Publications
307 results found
Lehtinen S, Chewapreecha C, Lees J, et al., 2020, Horizontal gene transfer rate is not the primary determinant of observed antibiotic resistance frequencies in <i>Streptococcus pneumoniae</i>, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548
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- Citations: 11
Bbosa N, Ssemwanga D, Ssekagiri A, et al., 2020, Phylogenetic and demographic characterization of directed HIV-1 transmission using deep sequences from high-risk and general population cohorts/groups in Uganda, Viruses, Vol: 12, ISSN: 1999-4915
Across sub-Saharan Africa, key populations with elevated HIV-1 incidence and/or prevalence have been identified, but their contribution to disease spread remains unclear. We performed viral deep-sequence phylogenetic analyses to quantify transmission dynamics between the general population (GP), fisherfolk communities (FF), and women at high risk of infection and their clients (WHR) in central and southwestern Uganda. Between August 2014 and August 2017, 6185 HIV-1 positive individuals were enrolled in 3 GP and 10 FF communities, 3 WHR enrollment sites. A total of 2531 antiretroviral therapy (ART) naïve participants with plasma viral load >1000 copies/mL were deep-sequenced. One hundred and twenty-three transmission networks were reconstructed, including 105 phylogenetically highly supported source-recipient pairs. Only one pair involved a WHR and male participant, suggesting that improved population sampling is needed to assess empirically the role of WHR to the transmission dynamics. More transmissions were observed from the GP communities to FF communities than vice versa, with an estimated flow ratio of 1.56 (95% CrI 0.68-3.72), indicating that fishing communities on Lake Victoria are not a net source of transmission flow to neighboring communities further inland. Men contributed disproportionally to HIV-1 transmission flow regardless of age, suggesting that prevention efforts need to better aid men to engage with and stay in care.
Ferretti L, Wymant C, Kendall M, et al., 2020, Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing
<jats:title>Abstract</jats:title><jats:p>The newly emergent human virus SARS-CoV-2 is resulting in high fatality rates and incapacitated health systems. Preventing further transmission is a priority. We analysed key parameters of epidemic spread to estimate the contribution of different transmission routes and determine requirements for case isolation and contact-tracing needed to stop the epidemic. We conclude that viral spread is too fast to be contained by manual contact tracing, but could be controlled if this process was faster, more efficient and happened at scale. A contact-tracing App which builds a memory of proximity contacts and immediately notifies contacts of positive cases can achieve epidemic control if used by enough people. By targeting recommendations to only those at risk, epidemics could be contained without need for mass quarantines (‘lock-downs’) that are harmful to society. We discuss the ethical requirements for an intervention of this kind.</jats:p>
Ratmann O, Kagaayi J, Hall M, et al., 2020, Quantifying HIV transmission flow between high-prevalence hotspots and surrounding communities: a population-based study in Rakai, Uganda, The Lancet HIV, Vol: 7, Pages: e173-e183, ISSN: 2352-3018
BackgroundInternational and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda.MethodsWe did a population-based survey in Rakai, Uganda, using data from the Rakai Community Cohort Study. The study surveyed all individuals aged 15–49 years in four high-prevalence Lake Victoria fishing communities and 36 neighbouring inland communities. Viral RNA was deep sequenced from participants infected with HIV who were antiretroviral therapy-naive during the observation period. Phylogenetic analysis was used to infer partial HIV transmission networks, including direction of transmission. Reconstructed networks were interpreted through data for current residence and migration history. HIV transmission flows within and between high-prevalence and low-prevalence areas were quantified adjusting for incomplete sampling of the population.FindingsBetween Aug 10, 2011, and Jan 30, 2015, data were collected for the Rakai Community Cohort Study. 25 882 individuals participated, including an estimated 75·7% of the lakeside population and 16·2% of the inland population in the Rakai region of Uganda. 5142 participants were HIV-positive (2703 [13·7%] in inland and 2439 [40·1%] in fishing communities). 3878 (75·4%) people who were HIV-positive did not report antiretroviral therapy use, of whom 2652 (68·4%) had virus deep-sequenced at sufficient quality for phylogenetic analysis. 446 transmission networks were reconstructed, including 293 linked pairs with inferred direction of transmission. Adjusting for incomplete sampling, an estimated 5·7% (95% credibility interval 4·4–7·3) of transmissions occurred within lakeside areas, 89·2% (86·0–91·
Pellis L, Cauchemez S, Ferguson NM, et al., 2020, Systematic selection between age and household structure for models aimed at emerging epidemic predictions, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
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- Citations: 17
Grant HE, Hodcroft EB, Ssemwanga D, et al., 2020, Pervasive and non-random recombination in near full-length HIV genomes from Uganda., Virus Evol, Vol: 6, Pages: 1-12, ISSN: 2057-1577
Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D, that have been co-circulating for 50 years, frequently recombining in dually infected patients. Here, we investigate the frequency of recombinants in this population and the location of breakpoints along the genome. As part of the PANGEA-HIV consortium, 1,472 consensus genome sequences over 5 kb have been obtained from 1,857 samples collected by the MRC/UVRI & LSHTM Research unit in Uganda, 465 (31.6 per cent) of which were near full-length sequences (>8 kb). Using the subtyping tool SCUEAL, we find that of the near full-length dataset, 233 (50.1 per cent) genomes contained only one subtype, 30.8 per cent A1 (n = 143), 17.6 per cent D (n = 82), and 1.7 per cent C (n = 8), while 49.9 per cent (n = 232) contained more than one subtype (including A1/D (n = 164), A1/C (n = 13), C/D (n = 9); A1/C/D (n = 13), and 33 complex types). K-means clustering of the recombinant A1/D genomes revealed a section of envelope (C2gp120-TMgp41) is often inherited intact, whilst a generalized linear model was used to demonstrate significantly fewer breakpoints in the gag-pol and envelope C2-TM regions compared with accessory gene regions. Despite similar recombination patterns in many recombinants, no clearly supported circulating recombinant form (CRF) was found, there was limited evidence of the transmission of breakpoints, and the vast majority (153/164; 93 per cent) of the A1/D recombinants appear to be unique recombinant forms. Thus, recombination is pervasive with clear biases in breakpoint location, but CRFs are not a significant feature, characteristic of a complex, and diverse epidemic.
Downs LO, Vawda S, Bester PA, et al., 2020, Bimodal distribution and set point HBV DNA viral loads in chronic infection: retrospective analysis of cohorts from the UK and South Africa
<jats:title>Abstract</jats:title><jats:p>Hepatitis B virus (HBV) DNA viral loads (VL) show wide variation between individuals with chronic hepatitis B (CHB) infection, and are used to determine treatment eligibility. There are few refined descriptions of VL distribution in CHB, and limited understanding of the biology that underpins these patterns. We set out to describe the VL distribution in independent cohorts from the UK and South Africa, to identify associated host characteristics, and to compare with VL in HIV-1 and hepatitis C (HCV) infection. We show the presence of a set-point in chronic HBV infection and report significant differences in the viral load distribution of HBV when compared to HIV and HCV.</jats:p>
Ferretti L, Ledda A, Wymant C, et al., 2020, The Timing of COVID-19 Transmission, SSRN Electronic Journal
Downs LO, Vawda S, Bester PA, et al., 2020, Bimodal distribution and set point HBV DNA viral loads in chronic infection: retrospective analysis of cohorts from the UK and South Africa., Wellcome Open Res, Vol: 5, ISSN: 2398-502X
Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.
Ryu S, Cowling BJ, Wu P, et al., 2019, Case-based surveillance of antimicrobial resistance with full susceptibility profiles, JAC-ANTIMICROBIAL RESISTANCE, Vol: 1
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- Citations: 13
Rose R, Hall M, Redd AD, et al., 2019, Phylogenetic Methods Inconsistently Predict the Direction of HIV Transmission Among Heterosexual Pairs in the HPTN 052 Cohort, JOURNAL OF INFECTIOUS DISEASES, Vol: 220, Pages: 1406-1413, ISSN: 0022-1899
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- Citations: 12
Stirrup OT, Sabin CA, Phillips AN, et al., 2019, Associations between baseline characteristics, CD4 cell count response and virological failure on first-line efavirenz, Journal of virus eradication, Vol: 5, Pages: 204-211, ISSN: 2055-6640
ObjectivesThe aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance.MethodsWe conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale.ResultsA total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09–0.62), lower CD4 recovery (0.04, 0.00–0.17) and higher CD4 variability (4.40, 1.22–12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be <2% at 3 years for baseline CD4 ≥350 cells/μL.ConclusionLower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance.
Hall MD, Holden MTG, Srisomang P, et al., 2019, Improved characterisation of MRSA transmission using within-host bacterial sequence diversity, ELIFE, Vol: 8, ISSN: 2050-084X
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- Citations: 23
Mbisa JL, Kirwan P, Tostevin A, et al., 2019, Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction, CLINICAL INFECTIOUS DISEASES, Vol: 69, Pages: 1136-1143, ISSN: 1058-4838
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- Citations: 7
Kwun M, Oggioni MR, Bentley SD, et al., 2019, Synergistic activity of mobile genetic element defences in Streptococcus pneumoniae, Genes, Vol: 10, ISSN: 2073-4425
A diverse set of mobile genetic elements (MGEs) transmit between Streptococcus pneumoniae cells, but many isolates remain uninfected. The best-characterised defences against horizontal transmission of MGEs are restriction-modification systems (RMSs), of which there are two phase-variable examples in S. pneumoniae. Additionally, the transformation machinery has been proposed to limit vertical transmission of chromosomally integrated MGEs. This work describes how these mechanisms can act in concert. Experimental data demonstrate RMS phase variation occurs at a sub-maximal rate. Simulations suggest this may be optimal if MGEs are sometimes vertically inherited, as it reduces the probability that an infected cell will switch between RMS variants while the MGE is invading the population, and thereby undermine the restriction barrier. Such vertically inherited MGEs can be deleted by transformation. The lack of between-strain transformation hotspots at known prophage att sites suggests transformation cannot remove an MGE from a strain in which it is fixed. However, simulations confirmed that transformation was nevertheless effective at preventing the spread of MGEs into a previously uninfected cell population, if a recombination barrier existed between co-colonising strains. Further simulations combining these effects of phase variable RMSs and transformation found they synergistically inhibited MGEs spreading, through limiting both vertical and horizontal transmission.
Le Vu S, Ratmann O, Delpech V, et al., 2019, HIV-1 transmission patterns in men who have sex with men: insights from genetic source attribution analysis, AIDS Research and Human Retroviruses, Vol: 39, Pages: 805-813, ISSN: 0889-2229
BACKGROUND: Near 60% of new HIV infections in the United Kingdom are estimated to occur in men who have sex with men (MSM). Age-disassortative partnerships in MSM have been suggested to spread the HIV epidemics in many Western developed countries and to contribute to ethnic disparities in infection rates. Understanding these mixing patterns in transmission can help to determine which groups are at a greater risk and guide public health interventions. METHODS: We analyzed combined epidemiologic data and viral sequences from MSM diagnosed with HIV at the national level. We applied a phylodynamic source attribution model to infer patterns of transmission between groups of patients. RESULTS: From pair probabilities of transmission between 14 603 MSM patients, we found that potential transmitters of HIV subtype B were on average 8 months older than recipients. We also found a moderate overall assortativity of transmission by ethnic group and a stronger assortativity by region. CONCLUSIONS: Our findings suggest that there is only a modest net flow of transmissions from older to young MSM in subtype B epidemics and that young MSM, both for Black or White groups, are more likely to be infected by one another than expected in a sexual network with random mixing.
Hayes RJ, Donnell D, Floyd S, et al., 2019, Effect of universal testing and treatment on HIV incidence - HPTN 071 (PopART)., New England Journal of Medicine, Vol: 381, Pages: 207-218, ISSN: 0028-4793
BACKGROUND: A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent. METHODS: In the HPTN 071 (PopART) community-randomized trial conducted from 2013 through 2018, we randomly assigned 21 communities in Zambia and South Africa (total population, approximately 1 million) to group A (combination prevention intervention with universal antiretroviral therapy [ART]), group B (the prevention intervention with ART provided according to local guidelines [universal since 2016]), or group C (standard care). The prevention intervention included home-based HIV testing delivered by community workers, who also supported linkage to HIV care and ART adherence. The primary outcome, HIV incidence between months 12 and 36, was measured in a population cohort of approximately 2000 randomly sampled adults (18 to 44 years of age) per community. Viral suppression (<400 copies of HIV RNA per milliliter) was assessed in all HIV-positive participants at 24 months. RESULTS: The population cohort included 48,301 participants. Baseline HIV prevalence was 21% or 22% in each group. Between months 12 and 36, a total of 553 new HIV infections were observed during 39,702 person-years (1.4 per 100 person-years; women, 1.7; men, 0.8). The adjusted rate ratio for group A as compared with group C was 0.93 (95% confidence interval [CI], 0.74 to 1.18; P = 0.51) and for group B as compared with group C was 0.70 (95% CI, 0.55 to 0.88; P = 0.006). The percentage of HIV-positive participants with viral suppression at 24 months was 71.9% in group A, 67.5% in group B, and 60.2% in group C. The estimated percentage of HIV-positive adults in the community who were receiving ART at 36 months was 81% in group A and 80% in group B. CONCLUSIONS: A combination prevention intervention with ART provided according to local guidelines resulted in a 30% lower inciden
Probert W, Hall M, Xi X, et al., 2019, Quantifying the contribution of different aged men and women to onwards transmission of HIV-1 in generalised epidemics in sub-Saharan Africa: A modelling and phylogenetics approach from the HPTN071 (PopART) trial, 10th IAS Conference on HIV Science, Publisher: JOHN WILEY & SONS LTD, Pages: 107-107
Lehtinen S, Chewapreecha C, Lees J, et al., 2019, Horizontal gene transfer rate is not the primary determinant of observed antibiotic resistance frequencies in <i>Streptococcus pneumoniae</i>
<jats:p>The extent to which evolution is constrained by the rate at which horizontal gene transfer (HGT) allows DNA to move between genetic lineages is an open question, which we address in the context of antibiotic resistance in <jats:italic>Streptococcus pneumoniae</jats:italic>. We analyze microbiological, genomic and epidemiological data from the largest-to-date sequenced pneumococcal carriage study in 955 infants from a refugee camp on the Thailand-Myanmar border. Using a unified framework, we simultaneously test prior hypotheses on rates of HGT and a key evolutionary covariate (duration of carriage) as determinants of resistance frequencies. We conclude that in this setting, there is only weak evidence for the rate of HGT playing a role in the evolutionary dynamics of resistance. Instead, observed resistance frequencies are best explained as the outcome of selection acting on a pool of variants, irrespective of the rate at which resistance determinants move between genetic lineages.</jats:p>
Lehtinen S, Blanquart F, Lipsitch M, et al., 2019, On the evolutionary ecology of multidrug resistance in bacteria, PLoS Pathogens, Vol: 15, ISSN: 1553-7366
Resistance against different antibiotics appears on the same bacterial strains more oftenthan expected by chance, leading to high frequencies of multidrug resistance. There are multiple explanations for this observation, but these tend to be specific to subsets of antibioticsand/or bacterial species, whereas the trend is pervasive. Here, we consider the questionin terms of strain ecology: explaining why resistance to different antibiotics is often seen onthe same strain requires an understanding of the competition between strains with differentresistance profiles. This work builds on models originally proposed to explain another aspectof strain competition: the stable coexistence of antibiotic sensitivity and resistance observedin a number of bacterial species. We first identify a partial structural similarity in these models: either strain or host population structure stratifies the pathogen population into evolutionarily independent sub-populations and introduces variation in the fitness effect of resistancebetween these sub-populations, thus creating niches for sensitivity and resistance. We thengeneralise this unified underlying model to multidrug resistance and show that models withthis structure predict high levels of association between resistance to different drugs andhigh multidrug resistance frequencies. We test predictions from this model in six bacterialdatasets and find them to be qualitatively consistent with observed trends. The higher thanexpected frequencies of multidrug resistance are often interpreted as evidence that thesestrains are out-competing strains with lower resistance multiplicity. Our work provides analternative explanation that is compatible with long-term stability in resistance frequencies.
Abeler-Dorner L, Grabowski MK, Rambaut A, et al., 2019, PANGEA-HIV 2: Phylogenetics and networks for generalised epidemics in Africa, Current Opinion in HIV and AIDS, Vol: 14, Pages: 173-180, ISSN: 1746-630X
Purpose of review The HIV epidemic in sub-Saharan Africa is far from being under control and the ambitious UNAIDS targets are unlikely to be met by 2020 as declines in per-capita incidence being largely offset by demographic trends. There is an increasing number of proven and specific HIV prevention tools, but little consensus on how best to deploy them.Recent findings Traditionally, phylogenetics has been used in HIV research to reconstruct the history of the epidemic and date zoonotic infections, whereas more recent publications focus on HIV diversity and drug resistance. However, it is also the most powerful method of source attribution available for the study of HIV transmission. The PANGEA (Phylogenetics And Networks for Generalized Epidemics in Africa) consortium has generated over 18 000 NGS HIV sequences from five countries in sub-Saharan Africa. Using phylogenetic methods, we will identify characteristics of individuals or groups, which are most likely to be at risk of infection or at risk of infecting others.Summary Combining phylogenetics, phylodynamics and epidemiology will allow PANGEA to highlight where prevention efforts should be focussed to reduce the HIV epidemic most effectively. To maximise the public health benefit of the data, PANGEA offers accreditation to external researchers, allowing them to access the data and join the consortium. We also welcome submissions of other HIV sequences from sub-Saharan Africa to the database.
Ratmann O, Grabowski MK, Hall M, et al., 2019, Inferring HIV-1 transmission networks and sources of epidemic spread in Africa with deep-sequence phylogenetic analysis, Nature Communications, Vol: 10, ISSN: 2041-1723
To prevent new infections with human immunodeficiency virus type 1 (HIV-1) in sub-Saharan Africa, UNAIDS recommends targeting interventions to populations that are at high risk of acquiring and passing on the virus. Yet it is often unclear who and where these ‘source’ populations are. Here we demonstrate how viral deep-sequencing can be used to reconstruct HIV-1 transmission networks and to infer the direction of transmission in these networks. We are able to deep-sequence virus from a large population-based sample of infected individuals in Rakai District, Uganda, reconstruct partial transmission networks, and infer the direction of transmission within them at an estimated error rate of 16.3% [8.8–28.3%]. With this error rate, deep-sequence phylogenetics cannot be used against individuals in legal contexts, but is sufficiently low for population-level inferences into the sources of epidemic spread. The technique presents new opportunities for characterizing source populations and for targeting of HIV-1 prevention interventions in Africa.
Geretti AM, White E, Orkin C, et al., 2019, Virological outcomes of boosted protease inhibitor-based first-line ART in subjects harbouring thymidine analogue-associated mutations as the sole form of transmitted drug resistance, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 746-753, ISSN: 0305-7453
ObjectivesIn subjects with transmitted thymidine analogue mutations (TAMs), boosted PIs (PI/b) are often chosen to overcome possible resistance to the NRTI backbone. However, data to guide treatment selection are limited. Our aim was to obtain firmer guidance for clinical practice using real-world cohort data.MethodsWe analysed 1710 subjects who started a PI/b in combination with tenofovir or abacavir plus emtricitabine or lamivudine, and compared their virological outcomes with those of 4889 patients who started an NNRTI (predominantly efavirenz), according to the presence of ≥1 TAM as the sole form of transmitted drug resistance.ResultsParticipants with ≥1 TAM comprised predominantly MSM (213 of 269, 79.2%), subjects of white ethnicity (206 of 269, 76.6%) and HIV-1 subtype B infections (234 of 269, 87.0%). Most (203 of 269, 75.5%) had singleton TAMs, commonly a revertant of T215Y or T215F (112 of 269, 41.6%). Over a median of 2.5 years of follow-up, 834 of 6599 (12.6%) subjects experienced viraemia (HIV-1 RNA >50 copies/mL). The adjusted HR for viraemia was 2.17 with PI/b versus NNRTI-based therapy (95% CI 1.88–2.51; P < 0.001). Other independent predictors of viraemia included injecting drug use, black ethnicity, higher viral load and lower CD4 cell count at baseline, and receiving abacavir instead of tenofovir. Resistance showed no overall impact (adjusted HR 0.77 with ≥1 TAM versus no resistance; 95% CI 0.54–1.10; P = 0.15).ConclusionsIn this cohort, patients harbouring ≥1 TAM as the sole form of transmitted drug resistance gained no apparent virological advantage from starting first-line ART with a PI/b.
Mulubwa C, Hensen B, Phiri MM, et al., 2019, Community based distribution of oral HIV self-testing kits in Zambia: a cluster-randomised trial nested in four HPTN 071 (PopART) intervention communities, Lancet HIV, Vol: 6, Pages: E81-E92, ISSN: 2405-4704
BackgroundThe HPTN 071 (PopART) cluster-randomised trial provided door-to-door HIV testing services to a large proportion of individuals residing in 21 intervention communities in Zambia and South Africa from 2014 to 2017 and reached the UNAIDS first 90 target among women in Zambia, yet gaps remained among men and young adults. This cluster-randomised study nested in the HPTN 071 (PopART) trial sought to increase knowledge of HIV status across all groups by offering the choice of oral HIV self-testing in addition to routine door-to-door HIV testing services.MethodsWe nested this cluster-randomised trial in four HTPN 071 (PopART) intervention communities in northern Zambia. 66 zones (clusters) in these communities were randomly allocated (1:1) to either oral HIV self-testing plus routine door-to-door HIV testing services (HIV self-testing group) or the PopART standard of care of door-to-door HIV testing services alone (non- HIV self-testing group) over a 3-month period. All individuals aged 16 years or older were eligible for HIV testing. Randomisation was achieved by randomly selecting one allocation from a list of 10 000 possible allocations during a public ceremony. In HIV self-testing zones, trained lay-counsellors (known as community HIV care providers) visited households and offered eligible individuals the choice of HIV testing using HIV self-testing or routine door-to-door HIV testing services. For individuals aged 18 years or older whose partner was absent during the household visit, an HIV self-test kit could be left for secondary distribution to the absent partner. The primary outcome was knowledge of HIV status (defined as self-reporting HIV positive to the community HIV care providers or accepting an offer of HIV testing services). Outcomes were measured among households that were first visited, and individuals first enumerated as a household member during the HIV self-testing intervention period. We analysed data at the individual level using population
Thompson RN, Wymant C, Spriggs RA, et al., 2019, Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission, Virus Evolution, Vol: 5, ISSN: 2057-1577
Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment), acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmissions, when trying to discern the complex factors governing
Coltart CEM, Hoppe A, Parker M, et al., 2018, Ethical considerations in global HIV phylogenetic research, LANCET HIV, Vol: 5, Pages: E656-E666, ISSN: 2352-3018
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- Citations: 30
Azarian T, Martinez PP, Arnold BJ, et al., 2018, Predicting evolution using frequency-dependent selection in bacterial populations
<jats:title>Abstract</jats:title><jats:p>Predicting how pathogen populations will change over time is challenging. Such has been the case with <jats:italic>Streptococcus pneumoniae</jats:italic>, an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to predict changes in the pneumococcal population after vaccination, hypothesizing that these frequencies reflect negative frequency-dependent selection (NFDS) on the gene products. We find that the standardized predicted fitness of a strain estimated by an NFDS-based model at the time the vaccine is introduced enables to predict whether the strain increases or decreases in prevalence following vaccination. Further, we are able to forecast the equilibrium post-vaccine population composition and assess the invasion capacity of emerging lineages. Overall, we provide a method for predicting the impact of an intervention on pneumococcal populations with potential application to other bacterial pathogens in which NFDS is a driving force.</jats:p>
Thompson RN, Wymant C, Spriggs RA, et al., 2018, Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission
<jats:title>ABSTRACT</jats:title><jats:p>Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment) acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmiss
Bonsall D, Golubchik T, Cesare MD, et al., 2018, A comprehensive genomics solution for HIV surveillance and clinical monitoring in a global health setting
<jats:title>Abstract</jats:title><jats:p>High-throughput viral genetic sequencing is needed to monitor the spread of drug resistance, direct optimal antiretroviral regimes, and to identify transmission dynamics in generalised HIV epidemics. Public health efforts to sequence HIV genomes at scale face three major technical challenges: (i) minimising assay cost and protocol complexity, (ii) maximising sensitivity, and (iii) recovering accurate and unbiased sequences of both the genome consensus and the within-host viral diversity. Here we present a novel, high-throughput, virus-enriched sequencing method and computational pipeline tailored specifically to HIV (veSEQ-HIV), which addresses all three technical challenges, and can be used directly on leftover blood drawn for routine CD4 testing. We demonstrate its performance on 1,620 plasma samples collected from consenting individuals attending 10 large urban clinics in Zambia, partners of HPTN 071 (PopART). We show that veSEQ-HIV consistently recovers complete HIV genomes from the majority of samples of different subtypes, and is also quantitative: the number of HIV reads per sample obtained by veSEQ-HIV estimates viral load without the need for additional testing. Both quantitativity and sensitivity were assessed on a subset of 126 samples with clinically measured viral loads, and with standardized quantification controls (VL 100 – 5,000,000 RNA copies/ml). Complete HIV genomes were recovered from 93% (85/91) of samples when viral load was over 1,000 copies per ml. The quantitative nature of the assay implies that variant frequencies estimated with veSEQ-HIV are representative of true variant frequencies in the sample. Detection of minority variants can be exploited for epidemiological analysis of transmission and drug resistance, and we show how the information contained in individual reads of a veSEQ-HIV sample can be used to detect linkage between multiple mutations associated with resistance
Ratmann O, Grabowski MK, Hall M, et al., 2018, High prevalence fishing communities are not a major source of new HIV infections to the inland populations in Rakai District, Uganda: implications for geo-spatially targeted HIV prevention interventions, Publisher: JOHN WILEY & SONS LTD, Pages: 70-71
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