Annals of Indian Academy of Neurology
REVIEW ARTICLE
Year
: 2007  |  Volume : 10  |  Issue : 2  |  Page : 81--87

Distal sensory polyneuropathy in human immunodeficiency virus patients and nucleoside analogue antiretroviral agents


Jimmy Jose1, Kavitha Saravu2, Beena Jimmy1, BA Shastry1,  
1 Department of Clinical Pharmacy, 4th Floor Shirdi Sai Baba Cancer Hospital, Kasturba Hospital, Manipal, India
2 Department of Medicine, Kasturba Medical College, Manipal, India

Correspondence Address:
Jimmy Jose
Department of Clinical Pharmacy, 4th Floor, Shirdi Sai Baba Cancer Hospital, Kasturba Hospital, Manipal - 576 104, Karnataka
India

Abstract

Distal sensory polyneuropathy, which occur commonly in human immunodeficiency virus (HIV) patients can occur as a consequence of the disease itself or the antiretroviral treatment the patient is receiving. Among the antiretroviral agents, nucleoside analogues are commonly associated with neuropathy and the main underlying mechanism is thought to be the mitochondrial toxicity exhibited by these agents. Clinical presentation of antiretroviral induced neuropathy is similar to that associated with the HIV infection and in many patients they may overlap. Treatment is primarily symptomatic and certain pathogenesis-based approaches have shown promising results.



How to cite this article:
Jose J, Saravu K, Jimmy B, Shastry B A. Distal sensory polyneuropathy in human immunodeficiency virus patients and nucleoside analogue antiretroviral agents.Ann Indian Acad Neurol 2007;10:81-87


How to cite this URL:
Jose J, Saravu K, Jimmy B, Shastry B A. Distal sensory polyneuropathy in human immunodeficiency virus patients and nucleoside analogue antiretroviral agents. Ann Indian Acad Neurol [serial online] 2007 [cited 2019 Jun 25 ];10:81-87
Available from: http://www.annalsofian.org/text.asp?2007/10/2/81/33214


Full Text

 Introduction



Peripheral neuropathy is a common adverse experience in patients with human immunodeficiency virus (HIV) infection and is the most common neurological complication in these groups of patients.[1],[2],[3],[4],[5] But usually these neuropathies are overlooked or incorrectly diagnosed in patients with HIV.[6] There are at least six patterns of HIV associated neuropathy [Table 1].[7] Different forms of peripheral neuropathy occurs with varying frequency at different stages of HIV disease.[8] The frequency and spectrum of these neuropathies are changing, as the various toxic and immunological factors are modified by new treatment strategies.[9] Early in the course of HIV infection, patients may develop accute inflammatory demyelinating polyneuropathy (AIDP). In other patients, a progressive or relapsing -remitting inflammatory neuropathy resembling chronic IDP has been noted. Cerebrospinal fluid lymphocytic pleocytosis (10 to 50 cells/mm 3 ) is helpful in the diagnosis of HIV-associated IDP. Plasma exchange or intravenous immunoglobulin has been tried with variable success. Glucocorticoids should be reserved for severe cases of chronic IDP refractory to other measures.[7] Symptomatic HIV infected patients may develop mononeuritis multiplex which is characterized by asymmetric peripheral and cranial nerve lesions resulting in motor weakness and sensory loss. In advanced HIV infection, multiple nerves in two or more extremities or cranial nerves are affected. Treatment includes immunomodulation or anti-CMV therapy.[7],[10] Patients with acute immune deficiency syndrome (AIDS) may also develop subacute polyradiculopathy mainly due to CMV. It commonly affects lumbosacral roots and cauda equina resulting in pain and asymmetric weakness of lower limbs, sacral paresthesia, areflexia, ascending sensory loss and urinary retention and usually responds to anti-CMV therapy such as gancyclovir or foscarnet.[11] Other causes for acute polyradiculopathy in one series were mycobacterium tuberculosis, cryptococcal meningitis and meningeal lymphomatosis.[12] Autonomic neuropathy may be caused by central or peripheral nervous system abnormalities and is common in all stages of HIV-infection. Treatment is supportive with correction of metabolic or toxic causes.[13] Diffuse infiltrative lymphocytosis syndrome presents as a Sjogren's-like disorder with CD8 T cell infiltration of multiple organs. Antiretroviral therapy and steroids may be effective treatments.[7] Additionally, recurrent zoster infections and multidermatomal involvement are common in HIV patients and acyclovir or famcyclovir are the drugs of choice.

But, the most common form of peripheral neuropathy in this patient population is distal sensory polyneuropathy (DSP).[7],[14] There are two forms of DSP in HIV patients; one solely associated with the HIV disease itself and other one is antiretroviral induced toxic neuropathy (ATN).[15],[16],[17],[18],[19] The present review mainly focuses on DSP with antiretrovirals as the possible etiology.

Whereas symptomatic neuropathies occur in approximately 10% to 15% of HIV-1-infected patients overall, pathologic evidence of peripheral nerve involvement is present in virtually all end-stage AIDS patients.[13] Even though after the introduction of highly active antiretroviral therapy (HAART) the incidence of HIV associated neurological disease including HIV associated dementia and CNS opportunistic infections have fallen,[4],[20] the rates of HIV associated DSP has increased with reported prevalence rates exceeding 50%.[21],[22] A study of 252 patients enrolled in a pre-HAART trial of HIV-infected individuals at high risk of complications, the estimated one year incidence rate of symptomatic DSP was 36% and for both asymptomatic and symptomatic neuropathy it was 52%.[23] There are quite a few additions to the existing data on the epidemiology of HIV associated neuropathy. In a recently published study by Schifitto et al[24] in the Northeast AIDS Dementia Consortium the one year incidence of symptomatic neuropathy in the evaluated cohort of patients was 21%. In a retrospective evaluation of risk factors associated with the development of DSP in the HAART era conducted by Lichtenstein and the HIV outpatient study investigators, the incidence of DSP was 13%.[15] In contrast, the study by a Spanish group in 108 patients found a low incidence (1.8%) of symptomatic neuropathy, even though subclinical or asymptomatic neuropathy was high (66%).[16]

ATN may be a synergistic consequence of HIV infection together with the neurotoxic effects of select antiretroviral drugs, because some HIV-uninfected animals, treated with neurotoxic antiretroviral drugs, do not develop an antiretroviral induced toxic neuropathy -like phenotype.[25] Among the antiretroviral therapy, nucleoside analogue antiretrovirals and nucleoside analogue reverse transcriptase inhibitors (NRTIs) are the major contributors to peripheral neuropathy.[26] During the development of zalcitabine, didanosine and stavudine in the late 1980s and early 1990s, phase I/II dose finding studies unexpectedly revealed dose-dependent DSP as the major treatment-limiting adverse effect.[27],[28],[29],[30],[31],[32],[33] NRTIs is an important class of agent in the treatment regimens for patients with HIV infection. The development of peripheral neuropathy with NRTIs is one of the factors which need to be considered when selecting appropriate combination regimens for HIV-infected individuals.[29] ATN in many instances could be a contributing for noncompliance with the therapy and abrupt withdrawal of the antiretroviral regimen. There are many outstanding questions regarding the epidemiology, mechanism, risk factors, and treatment of this complication of antiretroviral regimen. A review on this aspect will be useful for an improved understanding of this important and increasingly common complication.

 Mechanism



There are several theories for the mechanism of NRTI-related peripheral neuropathy, with the weight of evidence pointing to mitochondrial toxicity due to its property of inhibiting human DNA polymerase.[34] In vitro studies indicate a graded inhibition of this critical enzyme, with zalcitabine showing the greatest degree of inhibition, followed by didanosine and stavudine. Zidovudine, abacavir and lamivudine show minimal inhibition.[35],[36] Zalcitabine and didanosine have been shown to reduce mitochondrial DNA, leading to destruction of mitochondria and increase in intracellular lactate levels using the in vitro model of nerve cells.[37] Results of in vitro experiments on human lymphoblastoid cell lines show the relative potency of these compounds in reducing mitochondrial DNA to be zalcitabine> stavudine>didanosine.[34] The agents show almost a similar pattern for the risk of neuropathy in clinical practice as well.[29] One possible mechanism to explain the enhanced susceptibility for toxic neuropathy in some but not all individuals exposed to NRTIs could be genetic variations in DNA polymerase.[26] Keswani et al[38] has reported based on their in vitro studies that these agents can cause direct mitochondrial toxicity through inhibition of the mitochondrial trasmembrane potential difference. Direct histopathological evidence of mitochondrial alterations in human nerve specimens with ATN was demonstrated by Dalakas et al .[39] Using quantitative methods and sural nerve specimens from four HIV infected patients with zalcitabine associated neuropathy, an increased number of abnormal mitochondria in the axons and Schwann cells, as well as mitochondrial DNA depletion was demonstrated.

Mitochondrial dysfunction may be an independent cause of neurological disease, as seen in inherited disorders, but it is also possible that a reduction in mitochondrial DNA unmasks pre-existing sub-clinical nerve damage due to HIV. Peripheral neuropathy may be an early marker of mitochondrial dysfunction, which is now believed to contribute to the development of antiretroviral induced myopathy, lipodystrophy and lactic acidosis.[34] Not surprisingly many of the manifestations of mitochondrial dysfunction reported in inherited and acquired disease have been described during NRTI therapy.[34],[40],[41]

Additional mechanism postulated to be involved in the development of NRTI related neuropathy is a low level of acetyl-L-carnitine.[42],[43] The level of acetyl -L-carnitine in patients who developed ATN were lower compared to those who did not in two studies.[42],[43] Acetyl carnitine has shown to have neuroprotective effects and may increase the rate of peripheral nerve regeneration after injury by promoting the release of nerve growth factor.[44]

 Agents Implicated



Agents implicated in the development of neuropathy are mainly zalcitabine, stavudine and didanosine, with first two showing a similar rate of peripheral neuropathy and didanosine at a lower rate.[5],[9],[34],[45],[46],[47] It is generally accepted that zidovudine, lamivudine and abacavir are not or minimally associated with peripheral neuropathy compared to the above-mentioned agents.[9],[34] Data from large studies indicate an overall incidence of peripheral neuropathy of 25% and 23% with zalcitabine and stavudine respectively.[29],[48] Didanosine is having a lesser incidence (14%) as observed in a large study.[49] Incidence of drug withdrawal due to neuropathy was 10%, 13% and 6% for zalcitabine, stavudine and didanosine, respectively.[29],[48],[50] A recently conducted prospective study in an international cohort also demonstrated that exposure to stavudine and didanosine is significantly associated with a heightened risk for symptomatic sensory neuropahty.[47] Combination therapy of neurotoxic NRTIs (double dideoxynucleoside regimens; didanosine and stavudine) have shown to have higher rates of neuropathy. Further, co-administration of hydroxyurea with didanosine and stavudine in HIV patients also increases the risk of neuropathy (this is more likely due to the increased cellular effect of these agents in the presence of hyroxyurea).[1]

Risk factors

Careful assessment of the patients prior to the introduction of one of the potentially neurotoxic nucleoside analogues should be conducted to exclude those who are at risk of developing peripheral neuropathy with these agents [Table 2]. Peripheral neuropathy in HIV patients undergoing antiretroviral therapy is likely to be multifactorial in origin; although drugs may themselves cause peripheral neuropathy, they may also merely unmask a preexistent subclinical distal neuropathy.[2] In this way, drugs that are otherwise well-tolerated by the majority of the people may appear to be profoundly neurotoxic because of the reduced neurological reserve of the population in which they are used.[1]

Clinical presentation and other findings

The clinical presentation of peripheral neuropathy resulting from nucleoside analogue treatment is similar to HIV associated DSP (usually not easily distinguishable) and in many patients they may overlap.[52] The small diameter nociceptive sensory axons and their respective soma in the dorsal root ganglia are the principal cellular structures affected in both.[53] Both present as a length dependent sensory neuropathy (i.e., feet affected first) manifested by pain in the ankles or the feet in over 65% of individuals and paraesthesias in 40%. Neurological examination shows abnormal sensory thresholds in up to 85% of individuals and reduced or absent ankle reflexes in up to 96%. Motor findings are uncommon, with only a third of patients having distal weakness.[54] However, the drug-related neuropathies are more likely to be painful, have an abrupt onset and rapidly progress.[29],[36] The defining clinical features consistent with drug -associated peripheral neuropathy includes pain, numbness and paresthesia. Patients may report gradual worsening over days or weeks. Eventually, numbness becomes the prominent feature. The symptoms are bilateral, symmetrical and distal in nature and there should not be any other identifiable causes. Symptoms often predominate in the absence of objective signs of sensory loss. Lower extremities are more affected than the upper.[34]

Other factors which would be of benefit in establishing a causation to the suspected drug is relating the onset of neuropathy to the commencement of treatment.[29] Pain when therapy is stopped should resolve within 8-16 weeks, although the signs of neuropathy may remain much longer.[1] After stopping the culprit drug there may be a paradoxical worsening of neuropathic symptoms over a period of four to eight weeks (coasting).[36] Mitochondrial toxicity may account for many of the long-term features of NRTI-associated peripheral neuropathy, including the delayed onset (as mtDNA levels gradually decline) and initial worsening of the neuropathic symptoms after stopping the drug (since the restoration of mtDNA levels is gradual, abnormal signaling may occur during recovery).[34]

The electrophysiological changes are similar to those seen in HIV associated DSP, suggesting axonopathy affecting sensory and motor axons.[27],[34],[42],[52],[55],[56] Results of nerve biopsies from patients with NRTI associated neuropathy have revealed mitochondria with disrupted cristae.[42] In a study comparing the nerve biopsy characteristics in specimens of AIDS patients with zalcitabine-related neuropathy with those of HIV-related neuropathy never treated with zalcitabine and from patients with other axonal neuropathies, a varying degree of axonal dropout and axonal degeneration was noted in all the diseased nerves, regardless of cause.[57] No unique feature characteristic of each neuropathy (zalcitabine, HIV, others) was noted. But, the degree of axonal degeneration and formation of myelin ovoids, however, appeared prominent in the specimens of patients were zalcitabine-induced neuropathy was suspected. Nerve biopsy findings in a patient with suspected lamivudine-induced neuropathy showed severe loss of myelinated fibres, some regenerative clusters and thickening of the perineural cells [58]

 Treatment of Neuropathic Pain



The number of large randomized clinical studies, which have tried to evaluate the efficacy of various agents in the management of HIV neuropathy is minimal. Further, studies specifically on the management of antiretroviral-induced neurotoxicity are less; in most of the studies this group of patients was a subset for the studies on treatment of HIV related neuropathy. As with the treatment of painful sensory neuropathy in general, the management of this group of patients can be difficult.[59]

Pain is the main determinant of additional therapy.[34] Most approaches have focused on symptomatic treatments, rather than efforts to block the pathophysiological processes or to stimulate nerve fiber regeneration.[54] Nonsteroidal and opiate analgesics may be of immediate benefit. However, agents like amitryptilline (25-75 mg at night) may be beneficial for the more constant pain component even though the same was not confirmed in a large controlled trial.[60] Certain patients may require antidepressant dosage levels (100 to 150 mg/day) of amitryptilline for benefit, although there may be dose limiting toxicities such as sedation.[7]

Agents such as carbamazepine, sodium valproate, gabapentin and lamotrigine may be better to alleviate severe lancinating pain. Carbamazepine has the disadvantage of being a hepatic enzyme-inducer, thereby affecting the metabolism of some antiretroviral agents, including both protease inhibitors and non nucleoside analogue reverse transcriptase inhibitors.[34] Further, the use of carbamazepine may be limited by the development of leukopenia, particularly in patients with HIV, where leukopenia and anemia are often already present.[7]

Gabapentin has the advantage that it may not significantly interact with the metabolism of antiretroviral drugs. A starting dose of 300 mg at night can be gradually increased to 300 mg three times daily. A preliminary report from the experience of using gabapentin in painful HIV related neuropathy (disease related or antiretroviral induced) showed gabapentin effective in producing significant relief in pain as demonstrated by the improvement in the Visual Analogue Scale and interference of pain with sleep rating.[61] This study had the limitation of a small study population size and lack of a placebo controlled arm. A placebo-controlled trial of gabapentin by the German Neuro AIDS Working Group in 27 patients showed an effect on pain scores.[62]

Lamotrigine was found to be a effective treatment option for HIV associated neuropathy in patients receiving neurotoxic antiretroviral agents in a double-blind randomized placebo controlled study conducted by Simpson et al .[63] Compared to placebo, patients treated with lamotrigine had significantly greater improvement as assessed by various scales including Visual Analogue Scale for Pain Intensity, the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain. Rash was observed as the most common adverse effect. In order to minimize the occurrence of allergic rash, lamotrigine should be initiated at a low dosage (e.g., 25 mg/day or every other day) and this increased over approximately six to eight weeks to 300 to 400 mg/day.[7]

Even though capsaicin has been found to be effective in relieving pain associated with other neuropathic pain syndromes, it was shown to be ineffective in relieving pain in HIV associated sensory neuropathy in a multicenter study conducted by Paice, et al .[64]

In an open label trial, a 5% topical lidocaine gel was effective in reducing pain in AIDS-associated DSP.[65] But a more recent trial demonstrated the same as an ineffective agent for treating HIV associated sensory neuropathy including no difference in effect between patients exposed to neurtoxic antiretrovirals and those who did not.[66]

Therapies, which focus on the actual pathophysiological mechanisms underlying the neuropathy have also been studied in certain small trials. Acetyl-L-carnitine has been tried in certain small-scale uncontrolled trials, with conflicting outcomes that need to be confirmed by larger randomized controlled studies.[67] While assessing the efficacy of oral acetyl L-carnitine (1500 mg twice daily) in HIV patients with established antiretroviral induced toxic neuropathy, Hart et al , reported an improvement in epidermal nerve fiber density as well as the symptoms of neuropathy in patients treated with this agent.[68] In another study of HIV infected patients with sensory neuropathy, acetyl L carnitine administration intramuscularly or intravenously at doses ranging from 0.5-1.0 g/day for three weeks resulted in improvement in majority of the patients.[69] Two recent studies performed using acetyl carnitine also showed positive results, even though they had the disadvantage of being open label studies.[70],[71]

In addition, several new agents, such neurophilins, which could stimulate nerve fiber repair and nerve growth factors is under trial.[35],[72] Recombinant human nerve growth factor (rhNGF) acts as a trophic factor in the developing and damaged peripheral nervous system.[73] In a phase II clinical trial in 270 patients with painful HIV neuropathy, subcutaneous rhNGF was superior to placebo in reducing pain after 18weeks of treatment.[74]

 Further Antiretroviral Therapy



The issue of stopping the neruotoxic agent, in practice is usually a difficult decision; especially if there is a good response to the antiretroviral therapy. Lowering the dose of an offending drug raises the possibilities of HIV viral resistance.[59] If a decision is made to discontinue the suspected nucleoside analogue, a careful assessment of the remaining treatment options needs to be made. Avoiding suboptimal antiviral cover needs to be taken in account. The suspected neruotoxic agent could be substituted with a nucleoside analogue, which is less associated with peripheral neurotoxic effects (e.g., zidovudine, lamivudine, abacavir).[9],[29] In patients who interrupt therapy, reintroduction may be attempted once symptoms have resolved and many patients may tolerate recommencement of the same NRTIs. But this should be done only with careful clinical monitoring for toxicity. Future options may have to be modified depending on the agents practically possible for the individual patient.[34]

 Conclusion



NRTI induced neuropathy is becoming an important complication of HAART therapy. Early identification and management of this complication is critical. Further management of these patients is usually a clinician's challenge. Symptomatic management and considerations on withdrawing the neurotoxic agent (replacing with less neurotoxic agents) depending on severity of neuropathy and available alternatives for the patient, appears to be the suitable approach. Efficacy and safety of the various symptomatic agents are becoming more clear with the data from various small trials, even though more specific trials in larger patient groups is required. Considering the pathogenesis based treatment approaches, acetyl carnitine has shown promising results which need to be tested in larger patient population, while the benefit of other agents is being evaluated in the ongoing studies. A better understanding of prevailing mechanisms of neuropathy in these patients will also allow for more effective interventions.

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