Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.

HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning TNF and seven neighboring genes (the TNF-block) in Indonesians (n = 202; 34/168 cases) and South Africans (n = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of BAT1 (alternatively DDX39B) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and >500 copies of HIV RNA/mL (model p = 0.0011, Pseudo R2 = 0.09). rs4947324*T (between NFKBIL1 and LTA) independently associated with reduced risk of HIV-SN and shared haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: p = 0.0003, Pseudo R2 = 0.22). These results confirm TNF-block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use.

Neurotoxic antiretroviral therapy (ART) such as stavudine has been now replaced with safer therapies, reducing the prevalence of neuropathy from 34% to 15% in HIV+ Indonesians. However, it is unclear whether the residual cases display damage to small or large nerve fibers and whether both are influenced by known risk factors, including alleles of CAMKK2 associated with neuropathy in HIV patients. The encoded protein influences the growth and repair of nerve fibers. HIV-positive adults on ART for >12 months without exposure to stavudine were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen (BPNS). Large fiber neuropathy was assessed by nerve conduction (NC) and small fiber neuropathy using stimulated skin wrinkling (SSW) applied to the fingers. CAMKK2 alleles were assessed by TaqMan OpenArray technology. Neuropathy diagnoses were more common with SSW than BPNS (49/173 vs 26/185, χ; P = 0.0009), with poor alignment between these outcomes (P = 0.60). NC and BPNS diagnosed neuropathy at similar frequencies (29/151 vs 26/185; P = 0.12) and were aligned (P < 0.0001). In bivariate analyses, all diagnoses were associated with patients' age and persistent HIV replication, with minor effects from CD4 T-cell counts and time on ART. CAMKK2 alleles associated with neuropathy diagnosed with BPNS and SSW but not NC. Multivariable analyses confirmed the importance of age and HIV replication, with distinct CAMKK2 polymorphisms affecting BPNS and SSW. Paradoxically, height was protective against skin wrinkling. Overall the data link CAMKK2 genotypes with small rather than large fiber damage. SSW may reflect pathology distinct from that identified using BPNS.

Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) is a common neurological complication of HIV infection. It affected 57% of South African patients whose antiretroviral therapy (ART) included stavudine and was influenced by genotypes of the P2X-block (P2X7R, P2X4R and CAMKK2). We investigate associations between HIV-SN and P2X-block genotypes in patients who never received stavudine. An adjacent gene, ANAPC5, was included. 75 HIV+ individuals were assessed using the Brief Peripheral Neuropathy Screen before treatment and after 6-8 months on stavudine-free regimens. DNA was genotyped for 48 polymorphisms across the four genes using an OpenArray™ platform. Haplotypes were derived using fastPHASE. Associations with HIV-SN were assessed using bivariate and multivariate analyses. Nine individuals (12%) were diagnosed with HIV-SN prior to ART and a further 20 individuals (27%) developed HIV-SN within 6-8 months. Five polymorphisms, rs503720*G (OR = 133) in P2X7R, rs10849861*A (OR = 5.99), rs1653586*T (OR = 67.8) and rs11065504*C (OR = 0.02) in CAMKK2, and rs2089886*A (OR = 6.68) in ANAPC5, associated with HIV-SN after adjusting for body weight, nadir CD4 T-cell counts and prior tuberculosis (model p < 0.0001, n = 69, Pseudo R2 = 0.54). Three CAMKK2 haplotypes were associated with HIV-SN (OR = 2.82, 3.42 and 6.85) after adjusting for body weight, nadir CD4 T-cell counts and prior tuberculosis (model p < 0.0005, n = 71, Pseudo R2 = 0.26). The results support a role for CAMKK2 in HIV-SN, independent of mechanisms invoked by stavudine. SIGNIFICANCE STATEMENT: HIV-associated sensory neuropathy (HIV-SN) remains a clinically relevant complication of HIV infection and its treatment, affecting 38% of patients treated without neurotoxic stavudine. HIV-SN can impact an individual's ability to work and quality of life, with few effective therapeutic options, so an understanding of the underlying mechanisms would have clinical value. We confirm that CAMKK2 polymorphisms and haplotypes influence susceptibility to HIV-SN in South Africans treated without stavudine. This provides further evidence for a role for the protein encoded by CAMKK2 in the pathogenesis of HIV-SN, independent of mechanisms initiated by stavudine.

HIV-associated sensory neuropathy (HIV-SN) is a common and often painful neurological condition associated with HIV-infection and its treatment. However, data on the incidence of HIV-SN in neuropathy-free individuals initiating combination antiretroviral therapies (cART) that do not contain the neurotoxic agent stavudine are lacking. We investigated the six-month incidence of HIV-SN in ART naïve individuals initiating tenofovir (TDF)-based cART, and the clinical factors associated with the development of HIV-SN. 120 neuropathy-free and ART naïve individuals initiating cART at a single centre in Johannesburg, South Africa were enrolled. Participants were screened for HIV-SN at study enrolment and then approximately every two-months for a period of approximately six-months. Symptomatic HIV-SN was defined by the presence of at least one symptom (pain/burning, numbness, paraesthesias) and at least two clinical signs (reduced vibration sense, absent ankle reflexes or pin-prick hypoaesthesia). Asymptomatic HIV-SN required at least two clinical signs only. A total of 88% of the cohort completed three visits within the six-month period. Eleven individuals developed asymptomatic HIV-SN and nine developed symptomatic HIV-SN, giving a six-month cumulative incidence of neuropathy of 140 cases per 1000 patients (95% CI: 80 - 210) at an incidence rate of 0.37 (95% CI: 0.2 - 0.5) per person year. Increasing height and active tuberculosis (TB) disease were independently associated with the risk of developing HIV-SN (p < 0.05). We found that within the first six months of starting cART, incident SN persists in the post-stavudine era, but may be asymptomatic.

HIV-associated sensory neuropathy (HIV-SN) is a debilitating neurological complication of HIV infection potentiated by the antiretroviral drug stavudine. While stavudine is no longer used, HIV-SN now affects around 15% of HIV+ Indonesians. Here, we investigate whether polymorphisms within the P2X-block (P2X4R, P2X7R, CAMKK2) and/or ANAPC5 mark susceptibility to HIV-SN in this setting. As polymorphisms in these genes associated with HIV-SN in African HIV patients receiving stavudine, the comparison can identify mechanisms independent of stavudine. HIV patients who had never used stavudine (n = 202) attending clinics in Jakarta were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Open-array technology was used to type 48 polymorphisms spanning the four genes. Haplotypes were derived for each gene using fastPHASE. Haplogroups were constructed with median-joining methods. Multivariable models optimally predicting HIV-SN were based on factors achieving p < 0.2 in bivariate analyses. Minor alleles of three co-inherited polymorphisms in CAMKK2 (rs7975295*C, rs1560568*A, rs1132780*T) associated with a reduced prevalence of HIV-SN individually and after adjusting for lower CD4 T cell count and viremia (p = 0.0002, pseudo R2 = 0.11). The optimal model for haplotypes linked HIV-SN with viremia and lower current CD4 T cell count, plus CAMKK2 haplotypes 6 and 11 and P2X7R haplotypes 2 and 12 (p = 0.0002; pseudo R2 = 0.11). CAMKK2 haplogroup A (includes 16 haplotypes and all instances of rs7975295*C, rs1560568*A, rs1132780*T) associated with reduced rates of HIV-SN (p = 0.02, OR = 0.43 CI = 0.21–0.88). These findings support a protective role for these three alleles, suggesting a role in the pathogenesis of HIV-SN that is independent of stavudine.

Sensory neuropathy (SN) is a common and often painful neurological condition associated with HIV‐infection and its treatment. However, data on the incidence of SN in neuropathy‐free individuals initiating combination antiretroviral therapies (cART) that do not contain the neurotoxic agent stavudine are lacking.

This paper describes the people, activities and methods of consumer engagement in a complex research project, and reflects on the influence this had on the research and people involved, and enablers and challenges of engagement. The 2.5-year Integrating and Deriving Evidence Experiences and Preferences (IN-DEEP) study was conducted to develop online consumer summaries of multiple sclerosis (MS) treatment evidence in partnership with a three-member consumer advisory group. Engagement methods included 6-monthly face-to-face meetings and email contact. Advisory group members were active in planning, conduct and dissemination and translational phases of the research. Engaging consumers in this way improved the quality of the research process and outputs by: being more responsive to, and reflective of, the experiences of Australians with MS; expanding the research reach and depth; and improving the researchers' capacity to manage study challenges. Advisory group members found contributing their expertise to MS research satisfying and empowering, whereas researchers gained confidence in the research direction. Managing the unpredictability of MS was a substantive challenge; the key enabler was the 'brokering role' of the researcher based at an MS organisation. Meaningfully engaging consumers with a range of skills, experiences and networks can make important and unforeseen contributions to research success.

Objective: HIV-associated sensory neuropathy (HIV-SN) remains common in HIV+ individuals receiving antiretroviral therapy (ART), even though neurotoxic antiretroviral drugs (e.g. stavudine) have been phased out of use. Accumulating evidence indicates that the neuropathy is immune-mediated. We hypothesize that chemokines produced locally in the skin promote migration of macrophages and T cells into the tissue, damaging cutaneous nerves causing HIV-SN. Design: We assessed chemokine receptor expression on infiltrating CD14(+) and CD3(+) cells around cutaneous nerves in standardized skin biopsies from HIV-SN+ patients (n = 5), HIV-SN- patients (n = 9) and healthy controls (n = 4). Methods: The AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen was used to assess Indonesian HIV+ patients receiving ART without stavudine (case definition: bilateral presence of at least one symptom and at least one sign of neuropathy). Distal leg skin biopsies were stained to visualize chemokine receptors (CCR2, CCR5, CXCR3, CXCR4, CX3CR1), infiltrating CD3(+) and CD14(+) cells, and protein-gene-product 9.5 on nerves, using immunohistochemistry and 4-colour confocal microscopy. Results: Intraepidermal nerve fibre density was variable in patients without HIV-SN and generally lower in those with HIV-SN. CX3CR1 was more evident on CD14(+) cells whereas CCR2, CCR5, CXCR3 and CXCR4 were more common on CD3(+) cells. Expression of CX3CR1, CCR2 and CCR5 was more common in HIV-SN+ patients than those without HIV-SN. CXCR3 and CXCR4 were upregulated in all HIV+ patients, compared with healthy controls. Conclusion: Inflammatory macrophages expressing CX3CR1 and T cells expressing CCR2 and CCR5 may participate in peripheral nerve damage leading to HIV-SN in HIV+ patients treated without stavudine. Further characterization of these cells is warranted. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.

HIV-associated sensory neuropathy (HIV-SN) is a common, and frequently painful complication of HIV, but factors that determine the presence of pain are unresolved. We investigated: (i) if psychological factors associated with painful (n = 125) versus non-painful HIV-SN (n = 72), and (ii) if pain and psychological factors affected quality of life (QoL). We assessed anxiety and depression using the Hopkins Symptoms Checklist-25. Pain catastrophizing and QoL were assessed using the Pain Catastrophizing Scale and Euroqol-5D, respectively. Presence of neuropathy was detected using the Brief Neuropathy Screening Tool, and pain was characterised using the Wisconsin Brief Pain Questionnaire. Overall, there was a high burden of pain, depression and anxiety in the cohort. None of the psychological variables associated with having painful HIV-SN. Greater depressive symptoms and presence of pain were independently associated with lower QoL. In those participants with painful HIV-SN, greater depressive symptom scores were associated with increased pain intensity. In conclusion, in a cohort with high background levels of psychological dysfunction, psychological factors do not predict the presence of pain, but both depression and presence of pain are associated with poor quality of life.

Untreated HIV infection is associated with progressive CD4+ T cell depletion, which is generally recovered with combination antiretroviral therapy (cART). However, a significant proportion of cART-treated individuals have poor CD4+ T cell reconstitution. We investigated associations between HIV disease progression and CD4+ T cell glucose transporter-1 (Glut1) expression. We also investigated the association between these variables and specific single nucleotide polymorphisms (SNPs) within the Glut1 regulatory gene AKT (rs1130214, rs2494732, rs1130233, and rs3730358) and in the Glut1-expressing gene SLC2A1 (rs1385129 and rs841853) and antisense RNA 1 region SLC2A1-AS1 (rs710218). High CD4+Glut1+ T cell percentage is associated with rapid CD4+ T cell decline in HIV-positive treatment-naïve individuals and poor T cell recovery in HIV-positive individuals on cART. Evidence suggests that poor CD4+ T cell recovery in treated HIV-positive individuals is linked to the homozygous genotype (GG) associated with SLC2A1 SNP rs1385129 when compared to those with a recessive allele (GA/AA) (odds ratio = 4.67; P = 0.04). Furthermore, poor response to therapy is less likely among Australian participants when compared against American participants (odds ratio: 0.12; P = 0.01) despite there being no difference in prevalence of a specific genotype for any of the SNPs analyzed between nationalities. Finally, CD4+Glut1+ T cell percentage is elevated among those with a homozygous dominant genotype for SNPs rs1385129 (GG) and rs710218 (AA) when compared to those with a recessive allele (GA/AA and AT/TT respectively) (P < 0.04). The heterozygous genotype associated with AKT SNP 1130214 (GT) had a higher CD4+Glut1+ T cell percentage when compared to the dominant homozygous genotype (GG) (P = 0.0068). The frequency of circulating CD4+Glut1+ T cells and the rs1385129 SLC2A1 SNP may predict the rate of HIV disease progression and CD4+ T cell recovery in untreated and treated infection, respectively.

Background and Aims: In earlier work, we identified that people affected by multiple sclerosis (MS) can have difficulty finding online treatment information that is up to date, trustworthy. understandable, and applicable to personal circumstances, but does not provoke confusion or negative emotional consequences. The objective was to develop online consumer summaries of MS treatment evidence (derived from Cochrane Reviews) that respond to identified treatment information needs of people affected by MS. Methods: A 2-phase mixed-methods project, conducted in partnership with consumers and an MS organisation. Phase 1 included review panels with consumers (Australians affected by MS) and health professionals to test paper-based treatment summaries before development, and pilot testing of the website. Phase 2 involved an online survey after website launch. Results: Eighty-three participants (85% affected by MS) took part. Phase 1 participants strongly endorsed key review summary components, including layering information, and additional sections to aid personal applicability. Participants additionally suggested questions for health professionals. Participants across both phases were receptive to the idea of being provided with Cochrane Review summaries online but were seeking other types of evidence and information, such as personal experiences and the latest experimental treatments, which could not be provided. While the small survey sample size (n = 58) limits application of the results to a broader population, the website was viewed favourably. as a useful, understandable, and trustworthy information source. Conclusion: We describe a partnership approach to developing online evidence-based treatment information, underpinned by an in-depth understanding of consumers' information needs.

To the Editors: INTRODUCTION Antiretroviral therapy (ART) reduces morbidity and increases life expectancy among people living with HIV, but some patients still experience symptoms, including sensory neuropathy (HIV-SN). Neuropathies resulting from HIV infection itself and toxic side effects of ART have similar presentations and include neuropathic pain, tingling, and numbness.1–3 Neuropathy was the dose-limiting toxicity in early trials of some of the nucleoside analogue reverse transcriptase inhibitors used to treat HIV: zalcitabine (ddC), didanosine (ddI), and stavudine (d4T). Hence, rates of HIV-SN rose when these drugs entered clinical use and exposure to ART emerged as a neuropathy risk factor. Stavudine was used in first-line ART until well into the 21st century, especially in resource-limited countries. The prevalence of HIV-SN in patients receiving stavudine at Cipto Mangunkusumo Hospital, Jakarta, Indonesia, in 2006 was 34%. In this cohort, the observed associations with HIV-SN among stavudine-treated patients were increasing age and height.4,5 In black South African patients with HIV exposed to stavudine, identical assessment methods revealed an HIV-SN prevalence of 57%.6 Again, age and height were the observed associations with HIV-SN. The association between increasing age and HIV-SN was evident in a large US-based cohort study, where the prevalence of HIV-SN increased with age and time on ART despite a decline in the use of neurotoxic ART.7 The use of stavudine declined as alternative treatments became available. However, some patients with HIV still complain of burning and tingling sensations in their legs and arms—likely symptoms of HIV-SN. Here, we describe the prevalence of HIV-SN in an Indonesian population receiving ART without stavudine. We also examined associations with HIV-SN in this setting. The populations served by our clinic are similar to 2006, and the HIV-SN assessment methods were identical to the previous study.4 Since 2014, health care for all Indonesians has been covered by government insurance. With more people aware of health issues and seeking treatment, numbers of patients in the clinics have increased. METHODS HIV-positive adults who had used ART for at least 12 months but who had never been exposed to stavudine were screened for neuropathy at POKDISUS HIV Care Clinic, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Patients with any history of another condition that might be associated with a neuropathy, or any condition preventing the patient from being able to provide informed consent, were excluded. Neuropathy was assessed using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen (ACTG-BPNS) and defined as present if the individual had one or more of the lower-limb neuropathic symptoms (pain, aching or burning, pins and needles, or numbness), plus absent ankle reflexes or reduced vibration sense at the great toe (vibration of a 128-Hz tuning fork felt for 10 seconds or less). We did not diagnose neuropathy in patients with only asymptomatic neuropathic signs, as the presence of both symptoms and signs on the ACTG-BPNS tool better associated with impaired peripheral nerve function and pathology.8 BPNS and nerve conduction study were assessed by a neurologist (F.O.) and a trained general practitioner (D.D.S.). Patient height and weight were measured during the study assessment. Laboratory, clinical, and demographic data were collected from the medical file. Plasma HIV RNA was measured using a Cobas Amplicor Monitor (Roche Molecular Diagnostics, Pleasanton, CA). The study was approved by the Ethics Committee of the Faculty of Medicine, University of Indonesia (579/UN2.F1/ETIK/2014). All participants gave written informed consent. Statistical analyses were performed using SPSS version 20.0. Demographic, clinical, and treatment details of patients with and without neuropathy were compared using χ2 tests (dichotomous variables), Mann–Whitney tests [non-normally distributed continuous variables, described using median (range)] or unpaired t tests (normally distributed continuous variables, described using mean ± SD). Demographic and clinical details in cohorts surveyed in 2006 and 2016 were also compared using these methods. Multivariate analyses of associations with neuropathy in 2016 were performed using multiple logistic regression modeling including all factors with P < 0.25 on univariate analyses, followed by a stepwise removal process. Odds ratios (ORs) and 95% confidence intervals (95% CIs) are presented. RESULTS AND DISCUSSION After screening 2596 patients in 2016, 2399 patients were excluded because of either previous use of stavudine (684 patients), <12 months on ART (831 patients), withdrawal from ART (119 patients), diabetes mellitus (8 patients), history of stroke (8 patients), schizophrenia (3 patients), vasculitis (22 patients), deafness (2 patients), blindness (7 patients), hyperthyroid state (3 patients), systemic lupus erythematous (4 patients), cytomegalovirus (CMV) radiculopathy (1 patient), a history of cancer chemotherapy (6 patients), or refusal to participate (701 patients). One hundred ninety-seven patients were tested for neuropathy. Demographic and clinical details are described in Table 1.TABLE 1.: Univariate Analyses of Risk Factors for HIV-SN in 2016 and 2006Twenty-eight patients (14.2%) were assessed as having neuropathy based on the ACTG-BPNS. Most were male (71%) and of Malay ethnicity (95%). Lamivudine was used by all patients, and zidovudine and nevirapine were used by more than 50% of patients, but choice of antiretroviral regimen was not associated with HIV-SN. More than 500 copies of HIV RNA per mL and a nadir CD4+ T-cell count below 200 cells per μL were associated with HIV-SN on univariate analyses. Although one might expect these parameters to mark the same people, patients with and without >500 copies HIV RNA per mL had similar nadir CD4 T-cell counts (P = 0.31), so they seem to be distinct factors. Before the era of combination ART, HIV-SN was associated with lower CD4 T-cell counts and higher plasma HIV RNA.9 When patients receive effective therapy, CD4 T-cell counts typically improve and may not register as a risk factor,10 but a lower nadir CD4 T-cell count has been described in patients on ART with HIV-SN,11 as observed here. Neither height, body mass index, ethnicity, mode of HIV transmission, ART duration (Table 1), occupation, nor educational status (not shown) was associated with HIV-SN. Age, current CD4 T-cell count, isoniazid/pyridoxine therapy (consequent to tuberculosis),12 and hepatitis C antibody were weakly associated with HIV-SN (0.05 < P < 0.10). We also assessed CMV antibodies because CMV is implicated in vascular pathology, and antibodies may be used as a metric of the burden of CMV.13 However, levels of CMV antibodies were not associated with HIV-SN. All factors associating even weakly with HIV-SN (P < 0.2 on univariate analyses; age, nadir <200 CD4 T cells, current CD4 T cells, hepatitis C antibody, HIV RNA, and isoniazid/pyridoxine) were included in logistic regression modeling in a multivariate analysis, followed by a stepwise removal procedure. Carriage of >500 copies HIV RNA per mL (P = 0.01, OR 5.2, 95% CI: 1.5 to 18) and increasing age (P = 0.06, OR 1.1, 95% CI: 0.9 to 1.1) were independently associated with the HIV-SN (model P = 0.001, pseudo R2 = 0.06). The association with HIV RNA levels is consistent with data from the preantiretroviral era9,14 and suggests that HIV-SN observed in these patients may have developed before ART. We then compared the data with that obtained in the same clinic when 96 patients receiving stavudine were assessed using the ACTG-BPNS in 2006.4 Compared with 2006, in 2016, the proportion of women were higher (13.5% in 2006 vs 28.9% in 2016; P = 0.003, OR 2.6, 95% CI: 1.3 to 5), fewer patients had tuberculosis and received isoniazid/pyridoxine (58.3% in 2006 vs 45.2% in 2016; P = 0.05, OR 0.6, 95% CI: 0.4 to 1), the patients were older (30.2 ± 7.1 years in 2006 vs 35.7 ± 5.9 in 2016; P < 0.001, mean difference 5.4, 95% CI: 3.7 to 7 years) and shorter (167 ± 7.2 cm in 2006 vs 165 ± 7.7 cm in 2016; P = 0.03, mean difference 2.1, 95% CI: 0.3 to 3.9), fewer patients had nadir counts <200 CD4 T cells (85% in 2006 vs 67% in 2016; P = 0.001, OR 0.4, 95% CI: 0.2 to 0.7), fewer patients had current counts <200 CD4 T cells (40% in 2006 vs 8.6% in 2016; P < 0.001, OR 0.1, 95% CI: 0.1 to 0.3), and the prevalence of HIV-SN was lower (34% in 2006 vs 14.2% in 2016; P < 0.001, OR 0.3, 95% CI: 0.2 to 0.6). In 2006, age (P = 0.04, OR 1.1, 95% CI: 1 to 1.1) and height (P = 0.01, OR 1.1, 95% CI: 1 to 1.2) independently associated with the HIV-SN (model P = 0.008, pseudo R2 = 0.08).4,5 The lower observed prevalence of HIV-SN among patients with HIV in our clinic who had never used stavudine compared with stavudine-exposed patients in 2006 is striking, as the 2016 cohort was older and included more women than the cohort studied in 2006, when female sex associated with resistance to HIV-SN. It is therefore likely that lack of stavudine exposure is central to the lower neuropathy prevalence observed in the current study. Fewer patients in the current cohort had been treated for tuberculosis, compared with 2006, and the lower rate of isoniazid exposure may have impacted neuropathy prevalence. Patients with tuberculosis were prescribed standard therapy, including pyridoxine supplementation (25 mg/d) throughout isoniazid use. Neuropathy was recognized as a side effect of isoniazid in the 1970s and has been described in 0.2%–10% of patients receiving this drug.12 Although the use of isoniazid was not associated with HIV-SN in 2006, it was weakly associated with HIV-SN in 2016. However, this was not independent of other observed associations, and the lower frequency of isoniazid use in the current cohort is unlikely to explain the lower observed HIV-SN prevalence. Overall, we show that HIV-SN remains common, affecting >14% of those treated for HIV in our clinic, although patients no longer use stavudine. Increasing age is a known risk factor for HIV-SN.5,7 Here, patients with HIV-SN were marginally older that those without neuropathy in both 2006 and 2016. Although links between HIV-SN and patient age on ART have been attributed to improved life expectancy, prolonged exposure to neurotoxic effects of stavudine and other potentially neurotoxic ART complicates these analyses.1,10 Here, other factors associated with HIV-SN in patients never exposed to stavudine (2016 cohort) mirror associations with neuropathy among patients with HIV in the pre-ART era, namely HIV replication and low nadir CD4 T-cell count,9 highlighting the need for longitudinal studies as patients begin ART. Future work is needed to clarify the degree to which earlier initiation of treatment, as recommended by the World Health Organization,15 may prevent the development of HIV-SN. As even mild levels of HIV-SN impair quality of life, work is needed to understand why so many patients are still affected and to inform efforts to prevent HIV-SN.

Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n = 124) and healthy controls (n = 229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies >1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p ≤ 0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p < 0.0001; R 2  = 0.05). Examination of individual alleles within these haplotypes implicated P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease.

A 25-year-old woman who was diagnosed at 2.2 years of age with perinatally acquired HIV infection [1] and with no history of opportunistic infection commenced antiretrovirals at 3.5 years of age when her CD4+ cell count (%) was 716 cells/μl (11%; Fig. 1). Consistent with practise at that time, she initially received zidovudine, then zidovudine with lamivudine prior to starting three-drug combination antiretroviral therapy (ART) at age 4.9 years. HIV genotype performed retrospectively on a sample taken at 4.8 years of age revealed high-level resistance to thymidine analogues and lamivudine (reverse transcriptase mutations: M41LM, M184V, L210LW, T215NSTY). She achieved virological suppression on ART from 7.5 to 23 years of age with 26 of 33 plasma samples having an HIV RNA below the limit of assay quantification (range 20–400 copies/ml) with HIV RNA being 37–309 copies/ml when detected. The patient elected to stop ART in April 2015 and over the following 2 years without ART was asymptomatic, had four viral loads ranging from less than 20 to 104 copies/l with no significant changes in CD4+ T-cell counts (704–869 cells/μl) and percentage (47–51%).Fig. 1: Summary of antiretroviral therapy, plasma HIV RNA, CD4+ cell count percentage, and HLA genotype in an adult with PTC.Plasma HIV RNA and CD4+ T-cell count percentage are shown together with the antiretrovirals (boxes at the top of the graph). 3TC, lamivudine; ABC, abacavir; AZT, zidovudine; d4T, stavudine; IDV, indinavir; NFV, nelfinavir; NVP, nevirapine; PTC, post-treatment control; TDF, tenofovir disoproxil fumarate.She was infected with a subtype B virus. She was homozygous for wild-type CCR5 and 4-digit HLA typing was performed (summarised in Fig. 1). Cell-associated unspliced (CA-US) HIV RNA and DNA on sorted CD4+ T cells from peripheral blood mononuclear cells collected 16 months after cessation of ART was assessed as previously described [2]. CA-US HIV RNA was 2.4 log10 copies/million copies 18S and HIV DNA was 0.9 log10/million cell equivalents. CA-US HIV RNA and DNA was also assessed in CD4+ T-cell subpopulations sorted based on the expression of CD45RA, CCR7, and CD27 into naïve (0.8%), central (0.6%), transitional (23.1%), effector memory (0.7%), and terminally differentiated (71.9%), populations. All cells were infected, with highest to lowest levels of CA-US HIV RNA in the order: central memory, naïve, transitional memory, effector memory and then terminally differentiated. Levels of HIV DNA were highest to lowest in the order: central memory, effector memory, naïve, transitional memory and than terminally differentiated. RNA/DNA ratios were higher for central (29.3) and naïve (15.1) compared with transitional (8.8.), effector memory (2.7), and terminally differentiated (0). Long-term virological control of HIV RNA below detectable limits of commercial assays has been well described in less than 1% of people with HIV naïve to ART and is associated with a specific HLA profile (elite controllers) [3,4]. More recently, long-term virological control has been reported after ART cessation in adults and one perinatally infected child who were treated very early after infection and subsequently stopped therapy [post-treatment control (PTC)]. In these individuals similar HLA profiles to elite controllers were not identified and most had weak HIV-specific CD8+ T-cell responses in blood [5,6]. PTC after starting ART in established chronic infection is far rarer but has also been described. Of four adult PTCs, two individuals infected with subtype B virus had transient rebound in HIV RNA before achieving undetectable levels and then had immunological decline and/or infectious complications requiring ART reinitiation. The other two individuals had no viral rebound following ART cessation and maintained immunological control with viral blips up to 1000 copies/ml. Notably these four individuals had no favourable HLA B alleles and for the three who had samples available, there were low to undetectable levels of HIV DNA, unspliced, and multiple spliced HIV RNA [7–9]. The individual in this report is unique in the literature as she demonstrates PTC in perinatally acquired HIV, following established chronic infection and a prolonged period of effective ART. Cell-associated HIV RNA and DNA were easily detectable unlike previous individuals [7,8] and were detected in all T-cell subsets including naïve T cells, in contrast to 9 of 11 adult PTCs treated in early infection who did not have detectable HIV DNA in naïve T cells [6]. This individual does not exhibit the 'classic' HLA B alleles seen in elite controllers [5–8] but does have HLA-B14 : 02/C08 : 02, more recently associated with elite controller [10]. Notably, patterns of HLA-C allele expression were not described in other adult PTCs reported. Interestingly, in another recently described perinatally infected PTC A23 : 01 (homozygous) and C08 : 02 alleles were present as seen in our case, but limited conclusions can be drawn based on these two reports. In conclusion, the unique combination of perinatal acquisition, established viremia before prolonged ART and a favourable HLA allele may have led to enhanced HIV-specific immune responses that in later life allowed for control without ART, even when there was evidence of HIV persistence in all T-cell subsets, including naïve T cells. PTC can occur following initiation of ART in chronic perinatally acquired HIV infection. Establishing a large international cohort of similar individuals will be needed to define the predictors of PTC. Acknowledgements J.H.M. is an NHMRC early career fellow and S.R.L. is an NHMRC practitioner fellow. J.H.M. and C.C. acknowledge the Victorian Operational Infrastructure Support Program (Department of Health, Victoria, Australia) to the Burnet Institute. J.H.M.'s institution has received grant funding from Merck, Viiv, Bristol Myers Squibb, Pfizer and Gilead and funding for attendance at advisory boards for Gilead and Viiv. S.R.L. is supported by NIH (U19 AI096109, UM1 AI126611), American Foundation for AIDS Research (amfAR), Wellcome Trust and has investigator initiated clinical trials funded by Viiv, Gilead, and Merck. Conflicts of interest There are no conflicts of interest.

Despite the use of safer antiretroviral medications, the rate of HIV-associated sensory neuropathy (HIV-SN), the most common neurological complication of HIV, remains high. This condition is often painful and has a negative effect on quality of life. Up to 90% of those with HIV-SN experience pain for which there is no effective analgesic treatment. Genetic factors are implicated, but there is a lack of a comprehensive body of research for African populations. This knowledge gap is even more pertinent as Africans are most affected by HIV. However, recent studies performed in Southern African populations have identified genes displaying potential as genetic markers for HIV-SN and HIV-SN-associated pain in Africans. Here, we review the published studies to describe current knowledge of genetic risk factors for this disease in Africa.

Chronic immune activation persists despite antiretroviral therapy (ART) in HIV+ individuals and underpins an increased risk of age-related co-morbidities. We assessed the Frailty Index in older HIV+ Australian men on ART. Immunometabolic markers on monocytes and T cells were analyzed using flow cytometry, plasma innate immune activation markers by ELISA, and lipidomic profiling by mass spectrometry. The study population consisted of 80 HIV+ men with a median age of 59 (IQR, 56–65), and most had an undetectable viral load (92%). 24% were frail, and 76% were non-frail. Frailty was associated with elevated Glucose transporter-1 (Glut1) expression on the total monocytes (p=0.04), increased plasma levels of innate immune activation marker sCD163 (OR, 4.8; CI 1.4–15.9, p=0.01), phosphatidylethanolamine PE(36:3) (OR, 5.1; CI 1.7–15.5, p=0.004) and triacylglycerol TG(16:1_18:1_18:1) (OR, 3.4; CI 1.3–9.2, p=0.02), but decreased expression of GM3 ganglioside, GM3(d18:1/18:0) (OR, 0.1; CI 0.0–0.6, p=0.01) and monohexosylceramide HexCerd(d18:1/22:0) (OR, 0.1; CI 0.0–0.5, p=0.004). There is a strong inverse correlation between quality of life and the concentration of PE(36:3) (ρ=−0.33, p=0.004) and PE(36:4) (ρ=−0.37, p=0.001). These data suggest that frailty is associated with increased innate immune activation and abnormal lipidomic profile. These markers should be investigated in larger, longitudinal studies to determine their potential as biomarkers for frailty.

Ventriculoperitoneal (VP) shunt insertion is a common neurosurgical procedure, essentially unchanged in recent years, with high revision rates. We aimed to identify potentially modifiable associations with shunt failure. One hundred and forty patients who underwent insertion of a VP shunt from 2005-2009 were followed for 5-9years. Age at shunt insertion ranged from 0 to 91years (median 44, 26% <18years). The main causes of hydrocephalus were congenital (26%), tumour-related (25%), post-haemorrhagic (24%) or normal pressure hydrocephalus (19%). Fifty-eight (42%) patients required ⩾1 shunt revision. Of these, 50 (88%) were for proximal catheter blockage. The median time to first revision was 108days. Early post-operative CT scans were available in 105 patients. Using a formal grading system, catheter placement was considered excellent in 49 (47%) but poor (extraventricular) in 13 (12%). On univariate analysis, younger age, poor ventricular catheter placement and use of a non-programmable valve were associated with shunt failure. On logistic regression modelling, the independent associations with VP shunt failure were poor catheter placement (odds ratio [OR] 4.9, 95% confidence interval [CI] 1.3-18.9, p=0.02) and use of a non-programmable valve (OR 0.4, 95% CI 0.2-1.0, p=0.04). In conclusion, poor catheter placement (revision rate 77%) was found to be the strongest predictor of shunt failure, with no difference in revisions between excellent (43%) and moderate (43%) catheter placement. Avoiding poor placement in those with mild or moderate ventriculomegaly may best reduce VP shunt failures. There may also be an influence of valve choice on VP shunt survival.

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; R 2 = 0.19) or haplotypes (model p < 0.0001; R 2 = 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.