Daniela Bezemer

A resurgent HIV-1 epidemic among men who have sex with men in the era of potent antiretroviral therapy

Objective:Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. Design:We focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. Methods:We used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. Results:We show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, the risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000–2004 (95% confidence interval 0.98–1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. Conclusion:We provide the first detailed quantitative analysis of the HIV epidemic in a well defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Transmission networks of HIV-1 among men having sex with men in the Netherlands

Objective: To obtain insight in the HIV-1 transmission networks among men having sex with men (MSM) in the Netherlands. Design: A phylogenetic tree was constructed from polymerase sequences isolated from 2877 HIV-1 subtype B-infected patients monitored as part of the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide observational cohort. Methods: For MSM with a known date of infection, the most similar sequences were selected as potential transmission pairs when they clustered with bootstrap value of at least 99%. Time from infection to onward transmission was estimated as the median time between dates of infection for each transmission pair. The source of infections with a resistant strain was traced using the entire phylogenetic tree. Results: Of sequences from 403 MSM with a known date of infection between 1987 and 2007, 175 (43%) formed 63 clusters. Median time to onward transmission was 1.4 years (interquartile range 0.6–2.7). Twenty-four (6%) MSM carried a virus with resistance-related mutations, 13 of these were in eight clusters together with sequences from 28 other patients in the entire phylogenetic tree. Six clusters contained sequences obtained from 29 men all presenting the same resistance-related mutations. Conclusion: From our selection of likely transmission pairs, we conclude that onward transmission of HIV-1 from infected MSM in the Netherlands happens both during and after primary infection. Transmission of resistant strains from the antiretroviral therapy-treated population is limited, but strains with resistance-related mutations have formed subepidemics.

Resurgence of HIV infection among men who have sex with men in Switzerland: mathematical modelling study

Background New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. Methodology/Principal Findings The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995–1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. Conclusions/Significance The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions.

27 years of the HIV epidemic amongst men having sex with men in the Netherlands: An in depth mathematical model-based analysis

BACKGROUND There has been increasing concern about a resurgent epidemic of HIV-1 amongst men having sex with men in the Netherlands, which has parallels with similar epidemics now occurring in many other countries. METHODS A transmission model applicable to HIV-1 epidemics, including the use of antiretroviral therapy, is presented in a set of ordinary differential equations. The model is fitted by maximum likelihood to national HIV-1 and AIDS diagnosis data from 1980 to 2006, estimating parameters on average changes in unsafe sex and time to diagnosis. Robustness is studied with a detailed univariate sensitivity analysis, and a range of hypothetical scenarios are explored for the past and next decade. RESULTS With a reproduction number around the epidemic threshold one, the HIV-1 epidemic amongst men having sex with men in the Netherlands is still not under control. Scenario analysis showed that in the absence of antiretroviral therapy limiting infectiousness in treated patients, the epidemic could have been more than double its current size. Ninety percent of new HIV transmissions are estimated to take place before diagnosis of the index case. Decreasing time from infection to diagnosis, which was 2.5 years on average in 2006, can prevent many future infections. CONCLUSIONS Sexual risk behaviour amongst men having sex with men who are not aware of their infection is the most likely factor driving this epidemic.

Viral load levels measured at set-point have risen over the last decade of the HIV epidemic in the Netherlands.

Background HIV-1 RNA plasma concentration at viral set-point is associated not only with disease outcome but also with the transmission dynamics of HIV-1. We investigated whether plasma HIV-1 RNA concentration and CD4 cell count at viral set-point have changed over time in the HIV epidemic in the Netherlands. Methodology/Principal Findings We selected 906 therapy-naïve patients with at least one plasma HIV-1 RNA concentration measured 9 to 27 months after estimated seroconversion. Changes in HIV-1 RNA and CD4 cell count at viral set-point over time were analysed using linear regression models. The ATHENA national observational cohort contributed all patients who seroconverted in or after 1996; the Amsterdam Cohort Studies (ACS) contributed seroconverters before 1996. The mean of the first HIV-1 RNA concentration measured 9–27 months after seroconversion was 4.30 log10 copies/ml (95% CI 4.17–4.42) for seroconverters from 1984 through 1995 (n = 163); 4.27 (4.16–4.37) for seroconverters 1996–2002 (n = 232), and 4.59 (4.52–4.66) for seroconverters 2003–2007 (n = 511). Compared to patients seroconverting between 2003–2007, the adjusted mean HIV-1 RNA concentration at set-point was 0.28 log10 copies/ml (95% CI 0.16–0.40; p<0.0001) and 0.26 (0.11–0.41; p = 0.0006) lower for those seroconverting between 1996–2002 and 1984–1995, respectively. Results were robust regardless of type of HIV-1 RNA assay, HIV-1 subtype, and interval between measurement and seroconversion. CD4 cell count at viral set-point declined over calendar time at approximately 5 cells/mm3/year. Conclusion The HIV-1 RNA plasma concentration at viral set-point has increased over the last decade of the HIV epidemic in the Netherlands. This is accompanied by a decreasing CD4 cell count over the period 1984–2007 and may have implications for both the course of the HIV infection and the epidemic.

Sources of HIV infection among men having sex with men and implications for prevention

Available antiretrovirals both for treatment and prevention and more comprehensive HIV testing would have prevented the majority of past, annual HIV transmissions among MSM in the Netherlands, but none of the three interventions in isolation. The ART of HIV prevention Despite the relative success of antiretroviral therapy (ART) for individuals infected with HIV, the rate of new diagnoses has remained fairly constant in vulnerable population groups, particularly men having sex with men (MSM). Now, ART is also available in the United States to uninfected individuals to directly prevent infection with the virus. Ratmann et al. were able to reconstruct ~600 past transmission events among men having sex with men in the Netherlands, and examined probable sources of transmission. They found that the large majority of new infections is neither attributable to ineffective ART nor inadequate retention in care. Rather, many of these cases could have been averted with more comprehensive HIV testing and a broader use of ART that includes provision to uninfected men as well as starting ART as soon as possible among newly diagnosed men. These findings support making ART for pre-exposure prophylaxis available worldwide, and especially in countries with high retention in care and high ART coverage among infected MSM. New HIV diagnoses among men having sex with men (MSM) have not decreased appreciably in most countries, even though care and prevention services have been scaled up substantially in the past 20 years. To maximize the impact of prevention strategies, it is crucial to quantify the sources of transmission at the population level. We used viral sequence and clinical patient data from one of Europe’s nationwide cohort studies to estimate probable sources of transmission for 617 recently infected MSM. Seventy-one percent of transmissions were from undiagnosed men, 6% from men who had initiated antiretroviral therapy (ART), 1% from men with no contact to care for at least 18 months, and 43% from those in their first year of infection. The lack of substantial reductions in incidence among Dutch MSM is not a result of ineffective ART provision or inadequate retention in care. In counterfactual modeling scenarios, 19% of these past cases could have been averted with current annual testing coverage and immediate ART to those testing positive. Sixty-six percent of these cases could have been averted with available antiretrovirals (immediate ART provided to all MSM testing positive, and preexposure antiretroviral prophylaxis taken by half of all who test negative for HIV), but only if half of all men at risk of transmission had tested annually. With increasing sequence coverage, molecular epidemiological analyses can be a key tool to direct HIV prevention strategies to the predominant sources of infection, and help send HIV epidemics among MSM into a decisive decline.

Dispersion of the HIV-1 Epidemic in Men Who Have Sex with Men in the Netherlands : A Combined Mathematical Model and Phylogenetic Analysis

Background The HIV-1 subtype B epidemic amongst men who have sex with men (MSM) is resurgent in many countries despite the widespread use of effective combination antiretroviral therapy (cART). In this combined mathematical and phylogenetic study of observational data, we aimed to find out the extent to which the resurgent epidemic is the result of newly introduced strains or of growth of already circulating strains. Methods and Findings As of November 2011, the ATHENA observational HIV cohort of all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who were diagnosed between 1981 and 1995 were included in the cohort if they were still alive in 1996. The ten most similar sequences to each ATHENA sequence were selected from the Los Alamos HIV Sequence Database, and a phylogenetic tree was created of a total of 8,320 sequences. Large transmission clusters that included ≥10 ATHENA sequences were selected, with a local support value ≥ 0.9 and median pairwise patristic distance below the fifth percentile of distances in the whole tree. Time-varying reproduction numbers of the large MSM-majority clusters were estimated through mathematical modeling. We identified 106 large transmission clusters, including 3,061 (52%) ATHENA and 652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the cohort in the Netherlands (2,128 of 4,288) were included in 91 large MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority clusters were already circulating before 1996, when cART was introduced, and have persisted to the present. Overall, 1,226 (35%) of the 3,460 diagnoses among MSM since 1996 were found in these 54 long-standing clusters. The reproduction numbers of all large MSM-majority clusters were around the epidemic threshold value of one over the whole study period. A tendency towards higher numbers was visible in recent years, especially in the more recently introduced clusters. The mean age of MSM at diagnosis increased by 0.45 years/year within clusters, but new clusters appeared with lower mean age. Major strengths of this study are the high proportion of HIV-positive MSM with a sequence in this study and the combined application of phylogenetic and modeling approaches. Main limitations are the assumption that the sampled population is representative of the overall HIV-positive population and the assumption that the diagnosis interval distribution is similar between clusters. Conclusions The resurgent HIV epidemic amongst MSM in the Netherlands is driven by several large, persistent, self-sustaining, and, in many cases, growing sub-epidemics shifting towards new generations of MSM. Many of the sub-epidemics have been present since the early epidemic, to which new sub-epidemics are being added.

Estimating HIV Incidence, Time to Diagnosis, and the Undiagnosed HIV Epidemic Using Routine Surveillance Data.

Background: Estimates of the size of the undiagnosed HIV-infected population are important to understand the HIV epidemic and to plan interventions, including “test-and-treat” strategies. Methods: We developed a multi-state back-calculation model to estimate HIV incidence, time between infection and diagnosis, and the undiagnosed population by CD4 count strata, using surveillance data on new HIV and AIDS diagnoses. The HIV incidence curve was modelled using cubic splines. The model was tested on simulated data and applied to surveillance data on men who have sex with men in The Netherlands. Results: The number of HIV infections could be estimated accurately using simulated data, with most values within the 95% confidence intervals of model predictions. When applying the model to Dutch surveillance data, 15,400 (95% confidence interval [CI] = 15,000, 16,000) men who have sex with men were estimated to have been infected between 1980 and 2011. HIV incidence showed a bimodal distribution, with peaks around 1985 and 2005 and a decline in recent years. Mean time to diagnosis was 6.1 (95% CI = 5.8, 6.4) years between 1984 and 1995 and decreased to 2.6 (2.3, 3.0) years in 2011. By the end of 2011, 11,500 (11,000, 12,000) men who have sex with men in The Netherlands were estimated to be living with HIV, of whom 1,750 (1,450, 2,200) were still undiagnosed. Of the undiagnosed men who have sex with men, 29% (22, 37) were infected for less than 1 year, and 16% (13, 20) for more than 5 years. Conclusions: This multi-state back-calculation model will be useful to estimate HIV incidence, time to diagnosis, and the undiagnosed HIV epidemic based on routine surveillance data.

Increasing sexual risk behaviour among Dutch men who have sex with men: mathematical models versus prospective cohort data.

Changes in risk behaviour among men who have sex with men (MSM) in the Netherlands were estimated by fitting a mathematical model to annual HIV and AIDS diagnoses in the period 1980–2009 and, independently, from rates of unprotected anal intercourse in a prospective cohort study in Amsterdam. The agreement between the two approaches was very good, confirming that in terms of incidence, increasing risk behaviour between MSM is offsetting benefits offered by enhanced testing and treatment.

Lower mortality and earlier start of combination antiretroviral therapy in patients tested repeatedly for HIV than in those with a positive first test

Background:Early diagnosis of HIV-1 infection will probably beneficially impact onward transmission and life expectancy. We compared mortality rates and CD4 cell counts at start of combination antiretroviral therapy (cART) in patients with different frequencies of diagnostic testing for HIV. Methods:Patients infected with HIV-1 through sexual contact and in follow-up anytime from 2004 through 2008 were selected from the AIDS Therapy Evaluation in the Netherlands national observational HIV cohort and stratified into three groups: patients without a prior negative HIV antibody test (i.e., with a positive first-test result); patients with 1–2 years between the last negative and first positive test; and patients with less than 1 year between tests. Outcome measures were mortality from 2004 through 2008 and CD4 cell count at cART initiation. Results:Of 5494 patients, the mortality rate was highest among the 4067 patients with a positive first test (1.33/100 person-years) and the adjusted relative risk of mortality was 0.50 in 561 patients with tests 1–2 years apart (P = 0.04 compared to patients with a positive first test) and 0.49 (P = 0.02) when tests were less than 1 year apart (n = 866). In patients with a positive first test, 48% had CD4 cell counts less than 200 cells/μl at cART initiation; this proportion was 23–26% in the two groups of repeatedly tested patients (adjusted odds ratio compared to patients with a positive first test 0.43 and 0.37, respectively; both P < 0.0001). Conclusion:Frequent repeated testing for HIV may improve the rate of timely diagnosis and treatment, thereby preventing disease progression.