Jacquita S. Affandi

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).

Age and height predict neuropathy risk in patients with HIV prescribed stavudine

Objective: Sensory neuropathy is a common problem in HIV-infected patients and is the dose-limiting toxicity of stavudine. Affordable methods of predicting neuropathy risk are needed to guide prescribing in countries where some use of stavudine remains an economic necessity. We therefore aimed to identify factors predictive of neuropathy risk before antiretroviral use. Methods: A total of 294 patients attending clinics in Melbourne, Kuala Lumpur, and Jakarta were enrolled in a cross-sectional neuropathy screening program in 2006. Neuropathy was defined by the presence of symptoms and signs on the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Demographic, laboratory, and treatment details were considered as possible risk factors for neuropathy. The role of patient demographics in predicting stavudine neuropathy were then assessed in 181 patients who reported that they were free of neuropathy symptoms when first prescribed this drug. Results: The prevalence of neuropathy was 42% in Melbourne (n = 100), 19% in Kuala Lumpur (n = 98), and 34% in Jakarta (n = 96). In addition to treatment exposures, increasing age (p = 0.002) and height (p = 0.001) were independently associated with neuropathy. Age and height cutoffs of ≥170 cm or ≥40 years predicted neuropathy. Among 181 patients who were asymptomatic before stavudine exposure, the risk of neuropathy following stavudine was 20% in younger, shorter patients, compared with 66% in older, taller individuals. Conclusions: Stavudine neuropathy risk increases with patient age and height. Prioritizing older and taller patients for alternative agents would be an inexpensive strategy to reduce neuropathy rates in countries where the burden of HIV disease limits treatment options.

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.

Can immunogenetics illuminate the diverse manifestations of respiratory infections

Improved technologies for high-throughput genotyping and the establishment of well-defined cohorts prompted hope that polymorphisms would be discovered that define a patients’ risk of respiratory disease or aid in diagnosis. Genetic pitfalls encountered in this quest include genotyping errors, ethnic differences and linkage dysequilibrium. Differences in the definition of the disease phenotype also create discrepancies, so immunogenetic testing has not yet reached the clinic. However, associations between a polymorphism and a disease phenotype place the gene or one in linkage dysequilibrium on the path to the disease. Here we review studies of immune-related genes that are illuminating the immunopathogenesis of community-acquired pneumonia and mycobacterial infections.

Searching for an immunogenetic factor that will illuminate susceptibility to non-tuberculous mycobacterial disease.

The incidence of pulmonary non-tuberculous mycobacteria (NTM) disease in otherwise healthy adults is increasing as the population ages. The organisms are ubiquitous so susceptibility probably reflects a deficiency in a protective immune response. Here we investigate if singlenucleotide polymorphisms (SNP) affecting cytokines, chemokines and their receptors associate with pulmonary NTM disease. Samples from NTM patients (n=79) and healthy controls (n=188) were genotyped using TaqMan probes. Of the 16 SNPs assessed, IL28B-rs8099917*TG (rs8099917; P=0.01, OR=2.2), TNFA-1031*CC (rs1799964; p=0.02, OR=0.48) and IL10-1082*AA (rs1800896; P=0.001, OR=0.33) were significantly associated with NTM disease. IL28B-rs8099917 and IL10-1082 have been associated with perturbations of the Th1/Th2 balance, whilst TNFA-1031*CC associates with sensory neuropathy in HIV patients. IL10-1082 warrants further investigation because we observed high production of IL-10 in blood mononuclear cells from NTM patients.

The search for a genetic factor associating with immune restoration disease in HIV patients co-infected with Mycobacterium tuberculosis

BACKGROUND: Up to 43% of HIV-infected patients co-infected with Mycobacterium tuberculosis experience exacerbations of tuberculosis (TB) after commencing antiretroviral therapy (ART). These are termed immune restoration disease (IRD). It is unclear why individual susceptibility varies. OBJECTIVE: We investigate if single nucleotide polymorphisms (SNP) in genes encoding cytokines, chemokines and their receptors associate with development of an IRD event in patients of two different ethnicities. METHODS: DNA samples were available from small well-characterised groups of HIV patients treated in Cambodia (TB-IRD, n = 17; HIV+TB+ controls, n = 55) and India (TB-IRD, n = 19; HIV+TB+ controls, n = 43). HIV patients with a TB diagnosis but no evidence of IRD were included to control for susceptibility to TB per se. Sixteen SNP implicated in inflammation or mycobacterial disease were genotyped. RESULTS: Susceptibility to TB-IRD associated with carriage of TNFA-1031*T (rs1799964; P=0.05) and SLC11A1 D543N*G (rs17235409; P=0.04) in Cambodian patients and carriage of IL18-607*G (rs1946518; P=0.02) and VDR FokI (F/f)*T (rs10735810; P=0.05) in Indian patients. CONCLUSIONS: Associations between polymorphisms in immune-related genes and TB-IRD were found, but none were common across two ethnicities.