Trends and Predictors of Transmitted Drug Resistance (TDR) and Clusters with TDR in a Local Belgian HIV-1 Epidemic

<div><p>We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7–11.9), 6.5% (CI: 5.0–8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4–3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4–3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures.</p></div

Characteristics of transmission clusters containing Leuven patients with TDR.

<p>Abbreviations: ARCL: AIDS Reference Center Leuven, CRF: Circulating recombinant form, ESAR: European Society for Translational Antiviral Research, IVDU: intravenous drug user, NRTI: nucleoside reverse transcriptase inhibitors, NNRTI: non-nucleoside reverse transcriptase inhibitors, MSM: men who have sex with men, MTCT: mother to child transmission, PI: protease inhibitors,^†Patient ID includes patients of the Leuven cohort (bold and italics), ESAR controls and accession numbers of NCBI database *Control sequences have available year of sampling. ^‡Control sequences with year of diagnosis available. ^§Sequences were also included when the patient was on antiretroviral treatment.</p

Additional file 1: of Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe

Table S1. Demographic and virological characteristics of HBV genotype-D drug-naĂŻve patients. (DOCX 12 kb

Prevalence of TDRM in patients diagnosed from 2002 through 2007.

<p>Prevalence of TDRM is shown for any of the drug classes (any class), nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) in <b>(A)</b> Men having sex with men (MSM), and in <b>(B)</b> heterosexuals (HSX). The p-values of the time trends are shown on the right side of the graph.</p

Prevalence of TDRM by drug classes in three risk groups.

<p>Prevalences are shown of resistance to at least one of the drug classes (Any), nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) in men who have sex with men (MSM), heterosexuals (HSX), and injection drug users (IDU). * = p<0.001 in comparison with MSM</p

Temporal trends in the yearly proportion of individuals having one or more surveillance drug-resistance mutations in low- and middle-income countries of south and southeast Asia.

<p>The <i>x</i>-axes represent the number of years since ARV scale-up for each isolate. The diameter of each circle is proportional to the number of samples sequenced that year. The fitted line shows the fixed effect of years since ARV scale-up in generalized linear mixed model regression.</p

Study-level estimates of transmitted drug resistance in seven geo-economic regions.

<p>Data are median (IQR) of study-level prevalence of individuals with any (overall) and NRTI-, NNRTI-, and PI-associated SDRMs by region; the number of studies conducted is indicated for each region (<i>n</i>). Latin America/Caribbean includes three studies from Caribbean countries. Three studies from North Africa and two studies from Australia are not included in this table but are summarized in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001810#pmed.1001810.s004" target="_blank">S1 Table</a>.</p><p>Study-level estimates of transmitted drug resistance in seven geo-economic regions.</p

Flow chart showing the derivation of study sets meeting meta-analysis inclusion criteria: studies of representative ARV-naïve populations of 25 or more individuals with published RT sequences with or without protease sequences.

<p>Flow chart showing the derivation of study sets meeting meta-analysis inclusion criteria: studies of representative ARV-naïve populations of 25 or more individuals with published RT sequences with or without protease sequences.</p

Temporal trends in the yearly proportion of individuals having one or more surveillance drug-resistance mutations in Europe (and Israel).

<p>The <i>x</i>-axes represent the calendar year of the sample. The diameter of each circle is proportional to the number of samples sequenced that year. The fitted line shows the fixed effect of sample year in generalized linear mixed model regression.</p