I have always had doubts about PrEP and social responsibility, but after listening to some of these very informative talks,it has occurred to me that people have the right to access this treatment.I listened with interest that it has yet to be approved by the PBAC for this reason but it raises the question that if it was a socially acceptable disease would PrEP be approved by the PBAC straight away.

It seems the eligibility to qualify for PrEP is high risk behaviours, but if I am HIV positive should my negative partner not be able to qualify for PrEP? Could not making PrEP widely available be a means to ending the stigma associated with HIV.

These talks have raised many issues with me:

1) Do people now stop using condoms (I know some people who have utilised PrEP for this !!!)

2) If a high risk client is not adhering to safe sex, then will their adherence to PrEP be any better?

These talks has left me in two minds: that we seem to be encouraging a society of little or no responsibility.

But on the other hand people have the right to have sex without a condom.

a good start to the day with  great welcome by Aunty Carol Currie, there was an interesting talk by the QLD minister for health on future directions  for health care in the sexual health sector.

Robert Mitchell  provided an excellent insight into future directions for HIV care and the big need for people with HIV to be included on any decision making authorities

Bridget Haire highlighted the poor uptake of the use of PreP by government Authorities

Professor Cohen provided a talk on the prevention of utilising antiretrovirals to prevent HIV,his trials have shown that with antiretrovirals and counselling ,96% of trial couples did not become HIV positive.

Transmissions have plummeted with the use of antiretrovirals as a preventative measure

Hurrah finally some form of preventative measure,but you do have to think about the side effects of the antiretrovirals and the accessibility  of these melds to the people that most need them.

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.

This entertaining session presented a number of varying cases to highlight the promises PrEP may bring but also the pitfalls.

It emphasized the importance of "hearing the patient", as to their psychological and sexual needs.

In South Africa, Dr Abdool Karim expressed that women need PrEP type product that they can initiate themselves , independent from their partners knowledge , as a study of seroconversion rates still revealed 9.1%seroconversion in young women. She also reported an association between HPV acquisition and HIV acquisition.

Dr Raphael Landovitz from L.A. Introduced a new term "the dribble effect", which refers to lowering of serum levels of Truvada as some doses are missed , but those lower drug doses may still give some protection. It is still to be determined what the ideal treatment protocol is and also what are the lower serum levels that still offer some protection, before development of resistance may occur.

So far  Truvada toxicity has been minimal with most serum creatinines recovering  to normal.

a major issue will be cost as it is not yet funded in Australia.

 who will be keen to take it and how often it will need to be taken was explored in different scenarios which included the discordant MSM couple, the monogamous African woman, and the bipolar personality.

Dr  Landovitz stated the numbers were too low in the Ipergay trial to determine the efficacy of that regime.

we have lots to learn in the era of PrEP but it appears to be very promising as another way to prevent  further HIV seroconversions

Tuesday mornings Oral Abstract session was titled PreP: Demonstration for Implementation presented the initial findings from at least four studies into issues such as adherence and uptake. The studies examined some key affected populations. 

Of particular interest was an abstract from the U.S about PreP in Young MSM (YMSM) and transgendered women by the adolescent trials network (ATN) study 110. YMSM are at particularly high risk of HIV acquisition and remain relatively understudied with respect to PreP.

The ATN 110 study has some locally relevant points. 

ATN 110 was an open label study or once daily TDF/FTC across 12 U.S cities of men aged between 18-22. 

The primary objectives were to 

• provide additional safety data on FTC/TDF use in YMSM
• to examine the acceptability, patterns of use, rates of adherence and drug levels when YMSM are provided open label Truvada and 
• to examine patterns of sexual behaviour when YMSM are provided PreP

The 200 enrolled participants had self-reported high sexual risk in the last 6 months and were HIV negative. 

The mean age of participants was 20 years, 78% identified as gay, more than 80% reported condoles anal intercourse in the last six months, almost 60% receptive anal intercourse and 22% were positive for an STI at screening. More then 50% were black.

There were very few adverse events but 25 discontinued primarily due to personal choice or a self perceived change in their sexual risk.

Study participants were incentivised $25 per visit and had study visits at weeks 4,8,12; then three monthly. 

There were 4 seroconversions by week 48. All four had undetectable levels of Truvada, None of them had drug resistant virus.

Generally, participants reporting higher sexual risk had higher levels of Truvada. This remained consistent though to week 48. The mean number of parterns and condomless sex acts was mostly unchanged. STI rates remained as high as there were at baseline.

Notably, adherence decreased for all participants over the 48 weeks. Adherence appeared to decrease as the study visits decreased in frequency. Some qualitative research will be done some time in the future. This could infer that YMSM may need more rigorous follow up or an ‘enhanced visit schedule’

Wednesday’s Plenary will further examine PreP

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.

Just to add to Bk’s post…. In each site for HPTN 062   qualitative research in the form of in depth interviews were carried out with some participants. Rivet Amico found that in Africa, women’s adherence very much had to do with their trust/mistrust of the study drug. When they were suspicious they had low adherence. When they had confidence the drug worked, when  they felt they had ownership  of the study they had good adherence. Stigma played an important role in adherence in Bangkok and Harlem. Participants were viewed as either being HIV infected or sexually promiscuous if seen taking the drug. On the other hand for some participants it greatly relieved the anxiety of HIV acquisition and gave them a sense of freedom. One participant who had come of age during the AIDS epidemic commented that this was the first time in his sexual life he had ever felt truly free. This freedom from anxiety has been something which many of the participants on the Prelude Study that I have met have commented on also.

In addition to the PK data BK presented there were interesting differences in the PK data between rectal and vaginal mucosa. Concentrations of TDF-DP were 10-100 times greater in the rectal tissue compared with vaginal tissue after a similar dosing period. Time to reach peak concentration was also slower in the cervix compared with rectum. The reason for lack of protection in the studies such as FEM-PREP was explained by lack of adherence but perhaps this also has something to do with it.

Francois Venter from South Africa gave a great plenary yesterday about Biomedical Interventions : Contrasting Implementation Changes. He called for less moralising from politicians in his country and more accountability when it comes to the issue of young women in his country being infected by older men. Stop talking about the morality of it and act by keeping the girls at school- an intervention which has shown makes  a difference.

The PROUD and IPERGAY studies offer us 2 dosing options for effective HIV prevention in high risk MSM:

1. Daily Truvada (Tenofovir/ Emtricitabine) 1 tablet

or

2. On- demand Truvada at the time of sexual exposure as follows:

- 2 tablets 2-24 hrs before sex

- 1 tablet 24 hrs later

- 1 tablet 48 hrs later

( if additional sexual encounters then continuing the regime so that 2 tablets over 48 hrs are taken after the last sexual encounter)

With the addition of PEP provided on-demand

Some additional considerations:

• Adherence to PrEP is obviously critical to its effectiveness
•  Condom use should continue to be promoted. Although neither study showed an increase in incidence of STIs in the PrEP group there is an ongoing concern that increased risk taking behaviour on PrEP will increase STI incidence.
• Side effects- most commonly GIT - nausea, diarrhoea, less common- headache, renal
• Renal monitoring- baseline and ongoing (? Frequency)
• Baseline and ongoing HIV and STI testing ( 3 monthly)
• Possible targets for PrEP- High risk MSM. For example anyone- with an STI in the last 6 months, in a HIV discordant relationship, who has unprotected anal sex, who use recreational drugs and/or binge drinks.

Plenary 1, Presented by Raphael Landovitz is available for viewing http://www.croiwebcasts.org/

The speaker address a number of the common concerns associated with PrEP:

• Decreased condome use, not being observed and high risk individuals self selecting for PrEP
• Resistance not emerging (at least in early data)
• Safety and adverse event (low and stop when PrEP stopped)
• Supporting adherence, needs to be multifaceted
• Optimal deployment is still to be determined

The big issue with all studies is that:

“Drugs don’t work in patients who don’t take them”

Interestingly Landovitz suggested that primary care providers are best placed to manage PrEP with their patients as they have long standing relationships and service negative patients. Specialists on the other hand see patients once they have HIV and may be in clinics which negative people avoid. He also suggested that generalists are least well equipped with information and education. This is a very interesting comment from the Australian perspective where so much HIV care happens in general practice.

He also suggested that optimal deployment will require a multi-pronged approach with information for health care providers, patients and from professional and clinical organisations and government providing clinical guidance. I recommend the talk, particularly for people wanting a comprehensive overview of contemporary PrEP science and implementation.

Three exciting and anticipated papers were presented in the Oral session #1 this morning.

Sheena McCormack (abst 22LB)presented the PROUD study, which was designed to see if previous results could be achieved in a "real world setting", 539 people were randomised to 2 years once daily dosing with Truvada and 545 to a one year delayed therapy arm. The study was stopped late last year due inferiority in the deferred arm. There was an 86% reduction in transmission in the treatment arm and the three seroconversions is this group were probably infected or sero-converting at the outset. There were few side effects and the study population was at high risk of HIV.

Jean-Michel Molina presented IPERGAY (abst 23LB) this study looked at "on-demand PrEP" to see if efficacy achieved in macacques treated before and after exposure could be achieved in a real-world setting. The regimen was 2 pills 2 - 24 hrs before sex, one after sex and a further pill 24 hrs after the first dose. If there was more than one encounter the daily PrEP was prescribed. The results were also an 86% reduction in transmission and transmissions were again observed in participants who were either infected at the start or who had ceased taking drug. This is a very important study as it provides an option for people who have only limited high risk exposures. Side effects were minimal and stopped when the drug was ceased. Importantly from a cost effective standpoint. 18 pills per year were required to avert and infection and the average was 16 pills per month or 4 pills per week. This study will require close further scrutiny and could be a game changer.

Bob Grant (abs #25), from the San Francisco AIDS Foundation looked at what would be required to achieve transmission reduction targets. He found a combination of PrEP, increased treatment and testing together had the greatest impact. Importantly he reported that people who were taking PrEP were at high risk. Other were interested in taking it or interested but wanted more information. These people were eligible and given access had the potential to drive down infection rates.

The talks are available on line at http://www.croiwebcasts.org/ I really suggest considerable attention is given to this important session.

Many presentations pushed the need to get going now with oral PrEP for it's already proven benefit, even though what we have isn't perfect, isn't used perfectly, and isn't going to be for everyone.

Interesting potential future options are suggested by macaque monkey trials investigating 3 monthly IM injections of GSK744, and vaginal rings releasing dapivirine. Both approaches seem much more likely to achieve uptake when further proven, and available. Abstracts #40LB and #41

Injectable GSK744 LA (long acting) is an analogue of Dolutegravir currently undergoing trials as a potential PrEP agent. Abstracts #39 and #40LB

Trials in rhesus macaques showed it to be 100% effective as PrEP. Quarterly injections protected against rectal SHIV infection, while monthly injections were protective against repeated vaginal exposure. 

Proposed dosage in man would be quarterly 800mg of GSK744 LA IM injection. Presented as 200mg/mL, it would be given as divided doses - 2x2mL gluteal injections).

Clinical evaluation in high risk MSM with phase 2 safety & tolerability trials begin in the northern hemisphere spring 2014.

Dapivirine (DPV) & Maraviroc (MVC) vaginal rings were trialled as a PrEP device in the MTN-013 study. Vaginal rings provide sustained drug delivery, minimal user action is required and they are discrete. The rings were well tolerated with primarily mild to moderate adverse effects. Abstract #41

With DPV, 100,000 fold higher concentration of drug was found in vaginal fluid compared to plasma. The levels of DPV in cervical tissue dropped to below the lower limit of quantification (LLOQ) 3 days after ring removal. Vaginal MVC levels were 2-4 times lower than DPV, and MVC plasma levels and cervical tissue were below LLOQ.

Researchers found that the anti-HIV activity of DPV ex-vivo from cervical biopsies correlated to the concentration of drug.

In the FAME-02 study, DPV film and gel were trialled as delivery mechanisms for vaginal PrEP. Abstract #42LB

Films were akin to Listerine strips that dissolve on contact. Researchers found that subjects had difficulty using the film, with sticking to the finger and poor placement noted on follow up. Cervical levels of DPV were equivalent to 1 month of vaginal ring use (10^6 pg/mL). Vaginal drug levels were about 4 fold higher - reflecting tissue surface adherence. Similar plasma levels were seen for both film and gel, comparable to the vaginal ring.

This study could provide lower cost, on demand PrEP for women. Modified film size/shape could improve placement issues.

David Bangsberg, Abstract #7 was a thorough discussion on the impact of adherence problems in the PrEP studies.  He discussed complicated issues such as how the dynamics in a relationship affects PrEP adherence.  Craig Hendrix Abstract #61 was an excellent speaker and gave one of the clearest discussions on pharmacodynamics and pharmacokinetics to explain the heterogeneity of the results of all the PrEP trials I have ever heard.  I would encourage people like me who sometimes get lost in these concepts to watch his webcast.  He makes it simple.  This, coupled with Abstract #64 given by David Glidden who discussed choosing populations for maximal impact of PrEP certainly had me thinking about how we should be framing our policies on PrEP provision.  And again, if anyone is confused about concepts such as Number Needed to Treat and Population Attributable Fraction, it’s a webcast worth watching.

In my notes, I wrote “I love this talk” next to Nelly Mugo who works for the Kenya Medical Research Institute, Abstract #62.  And from the reaction of the attendees, everyone else did too.  She gave an inspiring talk on the field implementation of PrEP in a resource constrained setting, including the problems of vulnerable populations and the urgent need to get demonstration projects going and move to implementation.  She stressed, “this is an option that does not need the negotiation of safe sex”, and we know, that this negotiation is close to impossible for vulnerable populations.

I expected to hear many data rich talks at CROI, but the inclusion of a presentation on the Community Perspective On PrEP, Abstract #63 that involved a participant talking about his experience on a trial brought a human face to the numbers that I think we all need to be reminded off from time to time.

Getting away from PrEP.  The opening Bernard Fields Lecture was given by Paul Bieniasz from the Aaron Diamond AIDS Research Centre.  His lecture was on host restriction factors and the struggle between virus and host genomes and how they have evolved in both populations.  Being a clinician, I am constantly amazed at how scientists can manipulate viruses and host mechanisms and reminded that this is where drug development all starts. 

The Plenary on Tuesday morning.  Douglas Lowy Abstract #19 gave an update on HPV vaccines.  It was a nice overview, but nothing really new.  He did comment that Australia was the first country to have high uptake of the vaccine and that it showed a substantial reduction in HPV disease in women, but also conferred significant herd immunity, as HPV disease in men also declined (study published before vaccination commenced for boys).

Adeeba Kamarulzaman from the University of Malaysia Abstract #20, gave an excellent talk on HIV in People Who Inject Drugs (PWID, we commonly use IVDU here in Australia and I have not seen this acronym used here yet).  You could hear her exasperation as she presented the number of research studies and economic evidence that show harm minimisation efforts such as Needle Syringe Programs and Opiate Substitution therapy works to reduce HIV transmission.  “Do we really need another study?....I think it’s for the sceptics....”.  Her view was that so long as the “War on Drugs” and the criminalisation of drug use continues in the USA, there will be little that can be done for PWID.  It does not look promising, as there was a recent reversal of the lifting of the ban for federal funding for needle exchange programs in the US.

Hong-Ha Troung, presented more data from San Francisco characterising new HIV infections. STIs remain a significant cofactor in new infections and 57% of recent infections are related to clusters. The definition of cluster was quite restrictive and did not include sequential infections so perhaps underestimates related infections. Important for the Australian setting was the very strong take home message that STI testing, treatment and prevention messages must become decoupled from HIV prevention activities. Abstract #37

Alison Rodgers presented data from UCL on condomless sex. This work goes to the heart of what we are seeking which is greater understanding of the extent of the prevention benefit of treatment. The data looked impressive with no transmissions reported, in any of the arms where partners had a VL <200 copies. But Rodgers was eager to point out that the confidence levels meant that this did not translate to 100% protection and that this was particularly the case with the MSM group. A factor which makes answering this question difficult is that most studies are looking at condom use AND treatment. So it was useful to see an analysis of condomless sex. Abstract #153LB

The importance of adherence to PrEP was highlighted by a number of speakers throughout the day. A number of speakers in the Prevention and Epidemiology session Evolving Trends (Session O-3) made reference to poor performance being a result of lack of adherence rather than failure of prophylaxis. And many speakers reflected on this emphasising the need for a good understanding of the social and other pressures on study participants.

PrEP is getting attention from both developing and developed country settings. It is sobering that so few studies are actually underway. Nelly Mugo, Abstract #62, found that only 1 of 10 studies had actually started, yet drugs for use as PrEP have been licensed for a considerable time. 

This conference is a marathon. Day 4 and I am exhausted. So many people, protests and presentations to attend - it's quite overwhelming. One of the highlights for me yesterday was a packed oral poster session on PEP, PrEP and HIV testing held over lunch. The presenters only had 5 minutes each to present their key findings, and there was spirited discussion from the audience. A presentation by Antonio Urbina (St Luke's Roosevelt Hospital) reviewed the delivery of non-occupational post-exposure-prophylaxis (PEP) in emergency departments in New York City. 216 cases were reviewed. While apparently very successful (94% completed the course and only one person seroconverted), the audience questioned the intensity and length of the PEP regime - a 4 week course based on Combivir, which often causes nausea. There was debate about whether a shorter and better tolerated regime could be used. One of the other presenters in the session, Kristen Underhill (Yale) picked up on how negative experiences of antiretroviral drugs from a course of PEP can have lasting consequences. Kristen had conducted group interviews with gay and bisexual men in Rhode Island to explore the acceptability of HIV pre-exposure prophylaxis (PrEP). She found that men who had had a previous bad experience with PEP found the idea of PrEP very unappealing.

The other standout presentation was from Alex Carballo-Diéguez (HIV Center for Clinical and Behavioral Studies, NYC). Alex was reporting the results of his study of home HIV testing among 'high risk' HIV-negative gay men in New York City. A small group of men (n=32) was enrolled and given OraQuick oral fluid rapid test kits to use at home (the test has just been approved by the US FDA for sale over-the-counter). The men were encouraged to test themselves and their casual sex partners. Around 100 tests were performed. Telephone support/counselling was offered but rarely used. Five sexual partners tested positive for HIV during the study. Very few adverse incidents were reported. When quizzed by a member of the audience who was concerned about relying on a test with a longer window period than a lab-based HIV test, Alex noted, "Sometimes when looking for the optimal, we overlook the good enough." While debate will undoubtedly continue about the merits of home-based testing, I think this research illustrates that home testing can function pretty well as a harm reduction tool and, as Alex noted, can give gay men a greater sense of control over their health and HIV status. It's certainly motivated me to work with my colleagues in Sydney and Melbourne to do a similar study of home-based HIV testing.

In the US, 60% of new HIV infections are among the 2-5% of adult men who are gay, bisexual or other men who have sex with men (MSM), and rates of HIV diagnosis among MSM are increasing in many countries. It therefore seemed fitting that my warm-up to AIDS 2012 involved attending a pre-conference hosted by the MSM Global Forum. The early plenary speakers, including US Congresswoman Barbara Lee, former Australian High Court judge Michael Kirby and Dr Kevin Fenton (US CDC), highlighted the challenge of delivering effective HIV prevention and treatment when MSM in many countries are faced with hostile laws, violence and homophobia. The rights of MSM and transgender people are often precarious or non-existent and work to counter prejudice and protect these populations is vital but bruising work. 

It’s anticipated that much of the debate at AIDS 2012 will relate to developments in HIV prevention science, notably the preventative benefits of antiretroviral drugs when HIV-positive people are treated effectively (treatment as prevention) or when HIV-negative people take antiretrovirals (pre-exposure prophylaxis or PrEP). Kevin Fenton in particular spoke about how treatment as prevention and PrEP, when combined with existing strategies (such as condoms, treating STIs and so on), could dramatically reduce the sexual transmission of HIV among MSM, if targeted and implemented well. However, many in the field are uncertain about how to integrate, target, deliver and evaluate these strategies. 

A session on new prevention strategies featured Dr Robert Grant, lead investigator of the iPrEx trial of PrEP. Dr Grant echoed Kevin Fenton’s comments about implementation, admitting that despite the recent FDA approval of Truvada for use as PrEP, debate continues in the US about how best to target PrEP to MSM, how to facilitate access to those who will benefit most, and how to support those taking PrEP so that protection is maintained (PrEP’s efficacy is much higher among people who maintain a detectable level of the drug). Dr Grant raised some interesting issues about promoting effective PrEP use. He said that potential users should be told the realities of taking PrEP, rather than focusing on hypothetical risks. He said that potential users should be told that PrEP is highly effective if drug levels are maintained, but it is not as easy to take as you might think e.g. remembering to take pills, having to have regular HIV tests. Dr Grant argued against ‘intensive counselling’ or banning people from PrEP who report illicit drug use, saying this unnecessarily limits access and is not justified by the experience in trials. 

Dr Grant argued that MSM who have unprotected anal sex are generally still motivated to protect themselves from HIV and PrEP can help them. This point was echoed by Bruno Spire (from INSERM in France), saying it had been a motivation to set up the IPERGAY trial of intermittent PrEP dosing, currently enrolling gay men in France. In response to questions about how to justify the cost of PrEP, Dr Grant made the point that PrEP is cost-effective when you think of it as a short-term use of antiretrovirals to prevent HIV infection, life-long treatment and a higher risk of comorbid conditions. It will be interesting to see if this pragmatism about PrEP will be taken up in Australia.

People will recall that iPrEx investigators questioned whether adherance to prophylaxis was the cause for transmissions in the active arm of the iPrEx study. Late Breaker #31LB reports on this. They compare plasma drug levels to those in an unrelated observed therapy trial STRAND with doing at 2, 4 and 7 days per week. The active arm had an overall preventative effect of 90% but when broken down by similarity to the STRAND data they found 76% efficacy at 2 day per week dosing levels, 96% at 4 and 99% at daily.

You will find the paper on the CROI Website, as well as the Oral Abstract session from 6 March 2012 in the 10am session.