AIDS and AIDS-treatment NeuropathiesDerek Williams, R-PA, Anthony Geraci, MD, and David M. Simpson, MD

AddressMount Kisco Medical Group, 90 South Bedford Road, Mount Kisco, NY 10549, USA. E-mail: AGeraci@mkmg.com

Current Pain and Headache Reports 2002, 6:125–130Current Science Inc. ISSN 1531-3433Copyright © 2002 by Current Science Inc.

IntroductionThe face of AIDS is changing. The life expectancy of indi-viduals infected with HIV has increased dramatically dueto a better understanding of HIV infection, which in turnhas led to advances in medications used to treat HIV andassociated opportunistic infections. Along with increasedsurvival, there has been a decrease in the incidence of someneurologic complications of HIV infection. In the eraof highly active antiretroviral therapy (HAART), there hasbeen a decline in the incidence of neurologic diseases, suchas AIDS dementia, toxoplasmosis, and cytomegalovirus(CMV) infections [1,2]. Evidence that HAART improvesboth neurocognitive and sensory nerve function inHIV-infected patients is encouraging [3••,4], and providesa rationale for future studies on the nervous system effectsof aggressive antiretroviral therapy.

The neuromuscular complications of HIV are common(Table 1) [5]. The most common peripheral nerve disorderis distal symmetrical polyneuropathy (DSP), whichoccurs in more than 30% of patients with AIDS [6,7•].Asymptomatic DSP (signs of peripheral nerve dysfunctionwithout subjective pain) may occur in more than 50% ofpatients with less advanced disease [8], and can be demon-strated by abnormal nerve conduction studies (NCS) [7•].Current anti-HIV therapies incorporating nucleoside

analogue derivatives have well-documented dose-depen-dent toxicities, including DSP [9]. The relative benefit versustoxicity of these medications when used for aggressive HIVviral suppression in those predisposed to developingsymptomatic DSP is a subject of investigation.

Clinical Presentation and DiagnosisThe cardinal feature of DSP is pain. Classically, patientspresent with symmetrical paresthesias, dysthesias, anddistal numbness in the lower extremities. In advanced DSP,there may be similar symptoms in the upper extremities,as well as weakness of distal intrinsic muscle groups [10].Symptoms usually have an insidious onset, exceptwhen DSP is related to antiretroviral drugs, in which casethe symptoms may appear more rapidly [11]. The pain ofDSP is often described as burning, and patients maycomplain of hypersensitivity in their feet. Often, the degreeof pain reported by the patient is disproportionate toobjective findings on neurologic examination. Patientsmay have an antalgic gait and be unable to tolerate evenlight contact with clothing or bedsheets. Wearing socks orshoes increases their discomfort.

Neurologic examination demonstrates decreased orabsent ankle reflexes, elevated vibratory threshold,and reduction in pain sensation or hyperalgesia in a stock-ing and glove distribution. There may also be a decrease inpain and temperature sensation, but joint proprioceptionis typically relatively normal [10]. Depressed or absentankle reflexes are the most common sign of DSP [6,7•],and may be the only sign of neuropathy. Relatively normalankle reflexes, together with hyperactive knee reflexes,might indicate coexisting myelopathy, particularly whenextensor plantar responses are present.

The diagnosis of DSP is usually straightforward and canbe made based on signs and symptoms in conjunctionwith a comprehensive history and neurologic examination.Marra et al. [8] demonstrated that trained nonphysicianclinicians, such as physician assistants and nurse practit-ioners, can diagnose DSP with a sensitivity that is com-parable to a neurologist’s examination. Confirmation ofDSP can be made by nerve conduction studies (NCS).

The primary pathologic feature of DSP is axonal degen-eration, as evidenced by a disproportionate loss oflarge myelinated fibers of both sensory and motor nerves.[7•,12,13]. There is a percentage of patients with DSP,however, who have normal NCS, as well as those withoutclinical signs and symptoms of DSP with abnormal NCS.

AIDS and AIDS-treatment neuropathies are common in individuals infected with HIV. As patients live longer due to improved antiretroviral therapies, the impact of painful neuropathy on patients’ lives may increase. Several anti-retroviral medications are known to cause toxic neuro-pathy in patients with AIDS, but this may be outweighed by the beneficial effects of viral suppression. Current theories on the pathogenesis of AIDS neuropathies include mito-chondrial toxicity secondary to γ-DNA polymerase inhibition and subsequent abnormal mitochondrial DNA synthesis. Treatment of AIDS neuropathies is directed toward relief of symptoms; however, new evidence suggests that aggressive antiretroviral therapy may also be effective.

126 Neuropathic Pain

Tagliati et al. [7•] documented that 12 of 63 patients(19%) with clinical DSP had normal results of NCS, and26 of 103 patients (25%) without clinical DSP hadabnormal results. A negative examination in the presenceof clinical disease could be a result of an abnormality ofsmall nerve fibers [3••,7•], which are not examined byconventional NCS. The most common NCS abnormalityseen in patients with DSP is reduced or absent sural nerveaction potentials [7•]. In spite of the predominance of sen-sory complaints, motor fibers are usually affected as well.Generally, however, motor nerve conduction velocities areonly mildly reduced in relation to the reduction in ampli-tude [14]. NCS of the upper extremities may reveal reducedsensory and motor amplitudes of the median or ulnarnerves. F-wave and H-reflex latencies may be prolonged[7•]. Diagnostic modalities, such as quantitative sensorytesting and punch skin biopsy, are generally reserved forthe research setting [15,16]. Invasive studies, such as suralnerve biopsy, are rarely necessary in diagnosing DSP, butmay be helpful in complicated cases with atypical features.The electrophysiologic abnormalities in drug-induced andHIV-related DSP are indistinguishable [17].

In an ongoing attempt to develop more sensitive screen-ing examinations for DSP, some investigators have employedother tests or combinations of standard tests. Bouhassiraet al. [18] compared quantitative sensory testing (QST) withestablished electrodiagnostic studies, such as NCS. Theyfound that in NCS-confirmed painful and nonpainful DSP,QST revealed increases in thermal and mechanical thresh-olds, as well as pain thresholds. They concluded that QST canbe helpful in detecting sensory alterations in patients withpainful neuropathies, which might prove useful in quantify-ing DSP clinically, and for following the effects of treatmentson neuropathic pain [18].

PathophysiologySeveral observations support multifactorial etiologies forthe development and severity of DSP. Tagliati et al. [7•]

reported that older age and advanced HIV infection, asreflected by reduced CD4 lymphocyte counts, are assoc-iated with DSP. Low hemoglobin levels also correlatedwith DSP in that study, likely as a surrogate for advanceddisease and a relatively debilitated state. Plasma HIV RNAis an important predictor of neurologic outcomes. Individ-uals with plasma HIV RNA levels greater than 10,000copies/mL have a 2.3-fold greater hazard of sensory neur-opathy than those with less than 500 copies/mL [19••].Accordingly, aggressive antiretroviral therapy and suppres-sion of plasma HIV-1 viral burden improves sensory func-tion in HIV-infected patients, as measured by quantitativesensory testing [3••]. There are no data corroborating thisobservation or to indicate whether effective antiretroviraltherapy leads to clinical improvement in DSP. Althoughthe specific pathogenesis of this neuropathy has not yetbeen delineated, it has been linked to the use of nucleosideanalogue reverse transcriptase inhibitors (NRTIs)[9,17,20•]. Commonly referred to as d-drugs, didanosine(ddI), zalcitabine (ddC), and stavudine (d4T) are theNRTIs most implicated in DSP. Combinations of thesemedications with each other or with hydroxyurea [9,20•]and with other medications used to treat HIV-relatedconditions, such as isoniazid (INH) [21], vincristine [22],and thalidomide [23], are also known to cause DSP. Puta-tive contributing factors to the development of neuropathyinclude acetyl-cartinine and vitamin B12 deficiencies[5,24], and neurotoxicity caused by cytokines [25].

Antiretroviral Agents and Mitochondrial ToxicityDistal symmetrical polyneuropathy related to nucleosideanalogue toxicity is dose-dependent [26]. The dideoxy-nucleoside analogues ddI, ddC, and d4T produce well-recognized peripheral neurotoxicity (Table 2) [9]. Periph-eral neuropathy was first described in patients receivingddC [27] and is clinically and electrophysiologicallysimilar to HIV-related peripheral neuropathy. It has beentheorized that the neurotoxin is actually unmasking anexisting, silent peripheral neuropathy. Clinical and electro-physiologic abnormalities are similar to those in HIV-related neuropathy and indicate distal axonopathy[7•,17,27]. Stavudine may also cause peripheral neuro-toxicity. In a study of 36 patients taking a maximum d4Tdosage of 2 mg/kg/day, 20 (55%) developed dose-limitingperipheral neuropathy with identical features to ddC- andddI-induced neuropathy [28].

The occurrence of dideoxynucleoside toxic neuropathyis related to both daily and cumulative dosage [17], andappears to be most frequent with ddC. In a clinicaltrial comparing four different treatment regimens (ZDValone, ddI alone, ZDV plus ddI, ZDV plus ddC), the 6%incidence of HIV-related neuropathy was highest in theZDV plus ddC arm [29]. Risk factors for dideoxynucleosidetoxic neuropathy include a history of neuropathy, older

Table 1. Neuromuscular complications of HIV infection

Neuropathy Common Distal symmetrical polyneuropathy HIV-related Nucleoside analogue-related Less common Inflammatory polyneuropathy Chronic inflammatory demyelinating polyneuropathy Neuropathy due to opportunistic infections Progressive polyradiculopathy (cytomegalovirus) Mononeuritis multiplex (cytomegalovirus, hepatitis C)Myopathy HIV ? Nucleoside analogue-related

AIDS and AIDS-treatment Neuropathies • Williams et al. 127

age, poor nutrition, and more advanced HIV disease[7•,30]. Based on data from the Moore Clinic at JohnsHopkins University, the risk of dideoxynucleoside toxicneuropathy is additive or even synergistic for regimenscontaining ddI plus d4T combination when comparedwith ddI or d4T alone [20•]. We anticipate that as combi-nation dideoxynucleoside therapy is employed morewidely and for longer periods, the incidence of drug-induced neuropathy will probably rise in patients withadvanced HIV disease [20•].

Nucleoside analogue-related neuropathy may be due,in part, to their effects on mitochondrial DNA synthesis[27,31,32]. There are several mechanisms by which NRTIsare believed to interfere with mitochondrial DNA synthe-sis. These may be linked by the fact that they provide analternative substrate for mitochondrial g-DNA polymerasebecause they are derivatives of the endogenous nucleo-sides: adenosine, guanosine, thymidine, and cytidine [31].The five major human cellular DNA polymerases are alpha(a), beta (b), delta (d), epsilon (e), and gamma (g). Onlyg-DNA polymerase is located in mitochondria, whereasthe others reside in the nucleus [31]. Inhibition of g-DNApolymerase activity would be expected to result in mito-chondrial (mt)DNA depletion. However, although inhibi-tion of g-DNA polymerase occurs with nucleosideanalogue use, tissue-specific effects are not well understood[33], and there are no data that establish an association ofmitochondrial dysfunction with peripheral neuropathy inpatients taking these medications. Brinkman et al. [34•]have hypothesized that mitochondrial toxicity due to

nucleoside analogue reverse transcriptase inhibitors is, inpart, responsible for antiretroviral-related lipodystrophy.This syndrome bears resemblance to multiple symmetricallipomatosis, which includes peripheral neuropathy as aprominent feature. Several investigators have demon-strated point mutations and multiple or single mtDNAdeletions in this disorder and other inherited mito-chondrial diseases, leading to impaired cytochrome Coxidase function [35]. This in turn leads to impaired oxida-tive phosphorylation, anaerobic glycolysis, and formationof lactate. Other theories on the causes of mitochondrialtoxicity include the development of oxygen-free radicalsthat damage deoxyguanosine [36], involvement of theother DNA nucleosides [32], and mitochondrial-inducedapoptosis [31,37].

HydroxyureaHydroxyurea is an antimetabolite that is used for salvagetherapy in patients failing multiple antiretroviral regimens.When this agent is added to nucleoside analogue therapy,the incidence of peripheral neuropathy is increased [38].When combined with didanosine and/or stavudine,hydroxyurea increases the risk of DSP by several fold [39].The combination of ddI plus d4T also increases the risk ofneuropathy, but not to the same extent as when hydrox-yurea is added [20•,38]. It is thought that hydroxyureasupports the integration of ddI, and possibly also d4T, intothe mitochondrial matrix, thereby increasing the neuro-toxicity of the latter two medications [20•].

Table 2. Nucleoside analogue-related neuropathy

AgentDideoxynucleoside analogues Stavudine Didanosine Zalcitabine Synergistic effect from hydroxyureaDiagnosis Improvement after withdrawal of offending drug ? Elevated serum lactate levels Treatment Dosage Nonsteroidal anti-inflammatory agents Variable dose, depending on agent Acetaminophen 500–1000 mg every 4 to 6 hours Amitriptyline Up to 150 mg/day, at bedtime Carbamazepine 200–400 mg three times daily Phenytoin 100 mg three times daily Gabapentin 300–1200 mg three times daily Lamotrigine 200–250 mg twice daily Topical analgesics Lidoderm patch, ointment As needed Narcotic analgesics Oxycodone, morphine, fentanyl Variable dose

128 Neuropathic Pain

Plasma HIV Viral Load and CD4+ Cell CountThere is increasing evidence that elevated plasma-HIV RNAlevels may be a risk factor for the development of DSP[3••,19••]. In a retrospective review of 1604 AIDS-freeHIV-positive men from the Multicenter AIDS CohortStudy, Childs et al. [19••] showed that as HIV viral loadincreased, so too did the incidence of sensory neuropathy,and that individuals with viral loads greater than 10,000copies/mL had a greater than twofold increased hazard forDSP [19••]. There was also a trend for increased neuro-pathy risk by over 100% in men with CD4+ counts of lessthan 750 cells/mm3, but the relationship was much weakerthan for plasma HIV viral load.

TreatmentCurrently, there are no treatment modalities that reversethe pathology of HIV-associated DSP. The management ofpolyneuropathy in patients infected with HIV focuses onrelief of pain [40]; therefore, therapy is aimed largely atsymptom reduction. To this end, management of DSPemploys various pain-relieving modalities that includemedications to directly control the pain and approachesdirected at the source of the pain. Additionally, as notedearlier, HAART is effective in improving nerve function inDSP [3••] and decreasing the incidence of DSP [19••],even when neurotoxic drugs are part of the regimen. Themost recent debate in this area centers on the question ofthe utility of antiretroviral therapy for HIV RNA suppres-sion at the expense of neurotoxicity. Data from the AIDSClinical Trials Group (ACTG) 291 study of recombinanthuman nerve growth factor indicate that in a cohort of 236patients, suppression of plasma HIV RNA by nucleosideanalogue drugs resulted in lower maximum and globalpain scores [41]. These data suggest that virologic controlmight outweigh the potential for dideoxynucleosidetoxicity. Prospective studies are needed to furtherassess this hypothesis.

Discontinuation of neurotoxic agentsAs a first step, metabolic causes of neuropathy, such asunderlying diabetes mellitus, vitamin B12 deficiency, andother forms of neuropathy seen in HIV disease, should beidentified and corrected where possible. Identification andtreatment of alcohol abuse is imperative. Next, consider-ation should be given to neurotoxic medications such asddI, ddC, and d4T as a cause of DSP, and a trial of dosereduction or discontinuation of the offending agent(s)may be beneficial. If the decision is made to stop a nucleo-side analogue medication, the clinician and patient shouldbe aware that it may take 4 to 8 weeks for symptoms tosubside, and during this time the pain may actuallyincrease. This is referred to as the "coasting period" [17]. Insome instances, resolution of pain may take as long as 16weeks. Only about two thirds of patients will improve withantiretroviral drug discontinuation [42].

All patients on nucleoside analogue drug therapy forHIV should be assessed frequently for signs or symptomsof DSP, as this complication may be most easily reversedwhen it is diagnosed early [8]. DSP can often be preventedby modifying the drug dose or by changing to less neuro-toxic antiretroviral agents [42].

AnalgesicsAnalgesics are commonly prescribed for the treatment ofDSP. Clinicians might follow the step-wise recom-mendations of the World Health Organization for themanagement of chronic pain [43]. Some patients with mildsymptoms may respond to nonsteroidal anti-inflammatorydrugs or acetaminophen [9]. For refractory pain, treatmentwith topical lidocaine or capsaicin 0.075% may bebeneficial. A 5% lidocaine patch (Lidoderm; ENDO Phar-maceuticals, Chadds Ford, PA) was recently approved by theFood and Drug Administration for treatment of postherpeticneuralgia, and it has also shown efficacy in treating DSP-related pain [44]. In a small, open-label study of 30 patientswith DSP, application of either a 5% lidocaine patch orlidocaine gel applied directly to painful sites demonstratedthat this medication was effective in providing pain relief[44]. Although use of a topical anesthetic appears to besafe in treating the pain due to DSP, it will not be useful inpatients for whom pain is not a primary symptom. Analysisof data from a larger, double-blind, placebo-controlledstudy is underway. Ultimately, some patients with DSP maybe in such severe and debilitating pain that narcotic anal-gesia is required to provide relief.

Adjuvant therapySeveral medications with putative effects on nerve mem-branes have been investigated for the treatment of DSP. Tri-cyclic antidepressants, such as amitriptyline or desipramine,at doses of up to 150 mg/day can be used. The anti-arrhythmic drug, mexilitine, was investigated due to itsinhibitory effects on sodium conductance at the axonalmembrane. However, neither amitriptyline nor mexilitinewere superior to placebo in a placebo-controlled, double-blind trial [45]. Anticonvulsants, such as phenytoin and car-bamazepine, reduce neuropathic pain in patientswith diabetic neuropathy, and anecdotal experiencesuggests that they may also be effective in the treatmentof DSP. Oxcarbazepine, the dihydroketo analogue of carb-amazepine, potentially has a better pharmacokineticprofile in patients with HIV infection who are taking antiret-rovirals with extensive hepatic metabolism. Oxcarbazepinehas no autoinduction and low protein binding (NovartisPharmaceuticals, unpublished data). Clinical trials to assessthe efficacy of this drug are being planned. Lamotrigine andgabapentin are newer anticonvulsants that show promise inthe treatment of DSP. Gabapentin is an attractive therapy forpainful neuropathy due to its favorable pharmacokineticprofile and sparse drug-drug interactions. Reports of its effec-tiveness in AIDS-associated DSP are anecdotal [46], but it

AIDS and AIDS-treatment Neuropathies • Williams et al. 129

has been used successfully in other neuropathic conditions,particularly diabetes [47].

Lamotrigine, however, appears to be more effective intreating DSP-related pain, as demonstrated in a pilot studyby Simpson et al. [48]. The most common side effectreported from this study was the occurrence of an allergicrash, which resulted in premature discontinuation of studydrug in 25% of patients [10,48]. We have recently concludeda large, multicenter, double-blind, placebo-controlled studyof lamotrigine. In this study, the drug was gradually intro-duced over an 8-week period until a dosage of 400 mg/daywas attained. Although the data collected in this study arebeing analyzed, it is believed that lamotrigine will be bettertolerated when introduced gradually [10].

Recombinant human nerve growth factorRecombinant human nerve growth factor (rhNGF) hasbeen investigated as a therapy that might reverse or arrestthe neuropathic changes of DSP. Ample laboratory dataand studies of animal models point to rhNGF as a poten-tial treatment for peripheral neuropathy, in particulardiabetic and HIV-related neuropathies [49].

In a placebo-controlled ACTG study of 270 patientswith painful HIV neuropathy, subcutaneously adminis-tered rhNGF improved Gracely Pain Scale scores and sensi-tivity to pinprick. However, in that study, most secondarymeasures of nerve regeneration, including quantitativesensory tests and epidermal skin biopsies, did not improve[50]. In spite of these encouraging results, future develop-ment of rhNGF is uncertain, because Phase III studies ofrhNGF in diabetic neuropathy were negative.

Other therapiesSmall studies of capsaicin for painful HIV neuropathy havebeen generally unsuccessful [51]. A more recent study byPaice et al. [52] concluded that capsaicin is ineffective, as itshowed no significant differences in pain relief, sensoryperception, quality of life, or mood [52]. Acupuncture hasshown no significant difference in effectiveness in HIV-associated painful DSP, as compared with sham acupunc-ture points, which were used as placebo [53].

ConclusionsDistal symmetrical polyneuropathy is a frequent neuro-logic complication of HIV infection. Recent advances inantiretroviral therapy have led to an increasingly large poolof individuals who are surviving long enough to become atincreased risk for neurologic complications, such as DSP.Additionally, neurotoxic medications, such as the dideoxy-nucleoside drugs that are widely used in combinations ofHAART regimens, increase the risk of development of pain-ful neuropathy. Current research focuses on identifyingindividuals most at risk for DSP while taking neurotoxicHAART regimens, and on mechanisms of mitochondrialinjury that can lead to neuronal damage.

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