A Single-Nucleotide Polymorphism in ABCC4 Is Associated with Tenofovir-Related Beta2-Microglobulinuria in Thai Patients with HIV-1 Infection.

BACKGROUND: In Thailand, the combined generic anti-retroviral drug stavudine/lamivudine/nevirapine (d4T/3TC/NVP) has been used to treat human immunodeficiency virus (HIV)-infected individuals since 2001. Due to relatively frequent adverse effects, d4T gradually has been replaced with tenofovir disoproxil fumarate (TDF). Although the frequency of adverse drug effects with TDF is lower than that with d4T, TDF is known to induce kidney dysfunction, especially in the proximal tubules. It has been reported that renal tubular transporters, including members of the multi-drug resistant (MDR) protein family, are implicated in tenofovir extrusion and may, therefore, confer susceptibility to TDF-induced kidney tubular dysfunction (KTD). We have explored the association between KTD and polymorphisms in genes that encode adenosine triphosphate-binding cassette (ABC)-type MDRs. METHODS: HIV-infected patients receiving TDF-containing antiretroviral regimens for at least one year were enrolled in the study. The levels of beta2-microglobulin in urine and creatinine (Cr) were measured. Three single-nucleotide polymorphisms, ABCC2 C-24T (rs717620), ABCC2 G1429A (rs2273697), and ABCC4 T4976C (rs1059751), were analyzed using TaqMan SNP genotyping assays. RESULTS: A total of 273 HIV-infected patients were recruited. The median number of years of TDF treatment was 5.04 with interquartile range (IQR) of 3.9-6.7. Despite the length of treatment with TDF, 98.5% patients maintained an estimated glomerular filtration rate (eGFR) of >60 mL/min as calculated by the CKD-EPI formula. Fifty-four patients (19.8%) showed beta2-microglobulinuria (median 2636 µg/g Cr with IQR of 1519-13197 µg/g Cr). The allele frequency of ABCC4 T4976C among those 54 patients was 0.602, compared to 0.475 among the 219 remaining patients (p = 0.018). CONCLUSIONS: Approximately 20% of HIV-infected patients receiving TDF showed beta2-microglobulinuria. The C allele at position 4976 of the ABCC4 gene was associated with beta2-microglobulinuria in this population. This polymorphism may help to identify patients at greater risk for developing TDF-associated KTD.

Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.

BACKGROUND: The International Network for the Study of HIV-associated IRIS (INSHI) recently published criteria for tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) diagnosis. The performance of this definition and clinical manifestations of TB-IRIS were studied. METHODS: Antiretroviral therapy-naive HIV/TB Thai patients receiving antituberculous therapy were enrolled during 2006-2007 and prospectively followed through 24 weeks of antiretroviral therapy. Patients were defined as having paradoxical TB-IRIS if they fulfilled the 'study definition' by French 2004 and were confirmed by an external reviewer. All were later compared by the classification according to 'INSHI-2008'. RESULTS: For the 126 patients, median baseline CD4 cell count was 43 cells/microl and HIV-1 RNA was 5.9 log(10) Y copies/ml. Seventy-three (58%) had extrapulmonary/disseminated TB. Twenty-two (18%) and 21 (17%) fulfilled TB-IRIS criteria according to the study definition and INSHI-2008 definition, respectively. Two (2%) were diagnosed by study definition only and one (1%) by INSHI-2008 definition only. Twenty (16%) were concordantly diagnosed by both definitions and 103 (82%) were consistently negative. Eighteen (82%) had worsening of a preexisting site, whereas four (18%) had TB-IRIS in a new location. Lymph node enlargement (73%) and fever (59%) were common in TB-IRIS. Sensitivity and specificity of INSHI-2008 was 91% (95% confidence interval, 72-98%) and 99% (95% confidence interval, 95-99.8%), respectively. Positive predictive value was 95% and negative predictive value was 98%. By multivariate analysis, factors predicting TB-IRIS were extrapulmonary TB (odds ratio, 8.63) and disseminated TB (odds ratio, 4.17). CONCLUSION: There was high concordance between the INSHI-2008 and French 2004 definition for TB-IRIS diagnosis in HIV/TB patients with relatively high rate of paradoxical TB-IRIS. This suggests that lack of HIV-1 RNA and CD4 cell count monitoring does not impede the ability to diagnose TB-IRIS.

Risk factors for mortality in symptomatic hyperlactatemia among HIV-infected patients receiving antiretroviral therapy in a resource-limited setting.

OBJECTIVES: To determine the mortality rate and risk factors after experiencing symptomatic hyperlactatemia in HIV-infected patients receiving antiretroviral therapy (ART). METHODS: A retrospective cohort study was conducted among patients who were diagnosed with symptomatic hyperlactatemia (lactate >2.5mmol/l) between January 2004 and April 2006. All patients were followed until 3 months after the diagnosis. RESULTS: One hundred and twenty-five patients were included in the study. The mean+/-standard deviation (SD) age was 39.9+/-10.1 years and body weight was 58.2+/-16.9kg; 60.8% were male. Symptomatic hyperlactatemia in 114 (91.2%) was associated with receiving d4T, in five (4.0%) with d4T+ddI, in four (3.2%) with ZDV+ddI, and in two (1.6%) with ddI (d4T, stavudine; ddI, didanosine; ZDV, zidovudine). The median duration of ART was 13 months. Nine (7.2%) patients died. Patients who died had a higher mean lactate level (8.0 vs. 5.1mmol/l) and mean alanine aminotransferase (ALT; 164 vs. 48U/l) at the time of diagnosis when compared to those who survived (p<0.05). Patients who died had a lower mean weight than those who survived (48 vs. 59kg, p=0.008). By logistic regression, mortality was associated with patients whose body weight was <45kg (p=0.014, odds ratio (OR) 9.090, 95% confidence interval (CI) 1.575-52.632) and whose serum lactate was >10mmol/l (p=0.004, OR 20.372, 95% CI 2.610-159.001). CONCLUSIONS: The mortality rate of symptomatic hyperlactatemia among HIV-infected patients receiving ART is substantial. Almost all patients received d4T. Patients who have a low body weight and high serum lactate level are at a higher risk of mortality.