O Noel Gill

Determinants of HIV-1 transmission in men who have sex with men: a combined clinical, epidemiological and phylogenetic approach

Objectives:To identify biological factors associated with HIV transmission in men who have sex with men (MSM). Design:A longitudinal phylogenetic analysis of HIV-1 from an MSM cohort, incorporating clinical and epidemiological data. Methods:Potential individuals were HIV-infected MSM attending a sexual health clinic between 2000 and 2006. Individuals were classified such that they could move from recent to chronic infection categories. HIV-1 pol gene sequences were obtained from plasma virus or proviral DNA and clusters estimated by maximum likelihood and conservative genetic distance differences. The single most likely transmitter generating each recent infection was ascertained and risk factors around time of likely transmission explored using Poisson regression modelling. Results:Out of 1144 HIV-infected MSM, pol sequence data were obtained for 859 (75%); 159 out of 859 (19%) were recently HIV infected at diagnosis. A single most likely transmitter was identified for 41 out of 159 (26%), of which 11 were recently infected (27%) and 30 chronically infected. Factors associated with transmission in multivariable analysis were: younger age {rate ratio per 5 years older 0.68 [95% confidence interval (CI) 0.54–0.86], P = 0.0009}, higher viral load [rate ratio per log higher 1.61 (95% CI 1.15–2.25), P = 0.005], recent infection [rate ratio 3.88 (95% CI 1.76–8.55), P = 0.0008] and recent sexually transmitted disease [rate ratio 5.32 (95% CI 2.51–11.29), P = 0.0001]. HAART was highly protective in a univariable model, RR 0.14 (95% CI 0.07–0.27, P = 0.0001). Conclusion:Onward transmission of HIV among MSM is significantly associated with recent infection, sexually transmitted diseases and higher viral load, and reduced by effective HAART. The majority of new infections appear to occur from individuals whose infection was undiagnosed at the time of transmission.

HIV incidence in men who have sex with men in England and Wales 2001–10: a nationwide population study

Summary Background Control of HIV transmission could be achievable through an expansion of HIV testing of at-risk populations together with ready access and adherence to antiretroviral therapy. To examine whether increases in testing rates and antiretroviral therapy coverage correspond to the control of HIV transmission, we estimated HIV incidence in men who have sex with men (MSM) in England and Wales since 2001. Methods A CD4-staged back-calculation model of HIV incidence was used to disentangle the competing contributions of time-varying rates of diagnosis and HIV incidence to observed HIV diagnoses. Estimated trends in time to diagnosis, incidence, and undiagnosed infection in MSM were interpreted against a backdrop of increased HIV testing rates and antiretroviral-therapy coverage over the period 2001–10. Findings The observed 3·7 fold expansion in HIV testing in MSM was mirrored by a decline in the estimated mean time-to-diagnosis interval from 4·0 years (95% credible interval [CrI] 3·8–4·2) in 2001 to 3·2 years (2·6–3·8) by the end of 2010. However, neither HIV incidence (2300–2500 annual infections) nor the number of undiagnosed HIV infections (7370, 95% CrI 6990–7800, in 2001, and 7690, 5460–10 580, in 2010) changed throughout the decade, despite an increase in antiretroviral uptake from 69% in 2001 to 80% in 2010. Interpretation CD4 cell counts at HIV diagnosis are fundamental to the production of robust estimates of incidence based on HIV diagnosis data. Improved frequency and targeting of HIV testing, as well as the introduction of ART at higher CD4 counts than is currently recommended, could begin a decline in HIV transmission among MSM in England and Wales. Funding UK Medical Research Council, UK Health Protection Agency.

Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey

Objective To establish with improved accuracy the prevalence of disease related prion protein (PrPCJD) in the population of Britain and thereby guide a proportionate public health response to limit the threat of healthcare associated transmission of variant Creutzfeldt-Jakob disease (vCJD). Design Cross sectional opportunistic survey. Study samples Anonymised tonsil pairs removed at elective tonsillectomy throughout England and Scotland. Setting National anonymous tissue archive for England and Scotland. Main outcome measure Presence of PrPCJD determined by using two enzyme immunoassays based on different analytical principles, with further investigation by immunohistochemistry or immunoblotting of any samples reactive in either assay. Results Testing of 63 007 samples was completed by the end of September 2008. Of these, 12 753 were from the birth cohort in which most vCJD cases have arisen (1961-85) and 19 908 were from the 1986-95 cohort that would have been also exposed to bovine spongiform encephalopathy through infected meat or meat products. None of the samples tested was unequivocally reactive in both enzyme immunoassays. Only two samples were reactive in one or other enzyme immunoassay and equivocal in the other, and nine samples were equivocally reactive in both enzyme immunoassays. Two hundred and seventy six samples were initially reactive in one or other enzyme immunoassay; the repeat reactivity rate was 15% or less, depending on the enzyme immunoassay and cut-off definition. None of the samples (including all the 276 initially reactive in enzyme immunoassay) that were investigated by immunohistochemistry or immunoblotting was positive for the presence of PrPCJD. Conclusions The observed prevalence of PrPCJD in tonsils from the 1961-95 combined birth cohort was 0/32 661 with a 95% confidence interval of 0 to 113 per million. In the 1961-85 cohort, the prevalence of zero with a 95% confidence interval of 0 to 289 per million was lower than, but still consistent with, a previous survey of appendix tissue that showed a prevalence of 292 per million with a 95% confidence interval of 60 to 853 per million. Continuing to archive and test tonsil specimens, especially in older birth cohorts, and other complementary large scale anonymous tissue surveys, particularly of post-mortem tissues, will further refine the calculated prevalence of PrPCJD.

Assessing the impact of national anti-HIV sexual health campaigns: trends in the transmission of HIV and other sexually transmitted infections in England.

Objective: To assess the impact of the sexual component of AIDS and HIV campaigns on transmission of HIV and other sexually transmitted infections (STIs). Design: Comparison of time series data. Setting: England, 1971–1999. Outcome measures: HIV transmission and diagnoses among men who have sex with men (MSMs), rates of attendances and specific STI diagnoses (per 100 000 total population) at genitourinary medicine (GUM) clinics. Results: Awareness of AIDS and campaigns in 1983–4 among homosexual men coincided with substantial declines in transmission of HIV and diagnoses of syphilis among MSMs. During general population campaigns in 1986-7 new GUM clinic attendances requiring treatment fell by 117/105 in men and 42/105 in women. Rates for gonorrhoea fell by 81/105 and 43/105 and genital herpes by 6/105 and 4/105, respectively. Previous rises in genital wart rates were interrupted, while rates of attendances not requiring treatment (the “worried well”) increased by 47/105 and 58/105 for men and women, respectively. Since 1987 diagnoses of HIV among MSMs have not declined, averaging 1300–1400 annually. Following a period of unchanging rates there have been substantial increases in GUM attendances requiring treatment, notably for gonorrhoea, syphilis, and viral STIs since 1995. Conclusions: Self help initiatives and awareness among homosexual men in 1983–4 contributed significantly to a fall in HIV transmission among MSMs, and the general campaigns of 1986–7 were associated with similar effects on all STI transmission. Both effects seem to have occurred through changing sexual behaviour, and probably contributed to the UKs low national HIV prevalence. Bacterial STI incidence has increased significantly since 1995 and there is no evidence that recent prevention initiatives have reduced HIV transmission among MSMs, hence sexual health initiatives need to be comprehensively reinvigorated in England.

HIV incidence appears constant in men who have sex with men despite widespread use of effective antiretroviral therapy.

Objective: To estimate the trend in HIV incidence between 1995 and 2001 in men who have sex with men (MSM) attending sexually transmitted infection (STI) clinics in the UK. Design: The Serological Testing Algorithm for Recent HIV Seroconversion (STARHS) was applied to serum specimens from MSM attending 15 STI clinics collaborating in an HIV unlinked anonymous prevalence serosurvey. Methods: STARHS was performed on anti-HIV-1 positive specimens and HIV incidence rates determined. Specimens from MSM with previously diagnosed HIV or an AIDS defining condition were excluded. National data on uptake of antiretroviral therapy (ART), AIDS mortality and diagnoses of gonorrhoea in MSM were used to aid interpretation of the HIV incidence findings. Results: Of 43 100 specimens collected from MSM 3565 were anti-HIV-1 positive. Of these, 1645 were eligible and available for STARHS testing, of which 317 were deemed to come from recently acquired infections. The overall estimated annual incidence ranged from 1.5% (1999) to 3.3% (1996). In 2001 it was 2.45%, with a 3.1% incidence in London and 1.0% elsewhere. No significant trends in HIV incidence were found. Conclusions: Despite the widespread use of ART there was no significant decline in HIV incidence. Individuals whose HIV infection has been diagnosed should be less infectious. However, over 20% of infections in MSM remain undiagnosed, many with acute STI, and this pool of unmanaged HIV infection may be an important driver of the ongoing epidemic. Initiatives to diagnose and treat a greater proportion of HIV infections may be the key to reducing HIV incidence in MSM.

Surveillance of HIV-1 subtypes among heterosexuals in England and Wales, 1997-2000.

Summary:The molecular diversity and demographic characteristics among 976 anti-HIV-1-positive heterosexuals attending 15 sexually transmitted infection (STI) clinics participating in an unlinked anonymous HIV prevalence serosurvey in England and Wales during 1997–2000 were investigated. Subtypes were assigned by heteroduplex mobility assay or sequencing of the p17/p24 region of gag and the V3/V4 region of env and by sequencing of the protease gene. Overall, there was no significant change in the subtype distribution, with subtype C accounting for the majority (32%) of subtyped infections. Subtypes B (29%), A (12%), circulating recombinant forms (CRFs, 9%), unique recombinant forms (URFs, 8%), and subtypes D-H (8%) were also detected. Thirty-nine percent of infections in men were with subtype B, whereas subtype C was most common (38%) in women. Logistic regression analyses showed the relative risk (RR) of infection with a non-B subtype, compared with subtype B, to be greater in African-born individuals (RR = 28.9, P < 0.01), among newly diagnosed infections (RR = 3.4, P < 0.01), and in women (RR = 2.4, P < 0.01). These findings indicate a high level of genetic diversity among HIV-infected heterosexual STI clinic attendees in England and Wales. Recently, subtype C has become most prevalent, particularly in younger age groups, suggesting recent acquisition of this viral strain. The high proportion of non-B, CRF, and URF infections among UK-born individuals is consistent with mixing between migrants and UK-born individuals in England and Wales. As migration patterns change, continued monitoring of HIV genetic diversity will aid understanding of transmission patterns.

Declining Genital Warts in Young Women in England Associated With HPV 16/18 Vaccination: An Ecological Study

Background. Diagnoses of genital warts (GW) in genitourinary medicine (GUM) clinics have been increasing in England for many years. In 2008, an HPV immunization program began with a bivalent vaccine (Cervarix). This was expected to markedly reduce infections and disease due to human papillomavirus (HPV) 16/18 but not HPV 6/11 infections or disease. However, from 2009 to 2011 there were decreases in reported diagnoses of GW in young females at GUM clinics. Methods. Using data from GUM clinics and a sample of general practices (GPs) throughout England, we analyzed rates of GW diagnoses by age, year of diagnosis, and estimated immunization coverage. Results. The overall reduction in GW diagnoses at GUM clinics between 2008 and 2011 was 13.3% among 16- to 19-year-old females, with the greatest decline of 20.8% in 17-year-olds. Declines were positively associated with estimated immunization coverage. A similar pattern was seen in GP diagnoses, but not among older women, and for other GUM consultations. Conclusions. Several factors might contribute to declines in GW. However, the size and pattern of the declines strongly suggest that we are observing an unexpected, moderately protective effect of HPV 16/18 vaccination against GW.

Monitoring the emergence of community transmission of influenza A/H1N1 2009 in England: a cross sectional opportunistic survey of self sampled telephone callers to NHS Direct

Objective To evaluate ascertainment of the onset of community transmission of influenza A/H1N1 2009 (swine flu) in England during the earliest phase of the epidemic through comparing data from two surveillance systems. Design Cross sectional opportunistic survey. Study samples Results from self samples by consenting patients who had called the NHS Direct telephone health line with cold or flu symptoms, or both, and results from Health Protection Agency (HPA) regional microbiology laboratories on patients tested according to the clinical algorithm for the management of suspected cases of swine flu. Setting Six regions of England between 24 May and 30 June 2009. Main outcome measure Proportion of specimens with laboratory evidence of influenza A/H1N1 2009. Results Influenza A/H1N1 2009 infections were detected in 91 (7%) of the 1385 self sampled specimens tested. In addition, eight instances of influenza A/H3 infection and two cases of influenza B infection were detected. The weekly rate of change in the proportions of infected individuals according to self obtained samples closely matched the rate of increase in the proportions of infected people reported by HPA regional laboratories. Comparing the data from both systems showed that local community transmission was occurring in London and the West Midlands once HPA regional laboratories began detecting 100 or more influenza A/H1N1 2009 infections, or a proportion positive of over 20% of those tested, each week. Conclusions Trends in the proportion of patients with influenza A/H1N1 2009 across regions detected through clinical management were mirrored by the proportion of NHS Direct callers with laboratory confirmed infection. The initial concern that information from HPA regional laboratory reports would be too limited because it was based on testing patients with either travel associated risk or who were contacts of other influenza cases was unfounded. Reports from HPA regional laboratories could be used to recognise the extent to which local community transmission was occurring.

Prevalence of human papillomavirus (HPV) infections in sexually active adolescents and young women in England, prior to widespread HPV immunisation

INTRODUCTION The introduction of an HPV immunisation programme in England should result in a significant reduction in the prevalence of vaccine type infections in young women. Here we describe type-specific HPV prevalence in three samples of the young female population in England, prior to the beginning of mass immunisation in 2008. METHODS Residual vulva-vaginal swab samples from females aged under 25 years undergoing chlamydia testing as part of the National Chlamydia Screening Programme (NCSP) or Prevention of Pelvic Infection (POPI) trial were collected from sites across England, together with available demographic and sexual behaviour data. Residual samples were screened for HPV infection using the Hybrid Capture 2 (hc2) HPV DNA Test, including the high-risk (HR) and low-risk (LR) probes. Hc2 positive samples were genotyped using the Roche Linear Array (LA) HPV Genotyping Test. RESULTS A total of 3829 samples were included: 2369 from 16 to 24 year old NCSP participants, 275 from 13 to 15 year old NCSP participants and 1185 from 16 to 24 year old POPI participants. Variations in HPV prevalence between and within the different samples followed a pattern largely consistent with differences in sexual behaviour. The prevalence of total HR HPV infection, of HPV 16 and/or 18 (16/18) infection and of five HR HPV types closely related to HPV 16/18 (HPV 31, 33, 45, 52 or 58) amongst 16-24 year old NCSP participants was 35% (95% CI 33-37%), 18% (95% CI 16-19%), and 16% (95% CI 14-18%), respectively. Risk of HR HPV infection increased with age during the teen years and was higher in women who reported two or more sexual partners in the last year and in women with chlamydia infection. Approximately half of women with HPV 16/18 infection also had another non-vaccine HR HPV type present. CONCLUSIONS Prior to HPV immunisation, there was a high prevalence of HPV infections in the lower genital tract of young, sexually active females in England. The overall, type-specific, and multiple infection prevalence closely reflected age and sexual activity. These data provide a baseline against which the early impact of HPV immunisation on the prevalence of HPV 16/18 and closely related types in young women can be measured, in order to inform immunisation and cervical screening policies.

Does the recent increase in HIV diagnoses among men who have sex with men in the UK reflect a rise in HIV incidence or increased uptake of HIV testing

Objectives: To determine whether the increase in HIV diagnoses since 1997 among men who have sex with men (MSM) in the UK reflects a rise in HIV incidence or an increase in HIV testing. Methods: Estimates of HIV incidence were derived using data from UK HIV surveillance systems (HIV diagnoses; CD4 surveillance; unlinked anonymous surveys) for 1997–2004. Data on HIV testing were provided by KC60 statutory returns, voluntary testing and unlinked anonymous surveys in sentinel genitourinary medicine (GUM) clinics. Results: HIV diagnoses among MSM in the UK rose by 54% between 1997 and 2004 (from 1382 to 2124), with variation by age and geographical location. The number of HIV diagnoses among MSM <35 years of age in London showed no increase, but in all other groups it increased. Throughout the UK, uptake of HIV testing increased significantly among MSM attending GUM clinics between 1997 and 2004, including “at-risk” MSM (p<0.001). Direct incidence estimates (serological testing algorithm for recent HIV seroconversion assay) provided no evidence of a statistically significant increase or decrease in HIV incidence. Indirect estimates suggested that there may have been a rise in HIV incidence, but these estimates were influenced by the increased uptake of HIV testing. Conclusions: The number of HIV diagnoses increased among MSM in the UK between 1997 and 2004, except among younger MSM in London, in whom there was no change. The increase in HIV diagnoses among MSM in the UK since 1997 seems to reflect an increase in HIV testing rather than a rise in HIV incidence.