Recognizing Lower Extremity Effects Of Antiretroviral Drugs

By Robert G. Smith, DPM, MSc, RPh, CPed

     Acquired immune deficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) continues to be a major health problem worldwide. The Centers for Disease Control and Prevention (CDC) has estimated that approximately 40,000 people in the United States become infected with HIV each year.1 Human immunodeficiency virus infection and severe HIV-related disease have become leading causes of illness and death in the U.S. The cumulative estimated number of diagnoses of AIDS through 2005 in the United States and dependent areas was 988,376.2      The management of HIV/AIDS involves the complex coordination of many healthcare professionals. Better treatments have led to an increase in the number of people in the United States who are living with AIDS.2 In 2005, the estimated number of people living with AIDS in the United States was 437,982.2 The podiatric physician can provide education to the public regarding lower extremity manifestations of AIDS.3 Indeed, podiatric physicians can play an important role by identifying patients who are infected with HIV by being alert to the specific lower extremity signs and symptoms that may signal the presence of the infection.3 Further, podiatrists may be uniquely positioned to identify adverse effects from highly active antiretroviral therapy that affect the lower extremities of HIV-infected patients.

A Helpful Primer On Antiretroviral Therapy

     Currently, the available antiretroviral drugs used to treat patients with HIV infections are divided into four categories: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and entry inhibitors.4 Integrase inhibitors, a new class of antiretroviral drugs, are currently undergoing studies.5,6      Each class of HIV medications fights HIV in a different way. The primary difference among each class is the stage of HIV replication. The nucleoside reverse transcriptase inhibitors are synthetic analogs of naturally occurring deoxyribonucleosides that are phosphorylated intracellularly. They work by interfering with the HIV virus reverse transcriptase enzyme system that is responsible for viral replication by terminating chain elongation. Members of the non-nucleoside reverse transcriptase class are structurally diverse and have similar mechanisms of action. They inhibit the reverse transcriptase enzyme system directly without having to be intracellularly activated by binding to the system itself and making it unavailable for use by the virus. Both NRTIs and NNRTIs decrease transcription of HIV RNA to DNA.      The protease inhibitors are synthetic agents that are very potent and more active against the reverse transcriptase system when compared to both NRTI and NNRTI classes. Protein inhibitors target the protease enzyme, which cuts up long chains of genetic material into smaller pieces to complete viral replication. They act at the end of the HIV virus life cycle, resulting in the formation of immature non-infectious virons by preventing cleavage of the Gag-pol polyprotein. Fusion inhibitors, also known as entry inhibitors, work by blocking an important step in the process of HIV entry into the CD4+ cells known as fusion. By blocking the fusion, entry inhibitors may prevent HIV from entering and infecting CD4+ cells.4

What You Should Know About The Adverse Effects Of HIV Drugs

     A patient’s age may influence the presentation of adverse effects of highly active antiretroviral therapy. Gebo and Moore state the number of HIV patients over age 50 is increasing due to increased longevity in patients treated with highly active antiretroviral therapy.7 Further, Gebo reports that the percentage of all HIV cases in patients age 50 and older has increased from 17 percent in 2001 to 23 percent in 2004.8 Finally, Gebo asserts that toxicity associated with highly active antiretroviral therapy may be worse in older HIV patients and providers must be cognizant of drug-drug interaction and potential adverse effects of highly active antiretroviral therapy regimens when selecting an ideal regimen for older HIV patients.8      The podiatric physician must remember that each antiretroviral class of medications has specific adverse effects distinct to its respective class and an individual drug within a class may have adverse effects unique to itself. Further, it is important that the clinician achieve an understanding that the mechanism or cause of a given side effect may not be clear. Podiatrists should also appreciate the complicating issue that multiple drugs are used in an effective antiretroviral regimen, which may give rise to many adverse effects without clear or distinct mechanisms.9      In regard to the 28 frequently prescribed drugs for HIV/AIDS infection, there are intrinsic adverse effects that may have lower extremity implications.10-12 (See “A Guide To The Prevalence Of Adverse Effects With Antiretroviral Agents” on page 64 and “How To Grade The Severity Of Adverse Effects With Antiretroviral Agents” on page 68.) The adverse effects include nail changes, neuropathy, edema, bone, myalgia, arthralgia, fat changes, leg cramps and rash.

Paronychia: A Common Side Effect Of Antiretroviral Modalities?

     Physicians reported the first cases of paronychia, occurring as a possible complication of antiretroviral therapy, in patients infected with HIV in 1998 and 1999.10-12 A further review of the literature reveals case reports and retrospective cohort accounts of patients receiving antiretroviral therapy for HIV infection and the subsequent development of paronychias.13-22      Zerboni, et al., reported the onset of paronychia in 12 HIV-positive patients who were receiving lamivudine (Epivir, GlaxoSmithKline) during a three-month period.13 The clinical presentation of paronychia involved one great toe in five patients, both great toes in five patients, and fingernails as well as toenails in two patients.13,17,21 Interestingly enough, these patients did not have any risk factors for paronychia development.13,17,21      Bouscarat, et al., described 42 HIV individuals who presented with great toe paronychia secondary to ingrown nails and they had received the HIV treatment indinavir (Crixivan®, Merck).14,17,21 These 42 patients had no prior episodes of paronychia, psoriasis or local trauma.14 The medium time of onset for drug-induced ingrown toe nails was 120 days.14 These authors suggest that inhibition of endogenous proteases may be the explanation for initial hypertrophy of the nail fold and the subsequent development of pyogenic granuloma similar lesions.14,17      Additionally, Bouscarat, et al., suggest that disturbances of retinoic acid metabolism may be the underlying mechanism for nail changes one sees with patients receiving indinavir.14,21 On the other hand, Sass, et al., say there is considerable evidence that paronychia with pyogenic granuloma in the presence of indinavir therapy may be induced by impairment of the oxidative metabolism of retinoic acid through the inhibition of cytochrome p450 3A as opposed to impaired formation of 9-cis-retinoic acid.18      Sibel, et al., reported 50 HIV-infected men who were referred to them for the treatment of paronychia between the years 1995 to 1999.17 These patients’ drug regimens included combinations of the following medications: indinavir, stavudine (Zerit, Bristol-Myers Squibb), didanosine (Videx®, Bristol-Myers Squibb), lamivudine, zidovudine (Retrovir®, GlaxoSmithKline), nevirapine (Viramune®, Boehringer Ingelheim), delavirdine (Rescriptor®, Pfizer), nelfinavir (Viracept®, Agouron Pharmaceuticals) and ritonavir (Norvir®, Abbott Laboratories).17      Colson, et al., conducted a retrospective cohort of managed care patients who received protease inhibitors from 1996 through 1998.23 They identified 288 adults during this timeframe and that indinavir appeared to be part of their drug regimen 63 percent of the time.21 From this population, a total of 30 patients had at least one documented paronychia of the great toe during this timeframe.21 These authors concluded that indinavir and not lamivudine was strongly associated with great toe paronychia.21 James, et al., reported five cases of ingrown toenails associated with indinavir-ritonavir combination therapy.20      Garcia-Silva, et al., report that paronychias occur in 4 to 9 percent of the patients who receive indinavir.22 They suggest this adverse effect is not related to other epidemiological variables such as the patient’s sex, age, immune status or other risk factors.22 Even through the exact mechanism of indinavir induced retinoid-like effects is unclear, the following hypotheses for paronychia pathogenesis include: interference with retinoid metabolism by enhancing retinoic acid signaling pathway, increasing retinoic acid synthesis or reducing cytochrome p450 mediated retinoic acid oxidative metabolism.22

What You Should Know About Drug-Induced Peripheral Neuropathy

     There are many types of peripheral neuropathies one may see among patients with HIV but only a few appear to be HIV specific. The most common peripheral neuropathy in HIV infected patients is HIV associated distal sensory polyneuropathy.      There are two subtypes of distal sensory polyneuropathy. The first type is solely associated with HIV infection and the second type, a toxic polyneuropathy, is associated with antiretroviral treatments.23 Since the introduction of highly active antiretroviral therapy in 1996, central nervous system complications of HIV infections have declined dramatically. However, the incidence and prevalence of peripheral nervous system complications of HIV infection may be increasing.23      The podiatric clinician must be aware that preexisting neuropathy and a low CD4+ cell count, defined as less than 200 cells/mm3, are predisposing factors for peripheral neuropathy with all nucleoside or nucleotide reverse trancriptase inhibitors.9,24 Reliquet, et al., offer mechanisms for the resulting peripheral neuropathy from the use of nucleoside or nucleotide reverse trancriptase inhibitors.25 Low serum hydroxycobalamine levels result in an inhibitory effect on nervous growth factor and the interference with oxidative metabolism leads to a reduction in acetyl-carnitine production.25      In regard to nucleoside or nucleotide reverse transcriptase inhibitors, researchers believe the foundation of adverse effects (specifically lipoatrophy, lactic acidosis and peripheral neuropathy) from these medications is mitochondrial toxicity.9,26      Birkus, et al., reviewed in-vitro studies to develop a hierarchy of mitochondrial DNA polymerase-g inhibition which is as follows: zalcitabine (Hivid, Roche)> didanosine > stavudine > zidovudine > lamivudine = abacavir (Ziagen®, GlaxoSmithKline) = tenofovir (Viread, Gilead Sciences).9,24 The insights from Birkus and colleagues are validated by other researchers’ observations that zalcitabine is more neurotoxic than didanosine, stavudine and lamivudine, and the combination of didanosine and stavudine is more toxic than either drug alone.24      On the other hand, Cornblath and Hoke describe clinical data related to the induction of apoptosis as a contributor as well as the previously described mitochondrial toxicity.23 Further, Cornblath and Hoke argue against mitochondrial DNA polymerase-g inhibition and toxicity being the sole mechanism of nucleoside reverse trancriptase inhibitors’ neurotoxicity.23      In an investigational, retrospective, longitudinal cohort analysis of 2,515 patients with drug associated symmetrical peripheral neuropathy, Lichtenstein and colleagues noted a strong association of symmetrical peripheral neuropathy with protease inhibitor use.27 These authors did not observe symmetrical peripheral neuropathy with zidovudine, lamivudine or non-nucleoside reverse transcriptase inhibitors.27 These authors postulated that protease inhibitors act synergistically with some nucleoside analogues, either directly or indirectly, in individuals who are susceptible to peripheral neuropathy due to preexisting nerve injury.27      In their observational investigation regarding sensorimotor dysfunction as it relates to balance and gait, Bauer, et al., further validated that the use of zidovudine is associated with a lower prevalence and more moderate degree of neuropathy than other nucleoside reverse transcriptase inhibitors, especially didanosine and stavudine.28

Why One May See Osteoporosis And Osteopenia In Patients With HIV

     Low bone mineral density (BMD) is a recently recognized metabolic complication of HIV infection and its treatment.29 The most significant bone disorders affecting patients with HIV infection include osteopenia, osteoporosis and osteonecrosis. In patients with AIDS, the main suggested risk factors for the development of osteoporosis are the use of protease inhibitors, a longer duration of the infection, a lower body weight before antiretroviral therapy and a high viral load.30 Individuals with HIV infections who have received potent antiretroviral therapy have demonstrated an accelerated loss of bone mineral density.30      Glesby reviewed the results of preliminary studies that suggest antiretrovirals may have a direct effect on bone.31 Glesby suggests nucleoside analogues could theoretically contribute to bone demineralization directly through mitochondrial toxicity and may indirectly trigger the release of calcium hydroxyapatite from bone to buffer the lactic acid produced as a result of mitochondrial toxicity.31 Both Glesby and Martin, et al., suggest that indinavir is known to alter the activity of osteoblast alkaline phosphatase.31,32 Additionally, Glesby reports that indinavir inhibits “ex-vivo” bone-nodule formation and inhibits the in-vivo differentiation of bone marrow cells into osteoblasts.31      These investigators also state that other proteinase inhibitors may act similarly. However, one should interpret in-vitro data with caution.31,32 An example would be the data surrounding ritonavir activity as researchers have reported that it inhibits osteoclast differentiation.31 Tenofovir use has demonstrated metabolic bone abnormalities in adults with HIV infections and prescribing physicians should exercise caution with this modality in growing children.33      Osteonecrosis or avascular necrosis presentations in individuals treated with antiretroviral therapy remain uncommon. These presentations may be related to lipodsytrophy but this is difficult to investigate.31,32 However, both osteopenia and osteoporosis are of clinical importance to the podiatric physician as possible mechanisms for pathological fractures among patients with HIV infection. In the medical literature, one can find clinical case accounts of pathologic fractures in AIDS patients with osteopenia and osteoporosis induced by antiretroviral therapy.34,35      Guaraldi, et al., report a case of 51-year-old man on highly active antiretroviral therapy (HAART) who suffered a trivial trauma while walking as a result of a gait disorder associated with the AIDS dementia complex.34 At the time of the pathological fracture, the patient was taking stavudine, lamivudine and indinavir.34 He had mixed lipodystrophy syndrome but did not have a severe lipid metabolism disorder that could primarily be responsible for observed bone alterations.34      Forsyth, et al., report a case of a March fracture in a male patient with osteoporosis on long-term HAART.35 The 50-year-old patient presented with a left swollen painful foot after seven months of the following therapy: lopinavir, zidovudine, lamivudine and abacavir.35 The authors provided conservative treatment and the patient’s dual energy X-ray absorptiometery documented osteoporosis.35

What The Literature Reveals About Lipodystrophy And HIV

     Lipodystrophy reportedly occurs in 20 to 80 percent of patients receiving antiretroviral therapy.9,36-40 The components of fat redistribution syndrome include fat changes in the abdomen referred to as Crix belly or protease paunch, central obesity and peripheral fat wasting and subcutaneous fat atrophy.      The epidemiological prevalence of HIV lipodystrophy is highly variable in the literature due to a lack of acceptable case definitions, diagnostic criteria and heterogeneity of the studied populations among the investigators. The pattern of fat redistribution one sees in HIV lipodystrophy strongly resembles that of hypercortisolemic states without elevation in cortisol secretion or post receptor glucocorticoid signaling.36-38 Lipodystrophy or fat redistribution may cause physical discomfort for some patients. The diagnosis of fat deposition and fat atrophy is a subjective one that relies upon agreement between healthcare providers and patients.36      As a class, the nucleoside reverse transcriptase inhibitors may contribute to lipodystrophy through mitochondrial DNA toxicity.40 Kravcik offers clinically-based evidence to the link between nucleoside reverse transcriptase inhibitors and the development of lipoatrophy.36 The evidence he presents are summaries of the randomized clinical trails demonstrating fat loss with the following agents: lamivudine, didanosine, stavudine, efavirenz and nelfinavir.36 These clinical observational studies reveal that lipoatrophy can be slow to progress.      Finally, Kravcik’s review examines protease inhibitors as the class most associated with lipohypertrophy without a hierarchy of risk.36 The pathogenesis of protease inhibitors in lipodystrophy may be explained by Carr, et al., who revealed that inhibition of cytoplasmic retinoic acid binding protein type 1 by protease inhibitors may inhibit retinoic acid activation and thereby reduce peripheral adipocyte differentiation and increase apoptosis.39 Researchers have demonstrated that lipohypertrophy occurs among patients taking non-nucleoside reverse transcriptase inhibitors.36      In spite of these proposed mechanisms, the etiologies of various changes in body fat remain unclear as do the causes of the manifestations of HIV lipodystrophy and the long-term impact of this metabolic complication from antiretroviral agents.      Symptoms of lipodystrophy include atrophic changes consisting of subcutaneous fat atrophy in legs, buttocks, arms and nasolabial and malar fat pads. Often, the veins are present in limbs but varicosities are absent. As part of the healthcare team, podiatrists may find themselves in a position to recognize lower extremity symptoms of lipodystrophy. The DPM may advise the patient’s infectious disease specialist of his or her observations, or facilitate an otherwise appropriate referral.

Understanding Potential Dermatologic Side Effects

     The foremost dermatologic adverse effect reported by patients taking non-nucleoside reverse transcriptase inhibitors is a rash. These rashes usually appear on the chest, back, arms, face and lower extremities. Indeed, the appearance of a rash can indicate a potentially serious medication side effect.      The podiatric physician may find it helpful to use the following grading system developed by the Division of AIDS (a division of the National Institutes of Health) for grading rashes based on serverity.9,41      Grade one (mild) rashes are those described as localized macular with erythema and pruritus. Grade two (moderate) rashes are diffuse maculopapular, or morbilliform or target lesions. Grade three (severe) rashes appear as diffuse macular, maculopapular or morbilliform rash with vesicles or a limited number of bullae or superficial ulcerations of mucous membrane limited to one site. Grade four (potentially life-threatening) rashes involve extensive or generalized bullous lesions, suspected Stevens-Johnson syndrome or ulceration of mucous membrane involving two or more distinct mucosal sites or toxic epidermal necrolysis.41 It has been determined that 1 percent of the rashes reported from the use of amprenavir are potentially life threatening.12      Carr, et al., reported the occurrence and incidence of rash development secondary to non-nucleoside reverse transcriptase inhibitors. They noted a 17 percent incidence with nevirapine, a 10 percent incidence with efavirenz and an 18 percent incidence with delavirdine.42 Floridia, et al., assessed the frequency of rash among patients receiving antiretroviral therapy who had not received non-nucleoside reverse transcriptase inhibitors.43 These authors observed the occurrence of rash in 5 percent of patients receiving protease inhibitors within a few weeks. The patients in this study were at very low CD4 cell counts and were not receiving non-nucleoside reverse transcriptase inhibitors.43 Further, Floridia observed that women had a higher risk of rash than men.43

What About Thrombotic And Musculoskeletal Complications?

     Jacobson, et al., note uncertainty regarding the incidence of and risk factors for thrombosis in HIV-infected patients.44 These authors accentuate the uncertainty of protease inhibitors’ base therapy to promote thrombosis through the following pleiotropic effects: alterations in lipids, plasminogen activator inhibitor-1 and fibrinogen levels. In 2005, Klein, et al., reported that there were no published studies concerning the association between nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors and venous thrombosis.45 The role of antiretroviral therapies in promoting arterial and venous thrombosis requires further study.      The most common musculoskeletal side effects are myopathy, muscle pain or myalgia, and joint pain or arthralgia. Many antiretroviral agents are associated with presentation of this muscle weakness and pain of both the muscles and joints. Clinicians have observed muscle mass breakdown in patients who have been taking zidovudine for a prolonged time.

Keys To Managing Side Effects In The Lower Extremity

     Adverse effects or side effects from medications are difficult to avoid, and can make life difficult for the patient with HIV infection. Side effects are one of the main reasons why people living with HIV miss doses of their medication or discontinue their medications completely. Fortunately, physicians can often help control many antiretroviral medication side effects.      Treatment of mild rashes or moderate rashes depends upon the symptomatic presentation, and includes an antihistamine and/or a corticosteroid. Treatment of severe rashes would include discontinuation of the offending medication. In those cases of rashes induced by non-nucleoside reverse transcriptase inhibitors, Shibuyama, et al., suggest that one perform liver function tests because the presentation of a rash and heptatoxicity may occur simultaneously.9 In order to prevent skin rashes, advise the patient to drink plenty of water to promote good skin health and avoid harsh soaps that contain antibacterial chemicals and perfumes. Encouraging the patient to use a good skin moisturizer every day can keep his or her skin from getting too dry.      The most effective way of dealing with drug-induced peripheral neuropathy is to reduce the medication’s dosage or have the patient cease using it in consultation with the patient’s infectious diseases specialist. One may treat mild peripheral neuropathy with nonsteroidal antiinflammatory agents (NSAIDs). Applying topical creams and lotions containing salicylates may be effective. In regard to moderate to severe cases of peripheral neuropathy, physicians may employ tricyclic antidepressants, gabapentin (Neurontin, Pfizer) or pregabalin (Lyrica, Pfizer), valproic acid or an opioid pain reliever.      Cornblath and Hoke reported that the use of a lidocaine 5% gel was ineffective in the treatment of pain associated with HIV distal sensory polyneuropathy.23 Additionally, anecdotal reports of the benefit of B-complex vitamins have been published but these effects have not been well established. Some patients have found relief through acupuncture, acupressure, chiropractics and massage.      Patients can often manage joint and muscle pain with the use of an NSAID or acetaminophen. Glesby reports there is no available data to guide in the clinical management or prevention of osteopenia or osteoporosis in the HIV-infected patient.31 The podiatric physician can assist the patient’s primary care physician by reinforcing the recommendations of weightbearing exercises, a decrease in alcohol consumption and smoking cessation.31 The recommendation of a calcium and vitamin D supplementation may be appropriate for the podiatric physician to provide to their HIV infected patients. The role of estrogen, selective estrogen receptor modulators and bisphosphonates is uncertain.30,31      Currently, there are no treatments that have proven to be effective for body shape changes. The prescribing physician may prevent lipoatrophy by selecting a nucleoside reverse transcriptase inhibitor that has a lower affinity to DNA polymerase-g.9 Other preventive options would include dietary methods and exercise. Low-fat diets can also be beneficial in preventing fat accumulation. Testosterone replacement therapy or anabolic steroids may offer preventable measures in either hypogonadal or eugonadal men.9

In Conclusion

     In regard to patients with HIV infection, podiatric physicians may be able to identify adverse effects from highly active antiretroviral therapy in the lower extremities. Given the importance of adherence to antiretroviral therapy regimens for patients with HIV infection, podiatrists can play a key role in educating patients about these effects, treating these side effects and working in consultation with the patients’ infectious diseases specialist.      Dr. Smith practices at Shoe String Podiatry in Ormond Beach, Fla.



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