Antonia L. Wadley

HIV Neuropathy Risk Factors and Symptom Characterization in Stavudine-Exposed South Africans

CONTEXT HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of both HIV and neurotoxic antiretroviral medications such as stavudine. OBJECTIVES To determine the prevalence, risk factors, and clinical characteristics of symptomatic HIV-SN in a Black South African cohort of patients exposed to stavudine. METHODS HIV-positive Black South Africans (n=395) who had received stavudine for at least six months were recruited at the Virology Clinic of the Charlotte Maxeke Academic Johannesburg Hospital, South Africa, and screened for neuropathy using the AIDS Clinical Trials Group neuropathy screening tool. HIV-SN was defined as present if the patient had both symptoms and signs of peripheral neuropathy. If present, the distribution and intensity of symptoms were recorded. In addition, anthropomorphic, demographic, and clinical information were recorded and analyzed as risk factors. RESULTS The prevalence of symptomatic HIV-SN was 57% (226 of 395). Increasing age and height were independently associated with the development of SN among patients who had used stavudine. Pain was the primary symptom reported by participants with HIV-SN (76%, 172 of 226), followed by numbness (48%, 108 of 226), and pins and needles (46%, 105 of 226). About three-quarters of participants rated their symptoms as being of moderate to severe intensity. Symptoms were always present in the feet and only 23% experienced symptoms proximal to the feet. CONCLUSION HIV-SN was common in this population and frequently associated with moderate to severe pain in the feet. HIV-SN was significantly associated with increasing age and height, factors that could be measured at no added cost prior to stavudine prescription, allowing higher risk patients to be offered priority access to nonneurotoxic drugs.

HIV-Associated Sensory Neuropathy: Risk Factors and Genetics

HIV-associated sensory neuropathy (HIV-SN) remains a common neurological complication of HIV infection despite the introduction of effective antiretroviral therapies. Exposure to neurotoxic antiretroviral drugs and increasing age have consistently been identified as risk factors for HIV-SN, while comorbid conditions with underlying predisposition to cause peripheral neuropathy (eg, diabetes mellitus, malnutrition, isoniazid exposure), ethnicity, and increasing height also have been implicated. Genetic association studies have identified genes affecting mitochondrial function and genes involved in the inflammatory response that modify the risk for HIV-SN among patients exposed to neurotoxic antiretrovirals. However, there is a lack of data on clinical, demographic, and genetic risk factors for HIV-SN in the modern era, with the rate of HIV-SN remaining unacceptably high despite the introduction of safer medications. Thus, more work is required to identify the principal factors that increase an individual’s risk for HIV-SN so that effective preventative or therapeutic strategies can be implemented.

Hepatitis C seropositivity is not a risk factor for sensory neuropathy among patients with HIV

Background: Sensory neuropathy (SN) is common in patients with HIV. Hepatitis C (HCV) coinfection is often cited as an HIV-SN risk factor, but data to support this are lacking. This collaboration aimed to examine the association between HCV serostatus and SN risk among ambulatory HIV-positive patients. Methods: Patients with HIV were assessed in cross-sectional studies in Baltimore, Jakarta, Johannesburg, Kuala Lumpur, Melbourne, and Sydney for SN (defined by both supportive symptoms and signs). HCV seropositivity was assessed as an SN risk using a χ2 test, followed by logistic regression modeling to correct for treatment exposures and demographics. Results: A total of 837 patients of African, Asian, and Caucasian descent were studied. HCV seroprevalence varied by site (Baltimore n = 104, 61% HCV+; Jakarta 96, 51%; Johannesburg 300, 1%; Kuala Lumpur 97, 10%; Melbourne 206, 16%; Sydney 34, 18%). HCV seropositivity was not associated with increased SN risk at any site, but was associated with reduced SN risk in Melbourne (p = 0.003). On multivariate analyses, the independent associations with SN were increasing age, height, and stavudine exposure. HCV seropositivity was not independently associated with an increased SN risk at any site, but associated independently with reduced SN risk in Baltimore (p = 0.04) and Melbourne (p = 0.06). Conclusions: Hepatitis C (HCV) seropositivity was not associated with increased sensory neuropathy risk among HIV-positive patients at any site. While we were unable to assess HCV RNA or liver damage, the data suggest that HCV coinfection is not a major contributor to HIV-SN. HCV = hepatitis C; SN = sensory neuropathy.

KCNS1, but not GCH1, is associated with pain intensity in a black southern African population with HIV-associated sensory neuropathy: a genetic association study.

Abstract:KCNS1 and GCH1 were investigated for their association with pain intensity in black Southern Africans with HIV-associated sensory neuropathy. Previously associated single nucleotide polymorphisms (SNPs) were supplemented with population-specific tagSNPs. No SNPs in KCNS1 were individually associated with pain intensity. However, several haplotypes of population-specific tagSNPs correlated with pain intensity on univariate analysis and after correcting for age, gender, and CD4 T-cell count. This suggests that the haplotypes incorporate the causative SNP(s). No SNPs or haplotypes in GCH1 were associated with pain intensity. The study shows the importance of conducting association analyses in different ethnic groups, using population-based marker selection.

World Health Organization essential medicines lists: where are the drugs to treat neuropathic pain?

Neuropathic pain is a priority health issue [5], which currently is the topic of the 2014–2015 Global Year Against Neuropathic Pain campaign of the International Association for the Study of Pain (http://www.iasp-pain.org/GlobalYear/NeuropathicPain). Between 6% and 10% of adults are affected by chronic pain with neuropathic features [6,14,25], and this prevalence is significantly greater among individuals with specific conditions. For example, neuropathic pain is a common comorbidity in infectious diseases such as HIV, leprosy, and herpes zoster, and in non-infectious conditions such as diabetes mellitus, stroke, multiple sclerosis, and traumatic limb and spinal cord injury [7,13,16,19,21]. The pain is associated with significant decreases in quality of life and socioeconomic well-being, even more so than non-neuropathic chronic pain [9,20,22]. Developing and emerging countries share the greatest burden of conditions that predispose to development of neuropathic pain [5,10], and can ill afford the negative consequences of this pain. There are medicines with proven efficacy in the treatment of neuropathic pain [11,12]. Nevertheless, the pain can be difficult to treat, with significant inter-individual variation in efficacy within and between drug classes, independent of the presumed aetiology of the neuropathy [2,4]. Effective management of neuropathic pain within a population therefore requires access to a small, but crucial group of drug classes with proven efficacy. The World Health Organization’s (WHO) model list of essential medicines (http://www.who.int/selection_medicines/list/en/) presents those medicines deemed necessary to meet priority health needs, and local implementation of essential medicines policies is associated with improved quality use of medicines [15,18]. But, none of the analgesic medicines included in the WHO model list are recommended as first-line treatments for neuropathic pain [11]. Thus the WHO model list is not a good framework from which national policies on managing neuropathic pain can be structured and countries routinely adapt the model list according to local needs and resources [18]. To estimate the nominal availability of medicines recommended for the treatment of neuropathic pain in developing and emerging countries, we assessed national essential medicines lists (NEMLs) for the inclusion of recommended treatments. We also assessed whether the coverage of recommended drugs classes on these NEMLs was dependent on countries’ economic status.

Analysis of a previously identified "pain-protective" haplotype and individual polymorphisms in the GCH1 gene in Africans with HIV-associated sensory neuropathy: a genetic association study.

Abstract:We analyzed GTP cyclohydrolase 1 in symptomatic HIV-associated sensory neuropathy in Southern Africans including a “pain-protective” 3-SNP haplotype and 6 SNPs, analyzed individually and in a 6-SNP haplotype. The “pain-protective” 3-SNP haplotype and a 6-SNP haplotype containing these alleles associated with a reduced risk of pain. Another 3-SNP haplotype associated with increased presence of pain. Associations were lost after correction for age, gender, and CD4 T-cell count. Linkage disequilibrium differed between our cohort and Caucasians suggesting that these SNPs may not be ideal markers in Africans. Subsequently, the role of GTP cyclohydrolase 1 in painful HIV-associated sensory neuropathy remains possible.

Role of TNF block genetic variants in HIV-associated sensory neuropathy in black Southern Africans

HIV-associated sensory neuropathy (HIV-SN) is a common neurological complication of HIV infection. The TNF block is a region within the central MHC that contains many immunoregulatory genes. Polymorphisms and haplotypes of the TNF block have been associated with increased risk of HIV-SN in Asians and whites. Here we investigated genetic associations with HIV-SN in 342 black Southern Africans (190 cases and 152 neuropathy-free controls) using single nucleotide polymorphisms (SNPs) spanning the TNF block and a set of haplotypes defined by 31 SNPs in Asian and white populations (denoted FVa). We included population-appropriate tagSNPs derived from an African population (Yoruban, YRI, HapMap) and derived extended haplotypes comprising 61 SNPs (denoted FVa_ext b). We found no association between HIV-SN and carriage of two SNPs (TNF-1031/rs1799964*C and BAT1 (intron10)/rs9281523*C) associated with HIV-SN in whites and Asians. Additionally, a haplotype containing TNF-1031/rs1799964*C associated with increased risk of HIV-SN in Asians, but was not present in this African population. However, alleles of seven SNPs associated with reduced risk of HIV-SN (corrected for age, height and multiple comparisons). These were rs11796*A, rs3130059*G, rs2071594*C, NFKBIL1-62/rs2071592*A, rs2071591*A, LTA+252/rs909253*G, rs1041981*C. One haplotype (FV18_ext1), not containing these alleles, was associated with increased risk of HIV-SN after correction for age, height and multiple comparisons. Our results confirm the involvement of genes in the TNF block in altering risk for HIV-SN, but genotypes critical in this African population differed from those affecting HIV-SN in whites and Asians. These differences support the need for genetic association studies in diverse populations.

A polymorphism in IL4 may associate with sensory neuropathy in African HIV patients

INTRODUCTION Animal and in vitro models of HIV-associated sensory neuropathy suggest an inflammatory etiology. Previous genetic association studies of HIV-SN have been in small Caucasian or Asian cohorts. We assessed cytokine single nucleotide polymorphisms (SNPs) in a Black Southern African cohort. METHOD 342 black HIV-positive Southern Africans were recruited. 190 individuals had HIV-associated sensory neuropathy and 152 did not. DNA samples from all participants were genotyped for cytokine SNPs identified in studies of HIV disease and/or neuropathy. RESULTS IL4-590*T associated with an increased prevalence of HIV-SN including following correction for age, height and CD4 T-cell count. No other cytokine SNPs assessed displayed an association. DISCUSSION We identified a novel association between IL4-590*T and HIV-SN in African HIV-positive patients which warrants further investigation.

Polymorphisms in CAMKK2 may predict sensory neuropathy in African HIV patients

HIV-associated sensory neuropathy (HIV-SN) is the most common neurological condition associated with HIV. HIV-SN has characteristics of an inflammatory pathology caused by the virus itself and/or by antiretroviral treatment (ART). Here, we assess the impact of single-nucleotide polymorphisms (SNPs) in a cluster of three genes that affect inflammation and neuronal repair: P2X7R, P2X4R and CAMKK2. HIV-SN status was assessed using the Brief Peripheral Neuropathy Screening tool, with SN defined by bilateral symptoms and signs. Forty-five SNPs in P2X7R, P2X4R and CAMKK2 were genotyped using TaqMan fluorescent probes, in DNA samples from 153 HIV+ black Southern African patients exposed to stavudine. Haplotypes were derived using the fastPHASE algorithm, and SNP genotypes and haplotypes associated with HIV-SN were identified. Optimal logistic regression models included demographics (age and height), with SNPs (model p < 0.0001; R2 = 0.19) or haplotypes (model p < 0.0001; R2 = 0.18, n = 137 excluding patients carrying CAMKK2 haplotypes perfectly associated with SN). Overall, CAMKK2 exhibited the strongest associations with HIV-SN, with two SNPs and six haplotypes predicting SN status in black Southern Africans. This gene warrants further study.

Resilience does not explain the dissociation between chronic pain and physical activity in South Africans living with HIV

Pain burden is high in people living with HIV (PLWH), but the effect of this pain on functionality is equivocal. Resilience, the ability to cope with adversity, may promote adaptation to pain, so we hypothesised that higher resilience would correlate with less pain-related impairment of activity. We recruited 197 black South African PLWH, 99 with chronic pain (CP) and 98 patients without. We measured pain intensity and interference using the Brief Pain Inventory, and resilience using the Resilience Scale. Participants were generally highly resilient. Greater resilience correlated with better health-related quality of life, but not with pain intensity or interference. We also measured physical activity objectively, by actigraphy, in a subset of patients (37 with chronic pain and 31 without chronic pain), who wore accelerometers for two weeks. There was no difference in duration or intensity of activity between those with and without pain, and activity was not associated with resilience. In this sample, pain was not associated with altered physical activity. Resilience did not explain differences in pain intensity or pain interference but was associated with improved quality of life. Financial stresses and the fear of HIV stigma may have driven patients to conceal pain and to suppress its expected impairment of activity.