Case report
Achilles tendinopathy following Kaletra (lopinavir/ritonavir) use
International Journal of STD & AIDS 2014, Vol. 25(11) 833–835 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414523403 std.sagepub.com
FV Cresswell1, J Tomlins1, DR Churchill1, K Walker-Bone2 and D Richardson1
Abstract A multitude of rheumatologic manifestations have been associated with HIV infection and protease inhibitors use. We describe two cases that display a temporal relationship between initiating Kaletra and developing Achilles tendinopathy. Immediate and dramatic resolution of symptoms occurred on switching from Kaletra to an alternative agent. Clinicians may want to consider a trial of an alternative agent in individuals on Kaletra who experience Achilles tendinopathy. Adverse events must be formally reported so that our understanding of antiretrovirals may continually evolve and aid decisions about antiretroviral prescribing.
Keywords HIV, AIDS, antiretroviral therapy, treatment, toxicity, Achilles tendinopathy, tendinitis, Kaletra, lopinavir, protease inhibitors Date received: 20 October 2013; accepted: 14 January 2014
Introduction Rheumatological conditions have long been described in association with HIV, and several studies have shown that musculoskeletal pain is more common in people living with HIV.1 It has also been reported that immune reconstitution inflammatory syndrome can be responsible for novel autoimmune rheumatic disorders.2,3 In the era of effective antiretroviral therapy (ART), a shift from disease to drug-related morbidity is increasingly emerging. Protease inhibitors (PIs), in particular, have been linked to rheumatological manifestations: a European survey found arthralgia to be more common in patients receiving PIs than those on a non-PI-based regimen (35.5% vs. 26%, p < 0.01).4 Case reports have linked indinavir to frozen shoulder, tendonitis and aseptic monoarthritis.4,5 PIs are widely used in HIV post-exposure prophylaxis (PEP). It is important to give careful consideration to ART safety profiles in this context when balancing against a risk of HIV acquisition that may be extremely low. Achilles tendinopathy is an acute or chronic condition characterised by pain and swelling in the distal part of the tendon. Although more common in athletes, other risk factors exist including age, male gender and obesity.6 Fluoroquinolone use has been associated with Achilles
tendinopathy, particularly with concurrent corticosteroids or renal disease.7 Achilles problems can also be associated with sexually transmitted infections (STIs) such as disseminated gonococcal infection and chlamydia.8 Diagnosis is largely clinical but may be supported by ultrasound and magnetic resonance imaging (MRI) findings. Treatment includes short course non-steroidal antiinflammatory drugs, rest and physiotherapy. We present two cases of Achilles tendinopathy that may have been precipitated by Kaletra (lopinavir/ ritonavir). First, a well, HIV-negative patient receiving HIV PEP and second an HIV-positive patient on ART.
Case 1 A fit and well 18-year-old man attended our clinic for PEP following unprotected receptive anal intercourse with a partner of unknown HIV status. HIV pointof-care test was negative and it was deemed appropriate 1
Lawson Unit, Brighton and Sussex University Hospital, Brighton, UK MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 2
Corresponding author: FV Cresswell, Lawson Unit, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, UK. Email: [email protected]
Downloaded from std.sagepub.com at Freie Universitaet Berlin on May 9, 2015
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International Journal of STD & AIDS 25(11)
to start PEP. He received treatment with Truvada (tenofovir disoproxil/emtricitabine) and Kaletra. He was reviewed on day 4 when he complained of a two-day history of bilateral swollen and painful ankles. There was no history of fluoroquinolone or corticosteroid use nor recent sporting injury. Clinical examination found him to have an enlarged tender right Achilles tendon, and a rheumatology consultant felt this was acute Achilles tendinopathy precipitated by ART. It was felt Kaletra was the most likely culprit, so this was switched to raltegravir and he was prescribed oral ibuprofen. Three days later, he reported complete resolution of pain and reduced swelling of his right ankle. He completed the rest of the PEP without complications. His STI screen on day 14 was negative.
Case 2 A 43-year-old man was diagnosed with HIV in 2001 with a good CD4 count. He had mild asthma and used inhalers. He began taking Kaletra and Truvada with a CD4 count of 666 106/L. Nine months later, he began complaining of thickening and pain around both Achilles tendons. Subsequent ultrasound and MRI confirmed Achilles tendinosis (Figure 1). His symptoms failed to improve with anti-inflammatory medications, and he was reviewed by a consultant rheumatologist who suggested his Achilles problems may be related to ART. He had no documented fluoroquinolone or oral corticosteroid use. In absence of other therapeutic options, a switch from Kaletra to darunavir/ritonavir was tried. His Achilles pain resolved two days after switching, and he was able to start exercising regularly. He was not troubled by further Achilles tendon problems during the subsequent two years he attended our clinic.
Discussion The close temporal association between starting Kaletra and onset of symptoms in case 1 and a rapid resolution of symptoms on switching to an alternative agent in both cases has led us to believe there may be an association between Achilles tendinopathy and Kaletra. The pathophysiology of how Kaletra may cause tendonitis is not clear. Indinavir crystals have been isolated in the synovial fluid of patients with frozen shoulder, suggesting intra-tissue crystallisation may be a possibility.9 Extensive research carried out to unravel how fluoroquinolones cause tendon pathology has shown them to be cytotoxic to tendon tissue in vitro.10 These are the first case reports in the literature of Achilles tendinitis with PI use. This association may not have been previously documented as it is either a genuinely rare occurrence, because clinicians have not made an association between Achilles problems and ART or because of under-reporting. Proactive reporting of adverse incidents to the appropriate authority is critical in building a robust understanding of antiretroviral toxicity. In the UK, two other cases of tendinopathy with lopinavir have been reported through the yellow card system (www.mhra.gov.uk). It is important to be mindful of side-effect profiles, including more unusual symptoms, when prescribing ART, especially when there are other agents available. Clinicians could consider switching from Kaletra to an alternative agent if Achilles problems develop in the absence of other causative factors. Conflict of interest The authors declare no conflict of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
References
Figure 1. T2-weighted MRI of the right heel showing a fusiform swelling within the critical zone of the Achilles tendon to 7 mm consistent with Achilles tendinosis.
1. Lawson E and Walker-Bone K. The changing spectrum of rheumatic disease in HIV infection. Br Med Bull 2012; 103: 203–221. 2. Rivoisy C, Jaureguiberry S, M’Bappe P, et al. Tenosynovitis as a possible feature of immune reconstitution syndrome during highly active antiretroviral treatment (HAART). Bone Joint Spine 2009; 76: 550–552. 3. Nguyen BY and Reveille JD. Rheumatic manifestations associated with HIV in the highly active antiretroviral therapy era. Curr Opin in Rheumatol 2009; 21: 404–410. 4. Florence E, Schrooten W, Verdonck K, et al. Rheumatological complications associated with the use of indinavir and other protease inhibitors. Ann Rheum Dis 2002; 61: 82–84.
Downloaded from std.sagepub.com at Freie Universitaet Berlin on May 9, 2015
Cresswell et al.
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5. Grasland A, Ziza JM, Raguin G, et al. Adhesive capsulitis of shoulder and HIV virus infection: report of 8 cases. J Rheumatol 2000; 27: 2642–2646. 6. Holmes GB. Etiologic factors associated with symptomatic Achilles tendinopathy. Foot Ankle Int 2006; 27: 952–259. 7. Khaliq Y and Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis 2003; 36: 1404–1410. 8. Van der Linden PD, Sturkenboom MC, Herings RM, et al. Fluoroquinolones and Achilles tendon disorders: a case control study. BMJ 2002; 324: 1306–1307.
9. Brooks JI, Gallicano K, Garber G, et al. Acute monoarthritis complicating therapy with indinavir. AIDS 2000; 14: 2064–2065. 10. Pouzaud F, Bernard-Beaubois K, Thevenin M, et al. In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress. JPET 2004; 308: 394–402.
Downloaded from std.sagepub.com at Freie Universitaet Berlin on May 9, 2015
Achilles tendinopathy following Kaletra (lopinavir/ritonavir) use
International Journal of STD & AIDS 2014, Vol. 25(11) 833–835 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414523403 std.sagepub.com
FV Cresswell1, J Tomlins1, DR Churchill1, K Walker-Bone2 and D Richardson1
Abstract A multitude of rheumatologic manifestations have been associated with HIV infection and protease inhibitors use. We describe two cases that display a temporal relationship between initiating Kaletra and developing Achilles tendinopathy. Immediate and dramatic resolution of symptoms occurred on switching from Kaletra to an alternative agent. Clinicians may want to consider a trial of an alternative agent in individuals on Kaletra who experience Achilles tendinopathy. Adverse events must be formally reported so that our understanding of antiretrovirals may continually evolve and aid decisions about antiretroviral prescribing.
Keywords HIV, AIDS, antiretroviral therapy, treatment, toxicity, Achilles tendinopathy, tendinitis, Kaletra, lopinavir, protease inhibitors Date received: 20 October 2013; accepted: 14 January 2014
Introduction Rheumatological conditions have long been described in association with HIV, and several studies have shown that musculoskeletal pain is more common in people living with HIV.1 It has also been reported that immune reconstitution inflammatory syndrome can be responsible for novel autoimmune rheumatic disorders.2,3 In the era of effective antiretroviral therapy (ART), a shift from disease to drug-related morbidity is increasingly emerging. Protease inhibitors (PIs), in particular, have been linked to rheumatological manifestations: a European survey found arthralgia to be more common in patients receiving PIs than those on a non-PI-based regimen (35.5% vs. 26%, p < 0.01).4 Case reports have linked indinavir to frozen shoulder, tendonitis and aseptic monoarthritis.4,5 PIs are widely used in HIV post-exposure prophylaxis (PEP). It is important to give careful consideration to ART safety profiles in this context when balancing against a risk of HIV acquisition that may be extremely low. Achilles tendinopathy is an acute or chronic condition characterised by pain and swelling in the distal part of the tendon. Although more common in athletes, other risk factors exist including age, male gender and obesity.6 Fluoroquinolone use has been associated with Achilles
tendinopathy, particularly with concurrent corticosteroids or renal disease.7 Achilles problems can also be associated with sexually transmitted infections (STIs) such as disseminated gonococcal infection and chlamydia.8 Diagnosis is largely clinical but may be supported by ultrasound and magnetic resonance imaging (MRI) findings. Treatment includes short course non-steroidal antiinflammatory drugs, rest and physiotherapy. We present two cases of Achilles tendinopathy that may have been precipitated by Kaletra (lopinavir/ ritonavir). First, a well, HIV-negative patient receiving HIV PEP and second an HIV-positive patient on ART.
Case 1 A fit and well 18-year-old man attended our clinic for PEP following unprotected receptive anal intercourse with a partner of unknown HIV status. HIV pointof-care test was negative and it was deemed appropriate 1
Lawson Unit, Brighton and Sussex University Hospital, Brighton, UK MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 2
Corresponding author: FV Cresswell, Lawson Unit, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, UK. Email: [email protected]
Downloaded from std.sagepub.com at Freie Universitaet Berlin on May 9, 2015
834
International Journal of STD & AIDS 25(11)
to start PEP. He received treatment with Truvada (tenofovir disoproxil/emtricitabine) and Kaletra. He was reviewed on day 4 when he complained of a two-day history of bilateral swollen and painful ankles. There was no history of fluoroquinolone or corticosteroid use nor recent sporting injury. Clinical examination found him to have an enlarged tender right Achilles tendon, and a rheumatology consultant felt this was acute Achilles tendinopathy precipitated by ART. It was felt Kaletra was the most likely culprit, so this was switched to raltegravir and he was prescribed oral ibuprofen. Three days later, he reported complete resolution of pain and reduced swelling of his right ankle. He completed the rest of the PEP without complications. His STI screen on day 14 was negative.
Case 2 A 43-year-old man was diagnosed with HIV in 2001 with a good CD4 count. He had mild asthma and used inhalers. He began taking Kaletra and Truvada with a CD4 count of 666 106/L. Nine months later, he began complaining of thickening and pain around both Achilles tendons. Subsequent ultrasound and MRI confirmed Achilles tendinosis (Figure 1). His symptoms failed to improve with anti-inflammatory medications, and he was reviewed by a consultant rheumatologist who suggested his Achilles problems may be related to ART. He had no documented fluoroquinolone or oral corticosteroid use. In absence of other therapeutic options, a switch from Kaletra to darunavir/ritonavir was tried. His Achilles pain resolved two days after switching, and he was able to start exercising regularly. He was not troubled by further Achilles tendon problems during the subsequent two years he attended our clinic.
Discussion The close temporal association between starting Kaletra and onset of symptoms in case 1 and a rapid resolution of symptoms on switching to an alternative agent in both cases has led us to believe there may be an association between Achilles tendinopathy and Kaletra. The pathophysiology of how Kaletra may cause tendonitis is not clear. Indinavir crystals have been isolated in the synovial fluid of patients with frozen shoulder, suggesting intra-tissue crystallisation may be a possibility.9 Extensive research carried out to unravel how fluoroquinolones cause tendon pathology has shown them to be cytotoxic to tendon tissue in vitro.10 These are the first case reports in the literature of Achilles tendinitis with PI use. This association may not have been previously documented as it is either a genuinely rare occurrence, because clinicians have not made an association between Achilles problems and ART or because of under-reporting. Proactive reporting of adverse incidents to the appropriate authority is critical in building a robust understanding of antiretroviral toxicity. In the UK, two other cases of tendinopathy with lopinavir have been reported through the yellow card system (www.mhra.gov.uk). It is important to be mindful of side-effect profiles, including more unusual symptoms, when prescribing ART, especially when there are other agents available. Clinicians could consider switching from Kaletra to an alternative agent if Achilles problems develop in the absence of other causative factors. Conflict of interest The authors declare no conflict of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
References
Figure 1. T2-weighted MRI of the right heel showing a fusiform swelling within the critical zone of the Achilles tendon to 7 mm consistent with Achilles tendinosis.
1. Lawson E and Walker-Bone K. The changing spectrum of rheumatic disease in HIV infection. Br Med Bull 2012; 103: 203–221. 2. Rivoisy C, Jaureguiberry S, M’Bappe P, et al. Tenosynovitis as a possible feature of immune reconstitution syndrome during highly active antiretroviral treatment (HAART). Bone Joint Spine 2009; 76: 550–552. 3. Nguyen BY and Reveille JD. Rheumatic manifestations associated with HIV in the highly active antiretroviral therapy era. Curr Opin in Rheumatol 2009; 21: 404–410. 4. Florence E, Schrooten W, Verdonck K, et al. Rheumatological complications associated with the use of indinavir and other protease inhibitors. Ann Rheum Dis 2002; 61: 82–84.
Downloaded from std.sagepub.com at Freie Universitaet Berlin on May 9, 2015
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5. Grasland A, Ziza JM, Raguin G, et al. Adhesive capsulitis of shoulder and HIV virus infection: report of 8 cases. J Rheumatol 2000; 27: 2642–2646. 6. Holmes GB. Etiologic factors associated with symptomatic Achilles tendinopathy. Foot Ankle Int 2006; 27: 952–259. 7. Khaliq Y and Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis 2003; 36: 1404–1410. 8. Van der Linden PD, Sturkenboom MC, Herings RM, et al. Fluoroquinolones and Achilles tendon disorders: a case control study. BMJ 2002; 324: 1306–1307.
9. Brooks JI, Gallicano K, Garber G, et al. Acute monoarthritis complicating therapy with indinavir. AIDS 2000; 14: 2064–2065. 10. Pouzaud F, Bernard-Beaubois K, Thevenin M, et al. In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress. JPET 2004; 308: 394–402.
Downloaded from std.sagepub.com at Freie Universitaet Berlin on May 9, 2015
