A Single-Nucleotide Polymorphism in <i>ABCC4</i> Is Associated with Tenofovir-Related Beta2-Microglobulinuria in Thai Patients with HIV-1 Infection

<div><p>Background</p><p>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.</p><p>Methods</p><p>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, <i>ABCC2</i> C-24T (rs717620), <i>ABCC2 G1429A</i> (rs2273697), and <i>ABCC4</i> T4976C (rs1059751), were analyzed using TaqMan SNP genotyping assays.</p><p>Results</p><p>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 <i>ABCC4</i> T4976C among those 54 patients was 0.602, compared to 0.475 among the 219 remaining patients (p = 0.018).</p><p>Conclusions</p><p>Approximately 20% of HIV-infected patients receiving TDF showed beta2-microglobulinuria. The C allele at position 4976 of the <i>ABCC4</i> gene was associated with beta2-microglobulinuria in this population. This polymorphism may help to identify patients at greater risk for developing TDF-associated KTD.</p></div

Subjects and time of specimen collection.

<p>Subjects and time of specimen collection.</p

Estimation on the infection rates of the 2009 pandemic influenza in different groups of subjects after the first epide mic wave.

<p>Infection rate is determined by HI titer ≥40 in adults or ≥20 in children.</p

Comparison between HI antibody titers obtained from goose and turkey erythrocytes.

<p>Note: A/Thailand/104/2009(H1N1) was used as the test virus. GMT  =  geometric mean titer, CI  =  confidence intervals, RBC  =  red blood cells,</p><p>NA  =  Not applicable</p

Comparison between NT antibody titers obtained from RDE treated and RDE untreated sera.

<p>*There are significant differences between GMT of NT antibodies in RDE treated and untreated sera from all 7 serum settings (Wilcoxon Signed Ranks test, p<0.05).</p

Antibody titers by date after onset of symptom.

<p>(A) HI antibody titer; (B) NT antibody titer. Colored stacked bars give the proportion with titers of 10, 20, 40 and ≥80 while the line denotes the geometric mean titer with error bars indicating 95% confidence intervals.</p

Cross-reactive antibody to the 2009 pandemic A (H1N1) influenza virus in vaccinees who received trivalent influenza vaccine of the 2006 season (N = 71).

a<p>Seroconversion with post-vaccination antibody titer ≥40 to the 2009 pandemic virus.</p>b<p>A/New Caledonia/20/99 was used as the test antigen.</p

Genes that were involved in the most significantly down-regulated pathways such as Natural Killer Cell Signaling, Crosstalk between Dendritic Cells and Natural Killer Cells, CD28 Signaling in T Helper Cells, PKCθ Signaling in T Lymphocytes.

<p>The pathway names were shared between different groups but the activated genes in each pathway were different. Differentially expressed genes (FDR <0.05, fold change >2) were highlighted in grey.</p

Clinical manifestations of the patients in the study.

<p>Clinical manifestations of the patients in the study.</p

Interferon signaling pathways was highly up-regulated in moderate and mild influenza patients but was attenuated in patients with severe outcome.

<p>Up-regulated genes were highlighted in grey. IFNGR1 was the only gene that was up-regulated in severe patients while a large number of other genes were up-regulated in moderate and mild patients.</p