Day 1: Afternoon Session

Welcome back to the afternoon (evening really, my laptop ran out of juice). In case you were wondering, it did eventually stop raining. Also, apologies for the formatting error in my last post, I'm sorry you had to see that.

The afternoon session in the main theatre was PrEP and was fascinating. I chose share with you the EPIC-NSW analysis done by Associate Professor Rebecca Guy from the Kirby Institute at UNSW.

Quickly a bit of information for those not from NSW or familiar with this program. Expanded PrEP Implementation in Communities in New South Wales (EPIC-NSW) is a study commenced in March 2016 and was designed to provide free access to PrEP to people at high-risk of HIV infection for free. This is the result of an active partnership between NSW Health, the Kirby Institute, ACON and clinical services involved in the study. The study was planned to have a rapid rollout and high clinical coverage within target populations and now has enrolled over 7,500 participants.

Rebecca spoke to the study, highlighting the similarities and disparities in demographics of people enrolled in the study and with data for new HIV notifications in MSM. The data for HIV notifications was taken from 2015 and the EPIC-NSW data up to and including September 2017.

Rebecca told us how the data shows mostly similarity in the capture of population at risk within the age, locality (urban vs. regional and remote) and to a somewhat lesser degree people identifying as Aboriginal or Torres Straight Islander (ATSI). However the one area demonstrated to have a disparity between the data and HIV notifications is that of people born overseas. Rebecca’s analysis has shown that in particular, people born in South East Asia (SEA) and North East Asia (NEA) are not reflected within the EPIC-NSW enrolments. From the data above, the rate of HIV notifications for persons born in NEA or SEA are 2.5 and 2.4 times respectively compared to the numbers reflected within the EPIC-NSW data.

In 2017 ACON increased the number of culturally appropriate programs, advertisements and information was released, targeting these populations. Examples such as posters in other languages and programs and information targeted to particular language groups has coincided with a marked increase in the population reflected within the study.

Rebecca concluded that although we mostly have participation that reflects the population targeted, we still have work to be done in order to reach the goals of the EPIC-NSW study.

Through my position in a sexual health clinic, I have been involved with this study, although I am well and truly at the lower end of the food chain than Rebecca. It is worth recognising the impacts on changing information available and making culturally appropriate services available to engage an under represented population. This is a great example of how changes in strategy can have a significant effect, although as Rebecca said, there is more work to be done.

I will be back tomorrow and hopefully won't be writing so late, I am now more prepared for batteries running out mid session. See you tomorrow!

Just after lunch I attended a session chaired by Gus Cairns, an HIV activist from the UK who spoke passionately about the need for PrEP in Eastern Europe earlier in the conference. A few speakers provided their thoughts on what might be holding things up with PrEP:

Justyna Rowalska from Poland presented HIV practitioners perspectives on PrEP in East, Central and South-Eastern Europe, the findings of a survey of many clinicians about PrEP. The findings concluded that the main obstacle to prescribing is not being covered or paid by public health, and that there was no official medical approval for the medication in many countries yet. She stated most said they would prescribe it if it was approved, but that clinicians needed guidelines in their countries, wanted a government strategy that includes PrEP and off label approval.

Gennady Roshchupkin from Georgia then presented Georgia’s PrEP demonstration project that has recently commenced with 100 places in 2017 and a further 100 in 2018, funded by the Global Fund but proposed his concern about what will happen when/if the Global Fund revokes funding. He suggested that the logical solution would be to involve some local NGO’s but that they were used to deal with people in crisis, and PrEP isn’t really a crisis. He thinks co-payment schemes and de-medicalising the delivery of PrEP may also keep costs down.

The panel then commenced discussions. Italy’s comments are of note: Italy has no reimbursement for PrEP and most are sourcing over the internet. The panellist (I have not recorded his name, apologies) stated that the discussion should no longer be medical or scientific, it works, and medical staff need to start advocating for MSM and working with MSM if they are ever going to reach the 90 90 90 targets by 2020.

I saw many other presentations today which will be blogged about by my fellow ASHM scholarship recipients, all of which have been equally as thought provoking and my brain is ticking over with ideas to bring home to Clinic 275. Witnessing the European perspective has been really enlightening.

I’m very grateful to ASHM for the opportunity to attend this wonderful international event and strongly encourage other nurses to apply for scholarships in the future– sure, a bit of the science that was over my head but there was still plenty of research that I could sink my teeth into and learn a lot from. Buona sera from Milan, Emma

This morning I attended the Oral presentations for HIV/STI testing and management, looking at different studies around HIV risk.

Brendan Harney from Melbourne presented his study: Risk of HIV following repeat sexually transmissible infections among men who have sex with men in Victoria, Australia. 

This presentation was a retrospective study questioning, if MSM have repeat positive STI diagnoses, are they at an increased risk of HIV transmission? 

Out of 8941 MSM (median age 29, Australian born) surveyed at a busy Melbourne Sexual Health Centres, 2.5% were diagnosed as HIV positive.

Although repeat Chlamydia and Syphilis notifications were common, Rectal gonorrhoea was found to be the highest, with 13.5% of those with a repeat positive gonorrhoea rectal infection becoming HIV positive.

Conclusion? Repeat Gonorrhoea infections are strongly associated with a HIV infection, and that this data is key to looking at PrEP inclusion criteria and why we target specific groups and behavioural activities for PrEP enrolment studies. 

The short answer from Jeffery Klausner (UCLA, CA) is; Yes.

Jeffery spoke about the two studies and looked at those results.

Antibiotic prevention is nothing new; Rheumatic fever, travellers (Malaria), Lyme Disease, or Travellers Diarrhoea. 

With increasing Syphilis rates in MSM and the risk of facilitating HIV transmission, Doxycycline Prophylaxis could defiantly have a place.

As we already know, Doxycycline is a narrow spectrum antibiotic that is inexpensive.

Two RCT's were conducted; one study looked at daily 100mg Doxycycline for 30 men over 48 weeks (not behavioural intervention), on average most had 1mg/ml in samples with only a few having undetectable levels (?non adherence) which overall showed good levels.

• 73% reduction in Syphillis
• 70% reduction in other STI's (Chlamydia)

Study 2: On demand Doxycycline as PEP. RCT in HIV negative men on 200mg single dose up 24 hours after sex, maximum 72 hours post sex. NB: No more than six pills per week.

• 70-73% reduction in Syphilis and Chlamydia infections.
• No effect on Gonorrhoea. 
• Noted increase in GI side effects, (nausea, GI pain and vomiting), nil adverse events.

Both studies showed great results, but more research needs to be done (Australia is part of a trial at the moment), and concerns around long term safety as well as ?Resistance (MRSA) were raised.

Overall a great presentation looking at the future of condomless prevention of STI's in a time where we have over 6000 MSM using condomless HIV prevention in NSW (EPIC, NSW)

I attended the oral presentation sessions today on STI Surveillance with four different speakers on the topics of

1. "A tale of two halves, low extended-spectrum cephlasporin and high azithromycin resistance in Neisseria Gonorrhoea in Europe,2015.
2. Predictors of Persistent and Recurrent genital STI symptoms at sentinel surveillance cities in South Africa.
3. High Prevalence of Hepatitis C Virus among HIV negative MSM in Amsterdam PrEP project.
4. Origin and predictors of early repeat infections among HIV negative women with TV receiving a stat dose of 2g of Metronidazole. 

I will speak mostly about the HCV study in Amsterdam, but I just wanted to quickly mention number one. Each topic was around 15 minutes long, so limited time for questions or follow up.

1. Michelle Cole from GASP (Gonococcal Antimicrobial Surveillance Program) spoke about how they are testing resistance to gonorrhoea with Ceftriaxone, Cefixime and on every third year Gentamicin.
- Overall 2134 isolates were submitted from 24 countries and 1 x Ceftriaxone resistance was found.
- Five isolates had high Azithromycin resistance in 2014, and there was a high amount of resistance found in Heterosexual men and MSM compared with females.

Conclusions; high but stable resistance to Azithromycin and low overall resistance to Ceftriaxone and Cefixime. The speaker had raised discussion points around possible resistance; ?Mono Therapy, Azithromycin for NGU or the high use of Azithromycin in general?

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3. Roel Achterberg - Amsterdam, spoke about the study looking into HCV prevalence in HIV- men, specifically looking at the PrEP implementation program.

It was discussed that over the years, HCV emergence was noted in HIV+ MSM, not knowing why HIV- men were unaffected, questioning Biological, behavioural or network factors? The research question was asked; Is there HCV prevalence among MSM and Transgender persons starting PrEP, and do they cluster with HIV+ MSM?

Participants had a choice of daily or Event required PrEP (not available in Australia under trial). All were tested with HCV Antibody and HCV RnA.

• 376 participants 
• 18 Participants HCV+ (Ab and RNA)
• 1 RNA+ but Anti HCV Neg, 14 RNA and Anti -HCV pos, 3 HCV RNA Neg anti HCV pos.
• People with HCV reported more CLARS than others who were HCV negative.
• Chemsex was a high component.

Conclusion from the speaker was that HCV prevalence was higher than previously found with HIV negative MSM.

As EPIC data in Australia is still being collected and reviewed by the Kirby Institute, it will be interesting to see how our data compares to Amsterdam.

I spoke to Roel after the presentation and asked about continual testing and study with PrEP and if they noticed behavioural changes or rates of infection throughout PrEP, but this data was still not available for them also.

This morning started with a great presentation of two Plenaries, starting with Vaginal Microbiome Research by Jeanne Marrazo - ISSTDR President and Professor/Director of Infectious Disease at University of Alabama - Birmingham. The Plenary followed was PrEP implementation, covered by my other colleague, Tamara. 

Jeanne spoke around the importance of healthy vaginal Microbiome and the increased risk of acquiring HIV/STI's. Some of these topics are already known, but it's good to re visit the importance of education to clients and to increase health literacy.

The benefits of having an optimal vaginal environment will see lower levels of HIV in women, protection from pathogens such as Bacterial Vaginosis (BV), Chlamydia, Gonorrhoea and TV as well as optimal birth outcomes such as a normal birth weight, timing of delivery and fewer pregnancy associated infections.

What is optimal vaginal environment? <4.7ph is optimal and anything above would be consistent with BV, in line with other symptoms (NB: STIPU Australia say >4.5ph).

Jeanne discussed that overall, women with BV have a 60% higher risk of acquiring HIV through vaginal sex, and men who's female partner is HIV+ are more likely to acquire HIV if those women have BV. On this note, Jeanne also mentioned that yes BV is quite common in Sub Saharan Africa, and can considered "normal" but it's not optimal.

In conclusion, further research is needed and more data around HIV/BV transmission risk to women. An important point was raised at the end around PrEP (TDF/FTC) implementation in women, especially around vaginal mucosa versus rectal being less effective in early administration and also studies are showing Tenofivir can have reduced coverage when Gardnerella Vaginalis is present.

The second plenary by Sinead Delany-Moretlwe (blogged by Tamara) spoke about Tenofivir effectiveness in women and it showed a lower tolerance for missed doses in the female genital tract in comparison to protection in rectal tissue acquired much sooner. 

With PrEP studies in Australia mostly recruiting MSM, it's interesting to look at female vaginal health in relation to PrEP, considering future prescribing options and the importance of education around HIV risk, STI reduction strategies.

I haven't come across PrEP before - it is not easily accessible in Western Australia, although a few patients have obtained it through personal importation.  Hence, the sessions on PrEP were of particular importance to me as I'm sure they will be filtering through to WA very soon.  In particular I enjoyed the summary by Prof Jared Baeten, and I've tried to summarise my learning points below.  I've combined two of his talks into one.

Firstly, I love this quote that he put up (forgotten who said it though): all truth goes through three phases: it is ridiculed, violently opposed, and then accepted as self-evident.

• PrEP works: those who had tenofovir in their system had a >90% reduction in HIV transmission
• PrEP works for high risk patients
• a single agent may work as well as dual agents (e.g. TDF only = 85%, TDF/FTC = 93%)
• adherers adhere
• not everyone used PrEP, but those who did use it tended to be consistent users
• non-adherers rarely started adhering
• there wasn't much change in behaviour after 1 month
• surprisingly, real world effectiveness was better than efficacy in the studies
• ?adherence was better in real life than in the trials
• PrEP  has several additional benefits
• decreased anxiety
• increased communication and trust
• increased sexual pleasure and intimacy
• chance of developing eGRF <70 while on PrEP if your baseline is >90 is extremely small
• rising STI rates in the US have been happening for a while, even before the introduction of PrEP
• PrEP works even when STIs are present

Most of the informal feedback I've heard before today has been that PrEP is associated with an increase in STIs but if the data above is applicable to Australia, then perhaps that isn't quite true.  I think the evidence if favour of PrEP is mounting, and the major obstacle in Australia is probably the cost-benefit ratio...

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.

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Day 4’s morning session was focused largely on PrEP, making it interesting and relevant to the Australian context.

Chloe Orkin (from the Royal London Hospital) began by providing a brief summary of the current situation and future prospects for PrEP.

She noted the current use (as PrEP) of standard antiretrovirals; the development of new compounds from existing classes (e.g. EFdA [NRTI]; dapivirine, MIV-170 and IQP-0528 [NNRTIs]; cabotegravir and MK-2048 [IIs]; and entry inhibitors [vivriviroc, 5P12-RANTES, PIE-12, nifviroc and trimer-D-peptide]); as well as new compounds from new classes (VRC01 and griffithsin [Neutralising antibodies]).

She also mentioned novel means of drug formulation that’re being developed: rings, inserts, suppositories, gels, films, soft implants, injections and douche/enema.

Sheena McCormack (University College London) presented an update on the evidence for PrEP effectiveness.

She began by presenting the a summary of currently available evidence as below, reminding us that overall (especially in MSM) PrEP is very effective; that adherence was a major factor in many of the studies where effectiveness was less good (particularly in young black MSM in the USA and in heterosexual populations).

She focused on the PROUD (continuous truvada as PrEP; immediately or deferred) study which looked at effectiveness, risk compensation and STI rates This study showed an effectiveness of 86% (90% CI 64-96%), with NNT = 13 (90% CI 9-23) – Dr McCormack commented that this compares favourably with other medications (such as statins) that’re approved for preventive measures. She also commented that some of those in the immediate intervention (PrEP) arm had significantly more unprotected anal intercourse than those in the deferred arm, and that rates of unprotected anal intercourse in both arms were relatively high. In that study, a rectal STI indicated a 1 in 6 risk of HIV infection in the following year.

Australia’s EPIC study was mentioned, particularly with regard to the fact that it targeted those at high risk of HIV.

She provided a summary of worldwide PrEP demonstration projects between 2011-2015:

-       32 projects in 16 countries

-       8478 participants with 7061 cumulative years exposure

-       Total HIV seroconversions n=67

à Highest rates in MSM 18-25 years (7.7/100 person-years)

à However available intracellular data showed undetectable or very low tenofovir levels in nearly all of those with seroconversion while on PrEP.

Episodic vs daily dosing – the importance of choice to effectiveness

HPTN 067/ADAPT study was mentioned: this study compared the use of daily, twice weekly (and another tablet after sex) and episode-driven PrEP in 3 populations (Harlem MSM/TGW; Bangkok MSM/TGW; Cape Town WSM). It showed that in the Bangkok population (who were generally better educated and suffered less social disadvantage) there was little difference in effectiveness between treatment arms, whereas adherence was much poorer for event-based PrEP in the other two arms (compared with continuous PrEP). This suggests that a choice of event-based or continuous PrEP may be useful depending on the population in question, and that if a population is likely to be adherent to episodic PrEP, this may produce cost-savings (less drug used overall).

 HIV infection despite PrEP

Those two cases of HIV being contracted despite good adherence (and adequate drug levels) were mentioned, including the “Toronto case” and the second case recently reported of a MSM acquiring a strain of resistant HIV. This reinforces the importance of reminding those on PrEP that it is not 100% effective.

Possible use of maraviroc as PrEP

HPTN 069/ACTG 5305 (Phase II Study of Maraviroc-Based Regimens for HIV PrEP in MSM) was discussed. In this study of n=406 MSM, people were randomised to oral maraviroc (MVC) only; MVC+FTC; MVC+TDF or TDF+FTC. 5 seroconversions occurred (4 in MVC-only arm), but in 4 of those plasma drug levels were low or undetectable.

Dapivirine-impregnated vaginal ring as PrEP

ASPIRE (n=2629; 27% risk reduction) and Ring (n=1959; 31% reduction) studies. Both in Africa.

However risk reduction was 60% in women >25 years of age; based on further data from the studies poor adherence was thought to be responsible for the poorer effectiveness in younger women.

Dr McCormack also mentioned the possibility of including contraceptive drugs in the PrEP vaginal ring to provide combined PrEP/contraceptive effect.

Conclusions

-       Overwhelming evidence of effectiveness of biological efficacy of TDF+/-FTC – which is not compromised by STI or risk compensation.

-       Population effectiveness not compromised by resistance (to date)

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-       Heterosexuals have a choice of drug; MSM have a choice of regimen; women will soon have a choice of delivery method.

We have just heard from 7 speakers on the status of PrEP across Euro and North America. There is considerable support for PrEP and incredible consistency across the regions in both trends and challenges a s well as interest.

Clearly there is no debate about the efficacy of PrEP, thought there remain differences in choice about daily or on demand PrEP. There seems to be considerable comfort in the level of resistance, side-effects and toxicities, while these may be appearing they are at such low levels as to no impact support for PrEP.

There is also a very generalised concern about cost of PrEP, but a growing confidence that cost issues will be addressed. How to implement PrEP is where the differences are most striking. Many people are indicating that PrEP must be resourced by cutting back in other areas. Cost effectiveness remains linked to the cost of the drug ad the level of risk, but a number of speakers also introduced location or background prevalence into that assessment.

PrEP access, at least in a number of settings, does not match HIV transmission risk. One presenter gave a detailed account of where PrEP is accessed and by whom. Overwhelmingly PrEP access in the USA favours white MSM, yet black and hispanic MSM and women are at much greater risk. This is s strong take home message. We will need to make sure that PrEP can be assessed by at risk populations and communities at greater vulnerability.

Anthony Fauci from the National Institute of Allergy and Infectious Diseases (NIAID) & National Institute of Health (NIH), Bethesda, USA, presented an excellent keynote lecture on ending the HIV/AIDS pandemic.

He started by taking us through a timeline of HIV infection. Starting in the 1980s, when the mean life expectancy of a newly diagnosed 20 year old (not on ART) was ~12 years. We followed the science through time and today, over 35 years later, the mean life expectancy of a newly diagnosed 20 year old (on ART) is ~53 years.

What we've learned since the 1980's regarding the etiology, virology, pathogenesis, treatment and prevention have given us a better understanding on how all these advances should continue to be used in conjunction in order to end the HIV/AIDS epidemic.

We've discussed treatment as prevention (TasP) and looked at a traid of pivotal ART studies regarding the treatment of individuals with HIV infection:

• The SMART study showed that episodic ART is inferior to continuous ART
• The HPTN 052 study showed that early ART reduces HIV transmission to uninfected sexual partners by 93%
• The START study showed that early ART reduces serious illness or death by 57%

We are all aware of the continuum of care when our patients have a positive HIV test results, but we should also be very proactive in the continuum of prevention in those who test negative.

Despite our 90/90/90 targets, the numbers of newly diagnosed HIV infection have plateaued globally since 2009.

Continuing to improve access to ART and HIV prevention strategies, such as pre-exposure prophylaxis (PrEP) could dramatically decrease HIV-related deaths and the rate of new HIV infections.

The efficacy of PrEP has been proven in multiple studies and most recently the San Francisco Strut PrEP program showed no new HIV infections in >1200 men on PrEP in nurse-lead intervention over nearly 1.5 years. There were 82 new infection at that clinic among men not enrolled in the PrEP program.

The two main remaining scientific challenges for HIV identified are:

• Addressing HIV persistence
• eradicate the reservoir - classic "cure"
• control viral rebound - sustained virologic remission
• Development of a safe and effective preventative HIV vaccine 

Towards a HIV vaccine:

• The first signal of efficacy (31%) in a HIV vaccine clinical trail - RV144, was seen in: Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. S Rerks-Ngarm, et al. For the MOPH-TAVEG investigators. N Engl J Med 2009; 361:2209-2220. Dec 3, 2009
• Additional work since this study has lead to a large-scale HIV vaccine trial that will launch in November 2016 in South Africa: HVTN 702 modifeid RV144 prime-boost regime
• More work is also being done on Neutrolising Monoclonal Antibodies, discovered since 2009.

Conclusion:

Treatment + non-vaccine prevention + vaccine = durable end of the HIV/AIDS pandemic

Talk by Professor Ian McGowan on long-acting ARVs (LAARVs).

-       Research from NYC (MSM) indicates high rates of willingness, and that a majority would prefer an injection.

-       Research from Africa (women) indicates that injection/implant/vaginal ring (as PrEP) would be preferred.

Current development of LAARVs is both for treatment and prevention.

Requirements for LAARVs as injection:

-       Infrequent dosing (every 2-3 months)

-       Practical injection volume (<4mL)

-       Doesn’t require cold-chain storage

Rilpivirine and cabotegravir most likely candidates of current generation of medications.

-       Have only been evaluated in the context of clinical trials (phase 1 and 2); adherence data likely to vary in the real world (and depending on whether being given as PrEP or treatment)

-       Tolerability good; patient satisfaction overall good

-       Efficacy signal in cabotegravir (animal studies)

-       Injection-site reactions reasonably frequent over time (highest at first injection)

-       Long-acting rilpirivine detectable in tissue (plasma/endocervical and vaginal fluid) up to >500 days (!) later – which is concerning for risk of resistance. Therefore cabotegravir more promising for use as long-acting PrEP (and phase 3 studies planned) – cabotegravir involves 4 week oral lead-in then Q8 weekly injection.

Novel NRTI “EFdA” also promising based on animal modelling; currently at phase 1 studies in humans. Animal models indicate that long-acting formulation could be effective up to 1yr.

As mentioned elsewhere – TAF silicone tubing implant and biodegradable implants both promising for use as PrEP.

Main challenges with LAARVs:

-       Safety (need oral lead-in)

-       Acceptability (needs real-world data)

-       Adherence

-       Resistance

-       Pharmacokinetics

-       Delivery

Today there were a few other abstracts presented about Prep.

A Siegler presented a demonstration project about a home testing system for Prep in the US. This involved sending out kits for STI testing and taking a few drops of blood for tests as wel as a questionnaire. Interesting idea- parts of which might be useful for future planning of Prep systems. 

P-C Crouch presented a San Francisco implementation of non-physician based Prep program using nurse and peer support volunteers. This has been successful in delivering Prep to a lot of people there. Again, food for thought about how we may be able to do things differently, even though their model is really in response to the barriers in their health system which are different in Australia. Since November 2014, they have screened over 1250 people with 95.5% enrolment and 71% retention and no HIV seroconversions.

I Zablotska presented details of the EPIC- NSW Prep implementation - good to see this being presented on a world stage and we all await the results of this and the other state based programs.

R Heffron presented data about renal screening- comparing the 3 months screening in the Partner Prep study to the Partner demonstration project whi did it six-monthly. There showed no difference between the two, so it supported the US CDC guidelines of six month renal screening being recommended.

All in all, some things to think about as we use more Prep.

At the Prep symposia yesterday, here was discussion about microbicides research- which agents to use and wil there be a need with oral Prep proven effective, the long acting injectables and infuseable (VRC01) agents as a possible for the future, It was also mentioned the research around rectal microbicides, suppository being investigated, the idea of a douche that might deliver the agent and ongoing research in vaginal rings.

Overall a very informative an interesting conference- the best I have been to. There is a sense that the world is coming together demanding the best treatment and access for all. The program's being rolled out in developing countries can be very impressive which should inspire us to reach and exceed the 90-90-90 targets.

Of the plenary session today what really stood out was Anton Pozniaks session ‘TB and Co-infections: the long game.  During the session he reminded us that TB is now the leading cause of death for people living with HIV.  He detailed steps to disease elimination for TB, hepatitis B and C – a very long game indeed.

In ‘The Living with HIV: Long-Term Effects’ Amanda Mocroft (PDB0101) examined renal function in patients in the START study.  eGFR was significantly lower in the deferred arm versus the immediate treatment arm. This finding reached significance in the non-adjusted analysis despite the use of potentially nephrotoxic drugs such as tenofovir.  Yet another reason to start ART early.

PrEP has been a major theme at this conference.  More good news was provided by Jean-Michel Molinain the extension arm of the Ipergay study  (WEAC0102).   This study used intermittent PrEP and previously reported the high efficacy of PrEP with TDF/FTC taken ‘on demand’ in high risk MSM – an 86% relative reduction in HIV-incidence in the TDF/FTC arm vs Placebo (95% CI: 40-98, P=0.002).  All participants were offered open-label TDF/FTC.  During 515 person-years only 1 HIV infection occurred giving a risk of HIV of 0.19 (0.01-1.08) per 100 per year.  This patient reported that he had ceased PrEP.

 Also continuing good news for HIV/HCV co-infection.  In the ‘Bad Bugs’ session Norbert Bräu  (WEAB0301) presented the results of the ASTRAL-5 study Sofosbuvir/velpatasvir was given for 12 weeks to 106 patients.  The genotype distribution was 62% GT1a, 11% GT1b, 10% GT2, 11% GT3, and 5% GT4. No patient experienced confirmed HIV virologic rebound (HIV-1 RNA ≥400 copies/mL).  SVR rates were 95% overall, and 100% with cirrhosis and 97% the previously treated.

As this combination will be widely used in Australia the next session was very relevant. AnnieLuetkemeyer (WEAB0302)  presented ‘Drug-drug interactions studies between HCV antivirals sofosbuvir/velpatasvir and HIV antiretrovirals’.  This was a Phase 1 study conducted in healthy volunteers to evaluate potential drug-drug interactions (DDIs) between SOF/VEL and HIV antiretroviral (ARV).

-       Increased TFV exposure (~40%) was observed with SOF/VEL when administered as TDF

-       Decreased velpatasvir (53%) when given with efavirenz

The author concluded that all study combinations could be used except efavirenz-containing ART.  This is an important finding given the number of patients taking Atripla.

And for the rare patients who does not achieve SVR with DAA therapy with sofosbuvir/ledipasvir (Harvoni)?  Well they can be retreated with…. Harvoni for 6 months combined with ribavirin.   Annie Luetkemeyer  (WEPEB060) presented data on 9 HIV/HCV who had not cleared with 12 weeks of Harvoni who were then retreated with 8/9 achieving a SVR.

Nittaya Phanuphak (Thai Red Cross AIDS Research Center, Thailand) spoke at AIDS2016 on the topic 'Prevention Equity: How Innovations in HIV Testing and Prevention Technologies can Reduce Incidence Globally'.

She highlighted the inequality of health care in Thailand and outlined that the populations at highest risk for HIV have been missing out. She is involved in a 'Test and Start' program for MSM and Transgender Women in Thailand. The program provides clients with HIV rapid testing, with provision of PrEP (or ART) on the same day.

They have trained up MSM and Transgender Women to provide services for the LGBTI community through the clinic. By design, this creates a work force that is compassionate, caring and culturally aware of the target population.

Their clinic has enrolled over 300 patients in the PrEP Program so far, but they plan to roll this out to a further 3000 MSM and Transgender Women over the next 3 years.

They created the website www.adamslove.org to provide sexual health information and encourage clients to attend the clinic. Everyone loves tickets, so they provide online Eventbrite "concert tickets" that are exchanged for STI tests (Please note that a visit to the clinic is more important, but is much less fun than seeing a show).

Most clients have a phone or webcam and the clinic's sexual health nurse utilises this to conduct online medical consults, providing education in sexual health, counselling and guides patients through performing a home HIV screening test.

Nittaya Phanuphak gave a shout out to NSW in her talk, stating "NSW must be congratulated for their efforts to use PrEP. We hope to learn more from NSW in the next few years" - and we hope to learn more from you Nittaya. 

J-M Molina this morning presented the Ipergay extension study results. Participants of Ipergay were offered to go onto an open label extension study to remain on episodic use of Prep. Ipergay was the placebo controlled study of use of truvada 2-24 hours before and 24 and 48 hours after sex as Prep. Some new participants were also enrolled. There were 362 participants. There was 1 HIV seroconversion in a person who was not taking the Prep. The mean pills per month taken was 18, There was no significant increase in number of sexual partners. Self-reported adherence was slightly improved. There was a significant reduction in comdomless receptive anal sex, but the STI rate remianed the same. 

This study is very assuring for us in Australia as there are several such programmes that either have or about to begin. It is good to know that we should expect high levels of risk reduction with Prep, even though there is still active debate about episodic vs daily Prep. It would appear that episodic Prep is also very effective.

There were also many posters on Prep displayed today. INterestingly, there was a study from Amsterdam comparing acceptability of episodic versus daily Prep. 73% of participants preferred daily Prep. These men tended to be younge and had more sex. 

I think it would be good to have both options but I suppose patients may do it anyway.

Another poster from Thailand using Prep in MSM found it feasible as they were able to deliver Prep for USD1- which includes cost of their generic drug and associated services. I am to sure if this was a daily cost or per visit cost.

Many Prep posters about acceptability in many settings around the world- some in MSM, some in young females, some about newer topical methods, All ver promising for the future and nice to see many places taking Prep seriously as a method of eliminating new HIV infections

Day 1 plenaries continued the themes from the opening ceremony with great presentations on the epidemiology of the HIV pandemic from Steffanie Strathdee.  Alex Coutinho presented data on Universal Access, the stage beyond the 90:90:90 target set by WHO.  Some countries in Africa appear to be close to passing these benchmarks include Rwanda and Swaziland.  There were few dry eyes at the conference as Edwin Cameron, a South African judge described his life living openly as a HIV positive gay man since 1986.  He introduced his godson who has been living with HIV since his birth 22 years.

A Clinical highlight of the morning was the PrEP:New Drugs session.  Robert Grant (TUAC01) reviewed the risk of drug resistance versus the benefit of HIV prevention across 6 randomized clinical trials and one demonstration project. This study was of great interest to those doctors involved in PrEP studies in Australia so the take home messages are:

1)    FTC resistance occurred in 10 who received FTC/TDF PrEP, including 33% (5/15) with acute infection when starting PrEP, and in 3% (5/157) with established infection. 98 infections were prevented giving 10 (98/10) infections prevented for every FTC resistant infection.

2)    Tenofovir resistance occurred in 1 who received TDF PrEP, including 10% (1/10) with acute infection when starting PrEP, and none (of 90) with established infection. 53 infections were prevented by TDF PrEP giving 1 (53/1) infection prevented for every tenofovir resistant infection

3)    A screen for acute viral symptoms in PrEP assessments led to deferral of PrEP among 30 of 1603 (1.9%) of whom 2 (6.7%) were found to have acute HIV.  No acute infections were missed using this screen.

At the Late Breaker session K Rawlings presented data on the uptake of PrEP in the USA with almost 80 000 people started PrEP in the USA to end of 2915, 76% are men.  No data was available on longer term use of PrEP.

The highlight of the ‘Cancer and HIV’ program was a presentation by Andrew Grulich from Kirby Anal cancer in people with HIV  (TUSY0803).

To summarise.  Historically anal cancer is the third most common cancer in HIV +ve males after KS and lymphoma. In heterosexual males it is 10 x more common, in gay males it is 50 X more common than the general population with an incidence of up to 100 / 100  000. Following ART and CD4 recovery there has been a rapid decline in KS and lymphoma but only a slight decline in anal cancer incidence which remains high even with normal CD4.

In terms of primary prevention HPV vaccination results in a 75% reduction in high grade disease in young gay men but preliminary data did not show that it was effective in males older than 26 although further studies are needed.

In terms of secondary prevention – screening and treatment is complicated by the 75% prevalence of high risk virus with 30 – 40% high grade disease but there appears to be less progression to cancer compared with cervical disease.   Treatment pathways are currently uncertain. In comparison to colposcopy anosocpy requires much more training.

In terms of tertiary prevention detection of anal cancer remains controversial with some recommendations to perform annual PR examinations

In the epidemiology session Alison Rodger presented results from the PARTNER (TUAC0206).  This prospective, observational study enrolled 1166 HIV sero-discordant couples who reported condomless sex and HIV-1 RNA load suppressed to less than 200 copies/mL.  1166 enrolled couples, 548 heterosexual and 340 MSM provided had a median follow-up of 1.3 years. No HIV transmissions occurred within the studied couples.  11 infections occurred from ‘unlinked’ partners. This gave rate of within-couple HIV transmission of zero with upper 95% confidence limit of 0.30/100 couple-years, and for condomless anal sex 95% CI of 0.71 per 100 couple-years of follow-up. These results are very encouraging in terms of the tremendous value of treatment as prevention.

several prep presentations on Tuesday covering different aspects of prep.

Brocca-Cofano presented a study about using maraviroc on infant macaques as prep. The conclusion was that it offered no protection from SIV in infant macaques. This may be different in human populations.

Gulick then presented a phase II study on maraviroc tolerability in US women. There were 188 women in the study, 160 completed. This was a four arm double blind study comparing maraviroc, maraviroc + TDF , maraviroc + FTC , and TDF + FTC . This was a purely safety and tolerability study over 48 weeks and there was shown to be no difference between the four arms.

McGowan presented a study about the persistence of Rilpivirine after a single long acting injection. N=36, they compared plasma and genital fluid and rectal fluid  and compared either single dose, 600 or 1200mg vs 1200 every two months. In 7/7 of the participants who had 1200mg im single dose, there was Rilpivirine present in their genital fluid and plasma after 18 months. This raises issues about he use of this as prep due to concerns about development of resistance due to this long residual level of Rilpivirine . 

Grant presented a study about the benefits of prep relative to drug resistance. They showed that across all prep studies, the risk of drug resistance was very low 0.05% risk. Most of the resistance occurred in people who were HIV infected at entry into the trial. They concluded that the benefit of prep far outweighed the low risk of drug resistance. As this occurred mainly at the start of prep, it was important to exclude anyone who might have and acute vital illness from starting prep to ensure that it was not a HIV infection. It was also suggested that it might be important to do HIV Ag testing or dna before commencing prep.

Brown presented an interesting study about the use of dapavirine vaginal rings from the aspire study. The level of drug level in the ring after use gave an idea about adherence levels. After some stratification, they found that in the moderate to high adherence women, the risk reduction improved from 27% to 56-75% risk reduction.

late breakers

hosek presented data about the safety of prep in 15-17 yo msm in the US. The numbers were small -60 due to recruitemnt and consent issues but the conclusion was that it was are to use with no real differences. There is the bone data presented in the past that still needs clarification.

Rawlings presented data on prep use in the US between 2013-2015. This data was collected from prescription data with PEP and treatment prescriptions excluded. Almost 80,000 people used prep in this period, with a significant increase in men using prep in the last two years. The study also looked at seroconversion rates across multiple prep studies. They had about 8,500 participants and there was  a seroconversion rate of 1.03% in men, 0.25% in women.

The theme of access equality rights now is palpable. There is a mood of activism to overcome these barriers in HIV . Quite exciting to be around!

Wednesday 23^rd Feb Session TD-12

It’s Complicated: Renal Function and STIs in PrEP Users.

STI Data From Community-Based PrEP: Implementation Suggest Changes to CDC Guidelines.

Presenter: Sarit A Golub (NY, USA). Oral abstract an Poster.

Main findings of a review of STI screening in the context of PrEP;

Current CDC guidelines recommend screening at 6/12 intervals or earlier only if symptomatic.

They decided to screen all PrEP attendees routinely regardless of symptoms at 3/12 intervals.

They found that 77% of STIs would have been missed if they weren’t screened at the 3/12 routinely because of reporting as asymptomatic.

STIs screened were; Gc, CT, RPR in urethral and rectal samples. Pharyngeal testing was also done but not included in this study. The majority of PrEP attendees were between 22-40yrs of age.

Test of cure was only conducted on those that were documented as not having received first line therapy at the time of initial diagnosis. Current treatment for rectal CT was 1g Azithromycin, but 7 days Doxycycline was offered if TOC was +ve.

The researchers have also proposed a theory for why there was a spike in STI detection at 6/12. Anecdotal only, but PrEP attendees reported increased sexual risk activities after the 3 month initial HIV screen had come back negative, so they could actually believe that PrEP was effective for them.

Overall they are recommending that in light of many new PrEP guidelines and protocols being developed that STI screening of MSM on PrEP should be 3/12 regardless of symptoms.

These recommendations are in fact consistent with our current STIGMA guidelines for MSM screening that suggest testing up to 4 times per year.

http://stipu.nsw.gov.au/wp-content/uploads/STIGMA_Testing_Guidelines_Final_v5.pdf

Something additional to consider is that should and if PrEP be prescribed by any clinician, without S100 authority, then there may be a need for some re-education into promoting sexual health screening especially in the community general practice setting. 

This stream covered quite a range of issues in regards to PrEP and it's use.

Dr Zablotska told us that community surveys show informal prep is currently being used in AustraliaPrEP was being accessed were through state based PrEP demonstration projects or through self importation. It was important to know the likely eligibility and demand for PrEP in the community. Based on the highest risk group ie MSM and using national statistics, self reported data and guidelines - conservatively it was estimated that eligibility and demand for PrEP ranged from 2500 to 6000 cases.

Dr John de Wit presented data on the change in sexual behaviours and risk reduction in men who are on PrEP. Using baseline and 3 month questionnaires from VicPREP - nothing changed in subjects with regular partners, in either frequency of sex or risk reduction practices. In subjects with casual partners - there was no change either BUT there is a moderate reduction in condom use in casual partners, specifically an increase in 'never used a condom' and a decrease in 'most of the time' in the last 3 months.

This was definitely a difference between trials/extension projects vs demo projects. It is possible that there was a selective change in risk reduction practices, based on informed decision making to balance risk and pleasure. A focus on 'real world' use of PrEP would have to be on sustained education and support on sexual risk reduction strategies, including condom use. This would especially be important for other STIs. This was my take home message from these sessions.

Dr de Wit then spoke about the early experience of men using PrEP in the VicPREP demonstration project. Although 53.9% of subjects reported missing ANY prep doses, the median number of doses missed was 1 dose. This didn't alter the effectiveness of PrEP. The main reason? Forgetfulness!