ABSTRACT
Unsatisfactory treatment outcomes have been reported in patients coinfected with HIV/tuberculosis (TB). The aim of this study was to assess the influence of single-nucleotide polymorphisms (SNPs) in genes encoding for proteins involved in antitubercular drug disposition or effect. A pharmacogenetic study was conducted in Kampala, Uganda, where all analysis was performed. The impact of SNPs on antitubercular drug exposure, adverse events, and treatment outcomes was evaluated in patients coinfected with HIV/TB receiving treatments for both conditions. In 221 participants, N-acetyltransferase 2 (NAT2; rs1799930), solute carrier organic anion transporter family member 1B1 (SLCO1B1; rs4149032), and pregnane X receptor (PXR; rs2472677) variants affected isoniazid exposure in multivariate analysis. Most patients were deemed cured (163; 73.8%), yet PXR 63396TT carriers had a higher probability of death (P = 0.007) and of worsening peripheral neuropathy (P = 0.018). In this exploratory study in Ugandan patients coinfected with HIV/TB, genetic variants in PXR, SLCO1B1, and NAT2 were moderately associated with isoniazid exposure, whereas PXR 63396TT carriers showed worse outcomes.
Subject(s)
Arylamine N-Acetyltransferase/genetics , HIV Infections , Isoniazid , Liver-Specific Organic Anion Transporter 1/genetics , Pregnane X Receptor/genetics , Rifampin , Tuberculosis , Adult , Antitubercular Agents/adverse effects , Antitubercular Agents/pharmacokinetics , Correlation of Data , Female , HIV Infections/epidemiology , HIV Infections/genetics , HIV Infections/therapy , Humans , Isoniazid/adverse effects , Isoniazid/pharmacokinetics , Male , Outcome Assessment, Health Care , Pharmacogenomic Variants/genetics , Polymorphism, Single Nucleotide , Rifampin/adverse effects , Rifampin/pharmacokinetics , Tuberculosis/drug therapy , Tuberculosis/epidemiology , Tuberculosis/genetics , Uganda/epidemiologyABSTRACT
Most studies evaluating epidemiologic relationships between helminths and HIV have been conducted in the pre-ART era, and evidence of the impact of helminth infections on HIV disease progression remains conflicting. Less is known about helminth infection and clinical outcomes in HIV-infected adults receiving antiretroviral therapy (ART). We sampled HIV-infected adults for eight gastrointestinal parasites and correlated parasitic infection with demographic predictors, and clinical and immunologic outcomes. Contrasting with previous studies, we measured parasitic infection with a quantitative, highly sensitive and specific polymerase chain reaction (PCR) method. This cohort study enrolled HIV-infected Ugandans from August-September 2013 in Mbale, Uganda and collected stool and blood samples at enrollment. Real-time PCR quantified stool: Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Trichuris trichiura, Cryptosporidium spp., Entamoeba histolytica, and Giardia intestinalis infection. Generalized linear models assessed relationships between parasitic infection and clinical or demographic data. 35% of participants (71/202) tested positive for ≥1 helminth, mainly N. americanus (55/199, 28%), and 4.5% (9/202) were infected with ≥2 stool parasites. Participants with hookworm infection had lower average CD4+ cell counts (-94 cells/mcL, 95%CI: -141, -48 cells/mcL; p<0.001) after adjustment for sex, CD4+ nadir at clinic entry, and time on ART. The high prevalence of parasitic infection and correlation with decreased CD4+ concentrations highlight the need to re-examine the effects of invasive helminth co-infection in rural, HIV-infected populations in the era of widely available ART. Elucidating the relationship between hookworm infection and immune recovery could provide opportunities for health optimization, e.g. integrated deworming, in these vulnerable populations.
