Imperial College London

ProfessorChristopheFraser

Faculty of MedicineSchool of Public Health

Visiting Professor
 
 
 
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Contact

 

c.fraser Website

 
 
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Location

 

G28Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

205 results found

Azarian T, Martinez PP, Arnold BJ, Qiu X, Grant LR, Corander J, Fraser C, Croucher NJ, Hammitt LL, Reid R, Santosham M, Weatherholtz RC, Bentley SD, O'Brien KL, Lipsitch M, Hanage WPet al., 2020, Frequency-dependent selection can forecast evolution in Streptococcus pneumoniae, PLOS BIOLOGY, Vol: 18, ISSN: 1544-9173

Journal article

Kendall M, Milsom L, Abeler-Dorner L, Wymant C, Ferretti L, Briers M, Holmes C, Bonsall D, Abeler J, Fraser Cet al., 2020, COVID-19 incidence and R decreased on the Isle of Wight after the launch of the Test, Trace, Isolate programme

<jats:p>In May 2020 the UK introduced a Test, Trace, Isolate programme in response to the COVID-19 pandemic. The programme was first rolled out on the Isle of Wight and included Version 1 of the NHS contact tracing app. We used COVID-19 daily case data to infer incidence of new infections and estimate the reproduction number R for each of 150 Upper Tier Local Authorities in England, and at the National level, before and after the launch of the programme on the Isle of Wight. We used Bayesian and Maximum-Likelihood methods to estimate R, and compared the Isle of Wight to other areas using a synthetic control method. We observed significant decreases in incidence and R on the Isle of Wight immediately after the launch. These results are robust across each of our approaches. Our results show that the sub-epidemic on the Isle of Wight was controlled significantly more effectively than the sub-epidemics of most other Upper Tier Local Authorities, changing from having the third highest reproduction number R (of 150) before the intervention to the tenth lowest afterwards. The data is not yet available to establish a causal link. However, the findings highlight the need for further research to determine the causes of this reduction, as these might translate into local and national non-pharmaceutical intervention strategies in the period before a treatment or vaccination becomes available.</jats:p>

Journal article

Ferretti L, Wymant C, Kendall M, Zhao L, Nurtay A, Abeler-Dorner L, Parker M, Bonsall D, Fraser Cet al., 2020, Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing, SCIENCE, Vol: 368, Pages: 619-+, ISSN: 0036-8075

Journal article

Lehtinen S, Chewapreecha C, Lees J, Hanage WP, Lipsitch M, Croucher NJ, Bentley SD, Turner P, Fraser C, Mostowy RJet al., 2020, Horizontal gene transfer rate is not the primary determinant of observed antibiotic resistance frequencies in Streptococcus pneumoniae, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548

Journal article

Bbosa N, Ssemwanga D, Ssekagiri A, Xi X, Mayanja Y, Bahemuka U, Seeley J, Pillay D, Abeler-Dörner L, Golubchik T, Fraser C, Kaleebu P, Ratmann Oet 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.

Journal article

Ferretti L, Wymant C, Kendall M, Zhao L, Nurtay A, Abeler-Dörner L, Parker M, Bonsall D, Fraser Cet 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>

Journal article

Ratmann O, Kagaayi J, Hall M, Golubchick T, Kigozi G, Xi X, Wymant C, Nakigozi G, Abeler-Dörner L, Bonsall D, Gall A, Hoppe A, Kellam P, Bazaale J, Kalibbala S, Laeyendecker O, Lessler J, Nalugoda F, Chang LW, de Oliveira T, Pillay D, Quinn TC, Reynolds SJ, Spencer SEF, Ssekubugu R, Serwadda D, Wawer MJ, Gray RH, Fraser C, Grabowski MK, Ayles H, Bowden R, Calvez V, Cohen M, Dennis A, Essex M, Fidler S, Frampton D, Hayes R, Herbeck J, Kaleebu P, Kityo C, Lingappa J, Novitsky V, Paton N, Rambaut A, Seeley J, Ssemwanga D, Tanser F, Lutalo T, Galiwango R, Makumbi F, Sewankambo NK, Nabukalu D, Ndyanabo A, Ssekasanvu J, Nakawooya H, Nakukumba J, Kigozi GN, Nantume BS, Resty N, Kambasu J, Nalugemwa M, Nakabuye R, Ssebanobe L, Nankinga J, Kayiira A, Nanfuka G, Ahimbisibwe R, Tomusange S, Galiwango RM, Nakalanzi M, Otobi JO, Ankunda D, Ssembatya JL, Ssemanda JB, Kato E, Kairania R, Kisakye A, Batte J, Ludigo J, Nampijja A, Watya S, Nehemia K, Anyokot SM, Mwinike J, Kibumba G, Ssebowa P, Mondo G, Wasswa F, Nantongo A, Kakembo R, Galiwango J, Ssemango G, Redd AD, Santelli J, Kennedy CE, Wagman J, Tobian Aet 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·

Journal article

Pellis L, Cauchemez S, Ferguson NM, Fraser Cet al., 2020, Systematic selection between age and household structure for models aimed at emerging epidemic predictions, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723

Journal article

Rose R, Hall M, Redd AD, Lamers S, Barbier AE, Porcella SF, Hudelson SE, Piwowar-Manning E, McCauley M, Gamble T, Wilson EA, Kumwenda J, Hosseinipour MC, Hakim JG, Kumarasamy N, Chariyalertsak S, Pilotto JH, Grinsztejn B, Mills LA, Makhema J, Santos BR, Chen YQ, Quinn TC, Fraser C, Cohen MS, Eshleman SH, Laeyendecker Oet 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

Journal article

Kwun M, Oggioni MR, Bentley SD, Fraser C, Croucher Net 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.

Journal article

Le Vu S, Ratmann O, Delpech V, Brown AE, Gill ON, Tostevin A, Dunn D, Fraser C, Volz Eet 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.

Journal article

Hayes RJ, Donnell D, Floyd S, Mandla N, Bwalya J, Sabapathy K, Yang B, Phiri M, Schaap A, Eshleman SH, Piwowar-Manning E, Kosloff B, James A, Skalland T, Wilson E, Emel L, Macleod D, Dunbar R, Simwinga M, Makola N, Bond V, Hoddinott G, Moore A, Griffith S, Deshmane Sista N, Vermund SH, El-Sadr W, Burns DN, Hargreaves JR, Hauck K, Fraser C, Shanaube K, Bock P, Beyers N, Ayles H, Fidler S, HPTN 071 PopART Study Teamet 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

Journal article

Lehtinen S, Chewapreecha C, Lees J, Hanage WP, Lipsitch M, Croucher NJ, Bentley SD, Turner P, Fraser C, Mostowy RJet al., 2019, Horizontal gene transfer rate is not the primary determinant of observed antibiotic resistance frequencies in Streptococcus pneumoniae

<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>

Journal article

Lehtinen S, Blanquart F, Lipsitch M, Fraser C, Bentley SD, Croucher NJ, Lees JA, Turner Pet 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.

Journal article

Abeler-Dorner L, Grabowski MK, Rambaut A, Pillay D, Fraser C, Ayles H, Bonsall D, Bowden R, Calvez V, Essex M, Fidler S, Golubchik T, Hayes R, Herbeck JT, Kagaayi J, Kaleebu P, Lingappa JR, Novitsky V, Quinn TC, Ratmann O, Seeley J, Ssemwanga D, Tanser F, Wawer MJet 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.

Journal article

Ratmann O, Grabowski MK, Hall M, Golubchik T, Wymant C, Abeler-Dörner L, Bonsall D, Hoppe A, Brown AL, de Oliveira T, Gall A, Kellam P, Pillay D, Kagaayi J, Kigozi G, Quinn TC, Wawer MJ, Laeyendecker O, Serwadda D, Gray RH, Fraser Cet 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.

Journal article

Geretti AM, White E, Orkin C, Tostevin A, Tilston P, Chadwick D, Leen C, Sabin C, Dunn DT, Asboe D, Asboe D, Pozniak A, Cane P, Chadwick D, Churchill D, Clark D, Collins S, Delpech V, Douthwaite S, Dunn D, Fearnhill E, Porter K, Tostevin A, Stirrup O, Fraser C, Gunson R, Hale A, Hue S, Lazarus L, Leigh-Brown A, Mbisa T, Mackie N, Orkin C, Nastouli E, Pillay D, Phillips A, Sabin C, Smit E, Templeton K, Tilston P, Volz E, Williams I, Zhang H, Dawkins J, O'Shea S, Mullen J, Smit E, Mbisa T, Cox A, Tandy R, Fawcett T, Hopkins M, Tilston P, Booth C, Garcia-Diaz A, Renwick L, Schmid ML, Payne B, Chadwick D, Hubb J, Dustan S, Kirk S, Gunson R, Bradley-Stewart A, Ainsworth J, Allan S, Anderson J, Babiker A, Chadwick D, Churchill D, Delpech V, Dunn D, Gazzard B, Gilson R, Gompels M, Hay P, Hill T, Johnson M, Jose S, Kegg S, Leen C, Martin F, Mital D, Nelson M, Orkin C, Palfreeman A, Phillips A, Pillay D, Post F, Pritchard J, Sabin CA, Schwenk A, Tariq A, Trevelion R, Ustianowski A, Walsh J, Hill T, Jose S, Phillips A, Sabin CA, Thornton A, Huntington S, Dunn D, Glabay A, Shidfar S, Orkin C, Lynch J, Hand J, de Souza C, Churchill D, Perry N, Tilbury S, Youssef E, Churchill D, Gazzard B, Nelson M, Mabika T, Asboe D, Mandalia S, Anderson J, Munshi S, Post F, Adefisan A, Taylor C, Gleisner Z, Ibrahim F, Campbell L, Chadwick D, Baillie K, Gilson R, Brima N, Williams I, Ainsworth J, Schwenk A, Miller S, Wood C, Johnson M, Youle M, Lampe F, Smith C, Tsintas R, Chaloner C, Hutchinson S, Sabin CA, Phillips A, Hill T, Jose S, Huntington S, Thornton A, Walsh J, Mackie N, Winston A, Weber J, Ramzan F, Carder M, Leen C, Wilson A, Morris S, Gompels M, Allan S, Palfreeman A, Lewszuk A, Kegg S, Faleye A, Ogunbiyi V, Mitchell S, Hay P, Kemble C, Martin F, Russell-Sharpe S, Gravely J, Allan S, Harte A, Tariq A, Spencer H, Jones R, Pritchard J, Cumming S, Atkinson C, Mital D, Edgell V, Allen J, Ustianowski A, Murphy C, Gunder I, Delpech V, Trevelion Ret 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.

Journal article

Mulubwa C, Hensen B, Phiri MM, Shanaube K, Schaap AJ, Floyd S, Phiri CR, Bwalya C, Bond V, Simwinga M, Mwenge L, Fidler S, Hayes R, Mwinga A, Ayles H, Beyer N, Bock P, El-Sadr W, Cohen M, Eshleman S, Agyei Y, Piwowar-Manning E, Hoddinott G, Donnell D, Wilson E, Emel L, Noble H, Macleod D, Burns D, Fraser C, Cori A, Sista N, Griffith S, Moore A, Headen T, White R, Miller E, Hargreaves J, Hauck K, Thomas R, Limbada M, Bwalya J, Mwinga A, Pickles M, Sabapathy K, Dunbar R, Yang B, Smith PC, Vermund S, Mandla N, Makola N, van Deventer A, James A, Jennings K, Kruger J, Phiri M, Kosloff B, Kanema S, Sauter R, Probert W, Kumar R, Sakala E, Silumesi A, Skalland T, Yuhas Ket 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

Journal article

Thompson RN, Wymant C, Spriggs RA, Raghwani J, Fraser C, Lythgoe KAet 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

Journal article

Coltart CEM, Hoppe A, Parker M, Dawson L, Amon JJ, Simwinga M, Geller G, Henderson G, Laeyendecker O, Tucker JD, Eba P, Novitsky V, Vandamme A-M, Seeley J, Dallabetta G, Harling G, Grabowski MK, Godfrey-Faussett P, Fraser C, Cohen MS, Pillay Det al., 2018, Ethical considerations in global HIV phylogenetic research, LANCET HIV, Vol: 5, Pages: E656-E666, ISSN: 2352-3018

Journal article

Azarian T, Martinez PP, Arnold BJ, Grant LR, Corander J, Fraser C, Croucher NJ, Hammitt LL, Reid R, Santosham M, Weatherholtz RC, Bentley SD, OBrien KL, Lipsitch M, Hanage WPet 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>

Thesis dissertation

Raghwani J, Redd AD, Longosz AF, Wu C-H, Serwadda D, Martens C, Kagaayi J, Sewankambo N, Porcella SF, Grabowski MK, Quinn TC, Eller MA, Eller LA, Wabwire-Mangen F, Robb ML, Fraser C, Lythgoe KAet al., 2018, Evolution of HIV-1 within untreated individuals and at the population scale in Uganda, PLOS PATHOGENS, Vol: 14, ISSN: 1553-7366

Journal article

Le Vu S, Ratmann O, Delpech V, Brown AE, Gill ON, Tostevin A, Dunn D, Fraser C, Volz EMet al., 2018, Mixing patterns of HIV transmission among men who have sex with men in the United Kingdom, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Near 60% of new HIV infections in the United Kingdom are estimated to occur in men who have sex with men (MSM). Patterns of mixing between different risk groups of MSM have been suggested to spread the HIV epidemics through age-disassortative partnerships 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 prevention.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analyzed combined epidemiologic data and viral sequences from MSM diagnosed with HIV as of mid-2015 at the national level. We applied a phylodynamic source attribution model to infer patterns of transmission between groups of patients by age, ethnicity and region.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>From pair probabilities of transmission between 19 847 MSM patients, we found that potential transmitters of HIV subtype B were on average 5 months older than recipients. We also found a moderate overall assortativity of transmission by ethnic group and a stronger assortativity by region.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>

Working paper

Le Vu SOK, Ratmann O, Delpech V, Brown AE, Gill ON, Tostevin A, Fraser C, Volz EMet al., 2018, Comparison of cluster-based and source-attribution methods for estimating transmission risk using large HIV sequence databases, Epidemics, Vol: 23, Pages: 1-10, ISSN: 1755-4365

Phylogenetic clustering of HIV sequences from a random sample of patients can reveal epidemiological transmission patterns, but interpretation is hampered by limited theoretical support and statistical properties of clustering analysis remain poorly understood. Alternatively, source attribution methods allow fitting of HIV transmission models and thereby quantify aspects of disease transmission.A simulation study was conducted to assess error rates of clustering methods for detecting transmission risk factors. We modeled HIV epidemics among men having sex with men and generated phylogenies comparable to those that can be obtained from HIV surveillance data in the UK. Clustering and source attribution approaches were applied to evaluate their ability to identify patient attributes as transmission risk factors.We find that commonly used methods show a misleading association between cluster size or odds of clustering and covariates that are correlated with time since infection, regardless of their influence on transmission. Clustering methods usually have higher error rates and lower sensitivity than source attribution method for identifying transmission risk factors. But neither methods provide robust estimates of transmission risk ratios. Source attribution method can alleviate drawbacks from phylogenetic clustering but formal population genetic modeling may be required to estimate quantitative transmission risk factors.

Journal article

Blanquart F, Lehtinen S, Lipsitch M, Fraser Cet al., 2018, The evolution of antibiotic resistance in a structured host population, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 15, ISSN: 1742-5689

Journal article

van der Kuyl AC, Vink M, Zorgdrager F, Bakker M, Wymant C, Hall M, Gall A, Blanquart F, Berkhout B, Fraser C, Cornelissen Met al., 2018, The evolution of subtype B HIV-1 tat in the Netherlands during 1985-2012, VIRUS RESEARCH, Vol: 250, Pages: 51-64, ISSN: 0168-1702

Journal article

Volz E, Le Vu S, Ratmann O, Tostevin A, Orkin C, O'Shea S, Delpech V, Brown A, Fraser NGCet al., 2018, Molecular epidemiology of HIV-1 subtype B reveals heterogeneous transmission risk: Implications for intervention and control, Journal of Infectious Diseases, Vol: 217, Pages: 1522-1529, ISSN: 0022-1899

BackgroundThe impact of HIV pre-exposure prophylaxis (PrEP) depends on infections averted by protecting vulnerable individuals as well as infections averted by preventing transmission by those who would have been infected if not receiving PrEP. Analysis of HIV phylogenies reveals risk factors for transmission, which we examine as potential criteria for allocating PrEP.MethodsWe analyzed 6912 HIV-1 partial pol sequences from men who have sex with men (MSM) in the United Kingdom combined with global reference sequences and patient-level metadata. Population genetic models were developed that adjust for stage of infection, global migration of HIV lineages, and changing incidence of infection through time. Models were extended to simulate the effects of providing susceptible MSM with PrEP.ResultsWe found that young age <25 years confers higher risk of HIV transmission (relative risk = 2.52 [95% confidence interval, 2.32–2.73]) and that young MSM are more likely to transmit to one another than expected by chance. Simulated interventions indicate that 4-fold more infections can be averted over 5 years by focusing PrEP on young MSM.ConclusionsConcentrating PrEP doses on young individuals can avert more infections than random allocation.

Journal article

Stirrup OT, Dunn DT, Tostevin A, Sabin CA, Pozniak A, Asboe D, Cox A, Orkin C, Martin F, Cane P, Fairbrother K, Fearnhill E, Hubb J, Porter K, Babiker A, Lynch J, Hand J, de Souza C, Churchill D, Perry N, Tilbury S, Youssef E, Clark D, Gazzard B, Nelson M, Mabika T, Mandalia S, Anderson J, Munshi S, Post F, Adefisan A, Taylor C, Gleisner Z, Ibrahim F, Campbell L, Chadwick D, Baillie K, Gilson R, Brima N, Williams I, Ainsworth J, Schwenk A, Miller S, Wood C, Johnson M, Youle M, Lampe F, Smith C, Tsintas R, Chaloner C, Hutchinson S, Phillips A, Hill T, Jose S, Huntington S, Thornton A, Walsh J, Mackie N, Winston A, Weber J, Ramzan F, Carder M, Leen C, Wilson A, Morris S, Gompels M, Allan S, Palfreeman A, Lewszuk A, Kegg S, Faleye A, Ogunbiyi V, Mitchell S, Hay P, Kemble C, Russell-Sharpe S, Gravely J, Allan S, Harte A, Tariq A, Spencer H, Jones R, Pritchard J, Cumming S, Atkinson C, Mital D, Edgell V, Allen J, Ustianowski A, Murphy C, Gunder Iet al., 2018, Risk factors and outcomes for the Q151M and T69 insertion HIV-1 resistance mutations in historic UK data, AIDS Research and Therapy, Vol: 15, ISSN: 1742-6405

Background: The prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial concern in many low and middle-income countries. The Q151M and T69 insertion (T69i) resistance mutations in the viral reverse transcriptase gene can reduce susceptibility to all nucleoside/tide analogue reverse transcriptase inhibitors, motivating the present study to investigate the risk factors and outcomes associated with these mutations. Methods: We considered all data in the UK HIV Drug Resistance Database for blood samples obtained in the period 1997-2014. Where available, treatment history and patient outcomes were obtained through linkage to the UK Collaborative HIV Cohort study. A matched case-control approach was used to assess risk factors associated with the appearance of each of the mutations in ART-experienced patients, and survival analysis was used to investigate factors associated with viral suppression. A further analysis using matched controls was performed to investigate the impact of each mutation on survival. Results: A total of 180 patients with Q151M mutation and 85 with T69i mutation were identified, almost entirely from before 2006. Occurrence of both the Q151M and T69i mutations was strongly associated with cumulative period of virological failure while on ART, and for Q151M there was a particular positive association with use of stavudine and negative association with use of boosted-protease inhibitors. Subsequent viral suppression was negatively associated with viral load at sequencing for both mutations, and for Q151M we found a negative association with didanosine use but a positive association with boosted-protease inhibitor use. The results obtained in these analyses were also consistent with potentially large associations with other drugs. Analyses were inconclusive regarding associations between the mutations and mortality, but mortality was high for pati

Journal article

Croucher NJ, Apagyi KJ, Fraser C, 2018, Transformation asymmetry and the evolution of the bacterial accessory genome, Molecular Biology and Evolution, Vol: 35, Pages: 575-581, ISSN: 1537-1719

Bacterial transformation can insert or delete genomic islands (GIs), depending on the donor and recipient genotypes, if an homologous recombination spans the GI’s integration site and includes sufficiently long flanking homologous arms. Combining mathematical models of recombination with experiments using pneumococci found GI insertion rates declined geometrically with the GI’s size. The decrease in acquisition frequency with length (1.08x10−3 bp−1) was higher than a previous estimate of the analogous rate at which core genome recombinations terminated. Although most efficient for shorter GIs, transformation-mediated deletion frequencies did not vary consistently with GI length, with removal of 10 kb GIs approximately 50% as efficient as acquisition of base substitutions. Fragments of two kilobases, typical of transformation event sizes, could drive all these deletions independent of island length. The strong asymmetry of transformation, and its capacity to efficiently remove GIs, suggests non-mobile accessory loci will decline in frequency without preservation by selection.

Journal article

Wymant C, Blanquart F, Golubchik T, Gall A, Bakker M, Bezemer D, Croucher NJ, Hall M, Hillebregt M, Ong SH, Ratmann O, Albert J, Bannert N, Fellay J, Fransen K, Gourlay A, Grabowski MK, Gunsenheimer-Bartmeyer B, Günthard HF, Kivelä P, Kouyos R, Laeyendecker O, Liitsola K, Meyer L, Porter K, Ristola M, van Sighem A, Berkhout B, Cornelissen M, Kellam P, Reiss P, Fraser C, BEEHIVE Collaborationet al., 2018, Easy and accurate reconstruction of whole HIV genomes from short-read sequence data with shiver, Virus Evolution, Vol: 4, ISSN: 2057-1577

Studying the evolution of viruses and their molecular epidemiology relies on accurate viral sequence data, so that small differences between similar viruses can be meaningfully interpreted. Despite its higher throughput and more detailed minority variant data, next-generation sequencing has yet to be widely adopted for HIV. The difficulty of accurately reconstructing the consensus sequence of a quasispecies from reads (short fragments of DNA) in the presence of large between- and within-host diversity, including frequent indels, may have presented a barrier. In particular, mapping (aligning) reads to a reference sequence leads to biased loss of information; this bias can distort epidemiological and evolutionary conclusions. De novo assembly avoids this bias by aligning the reads to themselves, producing a set of sequences called contigs. However contigs provide only a partial summary of the reads, misassembly may result in their having an incorrect structure, and no information is available at parts of the genome where contigs could not be assembled. To address these problems we developed the tool shiver to pre-process reads for quality and contamination, then map them to a reference tailored to the sample using corrected contigs supplemented with the user's choice of existing reference sequences. Run with two commands per sample, it can easily be used for large heterogeneous data sets. We used shiver to reconstruct the consensus sequence and minority variant information from paired-end short-read whole-genome data produced with the Illumina platform, for sixty-five existing publicly available samples and fifty new samples. We show the systematic superiority of mapping to shiver's constructed reference compared with mapping the same reads to the closest of 3,249 real references: median values of 13 bases called differently and more accurately, 0 bases called differently and less accurately, and 205 bases of missing sequence recovered. We also successfully applied sh

Journal article

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