Andrew Grulich : Targeted rapid PrEP : Impact & Lessons Learned

Clay JonesHIV Endgame 3, PrEP

Andrew Grulich, Professor and Program Head HIV Epidemiology and Prevention Program, Kirby Institute, UNSW Sydney, Australia

Targeted Rapid PrEP: Impact & Lessons Learned

New South Wales was the first state in Australia to trial PrEP at a large scale. The high-level, targeted, rapid roll-out of PrEP led to a 25% decline in state-wide HIV diagnoses in MSM, and a 32% decline in early HIV infections in MSM in less than one year. Why was this approach so successful? What were the key take away messages? What can Ontario learn from Australia’s experience?

Descriptive Transcript

The HIV Endgame logo appears on screen. Text reads: Targeted rapid PrEP : Impact & Lessons Learned. Andrew Grulich, Kirby Institute, UNSW Sydney, Australia. Abigail Kroch stands in front of a dais and presents a PowerPoint document. The PowerPoint document occupies the right 3/4 of the screen.

Andrew Grulich:  Thank you, John, and thank you very much to the organizers for inviting me to come here today. It’s a long way from where I come, but every time I come to Canada I feel very comfortable and very familiar. We’re both very vast and quite lightly populated countries. We’re both engaged in a process of reconciliation with our indigenous populations, which we try to acknowledge at our meetings. And for some obscure reason, we both have the head of state of a small country in northwestern Europe on the back of our coinage. Why is that?

But perhaps more relevantly, we both have publicly funded health systems. Which I think is critical to responding to prevention in an equitable fashion, and is certainly critical critical to the way we’re responding to PREP role out in New South Wales in Australia.

These are my disclosures. The most important thing I’d highlight today is that Gilead did provide us with a proportion of the drug required for this rollout.

So I’m going to start with giving a little bit of context about why New South Wales decided PREP was such a critical part of the PREP response. Why we decided that we needed to do it in a rapid targeted and high-coverage fashion. Then talk mainly about the study results, and some future challenges that I think come from this. So a bit of context. New South Wales is about 80 percent of the size of Ontario.

So quite large, not quite as large as you are but a pretty large geographically speaking. Its population like Ontario’s is rather concentrated in small parts of it. And in New South Wales it’s along the coast, and that red area midway down along the coast in Sydney, where about 5 million of the state’s population of seven point seven million lives so it’s really rather concentrated with lots of very lightly populated areas. A critical part of the context is that our government decided, actually firstly in 2012 and that was after the initial results of HBT no.52, suggested that treatment was virtually completely effective at stopping transmission at least from that study in heterosexual people decided that we should have ambitious goals, and there should be quantitative goals for HIV reduction, and in the 2012 to 2015 strategy, and then repeated in the current strategy 2016 to of HIV in our state by 2020. And you’ll see that little equation there with the brackets of [TEST OFTEN],[TREAT EARLY] and [PREVENT]. So based on both treatment as prevention and a more broad category of prevent.

So a little bit more context.

Firstly, we have a an epidemic that is stabley, predominantly affects men who have sex with men. In the blue column there. So around about 80 percent of our infections have been in MSM for a very long time. That hasn’t changed you see around about 15 to 20 percent are in heterosexual people. We have a vanishingly small number of infections in injecting drug users. We have very high level needle and syringe programs in the state to try to ensure injectors always have access to clean needles, which from the point of view of HIV has worked very well. In that previous strategy to to get treatment as prevention maximized.

So we saw enormous increases in HIV testing. These are the increases in the number of tests in sexual health clinics. Sexual health clinics, publicly funded sexual health clinics in south-eastern Sydney. Southeastern Sydney as is the area where most of the gay community lives in Sydney, and is by far where most of the epidemic is. This was achieved through government targets at clinics being monitored very closely over time to ensure that these increasing tests were achieved, and then increased more and more, every year these clinics had targets for increasing these targets, it wasn’t always easy, there was a lot of grumbling, there wasn’t a lot of new resources. Clinics were asked to reprioritize for it, so, for example, sexual health clinics were asked to do less testing in asymptomatic young heterosexual people because the rates of STIs in HIV are low in that population, and to prioritize testing of priority populations, such as sex workers, men who have sex with men, and our indigenous population.

There was a huge change in treatment patterns in over this period in Australia. So prior to wait till the CD4 count dropped to 500, and then it was changed in late 2012, so that everybody should receive treatment. So this is a graph of the proportion of people on treatment within six months of HIV diagnosis. The blue line being for people with CD4 counts of less than 500, and you see that increase is only moderate, because even before then, the recommendation was that they should be on treatment, but the red line of people who had higher CD4 counts of greater than 500 at diagnosis. So it’s this extraordinary increase over just a minority of people getting on early treatment in those days to 80 percent by the end of 2015. So a very large increase in early treatment initiation. Such that by 2016, we estimated that the state had met the UN aids 90 90 90 goals and has remained above that since.

Despite all of that good work at the end of 2015, HIV diagnosis in the state was stable. That the four colors are just different quarters of the year. So you’ll see we were really stuck at about 350 new diagnoses per year, 80 percent of them in men who have sex with men. We did have a bit of a reduction from 2012, but 2012 was a single outlier. I could I could show that graph back about 15 years and it was changing very little. Around about 350 new diagnoses a year. So a very stable epidemic despite that increase in treatment. So when it came time to think about what we were going to do in 2016 to 2020, essentially the conclusion was made that although treatment as prevention was critical, it was not enough to lead to the reductions that the state had signed up to. And I come back again to the importance. And I will, again and again in conversation, to the importance of those quantitative targets, because we might have come to the conclusion oh there’s no increase we’re doing okay, but because we had those quantitative targets about reductions.

We said, “What’s happening?” We have to do something extra, we need to get this down. In 2015 the other thing that occurred, of course, was that we saw for the first time the results of PREP studies in developed country settings. But we had Ipergay before, which had about of 45 percent reductions, sorry not Ipergay, the iPrEx study before, but in Canadian iPergay study showed 86 percent reductions in PREP. And I think as soon as we saw those results, we thought this is something we need, this is something we need to roll out. The issue though was that PREP hadn’t been licensed in Australia, back then I think it was only licensed in the US. One other critical thing was that demonstration project, small-scale demonstration projects, and there were three or four of them around Australia, showed very high levels of adherence. And the conversation back then was very much about, “Will gay men take this drug?”, if they don’t take it they’ll become infected. The local studies, small-scale local studies were entirely reassuring about that. That gay men would take the drug, and that was backed up by what they were telling us, but also by blood levels, and there were zero infections in our pilot studies.

So based on all of that, and the fact that her government’s had signed up to these targets, our amazing Health Minister, Gillian Skinner, announced on Dec 1st implementation study. Because the drug wasn’t licensed, so it simply couldn’t be prescribed, it needed to be within a study. So this was a statewide large-scale implementation trial to commence on March 1st 2016, which happened to be about 3 days after the Mardi Gras Festival… Sorry the day before the Mardi Gras festival in Sydney. So there was a three month gap. You can imagine what that summer was like for us. We didn’t get much of a break that summer. So that’s why New South Wales decided it should roll out PREP, but I want to say a little bit about why it decided it should be targeted, it should be rapid, and it should be high level.

Essentially this was informed by local mathematical modeling, that if you targeted high-risk gay men with high levels of coverage in that group, and you rolled it out quickly, you could very substantially and quickly effect the epidemic. And the the graph there suggests in blue, suggested you could have enormous impacts if you could get those levels of coverage. Now the other thing about targeting of course which is important to government is that it’s far far less expensive to target a relatively small population than to give it to a large population. And I think there is no getting around that issue, that if you’re talking about preventive drugs, in situations where the government is the funder of the drugs, which is our situation you need to try to restrict it to people who will benefit most. It’s important to note that the modeling also showed that if you had lower levels of coverage, you’ve got much lower reductions in incidents, and that is because of the concept of herd protection. That by preventing one infection you would prevent that infection being passed potentially to many many more, and this is exactly the same concept that we think about in vaccines. That we try to get high levels of coverage to see population level effects of reduction of disease, and I think this is absolutely critical to the PREP response.

While there is no doubting the benefit of PREP to individuals, and I absolutely don’t want to play that down, but I am a public health physician. I think that you will hear at this conference the extraordinary benefit to individuals, not only in terms of HIV prevention, but in terms of mental health. But for a population level effect, if what you’re interested in is ending the HIV epidemic, then high-level coverage to achieve herd protection is utterly critical. So that’s the background, and now I’ll tell you a little bit about our study results, which were published in Lancet HIV just a month ago. But I’ll update those results as well. So our targeting was based on local epidemiological data. And I think this is important, that any targeting that you decide to do, needs to be based on your local epidemic. It’s the old WHO language of know your epidemic. In our setting the only population with a high enough incidence of HIV to justify prep is men who have sex with men. But also in some cases heterosexual sero discordant couples.

So we took data from this cohort study in Australia, in Sydney. Which suggested that rectal STIs or syphilis was associated with a very high HIV incidence of about three to seven per hundred person years, having condomless intercourse with an hiv-positive partner who had detectable viral load, very high incidents, having receptive condom less anal intercourse with casual partners, pretty high. And simply being a methamphetamine user also associated with an incidence of about two per hundred person years, so they were adapted into clinical criteria for who was eligible for PREP. Because we were looking for population level impact, we based the study throughout the state of New South Wales from the southern border to the northern border, that’s about 1200 kilometers. We were helped very much in this endeavor by the fact that we have a statewide network of publicly funded sexual health clinics. So at these clinics anybody can walk in the door and receive free sexual health care.

Normally in Australia to see a doctor, an Australian resident produces their Medicare card, and that gets them there. That the highly subsidized visit to the doctor. But at a sexual health clinic nobody is turned away, everybody gets free health care, with the philosophy that the only way to control STIs is by allowing people to be diagnosed and treated. Some of these clinics, I’m not sure if you have this sort of system in Ontario or not, but this is not a perfect system, there are large parts of the state that don’t have sexual health clinics, and some of those sexual health clinics on this map are very small. They’ll operate a day or two a week, but nevertheless they did allow us to roll out PREP across that very large network, and by the end of the study we had 30 clinics, which were part of the study. So we made a decision about sample size, which was really a pragmatic compromise between our desire based on the modeling to start all high-risk men who have sex with men on PREP quickly, and we set the time to do that within 12 months, but with considerations of how quickly, looking at the numbers and where they would likely occur, of whether this would be possible because this was not accompanied by a lot of funding, this was mostly sexual health clinics being asked to reprioritize, again to prioritize on the highest of the high-risk, some extra funds were provided at a few places which became overwhelmed.

The number we came up with was 3700 which was based on the male population between 18 and 69, the 2.3 percent we had who identified as gay. We had two national sex surveys over the last 20 years in Australia, which seem to have settled on a figure of about there, that doesn’t include bisexual men, that’s only men who identify as gay, and 8.6 percent of those who met one of those four risk criterias, which I showed you, and because that number was going to be too large, we put an additional requirement that essentially made us think that these people were the highest of the high, they had at least 10 sexual partners in the last six months, and they reported condomless anal intercourse frequently or Meth use frequently. But baseline assessments were very pragmatic. We tried to make this study as simple for clinics as as possible. So it had to meet the guidelines, they had to be adults – at the start of the study, and they had to be negative on a fourth generation HIV antibody test. We didn’t want people who simply tested positive on rapid tests, because we know that the window period is longer on a rapid test. We excluded people only if they had symptoms of acute HIV, or if they had evidence of impaired renal function. So the study had two outcomes. We had what’s traditionally called in this area of science an efficacy outcome, whether the treatment prevented infection within the cohort, so that’s the incidence in the population level effectiveness outcome. So this was looking at the statewide change, in the whole state of New South Wales in surveillance data, between the 12 months before we started recruitment and the 12 months after we finished recruiting the 3700. We focused on recent HIV infection, in the outcome, because as all of you who work in this field know, many people who are diagnosed today with HIV will have been infected last year, or the year before, or the year before.

Now clearly something you are doing today cannot prevent those infections, so we have a long standing surveillance system for recent infection in New South Wales, which is people who have evidence of an HIV negative test in the last 12 months, they have a Western blot which is not completely formed at diagnosis, or they have a diagnosis by a doctor of an HIV seroconversion illness. In terms of finding out who became infected in the protocol, we called HIV a serious adverse event which the doctors needed to tell us about. We were lucky enough to have a sentinel network called the Access Network, which is a sentinel system, which is statewide in those sexual health clinics, allowing us to look at the incidence of STIs and HIV, and also enables us to pick up any infection at any clinic. So if I was recruited at one clinic, but diagnosed at another, we would be able to detect that infection. In addition, we asked people to consent to data linkage with our state HIV register. We didn’t want to exclude people on this basis, so we made this a voluntary consent but 80 percent of our participants did consent to it. So we think we missed infections only, if people moved away, or if they stopped testing. That is a possibility. Our recruitment was shall we say out of this world.

It went much more quickly than we thought it would. We reached our protocol specified target of three thousand seven hundred in eight months. And when it became apparent three or four months before that we were going to do it, we put our heads together with government and said “What are we going to do?” We know our estimate is too low because we put those extra requirements. We know through the promotional work that our community-based organizations are doing. That gay men are loving this. What are we going to do? And the government to their eternal credit said let’s uncap the study. Let’s keep the let’s keep the criteria, as long as we are enrolling men who are at high risk and can meet the eligibility criteria we’ll stay open. So when we stop recruitment on April 30 this year, because we started to have national funding for the drug, we had nine thousand seven hundred participants. So the characteristics of participants largely reflected MSM at risk. I will say that the number aged 18-24 of eight percent was slightly lower than we wanted it to be. We think we are under recruiting younger men. It is as you would expect from our risk profile almost all-male. We did recruit by the end of the study, almost a hundred transgender people, but in the first three thousand seven hundred that number was much lower, and almost overwhelmingly the men identified as gay. That the number of by sexually identified men was rather low, and that may be a challenge for us into the future. Country of birth is important to us because like Ontario, New South Wales is an extremely ethnically diverse place.

And we did reasonably well with diversity but in the early stages we did notice under recruitment of Asian born gay and bisexual men, and adjusted our promotion. As you see in a minute. We wanted to have statewide coverage, but we knew uptake would be greatest in inner Sydney, where based on surveys that have been done, a group of seven postcodes, we call them the the gay suburbs of inner Sydney, where more than ten percent of the male population is gay. So thirty eight percent of the of the uptake is there. And the uptake mostly a mix of the public sexual health clinics and private general practices. I should mention that we have a number of gay men’s private practices, where men who are not generally and not poor men are paying some cash to go to the doctor, but to again to their credit a couple of these places said PREP visits are free, we want to help and we’ll make PREP visits free. So the follow up. Of the 3700 we had at least one HIV follow-up test in almost everybody, ninety seven percent. And we had an HIV test in the in the window around twelve months, about seventy five percent, so we do get some drop out, some men not testing in that period. We measured the medication possession ratio, the proportion of drugs dispensed that compared to the amount that would have been dispensed had a person taken the pill every single day. So the median a medication possession ratio was extremely high, reflecting that more than half of of men took the pills almost every day. The mean was lower though, and that’s because we had a small proportion of men, about three percent who came back for their one-month visit.

Because we did require men to come back up one month and then three monthly. Who didn’t come back again. We had another thirteen percent who came back once or twice. A similar proportion who came back about half the time and then medication possession ratio. So the key result within the cohort is that we had two confirmed new infectionS over about nearly four thousand person years. One of those was a man who was dispensed prep but did not take it. He took it home and then didn’t open the bottle. And another man who ceased PREP months prior to infection. So neither of those were due to drug failure. And the incidence rate calculates to is about one per 2000 person years, in a group we expected a much much higher rate. The primary outcome in terms of the population as I mentioned is comparing the twelve months prior to recruitment to the twelve months after recruitment. And just to be fair, and to make sure you don’t think this is all do just to the 3700 men getting prepped, by the end of that after period we had 7600 men on PREP. So it’s more than just the 3700. So this was the difference, and remember this is in a setting which had stable rates for 15 years. So you know this is a setting which we believed to be due to PREP.

Within 12 months we had a 32 percent decline in recent infections, and a 25 percent decline in all diagnoses overall. We had inequalities that are very important, and that we’re working to try to improve. The decrease was much larger in older gay men, so it was almost 50 percent in 35 plus year olds, and much less in the 18 to recruiting. By place of birth, we have seen a close to 50 percent decline in Australian-born gay men. Much lower declines in Asian born gay men, and in some other overseas born gay men as well. Largely in those gay men who come from countries where English is not their first language. And when we looked at geography, and this was a very striking finding, which was stronger than we were expecting I would have to say, that in inner Sydney we saw more than a of Sydney, which are highly ethnically diverse we saw very little decline. So in conclusion for this part, we got really quite striking low incidence in the cohort, a major reduction across the state, and we’ve highlighted these inequities which are real challenges for us in the future.

So in the last couple of minutes I want to speak on where to from here. I want to first talk about why this worked, and this really did take a lot of innovation. In Australia health is drugs are usually dealt with federally, but our health department purchased the drug and the State Health Department managed the drug supply. The clinics had to manage thousands and thousands of new patients. So nurse dispensing became a reality in many places. It was a study which required written consent. Group consent sessions were held, and in some places new doctors were employed. I cannot under emphasize the effect of our large community-based organization, ACON, in building demand. It was utterly critical to creating that amazingly rapid uptake. And the action of all these players had to be closely coordinated. And we call this partnership version 2.0, because we’ve had partnership forever in Australia, but this was a very closely managed partnership. Over the those first two years we had weekly meetings about the study management team with sexual health clinicians, with the Ministry of Health, with the community organizations, to quickly identify problems as they emerged, and to act on them.

It was really hard work, I have to say. But it worked. Community engagement. So our community group ACON did an amazing job. And I was talking to some colleagues here from Ontario, coming up here, and telling them the size of ACON. So ACON has about 200 staff, and gets about 10 million dollars a year in government funding, and another 5 million dollars a year in other funding. It is fantastic value for money. It does extraordinary work. It established a PREP mailing list. It devoted a full time person to this. It held community forms around the state. You know in pubs, and clubs, and bars. Some of them were small-scale. I spoke at many of these. Sometimes three people turned up, sometimes a hundred people turned up. And in fact once we had PREP then a lot of people did turn out. And then there were a lot of creative campaigns. These posters were everywhere around Sydney, and they were translated once we started realizing what an issue we had with Asian gay men.

We had campaigns designed for different environments, or the ones with the rude words are obviously designed for very certain places, such as sex on-premises venues. And we were careful, especially once we realized what was happening, to ensure that there were Asian faces in a lot of these campaigns. When we really began to see, this ACON really ramped up its work, and it had to. I should say ACON as a key performance indicator has been getting HIV infections down, it’s answerable to government, so it is very strongly invested in this field. These posters in in Chinese, in Vietnamese, in Thai and in other languages, including Portuguese actually because we have a quite a large Brazilian population in Sydney as well. We’re very familiar around Sydney, and we’re on the side of trains that are in in train stations, should I say in the relevant parts of Sydney it’s also really important to note that we didn’t just say it was all PREP, we said this is part of HIV prevention.

It’s not just PREP. So these these figures are saying “You know I do it with my doctor”, he’s an HIV positive man who’s saying he’s maintaining his undetectability by staying on treatment. “I do it every day”. I take my PREP pill. “I do it all the time”. I use condoms. Saying that there are many different ways of effective HIV prevention in this day in era. And now we are up to transition. So the study has finished recruitment, and we’re now transitioning across to the what we call the PBS, the Pharmaceutical Benefits Scheme. The way the English talk about the NHS and how much they love it. We talk about our PBS because this means that no matter who you are in Australia the most you will pay for any PBS drug use is $40 a month. And if you are unemployed or on a low wage, you’ll pay six dollars a month. So it does mean that the access to drug is not a problem unless you’re not an Australian citizen and an Australian permanent resident. And that is a big issue for us at the moment, because we have such large numbers of Asian students who are temporary residents, and are not covered by our system.

So looking into the future, the key issues for us are keeping going and making better, and I can report to you that 32 percent reduction is more like a forty five percent reduction now. The reduction in inner-city gay men is like elimination in the other city. It’s quite amazing. That sounded like Donald Trump, didn’t it. But I do want to get back to PREP requiring very high level coverages, and as we are seeing increases in condomless sex, that target is increasing. And we are closely managing coverage. And who is not taking PREP. Who should be on PREP. And we’re still challenged by these groups who we’re not targeting adequately. And one of the main ones that we’re facing now is that all of our targets thus far have used gay community, and I think as we get more and more to the margins, we’re going to start seeing a lot more, in a lot higher proportion of infections in men who don’t identify as gay, and we are struggling as to how we’re going to deal with that. I want to finish by thanking the large team of individuals who are responsible for implementing the study. Thank the participants of course, and Gilead for a provision of some of the study drug. And I’ll leave it there. Thank you. [Applause]