ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

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This was an interesting oral abstract session regarding community knowledge and approaches to pre-exposure prophylaxis.  PrEP was discussed in detail and covered topics like barriers to uptake of PrEP, preferences for prevention technologies, measuring adherence in PrEP users and how the health system and study designs of PrEP trials can facilitate rapid enrolment of those at high risk of HIV acquisition.

The first speaker was Adeline Bernier from France.  Although PrEP is already available in Norway and France through government subsidised programmes it has not been widely taken up in the rest of Europe.  She presented results from The Flash! PrEP in Europe (FPIE) online survey.  This was a community-based research study aiming to assess interest in and barriers to PrEP uptake amongst respondents from 11 European countries.  They found low knowledge of PrEP amongst at-risk groups, high interest in PrEP but low uptake.  Most commonly cited barrier to taking PrEP was fear of side effects.

Darrell Tan presented results from an MSM survey conducted with those undergoing routine HIV testing.  They asked questions regarding preferred method of PrEP delivery (oral, injectable, topical) and whether the reliability of different technologies would influence their decision on which method to use.   The results were many and varied.  Further analysis is required to understand what influences each individual’s preference for PrEP.

James Ayieko from Kenya presented results from the ongoing SEARCH trial, 18% of 4,064 participants took up the offer of PrEP within 30 days.  Participants’ perception of own risk did not always match that from a risk score.  This indicates further community-based education regarding risk is required for those considering PrEP.

Edwina Wright presented data from the Melbourne cohort of the PREPX trial. Recruitment to the PrEP trial was facilitated by a high community PrEP awareness and involvement of GPs and Pharmacists who were remunerated for their services.The high PrEP awareness in Australia contributed to the high enrolment of the ongoing PrEP study.

Rupa Patel presented data from a US study which found a good correlation between adherence measured by 3-month MPR (medication possession ratio) and 7-day self-report with TFV-DP (tenofovir diphosphate) blood levels in DBS (dried blood spot) of MSM taking daily oral PrEP.  The good correlation of the 3-month MPR and 7-day self-report with biological measures of adherence in PrEP users suggests that this could be ideal for measuring adherence in the clinic setting.

Hanne Zimmermann from the Netherlands presented data from a longitudinal semi-structured interview in MSM using PrEP.  This revealed that MSM switched between daily and event-driven PrEP use or even stopped PrEP based on their personal situation and risk exposure.  Individuals made decisions on PrEP use based on perception of their own risk.  The authors concluded that in order to successfully support future PrEP users, a tailored approach, addressing choices for PrEP regimens as a continuum of flexible and changeable choices, is essential.  Appropriate education would be an essential part of this strategy.

Elimination of Hepatitis C and HIV coinfection in Australia

 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.

As PrEP has now been used in the USA for about six years, Dr Jared Baeton compared PrEP to the developmental milestones reached by the average six year-old child.

 

  1. At six years old, we begin to understand cause and effect relationships.

    1. If you take PrEP, it works. As in, if you have good adherence, then it is close to 100% effective at preventing HIV transmission. Interestingly, studies have shown that those individuals at greatest risk of HIV appear to have a greater HIV risk reduction from PrEP. This suggests that those individuals at greatest risk of HIV also have the greatest adherence to PrEP.

       

  2. At the age of six, magical thinking fades quickly: PrEP is not perfect, and PrEP does not expect us to be perfect.

    1. PrEP is not perfect, but PrEP is safe. We have good data on kidney safety and bone safety for PrEP users. Also the risk of antiretroviral resistance appears to be limited to those who start PrEP in the context of an acute HIV infection, rather than those who seroconvert during PrEP use. He did not further expand on this thought, but perhaps those who seroconvert during PrEP use have such low adherence to PrEP that it does not result in the selection of resistant HIV variants.

    2. PrEP does not expect us to be perfect. In clinical trials, not everyone used PrEP, but those who did use it tended to be consistent users (Partners PrEP). Those who were not adherent at one month tended to never become adherent. Dr Baeton drew an analogy between PrEP adherence and flossing: Some of us floss every day, and tend to continue doing so, others rarely floss and never start flossing regularly.

       

  3. The average six year-old starts to understand the feelings of others. As a medical community we’re starting to understand what PrEP users want out of PrEP. And PrEP use has been shown to be associated with:

    1. Decreased anxiey

    2. Increased communication, trust, and HIV status disclosure

    3. Increased self-efficacy

    4. Increased sexual pleasure and intimacy

 

Stigma remains a key barrier to PrEP use: This includes stigma about ARVs, HIV and stigma about being at risk of HIV.

4. Six year-olds become more flexible in their thinking:

  • Success in PrEP adherence is achieved when PrEP is used during times of HIV exposure, this has been referred to as “prevention-effective adherence”. I think we need to develop some clear messaging around “prevention-effective adherence”, to assist people in

  • STIs will occur in persons using PrEP. People who need PrEP are at hight risk of STIs.

  • PrEP makes us think very differenctly about three decades of fear-based public health campaigns.

 

5. 6 year-olds start to understand more about his/her place in the world. PrEP is not a panacea, but it has the potential to form an important part of the toolbox of HIV prevention.

 

I think PrEP has come a long way over the last couple of years, including in Australia. In order to continue this trajectory, I think we need ongoing efforts to:

1. Obtain PBS-listing for PrEP

2. Prevent the emergency of PrEP-associated stigma, by framing the discussion around PrEP in a sex-positive manner.

3. Develop clear messaging around dosing regimens that do not involve daily PrEP. Some people do not need to be on PrEP continuously, and we need to have realistic conversations how these people can effectively manage their HIV risk without necessarily taking PrEP every day.

Associate Professor Rebecca Guy gave the Gallows Lecture.

The theme was new technologies for STI prevention and adult health checks with the target populations

- Aboriginal and Torres Straits Islanders People, 

- Gay men, 

- Mental health 

 

Resources and Notification of Partners. SMS technology is preferred. 

23% notified partner/s

Only 1/5 followed up in a clinic 

www.letthemknow.org.au

www.thedramadownunder.info

HOW is this going to change and effect my PRACTICE?

I will incorporate more IT into my clinical practice, as the Research has shown that clients and patients prefer SMS technology.  I have found this to be more effective approach in contacting those less engaged and harder to reach Clients, as it appears to be less intrusive means of contact & provides people the choice of when they want to make contact.

 

Other presentations on sexual health - Chlamydia 

Discussed health seeking behaviour. 

Focus on Adolescents

Low testing rates, 20 % people became re-infected in 1 year.

Issues are PID, infertility.

Gay men, increase risk HIV 

www.access-study.org

 

 

 

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Glasgow HIV 2016 has just opened.

It was interesting to hear new-comers to this meeting reflect on the three excellent presentations in the opening: Clarity, different perspectives, and reflections mixed with predictions. The sessions will be up on the Conference website shortly.

Tony Fauci, giving the Joep Lange and Jacqueline van Tongeren Memorial Lecture. Ending the HIV/AIDS pandemic: follow the science, reflected on the changes that have come about since he entered the field in 1981, following the publication of seminal articles in the MMRW. Fauci indicated that this is when he decided to change his career trajectory and concentrate on the, as then un-named, phenomenon which would become HIV.

Fauci sprinted through 30 years of HIV to focus on the more recent research which has redefined ending HIV. Namely the recognition that treatment reduces virus which in turn reduces transmission and that knowing ones status allows for interventions. But he did not stop there. He went on to cast and eye to the horizon and identified two areas where science has significant contributions to make.

HIV persistence, or stopping persistence, is a holy grail. This comes in two forms, eradicating HIV where HIV is made dormant while treatment is administered, yet re-emerges when treatment is stopped or controlling rebound, where interference at binding or replication sites reduces proliferation. This individualised therapy has shown to be useful in this strategy in cancer treatment and it has potential in HIV.

HIV vaccines, whether therapeutic or preventative are of course what everyone is hoping for. Fauci presented some realistic steps which are being made to transition vaccines from 32% effective to more like 50% effective, a point which he suggested could make significant inroads in reducing transmission, particularly in endemic settings and in combination with other strategies. He also discussed a number of new vaccine initiatives.

He ended with neat summary of why vaccinologists have not yet been rewarded. This I thought was a poignant rationale for continuing with vaccine development in the absence of any hitherto prizes. Most vaccines mimic the actual process of disease and immune response. That is not the case in HIV, so the vaccinologist needs not to copy the virus, but be much smarter than it.

 

Andrew Hill

Spoke about the potential to improve treatment access through the greater use of generic drugs. I can’t help thinking every time I hear Andrew talk that he is simplifying something in the greater economics and practicalities of capitalism or financial markets. But his arguments are very compelling.

Interestingly Andrew inserted discussion about Australia’s funding for hepatitis C treatment. Having just come from the USA where I was asked about details of the same, it seems to me that there are very different mechanisms in place in different countries which can result in very different approaches to price setting.

Two years ago at this meeting Andrew suggested it might be in the interests of the NHS budget to make a two pill (rather than single pill) regimen available to the UK public through the NHS. This brought criticism from at least one senior Australian clinician and commentator who thought that it would be unacceptable to expect patients to take a less convenient regimen.

Linda-Gail Bekker

As always presented clearly and passionately about the current experience of HIV in Africa and was able to compare and contrast this to other global settings. She is able to mix population and locational differences and introduce a third dimension of how these interact.

Adolescents were for a long time not a priority in HIV prevention. Key affected populations, are largely characterised as being “the-non-majority population”. While recognising this, she introduced an emerged KAP in Africa and that is adolescent women.

Linda-Gail was able to focus on trends which demonstrated changes for the good. It was very interesting to see a map where Australia was pink (on a blue to red scale) for increasing or sustained new infections. While our numbers might not be big they seem to be somewhat intransigent. Many African states have seen dramatic improvements. While more developed settings seem to be finding it difficult to make changes to address persistent, comparatively low-level, new infections. Something which Fauci also recognised in the USA. It would be interesting to see Andrew Hill’s economic assessment of the cost of these different interventions.

A great opening session which augers well for the coming days.

Levinia

 

 

Take home messages on the importance of the genital mucosa in transmission and pathogenesis

 

Beginning with a plenary presentation on day one of the Australasian HIV&AIDS conference the complexity and importance of understanding the relationship between STIs and HIV was laid bare.

Associate professor Jo-Ann Passmore, from the University of Cape Town gave a fantastic presentation with a few key messages. She was presenting data on the vaginal mucosa of South African women prior to acquisition of HIV infection and the role of STIs:

  • A healthy female genital mucosa is already an effective barrier to pathogens.
  • Inflammation in the genitals exacerbates the likelihood of HIV establishing an infection as the cytokines draw in the very cells HIV needs to infect.
  • The inflammation seen in the genitals is different compared to inflammation markers in the plasma.
  • STIs are a driver of inflammation.
  • There is heterogeneity between the various STI and inflammation (cytokine profiles) they induce.
  •  Chlamydia, the most prevalent STI is very inflammatory.
  • Using the inflammation markers, the researchers could identify 70% of HIV seroconverters.

 

Delving further into the proteins and associated inflammatory markers, Lyle Mckinnon presented data from the CAPRISA004 trial (Centre for the AIDS Programme of Research in South Africa), in Durban, South Africa which aimed to elucidate the mechanisms behind genital inflammation increasing HIV acquisition risk. They looked at the soluble mucosal proteome and associated cytokine expression in female Kenyan sex workers. Out of around 500 proteins measured, they found 3 that are involved in cell migration and 7 that decreased mucosal barrier function. These 10 proteins were the defining feature of women with elevated inflammatory cytokines and allowed them to predict which women had the highest inflammation.

Rather than being a helpful way to repair tissue and fight pathogens genital inflammation in this situation may be reducing the effective barrier of a healthy genital mucosa and increasing the risk of acquiring HIV. Genital inflammation may help to explain high rates of HIV transmission when the per –act transmission risk (1/1250 for vaginal intercourse) is low.

 

Next, Keith Fowke from the University of Manitoba gave a presentation on an innovative approach to reduce risk of HIV transmission – using low dose anti-inflammatory drugs.  

Keith set the scene by explaining that younger women have the highest risk of acquiring HIV based on their inflammation patterns and this may peak shortly after sexual debut or in the earlier years of sexual activity. Likewise, STIs are known to also be more inflammatory in younger people made worse by younger people having the highest rates!

In reference to female sex workers specifically; inflammation levels seem to decrease over time and markers of inflammation can increase from as little as a one month break from sex work. This suggests a model of mucosal tolerance over time with a peak risk of acquisition in between the stages of transactional sex and first identifying as a sex worker, arguably when these women are most at risk of acquiring HIV based on non-biological factors.

Taking this forward and with the acknowledgment that activated CD4+ T cells (caused by inflammation) are 1000x more susceptible to HIV infection than non activated cells it seems pertinent to consider modulating the inflammatory response as a prevention strategy.

The researchers identified 80 low risk women from Kenya and established baseline activation levels, then randomized them to take 6 weeks oral dose of either Aspirin (aka acetylsalicylic acid or ASA) or hydroxychloroquine (HCQ) which is used in the treatment of rheumatoid arthritis. They found a significant reduction in the percentage of CD4+ CCR5+ T cells in both PBMCS and cervical mononuclear cells (CMCs) for those taking aspirin and saw a similar reduction in CD4+ CCR5+ T cells in CMCs for those taking HCQ.

Besides the take home message that it works…..and aspirin in particular is already taken by many people around the world, the participants reported that taking the drugs were non-stigmatising, something which could have positive effects for adherence which in turn increases the efficacy of the prevention strategy.

 

Moving from one side of the perineum to the other, Andrew Harman from the Westmead Millennium Institute gave an informative and visually intriguing (pictures below) presentation on interventions at the mucosa or research working towards that end.

He outlined the research by first explaining about the large amount of heterogeneity between and within the immune cell subsets of the genital and anal tissues (dendritic cells in particular). Dendritic cells are of interest because of the role they play in transferring HIV from the epithelium to CD4 T cells.

Shockingly and relevant to the Australian epidemic concentrated amongst MSM, very little is known about the role  dendritic cells play in transferring HIV to CD4 T cells in the tissues of the colon and anus. This is in comparison to the female genital tract where the role of dendritic cells is much more understood.

The main reasons for this are that healthy human tissue is difficult to obtain, (especially anogenital tissues!) dendritic cells are hard to isolate and dissociate and even if they can be isolated, they are in small numbers.

So, over many years Andrew has had to establish collaborations with plastic surgeons, colorectal surgeons, urologists and gynaecologists to gain access to the full range of anogenital tissues – see image below for process of preparing human tissue. This has led to profiling of the various immune cell subsets in anogential tissues and in particular a novel population of rectal dendritic cells that can be identified by the combination of cell surface receptors proteins. If this can be characterised further it could lead to the translational goal of producing compounds that block these cell surface receptors, therefore preventing these cells playing a role in transferring HIV to CD4 T cells. Ideally a compound of this nature could be applied as a tissue type specific microbicide in the future – watch this space.

b2ap3_thumbnail_skin.JPG

 

 

PrEP Community Forum (aka Are you PrEPing for the future?)

What a privilege to attend this forum which featured amongst others Dr Robert Grant, named one of Time magazine’s most influential people in 2012 for being the father of “treatment as prevention.” Dr Grant highlighted the observation that PrEP use in San Francisco had reached a positive tipping point in the last few years, with increasing use of PrEP. How have they come to this point?

It's been driven by:
1) PrEP research and demonstration projects being run in San Francisco
2) The FDA approval for Truvada use in PrEP, and
3) Word of mouth and the use of social media

Dr Grant also reiterated that by using an intention to treat analysis, PrEP is efficacious - the analysis shows that in order to prevent 1 HIV infection, 13 to 18 people were required to be treated. The recommendation for PrEP is for daily dosing although the data shows that if users were taking PrEP 4 times or more per week, the benefits were maximised. Daily dosing provides for a high level of protection and is forgiving of the occasional missed dose. The exciting takeaway message I took was that currently, there are Phase 2 Trials in long acting injectable PrEP, which may come to fruition around 2020.

Dr Darren Russell spoke about PrEP in Australia and the current 'lay of the land'. Importantly, he announced that the HIV Foundation Queensland was in planning to roll out an affordable access program for low-income individuals via the Foundation, to counter the social and ethical inequities of access to PrEP in Queensland. Dr Russell also 'hypothesised' that Truvada for PrEP may obtain TGA approval in the first quarter of 2016 and hopefully PBS approval in the latter half of 2017 (all going well). Watch this space!

Most importantly, this forum highlighted the social science and personal impacts of PrEP - it's ability to mitigate the fear of HIV, the empowerment of users, the circumvention of condom difficulties to prevent HIV infection. We heard both from Chris Williams an early adopter and PrEP advocate and Dr Fiona Bisshop, a PrEP prescriber at Holdsworth House Medical Brisbane.

The final word? If you are not PrEP'd for the future, you better get with the program.

Daily dosing for PrEP seems to be taking precedence over other dosing schedules. This was cast into some doubt when the IPERGAY and PROUD studies were presented at CROI revealing and 86% reduction in transmission for both daily and event driven PrEP. But discussion about frequency of dosing remains. HPTN067 the ADAPT trial reported 2 of 3 arms comparing daily, twice weekly + one dose after event and one dose before and one dose after event dosing. The sites were Harlem and Bangkok. Daily dosing was best in both studies. Doses after sex event were most frequently missed. No risk compensation.

Less than daily dosing is probably effective at some level, but determining that level is the challenge. Having sufficient drug on board to maintain an effective therapeutic dose is the issue and this may be impacted by other host factors such as weight and metabolic rate. If 3 or 4 doses are sufficient to provide protection then this would provide significant cost savings against the cost of Truvada

On the topic of risk compensation, a passing comment was made that if anyone is going to see risk compensation and reduction in condom use it will be the Australians as they are the only people who use condoms.

The ground breaking HPTN052 trial was presented as a complete study yesterday. True to form, the data is compelling. Treatment prevents onward transmission. In a very small number of linked transmissions cause was attributable to not having drug on board, treatment failure and viral rebound, or transmission occurring very soon after treatment commencement, before viral suppression was achieved.

HPTN052 followed many thousands of patients in couples. Monitoring transmission ostensibly between partners. Unlinked transmissions, from a partner other than the study partner (who was on treatment) were more common than linked transmissions. Viral suppression is confirmed as the holy grail. Achieving this is the challenge.

 

 

 

Greetings  from Vancouver where the weather ( I am sorry to make you jealous) is absolutely gorgeous.

 

An interesting  satellite session on Rectal Microbicides, presented today by the Microbial Trials Network (MTN). Despite the proven effectiveness of PrEP there is still enthusiasm from sectors of the community for continued development of this alternative prevention tool. Not all MSM will be able to or want to take daily Tenofovir/FTC. Anal sex is also widely practiced by heterosexual couples particularly in Africa so there is much potential for use by these couples for the same reasons  vaginal microbicides are important.

 

The first ever Phase II trial to assess safety and acceptability of a rectal microbicide, MTN017 has just  been completed and was discussed by protocol chair Dr  Ross Cranston of University of Pittsburgh. Subjects were MSM and transgender females in multiple global locations

 

There were three treatment arms –

 

1.daily oral TDF/FTC

 

2.daily rectal reduced glycerin (RG)  tenofovir 1% gel (Phase 1 studies of ordinary tenofovir 1% gel found that when applied rectally it was associated with siginificant bloating, abdominal pain and diarrhoea. A reduced glycerin preparation was made which caused less osmosis in the rectum)

 

 or

 

3. RG TFV 1% gel used only before and after sex.

 

 Alll participants trialled all three methods and reported back on likelihood of ongoing use and ease of use. Data will likely be published in Feb 2016.

 

Several interesting ethical questions about the conduct of rectal microbicide trials  were raised by  Dr Ndebele of Medical Research Council of Zimbabwe. Most importantly, now that PrEP has proven to be so effective, should it also be provided as part of the comprehensive prevention package to trial participants, along with condoms and counselling regarding safe sex ?

 

I tend to think it should, as did most of the rest  of the audience, given UNAIDS Guidelines on ethical standards for HIV Prevention trials state “ participants should be offered state of the art risk reduction methods as they become available.”

 

This obviously raises many issues such as

 

- impact of cost

 

- the ethics of providing PrEP to participants in countries where there is little chance it will be available anytime soon and then withdrawing their access at the end of study and

 

- if uptake of PrEP were high amongst participants it would seem unlikely that you would be able to assess the efficacy of the microbicide.So what’s the point !

 

Dr Ian Mc Gowan another lead investigator discussed likely future directions for the MTN. This includes attempting to find a gel which could be used as a lube rather than inserted with the unpopular applicator currently used. The possibly of developing an alternative drug dapavirine which is more potent than tenofovir was also discussed.

 

The session wrapped up with a panel discussion between community representatives from the trial sites in the US, Canada and South Africa.

 

 They discussed

 

- how important  the development of rectal microbicides was for them as an alternative method for HIV prevention

 

- the importance of getting the product right so that it was an acceptable alternative

 

-the need for researchers to engage and invest in the community so that community members can participate meaningfully in trials  and

 

-the need for a gel that could be used both vaginally and rectally, being  useful for women for both types of sex and also to avoid the stigma for MSM in many countries when buying a product that idenitfied them as being engaged in anal sex.

 

It will be interesting to see how the MTN  goes. There are significant challenges and probably some sectors who will be sceptical of the need for rectal microbicides. However the more choices people have the better I think !

 

Slides for some of these presentations available on the IAS2015 website by clicking on the session on the Programme at a Glance.

 

 

 

 Greetings from Day 1 of IAS 2015,

Treatment as prevention (TasP) and the UN proposed ambitious 5-year treatment target of 90% of HIV+ve individuals being diagnosed, 90% of those diagnosed on efficacious treatments and 90% of those treated virally suppressed equating to 73% of all HIV+ve individual’s being virally supressed was the topic of discussion at the pre-conference workshop UN 90-90-90 Target Workshop: Lessons from the field.

There were four sessions spanning the day. After an opening speech by Michel Sidibé, Session One starting with RCT evidence to support immediate versus standard of care (SOC) ARV population-based roll out interventions and it’s utility to achieve the 90:90:90 target (SEARCH, HTPN071 (POPART), ANRS12249 and the Botswana Combination Prevention Protocol(BCPP). There was also some evidence reported for the utility of financial based incentives (FIs) to encourage linkage to care (HPTN065) and some discussion of acceptability of immediate ARV in sero-discordant couples (HPTN052) though 1-year follow-up results of HPTN052 will be presented Monday 2:30pm. The take home messages of session one included:

  • Largely testing rates, linkage to care and viral suppression levels achieved in SEARCH, POPART, ANRS12249, and BCPP were all high, around the 80% mark, however the big question of the impact of early ARV on HIV incidence in all of these trials is yet to be determined. Results so far look promising.
  • There still remain some pockets of the HIV+ve population which seem consistently hard to reach, primarily migratory young men in Africa. However while there were some gender disparities in linkage to care, once in care outcomes seemed similar for both genders. More social behavioural data from SEARCH, POPART and ANRS12249 to come.
  • There was evidence to support that immediate ARV does not have detrimental impacts on adherence to treatment i.e. HIV+ve people who feel healthy still seem to be good at take their drugs
  • The multi-disease approach undertaken by SEARCH, grouping testing for HIV with hypertension and diabetes was an encouraging approach
  • Financial based incentives did not show significant improvements in linking known HIV+ve individuals into care in the US, however they did show some efficacy in specific sub-groups, suggesting possibly that FI should be a target rather than a broad roll out. Some discussion over the ethics of FIs and the difficulty in implemented these strategies was highlighted in the discussion

Session Two largely covered evidence from cohorts. Evidence in achieving the 90-90-90 targets was presented for HIV cohorts in rural Malawi, Swaziland, KwaZulu-Natal and Rwanda, and evidence from the new cohort AFRICOS was presented. Lessons from this session included:

  • Results from rural Malawi where MSF task shifted ARV roll out from doctors to nurses which was later subsumed into the national program look very promising, 77% diagnosed, 84% on treatment and 91% of those virally suppressed. Again young men are those not linking to care.
  • The Early Access to ART for All (EAA) Study in Swaziland provided evidence for scalability feasibility and acceptability of the 90-90-90 target approach. Results supported initiating ARV on the same day as testing to avoid LTFU. While this may be difficult to implement if GART for first line is part of the recommended national guidelines in most of the developing world it is not.  Further lessons from KwaZulu-Natal presented by Frank Tanser showed barriers to care were distance from treatment centres (even in non-centralised settings) and gender.
  • The cascade of care in Rwanda looks close to the 90-90-90 target, with the epidemic now moving into older aged groups.

Session Three covered field implementation initiatives in China, Brazil, Thailand, and San Francisco. The ability for faith based organisations to engage people into care was also presented as well as some interesting results from a phylogenetic monitoring system that has been set up in British Colombia. Take home message from this post lunch, slightly jet-lagged session were:

  • In many settings described in this session, patients still had a median CD4 at diagnosis of less than 350 so it’s not really a question of immediate or deferred ARV rather engaging people in testing and linking to care. HIV peer intervention testing and self-testing has found to have encouraging results in Brazil. While a mixed facility and community-based testing model has improved diagnosis and linkage rates in Thai MSM and Transgender populations.
  • San Francisco has surpassed the 90-90-90 target and is now aiming for zero new infections. The RAPID program which enlisted individuals in immediate same-day ARV initiation looked promising. The difficulties in reaching that last 10% of the HIV+ve population in non-generalised epidemics was highlighted. How to reach specifically transgender populations was also discussed in question time, online outreach methods and linking ARV services with hormone therapy services were some of the suggestions.

  • Finally a population-wide HIV resistance database in British Colombia has been used for phylogenetic monitoring of outbreaks in real time. Fascinating results but a real potential for huge legal ramifications (two Supreme Court appearances later, Art Poon and colleagues in British Colombia have managed to resist forced disclosure of individuals). What a shame we live in a world where criminalization of sex in HIV+ve individuals is still common place!

And finally the workshop ending with presentations from donors, PEPFAR and the Global fund, and agencies, CDC who highlighting the cascade in the US, and the WHO and IAPAC who discussed soon to be released guidelines. The main highlight of this session was the (unofficial) report by Gottfried Hirnschall that the new WHO ‘When to Start’ guidelines including PrEP recommendations will likely be released in September of this year. These will (unofficially) include ART initiation for all regardless of CD4 count, PrEP for individuals with substantial risk (to be defined…), Option B+ as the recommended SOC and some suggestions for dose reduction strategies.

So finally, my overall conclusions of the workshop are the 90-90-90 UN target seems a difficult target but potentially achievable in some settings. Primarily generalised epidemics where the health system can support such targets with UNAIDs strengthening the provision of ART and donors getting on board, or non-generalised epidemics where innovation methods are employ and large amounts of resources can be mobilised in support of such efforts.  It will, however, be a specific challenge in other setting where either there isn’t a national health system to support such a roll out or there isn’t the resources to achieve these target where the epidemic remains localised in particularly hard-to-reach populations. As suggested by one of the attendees, perhaps there should be a fourth 90, 90% of countries achieving the 90-90-90 UN target by the year 2020?

 

For details of the workshop see http://www.treatmentaspreventionworkshop.org, for a live stream of the workshop see http://flash-vs.cfenet.ubc.ca/cfestream1.html

 

This symposium provided a great analysis of some of the issues confronting prevention efforts. Julie Overbaugh gave a great overview of HIV biology, particularly that period of time known variously as HIV stage 0, pre-seroconversion and/or early infection. She emphasised that this was the period before viral-load peaks and a time where it is very difficult to study what is happening in humans as they are not aware they are infected. Macaques provide the study model, but given the complexity of this period even slight differences between the hosts and the viruses might introduce great variation. So with that caveat she explained that there is considerable dissemination of virus int he first 1 - 3 days and by days 3 - 7 the reservoir is establishing in gut and lymph nodes. The impact of prevention diminishes as the reservoir is established.

She also suggested that there is selective pressure not just from the dominant virus but that CCR5 is more common in transmission that CXCR4 virus, making R5 inhibitors logical for PrEP. CCR5 virus is also more resistant to interferon, which is produced in a storm during infection. She lastly she compared cell to cell infection and cell free virus, and suggested that infection may be facilitated to hindered depending on whether cell to cell or cell free viruses are the target. Meaning that what drives transmission in breast feeding for example may be very different from what is important in vaginal transmission.

Christophe Fraser discussed phylogenetics and gave a detailed analysis of comprehensive sequencing of virus in the Netherlands. He suggested that about 69% of new infections were originating from the undiagnosed and ~24% from diagnosed but not on treatment and only 7% from people on ART. Immediate treatment could be expected to result in a reduction of between 25-30% of transmissions. PrEP and treatment might result in a reduction of 50-60% of infections, summarising that there is a lot to do to push prevention beyond where we are now.

Richard Elion building on the this reviewed optimising ART and looked at Treatment as Prevention. He made the statement that "we can't just treat our way out." He suggested that we need to better know where infections are occurring in populations and compared the treatment cascade between a number of countries. But to illustrate this point he then dissected the 19% of people with HIV in the USA who are estimated to have suppressed virus a number of ways: 6% of people under 30 and 28% over thirty; 16% black MSM and 34% Caucasian. He also questioned some of the definitions within the cascade. and challenged what was meant by "in care" when 74% are in continuous care while 26% are in only sporadic care.  He ended his talk by looking at how to engage the unengaged and identified: stigma, delivery methods, integration of bio-medical approaches and resourcing as the critical issues. This led seamlessly into the last talk.

Jeffrey Crowley looked at HIV criminalisation and suggested that laws are not protective, even though law makers might want them to be. And in places with a high prevalence it is unrealistic to expect the assumption of negativity. He pointed out the important role of health care workers in educating about HIV and pointed out that provisions such as anti-discrimination legislation are not sufficient alone to remove stigma.

Australia was referred to in the questions. A country which has excelled in the response but which is still seeing sustained incidence. The strong take-home message from this session was the importance of biomedical prevention to interrupt the the establishment of infection. This will challenge many attitudes but it may, in combination with treatment and testing, be the only way to significantly reduce new infections, particularly in settings, such as ours, where retention in care, treatment and viral suppression are approaching their maximum potential. 

The session was symposium S-5 4.00 pm - 6.00 pm Wednesday Advancing HIV prevention. You can view it from the webcast http://www.croiwebcasts.org/