Diagnosis delays in the UK according to pre- or post-migration acquisition of HIV

Objectives: To evaluate whether infection occurred pre- or post-migration and the associated diagnosis delay in migrants diagnosed with HIV in the UK. Design: We analysed a cohort of individuals diagnosed with HIV in the UK in 2014–2016 born in Africa or elsewhere in Europe. Inclusion criteria were arrival within 15 years before diagnosis, availability of HIV pol sequence and viral subtype shared by at least 10 individuals. Methods: We examined phylogenies for evidence of infection after entry into the UK and incorporated this information into a Bayesian analysis of timing of infection using biomarkers of CD4+ cell count, avidity assays, proportion of ambiguous nucleotides in viral sequences and last negative test dates where available. Results: 1256 individuals were included. The final model indicated that HIV was acquired post-migration for most men who have sex with men (MSM) born in Europe (posterior expectation 65%, 95% credibility interval 64%-67%) or Africa (65%, 62%-69%), whereas a minority (20%-30%) of men and women with heterosexual transmission acquired HIV post-migration. Estimated diagnosis delays were lower for MSM than for those with heterosexual transmission, and were lower for those with post-migration infection across all subgroups. For MSM acquiring HIV post-migration the estimated mean time to diagnosis was 5 years for all subgroups. Conclusions: Acquisition of HIV post-migration is common, particularly among MSM calling for prevention efforts aimed at migrant communities. Delays in diagnosis reinforce the need for targeted testing initiatives

HIV genetic diversity informs stage of HIV-1 infection among patients receiving antiretroviral therapy in Botswana

Background HIV-1 genetic diversity increases during infection and can help infer the time elapsed since infection. However the effect of antiretroviral treatment (ART) on the inference remains unknown. Methods Participants with estimated duration of HIV-1 infection based on repeated testing were sourced from cohorts in Botswana (n=1944). Full-length HIV genome sequencing was performed from proviral DNA. We optimized a machine learning model to classify infections as 1 year based on viral genetic diversity, demographic and clinical data. Results The best predictive model included variables for genetic diversity of HIV-1 gag, pol and env, viral load, age, sex and ART status. Most participants were on ART. Balanced accuracy was 90.6% (95%CI:86.7%-94.1%). We tested the algorithm among newly diagnosed participants with or without documented negative HIV tests. Among those without records, those who self-reported a negative HIV test within 1 year previously. There was no difference in classification between those self-reporting a negative HIV test <1 year, whether or not they had a record. Conclusions These results indicate that recency of HIV-1 infection can be inferred from viral sequence diversity even among patients on suppressive ART

Transmission of Non-B HIV Subtypes in the United Kingdom Is Increasingly Driven by Large Non-Heterosexual Transmission Clusters

BACKGROUND: The United Kingdom human immunodeficiency virus (HIV) epidemic was historically dominated by HIV subtype B transmission among men who have sex with men (MSM). Now 50% of diagnoses and prevalent infections are among heterosexual individuals and mainly involve non-B subtypes. Between 2002 and 2010, the prevalence of non-B diagnoses among MSM increased from 5.4% to 17%, and this study focused on the drivers of this change. METHODS: Growth between 2007 and 2009 in transmission clusters among 14 000 subtype A1, C, D, and G sequences from the United Kingdom HIV Drug Resistance Database was analysed by risk group. RESULTS: Of 1148 clusters containing at least 2 sequences in 2007, >75% were pairs and >90% were heterosexual. Most clusters (71.4%) did not grow during the study period. Growth was significantly lower for small clusters and higher for clusters of ≥7 sequences, with the highest growth observed for clusters comprising sequences from MSM and people who inject drugs (PWID). Risk group (P< .0001), cluster size (P< .0001), and subtype (P< .01) were predictive of growth in a generalized linear model. DISCUSSION: Despite the increase in non-B subtypes associated with heterosexual transmission, MSM and PWID are at risk for non-B infections. Crossover of subtype C from heterosexuals to MSM has led to the expansion of this subtype within the United Kingdom

Lack of Effectiveness of Antiretroviral Therapy in Preventing HIV Infection in Serodiscordant Couples in Uganda: An Observational Study.

BACKGROUND: We examined the real-world effectiveness of ART as an HIV prevention tool among HIV serodiscordant couples in a programmatic setting in a low-income country. METHODS: We enrolled individuals from HIV serodiscordant couples aged ≥18 years of age in Jinja, Uganda from June 2009 - June 2011. In one group of couples the HIV positive partner was receiving ART as they met clinical eligibility criteria (a CD4 cell count ≤250 cells/ μL or WHO Stage III/IV disease). In the second group the infected partner was not yet ART-eligible. We measured HIV incidence by testing the uninfected partner every three months. We conducted genetic linkage studies to determine the source of new infections in seroconverting participants. RESULTS: A total of 586 couples were enrolled of which 249 (42%) of the HIV positive participants were receiving ART at enrollment, and an additional 99 (17%) initiated ART during the study. The median duration of follow-up was 1.5 years. We found 9 new infections among partners of participants who had been receiving ART for at least three months and 8 new infections in partners of participants who had not received ART or received it for less than three months, for incidence rates of 2.09 per 100 person-years (PYRs) and 2.30 per 100 PYRs, respectively. The incidence rate ratio for ART-use was 0.91 (95% confidence interval 0.31-2.70; p=0.999). The hazard ratio for HIV seroconversion associated with ART-use by the positive partner was 1.07 (95% CI 0.41-2.80). A total of 5/7 (71%) of the transmissions on ART and 6/7 (86%) of those not on ART were genetically linked. CONCLUSION: Overall HIV incidence was low in comparison to previous studies of serodiscordant couples. However, ART-use was not associated with a reduced risk of HIV transmission in this study

Genetic evidence for the association between COVID-19 epidemic severity and timing of non-pharmaceutical interventions

Unprecedented public health interventions including travel restrictions and national lockdowns have been implemented to stem the COVID-19 epidemic, but the effectiveness of non- pharmaceutical interventions is still debated. We carried out a phylogenetic analysis of more than 29,000 publicly available whole genome SARS-CoV-2 sequences from 57 locations to estimate the time that the epidemic originated in different places. These estimates were examined in relation to the dates of the most stringent interventions in each location as well as to the number of cumulative COVID-19 deaths and phylodynamic estimates of epidemic size. Here we report that the time elapsed between epidemic origin and maximum intervention is associated with different measures of epidemic severity and explains 11% of the variance in reported deaths one month after the most stringent intervention. Locations where strong non-pharmaceutical interventions were implemented earlier experienced 30 much less severe COVID-19 morbidity and mortality during the period of study

A Direct Comparison of Two Densely Sampled HIV Epidemics: The UK and Switzerland

Phylogenetic clustering approaches can elucidate HIV transmission dynamics. Comparisons across countries are essential for evaluating public health policies. Here, we used a standardised approach to compare the UK HIV Drug Resistance Database and the Swiss HIV Cohort Study while maintaining data-protection requirements. Clusters were identified in subtype A1, B and C pol phylogenies. We generated degree distributions for each risk group and compared distributions between countries using Kolmogorov-Smirnov (KS) tests, Degree Distribution Quantification and Comparison (DDQC) and bootstrapping. We used logistic regression to predict cluster membership based on country, sampling date, risk group, ethnicity and sex. We analysed >8,000 Swiss and >30,000 UK subtype B sequences. At 4.5% genetic distance, the UK was more clustered and MSM and heterosexual degree distributions differed significantly by the KS test. The KS test is sensitive to variation in network scale, and jackknifing the UK MSM dataset to the size of the Swiss dataset removed the difference. Only heterosexuals varied based on the DDQC, due to UK male heterosexuals who clustered exclusively with MSM. Their removal eliminated this difference. In conclusion, the UK and Swiss HIV epidemics have similar underlying dynamics and observed differences in clustering are mainly due to different population sizes

Analysis of the History and Spread of HIV-1 in Uganda using phylodynamics

HIV prevalence has decreased in Uganda since the 1990s, but remains substantial within high-risk groups. Here, we reconstruct the history and spread of HIV subtypes A1 and D in Uganda and explore the transmission dynamics in high-risk populations. We analysed HIV pol sequences from female sex workers in Kampala (n = 42), Lake Victoria fisher-folk (n = 46) and a rural clinical cohort (n = 74), together with publicly available sequences from adjacent regions in Uganda (n = 412) and newly generated sequences from samples taken in Kampala in 1986 (n = 12). Of the sequences from the three Ugandan populations, 60 (37.1 %) were classified as subtype D, 54 (33.3 %) as subtype A1, 31 (19.1 %) as A1/D recombinants, six (3.7 %) as subtype C, one (0.6 %) as subtype G and 10 (6.2 %) as other recombinants. Among the A1/D recombinants we identified a new candidate circulating recombinant form. Phylodynamic and phylogeographic analyses using BEAST indicated that the Ugandan epidemics originated in 1960 (1950-1968) for subtype A1 and 1973 (1970-1977) for D, in rural south-western Uganda with subsequent spread to Kampala. They also showed extensive interconnection with adjacent countries. The sequence analysis shows both epidemics grew exponentially during the 1970s-1980s and decreased from 1992, which agrees with HIV prevalence reports in Uganda. Inclusion of sequences from the 1980s indicated the origin of both epidemics was more recent than expected and substantially narrowed the confidence intervals in comparison to previous estimates. We identified three transmission clusters and ten pairs, none of them including patients from different populations, suggesting active transmission within a structured transmission network

A pragmatic harm reduction approach to manage a large outbreak of wound botulism in people who inject drugs, Scotland 2015

Abstract Background People who inject drugs (PWID) are at an increased risk of wound botulism, a potentially fatal acute paralytic illness. During the first 6 months of 2015, a large outbreak of wound botulism was confirmed among PWID in Scotland, which resulted in the largest outbreak in Europe to date. Methods A multidisciplinary Incident Management Team (IMT) was convened to conduct an outbreak investigation, which consisted of enhanced surveillance of cases in order to characterise risk factors and identify potential sources of infection. Results Between the 24th of December 2014 and the 30th of May 2015, a total of 40 cases were reported across six regions in Scotland. The majority of the cases were male, over 30 and residents in Glasgow. All epidemiological evidence suggested a contaminated batch of heroin or cutting agent as the source of the outbreak. There are significant challenges associated with managing an outbreak among PWID, given their vulnerability and complex addiction needs. Thus, a pragmatic harm reduction approach was adopted which focused on reducing the risk of infection for those who continued to inject and limited consequences for those who got infected. Conclusions The management of this outbreak highlighted the importance and need for pragmatic harm reduction interventions which support the addiction needs of PWID during an outbreak of spore-forming bacteria. Given the scale of this outbreak, the experimental learning gained during this and similar outbreaks involving spore-forming bacteria in the UK was collated into national guidance to improve the management and investigation of future outbreaks among PWID

Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England

The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England1, was first identified in the UK in late summer to early autumn 20202. Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number

Automated analysis of phylogenetic clusters

BACKGROUND: As sequence data sets used for the investigation of pathogen transmission patterns increase in size, automated tools and standardized methods for cluster analysis have become necessary. We have developed an automated Cluster Picker which identifies monophyletic clades meeting user-input criteria for bootstrap support and maximum genetic distance within large phylogenetic trees. A second tool, the Cluster Matcher, automates the process of linking genetic data to epidemiological or clinical data, and matches clusters between runs of the Cluster Picker. RESULTS: We explore the effect of different bootstrap and genetic distance thresholds on clusters identified in a data set of publicly available HIV sequences, and compare these results to those of a previously published tool for cluster identification. To demonstrate their utility, we then use the Cluster Picker and Cluster Matcher together to investigate how clusters in the data set changed over time. We find that clusters containing sequences from more than one UK location at the first time point (multiple origin) were significantly more likely to grow than those representing only a single location. CONCLUSIONS: The Cluster Picker and Cluster Matcher can rapidly process phylogenetic trees containing tens of thousands of sequences. Together these tools will facilitate comparisons of pathogen transmission dynamics between studies and countries