Peripheral neuropathy: new data on risk factors, incidence and association with viral load
Paul Blanchard, HIV i-Base
HIV-associated distal sensory neuropathy (DSP, also known as peripheral neuropathy) is a painful and disabling condition affecting as many as 35% of patients with AIDS.
Typical symptoms include pain, paresthesias (usually burning) and numbness usually affecting both feet and occasionally progressing to involve both hands. Neurological testing may reveal reduced or absent ankle tendon reflexes, decreased vibratory sensation in the feet and decreased pain and temperature sensation in a stoking distribution.
Peripheral nerve damage may occur during the process of HIV-infection itself, and also due to toxicities of some antiretrovirals and other drugs used to treat opportunistic infections. Such toxic neuropathies are clinically indistinquishable from HIV-associated DSP. The risk of DSP is known to increase with higher HIV-1 viral load, lower CD4 T-cell counts, advanced disease and increasing age. Antiretroviral therapy impacts some of these risk factors (viral load and CD4 count) and may, therefore, reduce the risk of DSP. Paradoxically, however, if such antiretrovirals are neurotoxic, they may reduce these risk factors yet increase the incidence or severity of DSP. The relationship between such risk factors as viral load and DSP, especially during antiretroviral treatment is therefore an important consideration, particularly if neurotoxic antiretrovirals are being administered. Two recent papers published on DSP help to throw some light on this relationship.
Schifitto and colleagues assessed the incidence of and risk factors for DSP in the Dana cohort of HIV-positive patients . This is a cohort of 272 patients recruited from three study sites in the pre-HAART era (1994 – 95). These subjects were followed for up to 2.5 years with semiannual neurologic, neuropsychological, functional and laboratory assessments. Entry into the cohort was for HIV-positive patients who reported memory or concentration problems, and had a CD4 count less than 200 cells/mL. Patients were also included with CD4 counts < 300 cells/mL if they had evidence of cognitive impairment on neuropsychological testing. It may be assumed, therefore, that these patients were probably at risk for neurologic complications. DSP was diagnosed if subjects had reduced or absent ankle reflexes, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. They were further classified as asymptomatic DSP (ADSP) if despite these findings they had no pain or paraesthesias, or symptomatic DSP (SDSP) if paraesthesias or pain were reported.
At study entry 45% of the subjects were not showing signs of DSP according to the study criteria. ADSP was found in 20%, and SDSP in 35%.
Of the 89 subjects who did not have DSP at study entry and had at least one follow-up visit, 64 (72%) went on to develop DSP. The one year estimated incidence of DSP in these patients being 52%. Of the 128 subjects who did not have SDSP at study entry and who had at least one follow-up visit, 64 (50%) went on to develop SDSP. The one year estimated incidence for the development of SDSP in these patients being 36%.
Baseline variables did not differ at baseline between those subjects with ADSP and those subjects with no DSP. However, SDSP patients tended to be older, had higher b2-microglobulin levels and were neurologically and functionally more impaired than both ADSP patients and no DSP patients.
Time to DSP (ADSP or SDSP) and its association with various risk factors was determined. Only a history of AIDS diagnoses (HR = 1.89) and log CD4 cell count (HR = 0.69) were significantly associated with time to DSP. When time to symptomatic DSP was considered separately significant associations with time to diagnosis was found for AIDS diagnoses (HR = 2.13) and physical function score >22 (HR = 2.95). Subcategories of the neurological examination and a depression scale rating were also significantly associated with the time to development of SDSP. Sex, DHEA levels, CD4 cell count, presence of ADSP and, interestingly, dideoxynucleoside use within six months of study entry were not significantly associated with time to SDSP. The strongest predictor of SDSP on multiple regression analysis was physical function score.
In conclusion this study determined the risk of development of DSP in a cohort of patients who were probably already at increased risk of neurological disease due to the study entry criteria. Asymtomatic DSP was shown to be a very common finding in this group with moderately advanced HIV infection. Interestingly, however, the presence of ADSP was not a significant predictor of later development of symptomatic DSP, suggesting that ADSP and SDSP may not be part of a continuum. Importantly, in this cohort, the use of dideoxynucleoside drugs with a potential for neurotoxicity did not significantly increase the risk for DSP, in fact the trend was actually for a decrease in DSP with the use of these antiretrovirals. This might suggest that the effect of dideoxynucleosides in reducing viral turnover and enhancing immune function (and thereby reducing risk for DSP) may outweigh their potential neurotoxicity in some patients. Further support for such a relationship comes from the second study on DSP which looked at severity of DSP and its relationship to plasma HIV-1 RNA levels.
David Simpson and colleagues performed a substudy analysis of the ACTG 291 study of recombinant nerve growth factor for the treatment of painful DSP . This analysis attempted to determine the complex relationship between viral load, symptoms and signs of DSP and antiretroviral treatment. ACTG 291 was a double blind placebo controlled trial with all subjects enrolled having a clinical diagnosis of DSP. 236 subjects from ACTG 291 with baseline HIV-1 RNA levels were included in this analysis. These patients had moderately advanced HIV-disease with median CD4 counts of 180 cells/mL and median viral load of 3.35 log copies/mL at entry. Average pain score at baseline was 1.00 log on the Gracely scale (indicating a moderate degree of pain).
As precise viral loads were not available in the undetectable patients, separate analyses were performed for those 168 subjects with detectable HIV-1 RNA. For these subjects there was a significant correlation between viral load and both Gracely scale maximum pain score and global pain self-assessment. Median viral load was also found to be lower in those subjects with normal toe cooling thresholds than in those with abnormal thresholds.
At study entry 41% of subjects were taking dideoxynucleosides. A further 26% had used dideoxynucleosides (ddN) within eight – 26 weeks prior to study entry. Viral load did not differ significantly between those taking ddN compared to those not taking ddN. Both average and maximum pain levels did not differ between those who were or were not taking ddN.
The group concludes that these data suggest a significant association between plasma HIV-1 RNA and the severity of neuropathy. They go on to comment that “…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.”
- Schifitto G, McDermott MP, McArthur JC et al. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Neurology 2002 Jun 25;58(12):1764-8.
- Simpson DM, Haidich AB, Schifitto G et al. Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levels. AIDS 2002 Feb 15;16(3):407-12.