Issues In The Current Data On Toxic Neuropathies Implications For Future Clinical Trials

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Current data on the toxicity of dideoxynucleoside analogs in humans has been drawn largely from subject complaints during clinical treatment trials and from case reports. No large carefully controlled prospective neurological trial focused specifically on nucleoside-associated neuropathy in HIV has been performed, to date. In many clinical treatment trials, previous neuropathy was not an exclusion factor at entry. In others, detailed neurological examination to determine the prevalence of asymptomatic neuropathy at entry, and to confirm the origin of symptomatic complaints during the study, were not incorporated into the protocols. As a result, errors in attribution of symptoms or in the recognition of occult neuropathy may have occurred. Simpson and colleagues reanalyzed data from a large clinical trial of ZDV, ddI, ddC, and placebo in four combinations. Using criteria for DSP as described above, they reevaluated diagnoses made at the treatment sites. In 63% of reported cases of neuropathy, the site investigators were unable to determine the cause of the symptoms. On review, Simpson and colleagues were able to classify approximately half of these as DSP, and, therefore, potentially treatment related. Of subjects classified as having treatment related neuropathy, 27% did not have typical features of DSP as reflected in the criteria used by the reviewers, and were, therefore, considered unlikely to have medication-related toxic neuropathy (79). These findings suggest that data from studies not incorporating detailed baseline and serial neurological assessments may both underestimate or overestimate true treatment-related neurotoxicity. Furthermore, in addition to modifying the frequency of DSP, successful HAART might also modify the time-to-onset and rate of progression of neuropathies induced by nucleoside analog therapy, confounding the temporal characteristics currently used to discriminate HIV-asso-ciated DSP from toxic neuropathy.

The question of whether painful neuropathies appearing in association with nucleoside therapy represent exacerbation of a previously occult HIV-associ-ated distal sensory neuropathy, or whether they arise de novo as a result of nucleoside toxicity is of significant clinical importance. Neuropathy in advanced HIV infection seems to be common, and not infrequently asymptomatic. Marra and colleagues examined 226 subjects drawn from a large AIDS clinical trials unit and found DSP in 21%. Of the subjects with DSP, 71% had signs of neuropathy on examination but no symptoms. Individuals with DSP were more likely to have received dideoxynucleosides, they had more advanced HIV infection by Centers for Disease Control classification, and they had a trend toward lower CD4 counts (80).

Schiffito and associates determined the frequency of DSP in a cohort selected for cognitive symptoms and CD4 counts of fewer than 300 cells/mm3 or fewer than 200 cells/mm3. They found symptomatic DSP in 35% of subjects, and asymptomatic DSP in an additional 20% of subjects. In this cohort undergoing serial neurological evaluations, 72% of subjects without neuropathy at entry developed incident DSP during a period of 30 mo, with a 1 yr incidence of 52%. Among those with no neuropathy or asymptomatic neuropathy at entry, the 1-yr incidence of symptomatic DSP was 36%. Only 23% of the subjects were taking dideoxynucleosides and, interestingly, neither these subjects nor those with asymptomatic neuropathy were more likely to develop symptomatic DSP during the study (81).

In a series of 251 HIV-infected subjects undergoing clinical and neurophysio-logical assessments, Tagliati and coworkers found evidence of DSP in 38% of the entire cohort, and in 48% of subjects with AIDS. Of subjects with clinical features of DSP, 19% had normal electrodiagnostic studies, whereas, of those without clinical findings, 28% had abnormalities on the neurophysiological assessments suggestive of DSP (14).

The limitations of previous data and the frequency of asymptomatic polyneu-ropathy demonstrated in these studies underscore the need for any future clinical trial using potentially neurotoxic therapies, including nucleoside analogs, to incorporate a sufficiently detailed neurological screening at baseline and during the observation period to accurately assess and attribute incident neuropathy, and to determine risk factors for the emergence of incident neuropathy.

In some recent clinical trials incorporating dideoxynucleoside treatment regimens, fewer subjects have been noted to develop symptomatic painful neuropathy. Additionally, some individuals seem to experience improvement of neuropathic symptoms in association with dideoxynucleoside therapy, further confounding the determination of frequency and etiology of painful neuropathies in patients with advanced HIV infection who are treated with potentially neurotoxic therapies. Factors contributing to the emergence of treatment-related neuropathic toxicity need to be elucidated. Do host factors, such as genetic susceptibilities, predispose to the development of toxic neuropathy? Are there particular interactions among the multiplicity of drugs taken by HIV-infected patients and the multiorgan pathologies, particularly those affecting the liver or kidneys, which combine to increase the toxicity of a standard therapeutic dose of a dideoxynucleoside in a given individual? Are the beneficial effects of successful therapy on DSP partially masking the neurotox-icity of dideoxynucleoside therapy?

The risk of acquiring HIV-associated DSP s appears to be related to both increased plasma HIV viral load and decreased CD4 count (25,26,81). Successful treatment with current HAART may have the capacity to improve peripheral nerve function, as demonstrated in a study using serial QST assessments (82), and as reported in an earlier study of ddI, described above (48). Thus, HIV-associated DSP may become less prevalent with successful retro-viral suppression and control of other, as yet unidentified factors, offsetting an increased frequency of neuropathy induced by dideoxynucleoside components of HAART regimens. This offsetting effect was suggested in a retrospective study of a German cohort, in which the prevalence of DSP in a 2-yr period before the introduction of HAART was 42.5%, with a suspected rate of toxic neuropathy of 20.4%. In the following 2-yr period, during which subjects were placed on HAART in large numbers, the prevalence of DSP was reduced to 34.4%; however, the proportion of neuropathies attributed to nucleoside analog toxicity increased to 31.2% (28).

Recently, a small prospective study assessed serum lactate levels in patients with DSP, comparing those taking d4T to those without exposure to dideoxynucleosides, as well as to HIV-infected individuals without neuropathy taking d4T and non-HIV-infected controls. An elevated serum lactate level was found to be 90% sensitive and 90% specific in discriminating d4T-related toxic DSP from HIV-associated DSP (88). If results of this study are confirmed, the presence of a surrogate marker should contribute to the understanding of the pathogenesis of toxic DSP, and perhaps clarify the potential contributions of both the dideoxynucleoside- and HIV-related pathologies to the natural history of DSP.

Future controlled clinical trials which include longitudinal assessments both of symptomatic and asymptomatic neuropathy from onset of antiretroviral therapy, and epidemiological studies of the natural history of HIV-associated neuropathies in relation to HAART therapy to identify factors associated with their occurrence, may help to clarify which subjects are at risk of severe toxic neuropathies and provide prognostic indicators to facilitate modification of therapeutic regimens. Perhaps serum lactate levels will prove useful in this regard. It may be possible, with better understanding of the pathophysiology of these syndromes, to identify adjunctive therapeutic agents which protect against the emergence of toxic neuropathies, as has recently been suggested for acetyl-L-carnitine. In addition to detailed serial clinical assessments, better measurement tools may be required, including electrophysiological tests that are more sensitive, such as QST assessments (82), and pathological measurements, such as quantification of intraepidermal and, perhaps, dermal nerve fiber density obtained by skin biopsy (21-23,74). Treatments relieving neuropathic pain may not result in improvement of clinical, electrophysiological, or pathological measures of neuropathy, as was seen in the recent clinical trial of nerve growth factor (83,84). The natural history of such painful neuropathies relieved, but not resolved, after withdrawal of dideoxynucleosides, awaits elucidation in future studies. Will these prove to be aborted toxic neuropathies with incomplete resolution, or incident HIV-associated DSP exacerbated by a superimposed agent with some neurotoxicity, perhaps synergistic with primary neuropathological processes? Thus, most importantly, studies to improve our understanding of the mechanisms of toxicity in both HIV-associated DSP and nucleoside-associated toxic neuropathies are essential to provide the basis for future therapies that specifically target the pathophysiological mechanisms of these syndromes.

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