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Pre-treatment drug resistance and HIV-1 genetic diversity in the rural and urban settings of Northwest-Cameroon.

ABSTRACT: BACKGROUND:With the scale-up of antiretroviral therapy (ART), pre-treatment drug resistance (PDR) appears ?10% amongst ART-initiators in many developing countries, including Cameroon. Northwest region-Cameroon having the second epidemiological burden of HIV infection, generating data on PDR in these geographical settings, will enhance evidence-based decision-making. OBJECTIVES:We sought to ascertain levels of PDR and HIV-1 clade dispersal in rural and urban settings, and their potential association with subtype distribution and CD4-staging. METHODS:A cross-sectional study was conducted from February to May 2017 among patients recently diagnosed with HIV-infection and initiating ART at the Bamenda regional Hospital (urban setting) and the Mbingo Baptist hospital (rural setting). Protease and reverse transcriptase sequencing was performed using an in-house protocol and pre-treatment drug resistance mutations were interpreted using Stanford HIVdb.v8.3. Phylogeny was performed for subtype assignation. RESULTS:A total of 61 patient sequences were generated from ART initiators (median age: 37 years old; 57.4% female; median CD4 cell count: 184 [IQR: 35-387] in urban vs. 161 [IQR: 96-322] cells/mm3 in rural). Overall, the level of PDR was 9.8% (6/61). Of note, burden of PDR was almost doubled in urban (12.9% [4/31]) compared to rural setting 6.7% (2/30), p = 0.352). Fifteen (15) PDR mutations were found among four patients the urban settings [6 resistance mutations to NRTIs:[M41L (2), E44D (1), K65R (1), K70E (1), M184V/I (2), K219R (1)] and 6 resistance mutations to NNRTIs: K103N (1), E138A/G (2), V179E (1), M230L (1), K238T (1), P225H (1)] against two (02) mutations found in two patients in the rural setting[2 resistant mutations to NNRTIs: E138A (1) and Y188H (1)]. The rural setting showed more genetic diversity (8 subtypes) than the urban setting (5 subtypes), with CRF02_AG being the most prevalent clade (72.1% [44/61]). Of note, level of PDR was similar between patients infected with CRF02_AG and non-CRF02_AG infected (9.1% [4/44]) vs. 11.8% [2/17]), p = 1.000). Moreover, PDR appeared higher in patients with CD4 cell count <200 cells/mm3 compared to those with CD4 cell count ?200 cells/mm3 (14.7% [5/34]) vs. 3.7% [1/27]), p = 0.214). CONCLUSIONS:PDR is at a moderate rate in the Northwest region of Cameroon, with higher burden within urban populations. CRF02_AG is the most predominant clade in both urban and rural settings. No effect of HIV molecular epidemiology and CD4-staging on the presence of PDR in patients living in these settings was found. Our findings suggest close monitoring, NNRTI-sparing regimens or sequencing for patients initiating ART, especially in urban settings.

SUBMITTER: Fokam J

PROVIDER: S-EPMC7373288 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pre-treatment drug resistance and HIV-1 genetic diversity in the rural and urban settings of Northwest-Cameroon.

Fokam Joseph J Takou Desire D Teto Georges G Nforbih Shu E SE Kome Odine P OP Santoro Maria M MM Ngoufack Ezechiel S ES Eyongetah Mbuh M Palmer Denis D Fokunang Estella T ET Fokunang Charles N CN Colizzi Vittorio V Perno Carlo-Federico CF Ndjolo Alexis A

PloS one 20200721 7

<h4>Background</h4>With the scale-up of antiretroviral therapy (ART), pre-treatment drug resistance (PDR) appears ≥10% amongst ART-initiators in many developing countries, including Cameroon. Northwest region-Cameroon having the second epidemiological burden of HIV infection, generating data on PDR in these geographical settings, will enhance evidence-based decision-making.<h4>Objectives</h4>We sought to ascertain levels of PDR and HIV-1 clade dispersal in rural and urban settings, and their pot ...[more]

PMID: 32692778

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Project description:BACKGROUND:Antiretroviral therapy (ART) has improved the survival of HIV infected persons. However, rapid scale-up of ART and the high HIV-1 genetic variability, has greatly influenced the emergence of drug-resistant strains. This constitutes a potential threat to achieving the UNAIDS' 90-90-90 goals by 2020. We investigated the prevalent HIV-1 genotypes, drug resistance-associated mutations and assessed some predictors of the occurrence of these mutations. METHODS:This was a hospital-based cross-sectional study conducted between October 2010 and June 2012. Participants were consecutively enrolled from selected HIV treatment centers of the Southwest and Northwest regions of Cameroon. Viral load was determined with the automated Abbott Real-time HIV-1 m2000rt System. HIV genotyping and antiretroviral resistance mutations analysis were performed using Bayer's HIV-1 TRUGENE™ Genotyping Kit and OpenGene DNA Sequencing system. The drug resistance mutation was interpreted with the Stanford HIV database. Epidemiological data were obtained using pre-tested semi-structured questionnaires. RESULTS:Of the 387 participants, 239 were successfully genotyped. The median age of these participants was 33 years (interquartile range, IQR: 28-40 years), and a majority (65.7%) were female. A total of 29.3% of the participants were receiving ART. The median duration of ART was 10.5 months (IQR: 4-17.25 months). The median CD4 count and log10 viral load of study participants were 353.5 cells/ml (IQR:145-471) and 4.89 copies/ml (IQR: 3.91-5.55) respectively. CRF02 (A/G) (69%) was the most prevalent subtype followed by G (8.2%) and F (6.7%). Overall, resistance mutations were present in 37.1% of ART-experienced and 10.7% of ART-naive patients. Nucleoside reverse transcriptase inhibitors (NRTI) mutations occurred in 30% of ART-experienced and 2.4% of ART-naïve patients, while non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations occurred in 34.2% of ART-experienced and 10.1% of -naïve patients. M184V (8.4%, 20/239) and K103N (5.4%, 13/239) were the most prevalent mutations. Major protease inhibitor mutations occurred in 3 (1.3%) out of the 239 sequences. The duration of ART independently predicted the occurrence of resistance mutation among ART-experienced patients. CONCLUSION:The high resistance to NNRTIs, which are the main support to the backbone (NRTIs) first-line antiretroviral regimen in Cameroon, has prompted the need to rollout an integrase strand transfer inhibitor regimen (containing Dolutegravir) with a higher genetic barrier to resistance as the preferred first line regimen.

Project description:Atmospheric particulate matter (PM) is a recognized risk factor for the global burden of disease in human populations. We are presenting here the application of toxicogenomics in the evaluation of the toxic effects of organic content of atmospheric particle matter (PM), from urban and rural environments (city of Barcelona and village of La Pobla, NE Spain), using the developing zebrafish embryo. The main goal is to identify the metabolic pathways involved in the adverse effects observed in zebrafish embryos exposed to PM organic content from urban and rural environments, also allowing the selection of genes of interest that are differentially expressed. The relevance of particle size to the PM toxicity is also addressed. Indeed, the zebrafish embryos were exposed to PM of aerodynamic diameter larger than 7.2 Î¼m and smaller than 0.5 Î¼m (PM10 and PM0.5, respectively). PM0.5 concentrated biological and toxic activities linked to organic substances. Transcriptomic analyses showed strong induction of the AhR signalling pathway (a.k.a. dioxin-like activity) for embryos exposed to both rural and urban extracts, correlating with the concentrations of PAHs. Urban extracts, with strong contribution of traffic emissions, specifically de-regulated oxidative stress-related genes, as well as pancreatic and eye-lens specific genes, two organs known to be affected by air pollution in humans. Exposure to rural extracts, with high contribution of wood burning emissions, affected genes implicated in basic cellular functions, in agreement with their strong embryotoxicity. Extracts from rural and urban samples elicited both common and specific transcriptome responses, suggesting different potentially adverse outcomes depending on PM source and composition. The authors thank the financial support of the Spanish Ministry (project TEA-PARTICLE, grant number CGL2011-29621) and the Portuguese Foundation for Science and Technology for the doctoral grant of Sofia R. Mesquita (SFRH/BD/80710/2011) funded by the Program POPH-QREN through the Portuguese Ministry of Education and Science and the European Social Fund, and support through project PEst-C/MAR/LA0015/2013. The PM filter samples used in the present study were PM10 and PM0.5 from the urban site - total of 4 samples from 2 sampling months; and PM0.5 from the rural site - total of 2 samples from 2 sampling months (PM10 samples from the rural site were not tested due to their very low concentration in organic compounds, and insignificant biological activity, previously measured). Sampling occurred during the cold periods of the year 2012/2013. The organic fraction of PM samples was extracted by sonication using a mixture of dichloromethane:methanol. Then, the extracts were filtered, evaporated and re-dissolved in Dimethyl sulfoxide (DMSO). Zebrafish fertilized eggs were exposed to PM organic extracts (0.2% DMSO) from the urban and rural sites from 24 to 120h post-fertilization. Total RNA was isolated from whole embryos (pools of 20 individuals), using Trizol reagent protocol (Invitrogen Life Technologies, Carlsberg, CA). The microarray study was performed using the Agilent Two-colour D. rerio Oligo Microarray v3 platform, following the Agilent Microarray â?? Based Gene Expression Analysis protocol. Three biological replicates were performed for each PM sample and controls. Biological replicates, a technical replicate and a self-to-self, were simultaneously amplified and labelled using Cyanine 3 (Cy3) and Cyanine 5 (Cy5) dye. After cRNA purification (RNeasy Kit, Quiagen GmbH, Hilden, Germany), the cRNA concentration and labelling were quantified in the NanoDrop spectrophotometer, obtaining incorporation rates in the range of 15-20pmol of cyanide dye/Âµl cRNA and yield values > 0.825ug, as recommended. cRNA was fragmented and hybridized in 4x44K arrays, for 17h at 65oC. After the hybridization the array slides were washed, and immediately scanned using Microarray Scanner Agilent G2505C system. Data was extracted using Agilent Feature Extraction Software v10.5.1.1, and the quality of microarray data was evaluated using the Quality Control report provided by Agilent Software. Based on the microarray data analysis, 22 primers were selected and designed using Primer Express 2.0 software (Applied Biosystems, Foster City, CA). Genes were quantified by real-time PCR to validate the microarray data, and a subset of 13 genes were further selected by their robust behaviour in the validation assays, allowing to differentiate the toxic potential of PM from urban and rural sources.

Project description:Rapid emergence and spread of pyrethroid resistance in Anopheles gambiae populations is among the main factors affecting malaria vector control in Cameroon, but there is still not enough data on the exact pyrethroid resistance status across Cameroon. The present study assessed pyrethroid resistance profile in different eco-epidemiological settings in Cameroon. Susceptibility bioassay tests were performed with F0 An. gambiae females aged three to five days. Mosquito susceptibility to both permethrin and deltamethrin was assessed. Species of the An. gambiae s.l. complex were identified using molecular diagnostic tools. Target site mutations conferring resistance were detected using Taqman assays. Quantitative reverse transcription-real-time PCR (qRT-PCR) 3-plex TaqMan® assays were used for the quantification of detoxification genes implicated in pyrethroid resistance. An. gambiae, An. coluzzii and An. arabiensis were identified in the different settings. An. gambiae was dominant in Santchou, Kékem, Bélabo, Bertoua and Njombé, while An. coluzzii was abundant in Tibati and Kaélé. High frequencies of the kdr L1014F allele ranging from 43% to 100% were recorded in almost all sites. The L1014S kdr allele was detected at low frequency (4.10-10%) only in mosquito populations from Njombé and Tibati. The N1575Y mutation was recorded in Kaélé, Santchou, Tibati and Bertoua with a frequency varying from 2.10% to 11.70%. Six Cytochrome P450 genes (Cyp6p3, Cyp6m2, Cyp9k1, Cyp6p4, Cyp6z1, and Cyp4g16) were found to be overexpressed in at least one population. Analysis of cuticular hydrocarbon lipids indicated a significant increase in CHC content in mosquito populations from Kaélé and Njombé compared to Kékem, Bélabo and Bertoua populations. The study indicated high pyrethroid resistance across different ecological settings in Cameroon with different profile of resistance across the country. The present situation calls for further actions in order to mitigate the impact of insecticide resistance on vector control measures.

Dataset Information

Pre-treatment drug resistance and HIV-1 genetic diversity in the rural and urban settings of Northwest-Cameroon.

Publications

Pre-treatment drug resistance and HIV-1 genetic diversity in the rural and urban settings of Northwest-Cameroon.

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