Curr HIV/AIDS Rep DOI 10.1007/s11904-014-0211-2
COMPLICATIONS OF ANTIRETROVIRAL THERAPY (JM KILBY, SECTION EDITOR)
Understanding the Etiology and Management of HIV-Associated Peripheral Neuropathy Kara Stavros & David M. Simpson
# Springer Science+Business Media New York 2014
Abstract HIV may cause several forms of peripheral neuropathy, the most common of which is distal symmetric polyneuropathy (DSP) characterized by pain and sensory deficits in a stocking-glove distribution. The pathophysiology of DSP remains largely unknown but is thought to be related both to the neurotoxicity of HIV—through indirect immunomodulatory mechanisms—and to the neurotoxic effects of anti-retroviral therapies, most notably the dideoxynucleoside reverse transcription inhibitors or so-called d-drugs. Determining whether symptoms arise from the virus or the treatment poses a challenge to the clinician who must decide if a patient’s HAART regimen should be altered. Treatment of symptoms related to HIV-DSP is a difficult task and there is no evidence that the traditional agents used in chronic neuropathic pain are efficacious in the HIV-DSP population. Indeed few pharmacologic agents have proven efficacy in HIV-DSP – these include cannabis and the capsaicin 8 % dermal patch. As such, alternative, non-pharmacologic therapies are being investigated. More research is needed to further elucidate the complex pathophysiology of HIV-DSP which may yield additional therapies for these patients. Keywords HIV . Peripheral neuropathy . Distal symmetric polyneuropathy, DSP . Anti-retroviral . Pain
mononeuritis multiplex, inflammatory demyelinating polyneuropathy, polyradiculopathy, and autonomic dysregulation [1, 2••]. By far the most common of these is DSP, which can be asymptomatic or may be characterized by variable degrees of pain, paresthesias, and numbness in a symmetric, stocking-glove pattern in the extremities. HIV-DSP is thought to be produced by a multitude of mechanisms caused by the virus (see discussion below). However the clinical picture is complicated by the finding that many of the anti-retroviral therapies used today to treat HIV can cause a clinically indistinguishable, medication-induced DSP. While in the past the dideoxynucleoside reverse transcriptase inhibitors (the so-called d-drugs) were the most notorious for causing DSP there is now evidence that protease inhibitors can cause peripheral neuropathy as well [3]. Given that both the virus and the treatments for it can both cause DSP, the diagnosis and management of these patients may be challenging for the clinician, who may need to decide whether it is necessary to alter a patient’s drug regimen when faced with symptomatic DSP. In this review we will focus on HIV-DSP and review the pathophysiology and the proposed mechanisms of virusmediated neurotoxicity and medication-induced neurotoxicity. We will also review the current management of HIV-DSP.
Epidemiology and Risk Factors Introduction HIV is associated with numerous peripheral neuropathies. These include distal symmetric polyneuropathy (DSP), K. Stavros : D. M. Simpson (*) Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue Annenberg 2nd Floor, Box 1052, New York, NY 10029, USA e-mail: [email protected]
HIV-DSP is the most common neurologic complication of HIV and its prevalence has been rising in recent years. Incidence rates of HIV-DSP vary depending on the cohort studied however it is estimated that one third to one half of HIVinfected patients have DSP [4–6]. Numerous studies have been undertaken to elucidate the risk factors for DSP in the HIV population. Prior to the widespread use of HAART therapy, risk factors included low CD4 count, elevated plasma viral load, and the use of neurotoxic anti-retrovirals such as
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stavudine [7]. More recent studies have found that CD4 count and viral load either confer no additional risk of DSP [6, 7] or conversely that a higher CD4 count may be associated with DSP [8]. Robinson-Papp et al. [8] postulate that the association of DSP with higher CD4 counts that they found may reflect the longer life expectancy of HIV patients in the present day or may be owing to the fact that patients with lower CD4 counts often have more urgent medical issues that may overshadow chronic neuropathic symptoms. Other studies examining risk factors for HIV-DSP in the HAART era have noted increased risk in patients with a history of substance abuse [7, 8], older age [4, 7, 9], and greater height [4, 9]. One recent study found that the use of statins significantly decreases the risk of DSP in HIV patients [9].
Pathophysiology Neurotoxicity of HIV Frequent pathologic features seen in HIV-DSP include distal degeneration of long axons, macrophage infiltration, and a loss of neurons in the dorsal root ganglion (DRG) [10]. Several mechanisms for virally-mediated neurotoxicity have been proposed to explain these changes. Neurotoxicity may occur via direct infection of the peripheral nerve by the virus or by various indirect, immunomodulatory mechanisms. These indirect mechanisms include the release of potentially neurotoxic substances by infected macrophages, such as inflammatory cytokines (i.e., TNF-α, IL-1, IL-6), chemokines, and glutamates [11]. Infected macrophages may also release viral proteins such as gp120, the most well-studied envelope protein in DSP pathogenesis, which has been shown to cause DRG neuronal cell death [11, 12]. Additionally, evidence of mitochondrial dysfunction has been noted as a result of HIV infection in laboratory studies [13]. Neurotoxicity of Anti-retroviral Therapies As described above, the antiretroviral agents most traditionally associated with HIV-DSP are the d-drugs, particularly stavudine [14]. These drugs are thought to induce neurotoxicity by causing mitochondrial dysfunction [15, 16] through inhibition of polymerase gamma, an enzyme involved in mitochondrial DNA replication [11]. The d-drugs may affect mitochondrial DNA by various degrees [17]. The recent development of a promising rodent model of stavudine-induced peripheral neuropathy may spur more studies to help further elucidate the pathophysiology of antiretroviral neurotoxicity [18]. Due to their known neurotoxic side effects many of these drugs are avoided in the developed world today in favor of alternative treatments. However the d-drugs are still widely employed in the developing world, and in places where
resources are limited withdrawing these drugs is not a feasible option. The WHO 2013 consolidated guidelines for HAART therapy in HIV-infected patients recommends first line therapy with two nucleoside reverse transcriptase inhibitors (specifically tenofovir, emtricitabine, or lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz) [19]. They explicitly recommend the discontinuation of stavudine and worldwide efforts are underway to eliminate this drug from routine use due to its known toxicities including lipoatrophy, lactic acidosis, and peripheral neuropathy [19, 20]. The U.S. NIH guidelines are similar to the WHO recommendations with a basic regimen consisting of two nucleoside reverse transcriptase inhibitors plus one protease inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase strand transfer inhibitor, or CCR5 antagonist [21]. As nucleoside reverse transcriptase inhibitors remain a mainstay of HAART both in the U.S. and worldwide, it is important for clinicians to be aware of their possible neurotoxic side effects. While the d-drugs are well-established in causing DSP more recent studies suggest that it is not only the d-drugs, but protease inhibitors as well that can have a neurotoxic effect [3]. Pettersen et al. [3] found that exposure to protease inhibitors may contribute to DRG damage via loss of macrophagederived neurotrophic factors, thereby leading to peripheral neuropathy. However in a recent observational study Ellis et al. [22] examined current and past exposure to protease inhibitors in over 1000 HIV patients and concluded that the additional risk of peripheral neuropathy conferred by protease inhibitor use is small. Further investigation into the role of protease inhibitors in DSP is needed. It can be challenging to differentiate whether a patient’s symptoms arise from virally-mediated neurotoxicity or his/her current drug regimen as the clinical presentations may be indistinguishable. History of d-drug exposure and improvement in symptoms with drug withdrawal may be important clues. A recent observational study of HIV-DSP patients who consented to skin biopsies and nerve conduction studies showed that neurotoxic treatments were more likely to impair small fiber conduction while HIV itself is more likely to impair large fibers [23]. Making this distinction is of significance to the clinician, who may need to weigh the risk of altering the patient’s HAART regimen in the face of symptomatic DSP against upsetting well-controlled, stable HIV CD4 counts and viral loads. Also of note clinically is the concern that significant medication related DSP side effects may result in poor compliance with HAART. Central Pathways In addition to the neurotoxicity of HIV and anti-retroviral therapies it is important to consider the role of central mechanisms in DSP. Interestingly, a study by Morgello et al. [7] found an association between DSP and substance abuse. They
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postulated that since they were unable to find differences between the peripheral nerve biopsy specimens of patients with and without opiate addiction that the opiate related effect they found may be attributable to central mechanisms. Indeed all of the pain experienced by HIV-DSP patients may not be attributable to peripheral nerve damage alone and in a new paper by Keltner et al. [24••] a cross-sectional analysis of brain MRIs from HIV patients was undertaken. They found a significant correlation between the reported severity of DSP symptoms and smaller total cerebral cortical gray matter volume; this is similar to findings by other groups that other chronic pain syndromes are associated with smaller cortical gray matter volume and that treatment of the chronic pain can “normalize” brain volumes [24••]. While it is unclear at this time whether the DSP is the cause or the result of the change in gray matter, this adds insight into the chronic nature of these symptoms and the ways in which central mechanisms may regulate and potentiate pain in the peripheral nervous system. Further research is warranted into the complex pathophysiology of how the central and peripheral pathways coincide in HIV-DSP.
Clinical and Diagnostic Features HIV-DSP may be symptomatic or asymptomatic. Symptomatic patients may report numerous symptoms including pain, paresthesias, and numbness in the extremities, which are distally predominant and classically occur in a stockingglove distribution. On examination patients exhibit diminished sensation to pain, temperature, and vibration in the extremities and diminished or absent reflexes. The diagnosis of DSP is primarily made on a clinical basis, with a careful history and physical examination. Before making the diagnosis other common causes of peripheral neuropathy must be investigated and optimized if found to be abnormal. These may include diabetes mellitus, vitamin B12 deficiency, hypothyroidism, or alcoholism, among others. Confirmatory diagnostic tests may include electromyography (EMG), nerve conduction study, and skin biopsy. Nerve conduction studies in DSP may show a reduction in amplitude or absence of sural nerve sensory potentials while EMG may show active or chronic denervation patterns with evidence of re-innervation [1]. Skin biopsies typically show a reduction in epidermal nerve fiber density in DSP patients [1, 25] and may be useful in early detection of neuropathy [26].
Management Symptomatic Treatments While there have been numerous successful trials of pharmacologic therapies in chronic neuropathic pain, the trials in
patients with HIV-DSP are fewer and many of the agents found to be effective in chronic neuropathic pain have not been proven to be effective in HIV-DSP. In fact, a recent metaanalysis of 14 randomized controlled trials of pharmacologic treatments in HIV-DSP found that of the agents that have been tested in randomized controlled trials, only a few agents, including smoked cannabis and the capsaicin 8 % transdermal patch, have proven efficacy in this population [27]. Details of the randomized controlled trials of pharmacologic therapies in HIV-DSP are outlined in Table 1 and discussed further below. This difference in treatment efficacy may be reflective of a different underlying pathophysiology of HIV-DSP compared to other types of neuropathic pain, such as diabetic neuropathy. Given the poor efficacy of traditional neuropathic pharmacologic agents in these patients the investigation of alternative, non-pharmacologic treatments may be warranted. Non-pharmacologic Therapies Several non-pharmacologic therapies have been examined in this population. A recent trial by Anastasi et al. [28] randomized HIV-DSP patients to receive acupuncture complimented by burning of the mugwort root muxibustion (acu/moxa) versus sham acupuncture. They found a significant effect of acu/moxa on their first follow up visit, though afterward the treatment group retained only a non-significant trend towards superiority. Similarly, a larger randomized placebo controlled trial of acupuncture, amitriptyline, and the combination of the two in HIV-DSP patients showed that neither intervention was more effective than placebo [29]. Hypnosis is another alternative treatment that has been tested in this population with limited but promising results. In a recent trial by Dorfman et al. [30•] 36 HIV-DSP volunteers were trained in selfhypnosis for pain management; investigators found improvement in pain scores on the Short Form McGill Pain Questionnaire regardless of their current analgesic regimen. Lastly, a recent trial of lower extremity splinting, aimed to reduce sleep disturbances and discomfort from external stimuli, in a small 6-week study showed a trend toward improvement in pain in the interventional group but no significant difference [31]. More studies of alternative non-pharmacologic treatments of HIV-DSP pain are needed to explore opportunities for adjunctive therapy in this difficult-to-treat population. Pharmacologic Therapies Research in topical analgesic therapies in HIV-DSP has produced promising results particularly with capsaicin. An initial, randomized controlled trial in 2008 showed significant improvement of pain scores in HIV-DSP patients in the capsaicin 8 % transdermal patch group [32] and since then multiple other studies have confirmed the efficacy of the capsaicin patch [33, 34••, 35]. This is encouraging evidence for a
Smoked cannabis
Abrams et al. 2007 [45] Ellis et al. 2009 [46] Simpson et al. 2008 [32]
Pregabalin
Lamotrigine
Lamotrigine
Peptide T
Gabapentin
Prosaptide
rhNGF
Simpson et al. 2010 [40]
Simpson et al. 2003 [41]
Simpson et al. 2000 [42]
Simpson et al. 1996 [43]
Hahn et al. 2004 [39]
Evans et al. 2007 [49]
McArthur et al. 2000 [50]
Kieburtz et al. 1998 [37]
5 % lidocaine gel
Estanislao et al. 2004 [36] Harrison et al. 2013 [38] Shlay et al. 1998 [29]
50 patients with HIV-DSP assigned to smoke cannabis vs placebo cigarettes three times/day for 5 days Crossover trial of 28 patients with HIV-DSP who smoked cannabis or placebo four times/day for 5 days 307 patients randomized to receive topical capsaicin 8 % or a control, low concentration capsaicin patch and monitored for 12 weeks 494 patients with HIV-DSP received capsaicin 8 % dermal patch vs a control, low concentration patch and were monitored for 12 weeks Crossover trial of 64 patients randomized to placebo vs 5% lidocaine gel for 2 weeks
Population/size/duration
270 patients with HIV-DSP who received biweekly injections of placebo vs 0.1 mcg/kg rhNGF vs 0.3 mcg/kg rhNGF for 18 weeks
26 HIV-DSP patients randomized to placebo or gabapentin following a 4 week blinded and 2 week open treatment schedule 237 patients with HIV-DSP administered various doses of IM prosaptide vs placebo for 6 weeks
302 HIV-DSP patients randomized to either placebo or pregabalin participating in a 2 week dose adjustment period and 12 week maintenance phase. 92 patients with HIV-DSP who received placebo vs lamotrigine for a 7 week dose escalation phase followed by a 4 week maintenance phase 42 patients with HIV-DSP randomized to placebo vs 25 mg lamotrigine daily which was slowly titrated up to 300 mg daily. Study duration 14 weeks. 81 patients with HIV-DSP given intranasal peptide T 6 mg/day vs placebo for 12 weeks
Duloxetine, methadone, 15 HIV-DSP patients enrolled in this four-period and their combination crossover study but only 8 completed the trial Amitriptyline and 250 patients with HIV-DSP assigned to SAR vs standardized amitriptyline vs combination therapy with acupuncture regimen comparison to placebo for 14 weeks (SAR) Amitriptyline vs mexiletine 145 HIV-DSP patients assigned to amitriptyline vs mexiletine vs placebo for 10 weeks
Topical capsaicin 8 %
Clifford et al. 2012 [35]
Topical capsaicin 8 %
Smoked cannabis
Intervention
Study
Table 1 Randomized, placebo-controlled trials of pharmacologic treatments in HIV-DSP
Change from baseline weekly average of daily pain score using the Gracely Pain Scale and an electronic diary Change in pain by the Gracely Pain Scale
Improvement in pain by the VAS
Change in pain by the modified Gracely Pain Score
Change in pain on the Gracely scale.
Mean change in average pain by the Gracely Pain Scale
Change in pain intensity ratings (twice daily patients chose from a list of words that were assigned a numerical rating) Change in mean NPRS score.
Mean pain intensity measured in a daily pain diary Change in pain using the Gracely Pain Scale
Difference in average pain scores by the Gracely Pain Scale.
Percent change in NPRS from baseline.
Change in pain measured by the Descriptor Differential Scale Percent change in NPRS from baseline.
Daily pain diary using the VAS
Primary outcome measure
rhNGF significantly improved pain and was well-tolerated aside from injection site pain.
Prosaptide was safe but not effective in treating HIV neuropathic pain.
Significant decrease in pain scores on VAS in the gabapentin group.
Intranasal peptide T was safe but not effective for the treatment of HIV-DSP.
No significant difference between lamotrigine and placebo. Rash was a significant side effect.
No significant difference in pain compared to placebo.
Pregabalin was tolerated well but not significantly better than placebo.
Neither amitriptyline nor mexiletine provided significant relief compared to placebo.
No significant difference. High dropout and drug discontinuation rate, low recruitment. Neither acupuncture nor amitriptyline nor the combination of the two was more effective than placebo.
Pain reduction was not significantly different though there was a trend towards pain improvement in the treatment group. No significant difference between the two groups.
Cannabis was significantly effective in this population. Single application of the treatment provided significant pain relief in HIV-DSP.
Significant reduction in neuropathic pain.
Conclusion
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Abbreviations: DSP distal sensory polyneuropathy, rhNGF recombinant human nerve growth factor, SAR standardized acupuncture regimen, ALCAR acetyl L-carnitine, MPQ McGill pain questionnaire, NPRS numeric pain rating scale, VAS visual analogue scale
90 patients with HIV-DSP who received bid IM injections Pain assessment by multiple scales ALCAR significantly reduced weekly mean pain of ALCAR vs placebo for 2 weeks followed by including VAS, Total Symptom Score, ratings on the VAS. 42 days of oral ALCAR Clinical Global Impression of Change, and MPQ Acetyl L-carnitine (ALCAR) Youle et al. 2007 [47]
Study
Table 1 (continued)
Primary outcome measure
Conclusion Population/size/duration Intervention
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well-tolerated topical therapy which does not require frequent dosing. However additional topical agents, including a randomized trial of topical lidocaine gel, have not proven to be effective [36]. Traditional first line oral agents for pain—the non-opioid analgesics, over the counter medications such as acetaminophen and NSAIDs—have limited efficacy in the treatment of HIV-DSP. Many practitioners will adopt oral medications that have been used with success in patients with other types of neuropathic pain for use in patients with HIV-DSP, although as mentioned above these medications have not had notable success in HIV-DSP (see Table 1). These medications include anticonvulsants, anti-depressants, and opioids. Trials of antidepressants such as amitriptyline and duloxetine have produced disappointing results in HIVDSP without evidence of significant effect over placebo [29, 37, 38], though it is notable that the randomized trial of duloxetine was hampered by challenges with recruitment and high drop-out. Similarly, rigorous trials of anticonvulsants such as lamotrigine and pregabalin have not been found to significantly reduce HIVDSP pain, though a small trial of gabapentin showed positive results [39–42]. A single randomized trial of peptide T in HIV-DSP also did not yield significant results [43] and a trial of mexiletine was non-significant as well [37]. Opiates have been tested in combination with some of the agents listed above [38] and may be considered as an additive agent in severe/ refractory cases. However they should not be considered first line treatment in view of their non-specific effect, potential for abuse, and other side effects. Given the paucity of pharmacologic agents proven to significantly reduce neuropathic pain in this population it is reasonable to apply the principle of rational polypharmacy, which has been employed in other types of neuropathic pain [44] and allows for combining multiple agents on an individual basis to best treat patients’ pain. One last symptomatic therapy which is among the few that have yielded positive results in limited trials is smoked cannabis. Two randomized trials have shown evidence for efficacy with smoked cannabis [45, 46]. In both cases a small group of participants smoked cannabis for a total of 5 days and reported improvement in pain scores that were significantly better than those with placebo. More data would be needed to further establish the efficacy of this intervention, though it may not be a feasible therapy for chronic symptoms given the side effects and possible legal implications. Regenerative Treatments Regenerative treatments are therapies that aim not only to improve symptoms but to repair damage done by promoting nerve regrowth. Several agents of this type have been tested with mixed results. Youle et al. reported a randomized
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controlled trial of 90 patients receiving acetyl L-carnitine, which studies have shown to be important in mitochondrial function; it may also have numerous neurotrophic/supportive effects on peripheral nerves including activating nerve growth factor receptors [47]. They found that acetyl L-carnitine, when given intramuscularly reduced pain ratings in this population and subsequent treatment with oral acetyl L-carnitine improved symptoms as well. A subsequent open-label, single arm study of acetyl L-carnitine by Valcour et al. also yielded improvement in subjective pain scores but not by objective measures of intraepidermal nerve fiber density [48]. Another agent recently investigated was prosaptide, a neurotrophic factor that has had beneficial effects in animal models. However, a randomized controlled trial was safe but ineffective compared to placebo after a 6 week period [49]. Lastly while a trial of rhNGF produced reduction in pain of HIV-DSP it did not show evidence of nerve regeneration [50] and it is not currently clinically available.
Conclusions HIV-DSP is a common neurologic complication among HIVinfected individuals and may range in presentation from being asymptomatic to debilitating pain and sensory loss. Proposed pathophysiological mechanisms for the disease process include indirect effects of the virus, and antiretroviral-induced neurotoxicity via mitochondrial dysfunction. The pharmacologic treatments that have been proven to be effective in HIVDSP are few and studies of adjunctive, non-pharmacologic treatments are of interest. Notably, this plethora of “negative” studies of treatments for HIV-DSP begs the question of why multiple agents that are effective in chronic neuropathic pain in patients without HIV should be so inefficacious in HIVDSP. It remains to be seen whether these “negative” studies reflect a failure of the drugs themselves in these patients or a failure of the trials. More studies are needed to further elucidate these questions and foster a better understanding of the complex pathophysiology of the disease process, which will ultimately help guide future treatment trials.
Compliance with Ethics Guidelines Conflict of Interest Kara Stavros declares that she has no conflict of interest. David M. Simpson reports personal fees from Astellas, Acorda, Pfizer, Depomed, grants from Astellas, Pfizer, and outside the submitted work. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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controlled trials. AIDS Res Ther. 2013;10(1):5. An integrated analysis of two randomized control trials providing evidence that capsaicin transdermal 8 % patch significantly reduces pain in HIVDSP. Clifford DB, Simpson DM, Brown S, et al. A randomized, doubleblind, controlled study of NGX-4010, a capsaicin 8 % dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J Acquir Immune Defic Syndr. 2012;59(2):126– 33. Estanislao L, Carter K, McArthur J. A randomized controlled trial of 5 % lidocaine gel for HIV-assiociated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr. 2004;37(5): 1584–6. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. Neurology. 1998;51:1682–8. Harrison T, Lee A, et al. Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies. Pain Med. 2013;14(7):1039–47. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004;251:1260–6. Simpson DM, Schifitto G, Clifford DB. Pregabalin for painful HIV neuropathy: a randomized, double blind, placebo-controlled trial. Neurology. 2010;74(5):413–20. Simpson DM, McArthur J, Olney R. Lamotrigine for HIVassociated painful sensory neuropathies: a placebo-controlled trial. Neurology. 2003;60:1508–14. Simpson DM, Olney R, McArthur JC, et al. A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology. 2000;54(11):2115–9. Simpson D, Dorfman D, Olney RK, et al. Peptide T in the treatment of painful distal neuropathy associated with AIDS: results of a placebo-controlled trial. The peptide T neuropathy study group. Neurology. 1996;47(5):1254–9. Gilron I, Bailey J, Dongsheng T, et al. Morphine, gabapentin, or their combination for neuropathic pain. NEJM. 2005;352:1324–34. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIVassociated sensory neuropathy: a randomized placebo controlled trial. Neurology. 2007;68(7):515–21. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–80. Youle M, Osio M, ALCAR Study Group. A double-blind, parallel-group, placebo-controlled, multicenter study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med. 2007;8(4):241–50. Valcour V, Yeh TM, Bartt R, et al. Acetyl-l-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection. HIV Med. 2009;10(2):103–10. Evans SR, Kitch DW, et al. A randomized trial evaluating prosapide for HIV-associated sensory neuropathies: use of an electronic diary to record neuropathic pain. PLoS One. 2007;2(6):e551. McArthur JC, Yiannoutsos C, Simpson DM, et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS clinical trials group team 291. Neurology. 2000;54(5):1080–8.
COMPLICATIONS OF ANTIRETROVIRAL THERAPY (JM KILBY, SECTION EDITOR)
Understanding the Etiology and Management of HIV-Associated Peripheral Neuropathy Kara Stavros & David M. Simpson
# Springer Science+Business Media New York 2014
Abstract HIV may cause several forms of peripheral neuropathy, the most common of which is distal symmetric polyneuropathy (DSP) characterized by pain and sensory deficits in a stocking-glove distribution. The pathophysiology of DSP remains largely unknown but is thought to be related both to the neurotoxicity of HIV—through indirect immunomodulatory mechanisms—and to the neurotoxic effects of anti-retroviral therapies, most notably the dideoxynucleoside reverse transcription inhibitors or so-called d-drugs. Determining whether symptoms arise from the virus or the treatment poses a challenge to the clinician who must decide if a patient’s HAART regimen should be altered. Treatment of symptoms related to HIV-DSP is a difficult task and there is no evidence that the traditional agents used in chronic neuropathic pain are efficacious in the HIV-DSP population. Indeed few pharmacologic agents have proven efficacy in HIV-DSP – these include cannabis and the capsaicin 8 % dermal patch. As such, alternative, non-pharmacologic therapies are being investigated. More research is needed to further elucidate the complex pathophysiology of HIV-DSP which may yield additional therapies for these patients. Keywords HIV . Peripheral neuropathy . Distal symmetric polyneuropathy, DSP . Anti-retroviral . Pain
mononeuritis multiplex, inflammatory demyelinating polyneuropathy, polyradiculopathy, and autonomic dysregulation [1, 2••]. By far the most common of these is DSP, which can be asymptomatic or may be characterized by variable degrees of pain, paresthesias, and numbness in a symmetric, stocking-glove pattern in the extremities. HIV-DSP is thought to be produced by a multitude of mechanisms caused by the virus (see discussion below). However the clinical picture is complicated by the finding that many of the anti-retroviral therapies used today to treat HIV can cause a clinically indistinguishable, medication-induced DSP. While in the past the dideoxynucleoside reverse transcriptase inhibitors (the so-called d-drugs) were the most notorious for causing DSP there is now evidence that protease inhibitors can cause peripheral neuropathy as well [3]. Given that both the virus and the treatments for it can both cause DSP, the diagnosis and management of these patients may be challenging for the clinician, who may need to decide whether it is necessary to alter a patient’s drug regimen when faced with symptomatic DSP. In this review we will focus on HIV-DSP and review the pathophysiology and the proposed mechanisms of virusmediated neurotoxicity and medication-induced neurotoxicity. We will also review the current management of HIV-DSP.
Epidemiology and Risk Factors Introduction HIV is associated with numerous peripheral neuropathies. These include distal symmetric polyneuropathy (DSP), K. Stavros : D. M. Simpson (*) Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue Annenberg 2nd Floor, Box 1052, New York, NY 10029, USA e-mail: [email protected]
HIV-DSP is the most common neurologic complication of HIV and its prevalence has been rising in recent years. Incidence rates of HIV-DSP vary depending on the cohort studied however it is estimated that one third to one half of HIVinfected patients have DSP [4–6]. Numerous studies have been undertaken to elucidate the risk factors for DSP in the HIV population. Prior to the widespread use of HAART therapy, risk factors included low CD4 count, elevated plasma viral load, and the use of neurotoxic anti-retrovirals such as
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stavudine [7]. More recent studies have found that CD4 count and viral load either confer no additional risk of DSP [6, 7] or conversely that a higher CD4 count may be associated with DSP [8]. Robinson-Papp et al. [8] postulate that the association of DSP with higher CD4 counts that they found may reflect the longer life expectancy of HIV patients in the present day or may be owing to the fact that patients with lower CD4 counts often have more urgent medical issues that may overshadow chronic neuropathic symptoms. Other studies examining risk factors for HIV-DSP in the HAART era have noted increased risk in patients with a history of substance abuse [7, 8], older age [4, 7, 9], and greater height [4, 9]. One recent study found that the use of statins significantly decreases the risk of DSP in HIV patients [9].
Pathophysiology Neurotoxicity of HIV Frequent pathologic features seen in HIV-DSP include distal degeneration of long axons, macrophage infiltration, and a loss of neurons in the dorsal root ganglion (DRG) [10]. Several mechanisms for virally-mediated neurotoxicity have been proposed to explain these changes. Neurotoxicity may occur via direct infection of the peripheral nerve by the virus or by various indirect, immunomodulatory mechanisms. These indirect mechanisms include the release of potentially neurotoxic substances by infected macrophages, such as inflammatory cytokines (i.e., TNF-α, IL-1, IL-6), chemokines, and glutamates [11]. Infected macrophages may also release viral proteins such as gp120, the most well-studied envelope protein in DSP pathogenesis, which has been shown to cause DRG neuronal cell death [11, 12]. Additionally, evidence of mitochondrial dysfunction has been noted as a result of HIV infection in laboratory studies [13]. Neurotoxicity of Anti-retroviral Therapies As described above, the antiretroviral agents most traditionally associated with HIV-DSP are the d-drugs, particularly stavudine [14]. These drugs are thought to induce neurotoxicity by causing mitochondrial dysfunction [15, 16] through inhibition of polymerase gamma, an enzyme involved in mitochondrial DNA replication [11]. The d-drugs may affect mitochondrial DNA by various degrees [17]. The recent development of a promising rodent model of stavudine-induced peripheral neuropathy may spur more studies to help further elucidate the pathophysiology of antiretroviral neurotoxicity [18]. Due to their known neurotoxic side effects many of these drugs are avoided in the developed world today in favor of alternative treatments. However the d-drugs are still widely employed in the developing world, and in places where
resources are limited withdrawing these drugs is not a feasible option. The WHO 2013 consolidated guidelines for HAART therapy in HIV-infected patients recommends first line therapy with two nucleoside reverse transcriptase inhibitors (specifically tenofovir, emtricitabine, or lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz) [19]. They explicitly recommend the discontinuation of stavudine and worldwide efforts are underway to eliminate this drug from routine use due to its known toxicities including lipoatrophy, lactic acidosis, and peripheral neuropathy [19, 20]. The U.S. NIH guidelines are similar to the WHO recommendations with a basic regimen consisting of two nucleoside reverse transcriptase inhibitors plus one protease inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase strand transfer inhibitor, or CCR5 antagonist [21]. As nucleoside reverse transcriptase inhibitors remain a mainstay of HAART both in the U.S. and worldwide, it is important for clinicians to be aware of their possible neurotoxic side effects. While the d-drugs are well-established in causing DSP more recent studies suggest that it is not only the d-drugs, but protease inhibitors as well that can have a neurotoxic effect [3]. Pettersen et al. [3] found that exposure to protease inhibitors may contribute to DRG damage via loss of macrophagederived neurotrophic factors, thereby leading to peripheral neuropathy. However in a recent observational study Ellis et al. [22] examined current and past exposure to protease inhibitors in over 1000 HIV patients and concluded that the additional risk of peripheral neuropathy conferred by protease inhibitor use is small. Further investigation into the role of protease inhibitors in DSP is needed. It can be challenging to differentiate whether a patient’s symptoms arise from virally-mediated neurotoxicity or his/her current drug regimen as the clinical presentations may be indistinguishable. History of d-drug exposure and improvement in symptoms with drug withdrawal may be important clues. A recent observational study of HIV-DSP patients who consented to skin biopsies and nerve conduction studies showed that neurotoxic treatments were more likely to impair small fiber conduction while HIV itself is more likely to impair large fibers [23]. Making this distinction is of significance to the clinician, who may need to weigh the risk of altering the patient’s HAART regimen in the face of symptomatic DSP against upsetting well-controlled, stable HIV CD4 counts and viral loads. Also of note clinically is the concern that significant medication related DSP side effects may result in poor compliance with HAART. Central Pathways In addition to the neurotoxicity of HIV and anti-retroviral therapies it is important to consider the role of central mechanisms in DSP. Interestingly, a study by Morgello et al. [7] found an association between DSP and substance abuse. They
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postulated that since they were unable to find differences between the peripheral nerve biopsy specimens of patients with and without opiate addiction that the opiate related effect they found may be attributable to central mechanisms. Indeed all of the pain experienced by HIV-DSP patients may not be attributable to peripheral nerve damage alone and in a new paper by Keltner et al. [24••] a cross-sectional analysis of brain MRIs from HIV patients was undertaken. They found a significant correlation between the reported severity of DSP symptoms and smaller total cerebral cortical gray matter volume; this is similar to findings by other groups that other chronic pain syndromes are associated with smaller cortical gray matter volume and that treatment of the chronic pain can “normalize” brain volumes [24••]. While it is unclear at this time whether the DSP is the cause or the result of the change in gray matter, this adds insight into the chronic nature of these symptoms and the ways in which central mechanisms may regulate and potentiate pain in the peripheral nervous system. Further research is warranted into the complex pathophysiology of how the central and peripheral pathways coincide in HIV-DSP.
Clinical and Diagnostic Features HIV-DSP may be symptomatic or asymptomatic. Symptomatic patients may report numerous symptoms including pain, paresthesias, and numbness in the extremities, which are distally predominant and classically occur in a stockingglove distribution. On examination patients exhibit diminished sensation to pain, temperature, and vibration in the extremities and diminished or absent reflexes. The diagnosis of DSP is primarily made on a clinical basis, with a careful history and physical examination. Before making the diagnosis other common causes of peripheral neuropathy must be investigated and optimized if found to be abnormal. These may include diabetes mellitus, vitamin B12 deficiency, hypothyroidism, or alcoholism, among others. Confirmatory diagnostic tests may include electromyography (EMG), nerve conduction study, and skin biopsy. Nerve conduction studies in DSP may show a reduction in amplitude or absence of sural nerve sensory potentials while EMG may show active or chronic denervation patterns with evidence of re-innervation [1]. Skin biopsies typically show a reduction in epidermal nerve fiber density in DSP patients [1, 25] and may be useful in early detection of neuropathy [26].
Management Symptomatic Treatments While there have been numerous successful trials of pharmacologic therapies in chronic neuropathic pain, the trials in
patients with HIV-DSP are fewer and many of the agents found to be effective in chronic neuropathic pain have not been proven to be effective in HIV-DSP. In fact, a recent metaanalysis of 14 randomized controlled trials of pharmacologic treatments in HIV-DSP found that of the agents that have been tested in randomized controlled trials, only a few agents, including smoked cannabis and the capsaicin 8 % transdermal patch, have proven efficacy in this population [27]. Details of the randomized controlled trials of pharmacologic therapies in HIV-DSP are outlined in Table 1 and discussed further below. This difference in treatment efficacy may be reflective of a different underlying pathophysiology of HIV-DSP compared to other types of neuropathic pain, such as diabetic neuropathy. Given the poor efficacy of traditional neuropathic pharmacologic agents in these patients the investigation of alternative, non-pharmacologic treatments may be warranted. Non-pharmacologic Therapies Several non-pharmacologic therapies have been examined in this population. A recent trial by Anastasi et al. [28] randomized HIV-DSP patients to receive acupuncture complimented by burning of the mugwort root muxibustion (acu/moxa) versus sham acupuncture. They found a significant effect of acu/moxa on their first follow up visit, though afterward the treatment group retained only a non-significant trend towards superiority. Similarly, a larger randomized placebo controlled trial of acupuncture, amitriptyline, and the combination of the two in HIV-DSP patients showed that neither intervention was more effective than placebo [29]. Hypnosis is another alternative treatment that has been tested in this population with limited but promising results. In a recent trial by Dorfman et al. [30•] 36 HIV-DSP volunteers were trained in selfhypnosis for pain management; investigators found improvement in pain scores on the Short Form McGill Pain Questionnaire regardless of their current analgesic regimen. Lastly, a recent trial of lower extremity splinting, aimed to reduce sleep disturbances and discomfort from external stimuli, in a small 6-week study showed a trend toward improvement in pain in the interventional group but no significant difference [31]. More studies of alternative non-pharmacologic treatments of HIV-DSP pain are needed to explore opportunities for adjunctive therapy in this difficult-to-treat population. Pharmacologic Therapies Research in topical analgesic therapies in HIV-DSP has produced promising results particularly with capsaicin. An initial, randomized controlled trial in 2008 showed significant improvement of pain scores in HIV-DSP patients in the capsaicin 8 % transdermal patch group [32] and since then multiple other studies have confirmed the efficacy of the capsaicin patch [33, 34••, 35]. This is encouraging evidence for a
Smoked cannabis
Abrams et al. 2007 [45] Ellis et al. 2009 [46] Simpson et al. 2008 [32]
Pregabalin
Lamotrigine
Lamotrigine
Peptide T
Gabapentin
Prosaptide
rhNGF
Simpson et al. 2010 [40]
Simpson et al. 2003 [41]
Simpson et al. 2000 [42]
Simpson et al. 1996 [43]
Hahn et al. 2004 [39]
Evans et al. 2007 [49]
McArthur et al. 2000 [50]
Kieburtz et al. 1998 [37]
5 % lidocaine gel
Estanislao et al. 2004 [36] Harrison et al. 2013 [38] Shlay et al. 1998 [29]
50 patients with HIV-DSP assigned to smoke cannabis vs placebo cigarettes three times/day for 5 days Crossover trial of 28 patients with HIV-DSP who smoked cannabis or placebo four times/day for 5 days 307 patients randomized to receive topical capsaicin 8 % or a control, low concentration capsaicin patch and monitored for 12 weeks 494 patients with HIV-DSP received capsaicin 8 % dermal patch vs a control, low concentration patch and were monitored for 12 weeks Crossover trial of 64 patients randomized to placebo vs 5% lidocaine gel for 2 weeks
Population/size/duration
270 patients with HIV-DSP who received biweekly injections of placebo vs 0.1 mcg/kg rhNGF vs 0.3 mcg/kg rhNGF for 18 weeks
26 HIV-DSP patients randomized to placebo or gabapentin following a 4 week blinded and 2 week open treatment schedule 237 patients with HIV-DSP administered various doses of IM prosaptide vs placebo for 6 weeks
302 HIV-DSP patients randomized to either placebo or pregabalin participating in a 2 week dose adjustment period and 12 week maintenance phase. 92 patients with HIV-DSP who received placebo vs lamotrigine for a 7 week dose escalation phase followed by a 4 week maintenance phase 42 patients with HIV-DSP randomized to placebo vs 25 mg lamotrigine daily which was slowly titrated up to 300 mg daily. Study duration 14 weeks. 81 patients with HIV-DSP given intranasal peptide T 6 mg/day vs placebo for 12 weeks
Duloxetine, methadone, 15 HIV-DSP patients enrolled in this four-period and their combination crossover study but only 8 completed the trial Amitriptyline and 250 patients with HIV-DSP assigned to SAR vs standardized amitriptyline vs combination therapy with acupuncture regimen comparison to placebo for 14 weeks (SAR) Amitriptyline vs mexiletine 145 HIV-DSP patients assigned to amitriptyline vs mexiletine vs placebo for 10 weeks
Topical capsaicin 8 %
Clifford et al. 2012 [35]
Topical capsaicin 8 %
Smoked cannabis
Intervention
Study
Table 1 Randomized, placebo-controlled trials of pharmacologic treatments in HIV-DSP
Change from baseline weekly average of daily pain score using the Gracely Pain Scale and an electronic diary Change in pain by the Gracely Pain Scale
Improvement in pain by the VAS
Change in pain by the modified Gracely Pain Score
Change in pain on the Gracely scale.
Mean change in average pain by the Gracely Pain Scale
Change in pain intensity ratings (twice daily patients chose from a list of words that were assigned a numerical rating) Change in mean NPRS score.
Mean pain intensity measured in a daily pain diary Change in pain using the Gracely Pain Scale
Difference in average pain scores by the Gracely Pain Scale.
Percent change in NPRS from baseline.
Change in pain measured by the Descriptor Differential Scale Percent change in NPRS from baseline.
Daily pain diary using the VAS
Primary outcome measure
rhNGF significantly improved pain and was well-tolerated aside from injection site pain.
Prosaptide was safe but not effective in treating HIV neuropathic pain.
Significant decrease in pain scores on VAS in the gabapentin group.
Intranasal peptide T was safe but not effective for the treatment of HIV-DSP.
No significant difference between lamotrigine and placebo. Rash was a significant side effect.
No significant difference in pain compared to placebo.
Pregabalin was tolerated well but not significantly better than placebo.
Neither amitriptyline nor mexiletine provided significant relief compared to placebo.
No significant difference. High dropout and drug discontinuation rate, low recruitment. Neither acupuncture nor amitriptyline nor the combination of the two was more effective than placebo.
Pain reduction was not significantly different though there was a trend towards pain improvement in the treatment group. No significant difference between the two groups.
Cannabis was significantly effective in this population. Single application of the treatment provided significant pain relief in HIV-DSP.
Significant reduction in neuropathic pain.
Conclusion
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Abbreviations: DSP distal sensory polyneuropathy, rhNGF recombinant human nerve growth factor, SAR standardized acupuncture regimen, ALCAR acetyl L-carnitine, MPQ McGill pain questionnaire, NPRS numeric pain rating scale, VAS visual analogue scale
90 patients with HIV-DSP who received bid IM injections Pain assessment by multiple scales ALCAR significantly reduced weekly mean pain of ALCAR vs placebo for 2 weeks followed by including VAS, Total Symptom Score, ratings on the VAS. 42 days of oral ALCAR Clinical Global Impression of Change, and MPQ Acetyl L-carnitine (ALCAR) Youle et al. 2007 [47]
Study
Table 1 (continued)
Primary outcome measure
Conclusion Population/size/duration Intervention
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well-tolerated topical therapy which does not require frequent dosing. However additional topical agents, including a randomized trial of topical lidocaine gel, have not proven to be effective [36]. Traditional first line oral agents for pain—the non-opioid analgesics, over the counter medications such as acetaminophen and NSAIDs—have limited efficacy in the treatment of HIV-DSP. Many practitioners will adopt oral medications that have been used with success in patients with other types of neuropathic pain for use in patients with HIV-DSP, although as mentioned above these medications have not had notable success in HIV-DSP (see Table 1). These medications include anticonvulsants, anti-depressants, and opioids. Trials of antidepressants such as amitriptyline and duloxetine have produced disappointing results in HIVDSP without evidence of significant effect over placebo [29, 37, 38], though it is notable that the randomized trial of duloxetine was hampered by challenges with recruitment and high drop-out. Similarly, rigorous trials of anticonvulsants such as lamotrigine and pregabalin have not been found to significantly reduce HIVDSP pain, though a small trial of gabapentin showed positive results [39–42]. A single randomized trial of peptide T in HIV-DSP also did not yield significant results [43] and a trial of mexiletine was non-significant as well [37]. Opiates have been tested in combination with some of the agents listed above [38] and may be considered as an additive agent in severe/ refractory cases. However they should not be considered first line treatment in view of their non-specific effect, potential for abuse, and other side effects. Given the paucity of pharmacologic agents proven to significantly reduce neuropathic pain in this population it is reasonable to apply the principle of rational polypharmacy, which has been employed in other types of neuropathic pain [44] and allows for combining multiple agents on an individual basis to best treat patients’ pain. One last symptomatic therapy which is among the few that have yielded positive results in limited trials is smoked cannabis. Two randomized trials have shown evidence for efficacy with smoked cannabis [45, 46]. In both cases a small group of participants smoked cannabis for a total of 5 days and reported improvement in pain scores that were significantly better than those with placebo. More data would be needed to further establish the efficacy of this intervention, though it may not be a feasible therapy for chronic symptoms given the side effects and possible legal implications. Regenerative Treatments Regenerative treatments are therapies that aim not only to improve symptoms but to repair damage done by promoting nerve regrowth. Several agents of this type have been tested with mixed results. Youle et al. reported a randomized
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controlled trial of 90 patients receiving acetyl L-carnitine, which studies have shown to be important in mitochondrial function; it may also have numerous neurotrophic/supportive effects on peripheral nerves including activating nerve growth factor receptors [47]. They found that acetyl L-carnitine, when given intramuscularly reduced pain ratings in this population and subsequent treatment with oral acetyl L-carnitine improved symptoms as well. A subsequent open-label, single arm study of acetyl L-carnitine by Valcour et al. also yielded improvement in subjective pain scores but not by objective measures of intraepidermal nerve fiber density [48]. Another agent recently investigated was prosaptide, a neurotrophic factor that has had beneficial effects in animal models. However, a randomized controlled trial was safe but ineffective compared to placebo after a 6 week period [49]. Lastly while a trial of rhNGF produced reduction in pain of HIV-DSP it did not show evidence of nerve regeneration [50] and it is not currently clinically available.
Conclusions HIV-DSP is a common neurologic complication among HIVinfected individuals and may range in presentation from being asymptomatic to debilitating pain and sensory loss. Proposed pathophysiological mechanisms for the disease process include indirect effects of the virus, and antiretroviral-induced neurotoxicity via mitochondrial dysfunction. The pharmacologic treatments that have been proven to be effective in HIVDSP are few and studies of adjunctive, non-pharmacologic treatments are of interest. Notably, this plethora of “negative” studies of treatments for HIV-DSP begs the question of why multiple agents that are effective in chronic neuropathic pain in patients without HIV should be so inefficacious in HIVDSP. It remains to be seen whether these “negative” studies reflect a failure of the drugs themselves in these patients or a failure of the trials. More studies are needed to further elucidate these questions and foster a better understanding of the complex pathophysiology of the disease process, which will ultimately help guide future treatment trials.
Compliance with Ethics Guidelines Conflict of Interest Kara Stavros declares that she has no conflict of interest. David M. Simpson reports personal fees from Astellas, Acorda, Pfizer, Depomed, grants from Astellas, Pfizer, and outside the submitted work. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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