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Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levels
  David M. Simpson; Anna-Bettina Haidicha; Giovanni Schifittob; Constantin T. Yiannoutsosa; Anthony P. Geraci; Justin C. McArthurc; David A. Katzensteind; and the ACTG 291 study team*
From the Departments of Neurology and Clinical Neurophysiology, Mount Sinai School of Medicine, New York, New York, the a Harvard School of Public Health, Boston, Massachusetts, the b Department of Neurology, University of Rochester, New York, the c Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, Maryland, and the d Department of Medicine, Stanford University, California, USA. *See Appendix.
AIDS 2002;16:407-412
Objective: To determine if there is an association between plasma HIV-1 RNA levels and severity of HIV-associated distal symmetrical polyneuropathy (DSP).
Design: Substudy of AIDS Clinical Trials Group Protocol 291, a double-blind, placebo-controlled study of recombinant human nerve growth factor for the treatment of painful DSP.
Methods: Two-hundred and thirty-six subjects had plasma HIV-1 RNA load assayed at baseline. Mean and maximum neuropathic pain was assessed once daily by the Gracely Pain Scale. Other measures included subjects¹ global pain assessment and quantitative sensory tests (QST). These values were correlated with baseline HIV-1 RNA levels.
Results: Among 168 subjects with detectable plasma HIV-1 RNA, there was a significant correlation between plasma HIV-1 RNA and the severity of maximum and global pain, and toe cooling thresholds. Maximum and global pain assessment correlated with plasma HIV-1 RNA in individuals with detectable viral load (r, 0.162 and 0.194; P = 0.04 and 0.01, respectively).
Conclusions: There is an association between plasma HIV-1 RNA levels and the severity of pain and QST results in HIV-associated DSP. Further studies are needed to determine if aggressive use of antiretroviral drugs, including the use of dideoxynucleosides, may be of benefit to prevent or improve peripheral neuropathy.
HIV infection is associated with a variety of central and peripheral nerve disorders including distal symmetrical polyneuropathy (DSP), also called painful sensory neuropathy [1-4]. The risk of DSP is increased with higher plasma HIV-1 viral level, low CD4 cell counts, advanced disease and increased age [1,3]. Highly active antiretroviral therapy (HAART) that suppresses HIV replication has dramatically improved the prognosis of HIV infection [5,6]. While the impact of antiretroviral (ARV) therapy on the clinical features of DSP is not known, virological response to HAART is associated with improvement in thermal perception thresholds [7].
Although dideoxynucleoside (ddN) reverse transcriptase inhibitors remain an important component of effective ARV therapies, their use may be limited by the development of toxic neuropathy. DSP was identified as a dose-limiting toxicity in early clinical trials of the ddN ARV, didanosine (ddI), zalcitabine (ddC) and stavudine (d4T) [8-11]. Effective ddN therapy, reflected in suppressed HIV-1 RNA level and increased CD4 cell count, may paradoxically diminish quality of life if the treatment precipitates an increase in neuropathic symptoms. The risk of these adverse affects is considerably increased when ddNs are used as two-drug combinations, such as ddI and d4T [12].
Treatments to relieve symptoms of HIV-associated DSP have thus far proven largely ineffective [13]. Some patients may be reluctant to start ARV therapy that has any potential for causing or exacerbating painful neuropathy, even if it is necessary for virological control. However many clinicians continue effective although neurotoxic ARV in the setting of peripheral neuropathy, especially when alternative options are limited.
Thus, the risk of DSP and increased neuropathic symptoms is increased, with higher levels of plasma viremia and low CD4 cell counts, and by the treatments (ddN ARV), which suppress viremia and increase CD4 cell count. The relationship between HIV viremia and DSP is therefore an important consideration, especially for patients who are being treated with an ARV regimen that contains a ddN. Furthermore while the pathogenesis of HIV-associated DSP is not known, the presence of an association between HIV-1 viral load and neuropathy severity would provide further support for a role of HIV or its byproducts. Among a clinical trial cohort of patients with DSP, most of whom were on stable ARV regimens, we examined the relationship between the severity of DSP and HIV-1 plasma viremia.
Among those 168 subjects with detectable viral load, there was a significant correlation between plasma HIV-1 RNA and Gracely maximum pain score (Table 2). Within this group, the median plasma HIV-1 RNA level among 36 subjects with less than moderate maximum pain was 3.81 log10 copies/ml compared to 4.51 log10 copies/ml among 130 subjects with moderate or higher maximum pain (P = 0.017). A similar correlation between pain and VL was observed with patient global pain assessment.
Previous studies indicate that increased plasma HIV-1 viral load is associated with an increased risk of DSP [1] and abnormal sensory nerve function as measured by QST [7]. Pain intensity due to DSP might be expected to follow the same relationship, unless confounded by the use of neurotoxic ARV. In this study, we found an association between elevated plasma HIV-1 RNA levels and the severity of neuropathic pain due to HIV-associated DSP. While pain is a subjective measure, and it is possible that patients failing HIV therapy, with higher viral load, might express their frustration with increased reporting of pain, HIV-1 RNA was also associated with objective measures of quantitative sensory nerve function. Notably, toe cooling thresholds in the lower extremities were affected, consistent with the clinical observation that DSP preferentially affects distal small fiber function.
The correlations between neuropathic severity and HIV-1 RNA were present only in the group with detectable viral load. It is possible that the lack of precise viral load measures in the undetectable group limited the ability to detect these associations in the total cohort. A limitation of this study is that patients without DSP were not available for comparison. While this trial was not designed to investigate the association between ddN usage and virologic response specifically, ddN use was not associated with increased neuropathic pain.
In conclusion, there does appear to be a significant, albeit weak, association between plasma HIV-1 RNA and the severity of neuropathy. This fits with prevailing theories that advanced HIV disease is associated with immune dysregulation and macrophage activation within the peripheral nervous system, leading to neuropathic damage [18]. Martin et al. reported that HIV virological suppression leads to improvement in quantitative thermal thresholds [7]. However that study provided no clinical characterization of those patients, such as painful symptoms, in contrast with the current report.
Our results provide further support for the aggressive control of HIV viral load, in order to minimize the severity of neuropathy. These data also suggest that, at least for mild neuropathy, use of ddN does not necessarily increase neuropathic symptoms. However, caution must be taken in using ddN, especially as double regimens (i.e., d4T and ddI) with hydroxyurea, where rates of neuropathy as high as 26% can be anticipated [12]. The risk-to-benefit ratio of aggressive use of ddN, in terms of virological control and neuropathic symptoms, probably differs based on the stage of disease and level of immunosuppression, and requires further investigation in prospective studies.
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