Catherine L. Cherry

HIV-associated sensory neuropathies

Peripheral neuropathy has emerged as the most common neurological complication of HIV infection [1– 4]. There are several discrete types of HIV-associated neuropathy, which can be classified according to the timing of their appearance during HIV infection, their etiology and whether they are primarily axonal or demyelinating (Table 1). Some represent a consequence of HIV infection producing neuropathological damage [e.g., distal symmetrical polyneuropathy (DSP)], while others are related to opportunistic pathogens [e.g., cytomegalovirus (CMV) polyradiculitis]. An increasingly common group is that which occurs as a result of treatment toxicity [e.g., toxic neuropathy from antiretroviral drugs (TNA) and lactic acidosis syndrome].

Improvements in lipoatrophy, mitochondrial Dna levels and fat apoptosis after replacing stavudine with abacavir or zidovudine

Objective:To determine if stavudine (α4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase inhibitor. As apoptosis and dysfunction of electron transport chain (ETC) activities may underlie mitochondrial toxicity, these parameters were also evaluated. Design:The 16 participants (on d4T for >3 years; with lipoatrophy and/or hyperlactatemia) substituted abacavir or zidovudine for stavudine in their antiretroviral regimen. Key parameters including dual-energy X-ray absorptiometry (DEXA) scans, fat apoptosis, mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC), skeletal muscle and fat, as well as skeletal muscle mitochondrial ETC activities were evaluated at study entry and at 48 weeks after the substitution. Methods:Quantitative PCR was used to evaluate mtDNA levels and the presence of deletions/rearrangements; CLIA-validated methods for ETC activities; terminal deoxynucleotidyl transferase dUTP-digoxigenin nick-end labeling assays to evaluate adipocyte apoptosis; and DEXA scans to measure changes in body fat. Results:MtDNA was depleted at study entry in muscle, adipose tissue and PBMC but levels rebounded with respective mean increases of 141%, 146%, and 369% at week 48. Corresponding fat improvements were noted with DEXA increases of 21%, 11%, and 16% in arm, leg, and trunk, respectively. Quantitative adipocyte apoptosis were significantly increased at baseline (P < 0.01 versus HIV-negative controls), with a significant reduction at week 48 (P < 0.05 versus baseline). Mean values for seven mitochondrial enzyme activities assays at entry indicated substantial loss of function (48% to 85% of controls) with significant improvement of complex I activity by week 48. Conclusions:Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.

Pharmacological Treatment of Painful HIV-Associated Sensory Neuropathy: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Background Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects ∼40% of HIV infected individuals treated with antiretroviral therapy (ART). The prevalence of HIV-SN has increased despite the more widespread use of ART. With the global HIV prevalence estimated at 33 million, and with infected individuals gaining increased access to ART, painful HIV-SN represents a large and expanding world health problem. There is an urgent need to develop effective pain management strategies for this condition. Method and Findings Objective: To evaluate the clinical effectiveness of analgesics in treating painful HIV-SN. Design: Systematic review and meta-analysis. Data sources: Medline, Cochrane central register of controlled trials, www.clinicaltrials.gov, www.controlled-trials.com and the reference lists of retrieved articles. Selection criteria: Prospective, double-blinded, randomised controlled trials (RCTs) investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method. Review methods: Four authors assessed the eligibility of articles for inclusion. Agreement of inclusion was reached by consensus and arbitration. Two authors conducted data extraction and analysis. Dichotomous outcome measures (≥30% and ≥50% pain reduction) were sought from RCTs reporting interventions with statistically significant efficacies greater than placebo. These data were used to calculate RR and NNT values. Results Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4g/day), pregabalin (1200mg/day), prosaptide (16mg/day), peptide-T (6mg/day), acetyl-L-carnitine (1g/day), mexilitine (600mg/day), lamotrigine (600mg/day) and topical capsaicin (0.075% q.d.s.). Conclusions Evidence of efficacy exists only for capsaicin 8%, smoked cannabis and rhNGF. However,rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy. Evaluation of novel management strategies for painful HIV-SN is urgently needed.

A six-month, supervised, aerobic and resistance exercise program improves self-efficacy in people with human immunodeficiency virus: A randomised controlled trial

QUESTION What is the effect of a six-month, supervised, aerobic and resistance exercise program on self-efficacy in men living with human immunodeficiency virus (HIV)? DESIGN Randomised, controlled trial. PARTICIPANTS 40 (5 dropouts) men living with HIV, aged 18 years or older. INTERVENTION The experimental group participated in a twice-weekly supervised aerobic and resistance exercise program for six months and the control group participated in a twice-weekly unsupervised walking program and attended a monthly group forum. OUTCOME MEASURES The primary outcome measure was self-efficacy using the General Self-Efficacy Scale. Secondary outcome measures were cardiovascular fitness using the Kasch Pulse Recovery test, and health-related quality of life using the Medical Outcomes Study HIV Health Survey. Measures were taken by an assessor blinded to group allocation. RESULTS By six months, the experimental group had improved their self-efficacy by 6.8 points (95% CI 3.9 to 9.7, p < 0.001) and improved their cardiovascular fitness by reducing their heart rate by 20.2 bpm (95% CI -25.8 to -14.6, p < 0.001) more than the control group. Health-related quality of life improved in only two out of the eleven dimensions: the experimental group improved their overall health by 20.8 points (95% CI 2.0 to 39.7, p = 0.03) and their cognitive function by 14 points (95% CI 0.7 to 27.3, p = 0.04) more than the control group. CONCLUSION The findings of this study add to the known benefits of exercise for the HIV-infected population.

Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993–2006

The aim of the study was to describe the prevalence of and risk factors for HIV‐associated sensory neuropathy (HIV‐SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)‐sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre‐HAART) and 2001 (frequent use of dNRTI‐containing HAART).

Brain Cell Reservoirs of Latent Virus in Presymptomatic HIV-Infected Individuals

We detected HIV-1 DNA in pure populations of perivascular macrophages, parenchymal microglia, and astrocytes, isolated using laser microdissection from brain tissue of five untreated individuals who died in the presymptomatic stage of infection from non-HIV causes. HIV-1 DNA was detected in the three cell populations, most consistently in perivascular macrophages, without evidence of productive infection. The percentage of PCR reactions detecting HIV-1 DNA in perivascular macrophages correlated inversely with peripheral blood CD4 counts. These findings demonstrate that brain cell reservoirs of latent HIV-1 exist before pathological HIV encephalitis and suggest that perivascular macrophage trafficking of latent virus into the brain increases with immunosuppression.

Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort

Objective: To explore the association between specific nucleoside reverse transcriptase inhibitors and sensory neuropathies (SNs) and define the modifying roles of hepatitis C (HCV), vitamin B12 deficiency, and impaired glucose tolerance. Methods: The authors conducted a prospective cohort study of 147 HIV-infected adults at two sites chosen to emphasize demographic differences. Standardized assessments included detailed antiretroviral histories, neurologic examinations, skin biopsies for epidermal nerve quantitation, and quantitative sensory testing. Results: There were significant differences between subjects at Johns Hopkins University (JHU) and Monash University (MU) in gender, race, HIV transmission route, and HCV seroprevalence. Symptomatic SN was present in 49% at JHU and 55% at MU (χ2 = 4.02, p = 0.134) and was significantly more common in those at least age 40 than younger patients (odds ratio [OR] = 2.87, 95% CI = 1.27, 6.49). After adjusting for site, age, and CD4 cell count, exposure to didanosine (ddI) or stavudine (d4T) was associated with an significantly increased likelihood of symptomatic SN (ddI: OR = 3.21, 95% CI: 1.56, 6.60; d4T: OR = 7.66, 95% CI: 2.89, 20.33). Plasma HIV RNA, lactate, and HCV were not associated with SN. Quantitative vibratory testing identified neuropathy with a positive predictive value of 76% and epidermal nerve fiber densities 59%. Conclusions: Exposure to stavudine and didanosine was significantly associated with a heightened risk for symptomatic sensory neuropathy. Reduced vibration thresholds and epidermal nerve fiber densities had the highest diagnostic efficiency of the laboratory indicators of neuropathy examined, but were relatively insensitive in isolation.

Evaluation of a clinical screening tool for HIV-associated sensory neuropathies

Objective: To evaluate the performance characteristics of a brief clinical neuropathy screening tool for use in sensory neuropathies complicating HIV infection. Methods: The authors assessed 80 patients using the Brief Peripheral Neuropathy Screen (BPNS). Patients were defined as having neuropathy if they had both symptoms and signs consistent with this diagnosis. All subjects underwent sensory threshold testing and lower limb epidermal nerve fiber quantification using punch skin biopsy as objective measures. Results: Individuals defined as having neuropathy using the BPNS (n = 37) performed less well on sensory threshold testing than other HIV-infected individuals (p < 0.0001 for warming, cooling, and vibration) and also had lower distal calf epidermal nerve fiber densities (p < 0.0001). Individuals who had symptoms but no neuropathic signs (n = 13) did not perform differently on any objective testing compared with neuropathy-free individuals, supporting the decision to require signs as well as symptoms as an operational criterion for the diagnosis of neuropathy. Of the symptoms listed in the screening tool, the presence of numbness had the greatest diagnostic efficiency for identifying those with neuropathy. Conclusion: The Brief Neuropathy Screening Tool (and the chosen definition of neuropathy) accurately detects those HIV-infected individuals with the greatest degree of peripheral nerve dysfunction and pathology. This is a valid neuropathy screening tool for use in the context of HIV infection, and is simple enough to be applicable in resource-limited settings.

Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat.

Objectives: Nucleoside reverse transcriptase inhibitors (NRTIs), particularly dideoxynucleoside analogs (ddNs), used in the treatment of HIV, inhibit mitochondrial DNA polymerase &ggr; in vitro. Mitochondrial DNA (mtDNA) depletion is proposed as the underlying mechanism of many of the in vivo side effects of these agents. A reliable and valid laboratory test to detect this is not yet available. The objective of this study was to correlate tissue mtDNA quantification in HIV‐infected patients with exposure to nucleoside analogs. Methods: 60 HIV‐infected adults underwent detailed clinical assessment and blood and tissue sampling. Clinical and antiretroviral treatment details were correlated with results of plasma lactate assays, and real‐time polymerase chain reaction quantification of mtDNA in peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from the lower limb. Results: Forty‐nine (82%) subjects were on combination antiretroviral therapy. Of these, 33 (55%) were currently receiving one or more ddNs (stavudine, didanosine, or zalcitabine). mtDNA in subcutaneous fat was lower in subjects currently on ddNs than in those not taking ddNs (mean [log10] 2.47 vs. 2.74, p = .002). Plasma lactate was somewhat higher in subjects currently taking ddNs than those on no antiretroviral treatment (median 1.5 vs. 1.0, p = .03), but was not significantly different in either of these groups compared with subjects on other NRTIs. mtDNA in PBMCs did not vary with treatment status. Conclusions: mtDNA in subcutaneous fat was significantly reduced in patients currently taking ddNs. mtDNA in PBMCs was independent of patient exposure to NRTIs.

Nucleoside analogues and neuropathy in the era of HAART

BACKGROUND Sensory neuropathies occur commonly in the setting of HIV infection. Sensory neuropathy (SN) is clearly associated with HIV itself, and in this context develops in association with increased macrophage activation in the peripheral nervous system. A clinically identical SN may also occur as a consequence of exposure to some HIV treatments. In this setting, impaired mitochondrial function is thought to play a role in the development of neurological dysfunction. OBJECTIVE This review explores the evidence for the neurotoxicity of HIV and HIV treatments, the effect of nucleoside reverse transcriptase inhibitors on mitochondria, and the likely associations between these. CONCLUSIONS Dideoxynucleotide drugs are commonly associated with SN. The nucleoside reverse transcriptase inhibitors inhibit mitochondrial DNA synthesis and may thus exacerbate existing viral-induced nerve damage.