Review: HIV and Myopathy

Abstract & Commentary

By Michael Rubin, MD Dr. Rubin is Professor, Clinical Neurology, New York-Presbyterian Hospital, Cornell Campus. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Viatris.

Synopsis: Introduction of HAART has dramatically modified the natural history of HIV disease by controlling viral replication, but, in turn, lengthening of the survival of HIV-infected individuals has been associated with an increasing prevalence of iatrogenic conditions.

Source: Authier FJ, et al. Skeletal Muscle Involvement in Human Immunodeficiency Virus (HIV)-Infected Patients in the Era of Highly Active Antiretroviral Therapy (HAART). Muscle Nerve. 2005:32:247-260.

Introduced in 1996, highly active antiretroviral therapy (HAART), comprising 2 nucleoside-analogue reverse-transcriptase inhibitors (NRTIs) combined with at least 1 protease inhibitor (PI), has transformed the natural history of human immunodeficiency virus (HIV) disease. Muscle involvement in the age of HAART is now substantively different from that seen previously, and is the subject of this review. It may be classified into 4 categories.

HIV-Associated Myopathy and Related Conditions

HIV polymyositis (PM) may occur at any stage of the disease and resembles that seen in idiopathic PM, with the subacute onset of proximal symmetric weakness without rash, facial, or extraocular muscle involvement. Serum creatine kinase (CK) is elevated, and needle electromyography ((EMG) demonstrates positive waves, complex repetitive discharges, and short duration, small amplitude polyphasic motor unit potentials. Diagnosis is achieved by muscle biopsy that reveals scattered necrotic basophilic fibers, intrafascicular mononuclear inflammatory cell infiltrates, and inflammatory cell invasion of non-necrotic fibers. CD8+ T cell endomysial infiltrates, sarcolemmal MHC class I antigen expression, and CD8+ T cells expressing MHC-I are seen on immunohistochemistry. Pathogenic mechanisms are similar in HIV and non-HIV PM, with the direct role of virus in HIV PM remaining uncertain. Treatment is similarly analogous to non-HIV PM, and includes corticosteroids, azathioprine, methotrexate, cyclophosphamide, cyclosporine, intravenous immunoglobulin (IVIG), and perhaps mycophenolate mofetil.

PM may be seen as one component of the diffuse infiltrative lymphocytosis syndrome (DILS), a rare complication of HIV usually presenting as painless enlargement of the parotid gland and associated with peripheral neuropathy, lymphocytic interstitial pneumonitis, renal tubular acidosis, lymphocytic hepatitis, and lymphoma. Diagnosis requires tissue confirmation of involvement in at least 3 organs, and treatment combines steroids with HAART. PM may also be seen pathologically in the HIV-wasting syndrome, which incorporates involuntary weight loss with either chronic diarrhea or weakness and more than 30 days of fever, in the absence of another explanation for these findings. Etiopathogenesis of the HIV-wasting syndrome remains an enigma, but may involve interleukin (IL)-1 beta and tumor necrosis factor-alpha, or over-expression of myostatin, a negative regulator of muscle growth. Vasculitis may present as myositis in HIV, with proximal weakness, elevated CK, and myopathic EMG, but this is more commonly seen in vasculitic peripheral neuropathy. Steroids are beneficial, but cytotoxic agents are contraindicated due to the immunodeficiency. Plasmapheresis may be helpful as well.

Rare HIV patients develop inclusion body myositis identical in all respects to the idiopathic form. Nemaline (rod) body myopathy is also reported as an early complication of HIV. Inflammation is not seen on muscle biopsy, but prednisone can be beneficial nevertheless, suggesting an autoimmune etiology. Myasthenia gravis, both seropositive and seronegative, may likewise be an early accompaniment of HIV but is usually transient, resolving with immune system failure. When necessary, it may be treated in a fashion similar to the autoimmune variety.

Muscle complications of antiretroviral therapy

Antiretroviral agents include NRTIs (zidovudine [AZT], stavudine [d4T], didanosine [ddI], zalcitabine [ddC], lamivudine [3TC]), non-NRTIs (nevirapine, delaviridine, efavirenz), and PIs (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir). AZT myopathy is a dose-related toxic myopathy resulting from medication-induced mitochondrial dysfunction. Atrophic ragged-red fibers with thick myofilamentous degradation and cytoplasmic-body formation, so-called AZT fibers, are seen histologically, but this entity is nonetheless contested, as biopsy in some patients may show no abnormalities, co-mingled inflammatory changes, or overwhelming myositis. Furthermore, ribavirin and interferon-alpha treated patients may also demonstrate these abnormalities.

Polypharmacy incorporating stavudine, a second NRTI, and a PI have been associated with the development of lactic acidosis, hepatic steatosis, pancreatitis, and mitochondrial myopathy. Reminiscent of Reye's syndrome, early diagnosis of this entity may be accomplished by following blood lactate levels and muscle and liver serum enzymes. Computerized tomography will also detect fatty infiltration of the liver.

Lipid accumulation on muscle biopsy may be seen in HIV-associated lipodystrophy syndrome. Seen after 12- 18 months of HAART treatment, and independent of HIV load, this syndrome is characterized by hyperlipidemia, insulin resistance, and central and peripheral fat accumulation. Etiology is multifactorial, including accumulation of nuclear sterol regulatory element binding proteins (nSREBPs), suppression of apolipoprotein B metabolism, and inhibition of the glucose transporter GLUT-4, all, directly or indirectly, a consequence of PI therapy.

Paradoxically, an inflammatory reaction in a revived immune system may have adverse effects in hitherto immunodeficient patients, resulting in otherwise typical polymyositis. Termed the HAART-related immune restoration inflammatory syndrome (IRIS), its development relates, in part, to the duration and extent of the immunodeficiency, the speed and degree of immune reconstitution, and genetic susceptibility.

Opportunistic Infections and Tumors of Muscle

Muscle infections primarily encompass focal myositis, most often due to S. aureus, but are also reported with cytomegalovirus, cryptococcus, mycobacterium, and toxoplasmosis. Treatment is antimicrobial and based on the organism. Non-Hodgkin's lymphoma is frequent in AIDS, and rarely may cause a focally enlarging muscle mass.

Rhabdomyolysis

Seen at all stages of HIV, rhabdomyolysis may be isolated or recurrent, may be drug-induced (didanosine, lamivudine, ritonavir, indinavir, trimethoprim-sulfamethoxazole), or may be seen in end-stage disease, with or without opportunistic muscle infection.

Commentary

Bottom line? HIV patients with myopathic symptoms, even those with normal serum creatine kinase and unremarkable EMG studies, warrant muscle biopsy. Without tissue, given the diverse possibilities, it's just a guessing game.