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 .
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 .
Treatments to relieve symptoms of HIV-associated DSP have thus far proven largely ineffective . 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.
This study was part of AIDS Clinical Trials Group (ACTG) Protocol 291, a placebo-controlled trial of recombinant human nerve growth factor for the treatment of DSP. The methods and primary results of this study have been reported previously . Two-hundred and seventy patients with HIV-associated DSP, most of whom were also receiving ARV therapy, were studied. Plasma HIV-1 RNA viral load (VL) (Roche Amplicor 1.0; limit of detection, ≥ 200 copies/ml) was assayed in 236 subjects at baseline. Subjects with VL ≤ 200 copies/ml were reassessed with the ultrasensitive assay (limit of detection, ≥ 50 copies/ml).
All subjects were enrolled with a clinical diagnosis of DSP, established by a standardized neurological evaluation performed by a neurologist. The diagnosis of DSP was based on primary symptoms of pain, burning or dysesthesia in both feet for at least 2 weeks, in combination with decreased pin, temperature perception or vibration, or absent ankle reflexes. History of ddN use was elicited from subjects at entry, and was defined as current use, recent use (interrupted 8–26 weeks prior to entry), or remote use (never used, or interrupted more than 26 weeks prior to entry).
Average and maximum pain was assessed once daily by the Gracely Pain Scale . Minimum criteria for study participation included a rating of ‘mild’ pain on the Gracely Pain Scale all the time, or ‘moderate’ pain for a total of at least 2 h a day. A weekly average of Gracely pain values was derived for statistical analysis. A global assessment of pain was also elicited by patients and investigators. Vibratory and cooling thresholds were determined with the Computer Assisted Sensory Evaluator (CASE IV, Stillwater, Minnesota, USA), with methods as described previously . Skin biopsy at the foot and thigh was performed to measure epidermal nerve fiber density, with methods as reported previously .
Subjective measures of pain intensity and objective measures of peripheral nerve function were correlated with plasma HIV-1 RNA levels. The statistical methods used were Fisher's Exact Test for comparison of proportions, and the Mann–Whitney Test (for two-sample comparisons) or the Kruskal–Wallis Test (for three-sample comparisons) for comparison of medians. Non-parametric (Spearman) correlations were estimated for the relationship between viral load and pain measures. All reported P values are two-tailed.
A total of 236 subjects participating in ACTG Protocol 291, and with baseline plasma HIV-1 RNA levels available, are included in the analysis. Subjects were predominantly Caucasian (87.3%) and male (97.9%). The mean age was 44 ± 8.6 years. The median CD4 cell count was 180 × 106 cells/l [95% confidence interval (CI), :12–694] and median HIV-1 RNA viral load was 3.35 log10/ml (95% CI, 1.70–5.80). VL was undetectable in 68 subjects (29%) and detectable in 168 (71%). VL did not differ according to age, race, or use of ddN (current use, recent use, or remote use;Table 1). As expected, subjects with low CD4 cell counts (< 100 × 106/l) had higher VL (P < 0.001). History of previous intravenous drug use was reported by 8.9% of subjects, and 38% were using opioid analgesics at study entry. Average pain score at baseline was 1.00 log10 (± 0.33 SD) on the Gracely scale, equivalent to a moderate degree of pain.
Plasma HIV-1 RNA and severity of pain
Patient assessment of mean, maximum and global pain at study entry in the total cohort demonstrated similar levels of median plasma HIV-1 RNA among those with less than moderate versus those with moderate or higher pain scores. As precise viral load values were not possible in the undetectable group, separate analyses were performed in subjects with detectable HIV-1 RNA. 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 (95% CI, 1.83–5.65 log10 copies/ml) compared to 4.51 log10 copies/ml (95% CI, 2.07–5.84 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.
Plasma HIV-1 RNA, antiretroviral drugs, and pain
Median plasma HIV-1 RNA was significantly lower among 203 subjects taking a protease inhibitor (PI)-containing regimen (3.15 log10 copies/ml; 95% CI, 1.70–5.77 log10 copies/ml), compared to the 25 subjects receiving only reverse transcriptase (RT) inhibitors (3.88 log10 copies/ml; 95% CI, 1.95–5.79 log10 copies/ml), and the eight subjects who were not receiving ARV drugs (4.58 log10 copies/ml; 95% CI, 3.89–5.88 log10 copies/ml;P = 0.017). Similarly, the percentage of patients with undetectable VL was greatest among those taking a PI (32%), compared to those on RT inhibitors only (12%), whereas all untreated subjects had detectable virus (P = 0.017). At baseline, 31% of subjects were taking d4T, 7% ddI, and 3% ddC. The corresponding previous users of d4T, ddI, and ddC, within 8–26 weeks prior to study entry, were 14%, 8%, and 4%, respectively. VL suppression did not differ significantly among those taking ddN compared to those not taking ddN (P = 0.556). Average and maximum pain levels did not differ between subjects who were or were not receiving ddN, with a median value of 1 log10 in both groups (P = 0.596 for average pain;P = 0.910 for maximum pain).
Plasma HIV-1 RNA and quantitative sensory testing
Quantitative sensory testing results in the total cohort revealed no relationship between plasma HIV-1 RNA levels and temperature or vibratory sensation in the upper and lower extremities (Table 3). Among subjects with detectable HIV-1 RNA, median VL was lower in 70 subjects with normal toe cooling thresholds (3.99 log10 copies/ml; 95% CI, 2.42–5.73 log10 copies/ml) than in 97 subjects with abnormal thresholds (4.67 log10 copies/ml; 95% CI, 1.86–5.85 log10 copies/ml;P = 0.033). There was no correlation between clinical perception of pin or temperature in the lower extremities and baseline plasma HIV-1 RNA levels either in the total cohort or in subjects with detectable HIV-1 RNA. There was a small but significant correlation between CD4 lymphocyte count and quantitative sensory tests (QST) percentile (PCT) results for toe cooling (r, −0.145;P = 0.028) and vibration (r, −0.189;P = 0.004). There was no correlation between CD4 cell count and pain or other QST measures. The association between epidermal fiber density and HIV-1 RNA will be reported separately.
Previous studies indicate that increased plasma HIV-1 viral load is associated with an increased risk of DSP  and abnormal sensory nerve function as measured by QST . 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 . Martin et al. reported that HIV virological suppression leads to improvement in quantitative thermal thresholds . 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 . 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.
The authors thank T. Baker Fann for expert technical assistance.
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Participating AIDS Clinical Trials Units, investigators and operational staff
Mount Sinai Center, NY, H. Sacks. A. Khan, P. Gerits; Johns Hopkins University, Baltimore, J. Bartlett, J. Maenza, K. Carter, R. Becker, V. Rexrod; Northwestern University, Evanston, B. Cohen, C. Cooper, R. Murphy, J. Phair; University of Kentucky Medical Center, Lexington, J.R. Berger, S. Ryan, A. Nath, R. Greenberg, S. Klenner, M. Ryan; University of Rochester, NY, R. Reichman, K. Kieburtz, M. Shoemaker; Massachusetts General Hospital and Harvard Medical School, Boston, B. Navia, M. Hirsch, E. McCarthy, T. Flynn; Stanford University, California, B. Adornato, D. Slamowitz, S. Valle, J. Norris; New York Presbyterian Hospital Cornell Campus, NY, M. Rubin, L. Ponticello, I. Zaprianova; University of North Carolina, Chapel Hill, C. Hall, C. Kapoor, C. Van der Horst, W. Robertson; University of California, Los Angeles, E. Singer, E. Miller, S.A. Chafey, R. Mitsuyasu; University of Texas, Gavelston, R. McKendall, R. Pollard; University of California, San Francisco, H. Hollander, M. Jacobson, R. Price, D. McGuire; Ohio State University, Columbus, M. Freimer, J. Mendell; Case Western Reserve University, Cleveland, M. Tucker, M. Lederman, R. McVey, A. Davidson; University of Washington, Seattle, C. Marra, D. Cummings, A.C. Collier; Washington University School of Medicine, St. Louis, D. Clifford, K. Gray, M. Glicksman, W. Powderly; Duke University, Durham, S. Hillman; Harvard School of Public Health, Boston, E. Caten; National Institute of Allergy and Infectious Diseases, B. Smith; AIDS Clinical Trials Group Operations, S. Shriver; Frontier Science and Technology Research Foundation, L. Millar; Genentech, Inc., C. Rask.