Alexander Hoare

Importance of promoting HIV testing for preventing secondary transmissions: modelling the Australian HIV epidemic among men who have sex with men.

BACKGROUND We address the research questions: (i) what proportion of new HIV infections is transmitted from people who are (a) undiagnosed, (b) in primary HIV infection (PHI), (c) on antiretroviral therapy?; and (ii) what is the expected epidemiological impact of (a) increasing the proportion of newly acquired HIV infections receiving early treatment, and (b) increasing HIV testing rates? METHODS We used a mathematical model to simulate HIV transmission in the population of men who have sex with men (MSM) in Australia. We calibrated the model using established biological and clinical data and a wide range of Australian MSM epidemiological and behavioural data sources. RESULTS We estimate that ~19% of all new HIV infections are transmitted from the ~3% of Australian HIV-infected MSM who are in PHI; ~31% of new HIV infections are estimated to be transmitted from the ~9% of MSM with undiagnosed HIV. We estimate that the average number of infections caused per HIV-infected MSM through the duration of PHI is ~0.14-0.28. CONCLUSIONS The epidemiological impact of increasing treatment in PHI would be modest due to insufficient detection of newly-infected individuals. In contrast, increases in HIV testing rates could have substantial epidemiological consequences. The benefit of testing will also increase over time. Promoting increases in the coverage and frequency of testing for HIV could be a highly-effective public health intervention, but the population-level impact of interventions based on promoting early treatment of patients diagnosed in PHI is likely to be small. Treating PHI requires further evaluation of its long-term effects on HIV-infected individuals.

Sampling and sensitivity analyses tools (SaSAT) for computational modelling

SaSAT (Sampling and Sensitivity Analysis Tools) is a user-friendly software package for applying uncertainty and sensitivity analyses to mathematical and computational models of arbitrary complexity and context. The toolbox is built in Matlab®, a numerical mathematical software package, and utilises algorithms contained in the Matlab® Statistics Toolbox. However, Matlab® is not required to use SaSAT as the software package is provided as an executable file with all the necessary supplementary files. The SaSAT package is also designed to work seamlessly with Microsoft Excel but no functionality is forfeited if that software is not available. A comprehensive suite of tools is provided to enable the following tasks to be easily performed: efficient and equitable sampling of parameter space by various methodologies; calculation of correlation coefficients; regression analysis; factor prioritisation; and graphical output of results, including response surfaces, tornado plots, and scatterplots. Use of SaSAT is exemplified by application to a simple epidemic model. To our knowledge, a number of the methods available in SaSAT for performing sensitivity analyses have not previously been used in epidemiological modelling and their usefulness in this context is demonstrated.

Frequent testing of highly sexually active gay men is required to control syphilis.

Background: The incidence of syphilis infections has been substantially increasing in gay men in the developed world. Methods: We developed an individual-based mathematical model describing syphilis transmission within a gay male population: we used the model to simulate the expected relative impact of numerous screening and treatment interventions, targeting different at-risk groups with various coverage and frequency rates and follow-up schedules. Results: The model predicts that increasing the proportion of gay men tested each year would have a relatively modest impact on syphilis incidence. However, increasing the frequency of testing can have a large impact, with the prevalence of syphilis reduced substantially if individuals are tested every 3 months. Targeting frequent screening at gay men who have large numbers of partners or who engage in group sex is a more efficient way of reducing syphilis epidemics. Contact tracing the regular partners of infected individuals is the most efficient intervention and can have a significant epidemiological impact with relatively high coverage rates. Conclusions: Increasing the frequency of testing and treatment are required to mitigate syphilis epidemics. Notifying and testing partners of infected men should occur where possible but the high rates required to reverse epidemic trends are likely to be infeasible. Contact tracing should be a secondary priority that is coupled with increases in the frequency of testing in the population. Encouraging testing among men not previously tested for syphilis is also recommended.

Increased HIV Testing Will Modestly Reduce HIV Incidence among Gay Men in NSW and Would Be Acceptable if HIV Testing Becomes Convenient

Objective Determine the acceptability and epidemiological impact of increases in HIV testing in gay men in New South Wales (NSW), Australia– particularly pertinent when considering treatment as prevention and the need to reduce undiagnosed infections. Methods We conducted an online survey and focus groups to assess whether increases in HIV testing would be acceptable to gay men in NSW. In parallel, we assessed the potential impact of increases in testing coverage and/or frequency using an individual-based model of HIV transmission. Results If sexual practices and the rate of initiating HIV treatment are unchanged then increasing HIV testing reduces infections. Increasing testing frequency has the largest impact, with a 13.8% reduction in HIV infections over 10 years if the ∼55–75% of men who test at least once per year increased their testing frequency to four times per year. If testing levels decrease from current levels then we expect an increase in HIV infections with a sharply rising trend over time. Increasing HIV testing would be acceptable if testing was more convenient. However, only ∼25% of men surveyed were ‘very likely’ to increase their level of HIV testing. Men delayed or avoided testing due to the slowness in obtaining results and if they believed they had not put themselves at risk. Conclusions An increase in HIV testing alone is unlikely to reduce HIV incidence substantially in NSW gay men– however, the relatively high testing levels need to continue to prevent an increase in HIV infections. In jurisdictions with lower levels of HIV testing, increases in testing coverage and frequency are likely to have a larger impact. Successful treatment as prevention interventions will require increases in testing rates; such increases would be acceptable to gay men in NSW but only if more convenient testing and rapid communication of results were available.

Spatial constraints within the chlamydial host cell inclusion predict interrupted development and persistence

BackgroundThe chlamydial developmental cycle involves the alternation between the metabolically inert elementary body (EB) and the replicating reticulate body (RB). The triggers that mediate the interchange between these particle types are unknown and yet this is crucial for understanding basic Chlamydia biology.Presentation of the hypothesisWe have proposed a hypothesis to explain key chlamydial developmental events whereby RBs are replicating strictly whilst in contact with the host cell membrane-derived inclusion via type three secretion (T3S) injectisomes. As the inclusion expands, the contact between each RB and the inclusion membrane decreases, eventually reaching a threshold, beyond which T3S is inactivated upon detachment and this is the signal for RB-to-EB differentiation.Testing the hypothesisWe explore this hypothesis through the development of a detailed mathematical model. The model uses knowledge and data of the biological system wherever available and simulates the chlamydial developmental cycle under the assumptions of the hypothesis in order to predict various outcomes and implications under a number of scenarios.Implications of the hypothesisWe show that the concept of in vitro persistent infection is not only consistent with the hypothesis but in fact an implication of it. We show that increasing the RB radius, and/or the maximum length of T3S needles mediating contact between RBs and the inclusion membrane, and/or the number of inclusions per infected cell, will contribute to the development of persistent infection. The RB radius is the most important determinant of whether persistent infection would ensue, and subsequently, the magnitude of the EB yield. We determine relationships between the length of the T3S needle and the RB radius within an inclusion, and between the RB radius and the number of inclusions per host cell to predict whether persistent infection or normal development would occur within a host cell. These results are all testable experimentally and could lead to significantly greater understanding of one of the most crucial steps in chlamydial development.

Hidden drug resistant HIV to emerge in the era of universal treatment access in Southeast Asia.

Background Universal access to first-line antiretroviral therapy (ART) for HIV infection is becoming more of a reality in most low and middle income countries in Asia. However, second-line therapies are relatively scarce. Methods and Findings We developed a mathematical model of an HIV epidemic in a Southeast Asian setting and used it to forecast the impact of treatment plans, without second-line options, on the potential degree of acquisition and transmission of drug resistant HIV strains. We show that after 10 years of universal treatment access, up to 20% of treatment-naïve individuals with HIV may have drug-resistant strains but it depends on the relative fitness of viral strains. Conclusions If viral load testing of people on ART is carried out on a yearly basis and virological failure leads to effective second-line therapy, then transmitted drug resistance could be reduced by 80%. Greater efforts are required for minimizing first-line failure, to detect virological failure earlier, and to procure access to second-line therapies.

Chemoprophylaxis is likely to be acceptable and could mitigate syphilis epidemics among populations of gay men.

Background: Over the last decade, syphilis epidemics have resurged around the world, particularly among gay men. An innovative public health response could be the use of chemoprophylaxis. We sought out to determine the acceptability of syphilis chemoprophylaxis and its likely population effectiveness if it were adopted. Methods: We conducted a mixed-methods study. An online survey (n = 2095 participants) and focus groups (n = 23 participants) were conducted to determine whether syphilis chemoprophylaxis is likely to be acceptable to gay men in Australia. We also developed an individual-based mathematical model that simulated a population of gay men, to explore the potential impact of introducing chemoprophylaxis. Results: Of the 2095 gay men surveyed, 52.7% (95% confidence interval, 50.6%–54.8%) indicated that they would be very likely or slightly likely to use chemoprophylaxis to reduce their chance of acquiring syphilis, increasing to 75.8% (95% confidence interval, 74.0%–77.6%) if chemoprophylaxis would help reduce infections in the gay community. In this model, 70% use-effectiveness of chemoprophylaxis used by 50% of gay men is expected to reduce the number of syphilis cases by ∼50% after 12 months and 85% after 10 years. The majority of the prevention efforts can be gained by targeting subpopulations of men with higher sexual activity. Conclusions: Chemoprophylaxis offers promise as an acceptable and effective intervention for mitigating syphilis epidemics. The outcomes of a planned placebo-controlled syphilis chemoprophylaxis trial are eagerly anticipated.

Increasing gay men’s testing rates and enhancing partner notification can reduce the incidence of syphilis

BACKGROUND We sought to determine whether gay men would be willing to increase syphilis testing and partner notification, and assessed the possible epidemiological impact these changes might have in the Australian population. METHODS We conducted an online survey (n=2306) and focus groups to determine whether interventions to increase testing for syphilis and enhanced partner notification are likely to be acceptable to gay men in Australia. An individual-based mathematical model was developed to estimate the potential population-level impact of changes in these factors. RESULTS Of all men surveyed, 37.3% felt they should test more frequently for sexually transmissible infections. Men who recent unprotected anal intercourse with casual partners and men who reported a higher number of partners were more likely to indicate a greater willingness to increase testing frequency. HIV-positive men were more likely to indicate that their frequency of syphilis testing was adequate, incorporated as part of their regular HIV monitoring. Lack of convenience was the main barrier reported. Partner notification was broadly acceptable, although perceived stigma presented a potential barrier. The mathematical model indicated that increasing testing rates would have a substantial impact on reducing rates of syphilis infection among gay men and partner notification would further reduce infections. CONCLUSIONS Interventions promoting testing for syphilis among gay men and increases in partner notification may be acceptable to gay men and are likely to result in decreased infection rates. Rapid testing and modern communication technologies could strengthen these interventions, and have an impact on the syphilis epidemic.

Could implementation of Australia’s National Gay Men’s Syphilis Action Plan have an indirect effect on the HIV epidemic?

OBJECTIVES The number of incident infections of syphilis and HIV have increased over the past decade across Australia, particularly among gay men. In other industrialised settings, syphilis epidemics have also resurged coincidentally with increases in HIV diagnoses. Sexually transmissible infections (STI) are a biologically plausible cofactor for increasing HIV transmission. We pose the question: could strategies purely targeting syphilis also have an indirect impact on HIV incidence? METHODS We developed an agent-based computer model that simulates the transmission and disease progression of HIV and syphilis among a population of sexually active gay men, calibrated to reflect the epidemics in Victoria, Australia. The model was informed by detailed behavioural data from a variety of sources and was used to investigate the potential epidemiological impact of different public health interventions. RESULTS Assuming that syphilis could act as a biological cofactor for HIV transmission, from no effect to increasing risk by five-fold, our model indicates that if Australias syphilis action plan is effectively implemented then the number of HIV infections could decrease by up to 48% over the next decade in the absence of any specific HIV interventions. CONCLUSION It is plausible that effective implementation of interventions targeting syphilis epidemics can have an indirect effect of mitigating the spread of HIV. The possible effects of STI should be considered in the design, implementation and evaluation of public health strategies and programs.

Will Changes in Gay Menʼs Sexual Behavior Reduce Syphilis Rates

Background: Reducing rates of partner change and increasing condom usage among gay men are obvious targets for potentially reducing syphilis transmission among gay men. Methods: We developed an agent-based stochastic model to examine syphilis transmission among a population of gay men, representative of gay men in Australia. This model was used to explore the potential impact of changes in sexual behavior over 1 month, 3 month, and indefinite time frames on syphilis epidemics. Results: Simulations of interventions showed that short-term reductions in rates of partner change and increased condom use would have negligible impact on the long-term trends of syphilis epidemics. If no interventions are introduced, then the model forecasts that the syphilis prevalence in the population could continue to rise, with an increase of 80% in the number of men infected with syphilis during the next decade. However, if changes in sexual behavior are maintained in the long-term, then syphilis epidemics can be mitigated. If condom use is sustained at 80% in partnerships that are HIV discordant or of unknown status, then the prevalence of syphilis is estimated to decrease by 9% over 10 years. Similarly, if partner acquisition rates decrease by 25%, then there will be a 22% reduction in syphilis prevalence. Conclusions: Interventions promoting partner reduction or increased condom use would be ineffective in the short-term, and would have limited prospects for success in the long-term unless very large changes in behavior are sustained. Complementary social research indicates that such long-term changes in behavior are unlikely to be adopted, and therefore other intervention strategies need to be developed to reduce syphilis among gay men.