As Australian clinicians, policy makers and communities affected by hepatitis C march into a new era of widespread, accessible Direct Acting Antivirals (DAAs), Dr Joseph Doyle from Melbourne’s Royal Alfred Hospital gave a timely presentation about the feasibility of eliminating HIV/Hepatitis C Virus co-infection.

The global burden of Hepatitis C Virus (HCV) infection is massive at 115-130 million people. Australia shares a relatively small burden of these infections, with an estimated 230 000 people living with HCV.  Globally, 2.2 million people are co-infected with both HCV and HIV. Between 7 and 10% of people living with HIV have HCV, with their odds of acquiring HCV six times that of the HIV-uninfected population.

As with HIV infection and the familiar 90-90-90 goal-posts, the WHO has set ambitious targets for viral hepatitis. By 2030, WHO aims to eliminate hepatitis C transmission, with 90% reductions in incidence, and 90% of those infected treated effectively. This is expected to prevent 7.1 million deaths between 2015 and 2030.

To achieve this, health policy makers must address specific gaps in:

-       Testing

-       Access to care

-       Treatment, and

-       Prevention

To be maximally effective, testing must be sufficiently frequent among populations at risk. Early diagnosis and treatment scale up to the point where 80% of all new cases of HCV were treated has been modelled to drastically reduce HCV incidence. Testing must be available at little or no cost to consumers, and provide reliable results. In Australia, antibody screening assays are widely available in organized laboratories with excellent quality assurance. Gaps persist in the diagnosis and assessment of hepatitis C: the current requirement for Nucleic Acid Amplification Testing (NAAT), genotyping, and assessment for fibrosis each presents a barrier to treatment. Multiple visits are often required to plan effective antiviral therapy, and each step represents a risk for disengagement. Algorithms for laboratories to deploy reflex HCV Ag/RNA testing in the event of reactive antibody screens would be useful. When these factors are combined models suggest improvements in treatment uptake and reductions in HCV incidence.

For hepatitis C and HIV coinfection, injecting drug use plays a role in up to half of cases. In contrast to HCV mono-infection, sexual transmission is also important, particularly among HIV+ men who have sex with men (MSM). Modelling suggests that sexual behavioural change could dramatically reduce sexual transmission of HCV, but the challenges to implementing this in an era of reducing condom use are considerable. Linking testing and early diagnosis with harm minimisation is important, and in some cohorts results in reduction of IDU risk behaviour.

Rates of testing for HCV are currently good among people living with HIV. Victorian data suggest that PLWHIV are tested an average of 1.4 times each year. Consideration should be given to increasing the frequency of testing, but restriction of this to higher risk individuals seems prudent.

Access to care has significantly improved in Australia in 2016. PBS-subsidised DAA therapy became available in March 2016, and unnecessary restrictions on prescribing for able prescribers were lifted in November of the same year. Australia wisely and bravely avoided the temptation to impose restrictions to access DAAs based on fibrosis, alcohol consumption and ongoing drug use. These aspects have seen the proliferation of interferon-free treatment in Australia. Interdisciplinary collaborations that have embraced participation by hepatologists, infectious disease physicians, sexual health physicians, public health professionals, virologists, general practitioners, and community members have liberated hepatitis C treatments from hospital environments to the community where much wider, more acceptable, sustainable implementation can develop. The multidisciplinary Consensus Statement on hepatitis C treatment has been instrumental in facilitating community provision of hepatitis C treatment.

Effective antiviral treatment of hepatitis C is the cornerstone of hepatitis C elimination. Although the safety and efficacy of the current generations of DAAs have provided extraordinary advances in the treatment of HCV infection, further advances are needed. The development of well-tolerated, safe, efficacious, pangenotypic regimens that require increasingly less reliance on fibrosis status and previous treatment history would be beneficial.

Communities at risk of coinfection include people who inject drugs and men who have sex with men predominantly, but those born overseas in countries with hig prevalence of both infections should not be neglected. 

Cost effectiveness of interferon-free DAAs is well-established for those with advanced liver disease, but the cost of treating those with early infection without fibrosis is well within Australia’s resources. 

Harm reduction strategies around injecting and sexual behaviour are an important part of primary prevention, but also crucial in preventing reinfection after successful therapy. Treatment offers opportunities to collaborate with harm reduction agencies, and reinforce messages of risk minimisation.

Although no highly efficacious vaccine for hepatitis C has been developed, the public health role of partially effective vaccines should be considered. The role for such vaccines will depend on the degree to which prevalence is reduced. If treatment uptake is high enough to reduce the prevalence of HCV to very low levels, a partially effective vaccine is unlikely to be of benefit. In the setting of ongoing high prevalence, or of high reinfection rated, a partially effective vaccine may be of considerable benefit.

Just as the HIV Cascade from the Kirby Institute’s Annual Surveillance Report informs HIV public health practice, so does the HCV care cascade. Priot to the introduction od DAAs in the community, only 2000 people accessed treatment for HCV. The introduction of HCV DAAs saw 27 000 HCV-infected people being treated by the end of July 2016, representing 13% of all people with HCV infection in Australia. We are on track to providing treatment to 40 000 people by the end of 2016. This enormous scale up of treatment for hepatitis C is unprecedented, and is a globally important public health intervention.

Networking models for HCV acquisition among PWID are well-described. Higher connectedness to communities with high HCV prevalence of confirms intuition. The high level of connectedness to others with HCV suggests strategies for increasing effective uptake among  networks. Similar strategies might be effective among sexual networks of MSM in whom HCV is prevalent. ‘Bringing your friends in’ is potentially effective for both PWID and MSM networks, suggesting a singular effective strategy for co-infected networks.

To meet the WHO targets regarding reduced transmission, modelling suggests Australia must treat 4 700 HCV-infected PWID annually. To meet WHO mortality targets, 5 600 HOV infected PWID must be treated annually according to modeling. Given the uptake of DAA treatment in its first year, Australia is on track for reducing both mortality and transmission targets. Costs for achieving this are estimated to be around $7 billion, but prudent deal-making on behalf of the federal government is likely to achieve thi results for substantially less cost.

Reducing HCV acquisition among PLWHIV requires an understanding of the complex environment in which HCV transmissions occur. Factors include rates of partner change, condom utilization, injecting behaviour, sexual dynamics that include group sex an use of sex toys, and concomitant partnerships. Agency-based modelling, which accounts for such complexity, suggests a greater efficacy in HCV incidence reduction than compartment based modelling, and supports the efficacy of providing treatment to those with high risk sexual or injecting networks.

How can this be implemented? The Co-EC Study examines the utility of nurse-facilitated hepatitis C treatment in community settings. This study demonstrated that most people aith coinfection can be treated safely and effectively in community settings, providing that collaborative care is available when needed.

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In summary, there are many parallels between HIV and Hepatitis C treatment. Treatment cascades are informative for both conditions, and there are many primary and secondary prevention messages that can be shared with benfit between sexual and injecting risk networks. Australia is on track to eliminate hepatitis C and HIV coinfection with its insightful, innovative adoption of community-based direct acting antiviral treatments for hepatitis C.

Dr Cindy Liu from George  Washington University presented interesting findings on the vaginal microbiome today. 

 The term ‘dysbiosis’ refers to an ecological imbalance in the microbiome that impairs health. It moves away from the classic concept of infectious disease as being caused by a single pathogen, and moves toward the appreciation of disease as disruption to a complex, dynamic ecosystem. Disruptions might be the loss of ‘good’ bacteria, dominance of ‘bad bacteria’, but the imbalance leads to events that impair function, or induce inflammation. 

Earlier today, Liu described anaerobic penile dysbiosis: the polymicrobial colonisation of the subpreputial space with anaerobic flora, and its role in HIV acquisition. In her afternoon session, she built on this to describe one of the classic vaginal dysbioses: bacterial vaginosis (BV). BV is characterised by the overgrowth of anaerobic microflora, and reduction of Lactobacilli, and is therefore a vaginal anaerobic dysbiosis. BV is a common condition, and its management is characterised by persistence, recurrence. It is also associated with an increased risk of HIV acquisition, as well as a range of adverse pregnancy outcomes and pelvic inflammatory disease.

What is the relationship between these penile and vaginal anaerobic dysbioses? Are these phenomena sexually transmissible? The anaerobic organisms implicated in both processes certainly have considerable overlap, and evidence from several quarters supports the sexual transmission of BV.

 Liu and her colleagues enrolled 165 uncircumcised HIV-negative Ugandan men and their female partners into the Rakai Health Sciences Cohort. Self-obtained vaginal swabs from female partners were assessed for BV using the Nugent score, while swabs from the coronal sulcus were collected from men for assessment of their microbiome using 16S rRNA amplification.

Penile microbiomes were found to fit into four distinct patterns, termed Community State Types, which ranged from microbiomes with low diversity and few anaerobes (CST 1-3) to communities with very high diversity and a rich population anaerobic flora (CST 4-7): so called anaerobic dysbiosis.  

 Bacterial vaginosis was found more frequently among female partners of men with anaerobic dysbiosis than in men with lower levels of diversity and less anaerobic flora. This supports the hypothesis that anaerobic penile and vaginal dysbiosis are sexually transmissible and results from sharing of anaerobes within heterosexual settings.

 Longitudinal studies are needed to prospectively observe transmission events between couples, as well as account for potential confounders such as hormonal factors, hygiene practices and so on. Higher resolution molecular identification tools to better describe phylogenetic relationships between organisms shared by the partners are needed to confirm transmissibility.  

 Cindy Liu from the Milken Institute School of Public Health, George Washington University presented her findings on the relationship between the penile microbiome and HIV susceptibility. Liu hypothesized that the penile microbiome drives pro-inflammatory responses and in turn increases HIV acquisition.

 The space underneath the foreskin is a unique environment with a characteristic microbiome. Analysing subpreputial swabs from men in Uganda, Liu and her colleagues used molecular techniques to investigate bacterial populations prior to and after male circumcision. 16S rRNA sequencing was employed to characterise bacteria to genus level, and a pan-bacterial DNA RT-PCR was used to quantify total bacterial load. Together, these were used to estimate the absolute abundance of specific bacterial taxa in the subpreputial space.

Prior to circumcision, the subpreputial space was characterised by a diverse bacterial community that varied between individuals and over timel. A wide variety of anaerobes, including Prevotella, Finegoldia, Peptoniphilius, and Aerococcus, were isolated in high numbers. Post-circumcision, the populations of these anaerobes reduced, and resembled flora from other skin. Anaerobes decreased, populations became less variable, and Lactobacilli increased.

 Expanding on this, the investigators examined the immunological responses to these changes in the microbiome. Langerhan cells, the antigen-presenting cells par excellence of mucosal surfaces, are thought to be integral to HIV acquisition. In the inactivated resting state, Langerhan cells ingest HIV virions, and lyse them prior to presenting the lysed products to lymphocytes at the lymph node. In activated Langerhan cells however, degradation of HIV virions is bypassed, resulting in presentation of intact virus to nodal lymphocytes and the commencement of viral replication. Anaerobic flora were postulated to be triggers for Langerhan cell activation.

  Liu found that IL-8, one of the key cytokines implicated in immune activation, was significantly higher among men colonised by Prevotella, and other key anaerobic organisms.  IL-8 is known to attract neutrophils along a chemotactic gradient, and induce them to release MIP 3a alpha and MCP-1, which in turn lead to recruitment and activation of CD4+ T lymphocytes, drawing them closer to the epithelial surface.

 This work supports the hypothesis that an anaerobic subpreputial microbiome induces pro-inflammatory local immune responses, and that these changes are negated by male circumcision.

 Further work on the correlation between the penile microbiome and HIV acquisition is keenly awaited. Liu’s current collaboration with the Kirby Institute will examine the role of the ‘dorsal slit’ modified circumcision commonly practiced in parts of PNG, and will hopefully give insight into this cultural practice’s potential role in HIV prevention.

Pharyngeal infection with Neisseria gonorrhoea represents a large, asymptomatic reservoir of infection, and is thought to be an important driver of transmission among men who have sex with men (MSM). Which sexual activities drive the transmission of gonorrhoea between the pharynx and other sites? Could it be oral sex? Rimming? Chemsex?

Kit Fairley, Professor of Public Health at University of Melbourne and Director of Melbourne Sexual Health, wonders if it might be all even more surprising - kissing. But not just any kissing - 'proper kissing with a tongue and all the rest of it.'

In  a thought-provoking presentation, Fairley points out that gonorrhoea rates are highest among young MSM, and fall with age. While this might suggest a degree of acquired immunity to gonorrhoea, it might simply reflect changes in kissing throughout the age spectrum. Rates of oral sex, the traditionally accepted route of transmission to the pharynx, do not fall with age. Furthermore, penile-oral sex relies on urethral gonorrhoea as the vehicle for transmission between pharynges of different partners. Urethral gonorrhoea, however, is almost always symptomatic, and urban MSM are quick to access health services early in the course of gonococcal urethritis. 'The penis' says Fairley 'is an innocent bystander in this whole affair.'

How plausible is this? Neisseria meningitidis, the organism from which N. gonnorhoeae evolved aeons ago, is readily transmitted through saliva, and kissing is a well-recognised and important route of transmission for the meningococcus. N. gonorrhoeae, or at least it's DNA, can be readily detected in saliva of those with pharyngeal infection. 

If this hypothesis is correct, something as simple as antibacterial mouthwash might crack the transmission dynamics of gonorrhoea and spare the need for cephalosporins. And besides, who wouldn't prefer to kiss a man with fresh, minty breath?

Bacterial vaginosis (BV) is a polymicrobial phenomenon that represents dybiosis or imbalance in the vaginal microflora. Gerald Murray today presented the findings of a cohort study that examined the relationship between the vaginal microbiome and BV.

298 women without BV underwent periodic assessment of their vaginal microbiota by 16s rRNA sequencing. Over two years of follow-up 51 women developed BV, giving an incidence of 9.75/100 woman-years. 

Certain taxa were associated with subsequent development of BV - a 1% increase in Gardnerella vagainalis conferred a 2% increase in BV. The poorly characterised, non-cultivable BBAV TM7 was associated with a 5-fold increase in BV, but Atopobium vaginae was not. 

Diversity of the vaginal flora was correlated with susceptibility to BV. Women with more diverse microbiome experienced greater fluctuations in flora between assessments, and these unstable microbiomes were more likely to develop BV. Interestingly, the acquisition of microbial changes associated with an increased BV susceptibility often preceded the development of clinically apparent BV by weeks or even months. 

Behavioural factors were also associated with the development of BV: a higher rate pf partner change and the acquisition of a new partner were associated with incident BV. This is consistent with the emerging view of BV as a sexually transmissible phenomenon. 

Then authors  hypothesise that BV is a sexually acquired instability in the vaginal microbiome that ultimately leads to a lack of resilience in a complex community.