department and this was cross-referenced with a separate record held by the departmental pharmacy to ensure full case ascertainment of HIV-infected individuals prescribed azathioprine between January 2008 and August 2012. Seven individuals received azathioprine during this period and mean age was 38 years (range 27–53 years). There were four female and three male individuals. Indications for azathioprine treatment included myositis; herpes simplex virus related immune reconstitution inflammatory syndrome (IRIS); myasthenia gravis; ulcerative colitis; cryptococcal meningitis related IRIS; tuberculosis-related IRIS and Mycobacterium avium complex related IRIS. All patients were receiving HAART. The medical notes were reviewed and immune parameters and haemoglobin levels recorded, as well as adverse outcomes including malignancy, infection and severe anaemia requiring blood transfusion. All individuals were tested for thiopurine methyltransferase activity prior to commencing treatment with azathioprine and were assessed as tolerant.
The median duration of azathioprine was 12 months (range: 0.1–65 months). Laboratory measurements were taken at baseline, after 1 month of azathioprine treatment and at the end of azathioprine treatment. During the first month of azathioprine treatment, there were no statistically significant falls in haemoglobin, white cell count, platelets, neutrophils, lymphocytes, CD4þ cell counts, CD8þ cell counts, CD4þ% or CD8þ%. Over the course of the treatment with azathioprine, the total white cell count fell significantly from median 6.8 to 3.6 109/l (P ¼ 0.037). There was a trend to significance in the decline in neutrophil count from a median 4.2 to 2.1 109/l (P ¼ 0.066), although there was no significant decline in total lymphocyte count or subsets (Table 1). No opportunistic infections occurred during or in the 6 months following cessation of azathioprine. Case 3 developed an Escherichia coli bacteraemia requiring antibiotic therapy. Case 5 developed a urinary tract infection with coagulase-negative Staphylococcus and Clostridium difficile colitis requiring hospital admission. Case 6 developed an upper respiratory tract infection (with no organism isolated) and an E. coli urinary tract infection. Case 6 developed anaemia and neutropaenia and subsequently stopped azathioprine therapy. No malignancies were diagnosed during and following cessation of treatment. Two individuals died during treatment with azathioprine: one due to complications of disseminated MAC-related IRIS with pneumonia after 4 days of treatment with azathioprine and one from cardiorespiratory arrest secondary to pre-existent left ventricular failure and poorly controlled diabetes after 14 days of therapy. Neither death was associated with the azathioprine therapy. Although no serious opportunistic infections or malignancies were reported and neither immune parameters,
Table 1. Affect of azathioprine therapy on blood parameters.
Median Median Median Median Median Median Median Median Median
haemoglobin (range, g/l) white cell count (range, 109/l) neutrophil count (range, 109/l) lymphocyte count (range, 109/l) platelet count (range, 109/l) CD4þ cell count (range, cells/ml) CD4þ% (range) CD8þ count (range, cells/ml) CD8þ% (range)
Baseline
After 1 month of azathioprine therapy
Mann–Whitney U-test
At end of azathioprine therapy
Mann–Whitney U-test (start vs. end)
124 (92–145) 6.8 (3.2–11.6) 4.2 (1.4–9.7) 1.7 (1.2–2.3) 241 (129–326) 436 (7–886) 28% (1.3–48) 601 (377–1002) 40% (32–76)
126 (10–135) 5.5 (2.9–7.5) 3.5 (1.9–6.6) 0.9 (0/7–1.5) 295 (199–363) 165 (136–503) 26% (18–37) 442 (224–547) 49% (34–62)
P ¼ 0.81 P ¼ 0.33 P ¼ 0.83 P ¼ 0.055 P ¼ 0.20 P ¼ 0.43 P ¼ 0.71 P ¼ 0.13 P ¼ 0.71
114 (90–140) 3.6 (1.3–6.5) 2.1 (0.6–3.7) 0.9 (0.3–2.0) 224 (162–289) 386 (123–609) 36% (24–57) 327 (28–861) 43% (27–62)
P ¼ 0.42 P ¼ 0.037 P ¼ 0.066 P ¼ 0.093 P ¼ 0.87 P ¼ 0.67 P ¼ 0.15 P ¼ 0.12 P ¼ 0.48
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
447
448
AIDS
2014, Vol 28 No 3
nor haemoglobin fell below critical levels, further data are needed before conclusions of the safety of azathioprine in the context of HIV-infected individuals are made. Where azathioprine is used in this context, immune parameters should be regularly monitored throughout treatment.
Tel: +44 (020) 33153570; fax: +44 (020) 33155628; e-mail: [email protected] Received: 16 September 2013; revised: 18 October 2013; accepted: 18 October 2013.
References
Acknowledgements Conflicts of interest There are no conflicts of interest. Florence E. Chamberlaina,b, Naila Dinanib, Gurmit K. Jagjit Singhb, Mark Bowerb and Mark Nelsonb, a Imperial College London, and bHIV/GUM Directorate, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. Correspondence to Florence Chamberlain, HIV/GUM Directorate, Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK.
1. Joint Formulary Committee. British National Formulary. 61. London: BMJ Group and Pharmaceutical Press; 2011. 2. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest [Online] 2003; 111:1122–1124. 3. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol [Online] 1992; 43:329–339. 4. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2013; 4:CD000545. 5. Keat A, Rowe I. Reiter’s syndrome and associated arthritidies. Rheum Dis Clin N Am 1991; 17:25–42. 6. Knopf L, Menkes DL. Comorbid HIV and myaesthenia gravis: case report and review of the literature. J Clin Neuromuscul Dis 2010; 12:80–84.
DOI:10.1097/QAD.0000000000000121
Mandibular osteonecrosis and dental exfoliation after trigeminal zoster in an HIV-infected patient: case report and review of the literature Herpes zoster is a classical concern among HIV-infected patients; its incidence can reach up to five cases per 100 persons per year [1]. Trigeminal nerve is a frequent localization (about 20% of cases) and its classical complications are postherpetic neuralgia, facial palsy, loss of earring and encephalitis. Less well known are the maxillofacial complications including periodontitis, tooth exfoliation and osteonecrosis of jaw (ONJ) [2]. We report such a case of mandibular osteonecrosis with teeth exfoliation and make a review of the literature.
Clinically, the patient was apyretic, the skin rash was localized in the region linked to the right mandibular branch of the trigeminal nerve, otoscopy showed purulent flow and oral examination showed precarious buccodental status but no acute abscess or periodontitis. The diagnosis of zoster was confirmed by genomic amplification of varicella zoster virus on peripheral blood samples and on cutaneous swab. The patient received 7 days of intravenous aciclovir [10 mg/kg three times daily (t.i.d.)] relayed with oral valaciclovir (1000 mg t.i.d.) for an overall 15-day treatment. He also received an antibiotic treatment by clindamycin.
A 50-year-old HIV-infected male patient was hospitalized for an extensive facial zoster associated with a perforated otitis and peripheral facial palsy (Ramsay–Hunt syndrome).
Amitryptilin (20 mg t.i.d.) was prescribed in prevention of postzoster neuralgia and had to be majored up to 60 mg t.i.d. because of important dysesthesia.
He was diagnosed for HIV in 1989 and treated from 1994. He was staged C3 in the CDC classification. His CD4þ T cell count was 314 cells/ml (20%) and viral load was less than 50 copies/ml. Ongoing combined antiretroviral therapy (cART) was etravirine, darunavir boosted with ritonavir and tenofovir/emtricitabine.
Complete resolution of the skin lesions was obtained within 3 weeks.
Other medical records were an opioid substitution by oral buprenorphine and allergy to penicillin and cotrimoxazole.
Clinical examination revealed an ulcero-necrotic gingivitis in the right mandible territory. It was associated with
Five weeks after the onset of the zoster, the patient experienced spontaneous, multiple (five) and nonalgic tooth exfoliation in the eruption territory.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
bone exposure with no bleeding at contact. Teeth 43 and 44 were mobile and were finally spontaneously exfoliated a few days later. Tomographic examination showed a well limited osteonecrosis next to the exfoliated teeth (Fig. 1). A conservative treatment was decided and anti-VZV therapy by valacyclovir (1000 mg t.i.d.) was restarted for 15 more days. A review of the literature allowed us to identify 45 cases in addition to the present case. The first case was reported in 1955 [3] and our case was, up to now, the third case associated with a Ramsay–Hunt syndrome. Thirty-three cases occurred along the HIV/AIDS era, of which 14 (42%) were documented to be HIV-positive, nine were HIV-negative and, for 10 patients, the status was unknown. The delay of appearance of ONJ after the zoster event was only reported in 14 cases, with a mean of 5 weeks (0.5–24). Among the 25 cases seronegative or of unknown status, nine presented a severe immunocompromising condition but, for seven of them, there was no evidence of an underlying morbidity. We missed information with respect to the determination of the specific roles of immune deficiency (HIV staging, cART) or the effect of zoster treatment on the onset of ONJ.
Se:200 Im:74
[A]
Anonyme Study date: 11/07/2013 Study time: 10:49:18 MRN: N/A
The mechanism of osteonecrosis during Herpes zoster infection is still debated and seems to be multifactorial. Ischemic injury of alveolar bone could be due to a local vasculitis [4], vasoconstriction through the sympathetic innervations [5], mechanic compression of the alveolar artery by the swelled alveolar nerve [6] or a hypercoagulable state. Nervous mechanisms could also be implicated, as there is an important role of innervations on regulation of bone mass [7]. Infectious process could play a role, either by direct odontoblast targeting by VZV or by superinfection with other agents (mostly by actinomyces species), and has been reported in other causes of ONJ [8]. With regard to prior oral condition, osteonecrosis of the jaw is a rare but disabling complication of trigeminal zoster. It is still poorly known and mostly reported in odontologic journals. Its incidence seems to be higher in HIV-infected patients, but more data are needed to reach any conclusion on the precise roles of immune status and antiretroviral regimen. Its pathogenia is still unclear but could include vascular, nervous and infectious factors. Being aware of this possible complication could lead the clinician to extend the length of VZV treatment when facing a trigeminal zoster in a patient with risk factors or underlying comorbidity.
Acknowledgements This work was not supported by any grants from any institution.
Conflicts of interest There are no conflicts of interest.
20.20 mm
[L]
[R]
[P]
C847 W3132
Fig. 1. Tomographic examination showing osteonecrosis in the left anterior part of mandibular.
Nicolas Cloareca, Olivia Zaegel-Fauchera, Sylvie Bregigeona, Carla E. Canoa, Cyril Chossegrosb,d, Benoit Wajszczakb and Isabelle Poizot-Martina,c,d, a APHM Sainte-Marguerite, Service d’immuno-he´matologie clinique, bAPHM Timone, Service de stomatologie et chirurgie maxillo-faciale, cInserm, U912 (SESSTIM), and dAix-Marseille Univ, Marseille, France. Correspondence to Nicolas Cloarec, MD, Service d’immuno-he´matologie Clinique, CHU Sainte Marguerite, 270, Boulevard Sainte Marguerite, BP29, 13274 Marseille Cedex 9, France. Tel: +33 (0)4 91 74 56 96; fax: +33 (0)4 91 74 50 69; e-mail: [email protected]
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
449
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AIDS
2014, Vol 28 No 3
Received: 4 September 2013; revised: 18 October 2013; accepted: 18 October 2013.
References 1. Hung CC, Hsiao CF, Wang JL, Chen MY, Hsieh SM, Sheng WH, Chang SC. Herpes zoster in HIV-1-infected patients in the era of highly active antiretroviral therapy: a prospective observational study. Int J STD AIDS 2005; 16:673. 2. Solomon CS, Coffiner MO, Chalfin HE. Herpes zoster revisited: implicated in root resorption. J Endod 1986; 12:210–213. 3. Dechaume, Decrozailles C, Garlopeau F, Robert J. Localized mandibular necrosis during trigeminal herpes. Revue Stomatol 1955; 56:516–521.
4. Melanson M, Chalk C, Georgevich L, Fett K, Lapierre Y, Duong H, et al. Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia: evidence for viral invasion of cerebral arteries. Neurology 1996; 47:569. 5. van Heerden WF, McEachen SE, Boy SC. Alveolar bone necrosis and tooth exfoliation secondary to herpes zoster in the setting of HIV/AIDS. AIDS 2005; 19:2183–2184. 6. Arikawa J, Mizushima J, Higaki Y, Hoshino J, Kawashima M. Mandibular alveolar bone necrosis after trigeminal herpes zoster. Int J Dermatol 2004; 43:136–137. 7. Takeda S, Karsenty G. Molecular bases of the sympathetic regulation of bone mass. Bone 2008; 42:837–840. 8. Naik NH, Russo TA. Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces. Clin Infect Dis 2009; 49:1729.
DOI:10.1097/QAD.0000000000000122
Reversible bone lesions induced by tenofovir disoproxil fumarate Metabolic bone disease is increasingly common in HIVinfected patients on antiretroviral therapy (ART) [1]. Manifestations of ART-induced bone disease include low bone mineral density, increased bone turnover, osteopenia, osteoporosis, and increased fracture risk [2–4]. To
our knowledge, reversible tenofovir disoproxil fumarate (TDF)-induced bone lesions have not been described. We describe a patient who developed diffuse foci of increased bone turnover on a TDF-containing regimen and which resolved upon discontinuation of TDF.
Fig. 1. Technetium bone scan.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
A 33-year-old Caucasian woman with HIV had multiple risk factors for metabolic bone disease including low BMI, Caucasian race, and tobacco use. A protease inhibitor-containing regimen was initiated and eventually included TDF, which continued unabated for 74 months. Severe lower-extremity pain began approximately 36 months after TDF was added, occurred with movement, and limited activities of daily living (ADL). Eventually, generalized pain extended to the wrists, upper arms, and thorax, and fluctuated in intensity for several months. At 74 months, pain was reported to be excruciating with significant overall impairment of ADL. Chemistries and serum markers for bone disease including vitamin D, parathyroid hormone, and calcium were within normal limits, with the exception of alkaline phosphatase and liver transaminases, each of which was greater than two and three times the upper limit of normal, respectively. Serum creatinine and blood urea nitrogen were normal. All antiretrovirals were discontinued due to severe bone pain. A technetium bone scan revealed multiple foci of increased activity in distal tibiae, bilateral calcaneus bones, multiple costovertebral junctions and ribs, sternum, sacroiliac joints, and right iliac and superior pubic ramus (Fig. 1). Shortly after these findings, the same protease inhibitor-containing regimen, without TDF, was resumed. The patient reported significant improvement in pain and function 3 months later, and a bone scan 11 months after stopping TDF was normal. Additionally, alkaline phosphatase declined shortly after TDF was discontinued and normalized 12 months later. In conclusion, reversible bone lesions detected by technetium bone scan present a unique finding and a likely manifestation of TDF-induced metabolic bone disease. In our patient, imaging abnormalities occurred after greater than 6 years of continued TDF use, and resolved after 11 months of TDF-sparing ART, whereas other risk factors for bone disease, including protease inhibitor use, remained constant. A bone scan may be useful for discriminating pain caused by metabolic bone
disease on long-term TDF from other types of chronic pain.
Acknowledgements Conflicts of interest Financial support: No financial support was received for the manuscript. Disclaimers: There are no conflicts of interest for Staci M. Lockhart or Douglas A. Drevets. Staci M. Lockhart and Douglas A. Drevets, University of Oklahoma Health Sciences Center, Oklahoma, USA. Correspondence to Staci M. Lockhart, 1110 N. Stonewall Avenue, CPB Room 223, Oklahoma City, OK 73104, USA. Tel: +1 405 271 6878 x47369; fax: +1 405 271 6430; e-mail: [email protected] Received: 21 October 2013; revised: 1 November 2013; accepted: 1 November 2013.
References 1. Brown TT, Qaquish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174. 2. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS 2012; 26:825– 831. 3. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Wijngaerden EV, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010; 51:963–972. 4. Yin MT, Kendall MA, Wu X, Tassiopoulos K, Hochberg M, Huang JS, et al. Fractures after antiretroviral initiation. AIDS 2012; 26:2175–2184.
DOI:10.1097/QAD.0000000000000138
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451
Azathioprine can be safely used in HIV-infected individuals Azathioprine is an immunosuppressive agent used following solid organ transplant and in the treatment of autoimmune diseases [1]; however, adverse events may be severe and, although often nonspecific, may include life-threatening myelosuppression [2–4]. As HIV infection is associated with a decline in CD4þ lymphocyte subset count, the benefits of administration of immunosuppressive agents in HIV-infected individuals need to be assessed carefully [5]. The efficacy and associated toxicity of azathioprine in HIVinfected individuals has not been well described with a single case report of an HIV-infected patient on highly active antiretroviral therapy (HAART) safely administered azathioprine for the treatment of myasthenia gravis [6]. A database of all HIV-infected patients is held within the department and this was cross-referenced with a separate record held by the departmental pharmacy to ensure full case ascertainment of HIV-infected individuals prescribed azathioprine between January 2008 and August 2012. Seven individuals received azathioprine during this period and mean age was 38 years (range 27–53 years). There were four female and three male individuals. Indications for azathioprine treatment included myositis; herpes simplex virus related immune reconstitution inflammatory syndrome (IRIS); myasthenia gravis; ulcerative colitis; cryptococcal meningitis related IRIS; tuberculosis-related IRIS and Mycobacterium avium complex related IRIS. All patients were receiving HAART. The medical notes were reviewed and immune parameters and haemoglobin levels recorded, as well as adverse outcomes including malignancy, infection and severe anaemia requiring blood transfusion. All individuals were tested for thiopurine methyltransferase activity prior to commencing treatment with azathioprine and were assessed as tolerant.
The median duration of azathioprine was 12 months (range: 0.1–65 months). Laboratory measurements were taken at baseline, after 1 month of azathioprine treatment and at the end of azathioprine treatment. During the first month of azathioprine treatment, there were no statistically significant falls in haemoglobin, white cell count, platelets, neutrophils, lymphocytes, CD4þ cell counts, CD8þ cell counts, CD4þ% or CD8þ%. Over the course of the treatment with azathioprine, the total white cell count fell significantly from median 6.8 to 3.6 109/l (P ¼ 0.037). There was a trend to significance in the decline in neutrophil count from a median 4.2 to 2.1 109/l (P ¼ 0.066), although there was no significant decline in total lymphocyte count or subsets (Table 1). No opportunistic infections occurred during or in the 6 months following cessation of azathioprine. Case 3 developed an Escherichia coli bacteraemia requiring antibiotic therapy. Case 5 developed a urinary tract infection with coagulase-negative Staphylococcus and Clostridium difficile colitis requiring hospital admission. Case 6 developed an upper respiratory tract infection (with no organism isolated) and an E. coli urinary tract infection. Case 6 developed anaemia and neutropaenia and subsequently stopped azathioprine therapy. No malignancies were diagnosed during and following cessation of treatment. Two individuals died during treatment with azathioprine: one due to complications of disseminated MAC-related IRIS with pneumonia after 4 days of treatment with azathioprine and one from cardiorespiratory arrest secondary to pre-existent left ventricular failure and poorly controlled diabetes after 14 days of therapy. Neither death was associated with the azathioprine therapy. Although no serious opportunistic infections or malignancies were reported and neither immune parameters,
Table 1. Affect of azathioprine therapy on blood parameters.
Median Median Median Median Median Median Median Median Median
haemoglobin (range, g/l) white cell count (range, 109/l) neutrophil count (range, 109/l) lymphocyte count (range, 109/l) platelet count (range, 109/l) CD4þ cell count (range, cells/ml) CD4þ% (range) CD8þ count (range, cells/ml) CD8þ% (range)
Baseline
After 1 month of azathioprine therapy
Mann–Whitney U-test
At end of azathioprine therapy
Mann–Whitney U-test (start vs. end)
124 (92–145) 6.8 (3.2–11.6) 4.2 (1.4–9.7) 1.7 (1.2–2.3) 241 (129–326) 436 (7–886) 28% (1.3–48) 601 (377–1002) 40% (32–76)
126 (10–135) 5.5 (2.9–7.5) 3.5 (1.9–6.6) 0.9 (0/7–1.5) 295 (199–363) 165 (136–503) 26% (18–37) 442 (224–547) 49% (34–62)
P ¼ 0.81 P ¼ 0.33 P ¼ 0.83 P ¼ 0.055 P ¼ 0.20 P ¼ 0.43 P ¼ 0.71 P ¼ 0.13 P ¼ 0.71
114 (90–140) 3.6 (1.3–6.5) 2.1 (0.6–3.7) 0.9 (0.3–2.0) 224 (162–289) 386 (123–609) 36% (24–57) 327 (28–861) 43% (27–62)
P ¼ 0.42 P ¼ 0.037 P ¼ 0.066 P ¼ 0.093 P ¼ 0.87 P ¼ 0.67 P ¼ 0.15 P ¼ 0.12 P ¼ 0.48
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
447
448
AIDS
2014, Vol 28 No 3
nor haemoglobin fell below critical levels, further data are needed before conclusions of the safety of azathioprine in the context of HIV-infected individuals are made. Where azathioprine is used in this context, immune parameters should be regularly monitored throughout treatment.
Tel: +44 (020) 33153570; fax: +44 (020) 33155628; e-mail: [email protected] Received: 16 September 2013; revised: 18 October 2013; accepted: 18 October 2013.
References
Acknowledgements Conflicts of interest There are no conflicts of interest. Florence E. Chamberlaina,b, Naila Dinanib, Gurmit K. Jagjit Singhb, Mark Bowerb and Mark Nelsonb, a Imperial College London, and bHIV/GUM Directorate, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. Correspondence to Florence Chamberlain, HIV/GUM Directorate, Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK.
1. Joint Formulary Committee. British National Formulary. 61. London: BMJ Group and Pharmaceutical Press; 2011. 2. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest [Online] 2003; 111:1122–1124. 3. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol [Online] 1992; 43:329–339. 4. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2013; 4:CD000545. 5. Keat A, Rowe I. Reiter’s syndrome and associated arthritidies. Rheum Dis Clin N Am 1991; 17:25–42. 6. Knopf L, Menkes DL. Comorbid HIV and myaesthenia gravis: case report and review of the literature. J Clin Neuromuscul Dis 2010; 12:80–84.
DOI:10.1097/QAD.0000000000000121
Mandibular osteonecrosis and dental exfoliation after trigeminal zoster in an HIV-infected patient: case report and review of the literature Herpes zoster is a classical concern among HIV-infected patients; its incidence can reach up to five cases per 100 persons per year [1]. Trigeminal nerve is a frequent localization (about 20% of cases) and its classical complications are postherpetic neuralgia, facial palsy, loss of earring and encephalitis. Less well known are the maxillofacial complications including periodontitis, tooth exfoliation and osteonecrosis of jaw (ONJ) [2]. We report such a case of mandibular osteonecrosis with teeth exfoliation and make a review of the literature.
Clinically, the patient was apyretic, the skin rash was localized in the region linked to the right mandibular branch of the trigeminal nerve, otoscopy showed purulent flow and oral examination showed precarious buccodental status but no acute abscess or periodontitis. The diagnosis of zoster was confirmed by genomic amplification of varicella zoster virus on peripheral blood samples and on cutaneous swab. The patient received 7 days of intravenous aciclovir [10 mg/kg three times daily (t.i.d.)] relayed with oral valaciclovir (1000 mg t.i.d.) for an overall 15-day treatment. He also received an antibiotic treatment by clindamycin.
A 50-year-old HIV-infected male patient was hospitalized for an extensive facial zoster associated with a perforated otitis and peripheral facial palsy (Ramsay–Hunt syndrome).
Amitryptilin (20 mg t.i.d.) was prescribed in prevention of postzoster neuralgia and had to be majored up to 60 mg t.i.d. because of important dysesthesia.
He was diagnosed for HIV in 1989 and treated from 1994. He was staged C3 in the CDC classification. His CD4þ T cell count was 314 cells/ml (20%) and viral load was less than 50 copies/ml. Ongoing combined antiretroviral therapy (cART) was etravirine, darunavir boosted with ritonavir and tenofovir/emtricitabine.
Complete resolution of the skin lesions was obtained within 3 weeks.
Other medical records were an opioid substitution by oral buprenorphine and allergy to penicillin and cotrimoxazole.
Clinical examination revealed an ulcero-necrotic gingivitis in the right mandible territory. It was associated with
Five weeks after the onset of the zoster, the patient experienced spontaneous, multiple (five) and nonalgic tooth exfoliation in the eruption territory.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
bone exposure with no bleeding at contact. Teeth 43 and 44 were mobile and were finally spontaneously exfoliated a few days later. Tomographic examination showed a well limited osteonecrosis next to the exfoliated teeth (Fig. 1). A conservative treatment was decided and anti-VZV therapy by valacyclovir (1000 mg t.i.d.) was restarted for 15 more days. A review of the literature allowed us to identify 45 cases in addition to the present case. The first case was reported in 1955 [3] and our case was, up to now, the third case associated with a Ramsay–Hunt syndrome. Thirty-three cases occurred along the HIV/AIDS era, of which 14 (42%) were documented to be HIV-positive, nine were HIV-negative and, for 10 patients, the status was unknown. The delay of appearance of ONJ after the zoster event was only reported in 14 cases, with a mean of 5 weeks (0.5–24). Among the 25 cases seronegative or of unknown status, nine presented a severe immunocompromising condition but, for seven of them, there was no evidence of an underlying morbidity. We missed information with respect to the determination of the specific roles of immune deficiency (HIV staging, cART) or the effect of zoster treatment on the onset of ONJ.
Se:200 Im:74
[A]
Anonyme Study date: 11/07/2013 Study time: 10:49:18 MRN: N/A
The mechanism of osteonecrosis during Herpes zoster infection is still debated and seems to be multifactorial. Ischemic injury of alveolar bone could be due to a local vasculitis [4], vasoconstriction through the sympathetic innervations [5], mechanic compression of the alveolar artery by the swelled alveolar nerve [6] or a hypercoagulable state. Nervous mechanisms could also be implicated, as there is an important role of innervations on regulation of bone mass [7]. Infectious process could play a role, either by direct odontoblast targeting by VZV or by superinfection with other agents (mostly by actinomyces species), and has been reported in other causes of ONJ [8]. With regard to prior oral condition, osteonecrosis of the jaw is a rare but disabling complication of trigeminal zoster. It is still poorly known and mostly reported in odontologic journals. Its incidence seems to be higher in HIV-infected patients, but more data are needed to reach any conclusion on the precise roles of immune status and antiretroviral regimen. Its pathogenia is still unclear but could include vascular, nervous and infectious factors. Being aware of this possible complication could lead the clinician to extend the length of VZV treatment when facing a trigeminal zoster in a patient with risk factors or underlying comorbidity.
Acknowledgements This work was not supported by any grants from any institution.
Conflicts of interest There are no conflicts of interest.
20.20 mm
[L]
[R]
[P]
C847 W3132
Fig. 1. Tomographic examination showing osteonecrosis in the left anterior part of mandibular.
Nicolas Cloareca, Olivia Zaegel-Fauchera, Sylvie Bregigeona, Carla E. Canoa, Cyril Chossegrosb,d, Benoit Wajszczakb and Isabelle Poizot-Martina,c,d, a APHM Sainte-Marguerite, Service d’immuno-he´matologie clinique, bAPHM Timone, Service de stomatologie et chirurgie maxillo-faciale, cInserm, U912 (SESSTIM), and dAix-Marseille Univ, Marseille, France. Correspondence to Nicolas Cloarec, MD, Service d’immuno-he´matologie Clinique, CHU Sainte Marguerite, 270, Boulevard Sainte Marguerite, BP29, 13274 Marseille Cedex 9, France. Tel: +33 (0)4 91 74 56 96; fax: +33 (0)4 91 74 50 69; e-mail: [email protected]
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AIDS
2014, Vol 28 No 3
Received: 4 September 2013; revised: 18 October 2013; accepted: 18 October 2013.
References 1. Hung CC, Hsiao CF, Wang JL, Chen MY, Hsieh SM, Sheng WH, Chang SC. Herpes zoster in HIV-1-infected patients in the era of highly active antiretroviral therapy: a prospective observational study. Int J STD AIDS 2005; 16:673. 2. Solomon CS, Coffiner MO, Chalfin HE. Herpes zoster revisited: implicated in root resorption. J Endod 1986; 12:210–213. 3. Dechaume, Decrozailles C, Garlopeau F, Robert J. Localized mandibular necrosis during trigeminal herpes. Revue Stomatol 1955; 56:516–521.
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DOI:10.1097/QAD.0000000000000122
Reversible bone lesions induced by tenofovir disoproxil fumarate Metabolic bone disease is increasingly common in HIVinfected patients on antiretroviral therapy (ART) [1]. Manifestations of ART-induced bone disease include low bone mineral density, increased bone turnover, osteopenia, osteoporosis, and increased fracture risk [2–4]. To
our knowledge, reversible tenofovir disoproxil fumarate (TDF)-induced bone lesions have not been described. We describe a patient who developed diffuse foci of increased bone turnover on a TDF-containing regimen and which resolved upon discontinuation of TDF.
Fig. 1. Technetium bone scan.
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Correspondence
A 33-year-old Caucasian woman with HIV had multiple risk factors for metabolic bone disease including low BMI, Caucasian race, and tobacco use. A protease inhibitor-containing regimen was initiated and eventually included TDF, which continued unabated for 74 months. Severe lower-extremity pain began approximately 36 months after TDF was added, occurred with movement, and limited activities of daily living (ADL). Eventually, generalized pain extended to the wrists, upper arms, and thorax, and fluctuated in intensity for several months. At 74 months, pain was reported to be excruciating with significant overall impairment of ADL. Chemistries and serum markers for bone disease including vitamin D, parathyroid hormone, and calcium were within normal limits, with the exception of alkaline phosphatase and liver transaminases, each of which was greater than two and three times the upper limit of normal, respectively. Serum creatinine and blood urea nitrogen were normal. All antiretrovirals were discontinued due to severe bone pain. A technetium bone scan revealed multiple foci of increased activity in distal tibiae, bilateral calcaneus bones, multiple costovertebral junctions and ribs, sternum, sacroiliac joints, and right iliac and superior pubic ramus (Fig. 1). Shortly after these findings, the same protease inhibitor-containing regimen, without TDF, was resumed. The patient reported significant improvement in pain and function 3 months later, and a bone scan 11 months after stopping TDF was normal. Additionally, alkaline phosphatase declined shortly after TDF was discontinued and normalized 12 months later. In conclusion, reversible bone lesions detected by technetium bone scan present a unique finding and a likely manifestation of TDF-induced metabolic bone disease. In our patient, imaging abnormalities occurred after greater than 6 years of continued TDF use, and resolved after 11 months of TDF-sparing ART, whereas other risk factors for bone disease, including protease inhibitor use, remained constant. A bone scan may be useful for discriminating pain caused by metabolic bone
disease on long-term TDF from other types of chronic pain.
Acknowledgements Conflicts of interest Financial support: No financial support was received for the manuscript. Disclaimers: There are no conflicts of interest for Staci M. Lockhart or Douglas A. Drevets. Staci M. Lockhart and Douglas A. Drevets, University of Oklahoma Health Sciences Center, Oklahoma, USA. Correspondence to Staci M. Lockhart, 1110 N. Stonewall Avenue, CPB Room 223, Oklahoma City, OK 73104, USA. Tel: +1 405 271 6878 x47369; fax: +1 405 271 6430; e-mail: [email protected] Received: 21 October 2013; revised: 1 November 2013; accepted: 1 November 2013.
References 1. Brown TT, Qaquish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174. 2. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS 2012; 26:825– 831. 3. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Wijngaerden EV, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010; 51:963–972. 4. Yin MT, Kendall MA, Wu X, Tassiopoulos K, Hochberg M, Huang JS, et al. Fractures after antiretroviral initiation. AIDS 2012; 26:2175–2184.
DOI:10.1097/QAD.0000000000000138
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